Principles and Practice of Geriatric Surgery, Second Edition

Principles and Practice of Geriatric Surgery

Ronnie Ann Rosenthal Michael E. Zenilman Mark R. Katlic Editors

Principles and Practice of Geriatric Surgery Second Edition

Editors Ronnie Ann Rosenthal, MD Professor Department of Surgery Yale University School of Medicine New Haven, CT and Chief, Surgical Service Department of Veterans Affairs VA Connecticut Healthcare System West Haven, CT, USA [email protected]

Mark R. Katlic, MD Division of Thoracic Surgery Director, Regional Ambulatory Campus Geisinger Wyoming Valley Medical Center Wilkes-Barre, PA, USA [email protected]

Michael E. Zenilman, MD Department of Surgery Johns Hopkins Medicine, Baltimore, MD and SUNY Downstate School of Public Health, Brooklyn, NY [email protected]

ISBN 978-1-4419-6998-9 e-ISBN 978-1-4419-6999-6 DOI 10.1007/978-1-4419-6999-6 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2011929046 © Springer Science+Business Media, LLC 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Contents

Section I  Physiology of Aging   1. Invited Commentary................................................................................................. Jesse Roth

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  2. Cell and Molecular Aging........................................................................................ Priyamvada Rai and Bruce R. Troen

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  3. Cancer, Carcinogenesis, and Aging......................................................................... 39 Lodovico Balducci   4. Effects of Aging on Immune Function.................................................................... 49 Raymond P. Stowe and James S. Goodwin   5. Hematological Changes, Anemia, and Bleeding in Older Persons....................... 69 Bruce O. Hough and Gurkamal S. Chatta   6. Invited Commentary................................................................................................. 83 Stanley J. Dudrick   7. Nutrition..................................................................................................................... 87 Sandhya A. Lagoo-Deenadayalan and Danny O. Jacobs   8. Wound Healing in the Elderly................................................................................. 107 Guy P. Marti, Lixin Liu, Xianjie Zhang, Dongmei Xing, Denise C. King, Angela R. Kohli, Maura Reinblatt, William B. Greenough, and John W. Harmon   9. Frailty and Surgery in the Elderly.......................................................................... 129 Babak J. Orandi, Jordan M. Winter, Dorry L. Segev, and Martin A. Makary

Section II  Social/Societal Issues 10. Invited Commentary................................................................................................. 137 Michael E. Zenilman 11. The Demography of Aging and Disability.............................................................. 139 Samir K. Sinha and Colleen Christmas 12. Providing Surgical Care to an Aging Population: Implications for the Surgical Workforce................................................................ 153 David A. Etzioni and Clifford Y. Ko

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13. Defining Quality of Care in Geriatric Surgery...................................................... 171 Marcia L. McGory, Hiroko Kunitake, and Clifford Y. Ko 14. Ethics in Clinical Practice........................................................................................ 179 Margaret Drickamer 15. Teaching Geriatrics to Surgeons.............................................................................. 189 Hugh L. Willcox III, Darin L. Passer, and Richard M. Bell 16. Palliative Care and Decision Making at the End of Life....................................... 197 Melissa F. Perkal 17. Surgery in Centenarians........................................................................................... 211 Mark R. Katlic 18. The Effect of Advancing Age on Physician Performance...................................... 223 Jennifer F. Waljee and Lazar J. Greenfield

Section III  Perioperative Issues 19. Invited Commentary................................................................................................. 233 Ben Eiseman 20. Principles of Geriatric Surgery................................................................................ 235 Mark R. Katlic 21. Geriatric Models of Care.......................................................................................... 253 Elizabeth A. Capezuti, Marie Boltz, and Hongsoo Kim 22. Preoperative Evaluation of the Older Surgical Patient......................................... 267 Lisa M. Walke and Ronnie A. Rosenthal 23. Invited Commentary................................................................................................. 289 Jerry G. Reves 24. Physiologic Response to Anesthesia in the Elderly................................................ 291 Aaron N. LacKamp and Frederick E. Sieber 25. Choosing the Best Anesthetic Regimen................................................................... 305 Sheila R. Barnett 26. Acute Postoperative Pain Management in Elderly Patients................................. 321 Jack M. Berger 27. Drug Usage in Surgical Patients: Preventing Medication-Related Problems..... 343 Richard A. Marottoli, Sean M. Jeffery, and Roshini C. Pinto-Powell 28. Invited Commentary................................................................................................. 359 Donald D. Trunkey 29. Common Perioperative Complications in Older Patients..................................... 361 Sandhya A. Lagoo-Deenadayalan, Mark A. Newell, and Walter E. Pofahl

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30. Management and Outcomes of Intensive Care in the Geriatric Surgical Patient.............................................................................. 377 Gary T. Marshall and Scott R. Gunn 31. Care of the Injured Elderly...................................................................................... 391 Jay Menaker and Thomas M. Scalea 32. Maximizing Postoperative Functional Recovery.................................................... 411 Leo M. Cooney

Section IV  Endocrine System/Breast 33. Invited Commentary................................................................................................. 419 Samuel A. Wells 34. Surgical Disorders of the Thyroid in the Elderly................................................... 421 Leslie S. Wu, Julie Ann Sosa, and Robert Udelsman 35. Parathyroid Disease in the Elderly.......................................................................... 439 Leslie S. Wu, Sanziana A. Roman, and Robert Udelsman 36. Adrenal Tumors in Older Persons........................................................................... 455 Tobias Carling and Robert Udelsman 37. Benign Breast Disease in Elderly Women and Men............................................... 469 Kay O. Lovig and Barbara A. Ward 38. Breast Cancer in Elderly Women............................................................................ 479 Monica Morrow and Lisa S. Wiechmann 39. Diabetes in the Elderly.............................................................................................. 493 Klara Rosenquist and Kitt F. Petersen

Section V  Oral Cavity, Eyes, Ears, Nose and Throat 40. Invited Commentary................................................................................................. 499 Frank E. Lucente 41. Changes in the Oral Cavity with Age...................................................................... 501 Susan Pugliese and Ajay R. Kashi 42. Geriatric Ophthalmology......................................................................................... 513 Andrew G. Lee and Hilary A. Beaver 43. Anatomic and Physiologic Changes in the Ears, Nose, and Throat..................... 525 Ara A. Chalian and Sarah H. Kagan 44. Geriatric Dysphagia.................................................................................................. 539 Neil N. Chheda, Gregory N. Postma, and Michael M. Johns 45. Head and Neck Cancer in the Elderly..................................................................... 553 Babak Givi and Ashok R. Shaha

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Section VI  Respiratory System 46. Invited Commentary................................................................................................. 591 Earle W. Wilkins Jr. 47. Physiologic Changes in Respiratory Function....................................................... 595 Edward J. Campbell 48. Pulmonary Surgery for Malignant Disease in the Elderly.................................... 605 Sarah E. Billmeier and Michael T. Jaklitsch

Section VII  Cardiovascular System 49. Invited Commentary................................................................................................. 619 Timothy J. Gardner 50. Physiologic Changes in Cardiac Function with Aging.......................................... 621 Wilbert S. Aronow and William H. Frishman 51. Risk Factors for Atherosclerosis in the Elderly...................................................... 635 Wilbert S. Aronow and William H. Frishman 52. Cardiac Surgery in the Elderly................................................................................ 649 Margarita T. Camacho and Pooja R. Raval 53. Invited Commentary................................................................................................. 661 Frank J.Veith 54. Surgical Treatment of Vascular Occlusive Disease................................................ 663 Amanda Feigel and Alan Dardik 55. Natural History and Treatment of Extracranial Cerebrovascular Disease in the Elderly................................................................................................ 673 George H. Meier and Carlos Rosales 56. Natural History and Treatment of Aneurysms...................................................... 689 Michael Wilderman and Gregorio A. Sicard

Section VIII  Gastrointestinal System 57. Invited Commentary................................................................................................. 709 Courtney M. Townsend Jr. 58. Age-Related Changes in the Gastrointestinal Tract.............................................. 711 Nefertiti A. Brown, Joshua L. Levine, and Michael E. Zenilman 59. Benign Esophageal Diseases in the Elderly............................................................ 729 Prathima Kanumuri and Neal E. Seymour 60. Esophageal Cancer in the Elderly........................................................................... 747 Philip A. Rascoe, John C. Kucharczuk, and Larry R. Kaiser 61. Benign Diseases of Stomach and Duodenum.......................................................... 763 Daniel Borja-Cacho and Selwyn M. Vickers

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62. Gastric Cancer in the Elderly.................................................................................. 781 Daniel Albo, Daniel A. Anaya, and David H. Berger 63. Small Bowel Obstruction in the Elderly................................................................. 793 Kelley A. Sookraj and Wilbur B. Bowne 64. Lower Gastrointestinal Bleeding in the Elderly..................................................... 807 Sylvia S. Kim and Michael E. Zenilman 65. Ischemic Disorders of the Large and Small Bowel................................................ 819 Jack R. Oak and Gregorio A. Sicard 66. Surgery for Inflammatory Bowel Disease in the Elderly...................................... 837 Stefan D. Holubar and Bruce G. Wolff 67. Diverticulitis and Appendicitis in the Elderly........................................................ 857 Scott C. Thornton 68. Benign Colorectal Disease........................................................................................ 877 Elisa H. Birnbaum 69. Neoplastic Diseases of the Colon and Rectum........................................................ 889 Aundrea L. Oliver, Stanley W. Ashley, and Elizabeth Breen 70. Abdominal Wall Hernia in the Elderly................................................................... 907 Catherine Straub and Leigh Neumayer

Section IX  Hepatobiliary System 71. Invited Commentary................................................................................................. 929 Seymour I. Schwartz 72. Hepatobiliary and Pancreatic Function: Physiologic Changes............................. 931 Vadim Sherman and F. Charles Brunicardi 73. Benign Disease of the Gallbladder and Pancreas................................................... 945 Jennifer A. Wargo and Kim U. Kahng 74. Malignant Diseases of the Gallbladder and Bile Ducts......................................... 967 Steven A. Ahrendt and Thomas H. Magnuson 75. Benign and Malignant Neoplasms of the Exocrine Pancreas............................... 985 Kathryn M. Dalbec and Keith D. Lillimoe 76. Benign and Malignant Tumors of the Liver........................................................... 1007 Anita Kit Wan Chiu and Yuman Fong

Section X  Urogenital System 77. Invited Commentary................................................................................................. 1023 George W. Drach 78. Change in Renal Function, Fluids, and Electrolytes............................................. 1025 Juan F. Macías-Núñez and Manuel Martínez-Maldonado

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79. Urinary Incontinence in the Elderly....................................................................... 1039 Pat O'Donnell 80. Neoplasms of the Kidney and Bladder.................................................................... 1049 Edward M. Uchio, Juan S. Calderon, and Jonathan J. Hwang 81. Benign and Malignant Diseases of the Prostate..................................................... 1069 John A. Taylor III and Peter C. Albertsen 82. Benign Gynecologic Disorders in the Older Women............................................. 1083 Kimberly A. Gerten, W. Jerod Greer, C. Bryce Bowling, Thomas Wheeler II, and Holly E. Richter 83. Gynecologic Malignancies in the Elderly................................................................ 1101 Dan-Arin Silasi, Peter E. Schwartz, and Thomas J. Rutherford

Section XI  Nervous System 84. Invited Commentary................................................................................................. 1119 Dennis Spencer 85. Effects of Aging on the Nervous System................................................................. 1121 Howard A. Crystal, Pedro J. Torrico, Shefali Gandhi, and Paul J. Maccabee 86. Geriatric Neurosurgical Emergencies..................................................................... 1135 Toral R. Patel and Joseph T. King Jr. 87. Benign and Malignant Tumors of the Brain........................................................... 1151 Andrew D. Norden and Elizabeth B. Claus 88. Spinal Disorders and Nerve Compression Syndromes.......................................... 1165 Arash Yaghoobian and John M. Olsewski

Section XII  Musculoskeletal System and Soft Tissue 89. Invited Commentary................................................................................................. 1197 Roby C. Thompson Jr. 90. Age-Related Changes in Bone and Soft Tissue....................................................... 1201 David Rispler and Susan M. Day 91. Common Benign and Malignant Skin Lesions....................................................... 1221 Marcus A. McFerren and David J. Leffell 92. Surgical Management of Soft Tissue Sarcoma in the Geriatric Population........ 1245 Charlotte E. Ariyan and Murray F. Brennan 93. Pressure Sores in the Elderly................................................................................... 1257 Alexander Y. Lin and Mary H. McGrath 94. Orthopaedic Trauma in the Elderly........................................................................ 1273 William Min, Kenneth A. Egol, and Joseph D. Zuckerman

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95. Treatment of Degenerative Joint Diseases.............................................................. 1293 Philip J. Glassner, James Slover, and Joseph D. Zuckerman

Section XIII  Transplantation 96. Invited Commentary................................................................................................. 1319 Khalid M.H. Butt 97. Elderly Donors in Transplantation.......................................................................... 1321 Manuel Mendizabal, John W. Hsu, and Abraham Shaked 98. Elderly Transplant Recipients................................................................................. 1335 Aaron M. Winnick, Ilhan Karabicak, and Dale A. Distant Index................................................................................................................................... 1351

Contributors

Steven A. Ahrendt, MD Associate Professor of Surgery, Department of Surgery, University of Pittsburgh, UPMC Cancer Center, Pittsburgh, PA, USA Peter C. Albertsen, MD Professor, Department of Surgery, Division of Urology, University of Connecticut Health Center, Farmington, CT, USA Daniel Albo, MD, PhD Department of Surgery, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA Daniel A. Anaya, MD Assistant Professor of Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA Charlotte E. Ariyan, MD, PhD Assistant Attending, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Wilbert S. Aronow, MD, FACC, FAHA Cardiology Division, New York Medical College, Macy Pavilion, Valhalla, NY, USA Stanley W. Ashley, MD Frank Sawyer Professor and Vice Chair of Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Lodovico Balducci, MD Chief, Senior Adult Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA Asha G. Bale, MD Assistant Professor of Surgery, Department of Surgery, New Jersey Medical School/ University Hospital, Newark, NJ, USA Sheila R. Barnett, MD Department of Anesthesiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Hilary A. Beaver, MD Associate Professor, Department of Ophthalmology, University of Iowa, Iowa City, IA, USA Richard M. Bell, MD, FACS Professor and Chairman, Department of Surgery, University of South Carolina School of Medicine, Columbia, SC, USA

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David H. Berger, MD, MHCM Professor and Vice Chair, Chief Division of General Surgery and Surgical Oncology; Operative Care Line Executive, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA; Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA Jack M. Berger, MS, MD, PhD Professor of Clinical Anesthesiology, Department of Anesthesiology, Keck School of Medicine, University of Southern California, LAC + USC Medical Center, Los Angeles, CA, USA Sarah E. Billmeier, MD Resident, General Surgery, Brigham and Women’s Hospital, Boston, MA, USA Elisa H. Birnbaum, MD Professor of Surgery, Department of Surgery, Barnes Jewish Hospital, Washington University School of Medicine, St. Louis, MO, USA Marie Boltz, PhD, RN Assistant Professor, Hartford Institute for Geriatric Nursing, New York University College of Nursing, New York, NY, USA Daniel Borja-Cacho, MD Hepatobiliary Fellow, Department of Surgery, University of Minnesota, Minneapolis, MN, USA C. Bryce Bowling, MD Instructor/Fellow, Division of Women’s Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Alabama at Birmingham Medical Center, Birmingham, AL, USA Wilbur B. Bowne, MD Department of Surgery, SUNY Downstate Medical Center, Brooklyn, NY, USA Elizabeth Breen, MD Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Murray F. Brennan, MD Benno C. Schmidt Chair in Clinical Oncology, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Nefertiti A. Brown, MD Department of Surgery, SUNY Downstate Medical Center, Brooklyn, NY, USA F. Charles Brunicardi, MD Professor and Chairman, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA Khalid M.H. Butt, MD, FRCS(Eng), FACS Department of Surgery – Transplant Section, Westchester Medical Center, Valhalla, NY, USA Juan S. Calderon, MD Department of Urology, VA Connecticut Healthcare System, West Haven, CT, USA Margarita T. Camacho, MD Surgical Director, Cardiac Transplantation and Mechanical Heart Program, Department of Cardiothoracic Surgery, Newark Beth Israel Medical Center, Newark, NJ, USA

Contributors

Contributors

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Edward J. Campbell, MD Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA Elizabeth A. Capezuti, PhD, RN, FAAN Hartford Institute for Geriataric Nursing, NYU College of Nursing, New York, NY, USA Tobias Carling, MD, PhD Associate Professor of Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA Ara A. Chalian, MD Department of Otorhinolaryngology: Head and Neck Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Gurkamal S. Chatta, MD Associate Professor of Medicine, Division of Hematology-Oncology; Chief, Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Veterans Administration Public Health System, Pittsburgh, PA, USA Neil N. Chheda, MD Assistant Professor, Department of Otolaryngology, University of Florida, Gainesville, FL, USA Anita Kit Wan Chiu, MD Resident, Department of General Surgery, SUNY Downstate Medical Center, Brooklyn, NY, USA Colleen Christmas, MD Program Director, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA Elizabeth B. Claus, MD, PhD Attending Neurosurgeon, Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA Leo M. Cooney, Jr. MD Yale–New Haven Hospital, New Haven, CT, USA Howard A. Crystal, MD Professor of Neurology, Department of Neurology, SUNY Downstate Medical Center, Brooklyn, NY, USA Kathryn M. Dalbec, MD Department of Surgery, Indiana University Hospital, Indianapolis, IN, USA Alan Dardik, MD, PhD Associate Professor of Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA Susan M. Day, MD Orthopaedic Surgeon; Clinical Instructor, Department of Surgery, Michigan State University College of Human Medicine, Grand Rapids, MI, USA Edwin A. Deitch, MD Professor and Chairman, Department of Surgery, New Jersey Medical School/University Hospital, Newark, NJ, USA

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Dale A. Distant, MD Professor of Clinical Surgery, Department of Transplant Surgery, SUNY Downstate Medical Center, Brooklyn, NY, USA George W. Drach, MD, FACS Professor Emeritus of Urology in Surgery, Department of Surgery/Urology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Margaret Drickamer, MD Professor of Medicine, Department of Medicine (Geriatrics), Yale University School of Medicine, New Haven, CT, USA Stanley J. Dudrick, MD Professor of Surgery, Department of Surgery, Yale University School of Medicine, Saint Mary’s Hospital/Yale Affiliate, Waterbury, CT, USA Kenneth A. Egol, MD Associate Professor, Vice Chairman and Chief of Trauma, Department of Orthopaedic Surgery, New York University Hospital for Joint Diseases, New York, NY, USA Ben Eiseman, MD, MSc, FACS Department of Surgery, Denver Vetarans Affairs Hospital, University Hospital, Denver, CO, USA David A. Etzioni, MD, MSHS Department of Surgery, Mayo Clinic Arizona, Mayo Clinic College of Medicine, Phoenix, AZ, USA Amanda Feigel, MD Department of Surgery, Yale University School of Medicine, New Haven, CT, USA Yuman Fong, MD Murray F. Brennan Chair in Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA William H. Frishman, MD, MACP Rosenthal Professor & Chairman Cardiology Division, New York Medical College, Macy Pavilion, Valhalla, NY, USA Shefali Gandhi, DO, MPH Clinical Neurophysiology Fellow, Department of Neurology, SUNY Downstate Medical Center, Brooklyn, NY, USA Timothy J. Gardner, MD Center for Heart & Vascular Health, Christiana Health Care System, Newark, DE, USA Kimberly A. Gerten, MD Instructor/Fellow, Division of Women’s Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Alabama at Birmingham Medical Center, Birmingham, AL, USA Babak Givi, MD Head & Neck Surgery Fellow, Head & Neck Surgery Section, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA Philip J. Glassner, MD Resident, Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, NY, USA

Contributors

Contributors

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James S. Goodwin, MD Mitchell Distinguished Chair in Geriatric Medicine, University of Texas Medical Branch, Sealy Center on Aging, Galveston, TX, USA Lazar J. Greenfield, MD Professor of Surgery and Chair Emeritus, Department of Surgery, University of Michigan, Ann Arbor, MI, USA William B. Greenough, MD Professor, Division of Geriatric Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA W. Jerod Greer, MD Instructor/Fellow, Division of Women’s Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Alabama at Birmingham Medical Center, Birmingham, AL, USA Scott R. Gunn, MD Associate Professor of Critical Care Medicine and Emergency Medicine, Department of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA John W. Harmon, MD, FACS Professor of Surgery, Department of Surgery, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA Stefan D. Holubar, MD Colon and Rectal Surgery Fellow, Division of Colon and Rectal Surgery, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA Bruce O. Hough, MD Fellow, Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA John W. Hsu, MD Transplant Surgery Fellow, Division of Surgery, University of Pennsylvania Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Jonathan J. Hwang, MD Associate Professor, Department of Urology, Georgetown University School of Medicine, Washington Hospital Cancer/Georgetown University Hospital, Washington, DC, USA Danny O. Jacobs, MD, MPH David C. Sabiston, Jr. Professor and Chairman, Surgeon-in-Chief, Department of Surgery, Duke University Hospital, Durham, NC, USA Michael T. Jaklitsch, MD Associate Professor of Surgery, Department of Thoracic Surgery, Brigham and Women’s Hospital, Boston, MA, USA Sean M. Jeffery, PharmD Associate Clinical Professor; Adjunct Assistant Professor, University of Connecticut School of Pharmacy, Storrs, CT, USA; Yale University School of Medicine, VA Connecticut Healthcare System, West Haven, CT, USA

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Michael M. Johns, III MD Director – Emory Voice Center; Assistant Professor, Department of Otolaryngology, Emory University School of Medicine, Emory University Hospital, Atlanta, GA, USA Sarah H. Kagan, PhD, RN School of Nursing, University of Pennsylvania, Philadelphia, PA, USA Kim U. Kahng, MD Associate Director, Women’s Health Education Program, Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, USA Larry R. Kaiser, MD President, Alkek-Williams Distinguished Physician Endowed Chair; Professor of Cardiothoracic Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA Prathima Kanumuri, MD Department of Surgery, Baystate Medical Center, Springfield, MA, USA Ilhan Karabicak, MD Fellow, Department of Transplant Surgery, SUNY Downstate Medical Center, Brooklyn, NY, USA Ajay R. Kashi, DDS, MS PhD Candidate, Department of Orthopaedic Surgery and Rehabilitation Medicine, State University of New York Downstate Medical Center, Brooklyn, NY, USA Mark R. Katlic, MD, MMM, FACS Division of Thoracic Surgery, Director, Regional Ambulatory Campus Geisinger Wyoming Valley Medical Center, Wilkes-Barre, PA, USA Hongsoo Kim, PhD, MPH Assistant Professor, Department of Health Policy and Management, Graduate School of Public Health, Seoul National University, Seoul, South Korea Sylvia S. Kim, MD Assistant Professor of Surgery, Department of Colorectal and General Surgery, SUNY Downstate Medical Center, Brooklyn, NY, USA Denise C. King, RN, BSN, WCC Wound Program Manager, Department of Wound Management, Johns Hopkins Bayview Care Center, Baltimore, MD, USA Joseph T. King Jr., MD, MSCE Chief of Neurosurgery, VA Connecticut Healthcare System Chair, VA Neurosurgery Surgical Advisory Board; Associate Professor of Neurosurgery, Director of Outcomes Research, Department of Neurosurgery, Yale University School of Medicine, West Haven, CT, USA Clifford Y. Ko, MD, MS, MSHS, FACS Professor of Surgery and Health Services, Robert and Kelly Chair in Surgical Outcomes, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Angela R. Kohli, BSN, WOCN, CWCN Ambulatory Services Manager, Johns Hopkins Wound Healing Center/Dermatology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA John C. Kucharczuk, MD Assistant Professor of Surgery, Department of Thoracic Surgery, University of Pennsylvania, Philadelphia, PA, USA

Contributors

Contributors

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Hiroko Kunitake, MD Surgical Resident, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA Aaron N. LacKamp, MD Clinical Associate, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA Sandhya A. Lagoo-Deenadayalan, MD, PhD Assistant Professor of Surgery, Department of Surgery, Duke University Hospital, Durham, NC, USA Andrew G. Lee, MD Professor of Ophthalmology, Neurology and Neurosurgery, Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA David J. Leffell, MD David Paige Smith Professor of Dermatology & Surgery, Yale New Haven Hospital, Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA Joshua L. Levine, MD Director of Surgical Services, Department of Plastic and Reconstructive Surgery, New York Eye and Ear Infirmary, New York, NY, USA Keith D. Lillimoe, MD Jay L. Grosfeld Professor and Chairman, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA Alexander Y. Lin, MD Former Chief Resident, UCSF Plastic Surgery, University of California San Francisco, San Francisco, CA, USA; Assistant Professor of Surgery, Division of Plastic Surgery, Saint Louis University Director, St. Louis Cleft-Craniofacial Center, Cardinal Glennon Children’s Medical Center at SLU, St. Louis, MO, USA Lixin Liu, PhD Postdoctoral Fellow, Department of Surgery, Johns Hopkins Bayside Medical Center, Baltimore, MD, USA Kay O. Lovig, MD Department of Internal Medicine, Greenwich Hospital, Greenwich, CT, USA Frank E. Lucente, MD Vice-Dean for Graduate Medical Education; Professor, Department of Otolaryngology, Downstate Medical Center, State University of New York, Brooklyn, NY, USA Paul J. Maccabee, MD Professor of Neurology, Department of Neurology, State University Hospital of Brooklyn, Brooklyn, NY, USA Juan F. Macías-Núñez, MD, PhD Titular Professor of Medicine, Department of Nephrology, Chief Section of Nephrology, University Hospital, Salamanca, Spain Thomas H. Magnuson, MD John’s Hopkins Bayview Medical Center, Baltimore, MD, USA Martin A. Makary, MD The Mark Ravitch Chair, General Surgery, Associate Professor of Health Policy, Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA

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Richard A. Marottoli, MD, MPH Associate Professor of Medicine, Department of Internal Medicine (Geriatrics) Yale University School of Medicine, VA Connecticut Healthcare System, New Haven, CT, USA Gary T. Marshall, MD Assistant Professor of Surgery, Department of Trauma Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Guy P. Marti, MD Department of Surgery, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA Manuel Martínez-Maldonado, MD Executive Vice President for Research, University of Louisville; Professor of Medicine, Professor of Pharmacology and Toxicology, University of Louisville Medical School, Louisville, KY, USA Marcus A. McFerren, MD, PhD Resident Physician, Yale New Haven Hospital, Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA Marcia L. McGory, MD Resident Surgeon, Department of Surgery, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA Mary H. McGrath, MD, MPH, FACS Assistant Professor of Surgery, Division of Plastic Surgery, University of California San Francisco, San Francisco, CA, USA George H. Meier, MD Professor and Chief, Department of Vascular Surgery, University Hospital of Cincinnati, Cincinnati, OH, USA Jay Menaker, MD Assistant Professor, Department of Surgery, University of Maryland Medical Center, R. Adams Cowley Shock Trauma Center, Baltimore, MD, USA Manuel Mendizabal, MD Staff Hepatologist, Division of Hepatology and Liver Transplantation, Austral University Hospital Pilar, Buenos Aires, Argentina William Min, MD, MS, MBA Resident, Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, NY, USA Monica Morrow, MD Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Leigh Neumayer, MD, MS Professor of Surgery, Department of Surgery, University of Utah and Huntsman Cancer Hospital, Salt Lake City, UT, USA Mark A. Newell, MD Assistant Professor, Department of Surgery, Brody School of Medicine, East Carolina University, Pitt County Memorial Hospital, Greenville, NC, USA Andrew D. Norden, MD Department of Neurology, Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Contributors

Contributors

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Jack R. Oak, MD Vascular Surgery Fellow, Department of Vascular Surgery, Barnes-Jewish Hospital, University of Washington School of Medicine, St. Louis, MO, USA Pat O’Donnell, MD Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA Aundrea L. Oliver, MD Resident, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA John M. Olsewski, MD, FACS Associate Professor of Orthopaedic Surgery, Department of Orthopaedic Surgery, Albert Einstein College of Medicine, Bronx, NY, USA Babak J. Orandi, MC, MSc Halsted Surgery Resident, Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA Darin L. Passer, MD General Surgery Resident, Department of Surgery, University of South Carolina, Palmetto Health Richland, Columbia, SC, USA Toral R. Patel, MD Neurosurgery Resident, Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, USA Melissa F. Perkal, MD Assistant Professor, Department of Surgery, Yale University School of Medicine, West Haven, CT, USA; Surgical Service, Department of Veterans Affairs, VA Connecticut Healthcare System, West Haven, CT, USA Kitt F. Petersen, MD Associate Professor, Department of Internal Medicine (Endocrinology), Yale University School of Medicine, New Haven, CT, USA Roshini C. Pinto-Powell, MD Assistant Professor of Medicine, Department of General Internal Medicine, Dartmouth Medical School, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA Walter E. Pofahl, MD Vice Chairman, Department of Surgery, Brody School of Medicine, East Carolina University, Pitt County Memorial Hospital, Greenville, NC, USA Gregory N. Postma, MD Director, Center for Voice and Swallowing Disorders; Professor, Department of Otolaryngology, Medical College of Georgia, Augusta, GA, USA Susan Pugliese, DDS, RN Department of Dentistry, University Hospital of Brooklyn, State University of New York, Downstate Medical Center, Brooklyn, NY, USA Priyamvada Rai, PhD Assistant Professor, Department of Medicine, Division of Gerontology and Geriatric Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA Philip A. Rascoe, MD Department of Thoracic Surgery, University of Pennsylvania, Philadelphia, PA, USA

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Pooja R. Raval, BA Newark Beth Israel Hospital, Warren, NJ, USA Maura Reinblatt, MD Assistant Professor, Department of Plastic Surgery, John’s Hopkins Bayview Medical Center, Baltimore, MD, USA Jerry G. Reves, MD Vice President for Medical Affairs; Dean, College of Medicine; Professor, Department of Anesthesia and Perioperative Medicine, Cell and Molecular Pharmacology & Experimental Therapeutic, Medical University of South Carolina, Charleston, SC, USA Holly E. Richter, PhD, MD Professor, Department of Obstetrics and Gynecology, Division Director, Women’s Pelvic Medicine and Reconstructive Surgery, University of Alabama at Birmingham Medical Center, Birmingham, AL, USA David Rispler, MD Assistant Professor, Michigan State Orthopedic Residency Program, Grand Rapids Orthopedic Residency Program, Grand Rapids, MI, USA Sanziana A. Roman, MD Chief, Endocrine Surgery, Associate Professor, Yale University School of Medicine, New Haven, CT, USA Carlos Rosales, MD Vascular Surgery Fellow, Department of Vascular Surgery, University of Cincinnati, Cincinnati, OH, USA Klara Rosenquist, MD Department of Internal Medicine (Endocrinology), Yale University School of Medicine, New Haven, CT, USA Ronnie A. Rosenthal, MD Professor, Department of SurgeryYale University School of Medicine, New Haven; Chief Surgical Service, Department of Veterans Affairs, VA Connecticut Healthcare System, West Haven, CT, USA Jesse Roth, MD Professor of Medicine; Investigator; Former Professor and Chief, Geriatric Medicine and Gerontology; Former Scientific Director and Chief, Diabetes Branch, Feinstein Institute for Medical Research, Albert Einstein College of Medicine, North Shore-Long Island Jewish Health System, Whitestone, NY, USA` Thomas J. Rutherford, MD, PhD Associate Professor, Department of Obstetrics and Gynecology/Gynecologic Oncology, Yale University School of Medicine/Yale New Haven Hospital, New Haven, CT, USA Thomas M. Scalea, MD Physician in Chief, R. Adams Cowley Shock Trauma Center, Baltimore, MD, USA Peter E. Schwartz, MD Professor, Department of Obstetrics and Gynecology/Gynecologic Oncology, Yale University School of Medicine/Yale New Haven Hospital, New Haven, CT, USA Seymour I. Schwartz, MD, FACS Distinguished Alumni Professor of Surgery, Department of Surgery, University of Rochester, Strong Memorial Hospital, Rochester, NY, USA

Contributors

Contributors

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Dorry L. Segev, MD, PhD Associate Professor of Surgery, Department of Transplant Surgery, Johns Hopkins Hospital, Baltimore, MD, USA Neal E. Seymour, MD Division Chief General Surgery; Professor, Department of Surgery, Baystate Medical Center, Springfield, MA, USA; Tufts University School of Medicine, Springfield, MA, USA Ashok R. Shaha, MD Attending Surgeon, Professor of Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA Abraham Shaked, MD, PhD Professor of Surgery, Division of Surgery; Director, University of Pennsylvania Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Vadim Sherman, MD, MSc, FRCSC Assistant Professor of Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA Gregorio A. Sicard, MD Professor of Surgery, Vice Chair of the Department of Surgery, Barnes-Jewish Memorial Hospital/Washington University School of Medicine, St. Louis, MO, USA Frederick E. Sieber, MD Associate Professor; Chairman, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA Dan-Arin Silasi, MD Assistant Professor, Department of Obstetrics and Gynecology/Gynecologic Oncology, Yale University School of Medicine/Yale New Haven Hospital, New Haven, CT, USA Samir K. Sinha, MD, DPhil, FRCPC Director of Geriatrics, Mount Sinai and the University Health Network Hospitals, Division of Geriatric Medicine, University of Toronto, Suite 475 - 600 University Avenue, Toronto, Ontario CANADA, M5G 1X5 James Slover, MD, MS Assistant Professor, Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, NY, USA Kelley A. Sookraj, MD Department of Surgery, SUNY Downstate Medical Center, Brooklyn, NY, USA Julie Ann Sosa, MA, MD Associate Professor of Surgery, Department of Surgery, Maine Medical Center, Portland, ME, USA Dennis Spencer, MD Harvey and Kate Cushing Professor and Chair, Department of Neurosurgery, Yale University School of Medicine, Yale New Haven Hospital, New Haven, CT, USA Raymond P. Stowe, PhD Senior Scientist, Microgen Laboratories, La Marque, TX, USA Catherine M. Straub, BS, MD Department of General Surgery, University of Utah, Salt Lake City, UT, USA John A. Taylor III, MD Assistant Professor, Division of Urology, Department of Surgery, University of Connecticut Health Center, Farmington, CT, USA

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Roby C. Thompson Jr., MD Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, MN, USA Scott C. Thornton, MD, FACS, FASCRS Assistant Clinical Professor of Surgery, Department of General Surgery, Bridgeport Hospital, Yale University, Bridgeport, CT, USA Pedro J. Torrico, MD Resident, Department of Neurology, SUNY Downstate Medical Center, Whitestone, NY, USA Courtney M. Townsend Jr., MD Professor and John Woods Harris Distinguished Chairman, Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA Bruce R. Troen, MD Department of Medicine, Division of Gerontology and Geriatric Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami VA GRECC, Miami, FL, USA Donald D. Trunkey, MD Professor Emeritus, Department of Surgery, Oregon Health & Science University, Portland, OR, USA Edward M. Uchio, MD Chief of Urology; Assistant Professor of Surgery, Section of Urology, VA Connecticut Healthcare System, West Haven, CT, USA; Department of Surgery, Yale University School of Medicine, New Haven, CT, USA Robert Udelsman, MD, MBA William H. Carmalt Professor of Surgery and Oncology Chairman, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA Frank J. Veith, MD, FACS Professor of Surgery, Department of Surgery, New York University, Bronx, NY, USA Selwyn M. Vickers, MD Jay Phillips Professor and Chairman, Department of Surgery, University of Minnesota, Minneapolis, MN, USA Jennifer F. Waljee, MD, MPH, MS House Officer, Plastic and Reconstructive Surgery, Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA Lisa M. Walke, MD Associate Professor; Chief, Geriatrics Consult Service, Geriatrics & Extended Care Service, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA; VA Connecticut Healthcare System, West Haven, CT, USA Barbara A. Ward, MD Medical Director, Department of Surgery, The Breast Center at Greenwich Hospital, Greenwich, CT, USA Jennifer A. Wargo, MD Instructor of Surgery; Assistant in Surgery, Division of Surgical Oncology, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA Samuel A. Wells, Jr. MD Professor of Surgery, Department of Surgery, Washington University Medical Center, St. Louis, MO, USA

Contributors

Contributors

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Thomas Wheeler II, MD, MSPH Assistant Professor, Division of Women’s Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Alabama at Birmingham Medical Center, Birmingham, AL, USA Lisa S. Wiechmann, MD Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Michael Wilderman, MD Vascular Fellow, Division of Vascular Surgery, Barnes Jewish Hospital, Washington University, St. Louis, MO, USA Earle W. Wilkins, Jr. MD Clinical Professor of Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA Hugh L. Willcox, III MD Resident, Department of General Surgery, Palmetto Health Richland Hospital, Columbia, SC, USA Aaron M. Winnick, MD Fellow, Department of Transplant Surgery, SUNY Downstate Medical Center, Brooklyn, NY, USA Jordan M. Winter, MD Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA Bruce G. Wolff, MD Professor of Surgery, Department of Surgery; Chair, Division of Colon and Rectal Surgery, College of Medicine Mayo Clinic, Rochester, MN, USA Leslie S. Wu, MD Clinical Fellow, Department of Surgery, Maine Medical Center, Portland, ME, USA Dongmei Xing, MD, PhD Johns Hopkins University School of Medicine, Baltimore, MD, USA Arash Yaghoobian, MD Orthopaedic Resident, Department of Orthopaedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA Michael E. Zenilman, MD, FACS School of Public Health, SUNY Downstate, Brooklyn, NY; Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD Xianjie Zhang, MD, PhD Post-doctoral Fellow, Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA Joseph D. Zuckerman, MD Walter A. L. Thompson Professor of Orthopaedic Surgery and Chairman, Department of Orthopaedics, NYU Hospital for Joint Diseases, New York, NY, USA

Section I

Physiology of Aging

Chapter 1

Invited Commentary Jesse Roth

Get in league with the future. Horace Greeley

The Future By reading this piece, you are identifying yourself as a part of the vanguard in geriatric surgery. Textbooks of surgery and textbooks of geriatrics cover geriatric surgery very sparingly. You have chosen to tackle a textbook on geriatric surgery.

Demographics and Dollars The elderly are the fastest growing segment of the population, with the so-called old–old in the lead. The elderly are highly overrepresented in the hospital population and in the medical expenses column. The application more widely of basic well-established principles of care for the elderly will almost certainly reduce the number of elderly in the hospital and increase the return on money spent. Most important, we can expect better outcomes for the elderly patients, especially for those who were hospitalized. Hospitalization and surgery are each serious threats for the elderly patient.

Geriatrics Is a Frontier “Go West, young man,” [1] was an exhortation to move from the built up to the new, the frontier, the so-called cutting edge. Geriatrics as a branch of medicine is young and is having a

J. Roth () Feinstein Institute for Medical Research, Albert Einstein College of Medicine, North Shore-Long Island Jewish Health System, 149-37 Powells Cove Blvd, Whitestone 11357, NY, USA e-mail: [email protected]

growth spurt. The subspecialties in medicine are increasing their attention to issues related to care for the elderly. In geriatric surgery, the frontiers are open. History provides us with some models. Harvey Cushing was one of the twentieth century’s giants, a pioneer. In the early years of the twentieth century, with great daring and deep thought, he took principles of general surgery and very meticulously applied them to the brain. In addition to his skills in the operating theater, he gave his patients extraordinarily attentive care, before surgery as well as after. Indeed, infection rates on his patients in the pre-antibiotic area, would win a commendation medal today. Today we revere him as the father of neurosurgery [2]. Pediatrics emerged from adult medicine at about the same time [3]. Now pediatrics has a complete array of sub-specialists covering all aspects of care for the young. When I was a medical student 50 years ago, pediatric surgery was just coming into its own. Now it is a well-established subspecialty.

Quest for Excellence As the age of the patient increases, the gap grows that separates the good physician from the excellent physician. A similar gap shows itself as the age of the child decreases. The premature baby and the frail elderly share many features. One very big difference – pediatrics, pediatric surgery, pediatric nursing, neonatology, pediatric gastroenterology, pediatric endocrinology, and their cousins are well-developed areas of expertise with highly trained practitioners. Their counterparts in the care of the elderly are fewer and are less deeply trained. It is much more difficult for physicians involved in the care of an elderly patient to get expert help than it is for the doctor caring for a child. Worse yet, the adult physicians (and other medical providers) who are inadequately trained in geriatric care are often unaware of their deficiencies.

R.A. Rosenthal et al. (eds.), Principles and Practice of Geriatric Surgery, DOI 10.1007/978-1-4419-6999-6_1, © Springer Science+Business Media, LLC 2011

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Fifty years ago, all of us were deficient as well as unaware of our deficiencies in care of the elderly. I have clear memories of a man in his eighties cared for by me and by a surgeon. The surgery was successful but the patient had a series of complications and died. Today, I can think of many useful interventions that were unknown and unused by us in those days.

The Challenge The elderly patient is intrinsically more complex and challenging than the equally ill youngster. The young patient typically has one disease – complications and medications are few. The older patient classically has multiple conditions and a long list of medications, co-conspirators that blur the diagnosis and complicate the therapy. Laboratory values in young patients have established norms developed in young people. Normal ranges for the elderly are much less reliable, often guesses, appropriated with little testing from a much younger age group. Family responsibility for the young patient has a well-defined societal pattern whereas family links to the elderly patient are very variable and may require high level diplomacy. Yet, optimal outcomes for the young patient and for the old often require skillful and energetic family involvement. Medical decisions with an elderly patient require professional skills at their best. The physician may start with an evidence-based algorithm conceived on experience with younger patients but the plan needs to be custom made for the particular patient at hand. In addition to deciding which tests and which surgery should be done, an important part of the care is deciding which tests and which surgery should not be performed. Even when a patient fulfills all the criteria for surgery, good judgment may modify or veto that decision for an elderly patient.

J. Roth

recruit as advisors the minority of health care deliverers in your community who are skilled in caring for the geriatric patient. Learning, teaching, and research opportunities will abound.

Scientific Advances in Geriatrics The opening chapters of this book tackle several important scientific areas related to aging and the elderly patient. I recall meetings in geriatrics 20 years ago when the papers dealing with lab studies on aging fit a single track for 1 day. Now multiple tracks on multiple days are needed. The scientific basis of bone health, muscle wasting, and longevity are each a rich lode of discovery. The coming age of science in geriatrics is best epitomized by studies of cell aging that led to the 2009 Nobel Prize for pioneer work on telomeres.

The Road Ahead for the Physician Intense focus in a well-circumscribed area can add great value to the physician’s effort. These efforts often translate into shorter less expensive stays in the hospital, a language understood by administrators. At a time when burnout is increasingly widespread among physicians, these efforts can also be very rewarding to the professional soul. Treatment for burnout has a poor prognosis. Prevention is more likely to succeed. Given the large loan balances and uncertain retirement programs that burden young physicians, the journey ahead may be unexpectedly long. Passionate commitment to a segment of one’s professional life may be the key to a long happy satisfying medical career at this difficult time. Care for the elderly is energized by a pioneer spirit that makes it especially attractive for a long career.

Medical Care from Here to the Future Someday, care for the elderly will be totally in the hands of skilled caregivers who are highly trained in geriatrics, as exists now in pediatrics. Today, individual caregivers must gain multiple skills in many aspects of caring for the elderly. There are unique opportunities at your medical center to be among the pioneers who are importing best geriatric practices into surgery. In addition, you need to search for and

References 1. Ascribed to Horace Greeley 2. Bliss M (2005) Harvey cushing: a life in surgery. University of Toronto Press, Toronto 3. Markel H (2000) For the welfare of children: the origins of the relationship between us public health workers and pediatricians. Am J Public Health 90:893–899

Chapter 2

Cell and Molecular Aging* Priyamvada Rai and Bruce R. Troen

Every day you get older – that’s a law. Butch Cassidy to the Sundance Kid Aging seems to be the only available way to live a long life Daniel Francois Esprit Auber There is no such thing as a free lunch Anonymous

Introduction Discussions of aging invariably begin by establishing a satisfactory definition for the term aging and the related word senescence. Although the term aging is commonly used to refer to postmaturational processes that lead to diminished homeostasis and increased organismic vulnerability, the more correct term for this is senescence (derived from the Latin word “senescere,” meaning to grow old or to diminish), which explicitly refers to the process of growing old and sustaining related deterioration. Aging on the other hand can refer to any time-related process. We will use senescence to refer to cellular phenomena and aging to refer to changes, as organisms grow old. Gerontologists often categorize the process of aging into normal, usual, or successful aging. Normal aging involves inexorable and universal physiological changes, whereas usual aging includes age-related diseases. For example, menopause and the decline in renal function represent aspects of normal aging. In contrast, coronary artery disease is an example of usual aging and is not found in all older persons. Successful aging encompasses the concept of growing older without significant impairment of physiological, cognitive, * Portions of this chapter are reprinted with permission from Troen BR (2003) The biology of aging. Mt Sinai J Med 70(1):3–22. P. Rai () and B.R. Troen () Department of Medicine, Division of Gerontology and Geriatric Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami VA GRECC, Miami, FL, USA e-mail: [email protected]; [email protected]

and social function. This approach to aging enables the utilization of a conceptual framework that identifies intrinsic (developmental-genetic) versus extrinsic (stochastic) causes. However, accumulating evidence increasingly stresses the importance of both. Indeed, the altered homeostasis in older organisms is likely the result of a genetic program that determines the response to exogenous influences and thereby increases the predisposition to illness and death.

Life Span and Life Expectancy The average/median life span (also known as life expectancy) is represented by the age at which 50% of a given population survives, and maximum life span potential (MLSP) represents the longest-lived member(s) of the population or species. The average life span of humans has increased dramatically over time, yet the MLSP has remained approximately constant (Fig. 2.1) [1]. For 99% of our existence as a species, the average life expectancy for human was very short compared to the present. During the Bronze Age (circa 3,000 b.c.), the average life expectancy was 18 years due to disease and accidents. Average life expectancy in 275 b.c. was still only 26 years. By 1900, improved sanitation helped to improve the average life expectancy at birth for humans to 47 years, but infectious disease was still a major killer. As of 2005, better diet, health care, and reduced infant mortality had resulted in an average life expectancy of 77.8 years [2]. The increase in the average life expectancy has resulted in a compression of morbidity (a squaring

R.A. Rosenthal et al. (eds.), Principles and Practice of Geriatric Surgery, DOI 10.1007/978-1-4419-6999-6_2, © Springer Science+Business Media, LLC 2011

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Figure 2.1  Percent survival curve for humans at different times in history with varying environments, nutrition, and medical care. The 50% survival values have improved, but maximum life-span potential has remained the same (From Troen BR (2003) The biology of Aging. Mt Sinai J Med 70(1):3–22. Reprinted with permission of John Wiley & Sons, Inc.).

of the mortality curve) towards the end of the life span (Fig. 2.1). Of note, the ­longest-lived human for whom documentation exists was Jeanne Calment, who died at the age of 122 in August 1997. The longest-lived male was Christian Mortensen, who died in 1998 at the age of 115. As causes of early mortality have been eliminated through public-health measures and improved medical care, more individuals have approached the maximum life span. Between 1960 and 2000, the population of those aged 85 years and over grew 356%, whereas the elderly population in general rose 111%, and the entire U.S. population grew only 57% [3]. A number of physiological functions begin a progressive decline from the fourth decade onward, including the cardiovascular, pulmonary, renal, and immune systems. In women, this correlates with a decline in reproductive capacity. Interestingly, one study has shown that women who are fertile in their forties are nearly four times as likely to survive to the age of 100 than women who are not [4], suggesting that reproductive fitness later in life may be an indicator of longevity. The age of menopause has also been linked to life span. Controlling for socioeconomic factors, women who undergo menopause before the age of 40 are twice as likely to die before those who experience menopause after the age of 50 [5, 6]. These findings hold true even when a history of estrogen replacement therapy is taken into account, suggesting that reduced estrogen alone is not responsible for the ostensible reduction in life span. Another study found that while late reproduction correlated with increased longevity in postreproductive Sami women, maternal age at first birth and total fecundity did not appear to impact female longevity [7]. In males, although spermatogenesis per se does not show a significant age-related decline, testosterone levels fall with advancing age, and a few studies have linked reduced bioavailability of testosterone to age-related functional

P. Rai and B.R. Troen

degeneration [8, 9]. Therefore, it would appear that there is a link between reproductive health, aging, and life span (see the disposable soma theory discussed below). MLSP appears to be species-specific, implying a significant genetic component to the rate of aging. For example, humans have an MLSP 25- to 30-fold higher than mice. Some biodemographic estimates predict that elimination of most of the major killers such as cancer, cardiovascular disease, and diabetes would add no more than 10 years to the average life expectancy, but would not affect MLSP [10, 11]. This implies an upper limit to the MLSP. Some models suggest that genes operate by raising or lowering the relative risk of death by making cancer, coronary disease, or Alzheimer’s disease more likely, rather than by fixing the life span. One mathematical model predicts that if participants in the Framingham Heart Study had been able to maintain the levels of 11 different risk factors similar to those of a typical 30 year old, the men and women would have survived to an average age of 99.9 and 97.0 years, respectively [10]. There are three known regimens that can extend life span. The first two involve lowering ambient temperature and reducing exercise and are effective in poikilotherms (coldblooded species). A 10°C drop or the elimination of a housefly’s capacity to fly extends the maximum life span approximately 250% [12]. Both of these manipulations decrease the metabolic rate and are accompanied by decreases in free radical generation and oxidative damage to protein and DNA. The third intervention is caloric restriction, which can extend life span in yeast, worms, flies, grasshoppers, spiders, water fleas, hamsters, mice, rats, and dogs [13]. Dietary restriction without malnutrition can increase both the average and maximum life spans of mice and rats by more than 50% [14, 15]. Although calories are severely restricted (up to 40%), essential nutrients such as vitamins and minerals are maintained at levels equivalent to those found in ad libitum diets. The diet-restricted animals also exhibit a delay in the onset of physiological and pathological changes with aging [16]. These include hormone and lipid levels, female reproduction, immune function, nephropathy, cardiomyopathy, osteodystrophy, and malignancies. Size, weight, fat percentage, and some organ weights are markedly less in calorically restricted animals [17]. The specific metabolic rate, the amount of oxygen consumed per gram of tissue, decreased in rats subjected to caloric restriction [18, 19]. However, in one study, long-term food restriction did not alter the metabolic rate [20]. This finding suggests that the specific metabolic rate may not be a critical determinant of longevity. To date, life span extension in mammals by dietary restriction has been most convincingly demonstrated in rodents. However, dietary restriction in primates [21–24] and in humans [25, 26] does appear to improve a number of metabolic and cardiovascular disease risk parameters.

2  Cell and Molecular Aging

Characteristics of Aging There is evidence supporting at least five common characteristics of aging in mammals (Table 2.1): 1. Increased mortality with age after maturation: In the early nineteenth century, Gompertz first described the exponential increase in mortality with aging due to various causes, a phenomenon that still pertains today [27]. In 2005, the death rate for all causes at the age of 25–34 was 104.4/100,000 and at the age of 35–44 was 193.3/100,000. Death rates at the age of 65–74, 75–84, and 85 and over were 2,137.1/100,000, 5,260.0/100,000, and 13,798.6/100,000 respectively: a greater than 130-fold increase from young adults to the oldest group [28]. Indeed, the pattern of agerelated survival is similar across species, including invertebrates and single-cell organisms (Fig. 2.2). 2. Changes in biochemical composition in tissues with age: There are notable age-related decreases in lean body mass and total bone mass in humans [29, 30]. Although subcutaneous fat is either unchanged or declining, total fat remains the same [29]. Consequently, the percentage of adipose tissue increases with age. At the cellular level, Table 2.1  Characteristics of aging 1. Increased mortality with age after maturation 2. Changes in biochemical composition in tissues with age 3. Progressive decrease in physiological capacity with age 4. Reduced ability to respond adaptively to environmental stimuli with age 5. Increased susceptibility and vulnerability to disease

Figure 2.2  Viability curves from different model organisms have a similar characteristic shape. Representative mortality data are shown for Homo sapiens, Mus musculus, Caenorhabditis elegans, and Saccharomyces cerevisiae (From Troen BR (2003) The biology of Aging. Mt Sinai J Med 70(1):3–22. Reprinted with permission of John Wiley & Sons, Inc.).

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many markers of aging have been described in various tissues from different organisms [31]. Two of the first to be described were increases in lipofuscin (age pigment) [32] and increased cross-linking in extracellular matrix molecules such as collagen [33, 34]. Recent studies have shown that DNA damage markers such as gamma-H2AX and 53BP1 are upregulated in tissues of aged primates [35, 36] and mice [37], presumably arising from DNA double-strand breaks (DSB) and/or dysfunctional chromosome ends called telomeres. Additional examples include age-related changes in both the rates of transcription of specific genes and the rate of protein synthesis and numerous age-related alterations in posttranslational protein modifications, such as glycation and oxidation [38,  39]. For instance, the p16INK4a gene product has been found to be upregulated in a number of tissues from aging individuals and animals (see below). 3. Progressive decrease in physiological capacity with age: Many physiologic changes have been documented in both cross-sectional and longitudinal studies. Examples include declines in glomerular filtration rate, maximal heart rate, and vital capacity [40]. These decreases occur linearly from about the age of 30; however, the rate of physiological decline is quite heterogeneous from organ to organ and individual to individual [41, 42]. 4. Reduced ability to respond adaptively to environmental stimuli with age: A fundamental feature of senescence is the diminished ability to maintain homeostasis [43]. This is manifested, not primarily by changes in resting or basal parameters, but in the altered response to an external stimulus such as exercise or fasting. The loss of “reserve”

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can result in blunted maximum responses as well as in delays in reaching a peak level and in returning to basal levels. For example, the induction of hepatic tyrosine aminotransferase activity by fasting is both attenuated and delayed in old rodents [43]. The immune response also appears to be impaired in older individuals, leading to reduced ability to fight infections, less protection from vaccinations, higher incidences of autoimmunity, and impaired antigen affinity and class-switching by lymphocytes (reviewed by Dorshkind et al. [44]). 5. Increased susceptibility and vulnerability to disease: The incidence and mortality rates for many diseases increase with age and parallel the exponential increase in mortality with age [45]. For the five leading causes of death for people over 65 years of age, the relative increase in death rates compared to people aged between 25 and 44 is: heart disease – 92-fold, cancer – 43-fold, stroke – >100-fold, chronic lung disease – >100-fold, and pneumonia and influenza – 89-fold [46]. The basis for these dramatic rises in mortality is incompletely understood but presumably involves changes in the function of many types of cells that lead to tissue/organ dysfunction and systemic illness. Interestingly, a retrospective study of centenarians demonstrated that they live 90–95% of their lives in very good health and with a high level of functional independence [47]. The centenarians do suffer a 30–50% annual mortality at the end of their lives, but this represents a marked compression of morbidity towards the end of life and is close to the idealized survival curve in Figs. 2.1 and 2.2.

Mechanisms/Theories of Aging In an effort to adequately explain the phenotype of aged organisms, many speculations about the cause(s) of aging have been proposed. However, what is known about the fundamental molecular mechanisms involved in aging remains controversial and largely unproven. A major reason for this is the obvious complexity of the problem. Aging changes are manifested from the molecular to the organismal level; environmental factors affect experimental observations; secondary effects complicate elucidation of primary mechanisms; there exist a dearth of easily measurable “biomarkers” that are consistent over different tissues and species. No one unifying theory may exist since the mechanisms of aging could be quite distinct in different organisms, tissues, and cells, although there appear to be certain mechanisms, such as DNA damage, that are broadly conserved despite differences in specific response. Theories of aging have historically been divided into two general categories: developmental-genetic and stochastic (Table  2.2). The term “developmental-genetic” implies a more active genetic control of aging than likely exists. In

P. Rai and B.R. Troen Table 2.2  Theories of aging

Developmental/genetic Antagonistic pleiotropy theory Longevity-associated genes Disposable soma theory

Stochastic Free radical/oxidative stress Mitochondrial dysfunction theory DNA damage theory of aging

addition, as described below, these categories are not mutually exclusive, particularly when considering the free radical/ mitochondrial DNA theory of aging. Indeed, there is likely a spectrum from birth to senescence that reflects a decreasing influence of active genetic influences and an increasing effect of stochastic events. This would parallel the shift in importance in general versus species-specific genes.

Developmental/Genetic Theories A general framework for a plausible theory of aging begins with attempting to understand the evolutionary basis of senescence. Developmental-genetic theories consider the process of aging to be part of the genetically programmed and controlled continuum of development and maturation. Although this is an attractive notion, the diverse expression of aging effects is in sharp contrast to the tightly controlled and very precise processes of development. Also, evolution selects for the optimization of reproduction; the effects of genes expressed in later life probably do not play a large role in the evolution of a species. This class of theories is supported by the observation that the maximum life span is highly speciesspecific. As noted above, the maximum life span for humans is 30 times that of mice. In addition, studies comparing the longevity of monozygotic and dizygotic twins and nontwin siblings have shown a remarkable similarity between monozygotic twins that is not seen in the other two groups. However, it is also likely that the interplay of genetic responses to extrinsic stresses may modulate the extent of aging. An interesting example of this theory comes from a study by Niedernhofer et  al. who demonstrated that aging mice as well as normal adult mice treated with mitomycin C to elevate DNA damage levels showed a shift in gene expression that was very similar to that observed in a mouse model of XPF-ERCC deficiency, a novel genetic disorder associated with accelerated aging [48]. The alterations in the transcriptome reflected enhanced antioxidant and anabolic pathways and reduced insulin growth factor (IGF-1) signaling (a known longevity assurance mechanism), suggesting a systemic shift of the somatotrophic axis from growth to maintenance under genotoxic stress. Thus, in the model of

2  Cell and Molecular Aging

XFE/ERCC−/− progeroid syndrome, the phenotypic outcomes depend not just on DNA damaging stimuli, which likely cause a functional decline, but also on the genetic adaptive response to the damage mediated by the IGF metabolic pathway [48].

Antagonistic Pleiotropy Evolutionary pressures select for a minimum successful life: this includes the ability to reach reproductive age, procreate, and then care for offspring until weaned (so that they, in turn, will achieve reproductive age and continue the cycle) [49, 50]. Within this context, it is likely that the postreproductive/ parental physiology of an organism is an epigenetic and pleiotropic manifestation of the optimization for early fitness. Kirkwood proposes that three categories of genes may be involved in senescence [51]: (1) those that regulate somatic maintenance and repair, (2) negatively pleiotropic genes that enhance early survival but are disadvantageous later in life (antagonistic pleiotropy), and (3) harmful late-acting mutations upon which little evolutionary selection is exerted. The  presence of these genes may represent a spectrum from general to species-specific. Genes involved in cell maintenance and repair are likely to be present in all (or most) organisms, since such essential processes are similar across species. Late-acting mutations are probably species-specific because they are likely to be individualistic and random. Nonmaintenance pleiotropic genes could be universally found within a population or species, but may not be shared between species. An example of antagonistic pleiotropy would be the high expression of testosterone in a male gorilla that could lead to increased aggression and strength that would allow the male to become dominant and mate more frequently, but may eventually lead to a shortened life span due to increased atherosclerosis. Recent studies at the molecular genetic level have suggested that cellular senescence may be antagonistically pleiotropic because it prevents tumorigenesis but also contributes to organismal aging (see below).

Longevity Genes There is ample evidence in multiple species that MLSP is under genetic control, though the degree of heritability is likely to be less than 35% [52]. Despite this apparently low figure, genetic mutations can significantly modify senescence. In yeast, a number of genes affect both the average and maximum life span [53]. The products of these genes act in diverse ways, including modulating stress response, sensing nutritional status, increasing metabolic capacity, and silencing genes that promote aging. In the nematode (C. elegans), mutants with increased life span have revealed various genes

9

that appear to play a role [54]: age-1 – altered aging rate, daf-2 and daf-23 – activation of a delay in development, spe26 – reduced fertility, and clk-1 – altered biological clock. These genes alter stress resistance (particularly in response to ultraviolet light), development, signal transduction, and metabolic activity. The daf-2 gene appears to encode an insulin receptor family member [55]. Mutations in daf-2 can double the life span but require the daf-16 gene [56]. A mutation in the daf-16 gene suppresses the UV resistance and increased longevity of the other gene mutants, suggesting that it acts at a critical point downstream of the other genes [54]. The daf16 gene is a member of the hepatocyte nuclear factor-3/forkhead family of transcriptional regulators involved in a variety of signal transduction pathways, including insulin signaling [57]. A notable connection between single gene effects upon aging in yeast and higher eukaryotes was revealed by the finding that overexpression of the SIR2 gene and its homolog Sirt1 (sirtuin 1) extend life span in yeast and nematodes, respectively [58]. Sir2 (silent information regulator) is an NAD+-dependent histone deacetylase that silences transcription and stablizes repetitive DNA in yeast. Aging and DNA damage induce Sir protein complexes to relocalize to sites of genomic instability, resulting in desilencing of genes. Sirtuin genes can function as antiaging genes in yeast, worms, and  flies [59]. There are seven mammalian sirtuin genes whose protein products function as histone deacetylases (SIRT1,2,3,5,6,7) and/or ADP-ribosyltransferases (SIRT4,6). SIR2 and its homologs appear to exert their effects by linking metabolism to aging and also enhancing mitochondrial biogenesis and efficiency [59, 60] (see below). SIRT1 modulates the activity of multiple critical transcriptional regulators of metabolism, including FOXO1, FOXO3a, PPARa, PPARg, and PGC-1a, which in turn impacts fatty acid oxidation, gluconeogenesis and glycolysis, oxidative capacity, fat mobilization and adipogenesis, and insulin secretion. A line of Drosophila melanogaster has been identified that exhibits an approximately 35% increase in average life span and enhanced resistance to various forms of stress, including starvation, high temperature, and dietary paraquat, a free-radical generator [61]. The mutation responsible, dubbed methuselah, appears to reside within a single gene that is homologous to GTP-binding transmembrane domain receptors. Another single-gene mutation leads to almost a doubling of the average adult Drosophila life span without a decline in fertility or physical activity [62]. This gene, named Indy (for I’m not dead yet), is homologous to a mammalian sodium dicarboxylate cotransporter, which is a membrane protein that transports Kreb’s cycle intermediates. The investigators speculate that the mutation in the Indy gene may create a metabolic state that mimics caloric restriction. Previous studies have demonstrated that one group of long-lived flies is more resistant to oxidative stress [63], whereas another group exhibits resistance to starvation and desiccation [64].

10

Genetic analysis of longevity in mammals has not been as revealing. However, immune loci in mice and humans have been implicated in long-lived subjects [53]. In addition, a mutation in the gene encoding the signaling molecule p66(shc), which significantly enhances the resistance to oxidative stress, increases the mean life span of mice by 30% [65]. The Snell dwarf mouse contains a single-gene mutation that alters pituitary development and prevents the production of growth hormone, thyrotropin, and prolactin [66]. The dwarf mouse also exhibits an extended life span of 25–50% but is much smaller than normal mice. In contrast, the mice with the mutant p66 develop normally and are not significantly smaller than wild-type mice (see Table 2.3). There does appear to be a genetic component to longevity in humans. A number of mitochondrial DNA polymorphisms and variants are associated with life span (reviewed by De Benedictis et al. [67] and by Salvioli et al. [68]). The J haplogroup was found in a significantly greater percentage of male centenarians in northern Italy than in younger subjects. Interestingly, this same mitochondrial haplotype is overrepresented in a number of complex diseases [69], raising the possibility of an antagonistically pleiotropic gene or genes that exert deleterious effects in younger patients, but lead to better health at later ages (successful aging). To complicate matters further, mitochondrial DNA polymorphisms are present in different frequencies in various aged populations from Italy, Ireland, and Japan [70]. Single-nucleotide polymorphisms in nuclear chromosomal DNA that appear to be linked to either increases or decreases in life span have been identified in a variety of populations (reviewed by Capri et al. [71] and by Glatt et al. [72]). An interesting pattern is emerging that strongly suggests that polymorphisms in genes implicated in metabolic signaling, inflammation, and stress response pathways play a role in aging and longevity. Metabolic genes implicated include the cholesterol ester transport protein [73], Foxo3A [74, 75], Foxo1A [76], SIRT3 [77, 78], the IGF1 receptor [79], and the insulin-degrading enzyme [80]. Inflammatory genes implicated include IL-6 [81, 82], IL-2 [83], CRP [84, 85], and TNF [86]. A number of genes from both of the previous categories fall into the stress response domain. It is important to stress that many gene association studies uncover modest relationships that may pertain to specific population groups. Individual genes may contribute in only small ways to aging or longevity, and it is highly likely that multigenic impacts and interactions play more significant roles in modulating longevity within the context of environmental stresses and lifestyle behaviors. Furthermore, there is intriguing evidence that a number of gene variants may play a more important role in increasing the human “health span,” rather than extending actual life span [72]. Interestingly, the human epsilon 4 allele of apolipoprotein E (ApoE), which is associated with increased coronary

P. Rai and B.R. Troen

d­ isease and Alzheimer’s disease, is inversely correlated with longevity [87]. In contrast, the epsilon 2 allele of ApoE and an angiotensin-converting enzyme (ACE) allele are found more frequently in French centenarians [87], although the ApoE2 allele is associated with type III and IV hyperlipidemia, and the ACE allele predisposes to coronary disease. These findings further suggest that genes can exert pleiotropic age-dependent effects upon longevity. Further support for a genetic contribution to human longevity is provided by data demonstrating that siblings and parents of centenarians live longer [88]. In addition, centenarian offspring are significantly less likely to experience myocardial infarction, stroke, and diabetes and to die than offspring of noncentenarians [89]. Linkage analysis implicates the presence of a gene or genes on chromosome 4 that are associated with exceptional longevity [88]. Perls et al. note that a high percentage of centenarians had children while in their 40s (well before assisted reproduction). They, therefore, postulate that an evolutionary force to prolong the period of childbearing would lead to the selection of longevity-enabling genes. Collectively, these studies also raise the question whether some genes affect susceptibility to disease rather than alter intrinsic aging. In contrast to studies that uncover alterations in the expression of single genes during aging, Weindruch and Prolla and their colleagues have investigated the broad program of changes in gene expression that occur during aging and caloric restriction in mice and in monkeys [90–93]. A common theme is that aging induces a differential gene expression pattern in muscle and brain, consistent with inflammatory and oxidative stress and reduced expression of metabolic and biosynthetic genes. In muscle and brain from mice, caloric restriction either completely or partially prevented the agerelated changes in gene expression. Interestingly, caloric restriction did not ameliorate the aging-induced alteration in the program of gene expression seen in muscle from aging monkeys. So, even though the age-related changes in gene expression may be similar across species, the response to caloric restriction may not.

Disposable Soma Theory The disposable soma theory [94] postulates that indefinite maintenance of somatic cells and tissues is not favored by natural selection, which instead allots available energy and resources towards the reproductive health of the organism in the early years of life. The basic prediction of this theory is that while immortal germline cells are faithfully maintained, the reduced investment in somatic cells causes deterioration and accumulation of unrepaired damage. Thus, the primary genetic control of longevity operates through ability to modulate the investment in basic cellular maintenance systems in

Increased life span, reduced body weight, reduced food consumption and blood sugar levels Increased life span, resistance to superoxide radical-mediated damage, increased cellular resistance to apoptosis and to p53/p21 pathway induction Increased life span, reduced lipid accumulation in white adipose tissue, higher mitochondrial biogenesis and energy expenditure

uPA overexpression

CCAAT/enhancer binding protein (C/EBP) b

p66shc−/−

Increased mean life span, smaller adult size, low growth hormone (GH) levels

Improvement in aging phenotype Increase in median and maximum life span, delayed onset of cardiac pathology and cataracts, reduced oxidative damage, slightly reduced splenomegaly and splenic lymphoid neoplasia, reduced mitochondrial deletions in skeletal muscle Increased life span, resistance to oxidative stress, higher splenic telomerase activity, higher resistance to UV damage Delayed aging, increased cancer resistance, decreased oxidative damage, increased antioxidant expression Extended life span, reduced levels of ROS and oxidative damage in hepatocytes and ES cells from clk-deficient mice Increased life span, without accompanying dwarfism, reduced metabolic signaling or fertility, derived fibroblasts show reduced sensitivity to oxidants Increased life span, protected against age-related obesity and glucose intolerance, lowered insulin levels

Heterozygotic reduction of IGF1 signaling in the brain

Fat-specific insulin receptor knockout (FIRKO) mice (CR model)

IGFR1+/−

clk1−/−

SuperARF/p53 overexpression

Thioredoxin (TRX) overexpression

Model Catalase overexpression

Table 2.3  Genetic mouse models of life-span extension

Stochastic/free radical theory of aging

Mitochondrial/free radical theory of aging

30% increase in life span

20% increase in life span

~20% increase in life span

Genetic/developmental/ neuroendocrine theory of aging Genetic/developmental

~2 month increase in mean life span, no change in maximal life span

Genetic/developmental

~18% increase in mean life span

Stochastic/free radical theory of aging

15–30% life span extension with respect to wild-type littermates Genetic/developmental/ free radical theory of aging

DNA damage/free radical theory

16% increase in median life span

26% mean life span extension

Free radical theory of aging

Model of aging examined Free radical theory of aging

35% life-span extension

Life-span extension Life span extended by ~5 months

[406]

Knock-in replacement of the C/EBP a gene with the C/EBP b gene to generateb/b mice

(continued)

[65]

[405]

[104]

[404]

[403]

[402]

[380]

[136]

References [135]

Targeted mutation of p66shc gene (a cytoplasmic signal transducer in the mitogenic Ras pathway)

Chimeric uPA overexpression

Cre-recombinase-mediated deletion of exon 4 of the insulin receptor, leading to loss of insulin signaling in adipose tissue Conditional mutagenesis to generate brain-specific IGF-1 receptor heterozygous knockout mice

Transgenic mice generated via pronuclei microinjection of recombinant TRX, an enzyme involved in redox homeostasis and antioxidant defense Introduction of a single extra gene-dose each of ARF/INK4a/INK4b and p53 via bacterial artificial chromosomemediated genomic DNA transgenesis Homozygous inactivation of the mouse ortholog of the C. elegans gene, clk1 (an enzyme required for ubiquinone biosynthesis) Inactivation of the insulin growth factor receptor 1 (IGFR1) gene by Cre-mediated recombination

Genetics Targeted overexpression of human catalase (an antioxidant enzyme which detoxifies hydrogen peroxide)

2  Cell and Molecular Aging 11

Increased mean and median life span, increased antioxidant enzyme defense, reduced susceptibility to osteoporosis and fracture, protection against cardiomyopathy Increased life span, reduced size, delayed puberty and sterility in females, lower body temperature, reduced insulin levels and circulating glucose, reduced age-related adiposity, increased antioxidant activity and reduced oxidative damage Increased life span, reduced size, reduction in age-related immune dysfunction, delayed fertility, improved joint and cartilage health Increased life span, reduced size, reduced insulin signaling Increased life span, small size, stunted growth, normal fertility, reduced insulin signaling

Adenylyl cyclase (type 5) knockout

Little mouse (GHRHR)

Laron mouse (GHR/BP)

Snell dwarf mouse (Pit1dw)

Ames dwarf mouse (Prop-1)

Improvement in aging phenotype

Model

Table 2.3  (continued)

Genetic/developmental Genetic/developmental

~45% increase in life span 25% increase in mean life span, 15% increase in maximum life span relative to wild-type or heterozygous littermates

Genetic/developmental

Homozygous knockout of the growth hormone receptor Single nucleotide substitution (Asp60Gly) in the growth hormone releasing factor receptor

Two noncomplement-ing point mutations in Pit-1, pituitary-specific transcription factor-1

Recessive mutation in the Prop-1 (Prophet of Pit1) gene which encodes a homeobox transcription factor involved in hormonal regulation

Genetic/developmental

35–70% increase in life span, depending on sex and diet

~40% increase in life span

Deletion knockout of the AC5 gene, which catalyses formation of the signaling molecule, cAMP, from ATP

[408]

[410]

[409]

[408]

References [407]

Genetics

Genetic/developmental/ free radical theory aging

Model of aging examined

~30% increase in median life span

Life-span extension

12 P. Rai and B.R. Troen

2  Cell and Molecular Aging

relation to the level of environment hazard. Accordingly, one claim of this theory would be that there is a tradeoff between fertility and longevity, with long-lived populations exhibiting reduced fertility. One study that assessed correlations between the number of children and age of members of British aristocratic families noted that the longest-lived members had the fewest children [95]; however, the oldest women studied had a mean age of 68 years. As noted above, middle-aged women who give birth tend to live longer. These two disparate observations do not necessarily need to be contradictory in the context of the disposable soma theory, as longer-lived individuals may possess a genetic advantage that allows the tradeoffs between longevity and reproductive ability to take place later in life. Two other theories of longevity which may be broadly classed under the disposable soma theory of aging are the neuroendocrine theory and the immunologic theory of aging, both of which suggest aging is a result of declining somatic function. The neuroendocrine theory proposes that functional decrements in neurons and their associated hormones are central to the aging process [96]. An important version of this theory holds that the hypothalamic–pituitary– adrenal (HPA) axis is the master regulator of aging in the organism. Because the neuroendocrine system regulates early development, growth, puberty, control of the reproductive system, metabolism, and many other aspects of normal physiology, functional changes in this system could exert effects throughout the organism. The decline in female reproductive capacity is an obvious neuroendocrine agerelated change. Mounting evidence suggests both the ovary and the brain play key roles in the menopause (rather than the previously held view of ovarian exhaustion) [97]. The neuroendocrine theory of aging is supported by experiments that show that hypophesectomy, followed by the replacement of known hormones, maintains (and may extend) life span in rodents [98]. In addition, reductions in brain dopaminergic neurotransmission are more prominent in a shorter-lived rat strain [99]. Levodopa, a dopaminergic drug can prolong the mean life span in mice [100]. Treatment of rats with deprenyl facilitates the activity of the nigrostriatal dopaminergic neurons and protects these neurons from their age-related decay [101], and deprenyl increases both the average and maximum life span [102, 103]. Many human studies demonstrate gradually decreasing levels of peripheral hormones accompanied by normal levels of trophic hormones [96]. This suggests either increased response to the peripheral hormones by the HPA axis or inappropriately low expression of the stimulating hormone. However, many organisms with aging phenotypes similar to those of higher vertebrates lack complex neuroendocrine systems. The changes that occur in the neuroendocrine system may be due to fundamental age-related changes in all cells and are therefore secondary manifestations of the aging phenotype.

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However, the neuroendocrine theory received some validation via a study of aging phenotypes in a mouse model of reduced neuronal growth signaling. Partial inactivation of the IGF-1R receptor in the murine embryonic brain inhibits growth hormone and IGF signaling, leading to smaller size and an increased mean life span, apparently due to inhibition of the somatotrophic axis (see Table 2.3 [104]). The immunologic theory of aging is based upon two main observations: (1) the functional capacity of the immune system declines with age, as evidenced by a decreased response of T cells to mitogens and reduced resistance to infectious disease and (2) autoimmune phenomena increase with age, such as an increase in serum autoantibodies [105]. There is a shift to increasing proportions of memory T cells, accompanied by enhanced expression of the multidrug resistance p-glycoprotein [106]. Humoral (B cell mediated) immunity also declines with age, as evidenced by decreased antibody production and a disproportionate loss in the ability to make high-affinity IgG, IgA antibodies. In addition, differences in the MLSP of different strains of mice have been related to specific alleles in the major histocompatibility gene complex [107]. The genes in this region also contribute to the regulation of mixed-function oxidases (P-450 system), DNA repair, and free radical scavenging enzymes. Caruso et al. suggest that mouse and human histocompatibility genes may be associated with longevity via different mechanisms: in mice via susceptibility to lymphomas and in humans via infectious disease susceptibility [108]. There is also evidence that cytokine gene polymorphisms may interact with histocompatibility genes to influence longevity [108]. Although the immune system obviously plays a central role in health maintenance and survival through the life span, similar criticism can be directed at the immunologic theory as at the neuroendocrine theory. Complex immune systems are not present in organisms that share aspects of aging with higher organisms. In addition, the inability to distinguish between fundamental changes occurring in many types of cells and tissues, not just those of the immune system, and the secondary effects mediated by the aging-altered immune system make interpretation of the theory difficult. Proposed mechanistic studies of the immune theory include producing transgenic mice carrying the histocompatibility complex from a longer-lived rodent species to determine effects on disease incidence and life span. The discovery of caloric restriction as a means to extend organismal life span (at least in lower organisms and rodents) calls the disposable soma theory into question because it would predict reduced rather than increased life span in the face of limiting nutrient resources and consequently energy. Indeed, early studies of rodents fed on restricted diets reported a delay in the onset of puberty and lower reproductive capacity [109, 110]. A survey of the reproductive profiles of long-lived mice, including naturally long-lived

14

variants such as the Snell dwarf mouse as well as transgenic models such as FIRKO mice (see Table  2.3) also suggests that, as a general rule, mice with longer life span show reduced fecundity (reviewed by Partridge et  al. [111]). However, another study utilizing moderate caloric restriction (60% of normal dietary intake) of adult rodents discovered that CR conferred both increased fecundity in mice as well as increased survival of their pups [112], suggesting that an optimal balance in maintaining the reproductive axis without compromising the somatic axis may be achieved via nutritional interventions (see below).

Stochastic Theories Free Radical/Oxidative Stress Denham Harman proposed one of the oldest and most enduring theories of aging over 50 years ago when he postulated that most aging changes are due to molecular damage caused by free radicals [113, 114], which are incompletely reduced, highly reactive intermediates of oxygen. The term “free radical” is misleading because one of these intermediates is hydrogen peroxide, which contains no unpaired electrons and is therefore not a radical. The more accurate nomenclature for these intermediates is reactive oxygen species or ROS, and for the purposes of discussion herein and in the context of aging theories, we use the term free radical interchangeably with ROS, which likely is what Harman intended when he named his theory of aging. Aerobic metabolism generates the superoxide radical (O2•−), which is metabolized by superoxide dismutases to form hydrogen peroxide (H2O2) and oxygen [115]. Hydrogen peroxide can go on to form the extremely reactive hydroxyl radical (OH•). These oxygen-derived species can react with macromolecules in a self-perpetuating manner; they create free radicals out of subsequently attacked molecules, which in turn create free radicals out of other molecules thereby amplifying the effect of the initial free radical attack [12]. ROS appear to play a role in regulating differential gene expression, cell replication, differentiation, and apoptotic cell death (in part by acting as second messengers in signal transduction pathways) [116–118]. In addition, nonradical prooxidants, for instance metals such as iron and copper that catalyze formation of the hydroxyl radical, as well as high concentrations of certain antioxidants can together generate a retrograde redox regenerative cycle, leading to homeostatic imbalance and oxidative stress (reviewed by Valko et al. [119]). In lower organisms, the role of antioxidants on life-span extension is also complex. Increasing expression of the mitochondrial Mn-superoxide dismutase (aka SOD2) in flies has yielded conflicting results, with one study reporting

P. Rai and B.R. Troen

approximately 15% extension in mean and maximum life span without changes in oxygen consumption [120] and another reporting no significant effect on life span [121]. However, SOD2 reduction in flies reduces life span and mimics aging-related defects; progressive reduction in SOD2 activity correlates with further shortening of life span [122]. This dose-dependent effect of SOD2 on life span is consistent with overexpression of SOD2 in flies [120]. Overexpression of Cu, Zn-superoxide dismutase (aka SOD1), the cytosolic superoxide dismutase, has been reported to extend life span in flies by around 40–50% [123, 124]; however, the significance of these results to the oxidative stress theory of aging are undercut by the facts that the majority of life extension was seen in the shortest-lived flies or by overexpressing SOD1 in tissues where there was a clear deficiency of the enzyme. In ant colonies, where large differences exist in life span between queens and workers, SOD1 activity correlates mostly negatively with life span with the shorterlived males having higher SOD1 expression and activity compared to the long-lived queens [125]. Overexpression of catalase alone in transgenic flies also does not extend life span [126]. Some transgenic flies with increased expression of both Cu, Zn-superoxide dismutase and catalase, which act in tandem to remove superoxide and hydrogen peroxide, respectively, exhibit up to a one-third extension of average and maximum life span [126]. In addition, they exhibit increased resistance to oxidative damage and an increase in the metabolic potential (total amount of oxygen consumed during adult life per unit body weight). However, combinatorial overexpression of the major antioxidants, SOD1, SOD2, catalase, and thioredoxin reductase in relatively long-lived flies did not appear to enhance longevity [127]. It has also been shown that overexpressing glutathione reductase extends the life span of transgenic flies kept under hyperoxic or oxidant-treated conditions, but not under ambient conditions [128]. In C. elegans, a model system in which a number of longlived mutants have been identified, the role of oxidants and antioxidants is similarly complicated. Although nutrientsensing pathways appear to be a dominant mechanism of life-span determination in C. elegans, a causal role for oxidative stress in their aging still has neither been validated nor disproved. In long-lived worms that overexpress daf-2, ROS production was higher than in wild-type worms throughout the life span, but protein carbonylation was reduced [129]. The observed reduction in damage in the face of elevated ROS levels has been ascribed to compensatory protective effects due to enhanced enzymatic antioxidant activity from SOD proteins and glutathione-s-transferases [129–131]. However, treatment of wild-type C. elegans strains with SOD and catalase mimetics failed to extend life span despite increasing antioxidant activity [132]. Yet, the role of oxygen tension nevertheless appears to have an effect on life span and oxidative damage because worms kept at 1% oxygen

2  Cell and Molecular Aging

have lower carbonyl levels and show approximately 24% increase in life span relative to counterparts kept at ambient oxygen [133]. Production of ROS in the heart, kidney, and liver of a group of mammals was found to be inversely proportional to the maximum life span, although the activities of individual antioxidant enzymes were not consistently related to maximum life span [134]. However, catalase overexpression targeted to the mitochondria does increase life span and improve functional health of the mice as they age [135]. Transgenic mice that overexpress thioredoxin, another antioxidant protein, also exhibit about a 30% improvement in mean life span [136]. A series of studies has demonstrated that oxidative stress resistance of dermal fibroblasts correlates with the longevity of the species [137–139]. The studies discussed above illustrate the complexity behind the free radical theory of aging. Antioxidants, in general, only appear to have a significant effect on life-span extension if their levels/function are limiting or under conditions of stress. Thus, overexpression of enzymes that are already present at robust levels are not likely to have an effect on life span simply because increasing expression does not enhance catalytic efficiency of these enzymes, which are already operating at near optimal rates. Furthermore, given the importance of antioxidant enzymes to survival of aerobically respiring organisms, there is a certain amount of redundancy between different antioxidants, and different tissues require their individual actions to different extents. This heterogeneity and overlap of function may also be obscuring the effects of altering antioxidant levels in animal models of lifespan extension. Thus, rather than overexpressing antioxidants alone, a more viable strategy of life-span extension perhaps needs to center on reducing production of ROS by modulating mitochondrial function or the prooxidant factors, which contribute to the deleterious effects of oxygen radicals.

Mitochondrial Dysfunction Theory of Aging The mitochondrial DNA/oxidative stress hypothesis represents a synthesis of several theories and therefore comprises elements of both stochastic and developmental-genetic mechanisms of aging (see below). It is proposed that ROS contribute significantly to the somatic accumulation of mitochondrial DNA mutations, leading to the gradual loss of bioenergetic capacity and eventually resulting in aging and cell death [140–142]. Ozawa has dubbed this the “redox mechanism of mitochondrial aging” [143]. Mitochondrial DNA (mtDNA) undergoes a progressive age-related increase in oxygen free radical damage in skeletal muscle [144–146], the diaphragm [147, 148], cardiac muscle [149–152], and the brain [153, 154]. This exponential increase in damage

15

correlates with the increase in both point and deletional somatic mtDNA mutations seen with age. Interestingly, extrapolation of the curve to the point where 100% of cardiac mtDNA exhibits deletion mutations gives an age of 129 [143]. Mitochondrial DNA is maternally transmitted, continues to replicate throughout the life span of an organism in both proliferating and postmitotic (nonproliferating) cells and is subject to a much higher mutation rate than nuclear DNA. This is due, in large part, to inefficient repair mechanisms and its proximity to the mitochondrial membrane where reactive oxygen species are generated. Defects in mitochondrial respiration with age are found not only in normal tissues [155] but also in diseases that are increasingly manifested with age such as Parkinson’s disease [156, 157], Alzheimer’s disease [158, 159], Huntington’s Chorea [160], and other movement disorders [161]. Diseases for which mtDNA mutations have been found include Alzheimer’s [162, 163], Parkinson’s [153, 163–166], and a large number of skeletal and cardiac myopathies [147, 167–171]. Apoptosis has also been associated with mtDNA fragmentation [172]. As noted above, mitochondrial haplotype J is associated with human longevity. However, the role of inherited and somatic mutations in mitochondrial DNA during human aging is clearly complex, and additional studies are required to gain further insight (reviewed by Salvioli et al. [68].) The idea of mitochondrial involvement in aging postulates that accumulation of mtDNA damage leads to defective mitochondrial respiration, which in turn enhances oxygen free radical formation, leading to additional mtDNA damage. However, the reality appears not to be quite so simple. A mouse model has been developed to address the issue whether phenotypic aging of tissues depends on mitochondrial DNA mutations. These mice express an error-prone version of the major mitochondrial DNA polymerase, polgamma, generated by mutating the proofreading domain of the enzyme. The mutant mice show fairly uniform accumulation of both deletions and point mutations in the mitochondrial genomes of different tissues and an accelerated aging phenotype [173]. The observations from the mutant polgamma mouse model mirror previous findings regarding the role of mitochondrial mutations in aging. On the surface, these observations fit well with the free radical/oxidative stress theory of aging, since mutations in mitochondrial genes coding for respiratory chain enzymes could in principle result in leakier electron transfer, thus leading to increased accumulation of ROS. However, this does not appear to be the case in mouse embryonic fibroblasts derived from the mutant mice that, despite impaired respiration, show neither augmentation of ROS production nor sensitivity to oxidative stress-mediated cell death [174]. Lack of change in protein carbonylation levels is presented to support the idea that these mice suffer no elevation in oxidative stress, although

16

these lesions may not be appropriate as the sole marker of cellular oxidative damage as they are detected only if they are present in a degradation-resistant state [175]. Furthermore, since mitochondrial deletions in the pol-gamma mutant mice lead to linearized mitochondrial genomes, another possibility is that the premature aging phenotype observed in these mice is the result of a DNA damage response (DDR) (see below) rather than accruing directly due to mitochondrial dysfunction. Nevertheless, the pol-gamma mice provide an elegant and useful system in which to further explore the role of mitochondrial mutations and ROS in engendering the aging phenotype. In humans, specific mutations, while increasing with age, seldom account for more than several percent of the total mtDNA. However, some studies suggest that the total percentage of mtDNA affected by mutations is much greater, as much as 85%, and increases with age [143]. In addition, caloric restriction in mice retards the age-associated accumulation of mtDNA mutations [176]. Agents that bypass blocks in the respiratory chain such as coenzyme Q10, tocopherol, nicotinamide, and ascorbic acid would be predicted to ameliorate some of the effects of mitochondrial disease and aging. Withdrawal of coenzyme Q from the diet of nematodes extends the life span by approximately 60% [177]. Caloric restriction, which can extend life span, reduces oxidative damage in primates [178]. There are epidemiologic studies that appear to implicate dietary antioxidants in the reduction of vascular dementia, cardiovascular disease, and cancer in humans [179]. However, results to date, in treatment of patients with myopathies, have been variably or only anecdotally successful [143]. This suggests that a complex interaction exists between prooxidant and antioxidant forces in the cell and that regulation of the balance between the two may be the critical determinant in mitochondrial, and subsequently, cellular and tissue integrity during aging. An increasing number of studies have implicated mitochondrial biogenesis and efficiency as playing significant roles to enhance cellular fitness and organismal longevity [180]. Maintenance of energy production and prevention and/or amelioration of oxidative stress by mitochondria are key to healthy aging. As previously discussed, caloric restriction is the most reliable intervention to extend life span in a number of species, including mammals such as rodents, dogs, and rhesus monkeys [13]. Multiple signals modulate PGC1a activity and subsequent mitochondrial production and efficiency, such as AMP kinase, sirtuins, and nitric oxide, all of which can be increased by caloric restriction [180]. Furthermore, caloric restriction increases mitochondrial biogenesis in healthy humans [181]. However, perhaps the best intervention to enhance mitochondrial production and function is exercise, which can at least partly normalize age-related mitochondrial dysfunction [182] and can significantly reverse age-related transcriptional alterations [183].

P. Rai and B.R. Troen

DNA Damage Theory of Aging: Somatic Mutation, DNA Repair, Error Catastrophe Stochastic theories propose that aging is caused by random damage to vital molecules. The damage eventually accumulates to a level that results in the physiological decline associated with aging. The most prominent example is the somatic mutation theory of aging, which states that genetic damage from background radiation produces mutations that lead to functional failure and, ultimately, death [184, 185]. Exposure to ionizing radiation does shorten life span [186, 187]. However, analysis of survival curves of radiation-treated rodent populations reveals an increase in the initial mortality rate without an effect on the subsequent rate of aging [188]. The life-span shortening is probably due to increased cancer and glomerulosclerosis rather than accelerated aging per se [189]. The DNA repair theory is a more specific example of the somatic mutation theory. Impairment of genomic maintenance has been strongly implicated as a major causal factor in the aging process [190]. Defects in DNA repair mechanisms form the basis of a majority of human progeroid syndromes (see below). The ability to repair ultraviolet radiation-induced DNA damage in cell cultures derived from species with a variety of different life spans is directly correlated with the MLSP [191]. Unfortunately, there is not enough experimental support to conclude that these differences between species are a causative factor in aging. Although the prevailing belief has been that overall DNA repair capacity does not appear to change with age, several studies now indicate that repair of oxidative DNA damage lesions via base excision repair (BER) becomes more inefficient in aged mice [192, 193]. Caloric restriction can restore the age-related decline in BER [194]. Repair of DNA double-strand breaks (DSBs) is also compromised in replicatively senescent human fibroblasts [195] and in fibroblasts and lymphocytes taken from older humans [196]. Additionally, the site-specific repair of select regions of DNA appears to be important in several types of terminally differentiated cells [197]. Biochemically, oxidative DNA damage has been shown to affect specific DNA sequences more than others, with the most affected sequences corresponding to conserved motifs in transcriptional elements involved in the regulation of stress-response genes [198]. Studies in cultured human neurons show that promoters of genes involved in memory, stress protection, and neuronal survival sustain selective oxidative stress-mediated DNA damage and exhibit reduced BER [199]. Transcriptional profiling of the human frontal brain cortex reveals that the genes under the control of these promoter elements also show the most reduced function after the age of 40. Thus, DNA damage to specific areas of the neuronal genome appears to contribute to age-related cognitive decline. Future studies will need to focus upon repair rates of specific genes rather than indirect general measurements.

2  Cell and Molecular Aging

The error-catastrophe theory also centers on the role of DNA integrity in the aging process and proposes that random errors in synthesis eventually occur in proteins that synthesize DNA or other “template” molecules [200]. Generally, errors occurring in proteins are lost by natural turnover and simply replaced with error-free molecules. Error-containing molecules involved in the protein-synthesizing machinery, however, would introduce errors into the molecules that they produce. This could result in an amplification such that the subsequent rapid accumulation of error-containing molecules results in an “error catastrophe” that would be incompatible with normal function and life. Although there are numerous reports of altered proteins in aging, no direct evidence of age-dependent protein mis-synthesis has yet been reported. The altered proteins that do occur in aging cells and tissues are, instead, due to posttranslational modifications such as oxidation and glycation [201, 202]. The increases in altered proteins appear to be due to decreased clearance in older cells [203].

Models of Aging Accelerated Aging Syndromes in Humans Although no disease exists that is an exact phenocopy of normal aging, several human genetic diseases, including Hutchinson–Guilford syndrome (the “classic” early-onset progeria seen in children), Werner’s syndrome (“adult” progeria), Cockayne’s Syndrome or NFE Syndrome (another childhood-onset progeroid disease), and Down’s syndrome exhibit features of accelerated aging. Hutchinson–Guilford progeroid syndrome (HGPS) is an extremely rare autosomal recessive disease in which aging characteristics begin to develop within several years of birth [204]. These include wrinkled skin, stooped posture, early hair loss, and growth retardation. HGPS patients suffer from advanced atherosclerosis, and myocardial infarction is the usual cause of death by the age of 30. However, unlike Werner’s Syndrome patients (see below), these patients do not typically suffer from cataracts, glucose intolerance, and skin ulcers. HGPS is a laminopathy resulting from a single-nucleotide substitution (1824 C > T) in the lamin A gene, which encodes two components of the nuclear envelope, lamins A and C (reviewed by Meshorer and Gruenbaum [205]). The mutation leads to activation of a cryptic splice site and production of a truncated version of the precursor protein, prelamin A, denoted progerin or LA∆50 [206, 207], which then leads to formation of abnormal nuclear lamina and delayed nuclear reassembly, as well as DNA damage and chromosomal abnormalities [208–212].

17

Werner’s syndrome (WS) is an autosomally recessive inherited disease [204]. Patients prematurely develop arteriosclerosis, glucose intolerance, osteoporosis, early graying, loss of hair, skin atrophy, and hypogonadism (reviewed by Muftuoglu [213]). However, patients do not typically suffer from Alzheimer’s disease or hypertension. WS patients have an increased predisposition to cancer with a higher than usual incidence of sarcomatous (mesenchymal) tumors and develop cataracts in the posterior surface of the lens, not in the nucleus as is usually seen in older people. In addition, they develop laryngeal atrophy and ulcerations on the arm and legs. Most patients die before the age of 50, usually of myocardial infarction or cancer [214, 215]. The gene responsible for WS has been localized to chromosome 8 [216] and appears to be a helicase [217], an enzyme involved in unwinding DNA. DNA helicases play a critical role in DNA replication and repair. Cells from WS patients display chromosomal instability, shortened telomeres, elevated rates of gene mutation, and nonhomologous recombination (reviewed by Brosh and Bohr [218]). Furthermore, WS is characterized by hypersensitivity to the chemical carcinogen, 4-NQO [219, 220], crosslinking agents [221], and the topoisomerase inhibitor, camptothecin [222, 223], suggesting impairment of DNA repair mechanisms. Cockayne’s syndrome (CS) is a congenital autosomal recessive disorder characterized by stunted growth, extreme sensitivity to sunlight, retinopathy, deafness, nervous system abnormalities, and premature aging (reviewed by Stevnsner et  al. [224]). This is a progressive disease that becomes apparent after 1 year of age and leads to mortality by 12 years of age. There are rare variants, one of which manifests at birth and another which presents milder symptoms and appears in late childhood. CS results from mutations in the transcription-coupled repair (TCR) and global genomic (GG) repair proteins, ERCC6 and ERCC8, also known as Cockayne’s Syndrome B (CSB) and Cockayne’s Syndrome A (CSA), respectively. The CSA protein is a 396-amino acid protein with no known enzymatic activity [225] and is part of a multicomponent ubiquitin ligase complex that also includes the DNA damage binding protein DDB1 [226]. Not much is known about its specific role in producing the CS phenotype. CSB consists of 1,493 amino acids and is a member of the SWI2/SNF2 family of DNA-dependent ATPases [227]. Although there is no phenotypic difference in disease whether it arises from mutations in CSA or mutations in CSB, approximately 80% of CS cases have mutated CSB. Neither the site nor the specific nature of CSB mutations appears to correlate with severity of the disease, and in one patient, complete loss of the CSB gene product led to photosensitivity, but not CS [228], suggesting that there may be an environmental or epigenetic component to the disease. Surprisingly, unlike Werner’s syndrome and other DNA repair defect diseases, Cockayne’s syndrome patients do not have a significantly

18

higher incidence of cancer unless they also suffer xeroderma pigmentosum (XP), which is linked to a strong predisposition to skin cancer. People with Down’s syndrome have trisomy or a translocation involving chromosome 21 [204, 229]. They suffer from the early onset of vascular disease, glucose intolerance, hair loss, degenerative bone and joint disease, and increased cancer. The life span is apparently 50–70 years (not as short as previously believed, since earlier mortality may have represented neglect of these individuals). Dementia occurs earlier and more often in patients with Down’s syndrome than in the general population. Patients develop neuropathological changes similar to the changes seen in dementia of Alzheimer's type, including amyloid deposition and neurofibrillary tangles. This may be related to the presence of the b-amyloid gene on chromosome 21. Although not strictly classified as progeroid syndromes, two diseases that bear mention are Fanconi anemia (FA) and dyskeratosis congenita (DC). Fanconi anemia is a rare autosomal recessive blood disorder, associated with multiple clinical symptoms [230]. Classified as a developmental rather than progeroid disorder, FA is nevertheless characterized by several aspects of premature aging syndromes, including childhoodonset bone marrow failure, susceptibility to squamous cell carcinomas, and congenital deformities. Furthermore, FA patients exhibit growth hormone and thyroid hormone deficiencies, glucose intolerance, and premature infertility. There are 13 FANC genes in which biallelic mutations lead to FA (reviewed by Neveling et al. [231]). Their protein products can aggregate into different core protein complexes in the nucleus; one of the complexes acts as a ubiquitin ligase to modify another FANC complex, thereby facilitating its recruitment to chromatin foci in conjunction with the BRCA1, BRCA 2, and Rad51 DNA repair proteins. Not surprisingly, FA cells exhibit chromosomal instability and are highly susceptible to several forms of DNA damage, particularly interstrand cross-links (ICL), therefore displaying acute sensitivity to cisplatin, mitomycin, and nitrogen mustard. More significantly, cells derived from FA patients are uniquely sensitive to ambient air and show a definitive effect of oxygen concentration on formation of chromosomal aberrations [232]. Repeated hypoxia–reoxygenation cycles have been shown to induce premature senescence of bone marrow cells in a murine model of FA [233]. Together, these observations suggest that the dramatic bone marrow dysfunction and chromosomal aberrations observed in FA likely stem from ROS-mediated DNA damage to hematopoietic cells. Additionally, there is evidence that multimerization of FANC proteins and formation of nuclear complex 1 may be redoxdependent [234], suggesting that the observed sensitivity to  DNA damage may be compounded by an inability of mutated FANC proteins to facilitate recognition and repair of DNA damage. Thus, with its progeroid features and the

P. Rai and B.R. Troen

mechanistic convergence of oxidative stress and DNA ­damage in its etiology, FA appears to be the only human model for the stochastic theories of aging. Dyskeratosis congenita is a rare syndrome associated with severe bone marrow failure around the age of 30 years [235]. In addition, DC patients suffer from aging-associated pathologies such as increased risk of cardiopulmonary failure and malignancy, early graying of hair, changes in skin pigmentation, brittle nails, and immune system failure which manifests itself as mucosal leukoplakia. DC is also characterized by chromosomal instability and telomere shortening at the cellular level [236]. The X-linked version of DC results from mutations in the dyskerin gene DKC1 that appear to impair its association with TERC, the RNA component of ­telomerase, whereas the autosomal form arises from mutations in the TERC gene itself [237]. Additionally, DC patients exhibit a uniform reduction in TERC itself. Thus, DC is unique in being the only human syndrome with progeroid features associated with telomere dysfunction, long considered a major causative biomarker of aging (see below). Consistent with the classic theories of aging, the human progeroid syndromes discussed above suggest that the critical determinants of aging are likely to be oxidative stress levels, accumulation of DNA damage/chromosomal insta­ bility, and nonfunctional or reduced DNA repair mechanisms. These three features have formed the basis of a number of animal and cellular models of aging, which are discussed below and which recapitulate the phenomenon of aging to varying degrees.

Mouse Models of Aging The major murine models of aging are summarized in Table 2.4. These encompass defects in a fairly comprehensive cross-section of biological processes implicated in aging including DNA damage/repair, metabolic, and developmental processes. Some of these models display the gamut of aging-related morphology and pathologies besides the obligatory reduction in mean and/or maximal life span. For instance, the klotho mouse suffers from a defect in a single gene that codes for a membrane protein and exhibits a plethora of marked age-related phenotypes that are also seen in humans. These include reduced life span, decreased activity, premature thymic involution, skin atrophy, arteriosclerosis, osteoporosis, emphysema, and lipodystrophy. There are a number of strains of senescence-accelerated mice (SAM) that exhibit a variable aging phenotype consistent with multigenic effects. Despite the fact that none of the mouse models displays all of the phenotypes associated with human aging, they are likely to be valuable tools in permitting delineation of some of the molecular mechanisms of aging. Significantly, some of the mouse models display a more

Atm−/−

CSA−/− CSB−/−

WRN−/−

Senescenceaccelerated mouse (SAM)

Kl−/−

SIRT6−/−

Growth retardation, neurological dysfunction, infertility, malignant thymic lymphoma, sensitivity to X-ray irradiation

Significantly reduced life span, lymphopenia, reduced subcutaneous fat, lordokyphosis, osteopenia, reduced liver function and serum glucose Shortened life span, infertility, growth retardation, decreased spontaneous activity, premature thymic involution, ectopic calcification, skin atrophy, arteriosclerosis, osteoporosis, pulmonary emphysema, lipodystrophy Amyloidosis, neoplasms, hyperinflation of the lung, hearing impairment, osteoporosis, defects in learning and memory, cataracts, brain atrophy Premature loss of proliferative capacity in fibroblasts, sensitivity to topoisomerase inhibitors Growth retardation, neurological defects

Table 2.4  Mouse models of aging Model Similarities to human aging Mutant p53 Reduced life span, osteoporosis, (p53 m/+) lordokyphosis, organ degeneration, reduced wound healing, reduced subcutaneous adipose tissue, reduced ability to regrow hair p63-deficient Reduced life span, lordokyphosis, (−/−, −/+) alopecia, weight loss, cellular senescence markers in vivo and in primary keratinocytes XPF/ERCC1−/− Reduced life span, neurodegenerative symptoms, liver, skin and renal dysfunction, sarcopenia, kyphosis, premature senescence and sensitivity to oxidative insults in derived fibroblasts Mutant polReduced life span, weight loss, reduced gamma subcutaneous fat, alopecia, anemia, kyphosis, osteoporosis, reduced fertility Other aging phenotypes not discussed

Life span: ~4 weeks Onset of aging: ~3 weeks

Develop thymic lymphoma before 4.5 months of age

Almost normal life span

Not reported

Other age-related phenotypes are not observed or not examined

Other age-related phenotypes are not observed/examined

Mutant mice are apparently normal

Aging phenotypes are distributed among various SAMP strains

Susceptibility to cancer not discussed, no observed increase in oxidative stress

Life span: patient, 1 copy –> chart)

Plan Care with Patient and Others Around: Symptoms Functional and Self-Care Needs Psychosocial Issues Family Needs and Support Spiritual/Existential lssues Anticipatory Bereavement

Write Orders for Palliative Care Address: Pain Respiratory Symptoms Food, Fluids, Mouth care Bowel & Bladder management Emotional & Spiritual Support Family & Caregiver Support Assess and Manage Symptoms: , Rate Symptoms severity 0–4, continually modify care plan as needed

After Death Bereavement Support

Figure 16.2  A process diagram for improving care of dying patients (from [7] Copyright © 1998 American Medical Association. All rights reserved).

caregivers; in general accord with the patients’ and families’ wishes; and reasonably consistent with clinical, cultural, and ethical standards” [82].

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16  Palliative Care and Decision Making at the End of Life mortality in a heterogeneous hospice population? J Palliat Care 8(3):503–509 73. Lau F, Downing M, Lesperance M, Karlson N, Kuziemsky C, Yang J (2009) Using the palliative performance scale to provide meaningful survival estimates. J Pain Symptom Manage 38(1):134–144 74. Congressional Research Service (1997) The right to die: constitutional and statutory analysis (97-244A). Library of Congress, Washington, DC 75. Gabany JM (2000) Factors contributing to the quality of end of life care. J Am Acad Nurse Pract 12(11):472–474 76. Moye J, Karel MJ, Azar AR, Gurrera RJ (2004) Capacity to consent to treatment: empirical comparison of three instruments in older adults with and without dementia. Gerontologist 44:166–175 77. Hirschman KB, Joyce CM, James BD, Xie SX, Karlawish JH (2005) Do Alzheimer’s disease patients want to participate in a  treatment decision, and would their caregivers let them? Gerontologist 45:381–388

209 78. Teno JM, Shu JE, Casarett D, Spence C, Rhodes R, Connor S (2007) Timing of referral to hospice and quality of care: length of stay and bereaved family member’s perceptions of the timing of hospice referral. J Pain Symptom Manage 34(2):780–787 79. Marelli TM, Williams MA (2004) Hospice and palliative care handbook, 2nd edn. Mosby, FL, p 71 80. Goodlin SJ, Fisher E, Patterson JW, Wasson J (1998) End of life care for persons age 80 years or older. J Ambul Care Manage 21(3):34–39 81. Rhodes RL, Mitchell SL, Miller SC, Connor SR, Teno JM (2008) Bereaved family members’ evaluation of hospice care: overall satisfaction with services? J Pain Symptom Manage 35(4):365–371 82. Field MJ, Cassell CK (eds) (1997) Approaching death: improving care at the end of life. National Academy Press, Washington, DC 83. Reisfield GM, Wilson GR. Prognostication in heart failure. Fast fact #143. October 2005. http://www.eperc.mcw.edu/fastfacts 84. Childers JW, Arnold B, Curtis JR. Prognosis in end-stage COPD. Fast facts #141. August 2005. http://www.eperc.mcw.edu/fastfacts

Chapter 17

Surgery in Centenarians Mark R. Katlic

Ninety years is old, but 100 is news. – Belle Boone Beard [1]

The 100th anniversary of an individual’s birth still bestows an aura, a mystique, as the centenarian is as close to immortality as a human can be. This special prestige has been afforded the imprimatur of scientific study by Baker [2], who found that centenarians represented a striking exception to the inverted U curve of status across the life-span in Western culture. Baker’s data, derived from factorial survey analysis, fit the postulate that there is an “American arc of life” that gives maximum prestige to middle age and least prestige to young and old persons. Centenarians, however, were given unique status nearly equal to that of middle-aged individuals (Fig.  17.1), because “like four leaf clovers or quintuplets, centenarians are rare.” Even those who care for centenarians are affected. Nishikawa [3] found that family members who care for centenarians had a lower accumulated fatigue level, despite being older themselves and despite their subjects’ worse performance status, than those who cared for individuals aged 70–90 years. Webb and Williams described a case of acute tenosynovitis of the right wrist and hand (centenarian hand syndrome) resulting from the congratulatory handshakes of many friends and relatives on a man’s 100th birthday [4]. We have an inherent curiosity about our oldest old. What does he eat? What is her secret? Can it be bottled and sold? Decades ago one entrepreneur, Dr. Marie Davenport, became a professional centenarian, offering to teach her secrets of longevity to others for a fee [1]. Jeanne Calment, the world’s presumed oldest person when she died at 122  years, was interviewed weekly by the foreign press who sought her out in Arles, France [5]. In 1997, a popular magazine devoted its cover story to “How to Live to 100” [6].

M.R. Katlic (*) Division of Thoracic Surgery,

Director, Regional Ambulatory Campus Geisinger Wyoming Valley Medical Center, Wilkes-Barre, PA, USA e-mail: [email protected]

The mystique may wane, however, as more of us reach this milestone. The present paucity of centenarians results from high mortality rates and a much smaller overall ­population a century ago. Over the past 40–50 years the number of centenarians has nearly doubled every decade, owing chiefly to improved survival from the age of 80–100 years [7]. When Beard began her monumental, sedulous study of centenarians in 1940, there were 3,700 possible subjects living in the United States; when she ended it during the late 1970s there were at least 14,000 [8]. This number had reached 50,000 by the year 2000 [9], and may be over 200,000 in 2020, and 500,000 to 4 million in 2050 [10]. Some authors argue that even these projections are too conservative because they discount the possibility of future baby booms and assume slow rates of mortality decline and low levels of immigration [11]. Vaupel and Gowan calculated that if mortality is reduced 2% per year, by the year 2080, the number of centenarians in the United States would approach 19 million [12]. Surgical problems do not end on a person’s centennial. Surgeons will become increasingly familiar with these most senior citizens.

History Surgeons have written with increasing frequency about operations in the elderly, but the definition of “elderly” has changed. A report in 1907 listed 167 operations performed on patients older than 50 years [13], and even 20 years later Ochsner taught that “an elective operation for inguinal hernia in a patient older than 50 years was not justified” [14]. Brooks used a limit of 70 years as “advanced age” in his series of 293 operations reported in 1937 [15], and over the next few decades most authors considered patients above age 60–70  years to be elderly. More recent studies show that  good results can be expected in octogenarians and

R.A. Rosenthal et al. (eds.), Principles and Practice of Geriatric Surgery, DOI 10.1007/978-1-4419-6999-6_17, © Springer Science+Business Media, LLC 2011

211

212 Figure 17.1  Perceived status by age and sex of target individual. Triangles, men; squares, women. (Reprinted with permission from Baker [2]).

M.R. Katlic 4.5 P E R C E I V E D

4.0 3.5 3.0 2.5

S 2.0 T A 1.5 T U S 1.0 0.5 0

10

20

30

40

50

60

70

80

90

100

110

AGE OF TARGET INDIVIDUAL Perceived status by age and sex of target individual ( .men; . women).

n­ onagenarians [16, 17], even in those undergoing complex vascular [18, 19], cardiac [20], and cancer operations [21]. An occasional centenarian is included in these series, but most papers devoted to centenarians per se are case reports, some written 40 years ago. Welch and Whittemore [22] in 1954 presented a 100-year-old woman who recovered well from abdominoperineal resection of the rectum for carcinoma. The next year Maycock and Burns [23] discussed prostate surgery in two patents in this age group, and in 1957 Childress [24] successfully treated three femoral fractures under spinal anesthesia. In 1971, isolated cases of pacemaker placement [25] and below-knee amputation [26] were reported. A basket-size ovarian leiomyoma was excised from a 103-year-old woman because of bowel obstruction in 1979, allowing her to live at least two additional years [27]. Six patients aged 100–106 underwent pacemaker procedures with good results in the 1989 report of Cobler et al. [28]. During the 1990s greater numbers of patients were reported. There were three deaths (12.5% mortality) in McCann and Smith’s series of 24 patients undergoing a variety of operations, such as colon resection, ruptured aortic aneurysm repair, and hip prosthesis placement [29]. Cogbill’s 1992 series of 16 patients reported perioperative mortality of 6% and a 1-year survival of 69% after a variety of small operations [30]. In 1998, Warner [31] reported 42 procedures in 31 patients aged 100–107  years. There was one major complication

Figure 17.2  Survival following surgery for patients ³100 years of age. Numbers in parentheses represent number of patients alive and followed at yearly intervals during the first 3 years after surgery. (Reprinted with permission from Warner [31]).

(3%) and no mortality within 48 h of operation; 30-day mortality was 16.1%, none directly related to the operative procedure or perioperative morbidity. Subsequent mortality of these patients equaled that of matched peers from the general population (Fig. 17.2). Grey [32] reported a case of revision total hip arthroplasty. This author reported a series of major and minor procedures in six patients aged 100–104 years, all of whom survived (Table  17.1) [33]. The illustrative cases below are from that series.

100

100

3/M

4/F

General

General

Urgent

Urgent

Emergency

Elective

Above-knee amputation

Open reduction, internal fixation of right hip fracture Cholecystectomy

Removal of Enders rod pins

Elective

Right inguinal herniorrhaphy

None

6/M

5/F

104

101

None

General

Emergency

Suture ligation of bleeding rectal polypectomy site

Bleeding at excision site

None

Pneumonia, resolved; abdominal abscess, percutaneously drained

Acute gangrenous cholecystitis, protruding Enders rod pins

None

None

Emergency Local Squamous cell carcinoma of neck Gastroscopy with biopsy excised, basal cell carcinoma of nose excised and irradiated Source: Reprinted with permission from Katlic [33]. Copyright © American Medical Association. All rights reserved MI myocardial infarction, CHF congestive heart failure

Local

Elective

Colonoscopic resection of villous adenoma

Local

General

General

Urgent

Excision of right femoral head, cemented Moore prosthesis

None

CHF, atrial fibrillation, blind, basal cell carcinoma of face excised, adult-onset diabetes

Old MI, CHF, aortic stenosis, cataract extraction, cystocele repair, left hip open reduction internal fixation, arthritis, hiatus hernia

Hypertension, severe peripheral vascular disease, prostatectomy, chronic lung disease

Old MI, left radical mastectomy (13 years), arthritis

Complications None

Local

101

100

2/F

Anesthesia Local

Status Urgent

Table 17.1  Clinical summary of centenarians undergoing an operation Age Patient no./sex (years) Medical problems Operation 1/M 100 Old MI, sick sinus syndrome with Pacemaker generator replacement pacemaker, CHF, prostatectomy, cataract extraction, gout, arthritis, chronic renal failure

No

Died, age 105 years of gastric carcinoma

Died, age 102 years of CHF

Died, age 102 years of “old age”

No

No

Died, age 101 years of “old age”

Died, age 102 years of cerebrovascular disease

Follow-up Died, age 102 years of CHF

No

No

Death No

17  Surgery in Centenarians 213

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M.R. Katlic

Case Studies

Case 2

Case 1

A 100-year-old retired laborer was ambulatory at his nursing home until his toes became painful. He had a history of hypertension, chronic lung disease, and severe peripheral vascular disease and had undergone prostatectomy. On examination, he had a gangrenous right foot with Proteus cellulitis extending to the calf and an absence of leg pulses below the femoral arteries. He underwent amputation of the right leg above the knee while under general anesthesia (spinal anesthesia was aborted because of the patient’s agitation) and was discharged 11 days later. He had one later 4-day admission for bronchitis and died at age 101 years of “old age.”

A 100-year-old woman fractured her right hip in a nursing-home fall. She had a history of myocardial infarction, congestive heart failure, aortic stenosis, arthritis, and hiatus hernia. She had previously undergone cataract surgery, cystocele repair, and open reduction/internal fixation of a left hip fracture. Open reduction/internal fixation of her new fracture was performed under general anesthesia. During her ­second postoperative week she developed acute gangrenous cholecystitis, requiring emergency cholecystectomy. This episode was complicated by left lower lobe pneumonia, which resulted in antibiotic treatment, and by a localized intra-abdominal abscess, which was successfully treated with percutaneous drainage and antibiotics. Six weeks after admission she returned to her nursing home. Protruding Enders rod pins in her right leg led to pin removal under local anesthesia 8 months later. At 101  years of age, she underwent elective endoscopic resection of a rectal villous adenoma containing carcinoma in situ. Postoperative bleeding from the resection site mandated suture ligation under general anesthesia. She returned to her nursing home, where she lived two years. She died two weeks before her 103rd birthday.

Discussion Centenarians recover surprisingly well from surgery, leading one to speculate that the 100-year-old patient who has not already succumbed to a myocardial infarction or pulmonary embolus is less likely to do so, even in the perioperative milieu. The Mayo Clinic study of surgery in nonagenarians supports this finding, as neither pneumonia nor atherosclerosis with myocardial infarction was a major cause of postoperative death [15]. Certainly all that has been learned about surgery in the elderly should be applied to the centenarian. Clinical presentation of surgical problems may be subtle, preoperative preparation is essential, and scrupulous attention to detail intraoperatively and perioperatively yields great benefit. Virtually all studies of surgery in the elderly have also shown an up to threefold greater risk for emergency surgery than elective surgery. The worst complications in the author’s­

Case 3 A 101-year-old woman was ambulatory and independent at home, but suffered from a large right inguinal hernia. Her past history included congestive heart failure, atrial fibrillation, adult-onset diabetes mellitus, blindness, and a resected basal-cell carcinoma of the face. Elective right inguinal herniorrhaphy was completed under local anesthesia in the outpatient surgical unit. Postoperatively, stating that she would “rather wear out than rust out,” she took a 3-month cruise around the world and later lectured at a local college geriatric course. On the penultimate day of her life she completed a political poll. She died of congestive heart failure at age 102.

series, pneumonia and intraabdominal abscess, did occur after emergency surgery, but the patients generally tolerated even urgent operations well. Centenarians may be considered a natural model of successful aging. What is it about the 100-year-old that allowed him or her to enter this select age group?

Physiologic Changes in Centenarians The oldest-old manifest low frequencies of the E4 form of gene coding for apolipoprotein E, a protein linked to an increased risk of acquiring Alzheimer’s disease. Among healthy subjects age 90–103 years, 14% had at least one E4 gene, in contrast to 25% of subjects younger than age 65 [10]. It may be that many of those with E4 suffer early Alzheimer’s disease and do not survive to become centenarians. This cohort effect may explain some of the other

17  Surgery in Centenarians

p­ hysiologic and pathologic changes in centenarians described below. Silver found that dementia is not inevitable with aging and that dementia in centenarians is often not attributable to Alzheimer’s disease [34–36]. Morphologic changes occur in the brain with age – decreased brain weight, atrophy of the cerebral hemispheres, fall in the number of Purkinje cells in the cerebellum – but healthy aged subjects show little difference from young adults with respect to cerebral blood flow and oxygen uptake [37]. Hubbard et al. studied electroencephalograms in centenarians and found slowing of the posterior dominant rhythm, but there was no evidence of a progressive decrease in frequency between the ages of 80–100  years [38]. Wellpreserved mucociliary clearance in the lung of a centenarian was documented by Pavia and Thomson despite 80 years of smoking history [39]. An even more paradoxical finding was described by Mari’s group [40]. They found that a high proportion of 25 healthy centenarians had laboratory evidence of activation of the coagulation system, shown by high levels of enzymes, activation peptides, and enzyme-inhibitor complexes. Levels of factor X activation peptide were equal to those found in patients with disseminated intravascular coagulation. Even procoagulant proteins such as fibrinogen and factor VIII – predictors of cardiovascular disease in young adults – were elevated in centenarians; yet these individuals had no current or past thrombotic events. The authors concluded that significant alterations of these markers are still compatible with health and long life. A more recent study by this group found that the 4G allele and 4G/4G genotype associated with elevated levels of plasminogen activator inhibitor 1 (PAI-1), which predicts recurrence of myocardial infarction in young men, were even more frequent in centenarians than young adults. The homozygous genotype for the deletion of polymorphism of the angiotensin converting enzymes, which predisposes to coronary artery disease, is also paradoxically more frequent in centenarians than in adults of age 20–70  years [41]. Mannucci et al. speculated that occult factors compensate for these putatively unfavorable genotypes in centenarians (e.g., linkage dysequilibrium with a locus counteracting the bad effect of elevated PAI-1 levels offsets the risk of hypofibrinolysis). It may be that if an elderly person has already escaped thrombotic disease, it is advantageous to have decreased fibrinolysis [42]. A different genetic finding in centenarians – decreased frequency of the E4 allele of the gene, which encodes apolipoprotein E – would go along with decreased risk of ischemic heart disease [41]. Laboratory values in healthy centenarians may differ even from those of younger elderly adults: widening of the range for sodium levels to 132–146 mmol/L, slightly higher potassium and chloride, decreased total calcium, slight increase in ionized calcium, increased blood glucose, increased alkaline phosphatase and lactate dehydrogenase, slightly decreased

215

bilirubin and total protein, increased amylase likely due to decreased renal function, increased serum urea nitrogen and slightly increased creatinine, increased urinary albumin, elevated urate, decreased albumin, elevated carcinoembryonic antigen, decreased cholesterol and triglycerides, decreased vitamin B12, decreased zinc, slightly decreased thyroxine, increased prolactin, no change in corticotropin, decreased testosterone and estradiol, marked decrease in dehydroepiandrosterone, decreased progesterone, unchanged cortisol, slightly higher gastrin, lower erythrocyte, leukocyte, and platelet counts, slight decreases in hemoglobin, hematocrit, and iron [43]. Higher functioning centenarians appear to have higher levels of serum albumin [44]. Discussion of possible mechanisms for these findings is beyond the scope of this chapter. Franceschi asserted that a complex remodeling of the immune system occurs in healthy centenarians in contrast to the presumed progressive deterioration (especially with the T-cell branch) [45, 46]. Peripheral blood T cells and major T cell subsets are only slightly decreased despite age-related thymic involution. B lymphocytes are deceased despite data that several immunoglobulin classes are elevated in the serum. Interestingly, peripheral blood lymphocytes in centenarians appear resistant to the oxidative stress that causes irreversible cell damage in younger individuals; such stress may retard entrance into the cell cycle rather than cause permanent damage [47]. Centenarians are more likely to have low body weight [48, 49], possibly due to loss of muscle and fat [50]; a ­number of investigators have reported short stature even when the effects of aging are considered. Decreased bone mass, ­however, is not universally present [51]. Both male and female centenarians are more likely to have feminine or androgynous personality traits, rather than masculine ones and are more likely to have a type B behavior pattern (easygoing) [52].

Pathology in Centenarians Although atherosclerosis has been found in coronary, cerebral, femoral, and abdominal aortas of centenarians [53], the ascending aorta may be spared [48, 54]. Myocardial fibrosis is located chiefly in the left ventricle and septum, and cardiac amyloid deposition is characteristic [53]. Coronary disease at autopsy is common [55, 56], though perhaps less so in Japanese centenarians [57]. Pneumonia was found in 15 of 23 patients in Ishii and Sternby’s series and was also the most common cause of death [53]. Alveolar ectasia and decreased elastic fiber were also seen in the lungs. Interestingly, recent or old thromboembolism in the pulmonary arterial tree was common at autopsy despite the absence of clinical pulmonary emboli during life [53].

216

Determinants of Extreme Longevity Despite our fascination with centenarians, little is known about the influences – genetic, environmental, and medical – on their longevity. Vaupel’s group, in extensive studies of nearly 3,000 Danish twin pairs born during 1870–1900 estimated the heritability of longevity to be 0.26 for men and 0.23 for women; the sex difference resulted from the greater impact of unshared environmental factors in the women [68]. Other family studies have shown weak correlations for ­life-span between parents and offspring (0.01–0.05) and somewhat higher correlations between siblings (0.15–0.35) [69, 70] (Fig. 17.4) suggesting either that the genetic factors are nonadditive (genetic intralocus interaction) or there is a higher degree of shared environmental influences among sib-

100

Cancer Mortality Non-Cancer Mortality

Mortality Rate (per 100 dogs)

80

60

40

20

0

0

2

4 6 8 10 12 Age at Death (years)

14

16

Figure 17.3  Comparison of age-specific cancer and noncancer ­mortality for 345 Rottweiler dogs. Age-specific cancer and noncancer mortality rates were calculated at 2-year intervals from 0 to 14 years of age and expressed as the number of cancer or noncancer deaths per 100 dogs that entered the interval. (Reprinted with permission from Cooley [65]).

60 % Siblings Living to Age 90 Years

In the kidney, chronic pyelonephritis and atherosclerosis are usually pronounced; and the testes, ovaries, and uterus show atrophic changes [58]. In the gastrointestinal tract, the liver also shows atrophy and colonic diverticula are ­common. Gallstones are common (13/23 patients), and peptic ulcer is rare [58]. Osteoporosis is common [59], but not universal [51]. Similarly, in the brain, changes of Alzheimer’s disease are common but not universal; when present these may not correlate with clinical neurologic findings [60, 61]. Cancer as a cause of death was unusual in Ishii and Sternby’s autopsy series [59]; it represented 7.1% of Stanta’s 99 autopsies in centenarians [62], and 31% of Klatt and Meyer’s 32 patients [54]. The 7.1% rate in Stanta’s series was significantly different (p 70%) stated they would not want even a low-burden treatment if severe functional impairment or cognitive impairment was the expected outcome. As the likelihood of an adverse outcome increased, the number of patients who stated they would want treatment decreased. Thus, advance care planning that includes elucidation of patients’ treatment preferences and designation of surrogate decision makers is one of the most important components of preoperative assessment for older surgical patients.

Objectives of Preoperative Assessment Once these issues is addressed; the main thrust of the preoperative evaluation is to identify, and optimize, any coexisting disease processes or decline in physiologic reserve. With this

22  Preoperative Evaluation of the Older Surgical Patient

Do a thorough history including review of systems 2

DO the test

Do a complete physical exam

Over 80% of Americans aged ³65 have at least one chronic condition and 50% have at least two [17]. The prevalence of comorbid diseases clearly rises with increasing age. The agerelated increase in cardiac, pulmonary, renal, and hepatic comorbid conditions in a cohort of colon cancer patients over age 50 has previously been demonstrated [18]. The prevalence rates for some common chronic conditions experienced by older adults are depicted in Fig. 22.2 [1]. In a larger, more detailed review of comorbidity in elderly patients with colon cancer, Yancik et al. explored the increase in the number of additional conditions with age [19]. By age 75, patients with colon cancer had a mean of five disorders in addition to the primary cancer. For all adults, the influence of comorbid conditions on activity level increases substantially with age as demonstrated in Fig. 22.3 [3]. In addition, comorbid conditions more frequently contribute to the cancelation of surgery after hospital admission in older adults compared with younger adults [4].

8.6%

15.2%

Diabetes

Any Cancer

19.9%

Coronary Heart Disease

20.4%

Arthritic Symptoms*

35.9%

60%

50%

49.2%

Hypertension

40%

Stroke

30%

The general approach to the preoperative assessment is directed toward identifying those factors that place the patient at increased risk for postoperative complications or death. Although some of these factors are related to the surgical disease itself and to the type of operation required, the most important factors in the determination of risk are related to the overall health, function level, cognitive abilities, and nutritional status of the patient. Many studies have demonstrated comparable outcomes among older and younger adult surgical patients. A retrospective analysis of cardiac surgery among octogenarians in Germany demonstrated that morality was associated with comorbid conditions (e.g., chronic obstructive pulmonary disease or heart failure), nonelective surgery, and male gender, but not with age [13]. Follow-up with these patients 3–5 years after surgery revealed that approximately 85% were clinically better than they were prior to surgery. Another German study examined outcomes for colorectal cancer patients who underwent surgery. While mortality rates were higher for patients ³80 years than for patients 69 >70

157 1.9   82 1.2

24 11

>70

242 2.0

NS

>75 >75 >80

  75 4.5 NS 0.9   96 3.0

NS NS  7

mastectomy is an excellent method for obtaining local control of breast cancer with a minimum number of outpatient visits, and although elderly women can undergo the procedure safely, these results are obtained at the expense of cosmesis.

Breast-Conserving Surgery in the Elderly Since 1970, multiple prospective randomized trials have compared survival after breast conservation treatment to survival after mastectomy for stage I and II breast cancer. No survival advantage has been noted for mastectomy. Although most of these trials did not include women older than 70 years, the biologic rationale for breast preservation can be extrapolated to the elderly population. Several studies have suggested that elderly women may have a lower rate of breast recurrence after partial mastectomy and radiotherapy than their younger counterparts [39–41]. Fourquet et al. reported a 97% rate of control at 10 years for women older than 55 years compared to 85% for women aged 33–45 years and 71% for women aged 32 years or younger in a series of 518 patients [40]. Veronesi et al. [41] and Clark et al. [39] have also reported a decreasing frequency of breast recurrence with increasing age. Some of these differences in local failure rates may be due to a higher incidence of adverse pathologic features, such as an extensive intraductal component or lymphatic invasion in young women, but older women appear to have lower local failure rates even after correction for pathologic features. In addition, local recurrence rates can be affected by a number of treatment factors, such as the extent of surgical resection, the status of the surgical margin, and the use of adjuvant tamoxifen. In the National Surgical Adjuvant Breast Project (NSABP) B-14 trial, 2,644 axillary-node-negative patients, 38% of whom underwent breast-conserving therapy, were randomized to receive tamoxifen or placebo. After a median follow-up of 10 years, the rate of recurrence in the

T able  38.3  Contraindications to breast-conserving therapy with irradiation Two or more primary tumors in separate quadrants of the breast Diffuse malignant-appearing microcalcifications Prior therapeutic irradiation to the breast region that requires retreatment to an excessively high total radiation dose Persistent positive margins after reasonable surgical attempts Source: American College of Radiology [43]

breast was 14.5% in the placebo arm compared to 3.4% in the tamoxifen group [42]. Thus, in women treated with breast-conserving therapy, including breast irradiation and tamoxifen, the incidence of local failure is low, and the small risk of a second surgery is not an appropriate reason to recommend that elderly women routinely undergo mastectomy. The standard contraindications to breast-conserving therapy (Table  38.3) used to determine the suitability of young women for breast-conserving therapy are applicable in older women as well [43]. High rates of mastectomy in the elderly have been attributed to patient choice. Some studies have indeed shown that BCT is chosen less frequently as age increases [44–46]. In contrast, Bleicher et al. [47] examined the role of age in the surgery decision-making process by surveying 1,279 patients aged 79 or younger from two SEER program registries. A majority of patients (80.3%) underwent BCT. There were no differences in patient preference for mastectomy on the basis of age, and in a logistic regression analysis, age and comorbidities were not significant predictors of mastectomy use. The necessity for adjuvant radiotherapy in patients treated with breast conservation is a matter of particular interest in the elderly population. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview of randomized trials included ten trials of post-BCT radiotherapy with a total of 23,500 patients. The main analyses of local recurrence, breast cancer mortality, and overall mortality were stratified by age into five groups (70 years) [48]. The relative risk of recurrence, comparing those allocated to RT with those not, was about 0.3 in every trial, corresponding to a 5-year risk of local recurrence of 7% in the RT group versus 26% in the control. The absolute effects of post-BCS RT on local recurrence were greater in younger than in older women (5-year risk reductions of 22, 16, 12, and 11% for those aged 70 years, respectively). The proportional risk reduction for breast cancer mortality was less pronounced than that for local recurrence, with one breast cancer death averted at 15 years for every four local recurrences prevented in year 5. The lower absolute benefit of RT in older women coupled with the long follow-up period needed for mortality reductions to be observed makes it unlikely that RT will have a major impact upon survival in this population [48].

484

Figure  38.2  Overall survival in patients with ER-positive breast cancers 2 cm or less in size randomized to treatment with tamoxifen alone or tamoxifen plus irradiation. No survival difference between groups was observed (from Hughes et  al. [50] Copyright © 2004 Massachusetts Medical Society. All rights reserved).

A similar age-related difference in the magnitude of benefit achieved with a boost dose of radiation was demonstrated in a randomized trial by Bartelink et al. [49] Although the use of a boost resulted in a statistically significant reduction in local recurrence in all age groups, the absolute benefit ranged from 10.4% at 10 years in women aged less than 40 years to approximately 3% in those older than 60 years [49]. Although the value of RT in the setting of BCS in the general population, and to some extent in elderly patients, has been demonstrated, the argument that older age may be associated with lower rates of recurrence, less aggressive tumor biology, and increased comorbidity has prompted investigation into the need for RT after breast-conserving surgery in this subgroup of patients. Hughes et  al. [50] designed a prospective randomized trial that included 636 women aged 70 years or older who were randomly assigned to receive tamoxifen plus radiation therapy or tamoxifen alone to examine the benefit of RT in older women with small breast cancers. Eligibility criteria included ER-positive clinical stage I (tumor 150 ml) to be helpful. The individual who remains continent despite loose stool during attacks of colitis has undergone the most rigorous physiologic test of continence and would be a candidate for total abdominal colectomy (subtotal colectomy) with ileosigmoid or ileorectal anastomosis. Those occasionally incontinent of loose stool probably have less than perfect control, but this situation may be preferable to having a stoma; it merits discussion with the patient. The individual who is frankly incontinent would be best served by a proctocolectomy or a subtotal colectomy, ileostomy, and retained rectal stump. Although some authors have suggested use of an ileal pouch to improve compliance if resection is necessary to the level of the mid-rectum [42], this procedure is highly controversial, as known Crohn’s disease is widely considered an absolute contraindication to use of a pouch, given the 45% risk of pouch failure secondary to complications [75]. In the emergent setting, the guiding principle is to remove the site of disease as expeditiously as possible, avoid further complications, and perform a later staged procedure if necessary. In the setting of diffuse colonic involvement and megacolon, perforation, or hemorrhage, a subtotal colectomy with ileostomy is performed, and the rectum is either left long as a mucus fistula or short as an extraperitoneal stump. If hemorrhage is arising from the rectum in the face of diffuse disease, however, proctocolectomy cannot be avoided. Perforation resulting from localized disease in the colon is addressed with resection, proximal stoma, and mucus fistula or exclusion of the distal bowel. Perforation of localized rectal disease is approached by proximal colostomy and drainage of the pelvis, with proctectomy 3–6 months later.

Crohn’s disease manifestations in the perianal region include skin tags, fissures, ulcers, abscesses, fistulas, and anorectal stricture. These findings frequently occur after intestinal symptoms have resulted in a diagnosis of CD, but when perianal findings precede other symptoms, the diagnosis can present difficulties. Examination includes digital assessment, anoscopy, and rigid or flexible sigmoidoscopy. Discomfort may necessitate examination under anesthesia for full evaluation. Biopsy infrequently yields evidence of a granuloma, but other features are suggestive of CD: edematous, violaceous skin tags; fissures at sites other than the midline; indolent abscesses; complex fistulas; and stricturing without evidence of malignancy or prior anorectal surgery. A new diagnosis of CD should prompt evaluation of the entire gastrointestinal tract, although it is unclear whether disease activity more proximally affects perianal disease [76]. Therapy must be individualized, bearing in mind treatment principles of relief of symptoms and avoidance of additional complications. Careful consideration should be given to appropriate medical and surgical approaches. Perianal skin tags and hemorrhoids are best approached conservatively, with control of diarrhea, sitz baths, and analgesia; surgical therapy of either is associated with a high rate of poor outcomes [77]. Symptomatic fissures should be evaluated to rule out underlying sepsis and then approached initially with medical therapy. In selected cases and when conservative therapy has failed, lateral internal sphincterotomy may be beneficial. Careful consideration must be given to issues of continence, however, particularly in the elderly. Abscesses should be treated with incision and drainage, making the incision into the abscess cavity as close to the anus as possible to keep any subsequent fistula as short as possible. Management of perianal fistulas is often challenging. As with other situations, therapy is aimed at relieving symptoms; hence, in the absence of associated sepsis, an asymptomatic fistula may require no specific therapy. Simple low fistulas without accompanying proctitis may be managed successfully with fistulotomy [78], particularly when combined with therapy such as metronidazole or sulfasalazine [79]. When it is thought that sphincterotomy may result in fecal continence because the fistula is high or complex or because the elderly patient has borderline continence, other approaches are necessary. Noncutting setons achieve drainage without compromise of continence; despite the presence of a foreign body, most patients tolerate setons far better than undrained fistulas, particularly if the seton is of a soft material such as Silastic vessel loops [42]. If the rectal mucosa does not exhibit active disease, the patient may be a candidate for a rectal mucosal advancement flap. An overall success rate of 60% has been reported for this approach to low fistulas [80], but the success rate falls to approximately one-third in high,

848

complex fistulas [81]. An alternative approach is the use of fibrin glue, which has a lower success rate than with nonCrohn’s fistulas after a single application, but repeated applications may result in success and there is no risk of compromising the sphincter. Although anti-TNF-Ab therapy (infliximab) is showing promise in therapy of perianal CD that would otherwise be considered an indication for proctectomy; data in the elderly are still limited or absent. Creation of a diverting ileostomy is occasionally a useful means for controlling severe perianal disease, but only one-third of patients ever achieve successful reversal [42].

Ulcerative Colitis: Indications for Elective Surgery Failure of Medical Therapy An algorithmic approach to the surgical management of CUC is presented in Fig. 66.3. Medical therapy may be considered to have failed when maximal therapy has not controlled symptoms or when symptoms are abolished only at the expense of side effects from the medications themselves. The inability to wean steroids completely or to an acceptable level is also an indication for operation. Inability or unwillingness to comply with a medical regimen may prompt surgical intervention. Presence or Risk of Carcinoma An increased risk of colorectal cancer has been documented in those with extensive long-standing ulcerative colitis

S.D. Holubar and B.G. Wolff

[82,  83]. The magnitude of this risk is controversial, with population-based studies suggesting that the risk is lower than previously thought and most dependent on the extent and duration of colitis. It is best defined in patients whose disease onset occurred during childhood or the teenage years, those with extensive disease, and those whose duration of disease is more than 10 years; in these patients, the risk of developing cancer is reported to be 2% per year [84]. The risk in patients with later age of onset is not well defined. Monitoring by screening colonoscopy for dysplasia has limitations, including patient compliance and the finding that carcinoma may not have evidence of preceding dysplasia [85]. At the time of colectomy for dysplasia, more than 50% already have invasive cancer [86]. In the absence of an absolute indication (i.e., stricture, evidence of dysplasia or a dysplasia-associated mass, existing cancer [87]), the role of surgery is less clear, despite results of a decision analysis that suggest prophylactic colectomy improves survival more than surveillance [88]. In the elderly, later onset of disease and shorter duration of remaining life compared with younger patients probably results in surgery being used more for specific indications than for prophylaxis.

Indications for Emergency Surgery Fulminant Colitis The definition of fulminant colitis is identical to that described for CD, although the Truelove and Witts’ criteria may be useful in stratifying disease severity in CUC (Table 66.4) [89]. It is important to remember, particularly in the patient presenting with a fulminant first attack, that the differentiation

Figure 66.3  Surgery for elderly patients with chronic ulcerative colitis treatment algorithm.

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Table 66.4  Modified Truelove and Witts’ criteria of ulcerative colitis disease severity [89, 111] Variable Mild disease Moderate disease Severe disease No. stools (per 24 h) 6 Blood in stool Intermittent Occasional Frequent Temperature (°C) Normal >37.5 >37.5 Pulse (beats/min) Normal >90 >90 Hemoglobin Normal Anemia 10 Continuous >37.5 >90 Transfusion requirement >30 Dilatation Abdominal distention and tenderness

If the patient is incontinent of stool due to an incompetent sphincter (and not to poor compliance in a diseased rectum), the decision is simple: proctocolectomy and Brooke ileostomy. In the individual without compromise of the sphincter, consideration may be given to proctocolectomy and ileostomy, subtotal colectomy, (Fig. 66.4) and ileorectal anastomosis, or proctocolectomy, and IPAA (or ileal pouch-distal rectal anastomosis). Multiple studies have examined the role of restorative proctocolectomy in the elderly [91–102]. These have been summarized in Table 66.6. Advanced age has generally been considered a contraindication to IPAA because of the high risk of fecal incontinence in the elderly. The clinical results in carefully selected patients over the age of 50, however, are equivalent to those of younger patients. Anal sphincter strength does decline after the age of 70 [103], and few, if any, patients beyond this age are candidates for this operation.

Preoperative Preparation Many of the principles of preoperative preparation discussed for patients with CD apply equally to those with UC. They include correction of electrolyte abnormalities and severe anemia, bowel preparation, use of antibiotics, and stress doses of steroids. Possibly, the most important aspect differentiating the patient with UC from the one with CD is consideration given to reconstructive surgery in the form of the ileal pouch-anal anastomosis (IPAA), which should be avoided in the acute setting.

Operative Procedure Essentially, the choice of procedure (Table 66.5, Fig. 66.3) depends on the presentation of the patient (e.g., disease severity) and how much of the rectum is to be removed (all, part, or none), and if the anal sphincter is competent.

Operative Approach: Minimally Invasive (Laparoscopic) Surgery Similar to as seen in CD, MIS techniques are being increasingly used in CUC. Several recent studies from Mayo Clinic have demonstrated the applicability of MIS techniques to CUC, including subtotal colectomy, IPAA, TPC with BI [104–106]. In a case series of 50 patients with severe-tofulminant CUC who underwent MIS subtotal colectomy with Brooke ileostomy, the majority (95%) who subsequently underwent IPAA were performed laparoscopically with a median length of stay of 4 days for each procedure. Similarly in a case-matched study comparing open and LAP IPAA, the benefits typical of a LAP approach were demonstrated. Finally, in a case series of 43 patients who underwent MIS TPC-BI, and in whom the median age was 66 years, this procedure was demonstrated to be safe and feasible. Our preferred port placement for both LAP and HALS approaches to colectomy for CUC is shown in Fig. 66.5.

850

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Table 66.5  Choice of operation for ulcerative colitis in elderly patients Typical no. of stages Procedure Contraindications

Comments

3-, 2-, or 1-stagea IPAA

TPC with IPAA and DLI; 3-stage if follows STC with BI, rarely, if ever 1-stage without DLI

Incompetent sphincter Advanced age (relative) Need for pelvic irradiation

Risks related to multiple operations and general anesthestics Complete excision of disease Risk of pouchitis Risk of cancer in retained mucosa Easier/faster operation to perform Complete excision of disease Risk of pouchitis; increased risk of leak? Risk of cancer in retained mucosa Easier/faster operation to perform Complete excision of disease Risk of stoma-related complications

2-Stage (modified) IPAA

STC with BI followed by IPAA without DLI

None

1-Stagea

TPC with BI

None

2-, or 1-stage

TPC with IRA (straight IRA or ileal pouch-rectal anastomosis); infrequently 2-stage with DLI

Incompetent sphincter Advanced age (relative) Need for pelvic irradiation Noncompliant for follow-up

Easier/faster operation to perform Risk of pouchitis Increased risk of cancer in retained rectal mucosa

2-, or 1-stage

TPC with K-pouch; 2-stage if follows STC with BI

Most patients

Frequent reoperation Rarely recommended, even in young patients

2-, or 1-stage

STC with IRA; infrequently 2-stage with DLI

Incompetent sphincter Active rectal disease Noncompliant for follow-up

Incomplete excision of disease At risk for proctitis or development of rectal cancer

2-, or 1-stage

STC with BI

None

Easier/faster operation to perform Incomplete excision of disease At risk for proctitis or development of rectal cancer

2-, or 1-stage

Segmental colectomy with primary anastomosis

Most patients

Rarely if ever recommended due to incomplete excision of disease, even in young patients

Turnbull procedure (ileostomy with blowhole colostomy)

Almost all patients

Generally of historic interest only for the treatment of toxic megacolon in unstable patients; however, success with this procedure has recently been reported in 2 pregnant women with toxic megacolon [112] TPC total proctocolectomy, BI Brooke ileostomy, DLI diverting loop ileostomy, IPAA ileal pouch-anal anastomosis, IRA ileorectal anastomosis, STC subtotal colectomy, K-pouch continent ileostomy (Kock pouch) a Most commonly preferred surgical approaches in elderly patients Temporizing procedure

Figure 66.4  Chronic ulcerative colitis, subtotal colectomy, gross specimen. Note the complete carpeting of the colonic mucosa with pseudopolyps and foreshortening of the right, transverse, and left colon from an elderly woman with long-standing CUC.

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Table 66.6  Summary of recent studies of ileal pouch-anal anastomosis in the elderly Author Institution Year Study design Age (years)

Elderly (N)

Major findings/comments

Ho et al. [102]a

Cleveland Clinic, Florida

2006

Subgroup comparisons

>70

  17

No difference in length of stay, complications (40%), or pouch failure between >70 and 55

  65

No difference in complications. Incontinence more common, but did not affect QoL

Longo et al. [99]a

St. Louis University

2003

Population-based (Veterans) subgroup comparisons

>50

158

Of 46 patients >70 years, no IPAA’s were performed. 22% overall surgical morbidity; 4% mortality (all non-IPAA patients)

Delaney et al. [100]a

Cleveland Clinic, Ohio

2003

Subgroup comparisons

56–65 >65

154   42

Increased incontinence, night-time seepage in older groups; QoL decreased but not statistically

Farouk et al. [97]a

Mayo Clinic, Rochester

2000

Subgroup comparisons

>45

204 (1 year)   33 (12 years)

At 1 and 12 years, incontinence affected older group more often. Incontinence increased with time in older, but not younger, patients. Pouch excision due to incontinence not statistically different between group (45, n = 3)

Church [98]

Cleveland Clinic, Ohio

2000

Case report, 10-year follow-up

85

  1

Bowel function, QoL remained relatively stable; age is not necessarily a contraindication to IPAA

Takao et al. [96]

Cleveland Clinic, Florida

1998

Subgroup comparisons

>60

  17

Postoperative minor and transient functional impairment is not an age-related phenomenon

Tan et al. [95]

Queen Elizabeth Hospital

1997

Subgroup comparisons

>50

  28

Included 4 non-CUC patients. Higher incidence of IPAA stenosis in the elderly. Age did not impact functional outcomes

Bauer et al. [94]

Mount Sinai

1997

Subgroup comparisons

>50

  66

Elderly group with longer duration of disease, more dysplasia. Age did not impact functional outcomes

Reismann et al. [93]

Cleveland Clinic, Florida

1996

Subgroup comparisons

>60

  14

Older patients experience more nocturnal movements (2 vs. 1.1, p 50

  18

Anorectal manometry not statistically different between age groups before/after surgery. Age alone is not a contraindication to restorative surgery if anal sphincter is completely intact

High quality/recommended

a

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Figure  66.5  Laparoscopic port placement for total proctocolectomy. (a) Laparoscopic-assisted surgery; IPAA, TPC-BI, STC-EI. (b) Handassisted surgery; IPAA, TPC-BI, STC-EI. Dashed lines represent

CASE STUDY: REFRACTORY ULCERATIVE COLITIS IN AN OCTOGENARIAN An 83-year-old male with a 2-month history of CUC presented to the surgical service with refractory colitis despite 5-aminosalicylate dose escalation and 30 mg of prednisone daily. The patient complained of 8–14 bloody bowel movements per day. The patient’s body mass index was 25  kg/m2. The patient had multiple comorbidities including steroid-induced diabetes mellitus, chronic renal insufficiency, hyperlipidemia, iron-deficiency anemia, and a history of a type 5 peptic ulcer disease. Preoperatively, the patient’s Charlson score was 8 points, and American Society of Anesthesiology (ASA) score was 3. The patient has a history of a radical prostatectomy with postoperative external beam irradiation. Endoscopy revealed moderately active pancolitis with no evidence of dysplasia. Given the patient’s, age, comorbidities, and history of pelvic surgery and irradiation, we recommended a total proctocolectomy with end ileostomy. The patient underwent an uneventful laparoscopic total proctocolectomy, intersphincteric dissection, and Brooke ileostomy. Given the history of pelvic surgery and irradiation, the pelvic dissection was tedious; overall operative time was 444  min, estimated blood loss was

potential specimen extraction sites (copyrighted and used with permission of Mayo Foundation for Medical Education and Research, used with permission, all rights reserved).

450  ml, and he was transfused one unit of pack cells. There were no intraoperative complications, and the procedure was completed laparoscopically. Gross pathology revealed severely active pancolitis with a tubular adenoma with low-grade dysplasia in the descending colon. Postoperatively, the patient’s stoma began functioning on day 3, and he tolerated a regular diet. The patient was discharged home on postoperative day 4 but 2 days later returned to the hospital with left lower extremity swelling and was found to have an ileofemoral deep vein thrombosis, treated with anticoagulation. He suffered no other complications within 30 days. Subsequently, the patient had developed a partial small bowel obstruction related to a parastomal hernia, which was initially managed with a hernia belt. The hernia was enlarged, and the patient underwent an uneventful mesh repair and remains asymptomatic. This case demonstrates that: 1. Age alone is not a contraindication to laparoscopic colectomy (nor is it an absolute contraindication to IPAA). 2. Prior treatment of age-related cancers may affect surgical decision making and recommendations for restorative proctocolectomy. (continued)

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CASE STUDY  (continued) 3. The timing of surgical intervention for elderly patients with moderate-to-severe CUC must take into account the patients physiologic reserve and ability to tolerate ongoing bloody diarrhea. In the face of worsening anemia, renal insufficiency, a lower threshold for operation may be appropriate for elderly patients with active CUC. 4. The risks and benefits of surgical therapy for elderly patients with CUC must be weighted against the risks and benefits of escalated medical therapy with agents such as corticosteroids and infliximab. These agents

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66  Surgery for Inflammatory Bowel Disease in the Elderly 77. Jeffery PJ, Parks AG, Ritchie JK (1977) Treatment of haemorrhoids in patients with inflammatory bowel disease. Lancet 1(8021):1084–1085 78. Fry RD, Shemesh EI, Kodner IJ, Timmcke A (1989) Techniques and results in the management of anal and perianal Crohn’s disease. Surg Gynecol Obstet 168(1):42–48 79. Williamson PR, Hellinger MD, Larach SW, Ferrara A (1995) Twenty-year review of the surgical management of perianal Crohn’s disease. Dis Colon Rectum 38(4):389–392 80. Makowiec F, Jehle EC, Becker HD, Starlinger M (1995) Clinical course after transanal advancement flap repair of perianal fistula in patients with Crohn’s disease. Br J Surg 82(5):603–606 81. Crim RW, Fazio VW, Lavery IC (1990) Rectal advancement flap repair in Crohn’s patients – factors predictive of failure. Dis Colon Rectum 33:P3 82. Ekbom A, Helmick C, Zack M, Adami HO (1990) Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 323(18):1228–1233 83. Jess T, Loftus EV Jr, Velayos FS et al (2006) Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted county, Minnesota. Gastroenterology 130(4):1039–1046 84. Devroede G (1980) Colorectal cancer: prevention, epidemiology, and screening. Lippincott-Raven, Philadelphia 85. Reiser JR, Waye JD, Janowitz HD, Harpaz N (1994) Adenocarcinoma in strictures of ulcerative colitis without antecedent dysplasia by colonoscopy. Am J Gastroenterol 89(1):119–122 86. Blackstone MO, Riddell RH, Rogers BH, Levin B (1981) Dysplasia-associated lesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis: an indication for colectomy. Gastroenterology 80(2):366–374 87. Lennard-Jones JE (1995) Colitic cancer: supervision, surveillance, or surgery? Gastroenterology 109(4):1388–1391 88. Provenzale D, Kowdley KV, Arora S, Wong JB (1995) Prophylactic colectomy or surveillance for chronic ulcerative colitis? A decision analysis. Gastroenterology 109(4):1188–1196 89. Mahadevan U, Loftus EV Jr, Tremaine WJ et al (2002) Azathioprine or 6-mercaptopurine before colectomy for ulcerative colitis is not associated with increased postoperative complications. Inflamm Bowel Dis 8(5):311–316 90. Hawley PR (1988) Emergency surgery for ulcerative colitis. World J Surg 12(2):169–173 91. Lewis WG, Sagar PM, Holdsworth PJ et  al (1993) Restorative proctocolectomy with end to end pouch-anal anastomosis in patients over the age of fifty. Gut 34(7):948–952 92. Jorge JM, Wexner SD, James K et  al (1994) Recovery of anal sphincter function after the ileoanal reservoir procedure in patients over the age of fifty. Dis Colon Rectum 37(10):1002–1005 93. Reissman P, Teoh TA, Weiss EG et al (1996) Functional outcome of the double stapled ileoanal reservoir in patients more than 60 years of age. Am Surg 62(3):178–183 94. Bauer JJ, Gorfine SR, Gelernt IM et al (1997) Restorative proctocolectomy in patients older than fifty years. Dis Colon Rectum 40(5):562–565 95. Tan HT, Connolly AB, Morton D, Keighley MR (1997) Results of restorative proctocolectomy in the elderly. Int J Colorectal Dis 12(6):319–322

855 96. Takao Y, Gilliland R, Nogueras JJ et al (1998) Is age relevant to functional outcome after restorative proctocolectomy for ulcerative colitis?: prospective assessment of 122 cases. Ann Surg 227(2):187–194 97. Farouk R, Pemberton JH, Wolff BG et al (2000) Functional outcomes after ileal pouch-anal anastomosis for chronic ulcerative colitis. Ann Surg 231(6):919–926 98. Church JM (2000) Functional outcome and quality of life in an elderly patient with an ileal pouch-anal anastomosis: a 10-year follow up. Aust N Z J Surg 70(12):906–907 99. Longo WE, Virgo KS, Bahadursingh AN, Johnson FE (2003) Patterns of disease and surgical treatment among United States veterans more than 50 years of age with ulcerative colitis. Am J Surg 186(5):514–518 100. Delaney CP, Fazio VW, Remzi FH et al (2003) Prospective, agerelated analysis of surgical results, functional outcome, and quality of life after ileal pouch-anal anastomosis. Ann Surg 238(2):221–228 101. Chapman JR, Larson DW, Wolff BG et al (2005) Ileal pouch-anal anastomosis: does age at the time of surgery affect outcome? Arch Surg 140(6):534–539, discussion 539–540 102. Ho KS, Chang CC, Baig MK et al (2006) Ileal pouch anal anastomosis for ulcerative colitis is feasible for septuagenarians. Colorectal Dis 8(3):235–238 103. McHugh SM, Diamant NE (1987) Effect of age, gender, and parity on anal canal pressures. Contribution of impaired anal sphincter function to fecal incontinence. Dig Dis Sci 32(7): 726–736 104. Holubar S, Larson D, Dozois E et al (2009) Minimally invasive subtotal colectomy and ileal pouch-anal anastomosis for fulminant ulcerative colitis: feasibility and short-term outcomes. Dis Colon Rectum 52(2):187–192 105. Larson DW, Dozois EJ, Piotrowicz K et al (2005) Laparoscopicassisted vs. open ileal pouch-anal anastomosis: functional outcome in a case-matched series. Dis Colon Rectum 48(10): 1845–1850 106. Holubar S, Privitera A, Cima R et al (2009) Minimally invasive total proctocolectomy with Brooke ileostomy for ulcerative colitis. Inflamm Bowel Dis 15(9):1337–1342 107. Heresbach D, Alexandre JL, Bretagne JF et al (2004) Crohn’s disease in the over-60 age group: a population based study. Eur J Gastroenterol Hepatol 16(7):657–664 108. Triantafillidis JK, Emmanouilidis A, Nicolakis D et  al (2000) Crohn’s disease in the elderly: clinical features and long-term outcome of 19 Greek patients. Dig Liver Dis 32(6):498–503 109. Norris B, Solomon MJ, Eyers AA et al (1999) Abdominal surgery in the older Crohn’s population. Aust N Z J Surg 69(3): 199–204 110. Wagtmans MJ, Verspaget HW, Lamers CB, van Hogezand RA (1998) Crohn’s disease in the elderly: a comparison with young adults. J Clin Gastroenterol 27(2):129–133 111. Truelove SC, Witts LJ (1955) Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 2(4947):1041–1048 112. Ooi BS, Remzi FH, Fazio VW (2003) Turnbull-Blowhole colostomy for toxic ulcerative colitis in pregnancy: report of two cases. Dis Colon Rectum 46(1):111–115

Chapter 67

Diverticulitis and Appendicitis in the Elderly Scott C. Thornton

CASE STUDY MS is a 90-year-old woman with no significant comorbidities who lives on her own at home. She was hospitalized five times over 4 months with an initial diagnosis of unrelenting ischemic colitis of the descending colon. This was diagnosed by multiple CT scans and with endoscopic confirmation. Despite antibiotics and enteral supplementation, she had slow and progressive weight loss and increasing inability to eat. Indication for operation was failure to progress with medical therapy and inability to eat. Her albumin, prealbumin, and initial weight were 2.0, 9, and 92 pounds, respectively. She underwent a left colectomy with primary anastomosis and protective loop ileostomy. Operative finding, confirmed by pathologic examination, was retroperitoneal perforated diverticulitis

Elderly patients are often difficult to be correctly diagnosed due to nonroutine presentations. Once treated, they more frequently have complications with medical therapies aimed at cure. The following case presentation illustrates many of these problems found when treating older patients. This chapter deals with diverticular disease and appendicitis in the elderly. Diverticular disease increases in incidence with age and also appears to present with diffuse peritonitis more frequently in old than in young patients. Acute appendicitis in the elderly accounts for 5–10% of all appendicitis,

S.C. Thornton (*) Department of General Surgery, Bridgeport Hospital, Yale University, Bridgeport, CT, USA e-mail: [email protected]

with contained abscess (Hinchey class II). Her postoperative course was complicated by ileostomy dysfunction, resulting in watery diarrhea, which caused dehydration and electrolyte imbalance. She developed a lower extremity deep venous thrombosis and was started on warfarin after a vena cava filter was placed. After a single 5-mg dose of warfarin, her INR rose to ten, and she had a spontaneous intra-abdominal bleed requiring transfusion. Aging does not alter the pharmacokinetics of warfarin but may increase sensitivity to its anticoagulant effects. She was unable to eat due to newly diagnosed, severe esophagitis. This was treated medically, and a PEG was placed for enteral nutrition. She was ultimately ­discharged to an extended care facility 1  month after surgery. She maintained mental acuity throughout her illness and is anxiously awaiting the reversal of her ostomy.

and old patients tend to present more frequently with advanced disease than do young groups. There is good ­evidence that the elderly present more frequently in an atypical fashion with both of these diseases compared with their younger counterparts. Abdominal pain may be absent or not greatly perceived in older patients. Physiologic responses to stress and infection are also blunted in the elderly. Older patients are burdened with more comorbid conditions and less mental and physical reserves compared with their younger counterparts. Furthermore, it is well known that emergency operations in the elderly are associated with significantly higher mortality and morbidity rates than similar operations on younger patients. Thus, old patients present atypically, often with more advanced disease and have higher complication and death rates than the young. This chapter attempts to explain these findings.

R.A. Rosenthal et al. (eds.), Principles and Practice of Geriatric Surgery, DOI 10.1007/978-1-4419-6999-6_67, © Springer Science+Business Media, LLC 2011

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Diverticular Disease Etiology Diverticular disease is the fifth most costly digestive disease in the USA [1]. The cause of diverticulosis is unknown. Colonic diverticula are mucosal (and submucosal) herniations through the muscle wall of the colon. The sigmoid colon is affected in 96% of patients, with this area being the only site of diverticulosis in two-thirds of patients [2]. Acute diverticulitis can occur anywhere in the colon and has been reported in the rectum [3, 4]. Diverticula occur at the points of weakness where the blood supply to the mucosa penetrates the bowel wall. Most commonly, they occur between the mesenteric and antimesenteric taenia coli. Less commonly, they occur between the two antimesenteric taenia. Strong epidemiologic evidence suggests that a low-fiber diet has a substantial etiologic role in the development of diverticulosis [5, 6], and low-fiber intake has long been implicated as a cause of diverticulosis [5, 7]. In the USA, the incidence of diverticular disease has increased with decreasing fiber intake [8]. Vegetarians have been found to have a lower incidence of diverticular disease than nonvegetarians [9]. Other studies have confirmed these findings [10–14]. The current speculation is that a diet low in fiber decreases stool bulk. This in turn causes narrowing of the colonic lumen, prolongs intestinal transit time, and increases intraluminal pressures. Painter et al. [15] combined manometry and cineradiography and found that the increased intraluminal pressure may be due to simultaneous contractions of circular muscular bands causing occlusion of short segments of bowel. Contraction rings are thus formed in the sigmoid colon, which produces “segmentation” of these short segments of bowel. Contraction of the muscle wall of these sections can result in intraluminal pressures of 90  mmHg or more. This pulsion pressure may lead to mucosal herniation along the weak points of the bowel wall, resulting in diverticula. Others have found that the contractile response to eating is exaggerated in people with diverticulosis [16]. Although consistent with the speculation that elevated pressures are particularly significant in combination with or potentiated by low-fiber stools, experimentation with colomyotomy showed that decreased muscular activity did not affect intraluminal pressures [17]. Stool bulk may be related to intraluminal pressure only in that stool bulk increases the radius of the colon, thereby decreasing wall tension. Painter et al. suggested that a low-fiber diet causes a narrower colonic lumen, which allows the colon to segment more efficiently, increasing the segmental intraluminal pressures [15]. Lowfiber diets in rats has been shown to result in diverticulosis in 45% of subjects compared with only 9% in a group fed the highest fiber diet [18]. Further, a large, longitudinal study of

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males in the USA revealed a relatively straight line ­correlation between fiber intake and diverticular symptoms [19]. Exercise may also have a protective effect on the development of symptoms from diverticular disease [20]. Colonic dysmotility may contribute to diverticular disease. Abnormally slow wave patterns have been found in patients with symptomatic diverticular disease [21]. Furthermore, patients with symptomatic diverticular disease return to normal motility patterns with ingestion of bran, whereas those with asymptomatic diverticulosis have no change in motility with bran intake [22]. Others have disputed these findings [23]. Colonic transit times can be decreased by adding bran to the diet [24–26], and waterretaining fiber can decrease intraluminal pressure [27]. These findings lead to dietary modifications in attempts to alleviate diverticular symptoms. One report [28] implicated localized ischemia as a causative factor for antimesenteric free perforation of the colon from diverticulitis. In patients with multiple bilateral pseudodiverticula arranged in a double row about the antimesenteric taenia, the vascular supply to the middle area of the antimesenteric wall is compromised. Careful histologic studies showed that free perforation associated with diverticulitis has the same histologic characteristics as ischemic bowel perforations. It is well known that microvascular changes predisposing to microvascular ischemia occur in the elderly. The more aggressive disease and higher perforation rates found in the elderly [29–32] may be related to this ischemic process. Perhaps this is the reason why the elderly have higher free perforation rates when compared with younger patients. Investigators have also touched on whether an intrinsic change in bowel wall composition is necessary for the development of diverticula. Young people with collagen vascular diseases such as Marfan’s syndrome [33] have been reported with diverticular disease. Several authors have also documented an association of diverticular disease with degenerative disorders such as varicose veins [34], hiatal hernias [35], and arthritis [36]. The most important element with regard to strength of the colon wall is collagen [37]. Collagen fibrils in the left colon become more numerous but smaller in width with age, and this difference is greater with diverticular disease [38]. Similarly, elastin fibrils increase in number but decrease in quality with age [39]. Pace [39] found that colon wall thickness increases with age and is thickest in the distal colon. These factors combined to result in decreased tensile strength and decreased expandability of the aging colon wall [40]. Electron microscopic examination reveals that there is a two-time increase in elastin deposition and normal muscle cells in the muscle layer of diverticular diseased colon. The elastin is in a shortened form, which may account for the thickened, foreshortened bowel typically found at surgery [41].

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The distal sigmoid is the narrowest portion of the colon, and the distal sigmoid narrows with age [42]. The law of Laplace states that wall tension is directly proportional to the pressure times the diameter. Thus, as contractile pressures (as measured by wall tension) remain the same and the diameter is decreased, there is an increase in pressure delivered to the bowel wall. A simple example of Laplace’s law is blowing up a balloon. It is most difficult when there is no air in the balloon and becomes easier as the diameter increases. Similarly, increased pressures are required in the narrower distal sigmoid to propel stool. As the lumen narrows with age, higher pressures are required. This increased stress further damages the colon, causing decreased elasticity and more loss of tensile strength [40]. Comparison studies show that populations with a low incidence of diverticular disease have stronger, more elastic distal colons than industrialized populations [42], presumably due to years of more bulky stools keeping the lumen diameter large. Furthermore, with increasing wall tension pressures, there must be a concomitant decrease in microvascular perfusion [43], possibly adding further weight to the vascular theory of free perforation of diverticulitis [15]. The resulting increased intraluminal pressure causes long-term changes in the bowel wall, including decreased tensile strength, decreased diameter, and vascular changes which predispose to diverticular disease and the more frequent perforation seen in the elderly.

Epidemiology Diverticulosis is an entity particular to the dietary patterns of Western society. There are linear increases in size, number, incidence, and symptoms of diverticula with age [6, 44]. Diverticulae are commonly 5–10 mm in size and can occasionally be >2  cm. Giant diverticula have been described. Diverticulosis occurs in 2–5% of patients under age 40 and up to one-third of people over age 45. Two-thirds of people over age 85 have radiographic or pathologic evidence of diverticulosis [45]. Deckman and Cheskin [46] cited a prevalence in the USA as high as 33% with similar figures in European countries. In comparison, the prevalence in populations with higher per capita fiber intake is much lower. Diverticulosis is uncommon in developing parts of Africa and Asia and may be as low as 1% in Korea [35], with low incidences found in other similar populations [47–52]. Independent of age, prevalence is thought to be similar in men and women. However, in a large single institutional series by Rodkey and Welch [53], when sex and age were examined jointly, women over 70 years of age predominated over men by more than 3:1. The reverse was found in patients under 50 years of age, with more than twice as many men affected as women. This ratio was also substantiated by

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Ouriel and Schwartz [54], who found a predominance of men in the under-40 age group. Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been linked to diverticular disease [55], and others have implicated NSAIDs as a potential cause of acute diverticulitis [56–58]. Steroids have been linked to diverticulitis as well. Steroids also mask symptoms of infection which may cause delays in diagnosis, resulting in poor prognosis [59–61].

Pathogenesis Diverticulitis is the inflammatory process that originates within colonic pseudodiverticula. The particular mechanisms of both the local and systemic infections have not been well characterized. It has been hypothesized that diverticulitis constitutes the same end point of localized luminal obstruction found with other intraabdominal visceral inflammatory processes such as appendicitis and cholecystitis [62–64]. Obstruction of the neck of the diverticula, presumably with inspissated stool, creates a closed microenvironment characterized by fluid sequestration, stasis, and bacterial overgrowth. Deitch [65] showed that even in the absence of perforation, obstruction alone is sufficient for bacterial translocation across the intestinal barrier. As the diameter of the diverticulum expands to accommodate the increased intraluminal pressure, venous and then arterial pressures are overcome. This results in congestion, ischemic necrosis, and perforation. Others cannot find supporting pathologic evidence and suggest that perforation is likely the result of increased intraluminal pressure [46]. Activation of local and systemic inflammatory mediators, in combination with microscopic or macroscopic perforation and soiling of the peritoneum, leads to the clinical manifestations of the disease. The role of localized ischemia was discussed earlier [28]. Atypical, painful or chronic diverticular disease is a difficult-to-describe entity. It is described as chronic, intermittent left lower abdominal pain, not usually associated with typical findings of acute inflammation. Motility patterns may be abnormal in this subset of patients [67]. Pain is usually chronic, intermittent, and not associated with acute symptoms. Narrow stools and other changes in bowel habits may result. Attacks may come and go. Symptoms may be confused with irritable bowel syndrome. The diagnosis is difficult, with barium enema showing only diverticulosis and possibly spasm of the sigmoid colon. CAT scan does not reveal acute inflammation, and it does not respond to antibiotics or dietary modification. Endoscopic findings are generally nonspecific, although a tortuous colon may be found. Endoscopy may show edema or associated patchy colitis.

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Treatment is aimed at relieving symptoms. Bulk agents (psyllium seed) and a high-fiber diet are usually helpful. Differentiating between irritable bowel syndrome and painful diverticular disease is difficult as symptoms of bloating, distention, and intermittent nonspecific abdominal pain are common. Fortunately, IBS and painful diverticular disease are treated similarly with high-fiber diet and symptom control with moderate success. Uncommonly, sigmoid resection is required to produce relief. Appropriate patient selection is paramount in identifying who may respond to operative intervention and those who will not. When well chosen, sigmoid resection will relieve pain in 79–80% of patients [67].

Symptoms The spectrum of disease produced by diverticula ranges from completely symptom-free to vascular collapse secondary to systemic sepsis from peritonitis. About 10–25% of patients with diverticulosis progress to diverticulitis [68, 69]. Most of these patients never come to surgical attention [68, 69]. A small number, estimated at fewer than 25% of those with diverticulitis, require inpatient management of their disease [70]. Complicated cases involving sepsis, obstruction, fistula formation, or peritonitis constitute approximately 40% of all those admitted. Older patients present more often with complicated disease. The elderly present with diffuse peritonitis up to twice as frequently as younger patients [29, 31]. Typically, patients with diverticulitis seek medical care owing to mild or moderate peritoneal irritation often accompanied by a change in bowel habits. Crampy left lower quadrant pain is also common. Approximately two-thirds of patients complain of constipation or diarrhea [71]. Other associated symptoms may include a palpable mass, abdominal distension, dysuria, excessive flatus, nausea, and vomiting. About 30–40% of patients have occult blood in their stool [3]. Fever and pain are the most consistent indicators of acute disease, occurring 45% of the time. Septic shock with diffuse peritonitis may be the presenting picture. With the presence of a redundant sigmoid colon, suprapubic or right lower quadrant pain may manifest. Occasionally, the diagnosis of appendicitis is the indication for surgical exploration when a redundant sigmoid colon with diverticulitis is found to be the culprit. Considerable diagnostic overlap exists between diverticulitis and other acute abdominal processes. The spectrum of differential diagnoses ranges from relatively common urinary tract infections in the elderly to inflammatory bowel disease, colon cancer, closed loop obstruction, and ischemic bowel. These diagnoses and causes of abdominal pain must always be kept in mind during the initial evaluation.

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Symptoms of diverticular fistulas may lead to an accurate preoperative diagnosis. Pneumaturia and fecaluria are diagnostic of an enteric-vesicular fistula and in the appropriate patients are highly suggestive of a diverticular origin. Similarly, flatus or stool via the vagina leads to common bowel sources. Thigh abscesses, especially those with foulsmelling anaerobic pus, may originate from a diverticular abscess with tracking along the psoas muscle onto the skin. Many investigators have found atypical presentations of diverticular disease in the elderly [29, 72–76]. Wroblewski and Mikulowski [74] noted the absence of typical manifestation of peritonitis in the elderly to be associated with a poor outcome. They also found an absence of abdominal pain in half of their patients with peritonitis. Intraabdominal abscesses are the most common cause of fever of unknown origin in the elderly [77]. Others noted that elderly patients with intraabdominal infections have hypothermic temperatures more frequently than young patients. Similarly, old patients have less nausea, vomiting, diarrhea, and fever compared to the young [72]. Acute abdominal pain is more likely to require surgery in the elderly [78, 79]. France et al. [73] examined 12 old patients who died of diverticulitis: 75% did not have symptoms typical of their disease, 3 of the 12 did not have abdominal symptoms, and another’s symptoms did not warrant further investigation. Generalized peritonitis occurs in up to one-half of old patients [29, 30]. Old patients require operations more frequently, have free perforation more commonly, and have higher mortality rates than young patients [29–32, 80]. Watters et al. [29] attempted to explain this difference. They found that the mean time from the onset of symptoms to hospitalization for old and young patients with generalized diverticular peritonitis was the same. Thus, old patients have peritonitis and free perforation more frequently than the young do, and it is not due to a delay in seeking medical care. This finding suggests that the severity of disease in the elderly is determined early in its course and is independent of the passage of time. Another possible explanation is that symptoms begin later in the course of the disease in the elderly. The former explanation further supports the theory that ischemia is the cause of the more frequent diffuse peritonitis found in the elderly.

Diagnosis Diverticulitis is usually diagnosed based completely on clinical grounds. This presents a unique problem in the elderly because, as previously shown, they often present atypically, and abdominal pain is minimal or absent. A history of known diverticula seen by barium enema or endoscopy often aids the clinician. However, it is unnecessary to have previous knowledge of diverticula in a particular patient, as more elderly

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patients have diverticula than do not [46]. Useful serologic and hematologic tests include a complete blood count, serum electrolytes, urinalysis, and in the case of suspected ischemic bowel, arterial blood gas measurement for acid–base disturbances. White blood cell (WBC) can be normal in almost one-half of older patients [32]. Physical examination usually reveals peritoneal irritation to some extent. Mild left lower quadrant tenderness to generalized peritonitis may be found. Rectal examination may reveal a pelvic abscess. Several diagnostic modalities are helpful for establishing the diagnosis of diverticular disease and assessing the extent of inflammation. In preceding decades, contrast enema was the test of choice for diagnosis. Previous practice parameters of the American Society of Colon and Rectal Surgeons [81] cite a sensitivity of 94%, an accuracy of 77%, and a false-negative rate of 2–15% with water-soluble enemas. Contrast enemas in the setting of diverticular disease have been shown to be less reliable in identifying neoplastic growth compared with colonoscopy [82]. Radiographic findings include intramural or extramural sinus tracts, filling of the abscess cavity, or inferred extramural compression or spasm of the bowel lumen. Ultrasonography may also provide useful information in the setting of suspected diverticular disease. Investigators have found it to be 84–98% sensitive [83–85]. Ultrasonography can detect abnormal segments of bowel, those with mural thickening, peridiverticular inflammation and abscess, and linear echogenic foci suggestive of fistulous tracts. Unfortunately, this technique is both operator-dependent and limited by the body habitus of the patient. Zielke et al. [86] found that surgical residents were able to accurately diagnose diverticulitis in 84% of patients, with a 16% false-negative rate. Computed tomography (CT) has emerged as the imaging modality of choice for evaluating suspected diverticulitis [87–91]. Though in some studies it is comparable to contrast enema, other investigators have found a clear advantage regarding its diagnostic sensitivity and specificity [92]. Hulnick et al. [91] found that CT not only stages the extent of the inflammatory process more accurately, but it also better differentiates the varying gradations of pericolic inflammation. Furthermore, CT has the distinct advantage over a contrast enema because of its ability to identify both the intraluminal and extraluminal components of diverticular disease. It is also the diagnostic modality of choice for identifying colovesical and colovaginal fistulas. Findings suggestive of diverticulitis include inflammation of the pericolic fat, thickening of the sigmoid mesocolon, pericolic phlegmon, visualization of colonic diverticula themselves, and thickening of the colonic wall (see Fig. 67.1). CT is helpful for demonstrating the manifestations of intraabdominal abscess, particularly abscesses amenable to percutaneous drainage [87–91]. Despite these modalities, the diagnosis of diverticulitis can be obscure in the elderly [74].

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Figure 67.1  Acute diverticulitis of the sigmoid colon with paracolonic fat stranding.

Endoscopic evaluation is reserved until after the acute phase has resolved; it is used mainly to rule out carcinoma. CT colography is a new modality that noninvasively evaluates the contour of the colon lumen. It is especially helpful in cases where, due to stricture or obstruction, a colonoscope cannot traverse the diseased bowel. Colography can ensure that the proximal bowel does not harbor unsuspected neoplastic lesions.

Treatment Prevention of Symptoms High-fiber diet has been shown to decrease the formation of diverticulae in rats [19]. Examination of population-based per capita fiber intake reveals less diverticular disease with high average fiber intake [47, 50, 51]. High fiber intake in American males decreases the risk of diverticular symptoms. There is no evidence that increasing fiber intake can cause diverticulae to regress. It follows that high-fiber diet should be suggested to decrease the chance of diverticular symptoms [93]. There is no evidence to support the concept of avoiding food particles that can obstruct the neck of diverticulae. Accordingly, avoidance of seeds, nuts, popcorn, etc., has not been shown to cause acute disease. Most physicians suggest a high-fiber diet with bulk-producing supplements (psyllium seed) for patients with asymptomatic diverticulosis [94]. Fiber has been shown to decrease intraluminal pressures and colonic transit time [27, 95–97]. It also decreases symptoms attributed to diverticular disease [94, 95, 97–100]. Antispasmodic medications have not been shown to help.

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Uncomplicated Diverticulitis Most acute diverticulitis are treated by primary physicians on an outpatient basis. Those with only mild tenderness, no clinical peritoneal signs, and the ability to achieve satisfactory pain control and tolerate adequate fluids orally may be treated empirically on an outpatient basis [6]. Treatment consists of oral antibiotics covering anaerobic and gramnegative bacteria for at least 7 days and liquid diet until resolution of symptoms. Significant systemic signs of infection including high fever and leukocytosis suggest the need for hospital treatment. Resolution is common. There is no place for outpatient management in the setting of significant concurrent medical disease, immune compromise, or in those with altered mental status, or patients without appropriate supervision. Immune-compromised patients have a more aggressive disease path, are more likely to present with perforation, and have higher morbidity and mortality rates [60, 101]. Perkins et al. [101] found a 100% failure rate with conservative treatment of immune-compromised patients. Early surgical management is appropriate in this patient population. Due to the aggressive nature of diverticulitis, some have suggested elective sigmoid resection in patients with a single prior attack when they are candidates for organ transplantation with its attendant long-term immune suppression [102]. Patients on continuous peritoneal dialysis represent a special dilemma. CT scanning is usually nondiagnostic, and delay in treatment results in poor outcomes. After treatment, very few will be able to remain on peritoneal dialysis [103]. Patients who fail in outpatient therapy or who present with significant systemic symptoms should be admitted to the hospital. Hospital treatment consists of complete bowel rest and parenteral broad-spectrum antibiotics to cover anaerobic and gram-negative bacteria. Triple-antibiotic or single-agent therapy are both effective. Nasogastric suction is required only with persistent vomiting or evidence of bowel obstruction. Laboratory evaluation includes a complete blood count and urinalysis. CT should be done to confirm the diagnosis, quantify the extent of inflammation, and identify possible complicated diverticular disease. Conservative treatment of acute uncomplicated diverticulitis leads to resolution of symptoms in 70–100% of cases [2, 3, 46, 47, 53, 87, 104]. Oral intake is resumed with disappearance of symptoms. Following hospital discharge, oral antibiotics should be continued for 7–10 days. With complete resolution of the inflammation, patients should have endoscopic or radiographic evaluation of their colon to rule out carcinoma, and they should be started on long-term fiber supplementation. Psyllium seed or hydrophilic colloids have been shown to reduce recurrence by up to 70% [100]. Old studies suggest that one-fourth of patients who recover from their first attack will have further attacks requiring

S.C. Thornton

hospitalization [2, 105]. A recent study with a median 5-year follow-up revealed that 2 cm in size or with stromal invasion >1.0 mma, confined to the vulva or perineum, with negative nodes Stage II

Tumor of any size with extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with negative nodes

Stage III

Tumor of any size with or without extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with positive inguino-femoral lymph nodes (i) With 1 lymph node metastasis (³5 mm), or (ii) 1–2 lymph node metastasis(es) (b5 mm) (i) With 2 or more lymph node metastases (³5 mm), or (ii) 3 or more lymph node metastases (b5 mm) With positive nodes with extracapsular spread

IIIA IIIB IIIC Stage IV

Tumor invades other regional (2/3 upper urethra, 2/3 upper vagina), or distant structures IVA Tumor invades any of the following: (i) Upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or (ii) Fixed or ulcerated inguino-femoral lymph nodes IVB Any distant metastasis including pelvic lymph nodes Source: Reprinted from FIGO Committee on Gynecologic Oncology [175], with permission a The depth of invasion is defined as the measurement of the tumor from the epithelial–stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion

usually atrophic in nature. Dysplastic lesions and malignancies tend to be asymmetric in distribution and may be friable. Most commonly, patients present with the complaint of a vulvar lump or mass. A long history of vulvar burning or pruritus is frequently elicited. Most lesions occur initially on the labia majora and less frequently on the labia minora, clitoris, or perineum. Only approximately 5% of cases are multifocal. There is little consensus regarding the optimal method of management. There has been a gradual trend toward conservation in the management of dysplastic lesions (vulvar intraepithelial lesion, VIN grade 1–3). Current treatment modalities include carbon dioxide (CO2) laser vaporization or ablation and surgical excision. Recurrence rates after treatment have been reported to range from 10 to 50% and are thought to be related to the grade of VIN and margin status along with the multifocal nature of the condition and its relationship with HPV [14]. In the elderly, if chosen, surgical excision may be performed under local anesthesia. Generally, a 1-cm margin is adequate for noninvasive lesions. For extramammary Paget’s disease of the vulva, however, even 2-cm margins are often insufficient [15, 16].

For extramammary Paget’s disease of the vulva, it is sometimes necessary to perform extremely wide local excisions with skin grafts or advancement flaps to cover the defect [17]. Microscopically, positive margins following surgical excision of vulvar Paget’s disease is a frequent finding, and disease recurrence is common regardless of surgical margin status. Long-term monitoring of patients is recommended, and repeat surgical excision is often required [18]. The standard surgical management of women with invasive carcinomas of the vulva is a radical vulvectomy with bilateral inguinal–femoral lymphadenectomies [19]. The inguinal lymph nodes are the primary lymphatic drainage for the vulva and lower one-third of the vagina. The lymph node sampling is performed by removing an ellipse of skin in continuity with the underlying fat pad above the cribriform fascia present in the inguinal–femoral subcutaneous tissue. However, the cribriform fascia is difficult to identify in some women or may not be anatomically intact. This treatment can be modified if the tumor is unilateral, in which case a modified radical vulvectomy, effectively a unilateral radical excision of the labia in association with ipsilateral lymphadenectomy, is performed [20]. Data suggest that a woman with a unilateral vulvar cancer having negative ipsilateral inguinal lymph nodes is highly unlikely to have contralateral inguinal lymph node involvement [21]. If the lesion is less than 2 cm in diameter and is associated with minimal invasion (usually 5.0 mm with an extension of not >7.0 mm IB Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than stage IAa IB1 Clinically visible lesion £ 4.0 cm in greatest dimension IB2 Clinically visible lesion >4.0 cm in greatest dimension Stage II IIA IIA1 IIA2 IIB Stage III

IIIA IIIB Stage IV

Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina Without parametrial invasion Clinically visible lesion £ 4.0 cm in greatest dimension Clinically visible lesion > 4 cm in greatest dimension With obvious parametrial invasion The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or nonfunctioning kidneyb Tumor involves lower third of the vagina, with no extension to the pelvic wall Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney

The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV IVA Spread of the growth to adjacent organs IVB Spread to distant organs Source: Reprinted from FIGO Committee on Gynecologic Oncology [175], with permission a All macroscopically visible lesions – even with superficial invasion – are allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.00  mm and a horizontal extension of not >7.00 mm. Depth of invasion should not be >5.00 mm taken from the base of the epithelium of the original tissue – superficial or glandular. The depth of invasion should always be reported in mm, even in those cases with “early (minimal) stromal invasion” (~1 mm) The involvement of vascular/lymphatic spaces should not change the stage allotment. b On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. All cases with hydronephrosis or nonfunctioning kidney are included, unless they are known to be due to another cause

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with cervical cancer, in the developed world, CT, MRI, and 18-F FDG PET scans are routinely ordered and help in planning for the most appropriate treatment modality [65, 66]. Management of invasive cancer of the cervix is by radiation therapy or surgery. Surgery is performed in women with early-stage disease who can tolerate a radical hysterectomy with bilateral pelvic lymph node resection [67]. Patients with microinvasive cancer (2 mg/dl [177 mmol/L]), smoking, chronic obstructive pulmonary disease, peripheral vascular disease, cardiac disease (coronary artery disease, arrhythmias, heart failure), and systolic dysfunction (ejection fraction, 10  mm in maximal thickness or with >5  mm of midline shift are typically removed, regardless of symptoms [10]. The need for surgical evacuation of large asymptomatic chronic SDHs is less clear. Operative intervention for an acute SDH usually requires a generous craniotomy, evacuation of the hematoma, and control of bleeding. Depending on the degree of underlying parenchymal injury and edema, expansion duroplasty and bone flap removal may be necessary to accommodate swelling of the underlying brain and minimize dangerous increases in intracranial pressure (ICP). Operative intervention for a chronic SDH usually involves burr holes and removal of chronic liquefied hematoma via suction and irrigation, often followed by the placement of temporary postoperative subdural drains. A special consideration in the elderly population is the degree of underlying cerebral atrophy. Because the atrophic brain is often unable to expand and fill the subdural space even after the mass effect has been removed, bridging veins remain under tension and at risk for future traumatic injury, and recurrent chronic SDHs often form. Occasionally, craniotomies are performed for chronic SDHs if there is concern for significant membrane formation and therefore inadequate drainage of the loculated subdural hematoma through one or two burr holes. EDHs also occur as a result of trauma, but are much less common than SDHs, with an estimated incidence of 2.7–4.1% in TBI patients [10]. The increased adherence of the dura

mater to the skull in the elderly serves to tamponade bleeding into the epidural space, thus EDHs are unusual in the geriatric population. When present, EDHs are often associated with skull fractures. Traditionally thought to be of primarily arterial origin, recent studies have indicated that EDHs from venous injuries are quite common as well [10]. Clinically, patients with significant EDHs present with focal and diffuse brain pressure findings similar to those with SDHs. Signs and symptoms include headache, nausea/vomiting, diplopia, altered mental status, pupillary dilatation, seizures, dysphasia, and hemiparesis/hemiplegia. Additionally, some patients present with the classic “lucid interval”, an asymptomatic time period immediately following trauma before the onset of symptoms, attributed to the expansion of the hematoma as it slowly dissects between the skull and adherent dura, gradually increasing pressure on the underlying brain. On CT scan, EDHs appear as hyperdense biconvex extra-axial ­collections, which do not cross suture lines (Fig. 86.2a, b). Surgical evacuation of the hematoma is indicated for symptomatic lesions. EDH evacuation usually requires a craniotomy, with or without expansion duroplasty and bone flap removal, based on the extent of the underlying parenchymal injury and edema.

Intracerebral/Subarachnoid Hemorrhage In addition to extra-axial hematomas, patients with traumatic brain injuries often have intra-axial hemorrhages, either within the parenchyma of the brain or in the subarachnoid space. The management of traumatic intracerebral hemorrhages is similar to that of nontraumatic intracerebral ­hemorrhages. These lesions appear as hyperdense intra-axial collections on CT, which can vary in diameter from under a millimeter to several

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Figure 86.2  Noncontrast axial head CTs demonstrate (a) acute epidural hematoma – a ­hyperdense biconvex extra-axial collection and (b) in the same patient, a minimally displaced left frontal skull fracture adjacent to the epidural hematoma, the likely cause of the vascular injury producing the hematoma.

centimeters. Initial treatment should focus on blood pressure control, to prevent rebleeding, and management of ICPs. Frequent neurologic examinations should be performed to assess for acute decompensation and serial imaging studies should be performed to evaluate for rebleeding. In the event of elevated ICPs, medical management should be initiated, and in some cases, surgical decompression is required due to the degree of mass effect (Fig. 86.3) [10, 11]. Subarachnoid hemorrhages are also common sequelae of TBI. Although these hemorrhages seldom require surgical evacuation, they are often associated with seizures, altered mental status, and diffuse axonal injury, all of which can lead to significant morbidity and mortality. On CT, traumatic subarachnoid hemorrhages appear as layered, hyperdense lesions within the subarachnoid spaces, most commonly along the cortical surfaces. Patients with traumatic subarachnoid hemorrhages should be given prophylactic anticonvulsant medications for 7 days posttrauma [12]. Care should be taken in the administration of these medications to the elderly population, as they often have significant side effects including hypotension, cardiac arrhythmias, and confusion. Additionally, for those patients with traumatic subarachnoid hemorrhage and poor neurologic exam in the absence of a focal compressive lesion, placement of an ICP monitor is often required to measure ICPs, which require further management if elevated (Fig. 86.3) [10, 11].

Fractures

Figure 86.3  General schematic for the management of elevated intracra­ nial pressures.

The skull is a protective layer meant to absorb high-energy forces and to prevent direct intracranial parenchymal injury. In doing so, the skull is also placed at risk for fracture in the event of a significant trauma. Skull fractures can be loosely categorized into four groups: linear, depressed, skull base, and open, each of which has unique management strategies.

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Linear fractures are the most common type of skull f­ racture and are usually the result of low-energy trauma over a large surface area. These fractures are nondisplaced, ­seldom require surgical intervention and are treated with observation and expectant management [13]. Depressed skull fractures are usually the result of highenergy trauma over a small surface area. Clinically, depressed skull fractures often manifest with seizures, due to an underlying cortical injury, or as an epidural hematoma, due to laceration of a meningeal artery adherent to the skull. Those fractures that are depressed below the inner table of the adjacent normal bone typically require surgical elevation [13]. Skull base fractures occur in the context of severe trauma and can manifest with a variety of neurologic symptoms [13]. Often, skull base fractures are associated with additional intracranial injuries due to the magnitude of the causative trauma. Most significantly, skull base fractures can cause vascular injuries, commonly to the internal carotid arteries, as well as cerebrospinal fluid (CSF) leaks [14–16]. Therefore, all patients with skull base fractures should undergo computerized tomographic angiography (CTA) to rule out vascular injury [14, 15]. Additionally, they should be monitored closely for the evidence of CSF otorrhea or rhinorrhea. Management of vascular injuries should be deferred to an experienced neurovascular team, which includes both neurosurgeons and neurointerventionalists. Management of CSF leaks includes initial conservative treatment with bed rest and head of bed elevation to reduce the hydrostatic pressure gradient and CSF flow across the dural defect, allowing for the body to seal the breach. If the CSF leak persists despite these conservative measures, CSF diversion using a lumbar drain and/or surgical repair are needed to eliminate the leak to prevent bacterial ingress and subsequent meningitis [16]. Open skull fractures are defined as those lesions with an overlying skin laceration, such that there is a communication between the external environment and the intracranial space. These lesions are at particularly high risk for infection [17]. Open skull fractures often demonstrate significant pneumocephalus on imaging due to the abnormal communication with the external environment. Open skull fractures may be classified as either clean or contaminated. All patients with open skull fractures should receive tetanus toxoid, and those with contaminated fractures should also receive prophylactic antibiotics [17]. In most cases, these injuries require operative exploration for wound cleansing, debridement, and closure [13, 17].

Penetrating Trauma Penetrating brain injury (PBI) refers primarily to gunshot wounds to the head, although all foreign bodies that invade the cranial vault may be included in this group. The ­management

T.R. Patel and J.T. King Jr.

of PBI has undergone fundamental changes since initial descriptions in the early twentieth century, which were based primarily on military injuries. The current literature includes accounts of both civilian and military experiences. The former contains mostly reports of low-velocity injuries and self-inflicted wounds, while the later includes a higher percentage of high-velocity and shrapnel injuries [18]. Regardless of injury etiology, studies of both groups have derived similar conclusions, and current management recommendations are based on Class III evidence from both civilian and military case series [18]. The primary goals in the treatment of PBIs are infection prevention and ICP management. World War I trauma surgeons advocated extensive exploration and debridement of PBIs, with removal of all foreign bodies and bone fragments to decrease the risk of infections and seizures. Subsequent military and civilian studies have indicated that extensive exploration and debridement of PBIs is unnecessary and leads to higher rates of morbidity and mortality [18, 19]. Modern studies have demonstrated that the primary cause of PBI-related infections is a persistent CSF leak [18–20]. As such, during the initial management of a PBI, care should be taken to achieve good local debridement, followed by a watertight dural and scalp closure. Extensive brain debridement should be avoided to prevent injury to normal tissues. Additionally, prophylactic anticonvulsant medications should be given to prevent seizures [18]. Surgical evacuation of large intracranial hematomas may be necessary to manage elevated ICPs, and earlier surgery is associated with better outcomes [18, 21]. Additionally, intraparenchymal or intraventricular ICP monitors are often needed to follow the response to treatment. Increasing age is associated with poorer outcomes in patients with PBIs [22]. However, given that PBIs are relatively uncommon occurrences, and even more uncommon in the geriatric population, analyses of this association have been somewhat limited [22]. Of the studies which have examined the role of age in outcome from PBIs, two have demonstrated that increasing age is associated with higher mortality [21, 23]. It is likely that many of the same mechanisms which contribute to poor outcomes in the elderly from general TBIs play a role in PBIs.

Nontraumatic Vascular Lesions Neurovascular lesions constitute a broad spectrum of pathologies, yet common to each of these disease processes is precipitous neurologic decline from disruption of vital bloodflow to brain tissue. Population studies indicate that neurovascular diseases are more prevalent among the elderly [24]. Moreover, the geriatric population appears to fare worse from

86  Geriatric Neurosurgical Emergencies

neurovascular diseases than their younger counterparts [3]. This finding has significantly affected the treatment strategies for the elderly.

Aneurysms The accepted prevalence of intracranial aneurysms is 5% of the total population, although the prevalence in autopsy series has ranged from 0.2 to 7.9% [25–27]. It is postulated that most intracranial aneurysms develop as a result of combined hypertension, atherosclerosis, cigarette smoking, and congenital predisposition [27]. Most commonly, these lesions develop in the intracranial anterior circulation arterial blood vessels – carotid, anterior cerebral, middle cerebral, anterior communicating, and posterior communicating arteries – although posterior circulation aneurysms of the vertebrobasilar and posterior cerebral arteries account for approximately 15% of all lesions [25]. Ruptured intracranial aneurysms are one of the most devastating and challenging neurosurgical emergencies. The majority of ruptured intracranial aneurysms cause sudden-onset of worst headache of life, focal neurologic deficits, and symptoms of increased ICPs (nausea, vomiting, headache, and decreased level of consciousness). Brain imaging shows acute subarachnoid hemorrhage (SAH), although intraventricular and intraparenchymal hemorrhages are not uncommon (Fig. 86.4a, b) [25]. The initial management of these patients focuses on the treatment of elevated ICPs and strict blood pressure control to prevent aneurysm

Figure 86.4  (a) Noncontrast head CT demonstrates diffuse subarachnoid hemorrhage throughout the basal cisterns and bilateral Sylvian fissures, from a ruptured intracranial aneurysm and (b) contrast-enhanced cerebral CT angiogram reveals bilateral middle cerebral artery aneurysms (single arrows).

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rebleeding [28]. Additionally, the patient must be monitored closely for evidence of neurologic deterioration, which may be indicative of rebleeding, seizures, or hydrocephalus. Systolic blood pressures should be maintained 70 years) have been deemed poor candidates for surgical or endovascular treatment [40–44], based on the worse neurological condition of older patients when compared with their younger counterparts [42]. Elderly patients were traditionally treated conservatively, with only medical management of their SAH symptoms. Not surprisingly, this led to very poor outcomes, with the vast majority (>75%) of elderly patients suffering severe morbidity and mortality [40, 43]. Evidence showing improved outcomes in elderly patients who receive surgical or endovascular treatment when compared with medical management [43] has spurred a recent

T.R. Patel and J.T. King Jr.

trend toward offering geriatric patients with aneurysmal SAH definitive treatment for their aneurysm. However, it is clear that even with treatment, the geriatric population fares worse than their younger counterparts [42]. Using data from a multicenter randomized trial, it was found that with advancing age, patients have significantly worse admission neurological exams, thicker subarachnoid clots, and higher rates of intraventricular hemorrhage, hydrocephalus, and aneurysm rebleeding [42]. Additionally, older patients have higher incidences of preexisting medical comorbidities [42]. Interestingly, in this study, there were no age-related differences in time to presentation, timing of surgery, aneurysm size and location, or surgical complications. After controlling for the above factors, increasing age was still significantly associated with a poorer outcome [42]. This was thought to be related to the impaired ability of the aging brain to recover from acute stress, as well as the overall diminished cardiovascular reserve in older patients, which can lead to suboptimal cerebral perfusion [6, 42]. As endovascular technology evolves, it is likely that it will be used with increasing frequency in the elderly as a means to mitigate the risk of open surgery while still offering definitive therapy [41]. Regardless, it is clear that geriatric patients have better ­outcomes with definitive treatment than conservative treatment, although outcomes are worse than those in younger patients.

Vascular Malformations CNS vascular malformations are congenital vascular lesions that fall into four categories: arterio-venous malformations (AVMs), capillary telangiectasias, venous angiomas, and cavernous malformations [25]. Of these, AVMs are most prone to hemorrhages requiring emergency neurosurgical care and will therefore be the focus of this discussion. The prevalence of intracranial AVMs is not well known; hospital-based autopsy estimates range from 5 to 613 AVMs per 100,000 persons [45]. Anatomically, AVMs represent abnormal tangles of arteries and veins, with an absence of normal intervening capillary architecture, resulting in highflow arterio-venous shunting [25, 45]. AVMs are congenital and occur throughout the CNS [45]. Although they may cause a variety of neurologic symptoms, the most common presentation is intracranial hemorrhage (ICH), which is a neurologic emergency (Fig. 86.5a–c) [25, 46]. The management of AVM-related ICHs begins with strict blood pressure control to prevent rebleeding. Subsequently, if there is evidence of increased ICPs, medical management should be initiated, as previously described (Fig.  86.3) [10, 11]. If significant mass effect and concern for herniation exists, surgical evacuation of AVM-related ICHs can be

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Figure 86.5  (a) Noncontrast head CT demonstrates a large left frontotemporo-parietal intracranial hemorrhage with associated intraventricular hemorrhage, mass effect, and midline shift, (b) contrast-enhanced

cerebral CT angiogram reveals an underlying arterio-venous malformation, and (c) cerebral catheter angiogram confirms the presence of a large arterio-venous malformation.

p­ erformed; however, the surgical approach is much different than that for typical ICHs and is beyond the scope of this discussion. If possible, it is preferable to stabilize the patient medically and treat the AVM in a nonacute setting. Treatment options include open surgical resection, radiosurgery, and endovascular embolization. Most AVMs are diagnosed at an early age (~35  years), and patients who present with hemorrhage are even younger (~31  years) [45, 47]. Prospective data indicate that the patients at highest risk for future hemorrhages are those who have AVMs with deep locations, exclusively deep venous drainage, and a history of previous AVM-related ICH [48]. Additionally, the risk of future hemorrhages increases with age [48]. Given the rarity of this disease, there are no data on specific or different treatment strategies for the elderly population. However, it is likely elderly patients are more often treated with less invasive methods (i.e., radiosurgery and endovascular embolization) when possible, due to the perceived increased risks of open surgery with advanced age.

less frequent than ischemic strokes, they have much higher rates of associated death and disability [3]. Specifically, the 1-year mortality rate following hemorrhagic stroke is approximately 62% [24]. The most common risk factor for hemorrhagic stroke is hypertension, which is the focus of this discussion [24]. Amyloid angiopathy is also a significant cause of hemorrhagic stroke and will be discussed in detail later in this chapter. Advancing age, male sex, and alcohol and tobacco use are known risk factors for hypertensive hemorrhagic stroke (HHS). Additionally, blacks have an incidence of HHS that is twice that of whites [24]. HHSs most commonly occur from the rupture of small intracranial perforator arteries in deep regions of the brain (e.g., basal ganglia and brainstem), although cortical and cerebellar hemorrhages occur as well (Fig. 86.6) [24, 25, 50]. The initial management of HHS patients focuses on strict blood pressure control and treatment of elevated ICPs (Fig. 86.3) [10, 11]. The INTERACT randomized controlled trial demonstrated that intensive blood pressure control reduces subsequent hematoma growth, although clinical outcome data are lacking [51]. The role of surgical evacuation in the treatment of HHS is controversial. A recent randomized controlled trial (STICH) evaluated the role of early surgical intervention in supratentorial ICHs and determined that there was no overall benefit from early surgery as compared to initial medical management [49]. Given the deep location of many of these hemorrhages and the need to traverse normal intervening brain to evacuate them, it is not surprising that there was no clear benefit with surgical intervention in this study. On the other hand, anecdotal evidence suggests that superficial supratentorial HHSs with significant mass effect

Stroke Cerebrovascular accidents, or strokes, are a leading cause of morbidity and mortality, especially among the elderly [3]. Strokes can be either hemorrhagic or ischemic, both of which constitute neurologic emergencies that may require surgical intervention. Hemorrhagic strokes affect approximately 10–20 per 100,000 people each year [24, 49]. Although these events are

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trials (DESTINY, HAMLET, and DECIMAL) have been performed to evaluate the efficacy of early surgical decompression via hemicraniectomy and durotomy, to relieve the mass effect of the infracted and edematous brain [55–57]. The pooled analysis of these trials demonstrates a significant reduction in mortality; however, overall patient morbidity and functional outcomes remain unchanged despite surgical decompression [54]. It should be noted that these trials did not include patients greater than 60 years of age and therefore, surgical intervention in elderly patients should be considered on a case-by-case basis.

Amyloid Angiopathy

Figure 86.6  Noncontrast head CT demonstrates an acute basal ganglia hemorrhage with mass effect and intraventricular extension.

may respond well to surgical decompression and therefore these patients should be evaluated on a case-by-case basis with the assistance of a neurosurgical team. Alternatively, HHSs in the cerebellum respond much more favorably to surgical evacuation. Cerebellar hemorrhages have a propensity for early hydrocephalus and brainstem compression [24]. Craniotomy and decompression is the definitive treatment for this process and studies have shown that those patients with large cerebellar hematomas (volume greater than 40 mL) have a clear benefit from surgical intervention [24, 52]. Of note, significant research has also been performed to ascertain the role of recombinant-activated factor VIIa (rFVIIa) in the treatment of acute ICHs, including HHSs. The final results of the phase 3 randomized controlled trial (FAST) demonstrated that although rFVIIa reduces the growth of the hematoma, it does not result in any significant improvements in survival or functional outcome, and therefore, the use of rFVIIa for acute ICHs has not become part of standard practice [53]. Ischemic strokes (IS) account for the vast majority of all strokes, with an incidence of 300–500 cases per 100,000 people each year [3]. In general, management of IS should be directed by a neurology team. On rare occasions, IS may require surgical intervention. The role of surgical intervention has been well examined in patients with a “malignant” MCA infarction, where swelling from the damaged brain can cause rapid neurological deterioration and 1-year mortality rates reach up to 80% [54–57]. Several randomized ­controlled

Cerebral amyloid angiopathy (CAA) is an important cause of nontraumatic ICH, comprising approximately 10% of all ICHs and 30% of all lobar ICHs [25, 58]. Moreover, this pathology has a predilection for the elderly population, making its review particularly germane to this discussion [25, 58]. CAA is characterized by the deposition of beta-amyloid, a fibrillar protein, in the media and adventitia of small- and medium-sized arteries [25, 58]. The exact prevalence of CAA is difficult to determine due to the lack of definitive histopathology in most cases; however, it is well known that the prevalence of CAA increases with age and it is rarely identified in those less than 55 years of age [58]. CAA has an equal predilection for both sexes. Approximately 1/3 of ­people greater than 60 years of age have evidence of CAA on autopsy, and in individuals over 90 years of age, the prevalence of CAA exceeds 60% [58]. Studies have also demonstrated that those individuals who possess the E2 and E4 alleles of the apolipoprotein E gene have a significantly increased risk of developing CAA [25, 58]. Although CAA can cause progressive dementia, transient ischemic attacks, seizures, and ischemic stroke, arguably the most concerning manifestation is ICH, caused by the rupture of amyloid-laden vasculature [25, 58]. These hemorrhages are most frequently lobar and can be multifocal [25, 58]. The management of ICHs due to CAA is not significantly different from the management of hypertensive ICHs. Most hemorrhages do not require surgical intervention; however, if significant mass effect and neurologic deficits exist, craniotomy for evacuation and decompression can be considered. Unlike cerebral aneurysms and AVMs, ICHs due to CAA do not require treatment of a discrete, underlying vascular abnormality. Although the vasculature is altered in patients with CAA, it does not require unique surgical maneuvers to control bleeding. In contrast with ICHs due to hypertension, CAAassociated ICHs are typically more superficial and therefore more amenable to surgical intervention [25, 58]. Although no specific pharmacotherapy exists for the treatment of CAA,

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there is ongoing research into the development of antiamyloid medications and vaccinations [58]. Additionally, as discussed above, the use of rFVIIa has not resulted in a significant clinical benefit in this patient population [53].

Adverse Drug Reactions As the population ages, the use of antiplatelet and anticoagulant medications such as aspirin, clopidogrel, and warfarin, has increased dramatically. Protocols for managing patients with acute ischemic stroke using thrombolytic therapies, such as intravenous and intraarterial tissue plasminogen activator (tPA), have become more common [59]. Traditional guidelines recommend administration of tPA within 3 h of onset of stroke symptoms; however, many stroke centers now aim to administer tPA in an urgent fashion, within 60 min of onset of symptoms, for embolic stroke [59]. Given the potency of these medications, it is not surprising that some of their primary side effects include undesired bleeding, including ICHs [60, 61]. Patients who receive tPA and have early hypodensities on CT have significantly higher rates of ICH [62]. Patients who develop ICHs secondary to antiplatelet or anticoagulant therapies should have the offending medications discontinued immediately, followed by reversal of the platelet dysfunction and/or anticoagulation with the appropriate blood products and/or medications. The remainder of their management should follow that of other nontraumatic ICHs; strict blood pressure control should be employed and surgical decompression considered on a caseby-case basis for those patients with significant mass effect. In a study of surgical evacuation of ICH following administration of streptokinase for acute myocardial infarction, surgery was beneficial, although survival was dependent upon the time from the initiation of thrombolytic therapy to onset of stroke symptoms, initial Glasgow coma scale score, volume of ICH, and “baseline clinical characteristics” (defined as age, systolic blood pressure, Killip class, heart rate, infarct location, previous myocardial infarction, height, time to treatment, history of smoking, current smoking, diabetes, weight, history of coronary bypass surgery, type of thrombolytic agent, history of hypertension, and history of cerebrovascular disease) [63]. Importantly, all patients who are started on antiplatelet and anticoagulant medications should be counseled about the potential risk of ICH.

Sinus Thrombosis Intracranial venous sinus thrombosis (VST) is a relatively rare condition that constitutes a neurologic emergency.

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There are several factors which predispose individuals to developing VSTs, including: a hypercoagulable state, dehydration, adjacent tumor or infection, pregnancy, vasculitis, systemic inflammatory disorders, and local trauma [25, 64]. Although most intracranial VSTs become evident through headache and other symptoms of increased ICPs, a significant portion of patients develop seizures, intracranial infarcts, ICHs, or focal motor deficits [25, 64]. VSTs cause venous outflow obstruction and subsequent parenchymal edema and infarction [25, 64]. The primary goal in the treatment of VSTs is the prevention of thrombus propagation while allowing for natural thrombolysis and recanalization of the affected vessel. This is achieved with anticoagulation and is typically managed by a neurology team [25, 64]. However, endovascular thrombolysis of the clot/affected vessel using pharmacologic and mechanical techniques is sometimes indicated, and in cases with large ICHs, surgical decompression and evacuation is occasionally performed [64]. As compared to intracranial arterial thromboses, VSTs have an overall better prognosis [64]. In the largest series to date of patients with VSTs, there was a 13% rate of death or dependence at 6  months after ictus [64]. Risk factors associated with poor outcome include advancing age, male sex, altered mental status on admission, deep cerebral venous system thrombosis, ICH, malignancy, and CNS infection [64].

Infection Infections of the CNS are neurological emergencies, which must be treated in a timely fashion. Generally, CNS infections can be categorized by their location: meningeal, subdural, epidural, intraparenchymal, and intraventricular. Most CNS infections have bacterial, viral, or fungal etiologies; this discussion will focus on bacterial infections, as these most commonly require surgical intervention. Additionally, this discussion will be limited to intracranial CNS infections; a review of spinal CNS infections can be found in Chap. 87. Infections of the meninges, also known as meningitis, are the most common intracranial CNS infection [25]. Patients typically develop fever, headache, neck stiffness, photophobia, and malaise. Contrast-enhanced imaging studies often reveal diffuse meningeal enhancement, and CSF analysis demonstrates elevations in the nucleated white blood cell count. As meningitis is most often managed medically, without the need for surgical intervention, further discussion of its management is beyond the scope of this discussion. Infections of the epidural space, also known as epidural abscesses (EA), comprise approximately 2% of intracranial CNS infections [65]. These infections present with fever, headache, neck stiffness, photophobia, periorbital swelling,

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scalp tenderness, ear pain, nausea, vomiting, and lethargy. Imaging studies reveal an extra-axial, biconvex lesion with peripheral enhancement. Imaging studies may also reveal evidence of underlying osteomyelitis, sinusitis, or mastoiditis. Cranial EAs typically occur via direct extension of an adjacent sinusitis, although they may also be the result of hematogeneous spread from infections located throughout the body. They most commonly occur in adolescent males, though all age groups may be affected [65]. Treatment of cranial EAs involves surgical evacuation, followed by prolonged antibiotic therapy. If the adjacent bone appears to be involved, it must also be debrided and/or removed [65]. The most commonly isolated organisms in cranial EAs are microaerophilic or hemolytic streptococci; however, staphylococci may also be involved in cases of postoperative or posttraumatic infections [65]. Subdural infections, also known as subdural empyemas (SE), occur in 12–25% of intracranial CNS infections [65]. These infections present similarly to cranial EAs; however, focal neurologic deficits are more common given the direct contact with the cortical surface [65, 66]. Imaging studies reveal extra-axial, crescent-shaped collections with peripheral enhancement. As with cranial EAs, there is often evidence of adjacent osteomyelitis, sinusitis, or mastoiditis. Intracranial SEs typically occur in the setting of sinusitis, via direct extension or hematogenous spread, but may also occur as a result of trauma or neurosurgical intervention [65, 66]. Treatment involves prompt surgical evacuation, followed by prolonged antibiotic therapy [65, 66]. The most commonly isolated organisms in intracranial SEs are aerobic and anaerobic streptococci species, as well as staphylococci species [65, 66].

Intraparenchymal intracranial CNS infections, also known as brain abscesses (BA), are occurring with increasing ­frequency as the prevalence of immunocompromised individuals rises [65]. These infections cause fevers, headache, meningismus, malaise, seizures, and focal neurologic ­deficits – and they most often have a rapid progression of symptoms. On contrasted imaging studies, BAs appear as intra-axial lesions with marked peripheral enhancement and restricted diffusion on MRI (Fig.  86.7a–c). They can occur in the ­setting of sinusitis and mastoiditis, but are also commonly the result of bacteremia in the setting of congenital heart defects, bacterial endocarditis, dental abscesses, pulmonary infections, and acute diverticulitis [65]. Treatment consists of abscess drainage, often with the use of intra-operative stereotactic navigation systems, followed by prolonged antibiotic therapy [65]. The most commonly isolated organisms include aerobic and anaerobic streptococci and bacteroides species, staphylococci species, and fungal organisms in the immunocompromised [65]. Intraventricular CNS infections are rare entities. They commonly cause signs and symptoms of obstructive hydrocephalus: headache, nausea, vomiting, lethargy, and coma [25, 65]. Most often, intraventricular infections are caused by parasites (i.e., neurocysticercosis) [25]. Imaging studies reveal an intraventricular mass with a variable enhancement pattern and evidence of obstructive hydrocephalus. Surgical management of these lesions is usually curative. Medical management using antihelminthics remains controversial and should be discussed with an infectious disease specialist [25]. Of note, bacterial ventriculitis may also develop in the setting of a prolonged intracranial bacterial infection.

Figure  86.7  (a) Contrast-enhanced head CT demonstrates multiple hypodense ring-enhancing lesions, (b) T1-weighted contrast-enhanced brain MRI demonstrates multiple hypodense ring-enhancing lesions

with surrounding edema, and (c) diffusion-weighted brain MRI reveals restricted diffusion throughout the enhancing lesions, consistent with multiple brain abscesses.

86  Geriatric Neurosurgical Emergencies

As with ­intraventricular parasitic infections, individuals with bacterial ventriculitis typically develop symptoms of hydrocephalus. Imaging studies reveal diffusely enhancing ventricular walls. Management includes CSF diversion for elevated ICPs and prolonged antibiotic therapy. With the exception of meningitis, most CNS infections require neurosurgical intervention. Risks of prolonged, untreated CNS infections include VST, osteomyelitis, hydrocephalus, seizures, and catastrophic intraventricular BA rupture. Importantly, in the management and initial work-up of CNS infections, lumbar puncture is often considered. Although this can be performed safely in most patients with simple meningitis, for those patients with intracranial mass lesions, lumbar puncture should be deferred due to the risk of causing cerebral herniation [25]. Additionally, significant controversy exists regarding the use of steroids in the context of CNS infections [25]. This issue is best dealt with on a case-by-case basis, after careful review of the particular clinical scenario. Most CNS infections tend to occur in the young; however, the elderly population deserves special consideration for several reasons. First, geriatric patients often have nonspecific signs and symptoms in the setting of infection [3, 67]. This increases the need for vigilant physical examination and CNS imaging studies in this population. Additionally, the elderly population has a relative immunosenescence, therefore, their clinical course and response to therapy may be worse than a younger counterpart with a similar illness [67]. Finally, the elderly tend to have more frequent and more severe adverse drug effects, especially from antibiotics, and this should be taken into account when choosing the appropriate drug regimen [67].

Peripheral Nerve Injury Traumatic peripheral nerve injuries (PNIs) are relatively rare occurrences and are treated by a variety of specialists, including neurosurgeons, plastic surgeons, and orthopedic surgeons [68, 69]. Despite their rarity, PNIs can result in devastating functional loss and represent an important neurologic emergency. Clinically, they typically present in the setting of trauma with neurologic deficit confined to a single extremity [70]. PNIs often occur in tandem with bony fractures and peripheral vascular injuries [70]. Traumatic PNIs can be loosely categorized into three broad groups based on mechanism: stretch/avulsion injuries, lacerating injuries, and compressive injuries [71]. Stretch and avulsion injuries are the most common types of PNI [70, 71]. They are usually the result of motor vehicle accidents in which the torsional force of impact results in the movement of an extremity in one direction and the patient’s

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trunk in another [70]. This results in a stretching of nerve roots, which, if severe enough, can cause complete nerve root avulsion from the spinal cord. Spinal imaging studies may reveal pseudomeningoceles indicative of dural nerve root sleeve disruption and adjacent soft tissue injury. Penetrating and lacerating PNIs typically occur as a result of gunshot and knife wounds. They are the second most common type of PNI and are often associated with injuries of adjacent vascular structures [70, 71]. These injuries are usually discovered on physical exam, as the external signs of trauma can be quite obvious. Compressive PNIs often occur as a result of local hematomas, soft tissue swelling, and bony hypertrophy. They cause indirect neural injury via external compression [71]. Operative interventions for PNIs vary widely based on the mechanism of injury, extent of neurologic deficit, presence of additional injuries, and surgeon preference [72, 73]. Surgical interventions may involve decompression, direct repair, removal of neuromas, and nerve grafting or transposition [72, 74]. Nearly all interventions employ the use of preand postoperative electromyography, and intraoperative nerve action potential and somatosensory evoked potential recordings [72]. Given the increased incidence of osteoporosis and bony fractures in the elderly, it is likely that they are at increased risk for PNIs in the setting of trauma. Therefore, since early identification of PNIs can maximize the potential for a functional recovery, it is imperative that elderly patients undergo complete neurologic examination as part of their trauma evaluation.

Tumors Intracranial primary or metastatic tumors can cause medical emergencies via mass effect from tumor growth, edema in the surrounding brain, intratumoral hemorrhage, or seizures. Initial management should focus on the treatment of elevated ICP symptoms, blood pressure control, and seizure cessation. Further discussion of these lesions can be found in Chap. 87.

Conclusions Geriatric neurosurgical emergencies encompass a broad range of pathologies. Elderly patients have unique treatment challenges that must be accounted for by healthcare providers. The loss of cardiovascular reserve and the fundamental changes within the aging CNS appear to play a significant role in morbidity and mortality and should be carefully considered when treating and counseling geriatric patients with neurosurgical illnesses.

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Case Study History An 82-year-old male, with multiple medical problems, seeks medical attention after the acute onset of worst headache of life. He also notes nausea, photophobia, and neck pain. He denies trauma, numbness, weakness, tingling, seizures, chest pain, and shortness of breath. A noncontrast head CT (Fig. 86.8a) is obtained and the patient is subsequently transferred to a tertiary care center. During transfer, the patient is noted to become progressively lethargic. Past Medical History 1 . Hypertension 2. Coronary artery disease 3. Chronic renal failure 4. Type II diabetes mellitus 5. Atrial fibrillation Admission Neurologic Examination Temp: 99.1 degrees Fahrenheit, HR: 70 beats per minute, BP: 160/70 mmHg, RR: 10 breaths per minute, O2, Sat: 98% on 4 liters nasal cannula Lethargic, nonverbal

Figure  86.8  (a) Noncontrast head CT demonstrates diffuse subarachnoid hemorrhage involving the bilateral Sylvian fissures as well as intraventricular hemorrhage and hydrocephalus and

T.R. Patel and J.T. King Jr.

Opens eyes to noxious stimuli Pupils equally round and reactive to light, bilaterally Moving all extremities symmetrically, not following commands Localizes to noxious stimuli Unable to assess sensory function 2+ deep tendon reflexes throughout Toes downgoing, bilaterally

Relevant Admission Laboratory Values Na: 138 Troponin-I: 0.40 WBC: 8.9 k PLT: 228 k INR: 2.8

Clinical Course Upon arrival to the tertiary care center, the patient is intubated for airway protection. Subsequently, he is treated for hypertension and his systolic blood pressure is maintained below 140 mmHg. He is also given 1 g of IV phenytoin for seizure prophylaxis and 6  U of fresh frozen plasma to normalize coagulation. A cerebral CT angiogram is obtained (Fig.  86.8b), which demonstrates an anterior communicating artery aneurysm. The patient is

(b) contrast-enhanced cerebral CT angiogram reveals an anterior communicating artery aneurysm (single arrow)

(continued)

86  Geriatric Neurosurgical Emergencies

Case Study  (continued) transferred to the intensive care unit. His head of bed is elevated to 30°, he is sedated and hyperventilated, and a ventriculostomy catheter is placed to decompress hydrocephalus and manage elevated intracranial pressures. The patient’s examination improves over the next 24 h; specifically, he begins to follow commands. An echocardiogram is obtained because of the abnormally elevated cardiac enzymes. The patient is found to have an ejection fraction of 35%. A family discussion is held regarding the risks and benefits of treatment and the decision is made to pursue endovascular therapy. The following day, the patient is taken to the angiography suite where he undergoes successful coil embolization of his intracranial aneurysm. Over the next 2 weeks, he is monitored carefully in the intensive care unit for evidence of vasospasm. His hydrocephalus resolves during this time and the ventriculostomy catheter is discontinued. His neurologic exam slowly improves, although his cognitive function appears somewhat diminished to his family members. He is extubated successfully. His ejection fraction also improves to 45% over this time period. He is later transferred to the floor and subsequently to a rehabilitation facility.

Discussion Questions 1. What are the most important initial measures that should be taken when caring for a patient with a ruptured intracranial aneurysm? 2. What are the possible etiologies of the patient’s change in mental status during transfer to the tertiary care facility? 3. What is the clinical and operative significance of the elevated cardiac enzymes on admission? 4. What is the current standard of care for treatment of ruptured intracranial aneurysms in the elderly?

Discussion Answers 1. The most important initial measures to be taken when caring for a patient with a ruptured intracra-

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nial ­aneurysm include: strict blood pressure control, administration of prophylactic anticonvulsant ­medications, and ­management of elevated intracranial pressures, if present. 2. Possible etiologies of the patient’s change in mental status during transfer include: aneurysm rebleeding, hydrocephalus, and seizure. 3. Elevated cardiac enzymes in the setting of subarachnoid hemorrhage are associated with an increased risk of cardiogenic shock, pulmonary edema, and cerebral vasospasm. Elevated cardiac enzymes are also associated with higher rates of death and severe disability following aneurysmal subarachnoid hemorrhage. Therefore, when caring for patients with elevated cardiac enzymes, careful attention should be paid to optimizing their cardiopulmonary status. Moreover, in the setting of acutely elevated cardiac enzymes, it is often more judicious to treat patients with less invasive procedures (i.e., endovascular treatments) as opposed to maximally invasive procedures (i.e., open surgery), in order to minimize the degree of cardiac stress. 4. The current standard of care for treatment of ruptured intracranial aneurysms in the elderly is definitive surgical or endovascular repair in order to secure the aneurysm and prevent rebleeding. Aneurysm location, size, and configuration will often determine whether open surgery or endovascular techniques are the optimal approach to aneurysm repair. However, the patient’s overall systemic health should be evaluated, and if significant comorbidities exist, strong consideration should be given to less invasive endovascular procedures, even if open surgery might provide a more definitive repair. Previously, elderly patients were treated with conservative, medical management without aneurysm repair. However, longterm studies have demonstrated that elderly patients have significantly better outcomes with definitive management and thus, this has become the standard of care. Nonetheless, elderly patients still fare worse than their younger counterparts, and as such, providers should have an open discourse with the patient and their family to discuss the potential need for longterm hospitalization, rehabilitation, and home care, so that treatment plans are made in accordance with the patient’s wishes.

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86  Geriatric Neurosurgical Emergencies 44. Elliott JP, Le Roux PD (1998) Subarachnoid hemorrhage and ­cerebral aneurysms in the elderly. Neurosurg Clin N Am 9:587–594 45. Stapf C, Mohr JP, Pile-Spellman J, Solomon RA, Sacco RL, Connolly ES Jr (2001) Epidemiology and natural history of arteriovenous malformations. Neurosurg Focus 11:e1 46. Drake CG (1979) Cerebral arteriovenous malformations: considerations for and experience with surgical treatment in 166 cases. Clin Neurosurg 26:145–208 47. Stapf C, Mast H, Sciacca RR et al (2003) The New York Islands AVM Study: design, study progress, and initial results. Stroke 34:e29–e33 48. Stapf C, Mast H, Sciacca RR et al (2006) Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology 66:1350–1355 49. Mendelow AD, Gregson BA, Fernandes HM et al (2005) Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 365:387–397 50. Brott T, Broderick J, Kothari R et  al (1997) Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 28:1–5 51. Anderson CS, Huang Y, Wang JG et al (2008) Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol 7:391–399 52. Kobayashi S, Sato A, Kageyama Y, Nakamura H, Watanabe Y, Yamaura A (1994) Treatment of hypertensive cerebellar hemorrhage–surgical or conservative management? Neurosurgery 34: 246–250, discussion 50–1 53. Mayer SA, Brun NC, Begtrup K et al (2008) Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 358:2127–2137 54. Vahedi K, Hofmeijer J, Juettler E et al (2007) Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 6:215–222 55. Vahedi K, Vicaut E, Mateo J et al (2007) Sequential-design, multicenter, randomized, controlled trial of early decompressive craniectomy in malignant middle cerebral artery infarction (DECIMAL Trial). Stroke 38:2506–2517 56. Juttler E, Schwab S, Schmiedek P et  al (2007) Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY): a randomized, controlled trial. Stroke 38:2518–2525 57. Hofmeijer J, Amelink GJ, Algra A et al (2006) Hemicraniectomy after middle cerebral artery infarction with life-threatening edema trial (HAMLET). Protocol for a randomised controlled trial of decompressive surgery in space-occupying hemispheric infarction. Trials 7:29 58. Thanvi B, Robinson T (2006) Sporadic cerebral amyloid angiopathy–an important cause of cerebral haemorrhage in older people. Age Ageing 35:565–571 59. Adams HP Jr, del Zoppo G, Alberts MJ et al (2007) Guidelines for the early management of adults with ischemic stroke: a guideline

1149 from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 38:1655–1711 60. Wardlaw JM, Sandercock PA, Berge E (2003) Thrombolytic therapy with recombinant tissue plasminogen activator for acute ischemic stroke: where do we go from here? A cumulative meta-analysis. Stroke 34:1437–1442 61. Heuschmann PU, Kolominsky-Rabas PL, Roether J et  al (2004) Predictors of in-hospital mortality in patients with acute ischemic stroke treated with thrombolytic therapy. JAMA 292:1831–1838 62. Toni D, Fiorelli M, Bastianello S et al (1996) Hemorrhagic transformation of brain infarct: predictability in the first 5 hours from stroke onset and influence on clinical outcome. Neurology 46:341–345 63. Mahaffey KW, Granger CB, Sloan MA et al (1999) Neurosurgical evacuation of intracranial hemorrhage after thrombolytic therapy for acute myocardial infarction: experience from the GUSTO-I trial. Global Utilization of Streptokinase and tissue-plasminogen activator (tPA) for Occluded Coronary Arteries. Am Heart J 138:493–499 64. Ferro JM, Canhao P, Stam J, Bousser MG, Barinagarrementeria F (2004) Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 35:664–670 65. Hall WA, Truwit CL (2008) The surgical management of infections involving the cerebrum. Neurosurgery 62(Suppl 2):519–530, discussion 30-1 66. Osborn MK, Steinberg JP (2007) Subdural empyema and other suppurative complications of paranasal sinusitis. Lancet Infect Dis 7:62–67 67. Gavazzi G, Krause KH (2002) Ageing and infection. Lancet Infect Dis 2:659–666 68. Laws ER Jr (2003) Peripheral nerve surgery. J Neurosurg 98: 1157–1158 69. Maniker A, Passannante M (2003) Peripheral nerve surgery and neurosurgeons: results of a national survey of practice patterns and attitudes. J Neurosurg 98:1159–1164 70. Kim DH, Murovic JA, Tiel RL, Kline DG (2004) Mechanisms of injury in operative brachial plexus lesions. Neurosurg Focus 16:E2 71. Burnett MG, Zager EL (2004) Pathophysiology of peripheral nerve injury: a brief review. Neurosurg Focus 16:E1 72. Kim DH, Cho YJ, Tiel RL, Kline DG (2003) Outcomes of surgery in 1019 brachial plexus lesions treated at Louisiana State University Health Sciences Center. J Neurosurg 98:1005–1016 73. Belzberg AJ, Dorsi MJ, Storm PB, Moriarity JL (2004) Surgical repair of brachial plexus injury: a multinational survey of experienced peripheral nerve surgeons. J Neurosurg 101:365–376 74. Kim DH, Murovic JA, Tiel RL, Kline DG (2004) Penetrating injuries due to gunshot wounds involving the brachial plexus. Neurosurg Focus 16:E3

Chapter 87

Benign and Malignant Tumors of the Brain Andrew D. Norden and Elizabeth B. Claus

Introduction Data from the Central Brain Tumor Registry of the United States (CBTRUS) indicate that approximately 23,000 Americans were expected to be diagnosed with a primary cancer of the central nervous system (CNS) in 2007 [1]. The incidence rate of all primary malignant CNS tumors in the USA is estimated at 7.3 cases per 100,000 people annually [1]. Brain tumors are increasingly common as people age; approximately 15% of primary malignant brain tumors are diagnosed in individuals aged 70 years or more [2]. Survival rates among patients diagnosed with primary malignant brain tumors vary inversely with age. For example, among patients between the ages of 45 and 54, the 5-year survival rate is 24%, while this rate is only 5% for patients who are at least 75 years old (Table 87.1) [1]. In addition to those with primary brain tumors, up to 150,000 Americans are diagnosed each year with metastatic brain lesions [3], and many of these are elderly patients. This chapter provides a review and discussion of epidemiology and treatment of elderly patients with brain tumors. The focus is on primary tumors, but metastatic lesions will be addressed briefly as well.

Epidemiology and Prognosis Glioma Most primary brain tumors among the elderly are thought to be derived from glial cells and are therefore known as gliomas. Glial cells make up the supporting cells of the brain and assist neurons with a variety of structural, protective, and metabolic functions. Subcategories of glioma include A.D. Norden (*) Department of Neurology, Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, 44 Binney St, Boston, MA 02115, USA e-mail: [email protected]

astrocytoma, oligodendroglioma, and mixed glioma. According to the World Health Organization (WHO) classification, gliomas receive a histopathologic grade on the basis of microscopic features including cellularity, nuclear atypia, mitotic activity, vascular proliferation, and necrosis [4]. WHO grade I gliomas are typically localized, noninfiltrating lesions that occur predominantly in the pediatric population. Grade II tumors are diffuse, infiltrative neoplasms that usually occur in young adults with a mean age of 39 years [5]. Among elderly patients, the majority of gliomas are highgrade or malignant gliomas (Table 87.2). Subtypes include glioblastomas (GBM; WHO grade IV), anaplastic astrocytomas (WHO grade III), anaplastic oligodendrogliomas (WHO grade III), and anaplastic oligoastrocytomas (WHO grade III). GBMs are the most common malignant brain tumors in elderly patients; they represent nearly 20% of all brain tumors in adults and have an incidence rate of 3.1 per 100,000 person years. The median age of diagnosis is 64 years, and these tumors are 1.7 times more common in males [1]. Despite a number of recent advances, median survival among newly diagnosed GBM patients younger than 70 years who receive optimal therapy is only 14.6 months [6]. Fewer than 4% of patients achieve 5-year survival [1]. Most data suggest that elderly patients with newly diagnosed GBM have a median survival of less than 9 months [7, 8]. Indeed, age is among the most important prognostic factors in GBM [9]. An emerging body of literature suggests that molecular differences in brain tumors may explain prognostic variability between patients of different ages [10]. In one study of 140 GBM specimens, the prognostic significance of TP53 mutations, epidermal growth factor receptor amplification, CDKN2A/ p16 alterations, and loss of chromosome 1p depended upon patient age [11].

Meningioma Meningiomas are the most common primary intracranial tumors diagnosed in adults of all ages [1]. The prevalence

R.A. Rosenthal et al. (eds.), Principles and Practice of Geriatric Surgery, DOI 10.1007/978-1-4419-6999-6_87, © Springer Science+Business Media, LLC 2011

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Table  87.1  Five-year survival rates among patients with primary malignant brain tumors of the CNS Age (years) Five-year survival rate (%) 0–19 66.0 20–44 49.2 45–54 24.0 55–64 11.1 65–74   6.7 75 +   4.7 Source: CBTRUS (2008). Statistical Report: Primary Brain Tumors in the United States, 2000–2004. Published by the Central Brain Tumor Registry of the United States [1]

Table 87.2  Age-specific incidence rates per 100,000 people per year for selected brain tumor histologies Age at diagnosis (years) Histology 35–44 45–54 55–64 65–74 75–84 85+ Glioblastoma 1.20 Anaplastic 0.48 astrocytoma Anaplastic 0.22 oligodendroglioma

3.70 0.60

8.09 0.89

12.47 14.13 7.63   1.07   1.00 0.30

0.30

0.32

  0.34   0.27 Unknown

of meningioma is estimated to be approximately 97.5/100,000 in the USA with over 150,000 individuals currently diagnosed. Data from CBTRUS reveal an ageadjusted incidence rate (per 100,000 person years) of 5.04 and 2.46 for females and males, respectively [1]. The incidence of meningioma increases with age with a median age of diagnosis of approximately 64  years. Although generally considered benign (WHO grade I), approximately 8% of meningiomas display aggressive features such as increased cellularity, high nuclear to cytoplasmatic ratio, increased mitotic activity, patternless growth, and foci of necrosis and are classified as atypical tumors (WHO grade II). Approximately 2–3% of meningiomas exhibit frank malignant histological signs and are classified as anaplastic meningiomas (WHO grade III). Atypical and anaplastic meningiomas account for significant morbidity and mortality. Histology is an important predictor of tumor recurrence rates. Although detailed population-based data are not available, recurrence rates are estimated at 3–20% for benign meningiomas, 30–40% for atypical meningiomas, and 50–80% for anaplastic meningiomas.

Primary Central Nervous System Lymphoma Primary CNS lymphoma (PCNSL) is an unusual extranodal non-Hodgkin’s lymphoma variant that exclusively involves the nervous system and eyes. Only rarely is there spread to

the systemic compartment. PCNSL represents 3.1% of CNS tumors, with approximately 2,000 new diagnoses per year in the USA [1]. The reported incidence of PCNSL has increased over the past few decades, primarily due to increases in both immunocompromised individuals and the elderly. Between 1973 and 1984 in the USA, the incidence rate of PCNSL was 0.15 cases per 100,000 person years; between 1985 and 1997, the incidence rate more than tripled to 0.48 cases per 100,000 person years [12]. Reasons for the increase in incidence rates are controversial. Potential explanations include increased use of neuroimaging, changes in disease classification, and delayed response to a putative environmental toxin. Immunodeficiency is the strongest known risk factor for all subtypes of lymphoma, including PCNSL. Most immunocompetent patients with PCNSL are older adults, and there is a slight male preponderance. Although localized extranodal systemic non-Hodgkin’s lymphoma is compatible with longterm survival in 70% or more of patients, PCNSL is almost universally fatal. Factors that predict decreased survival among patients with PCNSL include age greater than 60 years, impaired performance status, elevated serum lactate dehydrogenase, increased cerebrospinal fluid protein, and involvement of deep brain structures. Depending upon the number of adverse prognostic factors, 2-year survival rates vary between 24 and 85% [13]. A recent analysis in preparation by our group indicates that survival rates among PCNSL patients are increasing over time, perhaps due in part to advances in the chemotherapeutic management of this disease.

Risk Factors The only well-validated risk factor for development of a glioma is exposure to ionizing radiation, generally in the form of therapeutic irradiation for cancer [14]. Radiationinduced brain tumors typically develop in young patients. A wide variety of environmental risk factors for primary brain tumors have been proposed [15]. The list of factors includes electromagnetic fields, trauma, occupational and industrial chemicals, medications including anticonvulsants, and viral infections, among others. Recent data show an intriguing association with atopy [16]. In a meta-analysis of 3,450 glioma patients, a history of atopy was associated with a relative risk for glioma diagnosis of 0.61 [17]. A history of an allergic condition or asthma was also protective. The biological basis for this association has yet to be elucidated. At present, no single risk factor has been consistently identified as being associated with cancer risk, particularly within the elderly population. For meningioma, the evidence for ionizing radiation is even more marked with relative risks as high as 10 [18]. Evidence of an association between hormones and meningioma

87  Benign and Malignant Tumors of the Brain

risk is suggested by a number of findings including the increased incidence of the disease in women versus men (2:1), the presence of estrogen and progesterone receptors on some meningiomas [19], a potential association between breast cancer and meningiomas [20], and an association in some studies between exogenous or endogenous hormones and meningioma risk [21]. These findings warrant consideration in the use of hormone replacement therapy in postmenopausal women.

Genetics Glioma With respect to inherited genetic syndromes for glioma, highly penetrant but relatively rare inherited genes may exist for glioma susceptibility [22]. Some hereditary syndromes such as tuberous sclerosis, neurofibromatosis types 1 and 2, nevoid basal cell carcinoma syndrome, Li-Fraumeni syndrome as well as syndromes involving adenomatous polyps may be associated with a genetic predisposition to glioma. In a population-based study of 500 adults with glioma in San Francisco, less than 1% of cases had a known hereditary syndrome (one had tuberous sclerosis and three had neurofibromatosis) [23]. With respect to familial aggregation, the reported relative risks of brain tumors among family members of brain tumor cases range from nearly one to ten, with a twofold rate seen in larger studies [24]. Not all studies of siblings, and no studies of twins, have supported a simple genetic etiology. Formal segregation analyses have provided evidence for a genetic component but no clear mode of inheritance with approximately 5% of cases estimated to be familial [24]. One linkage study has been reported with statistically significant linkage to 15q23–26.3 for 15 Finnish families with multiple cases of glioma [25]. These data suggest, as for most neoplasms, that glioma development and growth is likely a function of the effects of many genes that are relatively prevalent but not highly penetrant and that interact with environmental exposures to confer risk. An international effort to locate genes for glioma via the collection of families with two or more members affected with glioma is currently underway (GLIOGENE), and results from the first genome-wide association study of glioma are currently in press. Recently, the first examination of DNA repair gene variants and glioma was presented with evidence for such an association [26]. In the most recent and largest study to date of genetic polymorphisms and meningioma risk, Interphone study reported a statistically significant association with meningioma for 12 single nucleotide polymorphisms (SNPs) drawn from DNA repair genes.

1153

These investigators examined 1,127 tagging SNPs selected to capture most of the common variation in 136 DNA repair genes as well as an additional 388 putative functional SNPs (including 69 nonsynonymous coding SNPs that may identify the function of expressed proteins) in 631 cases and 637 controls drawn from five case/control series from the Interphone study. The Interphone study is a case/control project initially designed to examine the relationship between cell phone use and the risk of brain tumors, ­including meningioma. The group reported a novel and biologically intriguing association between meningioma risk and three variants in the gene that encodes breast cancer susceptibility gene 1-interacting protein 1 (BRIP1) (17q22) [26]. In addition to the study of inherited genes, scientists have attempted to elucidate the somatic genetic changes and pathways associated with the development of a number of ­primary brain tumors, including most prominently, those associated with the development of GBMs. GBM is considered to be a clinical manifestation of at least two pathways with respect to genetics (Fig.  87.1). One form appears to result from malignant progression of a low-grade astrocytoma. The ­timing of this transition or progression to a higher grade is variable, and it remains controversial whether aggressive therapy for a low-grade astrocytoma can prevent or delay the subsequent evolution of a GBM. There is evidence to suggest that the progression of tumor grade is associated with a series of genetic changes, similar to those seen for the progression from polyp to carcinoma in colon cancers. The second form of GBM appears to be a tumor that arises de novo in patients with no prior evidence of a low-grade glioma. When survival is measured for the two groups, there does not appear to be an advantage for either type. The latter de novo form is more commonly seen in the elderly population. Data indicate that the evolution of GBM from a low-grade glioma is genetically distinct from the de novo GBM. Tumors that progress from a low-grade glioma to GBM are associated with p53 mutation. In contrast, de  novo glioblastoma does not appear to manifest evidence of a p53 mutation; instead, these tumors have been shown to have amplification and mutation of epidermal growth factor receptor (EGFR) and amplification of MDM2, as well as loss of heterozygosity of chromosome 10 [27, 28]. Of interest is the fact that epidemiologic data from these studies suggest that advanced age is associated with EGFR and MDM2 amplifications, a condition not present in gliomas arising in younger patients.

Meningioma Few studies have examined the relationship between a ­personal diagnosis of meningioma and a family history of menin-gioma although evidence that such a history is

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Figure 87.1  Magnetic resonance imaging (MRI) scan of a ­glioblastoma. (a) T1-weighted axial image shows a hypointense lesion involving the right parieto-occipital lobe and corpus callosum, with (b) central

n­ ecrosis and peripheral enhancement following gadolinium administration. (c) T2-weighted image shows hyperintense signal and mass effect upon the ventricular system.

a­ ssociated with risk does exist. Using data from the Swedish Family Cancer Database, Hemminki and Li reported a statistically significant association between meningioma diagnosis and a parental history of meningioma [standardized incidence ratio (SIR): 2.5, 95% CI: 1.3, 4.3] [29]. A recently published hospital-based study found that the risk of meningioma was increased among persons reporting a benign brain tumor (OR: 4.5, 95% CI: 1.2, 15.0) [30]. Populationbased surveys suggest that highly penetrant but relatively rare inherited genes may exist for meningioma susceptibility, although it appears at present that these genes may be primarily seen in families with neurofibromatosis 2. Collections of families with multiple family members diagnosed with meningioma and who do not appear to carry inherited mutations in the NF2 gene are relatively rarely identified despite the fact that up to 1% of the adult population may harbor such a diagnosis, indicating a wide spectrum of phenotypic expression with respect to clinical import. At present no family based linkage studies of ­meningioma have been reported. Recently, data from Israel provide evidence for genetic predisposition to radiationassociated meningioma [31], highlighting the role of inherited genetic factors in meningioma risk modification. In the most recent and largest study to date of genetic polymorphisms and meningioma risk, investigators from the Interphone study examined that 1,127 tagging SNPs selected to capture common variation in 136 DNA repair genes as well as an additional 388 putative functional SNPs in a combined case/control series of 631 cases and 637 controls drawn from five case/control series from the Interphone study [26]. The group reported a novel association between meningioma risk and the SNP rs496851, which maps to intron 4 of the gene that encodes breast cancer susceptibility gene 1-interacting ­protein 1 (BRIP1) (mapped at 17q22).

Lymphoma There is virtually no published data about the potential hereditability of PCNSL. Due to the rarity of the disease, there is a limited understanding of its molecular pathogenesis, particularly in comparison to malignant glioma. While p53 mutations are rare, inactivation of the cell cycle regulators p14ARF and p16INK4A is commonly observed [32]. Other abnormalities include translocations of the BCL6 gene and 6q deletions; both of these appear to have prognostic significance [33].

Symptoms The presenting symptoms for intracranial lesions vary by tumor location, rate of growth, type of tumor, and age. In elderly patients, the most common presentations are confusion or mental status change, personality change, headache, seizure (often with associated motor or sensory deficits), and aphasia. However, any combination of neurologic symptoms is possible. Symptoms frequently develop over a period of weeks or months. Papilledema and nausea or vomiting are less common features in elderly patients, likely because posterior fossa tumors are uncommon in this age group. In some cases, the symptoms may be confused with more common conditions such as dementia (when cognitive complaints predominate) or cerebrovascular disease (when neurologic deficits develop acutely). The presenting symptoms may be subtle, particularly if the tumor is located in a clinically “silent” area of the brain such as the anterior frontal lobe or if it grows slowly (as is often the case, for example, with meningiomas). Tumor symptoms may present acutely, as with a seizure or hydrocephalus, when the flow of cerebrospinal fluid is suddenly blocked by the tumor.

87  Benign and Malignant Tumors of the Brain

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Figure  87.2  Molecular changes associated with glioma progression. PDGF/R platelet-derived growth factor/receptor, LOH loss of heterozygosity, CDK cyclin-dependent kinase, Rb retinoblastoma, PTEN phosphate and tensin homolog deleted on chromosome 10, EGFR epidermal

growth factor receptor, MDM2 murine double minute 2 (from Tysnes and Mahesparan [28]. Reprinted with kind permission from Springer Science+Business Media).

Diagnosis

Table 87.3  Distribution of incidental findings on brain MRI according to age Age (years) 45–59 60–74 75–97 (n=750) (n=993) (n=257) Finding

Most brain tumors in the elderly are now identified by neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI) scans (Fig. 87.2). Although these modalities are critical for tumor detection and often suggest the correct histologic diagnosis, tissue sampling is generally required before treatment can be initiated. These noninvasive tests are usually well tolerated by the elderly patient, but renal function may be adversely affected by iodinated contrast agents used in CT scanning. Elderly patients with impaired renal function may also be at risk for nephrogenic systemic fibrosis when they receive gadolinium-based contrast agents for MRI scanning [34]. In addition to CT and MRI, angiography may play a role in defining the vascular supply of tumors such as meningiomas, although in the elderly patient, the procedural risks may outweigh the benefits of any information gained [35]. In many instances, noninvasive vascular imaging with CT or MR angiography may be sufficient. The use of diagnostic imaging is of particular interest in the elderly, as its increased use in western countries has been proposed as one of the reasons for the reported increase in brain tumors among the elderly in the 1970s and 1980s. An intriguing population-based study recently reported incidental findings detected on brain MRI scans obtained in nearly 8,000 individuals [36]. Among the abnormalities observed were benign tumors (1.6%), pituitary macroadenomas

  4 (0.5) Meningioma – n (%) Infarct – n (%) 30 (4.0) Source: Data from Vernooij et al. [36]

10 (1.0) 68 (6.8)

  4 (1.6) 47 (18.3)

(0.3%), vestibular schwannomas (0.2%), and one possible low-grade glioma ( 4 mm2 in thickness with ulceration, 1 regional node with micrometastasesa T1-4a N2a MO Any invasive T excluding > 4 mm2 in thickness with ulceration, 2–3 regional nodes with micrometastases IIIB T1-4b N1a MO Any invasive T, 1 regional node with micrometastases T1-4b N2a MO Any invasive T, 2–3 regional nodes with micrometastases T1-4a N1b MO Any invasive T excluding > 4 mm2 in thickness with ulceration, 1 regional node with macrometastases T1-4a N2b MO Any invasive T excluding > 4 mm2 in thickness with ulceration, 2–3 regional macrometastases T1-a/b N2c MO In transit or satellite metastases without nodal metastases IIIC T1-4b N1b MO Any invasive T, 1 regional node with macrometastases T1-4b N2b MO Any invasive T, 2–3 regional macrometastases Any T N3 MO Any T, >/= 4 regional nodes including in-transit or satellite metastasis with positive metastatic nodes IV Any T Any N M1 Any lesion with distant skin, subcutaneous, lymph node, or organ metastases Source: Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science + Business Media, LLC, www.springlink.com a  Micrometastases now includes those seen on standard H&E staining or with melanoma-specific immunohistochemical markers

In situ lesions (Clark’s level I, TNM stage 0) are by definition noninvasive. The goal for treatment of these lesions is to remove all tumor cells locally. If standard excision is the method of choice, usually 0.5-cm margins are adequate for in situ lesions. However, if the tumor is clinically ill-defined, wider margins may be advisable. The tumor margins should be assessed with a Wood’s lamp and marked prior to administration of anesthesia. Lesions that have invaded the dermis and that are up to 1 mm in depth require excisional margins of 1  cm. Margins of 2  cm are recommended for lesions with a Breslow depth of 1.0– 4.0 mm. Any lesion more than 4 mm thick should undergo wide excision with margins up to 3- to 5-cm. The role of lymphadenectomy in malignant melanoma is controversial. Prophylactic lymphadenectomy is not indicated for in situ lesions, as they do not show evidence of metastasis. Sentinel lymph node biopsy, a procedure that permits biopsy of the first node that drains a regional lymphatic plexus and is thought to be representative of all nodes in that region, is advocated for all patients with primary melanomas >1 mm thick and for patients with highrisk thin (5  cm located on the face tend to carry the worst prognosis [122, 123]. The mainstay of treatment is local excision combined with radiotherapy. Other forms of treatment, such as chemotherapy, have not been shown to alter survival significantly [121] but may be useful for short-term palliation [124].

Conclusions Common cutaneous neoplasms that afflict the elderly arise from the epidermis or dermis and can be benign, premalignant, or malignant. Recognizing these lesions is important for providing care to a growing geriatric population. A regular, thorough skin examination enables physicians to monitor the elderly patient closely for the development of precancerous and cancerous lesions, which can ­ultimately be life-threatening. Minimizing the risk of malignant tumor development by avoiding precipitating factors such as UV radiation should be emphasized in this population.

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Case Study

Discussion

Recurrent Basal Cell Carcinoma On The Nose Of A 75-Year-Old Woman

Morpheaform BCCs and BCCs of mixed type that have morpheaform features are slow-growing, asymptomatic, and resemble scars, making them easily neglected by elderly patients. The clinical borders are indistinct, and the histologic tumor often extends far beyond what the clinical appearance would suggest. These cancers have a propensity for invasion and destruction of adjacent tissues, and they have a higher risk of recurrence than other subtypes of BCC. Superficially destructive procedures such as cryotherapy, electrodesiccation and curettage, topical imiquimod, or elliptical excision have an increased risk of recurrence as demonstrated in this case. Mohs micrographic surgery is the treatment of choice as it offers the most complete margin evaluation and provides for immediate reconstruction if indicated. Mohs surgery is an office procedure performed using local anesthesia and is generally well tolerated. To facilitate the procedure, there should be proper preoperative consultation that addresses mental status issues, medication use, anticoagulants, the need for prophylactic antibiotics, and comorbid conditions. In the perioperative period, elderly patients often require additional support including attention to positional and emotional comfort as well as monitoring for orthostatic hypotension, hypoglycemia, and cardiovascular events. Anxiety can often be allayed with casual conversation. Because of the large defects that may result from excision of morpheaform lesions, comorbidities such as diabetes, vascular disease, and the generalized slower wound healing in the elderly must be considered. It must be remembered that complex multistage repairs, while technically possible, may not be advisable in the elderly considering longer operative times and prolonged recovery. In the postoperative period, pain is most often managed with acetaminophen alone. When more potent analgesics are required, slower drug metabolism, decreased glomerular filtration rates, and potential drug interactions from polypharmacy must be considered. Additionally, the postoperative need for complex or prolonged dressing changes with uncommon materials should be avoided. In general, wound care instructions are discussed with the patient as well as any caregiver present. Before discharge, adequate time is provided for patients to ask questions including concerns for cosmesis and recurrence. As follow-up, we advocate same evening and 24-h phone calls with lesion checks at 1 week.

A 75-year-old woman presented with a slowly growing scar-like lesion at the junction of the right nasal ala and cheek. It was present for approximately 3 years. She noted a one-month history of a nonhealing lesion at the same site. Dermatologic history was significant for a BCC of the right nasal ala that was treated by electrodesiccation and curettage 5 years earlier. There was no history of radiation therapy. Her medical history was significant for insulin-dependent diabetes and hypertension. Social history was significant for loss of her husband 2 years ago. She lives alone. Examination of the right cheek and right nasal ala demonstrated a 1.5 × 1.5 cm irregular, indurated, smoothsurfaced, shiny plaque with an indistinct border. Within this lesion, on the right ala, was a 3-mm crusted telangiectatic papule with hemorrhagic crust. Laboratory data, including CBC, LFTs, and renal function tests were normal. A biopsy from the edge of the plaque demonstrated irregular, narrow, strand-like proliferations of palisading, basaloid tumor islands in a dense fibrous stroma that extended to the base of the biopsy. These histologic features were consistent with BCC, sclerosing or morpheaform subtype. Mohs surgery was selected as the treatment of choice The first stage of Mohs surgery revealed a BCC with distinct nodular and morpheaform features. There was a focal area of epidermal ulceration and a nodule of palisading basaloid tumor islands extending from the deep epidermis into the superficial and mid-dermis. In the deeper and lateral sections, there were morpheaform strands of basaloid cells extending to the margins of the specimen. The tumor was cleared after the second stage of Mohs surgery. The postoperative defect extended to the cartilage of the ala and measured 2.5 × 2.3  cm. The wound was repaired under local anesthesia only in the office setting with an auricular cartilage graft and subcutaneous hinge flap. The secondary defect was closed in a linear fashion, and the area over the graft was left to epithelialize by second intention.

91  Common Benign and Malignant Skin Lesions

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1241 27. Greenbaum SS (1991) The treatment of chondrodermatitis nodularis chronica helicis with injectable collagen. Int J Dermatol 30:291–294 28. Moncrieff M, Sassoon EM (2004) Effective treatment of chondrodermatitis nodularis chronica helicis using a conservative approach. Br J Dermatol 150(5):892–894 29. Lawrence CM (1991) The treatment of chondrodermatitis nodularis with cartilage removal alone. Arch Dermatol 127:530–535 30. Morganroth GS, Leffell DJ (1993) Nonexcisional treatment of benign and premalignant cutaneous lesions. Clin Plast Surg 20:91–104 31. Coldiron BM (1991) The surgical management of chondrodermatitis nodularis chronica helicis. J Dermatol Surg Oncol 17:902–904 32. de Ru JA, Lohuis PJ, Saleh HA, Vuyk HD (2002) Treatment of chondrodermatitis nodularis with removal of the underlying cartilage alone: retrospective analysis of experience in 37 lesions. J Laryngol Otol 116(9):677–681 33. Ormond P, Collins P (2004) Modified surgical excision for the treatment of chondrodermatitis nodularis. Dermatol Surg 30(2 Pt 1): 208–210 34. Long D, Maloney ME (1996) Surgical pearl: surgical planning in the treatment of chondrodermatitis nodularis chronica helicis of the antihelix. J Am Acad Dermatol 35:761–762 35. Rex J, Ribera M, Bielsa I, Mangas C, Xifra A, Ferrándiz C (2006) Narrow elliptical skin excision and cartilage shaving for treatment of chondrodermatitis nodularis. Dermatol Surg 32(3):400–404 36. Taylor MB (1991) Chondrodermatitis nodularis chronica helicis: successful treatment with the carbon dioxide laser. J Dermatol Surg Oncol 17:862–864 37. Taylor MB (1992) Chondrodermatitis nodularis chronica helicis. J Dermatol Surg Oncol 18:641 38. Bekhor PS (2006) Long-pulsed Nd:YAG laser treatment of venous lakes: report of a series of 34 cases. Dermatol Surg 32(9):1151–1154 39. Marks R, Rennie G, Selwood T (1988) The relationship of basal cell carcinomas and squamous cell carcinomas to solar keratoses. Arch Dermatol 124(7):1039–1042 40. Callen JP, Bickers DR, Moy RL (1997) Actinic keratoses. J Am Acad Dermatol 36(4):650–653 41. Ackerman AB, Mones JM (2006) Solar (actinic) keratosis is squamous cell carcinoma. Br J Dermatol 155(1):9–22 42. Graham G (1993) Advances in cryosurgery during the past decade. Cutis 12:365–372 43. Stockfleth E, Meyer T, Benninghoff B et al (2002) A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratosis. Arch Dermatol 138:1498–1502 44. Lebwohl M, Dinehart S, Whiting D et  al (2004) Imiquimod 5% cream for the treatment of actinic keratosis: results from two Phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 50:714–721 45. Ulrich C, Bichel J, Euvrard S, Guidi B, Proby CM, van de Kerkhof PC, Amerio P, Rønnevig J, Slade HB, Stockfleth E (2007) Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. Br J Dermatol 157(Suppl 2):25–31 46. Wolf JE Jr, Taylor JR, Tschen E et al (2001) Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol 40:709–713 47. Rivers JK, Arlette J, Shear N et  al (2002) Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol 146:94–100 48. Stritt A, Merk HF, Braathen LR, von Felbert V (2008) Photodynamic therapy in the treatment of actinic keratosis. Photochem Photobiol 84(2):388–398

1242 49. Robinson JK (1989) Actinic cheilitis: a prospective study comparing four treatment methods. Arch Otolaryngol Head Neck Surg 115:848–852 50. Picascia DD, Robinson JK (1987) Actinic cheilitis: a review of the etiology, differential diagnosis and treatment. J Am Acad Dermatol 17:255–264 51. Berking C, Herzinger T, Flaig MJ, Brenner M, Borelli C, Degitz K (2007) The efficacy of photodynamic therapy in actinic cheilitis of the lower lip: a prospective study of 15 patients. Dermatol Surg 33(7):825–830 52. Alexiades-Armenakas MR, Geronemus RG (2004) Laser-mediated photodynamic therapy of actinic cheilitis. J Drugs Dermatol 3(5):548–552 53. Smith KJ, Germain M, Yeager J, Skelton H (2002) Topical 5% imiquimod for the therapy of actinic cheilitis. J Am Acad Dermatol 47(4):497–501 54. Chakrabarty AK, Mraz S, Geisse JK, Anderson NJ (2005) Aphthous ulcers associated with imiquimod and the treatment of actinic cheilitis. J Am Acad Dermatol 52(2 Suppl 1):35–37 55. Ulrich C, Forschner T, Ulrich M, Stockfleth E, Sterry W, Termeer C (2007) Management of actinic cheilitis using diclofenac 3% gel: a report of six cases. Br J Dermatol 156(Suppl 3):43–46 56. Thappa DM, Garg BR, Tahduea J et  al (1997) Cutanous horn: a brief review and report of a case. J Dermatol 24:34–37 57. Yu RC, Pryce DW, MacFarlane AW et al (1991) A histopathological study of 643 cutaneous horns. Br J Dermatol 124:449–452 58. Sober AJ, Burnstein JM (1995) Precursors to skin cancer. Cancer 75:645–650 59. Morton CA, Whitehurst C, Moseley H et al (1996) Comparison of photodynamic therapy with cryotherapy in the treatment of Bowen’s disease. Br J Dermatol 135:766–771 60. Rosen T, Harting M, Gibson M (2007) Treatment of Bowen’s disease with topical 5% imiquimod cream: retrospective study. Dermatol Surg 33(4):427–431; discussion 431–432 61. Morton C, Horn M, Lehman J, Tack B, Bedane C, Tijoe M et  al (2005) A 24-month update of a placebo controlled European study comparing MAL-PDT with cryotherapy and 5-fluorouracil in patients with Bowen’s disease. J Eur Acad Dermatol Venereol 19(Suppl 2):237–238 62. Morton CA, Whitehurst C, Moore JV, MacKie RM (2000) Comparison of red and green light in the treatment of Bowen’s disease by photodynamic therapy. Br J Dermatol 143:767–772 63. Salim A, Leman JA, McColl JH, Chapman R, Morton CA (2003) Randomized comparison of photodynamic therapy with topical 5-fluorouracil in Bowen’s disease. Br J Dermatol 148:539–543 64. Weinstock MA, Sober AJ (1987) The risk of progression of lentigo maligna to lentigo maligna melanoma. Br J Dermatol 116:303–310 65. Somach SC, Taira JW, Pitha JV et al (1996) Pigmented lesions in actinically damaged skin. Arch Dermatol 132:1297–1302 66. Cohen LM (1995) Lentigo maligna and lentigo maligna melanoma. J Am Acad Dermatol 33:923–936 67. Coleman WP, Davis RS, Reed RI et al (1980) Treatment of lentigo maligna and lentigo maligna melanoma. J Dermatol Surg Oncol 6:476–479 68. National Institutes of Health Consensus Conference (1992) Diagnosis and treatment of early melanoma. JAMA 268:1314–1319 69. Demirci H, Johnson TM, Frueh BR, Musch DC, Fullen DR, Nelson CC (2008) Management of periocular cutaneous melanoma with a staged excision technique and permanent sections the square procedure. Ophthalmology 115(12):2295.e3–2300.e3 70. Anderson KW, Baker SR, Lowe L, Su L, Johnson TM (2001) Treatment of head and neck melanoma, lentigo maligna subtype: a practical surgical technique. Arch Facial Plast Surg 3(3):202–206 71. Huilgol SC, Selva D, Chen C, Hill DC, James CL, Gramp A, Malhotra R (2004) Surgical margins for lentigo maligna and lentigo

M.A. McFerren and D.J. Leffell maligna melanoma: the technique of mapped serial excision. Arch Dermatol 140(9):1087–1092 72. Temple CL, Arlette JP (2006) Mohs micrographic surgery in the treatment of lentigo maligna and melanoma. J Surg Oncol 94(4):287–292 73. Cohen LM, McCall MW, Zax RH (1998) Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma. A followup study. Dermatol Surg 24(6):673–677 74. Farshad A, Burg G, Panizzon R, Dummer R (2002) A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays. Br J Dermatol 146(6):1042–1046 75. Schmid-Wendtner MH, Brunner B, Konz B, Kaudewitz P, Wendtner CM, Peter RU, Plewig G, Volkenandt M (2000) Fractionated radiotherapy of lentigo maligna and lentigo maligna melanoma in 64 patients. J Am Acad Dermatol 43(3):477–482 76. Mahoney MH, Joseph MG, Temple C (2008) Topical imiquimod therapy for lentigo maligna. Ann Plast Surg 61(4):419–424 77. Arndt KA (1986) New pigmented macule appearing 4 years after argon laser treatment of lentigo maligna. J Am Acad Dermatol 14(6):1092 78. Orten SS, Waner M, Dinehart SM, Bardales RH, Flock ST (1999) Q-switched neodymium:yttrium-aluminum-garnet laser treatment of lentigo maligna. Otolaryngol Head Neck Surg 120(3):296–302 79. Thissen M, Westerhof W (1997) Lentigo maligna treated with ruby laser. Acta Derm Venereol 722:163 80. Silverberg N, Silverberg L (1989) Aging and the skin. Postgrad Med 86:131–144 81. Kwa RE, Campana K, Moy RL (1992) Biology of cutaneous squamous cell carcinoma. J Am Acad Dermatol 26:1–20 82. Proper SA, Rose PT, Fenske NA (1990) Non-melanomatous skin cancer in the elderly: diagnosis and management. Geriatrics 45:57–65 83. Lippman SM, Meyskens FL (1987) Treatment of advanced squamous cell carcinoma of the skin with isotretinoin. Ann Intern Med 107:494–501 84. Warner DM, Flowers F, Ramos-Caro FA (1995) Solitary keratoacanthoma (squamous cell carcinoma): surgical management. Int J Dermatol 34:17–19 85. Schwartz RA (1994) Keratoacanthoma. J Am Acad Dermatol 30:1–19 86. Fitzpatrick TB, Johnson RA, Palano MK et  al (1992) Color atlas and synopsis of clinical dermatology: common and serious diseases, 2nd edn. McGraw-Hill, New York 87. Hodak E, Jones RE, Akerman AB (1993) Solitary keratoacanthoma is a squamous cell carcinoma: three examples with metastases. Am J Dermatopathol 15:332–342 88. Larson PO (1987) Keratoacanthomas treated with Mohs’ micrographic surgery (chemosurgery). J Am Acad Dermatol 16:1040–1044 89. Annest NM, VanBeek MJ, Arpey CJ, Whitaker DC (2007) Intralesional methotrexate treatment for keratoacanthoma tumors: a retrospective study and review of the literature. J Am Acad Dermatol 56(6):989–993 90. Snow SN, Sahl W, Lo JS, Mohs FE, Warner T, Dekkinga JA, Feyzi J (1994) Metastatic basal cell carcinoma. Report of five cases. Cancer 73(2):328–335 91. von Domarus H, Stevens PJ (1984) Metastatic basal cell carcinoma. Report of five cases and review of 170 cases in the literature. J Am Acad Dermatol 10(6):1043–1060 92. Gloster HM, Brodland DF (1996) The epidemiology of skin cancer. Dermatol Surg 22:217–226 93. Keller KL, Fenske NA, Glass LF (1997) Cancer in the older patient. Clin Geriatr Med 13:339–361 94. Gross K, Kircik L, Kricorian G (2007) 5% 5-Fluorouracil cream for the treatment of small superficial basal cell carcinoma: efficacy, tolerability, cosmetic outcome, and patient satisfaction. Dermatol Surg 33(4):433–439

91  Common Benign and Malignant Skin Lesions 95. Gollnick H, Barona CG, Frank RG, Ruzicka T, Megahed M, Maus J, Munzel U (2008) Recurrence rate of superficial basal cell carcinoma following treatment with imiquimod 5% cream: conclusion of a 5-year long-term follow-up study in Europe. Eur J Dermatol 18(6):677–682 96. Rhodes LE, de Rie MA, Leifsdottir R, Yu RC, Bachmann I, Goulden V, Wong GA, Richard MA, Anstey A, Wolf P (2007) Five-year follow-up of a randomized, prospective trial of topical methyl aminolevulinate photodynamic therapy vs surgery for nodular basal cell carcinoma. Arch Dermatol 143(9):1131–1136 97. Peng Q, Warloe T, Berg K, Moan J, Kongshaug M, Giercksky KE, Nesland JM (1997) 5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges. Cancer 79(12): 2282–2308 98. Soleymani AD, Scheinfeld N, Vasil K, Bechtel MA (2008) Metastatic basal cell carcinoma presenting with unilateral upper extremity edema and lymphatic spread. J Am Acad Dermatol 59(2 Suppl 1):S1–S3 99. Jemal A, Devesa SS, Hartge P, Tucker MA (2001) Recent trends in cutaneous melanoma incidence among whites in the United States. J Natl Cancer Inst 93(9):678–683 100. Austin PF, Cruse CW, Lyman G, Schroer K, Glass F, Reintgen DS (1994) Age as a prognostic factor in the malignant melanoma population. Ann Surg Oncol 1(6):487–494 101. Ries LAG, Melbert D, Krapcho M, Stinchcomb DG, Howlader N, Horner MJ, Mariotto A, Miller BA, Feuer EJ, Altekruse SF, Lewis DR, Clegg L, Eisner MP, Reichman M, Edwards BK (eds). SEER cancer statistics review, 1975-2005. National Cancer Institute, Bethesda, MD. http://seer.cancer.gov/csr/1975_2005/. Accessed November, 2008 102. Mackie RM, Young D (1984) Human malignant melanoma. Int J Dermatol 23:433–443 103. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ, Sondak VK (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27(36):6199–6206 104. Lasithiotakis K, Leiter U, Meier F, Eigentler T, Metzler G, Moehrle M, Breuninger H, Garbe C (2008) Age and gender are significant independent predictors of survival in primary cutaneous melanoma. Cancer 112(8):1795–1804 105. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, Nieweg OE, Roses DF, Hoekstra HJ, Karakousis CP, Reintgen DS, Coventry BJ, Glass EC, Wang HJ, MSLT Group (2006) Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355(13):1307–1317; erratum in: N Engl J Med 2006 355(18):1944 106. Cormier JN, Xing Y, Ding M, Lee JE, Mansfield PF, Gershenwald JE, Ross MI, Du XL (2005) Population-based assessment of surgi-

1243 cal treatment trends for patients with melanoma in the era of ­sentinel lymph node biopsy. J Clin Oncol 23(25):6054–6062 107. Jack A, Boyes C, Aydin N, Alam K, Wallack M (2006) The treatment of melanoma with an emphasis on immunotherapeutic strategies. Surg Oncol 15(1):13–24 108. Fang L, Lonsdorf AS, Hwang ST (2008) Immunotherapy for advanced melanoma. J Invest Dermatol 128(11):2596–2605 109. Noorda EM, Vrouenraets BC, Nieweg OE, van Geel AN, Eggermont AM, Kroon BB (2002) Safety and efficacy of isolated limb perfusion in elderly melanoma patients. Ann Surg Oncol 9(10):968–974 110. Quan W Jr, Ramirez M, Taylor C, Quan F, Vinogradov M, Walker P (2005) Administration of high-dose continuous infusion interleukin-2 to patients age 70 or over. Cancer Biother Radiopharm 20(1):11–15 111. Bernstein SC, Brodland DG (1995) Melanoma in the geriatric patient. J Geriatr Dermatol 3:271–279 112. Fish FS (1996) Soft tissue sarcomas in dermatology. Dermatol Surg 22:268–273 113. Helwig EB, May D (1986) Atypical fibroxanthoma of the skin with metastases. Cancer 57:368 114. Davis JL, Randle HW, Zalla MJ et  al (1997) A comparison of Mohs micrographic surgery and wide excision for the treatment of atypical fibroxanthoma. Dermatol Surg 23:105–110 115. Huether MJ, Zitelli JA, Brodland DG (2001) Mohs micrographic surgery for the treatment of spindle cell tumors of the skin. J Am Acad Dermatol 44(4):656–659 116. Ratner D, Nelson BR, Brown MD et al (1993) Merkel cell carcinoma. J Am Acad Dermatol 29:143–156 117. Smith DE, Bielamowicz S, Kagan AR et al (1995) Cutaneous neuroendocrine (Merkel cell) carcinoma: a report of 35 cases. Am J Clin Oncol 18:199–203 118. Victor NS, Morton B, Smith JW (1996) Merkel cell cancer: is prophylactic lymph node dissection indicated? Am Surg 62:879–882 119. Eng TY, Boersma MG, Fuller CD, Goytia V, Jones WE III, Joyner M, Nguyen DD (2007) A comprehensive review of the treatment of Merkel cell carcinoma. Am J Clin Oncol 30(6):624–636 120. Krasagakis K, Almond-Roesler B, Zouboulis CC et  al (1997) Merkel cell carcinoma: report of ten cases with emphasis on clinical course, treatment, and in  vitro drug sensitivity. J Am Acad Dermatol 36:727–732 121. McDonagh DP, Liu J, Gaffey MJ et al (1996) Detection of Kaposi’s sarcoma-associated herpesvirus-like DNA sequence in angiosarcoma. Am J Pathol 149:1363–1368 122. Marc RJ, Poen JC, Tran LM et al (1996) Angiosarcoma: a report of 67 patients and a review of the literature. Cancer 77:2400–2406 123. Jones WE (1990) Some special skin tumors in the elderly. Br J Dermatol 122(Suppl 35):71–75 124. Mendenhall WM, Mendenhall CM, Werning JW, Reith JD, Mendenhall NP (2006) Cutaneous angiosarcoma. Am J Clin Oncol 29(5):524–528

Chapter 92

Surgical Management of Soft Tissue Sarcoma in the Geriatric Population Charlotte E. Ariyan and Murray F. Brennan

Introduction The management of soft tissue sarcomas in the elderly ­population requires a multidisciplinary approach. These rare tumors have a wide range of growth patterns and metastatic potential, much of which can be discerned by the pathologic subtype. Increasing age alone has repeatedly been demonstrated to have a negative impact on death from this disease. While surgery continues to be the primary treatment for ­sarcomas, radiation and chemotherapy have selective utility. The benefits of an aggressive approach must be weighed against the morbidity of treatment, particularly in the ­geriatric population.

Risk Factors The majority of soft tissue sarcomas have no defined cause and are secondary to sporadic multiple mutations. However, hereditary forms do exist and are important to recognize (Table 92.1), as the mutation confers a lifelong risk of disease that may be augmented by prior treatments such as chemotherapy or radiation. The retinoblastoma population is an example of this phenomenon. These patients present at a young age for treatment, which often involves radiation. Forty-year follow-up of patients with hereditary retinoblastoma has found secondary malignancy in 36% of the patients, many of which are sarcomas [1, 2]. Additional risk factors for sarcoma include environmental toxins. Radiation predisposes to the development of sarcomas, and can been seen after radiation for any cancer, but particularly breast cancer, Hodgkin’s disease, prostate ­cancer, and cervical cancer [3]. The majority of these radiationinduced sarcomas are high grade, and the ability to com-

C.E. Ariyan (*) Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA e-mail: [email protected]

pletely remove the new tumor predicts survival [4]. Chronic ­lymphedema predisposes to lymphangiosarcoma, or Stewart Treves syndrome [5]. Although there has been a suggestion that veterans exposed to Agent Orange have an elevated risk of sarcoma, this has never been shown to be a significant ­factor in case-controlled studies [6]. Vinyl chloride and polyvinyl chloride exposure are associated with an increased risk of hepatic angiosarcomas [7].

Staging Soft tissue sarcomas are classically defined by size, depth, grade, and presence of lymph node or distant metastasis [8]. The presence of lymph node metastasis is rare. There are over 50 different subtypes of sarcoma, with different potential for recurrence and metastasis. More recently, Memorial Sloan-Kettering Cancer Center (MSKCC) has developed a nomogram to predict survival from sarcoma [9]. The factors demonstrated to most accurately predict survival are sarcoma subtype, grade, size, anatomic site, depth, and patient age. This nomogram has been validated with patients at other institutions [9, 10].

Evaluation and Biopsy Most patients with soft tissue sarcomas present with an asymptomatic mass [11]. The differential diagnosis of a mass includes a hematoma, benign lipoma, lymphoma, germ cell tumor, and sarcoma. A history of an enlarging or changing lesion should raise the suspicion for a malignancy. Physical exam should focus differentiation between a soft, mobile lesion and one that is fixed or invading local structures. Imaging will assist in determining the features of the mass and its relation to neurovascular structures. An MRI will clearly demonstrate fat and muscle planes and may be more useful in the elderly population that tends to have an increased fat composition. A CT Scan will often clarify intra-­abdominal

R.A. Rosenthal et al. (eds.), Principles and Practice of Geriatric Surgery, DOI 10.1007/978-1-4419-6999-6_92, © Springer Science+Business Media, LLC 2011

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C.E. Ariyan and M.F. Brennan

Table 92.1  Risk factors for development of soft tissue sarcoma Risk factor Sarcoma

25 20 70 10 5

lesions with improved clarity. PET scans are rarely used as sarcomas tend not to be FDG avid. Some lesions will be homogeneous and small and can be observed. Any lesion that is changing, heterogeneous on imaging, or large should be considered for biopsy or removal. Biopsy can be performed by fine-needle aspiration (FNA), core-needle biopsy, incisional biopsy, or excisional biopsy. An FNA rarely provides enough tissue for utility. A core biopsy can be performed easily in the clinic with 95% accuracy [12]. An incisional biopsy provides an abundance of tissue; however, it requires a surgical procedure for the patient and risks the formation of hematoma postoperatively. This procedure must be carefully planned with a longitudinally oriented incision that can be incorporated in a future resection. Small tumors that are less than 5 cm and easily ­resectable can be removed by an excisional biopsy. The biopsy grade and histologic subtype will be the most important data gained from the biopsy. Integration of this information with the site, size, and depth will provide important prognostic information. This can be used to derive an optimal treatment plan for the patient.

Surgery for Sarcoma in the Geriatric Population Of over 7,000 adult sarcomas removed at MSKCC and maintained in our database, there is a difference in the histopathological subtype of soft tissue sarcomas based upon age. As shown in Fig. 92.1, the common subtypes such as malignant fibrous histiocytoma (MFH), liposarcoma, and leiomyosarcoma prevail in both groups; however, there are a few notable differences. Synovial cell sarcoma is classically a tumor of young patients. Desmoids are slow-growing tumors that tend not to metastasize; therefore, the low incidence of these patients seen in our database may reflect a referral bias of older patients. As the designation of MFH is being more

GIST

0

Other

Primarily high grade, multiple subtypes Lymphangiosarcoma

Desmoid

Postsurgical or parasitic

30

Synovial

Lymphedema

Soft tissue, osteogenic Malignant peripheral nerve sheath tumor Soft tissue, osteogenic

35

MFH

Radiation

Desmoid

Liposarcoma

Gardner’s syndrome/ APC mutation Li–Fraumeni syndrome/ p53 mutation Neurofibromatosis type 1/ NF-1 mutation Retinoblastoma/Rb mutation

Leiomyosarcoma

Gene mutation

40

Figure 92.1  Incidence of sarcoma subtypes over a 25-year period at Memorial Sloan-Kettering Cancer Center (MSKCC). The data is shown for the geriatric population, and for those patients under 70. The data is expressed as the total number of sarcomas (n = 7,531).

accurately defined in recent years, it is possible that the higher prevalence in the geriatric population reflects the imprecision of earlier diagnoses. The decision to operate on an extremity sarcoma in an elderly patient is based upon multiple factors. First, there must be an adequate understanding of the natural history of the disease in the absence of treatment. Second, there must be awareness of the additional therapies, namely radiation or chemotherapy. The morbidity of treatments, surgical or ­medical, must then be balanced with the risk associated with the tumor and the underlying condition of the patient. The major advancement in understanding the natural history of sarcomas comes from the ability to subtype sarcomas based on histopathology and molecular features. With this understanding, a physician can tailor the treatment to the individual patient. This review will focus on treatment of the most common types of sarcomas in the geriatric population.

Extremity/Truncal Sarcomas The primary treatment of an extremity or truncal sarcoma is surgical excision. The type of surgery is guided by subtype and anatomic location. In the geriatric population, the most common subtypes in the extremity are malignant fibrous ­histiocytoma (MFH), liposarcoma, and leiomyosarcoma as shown in Fig. 92.2. In the trunk, the most common subtypes are MFH, angiosarcoma, and liposarcoma. This is in contrast to the younger population, where synovial cell is observed

92  Surgical Management of Soft Tissue Sarcoma in the Geriatric Population

more often in the extremity, and desmoids are observed more often in the trunk. Additional therapy includes radiation and chemotherapy, which can be administered in an adjuvant or neoadjuvant fashion. 70

70

50 40 30

1247

Surgical Management The grade of the tumor and the size are the first items that will guide the treatment algorithm. Both can be obtained from the clinical exam, radiology studies, and possible biopsy. As shown in Fig. 92.3, any lesion less than 5 cm can be primarily removed, if it is in a location where the postoperative field of radiation would not cross a joint or damage a major neurovascular structure. Lesions greater than 10  cm should be biopsied, as some high-grade lesions can be offered neoadjuvant chemotherapy.

20 10

Role of Amputation Synovial

Leiomyosarcoma

Liposarcoma

MFH

0

Figure  92.2  Incidence of common extremity subtypes by age for patients. Data shown is percentage of total extremity lesions in the database at Memorial Sloan-Kettering Cancer Center (MSKCC) (n = 3,073).

A prospective, randomized trial published in 1982 did not demonstrate a survival advantage for amputation in patients with extremity sarcoma. Forty-three patients, all undergoing chemotherapy, consented to either amputation or wide excision (WE) with postoperative radiation. Analysis at 5 years demonstrated an increased local recurrence rate in patients with WE; however, there was no difference in disease-specific survival (DSS) at 5 years (71% vs. 78%, p = 0.75) [13]. The efficacy of

Extermity mass

< 5 cm

Surgical resection low grade

Negative margin

No further therapy

>5 cm

Surgical Resection high grade

Consider neoadjuvant chemotherapy if > 10 cm

Surgical resection

Positive margin

>1 cm margin

1 cm margin

5% round cell component) and pleomorphic [39–43]. A retrospective analysis of patients with extremity liposarcoma from MSKCC and UCLA compared patients who received chemotherapy to a similar cohort of patients who did not receive chemotherapy. There was no improvement in survival demonstrated with doxorubicin therapy; however, ifosfamide combined with doxorubicin therapy demonstrated an improved DSS at 5 years compared with no chemotherapy (92% vs. 65%, respectively, p = 0.0003) [44]. This translates into a 31% survival benefit for lesions >10 cm. Based on the results of this retrospective study, and in the absence of any prospective randomized data, neoadjuvant doxorubicin and ifosfamide chemotherapy can be offered only to elderly patients with large (>10 cm), extremity

C.E. Ariyan and M.F. Brennan

round cell or pleomorphic liposarcoma, with an excellent ­performance status. Dedifferentiated liposarcoma of the extremity is not sensitive to chemotherapy and has a lower risk of metastatic disease; therefore, chemotherapy is not used in this subtype. Synovial cell sarcoma is very uncommon in the geriatric population. This is a disease of young adults that is associated with a high risk of metastasis and death [45], and therefore, larger lesions are treated with systemic chemotherapy based on retrospective data [46].

Retroperitoneal Sarcoma Subtypes and Goals of Surgery The most common subtypes of retroperitoneal sarcomas, regardless of age, are liposarcomas and leiomyosarcomas as shown in Fig. 92.5. Retroperitoneal sarcomas can grow large without specific symptoms; therefore, they are often detected late, at which time they are often large (>10 cm) and encroach on major abdominal structures [47]. Upon presentation, a biopsy is performed when there is concern for a benign process or other malignancy that would not mandate surgical intervention. Additional tumors to consider are lymphomas, angiomyolipomas, pancreatic tail tumors, benign shwannomas, adrenal tumors, and metastatic germ cell tumors. While primary surgical resection obtaining negative margins is associated with improved survival, removal of adjacent organs is not always necessary [47]. If the mass does not encase the renal vessels or invade the renal hilum, a parenchymal-sparing capsular stripping can be performed without compromising disease-specific survival [48]. Surgical management of retroperitoneal liposarcomas must take into account the subtypes, which have been shown to be one of the most important factors in DSS. In a study of 177 patients, the well-differentiated subtype had a very good survival and much lower recurrence rate than the dedifferentiated liposarcoma. The local recurrence rate for patients with well-differentiated liposarcoma was 31% at 3 years compared with 83% at 3 years for dedifferentiated liposarcoma. The dedifferentiated subtype had a 30% risk of distant disease at 3 years. In contrast, well-differentiated liposarcoma rarely developed distant metastasis (1% risk of distant disease at 3 years) [48]. Leiomyosarcomas of the abdomen commonly involve vessels and can involve major structures such as the inferior vena cava. Surgical resection can safely be performed with IVC ligation as long as drainage of the kidneys is preserved [49]. Many abdominal leiomyosarcomas have now been classified as gastrointestinal stromal tumors (GIST) as discussed below.

92  Surgical Management of Soft Tissue Sarcoma in the Geriatric Population

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Figure 92.5  Subtypes of sarcoma in the retroperitoneum seen over a 25-year period at Memorial Sloan-Kettering Cancer Center (MSKCC). The majority of retroperitoneal tumors are either liposarcoma or leiomyosarcoma, which do not differ by age.

Radiation in Retroperitoneal Sarcomas Retroperitoneal sarcomas have a high local recurrence rate, with prevalence of 20–50% depending on the length of ­follow-up [47, 50, 51]. Median survival after local recurrence is only 28 months [47]; therefore, consideration has been given to both chemotherapy and radiation in retroperitoneal sarcomas. While there is little data to support the use of chemotherapy, radiation, which addresses the local treatment failure, has been considered. Radiation of the retroperitoneum is a difficult task as radiation cannot be delivered without risk to the surrounding vessels and intestine. However, small studies suggested that high-dose radiation improves local control [52, 53]. A prospective trial of preoperative radiation in patients undergoing a R0 or R1 resection demonstrated an improvement to 60% local recurrence-free survival in intermediate- or high-grade lesions, at a median follow-up of 40 months, with an associated increased morbidity [54]. Further multi-institutional randomized trials are needed to define the role of preoperative radiation therapy for the treatment of retroperitoneal sarcoma; however, these trials have closed secondary to poor accrual. Newer techniques of external beam radiotherapy such as IMRT may enable administration of radiotherapy with less toxicity to surrounding organs and vital structures.

Locally Recurrent Retroperitoneal Sarcoma Recurrence in retroperitoneal sarcomas is more difficult to treat, in part secondary to prior contamination and scarring of tissue planes, as well as the aggressive nature of the tumor. Surgical removal must not only remove the mass, but also any tissue plane violated in a previous resection such as drain

tracks or skin flaps. In difficult cases, the surgeon may have to remove the recurrent tumor with an adjacent neurovascular structure, and this should be carefully planned ahead of the operation. An alternative is to give a trial of neoadjuvant radiotherapy or chemotherapy before the tumor is excised to spare a major resection.

Abdominal Desmoid Abdominal desmoids can arise spontaneously or in association with familial adenomatous polyposis (FAP). Desmoid tumors arising in patients with FAP, commonly present in patients at a younger age, and they are related to the mutation in the adenomatosis polyposis (APC) gene, effecting b-catenin levels [55–58]. Sporadic desmoids have been linked to mutations in the b-catenin gene itself [59–63]. Regardless of the mutation, desmoids do not metastasize and have an unclear natural history. There have been multiple case reports of spontaneous regression of even multifocal tumors [64–67]. Patients on medical therapy fail to have progression of the tumor at least 50% of the time. Whether this is due to the inherent nature of the tumor itself or as a result of the medical therapy has not been clarified by a randomized trial. Most recently, a small clinical trial of abdominal desmoids with the anti-inflammatory suldinac and tamoxifen resulted in a 77% PR/CR [68]. At St. Mark’s hospital, all patients with intra-abdominal desmoids first receive medical therapy with suldinac. If there is tumor progression, tamoxifen or other chemotherapies are added. Only patients who fail these conservative measures are then considered for surgical intervention [69]. In the geriatric population, a trial of this more conservative treatment algorithm is warranted.

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GIST Treatment of Primary Disease Gastrointestinal stromal tumors (GIST) commonly present as asymptomatic pedunculated or submucosal masses arising in the gastrointestinal tract. On imaging, GIST tumors are well-circumscribed, low-density lesions, with possible areas of enhancement or necrosis. A suspected GIST should be removed for diagnosis and treatment if localized and the patient can tolerate the operation. Biopsy risks rupturing the mass and only complete resection offers the best chance of cure. The important factors of the primary tumor that predict risk of recurrence are the anatomic location of the GIST, size, and mitotic index. For example, a distal small bowel GIST greater than 5 cm with a mitotic index >5 per 50 highpower field (HPF) has an 85% chance of recurrence, while a tumor 3 cm to 1 year of imatinib at 400 mg daily or placebo. There was a significant improvement in recurrence-free survival with imatinib treatment, although no difference was seen in disease-specific survival [76]. Longer follow-up will help clarify if imatinib prevents, or merely delays, the onset of disease recurrence. It may be that therapy initiated at the time of disease recurrence will be equally effective.

Metastatic GIST Prior to imatinib, patients with metastatic GIST had a poor survival measured in months. However, recent trials have demonstrated that high-dose imatinib in metastatic disease can result in actual 2-year survival, with 50% of patients alive without disease progression [77]. This raises the question whether surgery should be utilized in conjunction with imatinib therapy to reduce tumor burden, or whether these patients should just be maintained on imatinib therapy. The major downside to imatinib is the development of resistant disease. Studies have demonstrated that resistance develops as soon as 6 months, with a median time to drug resistance of 20 months [77]. A recent study of 40 patients with metastatic GIST supports surgical intervention for those patients with disease that responded to imatinib. Patients with multifocal resistance, however, have a poor 1-year survival (36% alive at 1 year) and should not proceed to surgical debulking but should be considered for a clinical trial with a second line tyrosine kinase inhibitor [78].

Case Study 1

Discussion

A 73-year-old male with a history of retinoblastoma at age three for which he had eye enucleation and radiation. Past medical history also significant for coronary artery disease, resection of multiple lipomas, a partial nephrectomy for renal cell cancer, as well as an appendectomy. The patient’s mother and daughter also had retinoblastoma. The patient presented with a small mass on his face in the field of radiation. Biopsy was consistent with a high grade, 25. Oral contraceptive use. Hormone replacement therapy Age >60 years. Malignancy or current chemotherapy or radiation therapy. Major or laparoscopic surgery (>45 min). Confined to bed >72 h. Immobilizing cast 75 years. Factor V Leiden/activated protein C resistance. Risk factors of myocardial infarction, congestive heart failure, or chronic obstructive pulmonary disease. Congenital or acquired thrombophilia Major, elective lower extremity arthroplasty TKR, THR, Hip, pelvis or leg fracture within 1 month. Stroke within 1 month. Multiple trauma within 1 month. Acute spinal cord injury with paralysis within 1 month

2 Points

3 Points

5 Points

Risk factor points total

Recommendations

1 or less (low-risk) 2 or less (moderate-risk) 3 or 4 (high-risk) 5 or greater (highest risk)

Early and aggressive mobilization LDUH q12h, LMWH 3,400 U daily, with or without IPC LMWH >3,400 U daily, fondaparinux, and coumadins (INR 2–3). Dose-adjusted LDUH or LMWH may be used with or without IPC

Additional recommendations For elective THA

LMWH 12 h pre-operatively and/or 12–24 h after surgery, or 4–6 h after surgery at one half the dose initially followed by a full dose on the next day. Alternatively, fondaparinux (2.5 mg) started 6–8 h postoperative or coumadin started preoperatively or after surgery (INR target 2.5, range 2–3). Aspirin, dextran or IPC alone not recommended For elective TKA LWMH 12–24 h postoperative, fondaparinux 2.5 mg started 6–8 h post-operatively, or adjusted-dose warfarin administered preoperative and/or postoperatively and with INR range of 2–3 (target INR of 2.5). Optional use of IPC devices intraoperatively or immediately postoperatively. LDUH not recommended for sole use as prophylaxis For hip fractures LMWH or fondaparinux or adjusted-dose warfarin immediately administered postoperatively, with a target INR of 2.5 (range of 2–3) if bleeding is controlled; LDUH may be alternative (limited data). Aspirin alone is not recommended For knee arthroscopy No routine prophylaxis. Early mobilization. LMWH for patients with additional preexisting risk factors for DVT or prolonged tourniquet time For elective spine surgery No routine prophylaxis. High-risk patients should be treated with LDUH, LMWH, or perioperative IPC BMI body mass index; DVT deep venous thrombosis; IPC intermittent pneumatic compression; LDUH low-dose unfractionated heparin; LMWH low molecular weight heparin; PE pulmonary embolism; THA total hip arthroplasty; TKA total knee arthroplasty. Source: Data from Ennis [123]

94  Orthopaedic Trauma in the Elderly

anticoagulant-related bleeding for several reasons: increased anticoagulant effect of warfarin, increased prevalence of comorbidity, and incidence of adverse drug reactions. The indications for use of an inferior vena cava filter are wider in the older age group, not only for those in whom heparin is contraindicated, or has failed, but also for those who require treatment indefinitely with contraindications to oral anticoagulant [15]. The patient’s cognitive status pre- and postinjury is of significant importance when caring for the elderly. Since orthopaedic injuries and treatments usually require protracted physical therapy and rehabilitation, it is necessary for patients to comprehend instructions, clearly communicate, and perform multiple tasks. These requirements are further complicated by the effect of medications on elderly cognition. Individuals with Alzheimer’s disease, cognitive deficits from cerebrovascular insults, Parkinson’s disease, and other forms of dementia will have difficulty participating in the therapy required to attain preinjury functional status and may lead to a negative outcome in some instances. Their inability to meet rehabilitation goals may result in diminished functional and medical gains. These factors are important considerations when determining the feasibility and appropriateness of operative intervention. A radiographically perfect result does not always translate into a good functional outcome. For example, a comminuted distal radius fracture treated nonoperatively may result in suboptimal radiographic reduction, but their inability to cope with a lengthy rehabilitation course and associated operative complications makes the risks inherent with operative treatment more significant than the functional limitations potentially afforded by nonoperative modalities. In contrast, a patient with preinjury hemiplegia who sustains a humeral shaft fracture may not tolerate longterm immobilization of the functional upper extremity (the standard treatment) and may benefit from surgical intervention to allow earlier weight bearing, with use of the affected extremity for transfers and assisted ambulation. Decreased bone mass, or osteopenia, is often seen in older patients and is often the result of osteoporosis or osteomalacia. Osteoporosis is a decrease in bone density that does not affect mineralization, while osteomalacia results from decreased bone mineralization with or without changes in bone density. In either situation, less loading and stress are required to cause fractures as compared to normal bone. Factors affecting bone density, such as sedentary life, excessive consumption of alcohol, smoking, certain medications (antiseizure medications such as phenytoin, primidone, and phenobarbital, and certain selective serotonin reuptake inhibitors) and comorbid conditions (i.e., renal disease, malnutrition), also contribute to the patient’s overall medical condition [16, 17]. Not only should elderly patients with osteoporotic fractures be treated for those injuries but also with chemoprophylaxis and preventative measures to decrease the risk for

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future fractures [18]. However, the cornerstone of adequately treating and minimizing the effects of osteoporosis and related conditions is adequate intake of calcium and vitamin D. Osteopenia presents a problem with fracture stabilization and healing. It is difficult to attain stable fixation in fracture fragments that have decreased bone mass. Stable internal fixation is imperative to allow for early joint range of motion, weight bearing, and therapy without risking fracture displacement. Additionally, osteopenia increases the risk for nonunion since fracture callus in these patients is less dense and poorly organized. Fractures that have tenuous fixation, especially in the lower extremity, may preclude early ambulation, by protracting immobilization; further, “disuse” osteopenia may result. Bone remodels according to Wolff’s law, and the removal of external stresses can lead to significant bone loss. This situation can be reversed to varying degrees upon remobilization and reloading. Additionally, the use of hormone replacement therapy (HRT) is another option in treating bone loss. HRT’s effects were investigated by the Women’s Health Initiative Study Group. Their investigators found that women taking HRT had 34% fewer hip fractures and 24% fewer fractures than women not receiving hormones. However, the short-term use of HRT to relieve symptoms at the time of menopause does little to prevent fractures in women when they reach 75–80 years of age. Women who take estrogen to maintain bone density must continue taking estrogen because the beneficial effects on bones disappear when it is discontinued. Estrogens are still used to prevent osteoporosis but are not approved to treat a woman who has already been diagnosed with the condition [19]. When presented with osteoporotic patients, orthopaedic surgeons now have certain tools available to aid in the treatment of their injuries. Some of these include: the use of methylmethacrylate (cement) to augment screw fixation and the use of allograft and synthetic bone graft that act in an osteoconductive manner in situations of excessive bone loss [20, 21]. Calcium phosphate implants and cements have also been shown to be another adjuvant to treat these challenging fractures [22]. However, the recent introduction of locked plating technology and its theoretical enhanced fixation in osteoporotic bone has allowed for more secured fracture fixation, which may promote earlier mobilization and ambulation [23, 24]. Minimizing the complications of osteoporosis begins with medical treatment; the mainstay of which is calcium and vitamin D supplementation. In postmenopausal women, calcium supplementation alone can reduce the rate of loss or even increase bone mass. Women with osteoporosis who are older or have low calcium intake show the most benefit from calcium supplementation. The National Institutes of Health Consensus Conference recommends 1,000 mg of calcium a day for women of 65 years of age and younger on estrogen

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HRT, and 1,500 mg a day for women younger than 65 and not on estrogen HRT and for women older than 65 years of age. The most commonly used form of calcium supplementation is calcium carbonate, such as OsCal 500 or TUMS. Additionally, vitamin D deficiency is common in the elderly, often from a poor diet, low exposure to sunlight, or aging skin’s inability to synthesize vitamin D3. Vitamin D, 400 IU per day, should be added in these cases [25]. Estrogen replacement therapy stimulates bone formation, prevents bone loss, and has been shown to reduce the risk of fractures in various groups of women. For women who have retained their uterus, estrogen must be supplemented with progestin therapy to prevent potential changes in uterine tissue. Estrogen HRT may also alleviate menopausal symptoms and prevent heart disease. However, it may also increase the risk of breast cancer [25]. Bisphosphonates are a class of medications currently utilized to treat osteoporosis. Their mechanism of action is through the inhibition of osteoclasts, which are cells responsible for the resorption of bone. Examples of bisphosphonates include etidronate, pamidronate, and alendronate. Alendronate (Fosamax) has been shown to decrease the rate of bone mineral density loss at all skeletal sites and decrease the rate of fractures. However, the medication must be taken on an empty stomach and may cause gastrointestinal discomfort. It should not be taken by patients with a history of swallowing difficulties or abnormal narrowing of the esophagus [25]. Other pharmacologic treatment options include selective estrogen receptor modulators (SERM), which are used for breast cancer, those seeking alternatives for HRT, and osteoporosis. One type of SERM currently used to treat osteoporosis is raloxifene (Evista). This medication has demonstrated a beneficial effect on bone mineral density and is well tolerated. It is contraindicated in women who are pregnant or have a history of deep venous thromboses. Raloxifene has been found to cause an increase in BMD of the total body and hip similar to estrogen HRT, but has less of an effect on BMD of the lumbar spine. Raloxifene has also been shown to lower LDL cholesterol and is being studied as a way to prevent breast cancer [25]. Alternative medications to treat osteoporosis include calcitonin and parathyroid hormone (PTH) agonists. Approved for the treatment, but not prevention, of osteoporosis, calcitonin has been shown to prevent loss of spinal BMD, decrease the rate of vertebral fractures in women with osteoporosis, and possibly provide pain relief in some patients with fractures [25]. Calcitonin is a potent inhibitor of osteoclastic bone resorption; however, osteoclasts are able to escape from the inhibitory effects of calcitonin following continued exposure. Conversely, PTH agonists function as an anabolic agent to increase bone mass. A recent study has demonstrated that while PTH does decrease vertebral fractures and increase spinal bone density in postmenopausal osteoporosis

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and glucocorticoid-induced osteoporosis, this occurs at the expense of a decrease in radius bone density [26]. The longterm safety and nonvertebral fracture efficacy are still unknown [26, 27]. The patient’s preinjury ambulatory and function status can determine the type or the need for operative intervention. Studies have demonstrated that the ability of a patient to return to their preinjury level of ambulation and function is dependent upon their preexisting functional level, timing and type of operative treatment, and postoperative rehabilitation [28–31]. In Hagino’s study, they determined the following factors that significantly affected walking ability at the time of discharge for elderly hip-fracture patients: (1) age, (2) dementia, (3) residence before injury, (4) anemia, (5) electrolyte abnormality, (6) abnormal chest X-ray, and (7) chronic systemic disease. A scoring system based on these factors was able to predict the ambulation prognosis for these patients [32]. While elderly patients may have fractures that appear to be similar to those of younger patients, the comorbidities, physiologic reserves, and functional status make the musculoskeletal injury more than just “a simple fracture.” The elderly patient’s ability to cope with the metabolic and physiologic demands placed from these injuries is often poorer than their younger counterparts, and as such, treatment must incorporate a multidisciplinary approach. Understanding the preinjury level of function and comorbid status is imperative to work toward the goal of reestablishing the patient’s functionality. A multidisciplinary approach must be taken with input from the orthopaedic surgeon, geriatrician, anesthesiologist, physiatrist, therapist, and the caregiver.

Considerations in Elderly Trauma The treatment of the geriatric trauma patient assumes a more complex role due to the associated comorbidities and functional status impairments seen in the aged. The incidence of geriatric trauma is expected to increase, partly due to the increases in the elderly population and also the increased levels of activity seen in this patient group. Therefore, in treating the elderly traumatic patient, it is important to factor in the following considerations. While only compromising approximately 12% of the population, elderly patients account for approximately 28% of traumatic deaths. Elderly patients had twice the higher rate of mortality (after adjusting for Injury Severity Score and the Revised Trauma Score), and they were also more likely to succumb later [33]. While earlier literature had stated that the Injury Severity Score did not correlate to mortality in older patients, these studies were from series that included lower energy trauma

94  Orthopaedic Trauma in the Elderly

(such as slips and falls) into their overall study groups. However, if these injuries are excluded and then the actual traumatic mechanisms are examined, it has been conclusively demonstrated that the Injury Severity Scores correlate to mortality [34]. Additionally, Gallagher found that for patients older than sixty with Injury Severity Scores greater than fifteen, there was a 28% morbidity rate, a 36% 2-year mortality rate, and a 60% 2-year complication rate, with mortality rates increasing with patient age [35]. The timing of operative management of the elderly traumatic patient has been the subject of continued controversy. While medical optimization is necessary to minimize perioperative risks for the elderly, delays in operative management have been found to lead to significant increases in morbidity and mortality [28–31, 36]. However, the key to minimizing morbidity and mortality is to perform surgical intervention as soon as the patient is medically stabilized and adequately resuscitated. In the event that patients cannot obtain definitive treatment for their orthopaedic injuries due to underresuscitation, damage-control orthopaedics (by use of temporizing external fixation) may play a significant role. In the past 30 years, the role of the “trauma center” has played a vital part in the care and treatment of multiply injured patients. Recent studies have also shown that they, along with centers capable of aggressive intensive-care monitoring, have played a significant role in the care of the elderly traumatic patient. Meldon examined the Glasgow Coma Scale, the Injury Severity Score, and the role of acute care in octogenarians in different admission settings. He found that patients with an Injury Severity Score of 21–45 had a 56% survival rate if directly admitted to trauma centers as compared to an 8% survival rate if admitted directly to a community institution [37]. Other studies have also stressed the importance of referring traumatic elderly patients who require adequate resuscitation and monitoring to the appropriate facility initially, as delays in treatment and transfer resulted negatively in mortality rates [38].

Hip Fractures General Principles Hip fractures in the elderly can be devastating or fatal, and their effects on the patient’s functional and psychological status are significant. Currently, 250,000 hip fractures, at a total medical expenditure of approximately 9 billion dollars, occur annually in the United States. By 2040, 20% of the population will be older than 65 years of age, and the incidence of hip fractures is expected to double by the year 2050 due to aging trends [39–41].

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As individuals age, their chance of sustaining a hip fracture greatly increases, doubling every decade after 50 years. Hip fractures occur twice as often in females and are most frequently seen in Caucasian women (followed by Caucasian men, Afro-American women, and Afro-American men). This may be due to differences in bone density between different ethnic groups [42–44]. Institutionalized patients are also more likely to sustain hip fractures [45–47]. Typically, hip fractures in the elderly occur from lowenergy trauma (i.e., fall while walking on a flat surface). They can be intracapsular (femoral neck) or extracapsular (intertrochanteric or subtrochanteric). The location of the hip fracture has a significant impact on the healing potential of the fracture, and this has led to different methods of operative fixation. Vascularity is more significantly compromised with intracapsular fractures, and as such, the role of arthroplasty remains an integral treatment option as compared to extracapsular fractures. More than 90% of hip fractures in patients over 65 are femoral neck or intertrochanteric in origin with a slight predominance for intertrochanteric fractures in the octogenarians [48].

Presentation and Management Patients usually complain of hip and groin pain with an inability to bear weight on the affected extremity after sustaining a relatively low-energy fall. The supine patient will hold the affected extremity externally rotated with slight flexion at the hip; this position will present with a noticeable leg-length discrepancy. This position is one that yields the maximal capsular volume when there is a fracture hematoma, thus providing the most comfort [49]. During the evaluation of the patient, it is imperative that the physician ascertain the length of time from the onset of injury to presentation. Elderly patients who have been in positions of recumbency for prolonged periods will present with significant dehydration and electrolyte imbalance. These factors must be corrected before operative intervention. Additionally, the presence of pressure ulcers, rhabdomyolysis, and deep vein thromboses are likely following prolonged periods of immobilization. Evaluation of bony prominences, creatine phosphokinase, and Doppler ultrasonography, respectively, are warranted in any patient who presents after being “down” for an extended period of time. A throughout physical evaluation should include a neurovascular exam of the affected extremity, examination of each extremity and the spine for other injuries, documentation of any loss of consciousness, mental status exam, and assessment of skin integrity in appropriate areas. Medical consultation should be obtained to prepare the patient for possible surgery. Injury films, baseline labs, chest radiograph,

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Figure 94.1  Intertrochanteric hip fracture visualized on an AP view (a) and cross-table lateral view (b) of the right hip.

and electrocardiogram (EKG) should be attained at the time of presentation. Care should be taken when acquiring injury films, which must include an AP pelvis, a true AP of the affected hip, and a cross-table lateral of the hip (Fig. 94.1). Obtaining a frog-leg lateral in the case of a suspected hip fracture is detrimental by potentially causing pain, further displacing fracture fragments, and damaging vascular channels. Furthermore, a traction/internal rotation radiograph of the affected hip may aid in the diagnosis and surgical planning of the hip fracture [50]. Many centers have made a policy to acquire a baseline arterial blood gas (ABG) preoperatively, since hip fractures carry an inherent risk of deep venous thrombosis and pulmonary embolus (PE). However, a recent study has demonstrated that ABGs have poor positive predictive value for pulmonary embolism and add little to the positive predictive value or negative predictive value of a careful clinical examination. The study, therefore, concluded that acquisition of baseline ABGs as a routine part of the preoperative evaluation is not warranted [51]. The role of traction in hip fractures is debatable and subject to physician preference. While it may provide significant patient comfort in those with femoral shaft and subtrochanteric fractures, traction forces the hip into a less comfortable position (from its more comfortable flexed and externally rotated position). Therefore, it is not recommended that patients with hip fractures be placed into skeletal traction. To aid in patient comfort, however, a pillow under the affected limb may reduce pain. Furthermore, the

placement of a Foley catheter will eliminate the need for patient transfers to a bedpan, thereby reducing potential discomfort and further fracture displacement. When the diagnosis of hip fracture is suspected clinically, but not clear with routine radiography, other studies are indicated. As stated before, a traction/internal rotation view will help visualize the entire length of the femoral neck. This view is conducted by shooting an AP hip radiograph as the physician pulls traction at the ankle while internally rotating the hip 15° (the average amount of anteversion seen in the adult femoral neck). Care must be taken to avoid shearing the skin of the lower extremity while performing the maneuver. If question remains, CT scans, technetium bone scans, or MRI may detect presence of an occult hip fracture. However, CT scans have been found to be an inferior modality in detecting these fractures [52]. Both MRIs and bone scans are more sensitive than plain radiography in detecting occult hip fractures, but the bone scan can only detect fractures 2–3 days after injury. On the other hand, the MRI can detect occult fractures that are less than 24 h old [53]. Nonoperative care is reserved for selected patients who are nonambulatory and too ill to undergo anesthesia. Ultimately, the preferred treatment of a hip fracture is surgery. Operative stabilization or arthroplasty will decrease the period of nonweight bearing, risk of malunion/nonunion, cardiopulmonary complications, and mortality. Addition­ally, operative treatment has been shown to be the most economically advantageous as compared to nonoperative treatment [54].

94  Orthopaedic Trauma in the Elderly

The risk of deep venous thrombosis (DVT) or pulmonary embolism (PE) is a concern requiring preventive measures. Historically, warfarin has been considered the standard for prophylaxis. Currently, low-molecular-weight heparin (LMWH) has been used subcutaneously with good results, without the need for constant laboratory monitoring (as is required for warfarin). LMWH can be administered within 12–24 h postsurgically. In situations that will not permit the use of pharmacologic prophylaxis, an inferior vena cava filter may be used. Studies evaluating the use of subcutaneous unfractionated heparin for DVT prophylaxis in orthopaedic patients have demonstrated less efficacy as compared to warfarin and LMWH. However, continuous intravenous infusion of unfractionated heparin has been shown to be adequate prophylaxis in patients that are started on warfarin and awaiting therapeutic INR levels [55–58]. Preoperatively, patients should be given pharmacologic and mechanical prophylaxis (i.e., venodyne boots, pneumatic compression stockings, etc.). Twelve hours prior to surgery, pharmacologic prophylaxis should be withheld (to decrease intraoperative and immediate postoperative bleeding complications) while mechanical prophylaxis should be continued. The duration of DVT prophylaxis is still being debated. Prophylaxis is indicated while in the hospital after major surgery. There is evidence that the prevalence of asymptomatic deep vein thrombosis, detected by routine venography after major orthopedic surgery, is lower at hospital discharge in patients who have received 10 days rather than 5 days of prophylaxis. This observation supports the current ACCP recommendation for a minimum of 7–10 days of prophylaxis after hip and knee replacement, even if patients are discharged from the hospital within 7 days of surgery. As risk of DVT persists for up to 3 months after surgery, patients at high risk for postoperative DVT may benefit from extended prophylaxis (i.e., an additional 3 weeks after the first 7–10 days). Extended prophylaxis with low-molecular-weight heparin (LMWH) reduces the frequency of postdischarge DVT by approximately two-thirds after hip replacement; however, the resultant absolute reduction in the frequency of fatal pulmonary embolism is small (i.e., estimated at 1 per 2,500 patients). Indirect evidence suggests that compared with LMWH, efficacy of extended prophylaxis after hip replacement is greater with fondaparinux, similar with warfarin, and less with aspirin. Extended prophylaxis is expected to be of less benefit after knee than after hip replacement. In keeping with current ACCP recommendations, at a minimum, extended prophylaxis should be used after major orthopedic surgery in patients who have additional risk factors for DVT (i.e., previous DVT, cancer). If anticoagulant drug therapy is stopped after 7–10 days, an additional month of prophylaxis with aspirin should be considered [59].

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Outcomes As previously mentioned, the goal of hip fracture surgery is to restore the patient’s functional outcome. One study showed that at 1-year follow-up, 41% of patients regained their preinjury level of ambulatory function, 40% remained community or household ambulators but required assistive devices, 12% became solely household ambulators, and 8% became nonambulatory. The factors shown to improve the possibility of attaining the preinjury ambulatory status are outlined in Table 94.2 [28]. Initial mortality rates are increased in elderly patients with hip fracture compared to age-matched controls. Oneyear mortality can be as high as 25% [60, 61]. The highest rate is seen in the first 6 months, and these rates progressively decline to the same as those of age-matched controls by 1 year. Factors shown to negatively affect 1-year mortality rates are outlined in Table 94.1 [29]. Timing from injury to surgical stabilization has been a subject of debate. Multiple studies have cited conflicting recommendations, with some recommending immediate operative stabilization as the key to minimizing mortality [62]. However, other studies have also found no correlation between the delay of surgical intervention and patient mortality [63]. However, the majority of these studies have been based on retrospective reviews of patient records or heterogeneous population databases and were poorly controlled [60, 61, 64]. A prospective study from our institution, controlling for age, sex, and comorbidities, was comprised of 367 hip fracture patients who were not suffering from dementia, were capable of activities of daily living, and had ambulatory abilities prior to injury. The study demonstrated that a delay to surgical stabilization of more than two calendar days doubled mortality [30]. Similar findings were reported in a recent study by Moran that found that delays of greater than 4 days in patients medically fit for surgery led to higher mortality rates at 3 months and 1 year after injury [36]. Furthermore, another study also demonstrated that delays of operative management of hip fractures

Table 94.2  Hip fractures: factors influencing outcome Factors favorable to regaining Factors contributing to 1 year preinjury ambulatory status mortality Age below 85 years Preoperative ASA rating of I or II Intertrochanteric fracture Male sex Absence of dementia

Age over 85 years Preoperative ASA rating of III or IV Preinjury dependency in activities of daily living History of malignancy (excluding skin cancer) Development of one or more complications during hospitalization

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significantly worsened the ability to return to independent living, increased the risk of pressure ulcers, and increased the length of stay [31]. Postoperatively, disparities exist in the rehabilitation protocols outlined for these patients. Protocols range from nonweight bearing to immediate weight bearing as tolerated. Biomechanically, it has been shown that joint reactive forces are greater across the hip when comparing nonweight bearing to toe-touch weight bearing [65]. Additionally, balance and upper extremity strength are important issues to consider when asking the older adult to be limited in their weight bearing. When patients are allowed to weight bear as tolerated immediately postoperatively, they self-regulate the amount of weight on the injured extremity and gradually increase the amount of weight bearing over time [66, 67].

Femoral Neck Fractures Femoral neck fractures occur between the base of the femoral head and the intertrochanteric line. These fractures are considered intracapsular and, due to the location of the fracture relative to the femoral vascular anatomy, have significant effects on the blood supply to the femoral head. These implications weigh heavily on treatment options and their relative success rates. The main blood supply to the femoral head comes from branches off the medial and lateral femoral circumflex arteries (medial with much greater contribution). These arteries form an extracapsular ring at the base of the neck with ascending branches that are intracapsular, forming a network ending in bony perforators to the femoral head. The intracapsular extensions represent terminal vessels of the extracapsular ring; the ascending vessels are at significant risk during femoral neck fracture, especially when displaced. Minimal vascular contribution to the femoral head also comes from the ligamentum teres (Fig. 94.2). Many classifications have been used to describe femoral neck fractures. The most common classification is one derived by Garden in which Types I and II are nondisplaced while types III and IV represent displaced femoral neck fractures [68] (Fig. 94.3). Rates for future osteonecrosis of the femoral head or nonunion of the femoral neck fracture have ranged between 5 and 35%, with significantly higher rates in displaced fractures (5–10% for minimally displaced versus 20–35% for displaced) [68–72]. Nonunion requires reoperation in 75% of cases, while osteonecrosis requires revision surgery in only 30% of cases. Surgery is the treatment of choice for this injury. In situ pinning should be performed for only minimally displaced/ impacted fractures. Although these are inherently stable, they do have an 8–40% chance of displacement without

Figure 94.2  Contributing vessels to the major sources of blood supply to the proximal femur. Reprinted with permission from Browner, Jupiter, Levine, Trafton (2003) Skeletal trauma: basic science, management and reconstruction, 3rd ed. WB Saunders, Philadelphia. Copyright Elsevier (2003).

operative stabilization [73, 74]. Postoperatively, all patients should be allowed to weight-bear as tolerated with assistive devices, especially due to the difficulty the elderly have in following weight-bearing, gait, and balance guidelines. Furthermore, these patients will regulate their weight bearing based on pain [67]. In displaced fractures, obtaining and maintaining an adequate reduction with pinning is not always possible or advisable. In a physiologically younger patient, all efforts should be made for closed reduction and pinning, but in a physiologically older patient, there is a lower threshold for arthroplasty. This lower threshold is partly due to the lower demands that physiologically older patients would place on the implant, increasing its longevity. In a recent meta-analysis comparing internal fixation and arthroplasty for displaced femoral neck fractures, the authors found that arthroplasty significantly reduces the risk of revision surgery, but at the cost of greater infection rates, blood loss, and operative time [75]. Early reports raised concern for increased operative times and higher dislocation rates for primary total hip arthroplasty when performed for fractures as opposed to degenerative joint disease [56, 76]. However, Blomfeldt determined that a

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Figure  94.3  Modification of Garden Classification of femoral neck fractures into Displaced (III and IV) and Nondisplaced (I and II) categories. Reprinted with permission from Browner, Jupiter, Levine, Trafton (2003) Skeletal trauma: basic science, management and reconstruction, 3rd ed. WB Saunders, Philadelphia. Copyright Elsevier (2003).

total hip replacement provides better function than a bipolar hemiarthroplasty at 1 year postoperatively without increase the complication rate in the elderly [77]. Before entertaining the option of hip arthroplasty, one must ascertain if the patient can follow postoperative arthroplasty precautions to avoid dislocation. Neurologically impaired or cognitively impaired patients are suboptimal candidates. Currently, total hip arthroplasty is now the treatment of choice in the active elderly and, with improved implants and surgical technique, provides results that exceed those produced by hemiarthroplasty. In the rare case of nonoperative care for femoral neck fracture, early mobilization to a wheelchair, adequate anesthesia, decubitus precautions, and physical therapy as tolerated are begun as soon as the patient is able to tolerate such activity. However, this option results in poor outcomes and should be avoided in those that can tolerate the surgery and the rehabilitation protocol.

Intertrochanteric Fractures The intertrochanteric region is extracapsular, distal to the femoral neck between the greater and lesser trochanters. Since this region consists of metaphyseal bone with an abundant

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blood supply, there is less danger of healing complications as compared to what is noted for femoral neck fractures. An important area of the intertrochanteric region is the calcar femorale. Located posteromedially, this area is an area of dense cortical bone that acts as an internal strut for the significant forces transmitted through the hip. The disruption of this region creates an unstable fracture pattern, and therefore, the implant of choice for treatment is dependent on the integrity of the calcar femorale. The greater trochanter lies superolaterally and is the insertion site of the hip abductors and short external rotators. The lesser trochanter lies posteromedially and is the insertion site of the iliopsoas (Fig. 94.4). It is important to determine radiographically if these fractures are stable. The ability to obtain stability is based on cortical continuity of the calcar femorale. On plain radiographs, this stability is gauged by the lesser trochanter’s position. If the lesser trochanter is nondisplaced without comminution, then the fracture is termed stable while displacement and comminution represents an unstable fracture. Other markers of instability include fractures that propagate from a superomedial to inferolateral direction (also known as “reverse obliquity” fractures), fractures with excessive posterior sag, and intertrochanteric fractures that extend into the subtrochanteric region. Reduction attempts to establish stability are performed with axial traction, and progression from abduction to adduction. Internal rotation will lock the fracture fragments while axial traction is maintained in adduction [78] (Fig. 94.5). Surgery is the treatment of choice for almost all intertrochanteric fractures. Indications and goals for nonoperative treatment are similar to those mentioned for femoral neck fractures, but it should be noted that these fractures are often more difficult to manage nonoperatively because of pain and deformity associated with excessive muscle pull and fracture displacement. Closed reduction is attempted after spinal or general anesthesia has been initiated, usually on a fracture table. If reduction is unobtainable by closed means, an open reduction is performed. Commonly, a device incorporating a sliding screw and barrel inserted into the femoral neck with an accompanying side plate (also known as the “sliding hip screw”) or intramedullary component is used. The telescoping nature of the implant supplies stability and facilitates compression across the fracture site to stimulate bony healing. The intramedullary devices are currently recommended for more unstable intertrochanteric fracture patterns, while the sliding hip screw design is more appropriate for stable fractures. Currently, lesser trochanteric fractures are not reduced and stabilized with hardware [79]. Rarely, primary prosthetic replacement is indicated in cases of severe comminution. This implant differs from traditional arthroplasty components due to the disruption of the calcar femorale (a necessary structure for traditional arthroplasty components). Implanting these prostheses is associated

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b

a

Ischiofemoral ligament Greater trochanter Anterior interior iliac spine

Iliofemoral ligament

Greater trochanter Pubofemoral ligament

Trochanteric crest Lesser trochanter

Lesser trochanter Intertrochanteric line

Figure 94.4  Hip joint with significant structures and capsule. Anterior (a) and Posterior (b). Reprinted with permission from Browner, Jupiter, Levine, Trafton (2003) Skeletal trauma: basic science, management and reconstruction, 3rd ed. WB Saunders, Philadelphia. Copyright Elsevier (2003).

Figure 94.5  Nondisplaced and displaced stable (a) and unstable (b) intertrochanteric fractures. Reprinted with permission from Browner, Jupiter, Levine, Trafton (2003) Skeletal trauma: basic science, management and reconstruction, 3rd ed. WB Saunders, Philadelphia. Copyright Elsevier (2003).

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with prolonged operative time, increased blood loss, and higher rates of dislocation as compared to elective total hip arthroplasties [79]. Subtrochanteric Fractures The subtrochanteric region of the femur lies in the first 5 cm of the femur distal to the lesser trochanter. Fractures in this area are less frequent in the elderly than femoral neck or intertrochanteric fractures. Although these occur with highenergy situations in the young, they may follow a simple fall in aged individuals [43, 80]. Stability in these fractures is also based on the integrity of the posteromedial cortex [81]. Usually, these injuries are treated with an intramedullary nail or fixed angle sliding plate and screw implant. Osteonecrosis is rarely a concern with these extracapsular fractures [82, 83]. The challenge with operative fixation for subtrochanteric fracture lies in obtaining an anatomic reduction prior to implant insertion. The significant amount of displacement is due to the numerous deforming muscle forces in this region of the femur [84] (Fig. 94.6).

Figure  94.6  Subtrochanteric region of femur. Contributing muscle forces to displacement of fracture fragments. Reprinted with permission from Browner, Jupiter, Levine, Trafton (2003) Skeletal trauma: basic science, management and reconstruction, 3rd ed. WB Saunders, Philadelphia. Copyright Elsevier (2003).

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The operative treatment for subtrochanteric fractures requires adequate reduction prior to fixation. Fixation devices include intramedullary nail devices, fixed angle devices (such as blade plates or dynamic condylar screws), and locked plate devices. The use of a sliding hip screw has been found to yield unacceptable failure rates [85, 86].

Ankle Fractures Ankle fractures are very common fractures and on the rise in the geriatric population. The ankle joint consists of the distal aspects of the tibia and fibula (medial and lateral malleoli) and their articulation with the talar dome. The medial malleolus is connected to the navicular, calcaneus, and talus by the superficial and deep layers of the deltoid ligament. The lateral malleolus is connected to the talus and calcaneus by a three-ligament complex. The tibia and fibula maintain their relationship via a ligamentous complex known as the syndesmosis (which comprises of the anterior-inferior tibiofibular ligament, the interosseous ligament, the posterior tibiofibular ligament, and the transverse ligament) located distally (Fig. 94.7). These ligaments stabilize the ankle joint, or the mortise, by opposing the fibula in the fibular notch (also known as the incisura fibularis tibiae). Injuries to the ankle can occur by many mechanisms, with the majority being low-energy rotational injuries [87, 88]. Frequently, ligamentous and bony injury can result from a twisting mechanism. Injuries can be bony, ligamentous, or a combination of both. Because bony and/or ligamentous injuries may both produce an unstable ankle joint, negative radiographs do not clearly rule out the presence of an unstable joint. If ligamentous injury is suspected due to signs and symptoms medially in the presence of an isolated fibular fracture, an external rotation stress radiograph should be considered [89]. Patients with ankle injuries often complain of an inability to stand or ambulate along with tenderness around the ankle joint following trauma. The patient may present with swelling and ecchymosis around the ankle. The circumstances of the injury must be elicited to establish the mechanism of injury. Many injuries that may be overlooked during the evaluation of ankle fractures should be excluded through a screening exam. These include fractures of the proximal fibula, lateral process of the talus, anterior process of the calcaneus, and proximal fifth metatarsal [90]. A standard radiographic series includes three views of the ankle joint (AP, lateral, and mortise (15° internal rotation view)) and fulllength tibia/fibula films to exclude syndesmotic injury (also known as a Maisonneuve fracture, noticed by a fracture along the proximal fibula). Foot films may also be considered if the physical examination of the foot reveals suspected pathologies.

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a

c Deep anterior talotibial

Superficial talotibial

Calcaneotibial

Anterior talofibular

Posterior talofibular

Deep posterior talotibial

B Deep deltoid ligament

Naviculotibial

A

Superficial deltoid ligament

Fibulocalcaneal

b

IOL PITFL

AITFL

ITL AITFL

ANTERIOR

AITFL POSTERIOR

PITFL LATERAL

Figure 94.7  Ankle joint with ligamentous restraints: medial (a), syndesmosis (b), and lateral (c). Reprinted with permission from Browner, Jupiter, Levine, Trafton (2003) Skeletal trauma: basic science, man-

agement and reconstruction, 3rd ed. WB Saunders, Philadelphia. Copyright Elsevier (2003).

Treatment of ankle fractures depends on the mechanism of injury and stability of the fracture. An isolated fibula fracture occurring at or below the level of the tibia–talus articulation without medial-sided injury is considered stable and may be treated in a short leg cast or brace with early weight bearing. Fractures that are considered unstable are bimalleolar, bimalleolar equivalents, or those with a disruption of the syndesmosis (i.e., high fibula fracture with medial joint line tenderness, widening of the medial clear space of the tibia–talus articulation, or dissociation of the tibia–talus or tibia–fibula articulations). Slight malreduction may result in degenerative arthritis [89]. Surgery provides a stable reduction and allows the patient to begin early joint range of motion to help avoid later stiffness and risk of malreduction. In contrast with nonoperatively treated patients, surgically treated patients do not require long-leg immobilization and can be more easily mobilized with assistive devices. Operative intervention has been shown to achieve better fracture position and better patient satisfaction, although complications with hardware loosening have been seen in women with osteoporosis [91, 92]. The presence of diabetes,

vasculopathy, or history of smoking increases the risk for soft-tissue complications (i.e., infection, wound dehiscence, etc.) with surgery.

Proximal Humerus Fractures Proximal humerus fractures are frequently encountered in the geriatric population and occur four times more commonly in women [94]. Typically resulting from low-energy falls, the initial treatment of these fractures frequently requires immobilization, which interferes with activities of daily living. The majority of these fractures are stable and are best treated nonoperatively. The shoulder joint has a complex bony and soft tissue relationship. The round humeral head articulates with the relatively flatter and shallower glenoid to form a joint that, while able to enjoy a relatively larger and more unrestricted range of motion, relies heavily on its soft-tissue connections for its stability. The shoulder capsule envelops this joint to provide static stability. Superficial to the capsule, the rotator

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Figure 94.8  Shoulder joint with representation of rotator cuff restraints. Anterior and posterior views (from http:// www.nlm.nih.gov/medlineplus/ ency/imagepages/19622.htm).

cuff, composed of the supraspinatus, infraspinatus, teres minor, and subscapularis (Fig. 94.8), with the help of the deltoid and scapular rotators, provide dynamic stability to the shoulder throughout its active range of motion. Each of these rotator cuff muscles insert into specific points on the humeral head, and each provide a direct of motion and stabilization integral for proper shoulder function. Proximal humeral fractures result in relatively predictable fragments or parts based upon anatomic regions. Typically, they result in fragments that can be separated out as the humeral head, the greater tuberosity, the lesser tuberosity, and the shaft. Because of the typical insertion of the rotator cuff on some of these fragments, the pull of these muscles causes predictable directional displacement of these fracture fragments. As it is obvious to see that these fractures will affect the tension and function of these rotator cuff muscles, poorly treated proximal humerus fractures can significantly affect shoulder function and, therefore, patient outcome. Patients with proximal humerus fractures complain of an inability to move the arm secondary to pain. During assessment of these fractures, it is imperative that a thorough neurovascular examination documents the presence of intact vascularity (distal pulses may be intact despite vascular injury about the shoulder due to the rich collateral flow) and sensation about the lateral aspect of the deltoid (to rule out damage to the axillary nerve or musculocutaneous nerve). While it will be difficult to assess deltoid strength to document axillary nerve integrity, the patient may be capable of slightly tensing their deltoid to demonstrate the nerve’s function.

To adequately assess proximal humerus fractures radiographically, the physician should obtain at minimum three views of the shoulder. The shoulder “trauma series” includes the anteroposterior (AP), scapular “Y,” and axillary views. Of particular importance is the axillary view, which is imperative to adequately document the presence of associated dislocations of the humeral head. However, the axillary view, unlike the AP and scapular “Y” views, is not the view used to measure the amount of fracture displacement or angulation [94]. Minimally displaced fractures represent 80–85% of what is seen in the elderly for injuries to the proximal humerus [95]. Provided that the fracture fragments move as “a unit” on clinical examination, it can be assumed that the surrounding soft tissues and periosteum provide stability. As such, these injuries can be treated with a brief period of sling immobilization (for approximately 1 week), followed by range-of-motion exercises (progressing from passive to active-assisted over 4–6 weeks). Minimally displaced proximal humerus fractures usually result in painfree union [96, 97]. It is important to initiate early mobilization (as early as 72  h to less than 2 weeks) for impacted fracture that are treated nonoperatively, as it has been shown to help with quicker restoration of the physical capability and performance of the injured arm as compared to longer periods of immobilization (prior to commencement of therapy) [98, 99]. The role of surgical intervention has recently changed due to rising patient expectations and the innovation of fixation technologies. In the past, multifragment displaced fractures

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that do not “move as a unit” on exam were occasionally treated nonoperatively. However, with more emphasis and importance placed on restoring the anatomy of the bony fragments with the appropriate rotator cuff tension and orientation, more of these fractures are undergoing operative treatment. Currently, the role and timing of surgery has been the subject of debate; however, if the patient is medically capable of undergoing operative treatment and will benefit from a function shoulder, then operative intervention is considered. Acute fracture/dislocations of the proximal humerus, however, should be addressed with operative intervention. Past studies had demonstrated that acute hemiarthroplasty is superior to attempting surgical stabilization and conducting delayed hemiarthroplasty [100, 101]. However, a recent study has shown no differences in outcomes associated with pain and patient satisfaction comparing acute versus delayed hemiarthroplasty. All patients had variability in outcomes related to function, and the only difference seen in delayed hemiarthroplasty was increased amounts of scar tissue during the surgical exposure [102]. Overall, low-energy, minimally displaced fractures exhibit better functional outcome compared to high-energy three and four part fractures with associated rotator cuff injuries [103]. Prosthetic replacement results in predictable pain relief, but its ability to result in predictable functional outcomes is more variable [104, 105].

Distal Radius Fractures Fractures of the distal radius are frequently seen in elderly patients, particularly women, who fall on an outstretched hand. Predisposing factors are osteoporosis, increased incidence of falls in the elderly, dementia, poor eyesight, decreased coordination, medications, and history of strokes or transient ischemic attacks [106]. The wrist is composed of eight carpal bones and the distal radius and distal ulna. The articulations are maintained via a complex ligamentous network on both the dorsal and volar aspects of the wrist. Important factors in predicting a patient’s need for surgery and ultimate outcome include the amount of displacement of the fracture fragments (assessed by its amount of angulation, comminution, and shortening), articular surface involvement, and preinjury level of function [107]. While dorsally angulated distal radius fractures that heal in this position can lead to abnormal carpal bone kinematics that may cause significant functional limitations [108], the possibility and clinical significance for the elderly wrist to undergo such changes is questionable. The presentation of distal radius fractures is pain, swelling, and wrist deformity. The force responsible for a distal

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radius injury can be transmitted proximally and can result in elbow injury. Radiographic examination should consist of PA, lateral, and oblique views of both wrists. Views of the contralateral wrist help in evaluating the adequacy of reduction. The ability to determine the stability of a distal radius fracture was initially evaluated by the Lafontaine criteria [109]. Lafontaine suggested five factors to indicate instability: (1) initial dorsal angulation grater than 20°, (2) dorsal comminution, (3) radiocarpal intraarticular involvement, (4) associated ulna fractures, and (5) age greater than 60 years. However, recent studies have demonstrated that age was the only statistically significant risk factor in predicting secondary displacement and instability [110]. If the patient is physiologically active, has higher demands, and has an injury that involves the dominant extremity, treatment should be guided toward an anatomic reduction. Recent studies with the volar fixed-angle plate device for unstable distal radius fractures have shown it to provide stable internal fixation and allow early function [111]. However, in sedentary patients with low demands, functional outcomes are good despite the presence of deformity [112]. Common fracture patterns include: Colles (dorsally displaced articular surface with apex-volar angulation), Smith’s (volarly displaced articular surface with apex-dorsal angulation), Barton’s (volar or dorsal shear), nondisplaced, and concomitant fracture of the distal ulna [113] (Fig. 94.9). The goal of treatment is to restore function, enable painless range of motion, and maintain grip strength. Whether cast immobilization or surgery is conducted, finger range of motion is encouraged from the onset of injury since finger stiffness can adversely affect outcome. Acutely, distal radius fractures should be treated with a reduction and splint immobilization to grossly maintain alignment, protect neurovascular structures, and allow for swelling. Nondisplaced or stable, reduced fractures can ultimately be treated with a short-arm cast for 4–6 weeks. When anatomic reduction cannot be obtained or maintained, surgery, with external fixation or open reduction and internal fixation, is required. Implants and devices available to maintain anatomic reduction include plates, external fixators, pins, bone grafting, and calcium phosphate cement. Some of these implants and devices are used concurrently with the other implants or in isolation, depending on the fracture personality, patient factors, and surgeon familiarity. If an adequate reduction is not obtained and if range of motion exercises are not encouraged, the incidence of pain, stiffness, and decreased grip strength greatly increases. Anatomic reduction (stable fixation) combined with early therapy results in excellent outcomes for up to 90% of patients [114].

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Figure 94.9  Common patterns of distal radius fractures: Colles’ (a) and Bartons (b). Reprinted with permission from Browner, Jupiter, Levine, Trafton (2003) Skeletal trauma: basic science, management and reconstruction, 3rd ed. WB Saunders, Philadelphia. Copyright Elsevier (2003).

Metastatic Pathologic Fractures As neoplasms are prevalent in the elderly, pathologic or impending fractures are relatively common. With higher rates of survival for patients with cancer, the physician should

encounter more skeletal neoplasms than what was initially seen in the past. The most common form of cancer found in bone is a result of metastases [115]. Metastases usually arise from primary neoplasms in the prostate, breast, lung, kidney, and thyroid [116].

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Prostate, adenocarcinoma, Hodgkin’s lymphoma, and some breast cancers can be osteoblastic (“bone-forming” lesions that are radio-opaque on X-ray). Lung, kidney, thyroid, and some breast cancers are osteolytic (“bone-destroying” lesions that are radio-lucent on X-ray). Both osteoblastic and osteolytic tumors disrupt normal bony architecture and promote fractures. Most metastases affect the axial skeleton and the appendicular skeleton proximal to the knee and elbow. An exception is lung cancer, which is seen to metastasize distally. Multiple myeloma and lymphoma are common primary malignancies in older adults [117]. Nonoperative intervention includes casting and immobilization of the affected bone. Risks of immobilization include pneumonia, decubiti, and thromboembolic phenomena. Thromboembolism is especially a concern in this patient population, as their associated malignancies predispose these patients to a hypercoagulable state. Nonoperative treatment of patients with metastases is associated with higher rates of nonunion. Operative treatment is preferable in patients with impending and completed pathologic fractures. Internal stabilization with intramedullary rods is frequently used in instances of long-bone involvement. The literature suggests a minimum life expectancy (between 1 and 3 months) for operative intervention [117, 118]. Most importantly, the goal of operative stabilization is to improve the quality of remaining life. This decision should be made following discussion between the surgeon, oncologist, patient, and caregiver. Upper extremity surgery can potentially improve independence with activities of daily living by relieving pain and providing stability. Lower extremity surgery can promote ambulation or transfers in the remainder of life. Most importantly, surgical stabilization, with or without adjunctive chemotherapy and radiotherapy, can alleviate pain. Prior to undergoing surgery, a full-body bone scan and selected radiographs help determine sites of other metastases. Many authors advocate prophylactic internal fixation of impending pathologic fractures based on size and location of lesions [117]. The decision to proceed with prophylactic stabilization should be made based on the patient’s level of function, pain, and life expectancy.

The Role of Rehabilitation The role of rehabilitation is another important consideration in the treatment of geriatric trauma. Traumatic injuries may limit the patient’s ability to ambulate and perform activities of daily living, and these limitations may lead to progressive loss of functionality, associated morbidity and mortality from prolonged recumbency, and increased length of hospital

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stay [31]. In addition, treatments rendered to these patients have various weight-bearing and functional restrictions, and patients must be instructed and trained within these parameters to optimize their outcomes. As such, specific rehabilitation regimens, degrees of weight-bearing tolerances, and the length of rehabilitation have been extensively discussed in the literature. These rehabilitation services come in the form of physical and occupational therapists, social workers, case managers, and inpatient versus outpatient rehabilitation centers. The decision to use one or a combination of these services is dependent upon the patient’s injury, cognitive, functional, and social support status, the presence of polytrauma, the rendered treatment(s), and the type of rehabilitation desired by the treating physician. The role and effectiveness of an inpatient rehabilitation program in the geriatric trauma population have been examined in the literature. Kauh et al. performed a retrospective observational pilot study examining the discharge outcomes, postdischarge health care use, and death rates among patients treated in a postacute geriatric rehabilitation unit (GRU) housed within a skilled nursing facility (SNF) with those treated in a traditional SNF [119]. At discharge from the nursing facility, GRU patients showed greater improvement in activities of daily living and mobility, had a significantly shorter length of stay, and were discharged to home more often. At 1 year, GRU patients had significantly fewer hospital readmissions. While GRU patients also had fewer emergency department visits and days in the hospital at 1 year, these results were not significant. The authors concluded that GRU may be an effective means to improve patient outcomes and reduce undesirable health care use after an acute illness. Logters et al. examined strategies for postoperative care of patients with hip fractures, which included early discharge from the acute-care hospital and inpatient interdisciplinary rehabilitation facilities [120]. This prospective study examined the patient’s activities of daily living before, at the end of rehabilitation, and 1 year after trauma. In addition, patientrelated variables were correlated with these results. Ninety percent of patients improved their activities of daily living during rehabilitation. However, within 1 year, 40% of patients had deteriorations in their activities of daily living. Fifty-one percent of patients were reintegrated back to their homes, and patients who lived at home before trauma and were reintegrated back to their homes had significantly better activities of daily living at 1 year after trauma than patients who were living in a nursing-care facility before the trauma. The variables of age, level of cognition, and type of fracture had no influence on the long-term outcome. However, the study also noted that an extension of rehabilitation above the mean time period did not improve the sustainable clinical outcome

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and that their policy for early discharge to geriatric rehabilitation is associated with extension of overall hospital stay. Therefore, the authors concluded that the benefits noted in this study should be weighed against the related increased health care costs. However, there are other studies that do not demonstrate the benefits of inpatient rehabilitation. Koval et al. assessed the impact of an instituted intensive inpatient rehabilitation

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on outcomes after femoral neck or intertrochanteric fractures [121]. Comparing patients managed with an instituted inpatient rehabilitation program to those who were not, the authors noted no differences in the hospital discharge status or in the walking ability, place of residence, need for home assistance, or independence in basic and instrumental activities of daily living at the 6 and 12-month followup examinations.

Case Study The patient is an 85-year-old woman with a history of hypertension and coronary artery disease. She is a limited community ambulatory requiring the occasional use of a cane as an assistive device. The patient sustained a closed right distal femoral spiral fracture after a mechanical fall (Fig. 94.10). In the emergency room, the patient was placed into skeletal traction and admitted for treatment. After the patient was medically cleared for surgical intervention, she was taken to the operating room and treated with a periarticular locked plate. The decision to use this construct was based on the osteoporotic quality of her distal femur. There were no complications intraoperatively, and the patient was kept on antibiotic prophylaxis and initiated on DVT prophylaxis with enoxaparin. A continuous passive motion (CPM) machine was instituted on the first postoperative day to initiate passive range of motion to her right knee (from 0 to 90°). The CPM machine was continued for three days after surgery to maintain knee motion. The patient was kept nonweight bearing on her affected extremity for 6 weeks. Starting on the first postoperative day, the physical therapist assisted the patient with ambulation under these weightbearing parameters. The patient was subsequently transferred to an inpatient rehabilitation facility four days after surgery, and progressed well with the therapy program. The patient was discharged from the facility 3 weeks after admission. Radiographic examination of her affected extremity 6 weeks after surgery revealed callus formation along the fracture site (Fig.  94.11). At this point, the patient was permitted to perform partial weight-bearing activities with assistive devices. Three months after the surgery, the patient was nontender at the fracture site, and radiographs demonstrated adequate bony healing. The patient was then allowed to bear weight as tolerated.

Figure 94.10  Right distal femur spiral fracture: AP view (a) and lateral view (b).

Figure 94.11  Right distal femur spiral fracture status-post periarticular locked plate fixation.

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Conclusion Orthopaedic injuries are responsible for significant morbidity and mortality in the geriatric population. With increasing life-expectancy trends, orthopaedic problems are likely to increase. Ideally, treatment should focus on prevention of falls and management of osteoporosis. The primary goals of treatment are to decrease pain, allow mobilization, and return the patient to their prior level of functioning. Treatment must include patient education and rehabilitation. The improvement in functional outcomes borne from these interventions has been shown to result in decreased longterm cost to the health care system [122]. Acknowledgements  The authors wish to acknowledge Drs. Frank A. Liporace and Kenneth J. Koval for their work in this chapter.

References 1. Stevens JA, Olson S (2000) Reducing falls and resulting hip fractures among older women. MMWR Recomm Rep 49(RR-2):3–12 2. Kannus P, Parkkari J, Sievanen H, Heinonen A, Vuori I, Jarvinen M (1996) Epidemiology of hip fractures. Bone 18(1 suppl): 57S–63S 3. Zuckerman JD (1996) Hip fracture. N Engl J Med 334:1519–1525 4. Vu MQ, Weintraub N, Rubenstein LZ (2006) Falls in the nursing home: are they preventable? J Am Med Dir Assoc 7(3 Suppl): S53–S58, 52 5. Epstein CD, Peerless J, Martin J, Malangoni M (2002) Oxygen transport and organ dysfunction in the older trauma patient. Heart Lung 31(5):315–326 6. Johnson KD, Cadambi A, Seibert GB (1985) Incidence of adult respiratory distress syndrome in patients with multiple musculoskeletal injuries: effect of early operative stabilization of fractures. J Trauma 25(5):375–384 7. Davis FM, Woolner DF, Frampton C, Wikinson A, Grant A, Harrison RT, Roberts MTS, Thakada R (1987) Prospective, multicentre trial of mortality following general or spinal anaesthesia for hip fracture surgery in the elderly. Br J Anaesth 59:1080–1088 8. Valentin N, Lomholt B, Jensen JS, Hejgaard N, Kreiner S (1986) Spinal or general anaesthesia for surgery of the fractured hip? Br J Anaesth 58:284–291 9. Parker MJ, Handoll HH, Griffiths R (2004) Anaesthesia for hip fracture surgery in adults. Cochrane Database Syst Rev (4):CD000521 10. Covert CR, Fox GS (1989) Anaesthesia for hip surgery in the elderly. Can J Anaesth 36(3 Pt 1):311–319 11. Loder RT (1988) The influence of diabetes on the healing of closed fractures. Clin Orthop 232:210–216 12. Chaudhary SB, Liporace FA, Gandhi A, Donley BG, Pinzur MS, Lin SS (2008) Complications of ankle fracture in patient with diabetes. J Am Acad Orthop Surg 16(3):159–170 13. Geerts WM, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG (2004) Prevention of venous thromboembolism: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126:338S–411S 14. Caprini JA, Arcelus JI, Maksimovic D, Glase CJ, Sarayba JG, Hathaway K (2002) Thrombosis prophylaxis in orthopedic surgery: current clinical considerations. J South Orthop Assoc 11(4): 190–196

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Chapter 95

Treatment of Degenerative Joint Diseases Philip J. Glassner, James Slover, and Joseph D. Zuckerman

If 60 is the new 40, then 80 is the new 60. Nowhere is this more evident than in an adult orthopedic surgery practice. As the population ages, the number of patients developing knee and hip pain is increasing. Patients are living longer and desire, and expect, to maintain high levels of activity and function throughout their lives. There are many causes of knee and hip pain in the elderly, the most common being osteoarthritis. The purpose of this chapter is to review the treatment options for this highly prevalent disease and to briefly discuss the other causes of knee and hip pain that may be encountered in elderly patients. Osteoarthritis can be treated with nonoperative or operative modalities. Once nonoperative therapies such as ­nonsteroidal anti-inflammatory medications (NSAIDS), physical therapy, assistive devices, activity modification, weight loss, and injections have been exhausted, operative management should be considered. Total knee arthroplasty (TKA) and total hip arthroplasty (THA) are the most common procedures performed to maintain the quality of a patient’s life. In 2004, the number of total knee and total hip arthroplasties being performed annually in the United States was approximately 478,000 and 234,000 [1], respectively. Those numbers are expected to increase dramatically to 3.48 million TKAs and 572,000 THAs by the year 2030 [2]. Excellent outcomes, as defined by pain relief and improvement in quality of life, can be obtained in well over 90% of patients with a multidisciplinary team approach to this elderly population, including internal medicine and its subspecialties, rehabilitation medicine, and the orthopedic surgeon [3–5]. Throughout the course of this chapter, we discuss the underlying pathology of knee and hip pain, the preoperative evaluation, the operation, and the postoperative protocols, along with risks, complications, and outcomes of knee and hip arthroplasty.

P.J. Glassner (*) Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, NY, USA e-mail: [email protected]

Causes of Knee and Hip Pain The most common cause of joint pain in the elderly is osteoarthritis, a disease primarily affecting articular cartilage. Articular cartilage is composed primarily of water ­(65–80%), collagen (the majority being type II collagen), proteoglycans, and chondrocytes. The function of cartilage is to decrease friction in the joint and to aid in an even distribution of forces to the subchondral bone. Synovial fluid lubricates the articular cartilage and nourishes it via diffusion, as articular cartilage is avascular [6]. Osteoarthritis is characterized by changes in articular ­cartilage, including an increase in the water content of collagen, alterations in the proteoglycans, and a failure of the chondrocytes ability to repair the cartilage. This degenerative process increases pressure on the subchondral bone, leading to remodeling and sclerosis of the bone, the formation of osteophytes and subchondral cysts, and asymmetric joint space narrowing. These are the most common findings on radiographic evaluation. It is important to note in the evaluation process that there may be little correlation between the amount of joint degeneration seen on radiographs and the symptoms of the patient. That is to say, a patient with advanced degeneration on a radiograph may have very little pain, and vice versa. This pathologic process ultimately leads to complete destruction of the articular cartilage, with boneon-bone contact, and a stiff, painful joint. Another important component of the knee joint is the meniscus, which also aids in load distribution. It is a C-shaped fibrocartilaginous structure located between the femur and the tibia. Originally, the meniscus was thought to be an embryological remnant, and if torn a total menisectomy was performed. However, in 1948, a study by Fairbank demonstrated late radiographic development of osteoarthritis following total menisectomy [7]. More recent studies have shown a strong correlation between complete menisectomy and poor outcomes [8,9]. Osteoarthritis is usually idiopathic, but it may be secondary to trauma, infection, ligamentous instability, osteonecrosis, or

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underlying metabolic and neurologic disorders. The underlying cause of joint pain may also be from a hemorrhagic arthritis, such as from hemophilia or sickle cell disease, or it may be an inflammatory process. The inflammatory diseases that cause knee and hip arthritis include rheumatoid arthritis (RA), systemic lupus erythematous (SLE), psoriatic arthritis, spondyloarthropathies, and crystalline arthropathies. There are laboratory findings that commonly aid in the diagnosis of these conditions, such as positive rheumatoid factor (RF) in rheumatoid arthritis and SLE, and positive HLA-B27 in ankylosing spondylitis (AS). Further, there are specific physical exam findings, such as morning stiffness in RA, as well as the altered radiographic findings of symmetric joint space narrowing, osteoporosis, and protrusio acetabuli that may suggest an inflammatory arthritis. If, during the evaluation of a patient, there is concern for an inflammatory process, appropriate lab work should be obtained, and referral to a rheumatologist as indicated.

Nonoperative Management The typical presentation of a patient with degenerative joint disease is that of an insidious onset of pain and stiffness, leading to limitations in function and a decrease in quality of life. The management of a patient depends on the clinical symptoms and findings, as well as on the radiographic stage. Patients with early disease will often have pain after prolonged activity, commonly medial-sided or anterior patellofemoral complaints in the knee, and groin and thigh pain with hip disease. As the process progresses, patients may develop pain at rest, pain that interferes with sleep, or pain that limits activities of daily living, such as the ability to use public transportation or even put on shoes and socks. Pain can be referred from elsewhere, and therefore, it is always important to examine adjacent joints. For example, one should examine a patient’s hips when they complain of knee pain, as pain may be referred to the knee from the hip via the obturator nerve. In addition, when evaluating knee or hip pain, one must always examine the spine, as pain may be referred to either location from a lumbosacral spine disorder. Standard radiographs should be obtained based on the patient’s history and physical exam. When imaging the knee, one should obtain a weight-bearing AP view, a lateral view, and a sunrise view to visualize the patellofemoral joint. For the hip, one should obtain an AP pelvis and cross-table lateral radiographs. Spine films can also be ordered as indicated. Review of the images will assist in the management of the patient by assessing the severity of the arthritic changes,

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aiding the ability to evaluate other possible causes of pain, including fracture or tumor. Once a diagnosis of ­degenerative joint disease has been made, a treatment plan can be reached based on the underlying pathology and the severity of patient symptoms. When a patient presents with joint pain, an attempt is made to relieve the symptoms. Often, the first line of treatment is a nonsteroidal anti-inflammatory medication (NSAID). It is imperative to take a careful medical history to identify contraindications to the use of NSAIDs, such as ­gastritis, ulcers, or renal disease, before prescribing any medication. Newer medications, such as the COX-2 inhibitors ­(coxibs), were initially expected to cause a dramatic decrease in gastrointestinal side effects due to their mechanism of action. There are numerous studies comparing traditional NSAIDS with the coxibs, with some evidence of decreased upper GI complications with coxibs. However, there are other studies that show no statistically significant difference [10–12]. If a patient has a history of ulcers or gastritis, it is often prudent to prescribe a proton pump inhibitor (PPI) in conjunction with the NSAIDs to protect against gastric bleeding [13]. There has also been concern over increased risk of cardiac complications with the use of the COX-2 inhibitors. This began following the results of the VIGOR and APPROVe studies, where rofecoxib (Vioxx) was shown to cause a significant increase in the rate of myocardial infarction or stroke, which led to the removal of rofecoxib from the market. Studies have been performed since that time, on other COX-2 inhibitors, because of concern of a class effect of the drugs. A meta-analysis by Zhang in 2006 showed that a statistically significant increased risk of hypertension, renal dysfunction, ventricular fibrillation, and cardiac arrest were only associated with rofecoxib. There was no significant increase in the events with the use of celecoxib (Celebrex) or ibuprofen (Advil, Motrin) versus placebo [14]. If concerns remain after thorough evaluation, it may be prudent to have the patient consult with their medical physician prior to starting an NSAID. Acetaminophen can also be prescribed, and it is not associated with GI or kidney problems, but high doses can lead to hepatic dysfunction. Tramadol is another option, as it acts uniquely on the mu-opioid receptor, providing pain relief without the side-effect profile of opioid medications (i.e., dizziness, constipation, respiratory suppression) and without GI or cardiac side effects. However, tramadol use must be monitored closely in patients with impaired renal or hepatic function [12]. If medications do not provide sufficient pain relief, an intra-articular injection may be offered. Options include either a lidocaine and corticosteroid combination or a series of viscosupplementation injections. Viscosupplementation

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consists of a series of 3–5 weekly injections of hyaluronic acid (HA) products. Knee injections are performed by the physician in the office, but hip injections are typically ­performed by a radiologist, as they utilize fluoroscopic, ultrasound, or CT scan guidance. In addition to providing pain relief, intra-articular injections can be used as ­diagnostic tools, to confirm the location of a patient’s symptoms. The lidocaine should provide almost immediate relief, and if it does not, one must consider other sources of the pain, such as referred pain from another joint. The corticosteroid may take 7–10 days to take effect and has variable results. A recent meta-analysis of knee injections by Aroll et  al. showed consistently significant improvement at 2 weeks, and several studies showed improvement at 16–24 weeks [15]. A Cochrane review of intra-articular knee injections demonstrated no significant difference between corticosteroid and HA at 1–4 weeks but showed improved efficacy of HA at 5–13 weeks [16]. That same review showed triamcinolone hexacetonide to be superior to betamethasone with regard to pain relief at 4 weeks after injection [16]. Subsequent injections of corticosteroids generally provide a shorter period of pain relief (i.e., “diminishing returns”), such that it is uncommon to consider more than three ­injections in a specific joint. Physical therapy and the use of assistive ambulatory aids can be used in conjunction with medications. Although patients are often reluctant to use a cane or a walker, as they do not like the stigma of appearing disabled, they should be counseled that assistive devices provide significant relief by decreasing contact forces at the joint and providing greater stability during ambulation [17]. If a patient is willing to use a cane, it should be placed in the hand on the painless side for hips and on the painful side for knees. The role of formal physical therapy is to strengthen the muscles around the joint, improve or maintain range of motion, and attempt to decrease pain. A recent systematic review of physical therapy for patients with OA of the knee showed that weight loss and exercise are effective at reducing pain and improving function [18]. The same review demonstrated that modalities such as transcutaneous electrical nerve stimulation (TENS) and acupuncture can provide pain relief, but further research is needed in these areas as the quality of evidence is not as high [18]. A recent randomized controlled trial looking at the use of physical agents (i.e., heat packs, TENS, short-wave diathermy) prior to exercise demonstrated improved function and decreased pain as compared to a group who received exercise alone [19]. Physical therapy has also been shown to be beneficial for OA of the hip, although manual therapy may be more beneficial than exercise therapy as demonstrated in a study by Hoeksma. In this randomized trial, the manual therapy group  had significantly better outcomes in pain, stiffness,

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hip ­function, and range of motion at 5 weeks, with some benefit ­lasting as long as 6 months [20]. Furthermore, in both OA of the knee and hip, patients have had significant improvements in pain, range of motion, and quality of life following aquatic physical therapy regimens [21]. This most likely reflects the decreased impact this regimen places on the joints. If these nonoperative options fail to provide sufficient relief, and a patient’s quality of life is declining due to the joint pain and limited function, a discussion of surgical options can be undertaken with the patient. The role of arthroscopy for degenerative joint disease is controversial. Several studies of arthroscopic debridement of osteoarthritic knees have shown significant improvements in pain relief, with high rates of patient satisfaction at up to 4 years [22–24]. However, a recent randomized controlled trial in The New England Journal of Medicine, as well as a Cochrane review, showed no added benefit of arthroscopic lavage and debridement over optimized physical and medical therapy in elderly patients with osteoarthritis [25,26]. There are far fewer studies evaluating the role of arthroscopy for degenerative joint disease in the hip, and most studies are small series of a younger population with early osteoarthritis. These studies did demonstrate good short-term results with debridement or microfracture, and arthroscopy may have a place in delaying the need for THA in young patients [27–29]. At this time, there is no data to support hip arthroscopy in the elderly patient. If a patient has unicompartmental disease of the knee, one surgical option is a high tibial osteotomy (HTO). This procedure is generally performed on young, active patients without inflammatory disease. Another option for unicompartmental disease is a unicompartmental knee arthroplasty (UKA), in which only the diseased medial or lateral compartment is replaced. This surgery maintains bonestock in the unresurfaced compartments, as well as maintaining the cruciate ligaments. This is also performed in patients without inflammatory disease, those with a mechanical axis of no greater than 10° varus or 5° valgus, and with flexion contractures less than 15°. This surgical option is typically used in younger patients as their first knee surgery with the expectation of needing a later conversion to a TKA, or in elderly patients as their last knee surgery as they may not outlive the prosthesis. A long-term follow-up study showed a 90 and 76% survival of UKAs versus HTOs respectively at 10 years, which dropped to 88 and 65% at 15 years [30]. Second decade survivorship of UKAs has been shown to be less than 90% in several studies and is often due to degeneration of the opposite compartment [30–32]. If HTO or UKA are not indicated or have been performed and failed, it is time for the patient to consider a total joint arthroplasty.

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Once a patient is indicated for surgery, it is essential that they undergo a complete medical evaluation, so that their health is optimized prior to surgery. The patient will require routine labs including CBC, BMP, coagulation panel, and type and screen. An EKG and chest radiograph is also obtained. If there is any abnormality noted on EKG, or the patient has a history of cardiac disease, they should receive a cardiology evaluation, with consideration for a stress test and/or echocardiogram for further evaluation. The patient should also meet with the anesthesia team prior to the day of surgery so that they can address any concerns from their viewpoint. Patients often donate 1 or 2 units of their own blood prior to surgery, or as an alternative, receive erythropoietin (EPO) preoperatively. The decision on which, if either, method is chosen is currently controversial. The initial impetus for donating autologous blood was a concern over disease transmission in the 1980s and 1990s. This risk has decreased with current testing techniques, but it still estimated to be 1 in 493,000 for HIV; 2 in 63,000 for hepatitis B; and 1 in 103,000 for hepatitis C [33]. Guidelines regarding blood donation or premedication are based on preoperative hemoglobin. Generally, for a Hgb of 14–15 g/dl no intervention is needed; for a Hgb of 10–13 g/dl, preoperative EPO should be considered, as predonating would decrease their Hgb further, thus increasing the need for allogeneic transfusion; and for those with a Hgb  13 g/dl are often given the option of donating blood preoperatively, although studies have shown that approximately 44% of these units are discarded. These guidelines are for patients undergoing primary joint arthroplasties [34]. When a patient is expected to have an increased blood loss, such as with a revision procedure, those with Hgb > 13 g/dl are often encouraged to predonate blood. Several studies have demonstrated the effectiveness of EPO. The first orthopedic studies were in the mid 1990s and showed a decrease in the risk of postoperative allogeneic blood transfusion from 53% in the controls to 16% in the patients who received EPO, which was statistically significant. When these groups were further stratified to the patients with preoperative Hgb between 10 and 13  g/dl, the results were even more impressive, with controls having a 78% risk of transfusion versus 14% in the EPO group [35–37]. A study in 2007, attempted to elicit postoperative ­differences in vigor and strength in patients who donated autologous blood compared with those who used EPO (600  IU/kg once weekly for 3 weeks preoperatively and a fourth dose within 24 h postoperatively). The study did not show significant differences in vigor or hand strength, but showed a significant difference in the need for allogeneic transfusion, with only 3% of patients in the EPO group

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receiving allogeneic blood versus 14% in the autologous donor group [38]. This debate has lead to the development of patient-­specific strategies (PSS) in which algorithms are used to determine the appropriate management of a specific patient. These algorithms are procedure-specific, and even hospital- or individual surgeon-specific, so that operative blood losses may be accurately predicted. These estimates, combined with an evaluation of a patient’s hemoglobin, weight, and medical comorbidities have led to preoperative management ­strategies that have caused decreased transfusion rates of 20–56%, reduced wasted autologous blood by 50%, and increased use of EPO by 11% [39,40]. All patients donating autologous blood or receiving EPO should receive iron supplementation. There are contraindications to the use of EPO, including severe heart disease, vascular disease, or recent myocardial infarction or stroke. Further, the prescribing physician should inquire whether a patient’s insurance policy provides ­coverage of the injections, as this varies by company and by state. Screening for methicillin-resistant Staphylococcus aureus (MRSA) is sometimes performed prior to elective surgery to try to decrease the risk of postoperative infection. This is performed using nasal swab cultures and at times perineal or groin swabs. Studies have shown that up to 5.3% of patients admitted electively to general or orthopedic surgical wards are colonized with MRSA [41]. Risk factors for MRSA infection include male gender, age >70, prior hospital admission, prior antibiotic treatment, and living in a long-term care facility [42]. If a patient has a positive MRSA nasal swab, they can receive mupirocin nasal ointment in an attempt to decrease their postoperative risk of surgical site infection (SSI). For positive skin cultures, triclosan bathing is often used. A study by Sankar compared postoperative infections in patients undergoing elective total joint arthroplasties before and after the implementation of a MRSA screening and treatment protocol. One patient developed a postoperative SSI with MRSA, and this patient was in the preprotocol group. However, there was a significant difference in the overall infection rate between the two groups, with more MRSA lower respiratory infections developing in the preprotocol group. The increased infection rate in the preprotocol group resulted in an increased length of stay and increased cost of care. They concluded that screening elective orthopedic patients for MRSA decreased morbidity and was costeffective [42]. A similar study was performed by Wilcox, in which pre- and postprotocol MRSA SSI infection rates in orthopedic patients were compared after introducing an MRSA screening and treatment program. Their results were more impressive with a decrease in MRSA SSI from 23/1000 to 3.3/1000 ( p 30° at 1–2 year follow-up [70,71]. Prior to manipulation, the alignment and rotation of the components should be carefully assessed as it could be a factor in poor range of motion. If there is any concern for infection, this should also be evaluated. This is discussed in detail later in the chapter. If a manipulation is unsuccessful, or >3 months have passed since surgery, and the prior concerns have been addressed, an arthroscopic or open lysis of adhesions may be performed. The success rates of these procedures have been variable, with improvements between 16 and 62° reported [72,73]. Overall, 95% of TKA patients have excellent satisfaction and improvement in lifestyle [3]. There are, however, several important complications such as infection, VTE, PE, prosthetic loosening, and periprosthetic fracture, which is discussed later in combination with THA, as the evaluations are quite similar. Follow-up appointments at 6 weeks, 3,6 months, 1 year, and every 1–2 years thereafter (with radiographs obtained at each visit) are an essential part of patient management.

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Case Study The patient is a 78-year-old female who presented for evaluation of bilateral knee pain, left greater than right. The pain had been present for 5 years and had been worsening recently. The knee pain was worse with activity. She used a cane for ambulation and could ambulate only six blocks before needing to rest secondary to her knee pain. She denied low back or hip pain and denied numbness or tingling in the lower extremities. She had received viscosupplementation injections to the knee in the past, which provided 1 year of relief, but the pain had now worsened. She had been treated with a course of physical therapy with limited benefits, and she utilized NSAIDs in the past, but they were discontinued due to peptic ulcer disease. Her medical problems included hypertension, urinary incontinence, and hypercholesterolemia. Medications included Lipitor, Foltx, Monopril, and hydrochlorothiazide. Physical examination revealed a healthy appearing elderly female in no acute distress. She walked with an antalgic gait referable to the left lower extremity. Examination of the left knee showed a moderate effusion and tenderness to palpation over the medial joint line and distal medial femoral condyle. There was no ligamentous laxity, and range of motion was 5–130°, with pain on extreme flexion. She had 5/5 strength of her quadriceps and hamstrings. Distally motor and sensory function was intact, and distal pulses were palpable. Examination of the right knee did not show significant findings; range of motion was from 0 to 125°. Screening examination of both hips was unremarkable. Examination of the lumbosacral spine showed painless range of motion, and a negative straight leg raise bilaterally. Radiographs of the left knee showed an area of osteonecrosis of the medial femoral condyle with ­secondary osteoarthritis of the medial compartment (Figs. 95.2–95.4). Right knee radiographs showed moderate osteoarthritis, primarily in the lateral compartment, but less pronounced than the changes noted in the left knee. Left total knee arthroplasty was recommended, and after extensive discussion, the patient decided to proceed. During preoperative medical evaluation, cardiac problems were identified, for which she underwent angioplasty and placement of two stents without complications. Her surgery was postponed until she was able to temporarily discontinue anticoagulation (Plavix), and final clearance was obtained from her cardiologist. She underwent left TKA without complication (Figs. 95.5–95.7). Initial postoperative monitoring was in the surgical intensive care unit, due to her medical ­history.

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She was placed on lovenox and SCDs postoperatively for DVT prophylaxis. She received one unit of packed red blood cells for postoperative anemia, to which she responded appropriately. She started physical therapy on postoperative day 1 for weight bearing as tolerated ambulation and range of motion, with the assistance of a CPM machine. Postoperative day 4, she was transferred to the inpatient rehab facility at our institution. She continued to progress well and was discharged to home 1 week later. At 6-week follow-up, she was doing very well, ambulating with a single cane. Knee ROM was from 0 to 105°. She had regained good strength, and a straight leg raise could be performed without extensor lag. She continued to progress well. At 2 year follow-up, she had painless ROM of 0–115° (Fig. 95.8). She had been able to perform her daily activities, including using public transportation and going to the theater. Her right knee pain, however, had slowly worsened for which she had received intra-articular steroid injections with good relief. If the pain continues to worsen, she will likely become a candidate for a right total knee replacement.

Figure  95.2  Bilateral weight-bearing AP knee radiograph of a 78-year-old female with bilateral knee pain, left greater than right. It shows an area of osteonecrosis in the left medial distal femoral condyle, with secondary osteoarthritis. Osteoarthritis is also seen in the right knee, more pronounced in the lateral compartment. (continued)

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Case Study  (continued)

Figure 95.5  Postoperative bilateral AP knee radiograph showing a left cruciate retaining total knee arthroplasty.

Figure  95.3  Lateral radiograph of the left knee showing osteoarthritis and vascular calcifications.

Figure 95.4  Sunrise radiograph of the left knee, showing osteoarthritis of the patellofemoral articulation, with large medial and ­lateral osteophytes.

Figure  95.6  Postoperative lateral radiograph of the left knee, showing cruciate retaining total knee arthroplasty, with a resurfaced patella. (continued)

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Case Study  (continued)

Figure  95.7  Postoperative sunrise radiograph of the left knee which shows proper positioning of the resurfaced patella within the ­trochlear groove.

Total Hip Arthroplasty History of THA Total hip arthroplasty is one of the most successful operations performed today. This is only possible due to the extensive work that was performed to develop the modern day prosthesis, beginning in the late 1800s and early 1900s. As with the knee, early attempts at relieving pain and preserving motion in the hip utilized interpositional biologic or inorganic materials such as autologous fascia lata grafts and even gold. The initial attempts were by Sir Leopold Ollier in the late 1800s, but did not have much success until the early 1900s when Sir Robert Jones reported its long-term outcomes [74–76]. As these methods were largely unsuccessful, Smith-Peterson developed the “mold arthroplasty” in which glass, and later materials such as Pyrex, was applied over the bleeding cancellous bone of the femoral head and acetabulum. While patients did have some initial pain relief, the molds failed within a few months due to their brittle nature. In 1937, the development of vitallium (a metal alloy) provided a material with better durability, thus improving patient outcomes [74–76]. In addition to the interpositional arthroplasties, the Judet  brothers in France performed early attempts at hip

Figure 95.8  Bilateral weight-bearing AP radiograph, 2 years after left TKA which shows excellent component alignment, and worsening right knee osteoarthritis.

a­ rthroplasty. They developed an acrylic femoral head replacement, which, unfortunately, failed rapidly due to high wear rates [74]. These efforts did provide a stepping-stone for the development of stemmed, metallic endoprostheses, which are similar to those used today. The problem with these metallic prostheses was an increased wear rate within the acetabulum, leading to persistent and worsening pain. Attempts were made to resurface the acetabulum with metal as well, but due to the high friction between the surfaces, abundant metallic debris was produced, leading to osteolysis and loosening. Some of the most important contributions to total hip arthroplasty were made by Sir John Charnley. He was able to take all of the lessons learned by his predecessors and develop the low-frictional torque arthroplasty. This decrease in friction was obtained by using a 22-mm metallic head with a polytetrafluoroethylene acetabular cup, which lowered the coefficient of friction to near that of the native total hip. This procedure was further improved by his use of PMMA to cement both the stem and the cup in place, allowing adequate fixation and a more uniform load distribution. An important change was made when the polytetrafluoroethylene was replaced by high-density polyethylene, and later ultrahigh-molecular-weight polyethylene, greatly decreasing wear rates [74–77]. The prevalence of total hip arthroplasties being performed began to increase steadily in the 1970s, as Charnley’s patients

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were experiencing good results. Continued modifications in cementing techniques further improved outcomes. However, concerns over component loosening, especially in younger individuals, led to the development of prosthetic designs that could be inserted without the use of cement. This has been quite successful, largely due to improvements in materials, component design, and the use of hydroxyapatite, providing successful bony ingrowth and stability of the prostheses. The search for the ideal materials for total hip arthroplasty is ongoing. This is evident by the more recent developments of highly cross-linked polyethylene, ceramic femoral head, and acetabular shell components, as well as a return to resurfacing with metal components. These newer components are being developed due to advances in material properties and the machining/processing of these materials. Recent studies have shown improved wear rates and improved hip stability, which may lead to better long-term survival of the prostheses. This continual research will likely maintain the reputation of total hip arthroplasty as one of the most successful operations performed.

The Operation Prior to the surgery, the standard protocols discussed for the TKA apply regarding the preoperative discussion with the surgeon and anesthesiologist, as well as regarding surgical site verification. After induction of general or spinal/epidural anesthesia, the patient is most commonly placed in the lateral position with the operative limb up. The patient is maintained in this position by the use of a well-padded hip positioner that keeps the pelvis fixed and stable. This is used for the posterior and anterior-lateral approaches, which are the most common. The patient is at times placed supine for the direct lateral or direct anterior approach. We discuss the posterior approach with placement of press-fit metal on polyethylene components, as this is the most common. There is a brief discussion of the advantages and disadvantages of the other surgical approaches and components later in the chapter. The exact use of retractors and steps can vary, but here, we describe a common approach used at our institution. The limb is sterilely prepped and draped, followed by drawing out the skin incision with a marker, centered over the posterior 1/3 of the greater trochanter. From the tip of the greater trochanter it extends proximally about 4–6  cm and distally 4–6 cm in line with the shaft of the femur. The incision is made with a scalpel through the skin and subcutaneous tissues, down to the level of the deep fascia. Any bleeding is coagulated with an electrocautery. An incision centered over the trochanter is made with a scalpel through the fascia. Proximally, the gluteus maximus muscle belly is split bluntly. A Charnley retractor is now placed beneath the fascial edges,

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and perpendicular to the wound for exposure. The bursa over the greater trochanter is now visualized, and gently peeled off with the use of a long-tipped electrocautery. This exposes the short external rotators of the hip. A cobra retractor is placed beneath the gluteus minimus tendon, and the piriformis tendon is visualized. The knee of the patient is now on a sterile bump, keeping the femur parallel to the floor. An assistant begins to internally rotate the limb, placing tension on the short external rotators. They are detached directly from bone, beginning with the piriformis tendon proximally, then distally through the superior gemellus, obturator internus, inferior gemellus, and a portion of the quadratus femoris. This is carried distally until the lesser trochanter is visualized. Prior to taking down the rotators, the sciatic nerve is palpated and carefully protected to avoid injury. The external rotators may be released separate from the hip joint ­capsule, or the capsule and rotators may be released together. A T-shaped capsular incision is made exposing the femoral head and rim of the acetabulum. The external rotators and capsule are then tagged with sutures, so that they can be repaired at the end of the procedure. The hip is then dislocated by gentle flexion, adduction, and internal rotation. The bump is then repositioned beneath the patient’s knee, keeping the femur level. A trial broach is used to mark the correct angle of the femoral neck osteotomy. The level of the cut is determined from preoperative templating and measured with a ruler from the lesser trochanter. An oscillating saw is used to make the osteotomy, carefully protecting the soft tissues. The femoral head is then removed, exposing the acetabulum. A cobra or Hohmann retractor is used to retract the femur anteriorly for visualization. Steinman pins are placed superiorly and posteriorly, with a cloverleaf retractor placed inferior. This provides excellent acetabular exposure. The remaining labrum is excised from the rim of the acetabulum, followed by removal of the ligamentum teres from the acetabular floor. Reaming is performed to reshape the acetabulum to match the implant. Initial reaming is performed with a small size, often 43 mm, removing the degenerative floor of the acetabulum and medializing. The size is sequentially increased by either 1 or 2 mm until the appropriate size is reached based on the preoperative templating and intraoperative assessment. During reaming, one must carefully position the reamers to obtain appropriate anteversion (15–20°) and coronal tilt (35–45°). The last reamer used is typically 1–2  mm smaller than the final implant size, for noncemented components (cemented acetabular components are rarely used during hip arthroplasty). A trial acetabular cup is then placed to assess proper fit. If the fit is correct, the acetabular component is then placed, using an antenna on the impactor handle to confirm proper positioning. With the appropriate version aligned, the cup is impacted. If there is concern over cup

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stability, screws may be placed to augment fixation. The polyethylene liner is then placed within the cup and impacted into place. Attention is turned to the femur after the acetabulum is completed. The limb is internally rotated, placing the lower leg perpendicular to the ground. A retractor is placed beneath the proximal femur, allowing visualization of the femoral canal. Soft tissues remaining anterior to the greater trochanter and superior to the remaining femoral neck are removed. A box osteotome is used to open the femur proximally, followed by a starting broach that is placed down the femoral canal. The canal is then sequentially enlarged with reamers and broaches until the appropriate fit is obtained. This is also guided by the preoperative templating. One must maintain proper version of the stem throughout the process. A trial femoral neck and head are then placed on the femoral broach, with the size and offset determined preoperatively to give the patient appropriate soft tissue tension and leg length. The hip is reduced and taken through range of motion testing to assess stability of the hip. Further verifications of appropriate size are made intraoperatively and compared with preoperative templating. When appropriate stability and length have been obtained, the trials are removed and the final stem is impacted into place. A trial femoral head is again placed for a final check of stability and limb length before placing the head. The wound is extensively irrigated with sterile saline. Two drill holes are then placed through the greater trochanter to allow reattachment of the piriformis, capsule, and the other external rotators. The deep fascia is repaired with interrupted sutures, followed by a similar closure for the deep and subcutaneous layers. The skin may be closed with staples, sutures, or a subcuticular absorbable stitch with Dermabond. A sterile dressing is applied. The drapes and hip positioner are removed, and the patient is placed supine on the table, with special care to maintain the hip abducted and externally rotated, as the most common position of dislocation is flexion, adduction, and internal rotation. This is assisted by the use of an abduction pillow. Clinical limb length is assessed, followed by obtaining an AP pelvis radiograph to assess final component placement, and assure that the hip is reduced prior to moving the patient to the recovery room.

Postoperative Course The initial postoperative course is quite similar to the TKA, in which IV fluids, foley catheters, hemovac drains, and epidural/PCA pain pumps are discontinued, with a goal of early mobilization. At least, the patient should be out of bed to a

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hip chair (an elevated chair to prevent flexion of the hip beyond 90°), and an incentive spirometer is used to prevent atelectasis on POD #1. Routine labs, including BMP and CBC, are drawn and addressed as needed. If a patient’s hematocrit is less than 27 and the patient is symptomatic (i.e., tachycardic, hypotensive, weak, dizzy), the patient may require a blood transfusion. In a patient with medical comorbidities, such as CAD or history of MI, the goal hematocrit is often 30 or greater, based on the preoperative recommendations of the medical team. Ambulation is begun with a walker and instruction by a physical therapist. The patient will be weight bearing as tolerated (WBAT) unless there is a concern over initial ­stability of the components, or a complication such as a fracture occurred. The therapist will also review hip precautions and demonstrate basic exercises such as dorsi/plantar flexion of the ankles and heel slides in the bed. This routine will continue, usually twice per day, until POD 3 or 4, when the patient is cleared for transfer to home or to a rehab center. A home nurse will remove skin staples, or sutures, at 2 weeks postoperatively, and the patient will continue home therapy. The first follow-up visit is at 6 weeks, followed by visits at 3, 6 months, and 1 year. Evaluation of gait, range of motion, and strength will be performed at each visit with radiographs obtained annually unless there are symptoms that necessitate radiographic evaluation. By the 6th week visit, the patient will often have progressed to the use of a cane. The overall success rate of THA is >95%, making it one of the most successful surgeries performed. This is based on outcome studies regarding the relief of pain and return of function. A patient may progress from being wheelchairdependent due to pain to ambulating and returning to work. The longevity of the prostheses is excellent as well, with 95% lasting 10–15 years [4,5,78]. The use of alternate bearing surfaces, and advancing technologies, may continue to improve these results. These alternate bearings include ceramic and all metal surfaces. They are primarily used in the younger population. In the elderly population, the components are routinely a cobalt-chrome metal head with a highly cross-linked polyethylene liner within a metal acetabular shell. The femoral stem may be cemented in place if there are concerns over obtaining adequate fixation, while minimizing the risk of fracture, in brittle, osteoporotic bone. Based on a review of the literature, currently, the NIH recommends a hybrid THA in the elderly with a cemented femoral stem and a press-fit acetabular component. This is due to the excellent long-term outcomes obtained and the fact that when both components are cemented the acetabulum is usually the site of early loosening [79–81]. However, at our institution, we routinely press-fit both components with excellent results, which has been supported in several studies [82–85].

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Complications The complications after THA are very similar to those after TKA (including VTE, PE, MI, UTI, fracture, loosening, infection), the main difference being stiffness in TKA and dislocation and limb-length discrepancy in THA. It is possible to dislocate a TKA with extreme flexion in a ligamentously loose or unbalanced knee, but this is very rare. The dislocation rate after a primary THA has been shown to range between 0 and 7% across different studies [86–91]. The high variability is related to the type of surgical approach used. The highest rate of dislocation has been shown with the posterior approach, but with improved technique, including repair of the posterior soft tissues, these rates have decreased from 4% to less than 1% in several studies [86–91]. A further improvement has been obtained with the use of larger femoral heads, 32  mm and greater, which provide increased stability by increasing the head to neck ratio. This provides a larger arc of motion before impingement and levering of the femoral head [88,92]. The anterolateral and direct lateral approaches have had traditionally lower dislocation rates but may have higher risk of a postoperative abductor lurch [87,93]. These two factors have led to the development of new approaches, such as the direct anterior approach, with the goal of eliminating these two complications. This approach to THA was first described in 1947 but has been recently modified by Joel Matta. In this approach a small, 10-cm incision is made anteriorly over the hip, in which the hip joint may be exposed without the release of any musculature. The surgical window is between the tensor fascia lata and sartorius superficially, and the gluteus medius and rectus femoris in the deep layer. The technique is performed in the supine position on a specially designed fracture table, which allows free, independent movement of the limbs. Intraoperative fluoroscopy is also used to assist in appropriate component positioning, as well as in obtaining equal leg lengths. In Matta’s series of 494 consecutive THA, the dislocation rate was 0.61%, with leg lengths being within 3 mm on average. Further, as no muscles are detached, no postoperative hip precautions are needed, and patients often progress to independent ambulation at a faster rate [95]. While the early results of this technique are quite impressive, there is a steep learning curve, and it must be used in carefully selected patients. Morbidity from medical complications is best prevented by appropriate preoperative medical evaluations and postoperative regimens including VTE prophylaxis, early removal of indwelling catheters, and early mobilization. However, in spite of these measures, they are not all preventable. The more common, yet still rare, medical complications are myocardial infarctions/cardiac arrhythmias, VTE, PE, urinary tract infection, pneumonia, and Clostridium difficile

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infection. In a study by Parvizi et  al., 1,636 patients u­ ndergoing TJA had 104 major life-threatening complications, including: one cardiac arrest, 33 tachyarrythmias, 6 myocardial infractions, 10 cases of congestive heart failure/pulmonary edema, 14 cases of acute renal failure, and 1 death (.06%) during the initial hospital stay. Most of the minor complications were anemia, but they did have 50 urinary tract infections, 20 mental status changes (which all resolved), 4 pneumonia, and 5 cases of C. difficile infection. They found that increased age, high BMI (>30.5), and preexisting medical comorbidities were all risk factors for complications. However, they note that 58% of the patients who developed a complication had no predisposing risk factors. Further, greater than 90% of the complications occurred in the first 4 postoperative days. These last two points lead to the conclusion that all patients need careful postoperative monitoring and that early discharge (i.e., prior to postoperative day 4) may lead to greater overall morbidity and mortality [95]. In 2008, Parvizi conducted a more detailed study of C. difficile infection, finding a 0.16% incidence in 9,880 TJA, with increased risk associated with increased ASA score, receiving more than one postoperative antibiotic, and a prolonged hospital stay [96]. A study of over 10,000 patients who underwent TJA from the Mayo Clinic found similar results with the incidence of myocardial infarction 0.4%, PE 0.7%, VTE 1.5%, and death 0.5%. They also found a correlation with increasing age [97]. This is not to say that increasing age should be considered a contraindication to TJA, but rather to assure that appropriate preoperative evaluation is obtained and that any postoperative problems are treated aggressively with early involvement of the medical team. Two recent studies of TJA in patients in the 9th and 10th decades of life did find an increased risk of complications as compared to younger patients but had an overall low event rate with significant improvements in pain score and overall outcomes. The authors of both studies ­concluded that with careful patient selection, total joint arthroplasty could be an excellent option for elderly patients [98,99]. Complications related to the prostheses include aseptic loosening, periprosthetic fracture, and infection. Any patient with a TKA or THA who presents with pain following surgery must have all of these possibilities considered. Based on the history and physical examination, the physician should be able to narrow down these possibilities. If the patient did not have a fall or acute injury, then fracture is unlikely, and usually can be ruled out with routine radiographs. Patients with aseptic loosening may report start-up pain that is worse during the first few steps and then decreases. The pain is typically located about the groin, thigh, or knee. Radiographs assist in the evaluation by the detection of radiolucencies around the prosthesis. Whenever there is a concern of ­loosening, an infection must be ruled out, as the treatment protocols are quite different.

95  Treatment of Degenerative Joint Diseases

Infection should be considered if a patient reports a dull pain that has been persistent since the time of surgery. A history of fevers, chills, warmth or erythema of the operative site provoke obvious concern, as does a recent history of illness or surgical procedure in a potentially contaminated area, such as oral, vaginal, or lower GI procedures. There is a risk of seeding a prosthetic joint after any surgical procedure, but as the risk is increased following dental procedures, a protocol has been developed. The recommendation of the American Dental Association and the American Academy of Orthopaedic Surgeons is that for the first 2 years after joint arthroplasty, all patients undergoing high-risk dental procedures (i.e., tooth extractions, implantations, root canals, etc.) should receive prophylactic antibiotics. After 2 years, patients who have had previous infection of the artificial joint, inflammatory arthritis, type-1 diabetes mellitus, hemophilia, immunosuppression, history of prior or present malignancy, dental extractions, periodontal procedures, dental implantation, root canal work, cleaning if bleeding is anticipated, certain specialized local anesthetic injections, or placement of orthodontic bands should still receive prophylaxis. The standard is 2 g of oral amoxicillin 1–2 h before the procedure or 600 mg clindamycin for those with a penicillin allergy [100]. There have been several studies of infected TJA in association with dental procedures [101,102]; however, a recent literature review has found little scientific data to support the need for routine prophylaxis [103]. We feel that prophylaxis should be continued at this time due to the morbidity and cost associated with a total joint infection. Concern of infection should initially be evaluated with routine labs, including a CBC with differential, an erythrocyte sedimentation rate (ESR), and a C-reactive protein (CRP). These are used as markers for infection as CRP should return to normal, after transient postoperative elevation, in 2–3 weeks, and ESR by 1–2 months. The normal values for these markers depend on normalized values that vary by hospital but are ESR 10) with a hip aspiration cell count >3,000 had the highest combined sensitivity, specificity, positive and negative predictive values, and accuracy for an infection [104]. This coincided with a recent study by Della Valle, in which a level of >3,000 white blood cells/ml in aspirated fluid from a TKA was most predictive of infection [105]. Information can also be gathered from a Technitium-99 3-phase bone scan, followed by an indium-111/sulfur colloid scan as indicated. Technitium-99 scans are sensitive, but not specific for infection. The addition of indium-111 and sulfur colloid scans greatly increase specificity to 97% [106].

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A study evaluating the effectiveness of Indium-111-labeled WBC scans alone found that the sensitivity and specificity alone decreased, but they had a 95% negative predictive value, such that a negative scan is highly predictive of a joint not being infected [107]. If an infection is confirmed or strongly suspected, surgery is indicated. The most common organisms involved are S. aureus and S. epidermidis. The type of surgery performed depends on the acuteness of the infection. Infections have been classified by Coventry as acute (2 years). Currently, many consider an acute infection being 10 PMNs per high power field is positive) and intraoperative cultures [110,111]. The spacer remains in place for at least 3 months while the patient receives intravenous antibiotics. The levels of ESR and CRP will be monitored to assess response to the treatment. At the 3-month point, once antibiotics have been discontinued for approximately 6 weeks, and the ESR and CRP have normalized, the patient returns to the OR for the second stage of the procedure. This includes removal of the antibiotic spacer, extensive irrigation and debridement, and the evaluation of intraoperative frozen sections, gram stains, and cultures. If the frozen section is negative for infection (less than 10 PMNs per high power field), then a new prosthesis can be placed [112,113]. The type of prosthesis used is based on the remaining bone stock and ligamentous stability. In a revision THA, it may be necessary to use long-stemmed, modular femoral

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components so that distal fixation is obtained; or metallic augments for the acetabulum. In the knee, stemmed tibial and femoral components are often needed for adequate fixation with metal augments for areas of bone loss. The overall complication rates are higher than after a primary replacement, but two-stage revisions for infection have success rates of 85–90% for THA [108,114] and 90% for TKA [115]. The revision components used for a noninfected revision are similar, with good results obtained, but with an increased risk of postoperative complications and infections when compared with primary procedures. Excellent outcomes have been obtained in the elderly as demonstrated by Parvizi et  al. who showed significant functional improvement following revision THA performed in octogenarians with no increase in medical comorbidities as compared to a younger cohort [116]. For revision of TKA, successful outcomes have been obtained in 74–88% of patients [117–119]. Another significant complication is fracture. Periprosthetic fractures occur at a rate of approximately 2.3% for THA and 2% for TKA over the long term, with a slightly higher increased risk of fracture in the elderly [120,121]. Fractures around a THA are commonly described by the Vancouver classification, with the type of fracture guiding treatment. They are classified as A, B, or C as follows: Type A are proximal fractures of the trochanters, B are at the level of the stem, and C are below the tip of the prosthesis. Type A fractures can often be treated nonoperatively with modified weight bearing, type B fractures by a plate with cables and screws if the stem is well fixed or with conversion to a

Case Study The patient is 70-year-old male who presented for ­evaluation of left-hip pain. He reports a history of left femoral neck fracture 3 months prior to presentation, which was treated by internal fixation with three screws. Since the surgery, he has been ambulating with a walker, weight bearing as tolerated, but with significant pain in the groin and laterally about the hip. He denies any low back pain or neurological symptoms. His medical history is significant for hypertension, for which he is treated with Dyazide. Physical examination revealed a healthy-appearing older man, in no acute distress. Evaluation of the left lower extremity showed a healed incision about the lateral aspect of the left hip. There was tenderness to palpation over this region and pain with hip ROM. ROM was

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l­ong-stemmed prosthesis, and type C fractures by a plate with cables and screws [122,123]. The treatment of fractures around a TKA also depends on the location of the fracture. One classification describes fractures proximal to the femoral component, to the level of the component, or to within the area of the component [124]. A determining factor in treatment is whether the prosthesis is loose or well fixed which determines if it will be retained or removed. If the fracture is quite distal, the standard of care is open reduction with internal fixation (ORIF) using a plate and screw construct. If it is more proximal, there is some debate whether a plate or a retrograde intramedullary nail is better suited with good outcomes shown with both fixation constructs [125,126]. Fractures involving the acetabular component of a THA or the tibial component of a TKA are less common, as they tend to require a higher level of energy such as from a motor-vehicle accident or fall from height. An interesting recent development is the use of THA for the treatment of femoral neck fractures in the elderly. These were traditionally treated with a hemiarthroplasty or internal fixation using screws, unless a patient reported significant hip pain prior to the fracture, which suggested preexisting degenerative joint disease in which case a THA was preferred. However, several recent studies comparing hemiarthroplasty or ORIF to total hip arthroplasty in the active elderly patient have shown superior results in patients undergoing THA with respect to functional outcomes, relief of pain, and need for further surgery [127–130].

flexion to 90°, internal rotation to 0°, external rotation to 10°, and abduction to 10°. Quadriceps and hamstring strength were 4/5, limited by pain. Distal neurovascular function was intact. There was a limb length discrepancy of 1 cm with the left shorter than the right. Straight leg raise testing was negative bilaterally. He ambulated with an antalgic gait and obvious pain about the left hip. Radiographs revealed a vertically oriented left femoral neck fracture, which was treated with three cannulated screws. There was limited evidence of healing of the fracture with overall shortening, varus alignment, and backing out of the screws (Figs.  95.9 and 95.10). These findings suggested loss of fracture alignment and delayed healing. Based on these findings and the clinical exam, he was indicated for a removal of hardware from the left hip and conversion to left THA. (continued)

95  Treatment of Degenerative Joint Diseases

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Case Study  (continued)

Figure  95.9  AP pelvis radiograph of a 70-year-old man which shows a vertically oriented left femoral neck fracture, which was treated with cannulated screws. There is limited evidence of healing of the fracture with overall shortening, varus alignment, and backing out of the screws.

Figure 95.10  Cross-table lateral radiograph of the left hip, showing a left femoral neck fracture after fixation with cannulated screws.

After appropriate medical clearance, the patient underwent removal of the screws and conversion to a noncemented left THA with a metal head and ­polyethylene liner via a posterior approach, without

Figure 95.11  Postoperative AP pelvis radiograph, showing a noncemented left total hip arthroplasty, with two screws in the acetabular component for additional fixation.

complications (Fig. 95.11). He did well postoperatively and was placed on Arixtra and SCDs for DVT prophylaxis. He started physical therapy on postoperative day 1 and ambulated weight bearing as tolerated with a walker. He was discharged to home on POD 5 with home physical therapy. At the 6-week follow-up visit, he was doing very well, ambulating with part-time use of a single cane and often without assistive devices. He was participating in an outpatient physical therapy program walking on a treadmill. The incision was well healed, and limb lengths were clinically equal. Hip ROM was flexion to 90°, internal rotation to 10°, external rotation to 20°, and abduction to 30°. He was able to straight leg-raise without discomfort, and distal neurovascular function was intact. Radiographs showed the components to be in good position without signs of changes at the bone– prosthesis interface. He continued to progress well and at 1-year follow-up was ambulating without assistive devices and was painfree. Radiographs showed good alignment of the implant without complication (Figs. 95.12 and 95.13). (continued)

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Case Study  (continued)

Figure 95.13  Cross-table lateral radiograph of the left hip, 1 year after left THA, showing good component positioning, without evidence of complications.

Figure 95.12  AP pelvis radiograph, 1 year after left THA, showing good component positioning, without evidence of complications.

Conclusions As the elderly population continues to grow and stay active, the demand for total knee and total hip arthroplasty will grow along with it. Projections indicate that by 2030, these numbers are expected to grow to the staggering figures of 3.48 million TKAs and 572,000 THAs annually [2]. Modern surgical techniques and a multidisciplinary approach with close involvement of medical specialists will enable excellent outcomes in over 90% of patients. Orthopedic surgeons will continue to refine surgical techniques and implant design, while minimizing complications and carefully evaluating patient outcomes, to ensure that the success of TKA and THA is maintained and improved upon in the future.

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1313 patients undergoing major orthopedic surgery. Am J Orthop 25:544 38. Keating EM, Callaghan J et al (2007) A randomized, parallel-group, open-label trial of recombinant human erythropoietin vs preoperative autologous donation in primary total joint arthroplasty: effect on postoperative vigor and handgrip strength. J  Arthroplasty 22(3):325–333 39. Stulberg B, Zadzilka J (2007) Blood management issues using blood management strategies. J Arthroplasty 22(4 Suppl 1):95–98 40. Martinez V, Monsaingeon-Lion A et al (2007) Transfusion strategy for primary knee and hip arthroplasty: impact of an algorithm to lower transfusion rates and hospital costs. Br J Anaesth 99:794–800 41. Shams W, Rapp R (2004) Methicillin-resistant staphylococcal infections: an important consideration for orthopedic surgeons. Orthopedics 27(6):565–568 42. Sankar B, Hopgood P, Bell KM (2005) The role of MRSA screening in joint-replacement surgery. Int Orthop 29:160–163 43. Wilcox MH, Hall J et al (2003) Use of perioperative mupirocin to prevent methicillin-resistant Staphylococcus aureus (MRSA) orthopaedic surgical site infections. J Hosp Infect 54:196–201 44. Perl T, Cullen J et al (2002) Intranasal mupirocin to prevent postoperative Staphylococcus aureus infections. N Engl J Med 346:1871–1877 45. Kalmeijer MD, Coertjens H et al (2002) Surgical site infections in orthopedic surgery: the effect of mupirocin nasal ointment in a double-blind, randomized, placebo-controlled study. Clin Infect Dis 35:353–358 46. Burnett R, Clohisy J et al (2007) Failure of the American College of Chest Physicians-1A protocol for lovenox in clinical outcomes for thromboembolic prophylaxis. J Arthroplasty 22(3):317–324 47. Dorr L, Gendelman V et al (2007) Multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment. J Bone Joint Surg Am 89:2648–2657 48. Westrich G, Haas S et al (2000) Meta-analysis of thromboembolic prophylaxis after total knee arthroplasty. J Bone Joint Surg Br 82-B:795–800 49. Freedman K, Brookenthal K et al (2000) A meta-analysis of thromboembolic prophylaxis following elective total hip arthroplasty. J Bone Joint Surg Am 82-A(7):929–938 50. Sharrock N, Gonzalez Della Valle A et al (2008) Potent anticoagulants are associated with a higher all-cause mortality rate after hip and knee arthroplasty. Clin Orthop Relat Res 466:714–721 51. Tankersley WS, Hungerford DS (1995) Total knee arthroplasty in the very aged. Clin Orthop 316:45–49 52. Ferguson M (1861) Excision of the knee joint: recovery with a false joint and useful limb. Med Times Gaz 1:601 53. Hungerford DS, Krackow KA et al (1984) Total knee arthroplasty: a comprehensive approach. Williams & Wilkins, Baltimore 54. Campbell WC (1940) Interposition of vitallium plates in arthroplasties of the knee: preliminary report. Am J Surg 47:639–641 55. Scott WN, Rosbruch JD et  al (1978) Clinical and biomechanical evaluation of patella replacement in total knee arthroplasty. Orthop Trans 2:203 56. Dalury D, Jiranek W (1999) A comparison of the midvastus and paramedian approaches for total knee arthroplasty. J Arthroplasty 14(1):33–37 57. Keating EM, Faris P et al (1999) Comparison of the midvastus muscle-splitting approach with the median parapatellar approach in total knee arthroplasty. J Arthroplasty 14(1):29–32 58. Roysam GS, Oakley MJ (2001) Subvastus approach for total knee arthroplasty: a prospective, randomized, and observer-blinded trial. J Arthroplasty 16(4):454–457 59. Matsueda M, Gustillo R (2000) Subvastus and medial parapatellar approaches in total knee arthroplasty. Clin Orthop 371:161–168 60. Parker MJ, Livingstone V, Clifton R, McKee A (2007) Closed suction surgical wound drainage after orthopaedic surgery. Cochrane Database Syst Rev (3):CD001825. doi:10.1002/14651858.CD001825.pub2

1314 61. Parker MJ, Roberts CP et al (2004) Closed suction drainage for hip and knee arthroplasty: a meta-analysis. J Bone Joint Surg Am 86-A(6):1146–1152 62. Walmsley PJ, Kelly MB et  al (2005) A prospective, randomised, controlled trial of the use of drains in total hip arthroplasty. J Bone Joint Surg Br 87-B(10):1397–1401 63. Kumar S, Penematsa S et al (2007) Are drains required following a routine primary total joint arthroplasty? Int Orthop 31:593–596 64. Milne S, Brosseau L et al (2003) Continuous passive motion following total knee arthroplasty. Cochrane Database Syst Rev (2):CD004260. doi:10.1002/14651858.CD004260 65. Lensen T, Steyn M et al (2008) Effectiveness of prolonged use of continuous passive motion (CPM), as an adjunct to ­physiotherapy, after total knee arthroplasty. BMC Musculoskelet Disord 9:60 66. Bennett L, Brearly S et  al (2005) A comparison of 2 continuous passive motion protocols after total knee arthroplasty. J Arthroplasty 20(2):225–233 67. Denis M, Moffet H et al (2006) Effectiveness of continuous passive motion and conventional physical therapy after total knee arthroplasty: a randomized clinical trial. Phys Ther 86(2):174–185 68. Brosseau L, Milne S et  al (2004) Efficacy of continuous passive motion following total knee arthroplasty: a metaanalysis. J Rheumatol 31:2251–2264 69. Schurman DJ, Parker JN et al (1985) Total condylar knee replacement: a study of factors influencing range of motion as late as two years after arthroplasty. J Bone Joint Surg Am 67:1006–1014 70. Daluga D, Lombardi AV Jr et al (1991) Knee manipulation following total knee arthroplasty: analysis of prognostic variables. J Arthroplasty 6:119–128 71. Esler CN, Lock K et al (1999) Manipulation of total knee replacements: is the flexion gained retained? J Bone Joint Surg Br 81:27–29 72. Bong M, Di Cesare P (2004) Stiffness after total knee arthroplasty. J Am Acad Orthop Surg 12:164–171 73. Jerosch J, Aldawoudy A (2007) Arthroscopic treatment of patients with moderate arthrofibrosis after total knee replacement. Knee Surg Sports Traumatol Arthrosc 15:71–77 74. St. Clair S, Higuera C et al (2006) Hip and knee arthroplasty in the geriatric population. Clin Geriatr Med 22:515–533 75. Learmonth I, Young C et al (2007) The operation of the century: total hip replacement. Lancet 370(9597):1508–1520 76. Canale S, Beaty J (eds) (2008) Campbell’s operative orthopaedics, 11th edn. Mosby Elsevier, Philadelphia 77. Charnley J (1961) Arthroplasty of the hip: a new operation. Lancet 1:1129–1132 78. Levy R, Levy C et al (1995) Outcome and long-term results following total hip replacement in elderly patients. Clin Orthop Relat Res 316:25–30 79. Buckwalter A, Callaghan J et al (2006) Results of charnley total hip arthroplasty with use of improved femoral cementing techniques. A concise follow-up, at a minimum of twenty-five years, of a previous report. J Bone Joint Surg Am 88:1481–1485 80. Firestone D, Callaghan J et al (2007) Total hip arthroplasty with a cemented, polished, collared femoral stem and a cementless acetabular component: a follow-up study at a minimum of ten years. J Bone Joint Surg Am 89-A(1):126–132 81. Klapach A, Callaghan J et  al (2001) Charnley total hip arthroplasty with use of improved cementing techniques: a minimum twenty-year follow-up study. J Bone Joint Surg Am 83-A(12): 1840–1848 82. Meading J, Keating M et al (2004) Minimum ten-year follow-up of a straight-stemmed, plasma-sprayed, titanium-alloy, uncemented femoral component in primary total hip arthroplasty. J Bone Joint Surg Am 86-A(1):92–97

P. J. Glassner et al. 83. McLaughlin J, Lee K (2008) Total hip arthroplasty with an uncemented tapered femoral component. J Bone Joint Surg Am 90-A(6):1290–1296 84. Keisu K, Orozco F et al (2001) Primary cementless total hip arthroplasty in octogenarians: two to eleven year follow-up. J Bone Joint Surg Am 83-A(3):359–363 85. Lettich T, Tierney M et al (2007) Primary total hip arthroplasty with an uncemented femoral component: two- to seven-year results. J Arthroplasty 22(7 Supp 3):43–46 86. Kwon MS, Kuskowski M et al (2006) Does surgical approach affect total hip arthroplasty dislocation rates? Clin Orthop Relat Res 447:34–38 87. Masonis JL, Bourne RB (2002) Surgical approach, abductor function and total hip arthroplasty dislocation. Clin Orthop Relat Res 405:46–53 88. Sierra RJ, Raposo JM et  al (2005) Dislocation of primary THA done through a posterolateral approach in the elderly. Clin Orthop Relat Res 441:262–267 89. Tsai SJ, Wang CT et  al (2008) The effect of posterior capsule repair upon post-operative hip dislocation following primary total hip arthroplasty. BMC Musculoskelet Disord 9:29 90. Pellicci PM, Bostrom M et al (1998) Posterior approach to total hip replacement using enhanced posterior soft tissue repair. Clin Orthop 355:224–228 91. Jolles BM, Bogoch ER (2006) Posterior versus lateral surgical approach for total hip arthroplasty in adults with osteoarthritis. Cochrane Database Syst Rev (3):CD003828. doi:10.1002/14651858. CD003828.pub3 92. Peters C, McPherson E et al (2007) Reduction in early dislocation rate with large-diameter femoral heads in primary total hip arthroplasty. J Arthroplasty 22(6 Suppl 2):140–144 93. Baker AS, Bitounis VC (1989) Abductor function after total hip replacement – An electromyographic and clinical review. J Bone Joint Surg Br 71-B:47–50 94. Matta J, Shahrdar C et al (2005) Single-incision anterior approach for total hip arthroplasty on an orthopaedic table. Clin Orthop Relat Res 441:115–124 95. Parvizi J, Mui A et al (2007) Total joint arthroplasty: when do fatal or near-fatal complications occur? J Bone Joint Surg Am 89:27–32 96. Kurd M, Pulido L et  al (2008) Clostridium difficile infection after total joint arthroplasty: who is at risk? J Arthroplasty 23(6):839–842 97. Mantilla C, Horlocker T et  al (2002) Frequency of myocardial infarction, pulmonary embolism, deep venous thrombosis, and death following primary hip or knee arthroplasty. Anesthesiology 96:1140–1146 98. Kreder H, Berry G et al (2005) Arthroplasty in the octogenarian: quantifying the risks. J Arthroplasty 20(3):289–293 99. Berend M, Thong A et  al (2003) Total joint arthroplasty in the extremely elderly: hip and knee arthroplasty after entering the 89th year of life. J Arthroplasty 18(7):817–821 100. American Dental Association; American Academy of Orthopaedic Surgeons (1997) Advisory statement: antibiotic prophylaxis for dental patients with total joint replacements. J Am Dent Assoc 128:1004–1007 101. Waldman BJ, Mont MA, Hungerford DS (1997) Total knee arthroplasty infections associated with dental procedures. Clin Orthop 343:164–172 102. LaPorte D, Waldman B et  al (1999) Infections associated with dental procedures in total hip arthroplasty. J Bone Joint Surg Br 81-B(1):56–59 103. Uckay I, Pittet D et  al (2008) Antibiotic prophylaxis before ­invasive dental procedures in patients with arthroplasties of the hip and knee. J Bone Joint Surg Br 90B:833–838

95  Treatment of Degenerative Joint Diseases 104. Schinsky M, Della Valle C et al (2008) Perioperative testing for joint infection in patients undergoing revision total hip arthroplasty. J Bone Joint Surg Am 90:1869–1875 105. Della Valle C, Sporer S et al (2007) Preoperative testing for sepsis before revision total knee arthroplasty. J Arthroplasty 22 (6 Supp 2): 90–93 106. Palestro CJ, Kim CK et al (1990) Total-hip arthroplasty: periprosthetic indium-111-labeled leukocyte activity and complementary technetium-99m-sulfur colloid imaging in suspected infection. J Nucl Med 31(12):1950–1955 107. Scher DM, Pak K et al (2000) The predictive value of indium111 leukocyte scans in the diagnosis of infected total hip, knee, or resection arthroplasties. J Arthroplasty 15(3): 295–300 108. Tsukayama D, Estrada R et  al (1996) Infection after total hip arthroplasty: a study of the treatment of one hundred and six infections. J Bone Joint Surg Am 78A(4):512–523 109. Deirmengian C, Greenbaum J et al (2003) Open debridement of acute gram-positive infections after total knee arthroplasty. Clin Orthop Relat Res 416:129–134 110. Lonner JH, Desai P, Dicesare PE et  al (1996) The reliability of analysis of intraoperative frozen sections for identifying active infection during revision hip or knee arthroplasty. J Bone Joint Surg Am 78A(10):1553–1558 111. Della Valle C, Zuckerman J et al (2004) Periprosthetic sepsis. Clin Orthop 420:26–31 112. Della Valle CJ, Bogner BA, Desai P et  al (1999) Analysis of frozen sections of intraoperative specimens obtained at the time of reoperation after hip or knee resection arthroplasty for the treatment of infection. J Bone Joint Surg Am 81A(5): 684–689 113. Banit D, Kaufer H et al (2002) Intraoperative frozen section analysis in revision total joint arthroplasty. Clin Orthop Relat Res 401:230–238 114. Haddad FS, Muirhead-Allwood S et  al (2000) Two-stage uncemented revision hip arthroplasty for infection. J Bone Joint Surg Br 82(5):689–694 115. Hofman A, Goldberg T et  al (2005) Treatment of infected total knee arthroplasty using an articulating spacer: 2- to 12-year experience. Clin Orthop Relat Res 430:125–131

1315 116. Parvizi J, Pour A et  al (2007) Revision total hip arthroplasty in octogenarians: a case-control study. J Bone Joint Surg Am 89A(12):2612–2618 117. Peters C, Erickson J et al (2005) Revision total knee arthroplasty with modular components inserted with metaphyseal cement and stems without cement. J Arthroplasty 20(3):302–308 118. Bertin KC, Freeman MAR, Samuelson KM et al (1985) Stemmed revision arthroplasty for aseptic loosening of total knee arthroplasty. J Bone Joint Surg Br 67B:242 119. Peters CL, Hennessy R, Barden RM et  al (1997) Revision total knee arthroplasty with a cemented posteriorstabilized or constrained condylar prosthesis. J Arthroplasty 12:896 120. Cook R, Jenkins P et al (2008) Risk factors for periprosthetic fractures of the hip: a survivorship analysis. Clin Orthop Relat Res 466:1652–1656 121. Berry DJ (1999) Periprosthetic fractures after major joint replacement. Epidemiology: hip and knee. Orthop Clin North Am 30:183–190 122. Brady OH, Garbuz DS, Masri BA et al (2000) The reliability and validity of the Vancouver classification of femoral fractures after hip replacement. J Arthroplasty 15:59–62 123. Masri B, Meek R et al (2004) Periprosthetic fractures evaluation and treatment. Clin Orthop 420:80–95 124. Su E, DeWal H et al (2004) Periprosthetic femoral fractures above total knee replacements. J Am Acad Orthop Surg 12:12–20 125. Kim K, Egol K et al (2006) Periprosthetic fractures after total knee arthroplasties. Clin Orthop Relat Res 446:167–175 126. Haidukewych GJ (2007) Periprosthetic distal femur fracture: plate versus nail fixation. J Orthop Trauma 21(3):219–221 127. Blomfeldt R, Tornkvist H et al (2005) Comparison of internal fixation with total hip replacement for displaced femoral neck fractures. J Bone Joint Surg Am 87A(8):1680–1688 128. Johansson T, Bachrach-Lindström M (2006) The total costs of a displaced femoral neck fracture: comparison of internal fixation and total hip replacement: a randomised study of 146 hips. Int Orthop 30:1–6 129. Klein G, Parvizi J et  al (2006) Total hip arthroplasty for acute femoral neck fractures using a cementless tapered femoral stem. J Arthroplasty 21(8):1134–1140 130. Mouzopoulos G, Stamatakos M et al (2008) The four-year functional result after a displaced subcapital hip fracture treated with three different surgical options. Int Orthop 32:367–373

Section XIII

Transplantation

Chapter 96

Invited Commentary Khalid M.H. Butt

When asked to comment on organ transplantation in senior citizens, I reflected on the evolution of this restorative therapy over the past four decades, during which I have been a student of the subject while actively performing kidney transplants. End-stage failure of vital organs inevitably results in death unless function is replaced either by artificial means, as in the case of the kidney with dialysis therapy, or when a transplant is accomplished and the graft works (liver, heart, and lung). In the latter case, the quality of life is markedly improved and longevity may be nearly doubled with a successful kidney transplant. Justifiably then, if an organ is available and the patient is judged to have enough physiologic reserve to be able to withstand the vicissitudes of anesthesia, surgery, and the immunosuppressive regimen, transplantation remains the best therapy. Drawing on the steady advances in anesthesia and surgical technique (especially vascular) during the first half of the twentieth century, Joseph Murray and colleagues launched a new era by successfully performing the first kidney transplant between identical twins in 1954. This revolutionary life-preserving new therapy had to be applied cautiously. First, it was imperative to ascertain that no long-term harm was done to the donor, whose rights had to be vigorously protected. Our obligation to protect the donor’s interests had to be clearly enunciated. Second, the recipients needed to be observed for quite some time to determine any unforeseen complications and the durability of this treatment. Initially, only end-stage renal disease patients between the ages of 15 and 45 years with no significant involvement of any other organ system were offered kidney transplantation. During the sixties and seventies, broadening acceptance of the ­determination of death by neurologic criteria offered increased opportunities for recovery of organs from “heartbeating” cadavers. Extending transplantation horizons, Starzl

K.M.H. Butt (*) Department of Surgery – Transplant Section, Westchester Medical Center, 95 Grasslands Road, Valhalla, NY 10595, USA e-mail: [email protected]; [email protected]

s­ uccessfully transplanted liver in 1963, and in 1967, Barnard transplanted a heart. Incomplete understanding of the pathogenic mechanisms of immunologic allograft rejection, and our limited ability to halt and reverse this process continued to be the major concern into the eighties. Infections and malignancies as complications of immunosuppression took a heavy toll. With the discovery of cyclosporine, a calcineurin inhibitor and somewhat more specific immunosuppressive drugs, transplant outcomes started to improve. The introduction of other agents into our immunosuppressive armamentarium, and the evolution of more efficacious and safer combination regimens extended the spectrum of candidates for organ replacement at both ends, i.e., from infancy to the elderly (seventies and eighties). Age by itself, as a consideration of candidacy for organ transplantation, is no longer an overwhelming concern. Needless to say, age-associated maladies, like coronary and carotid artery disease, malignancy, general nutritional status and viability of the patient must be properly assessed. Results of kidney transplantation in the elderly (³65 years) are now comparable to those of younger adults. There still remains a societal concern. With little increase in the numbers of deceased-donor organs recovered over the past many years, paired with an ever-increasing demand, society, not the doctors, must decide how these precious resources are to be utilized. Allocating the organs in a manner that employs the best mix of justice (equality to all the patients waiting) and utility (getting the most value) continues to challenge the minds and hearts of all concerned. Family members of deceased donors, potential recipients and their families and friends, transplant doctors, other healthcare workers, scientists and researchers, lawyers and judges, politicians and public officials, social scientists, philosophers and ethicists all grapple with the task of developing the best schema. When the name of a criminal on death row pops up for heart transplantation, no amount of rational debate can overcome the strong emotions aroused. Elderly patients often garner a similar, though usually not as visceral, response. Eurotransplant, an organization of six European countries (covering a population of 118 million) collaborating in recovery and allocation of deceased donor organs, as well as

R.A. Rosenthal et al. (eds.), Principles and Practice of Geriatric Surgery, DOI 10.1007/978-1-4419-6999-6_96, © Springer Science+Business Media, LLC 2011

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transplant research, developed a Eurotransplant Seniors Program (ESP) about 10 years ago. They rapidly allocate a kidney recovered from a ³65-year-old donor to a ³65-yearold recipient who is not sensitized and is ready to receive a first transplant. Cold ischemia time is thus cut short, resulting in decreased incidence of delayed graft function, and survival results comparable to those of adults 12 h

³ 55 N/A N/A

> 55 CVA > 5 h

Past medical history

• Hypertension • Cr > 1.5 mg/dL

Hepatitis C

³ 20 pack/year smoking history

• • • •

Hepatitis C CAD Cocaine abuse Alcoholism

• Under sizing ( 5 days in recipients with PHT • PaO2/FiO2 30% mismatch) in • Pulmonary infiltrate on recipients with LVADs for acute CXR MI or multiple reoperations • Purulent secretions N/A non applicable; CVA cerebrovascular accident; Cr creatinine; CAD coronary artery disease; CXR chest X-ray; PHT pulmonary hypertension; LVADs left ventricular automated devices; MI myocardial infarction a ³ 60 or > 50 and at least two other variables b At least one variable present

Graft

N/A

• Macrovesicular steatosis > 30% • Vasopressor at time of procurement

increased mortality rate; however, the transplanted lungs exhibited ­adequate posttransplant function. Interestingly, a recent series of transplants with donors aged 50 and older found no difference in survival and functional reserve between the ECD recipients and a cohort of SCD recipients [11]. In addition, a subanalysis of those donors over 50 showed no difference in 1-year survival. It is concluded that the true cutoff for a potential lung donor is yet to be vigorously studied, and it may be at a different borderline than that currently defined. Once, the upper limit of donor age for transplantation of the heart was 35 years of age; nowadays, it is common for cardiac donors to be greater than 50 years of age. Nevertheless, the current definition of ECD for heart donors includes donors older than 55, as well as other variables such as prolonged ischemia times (>5 h), HCV infection, alcohol abuse, cocaine abuse, atraumatic intracranial hemorrhage, underand oversizing, and preexisting coronary artery disease (CAD) [12]. Despite data indicating increased initial posttransplant mortality risk, a review of the UNOS registry shows that mortality of patients on the waiting list is higher. As organs continue to remain a scarce resource for transplantation, it is predictable that the utilization of organs of older donors will continue to increase. Despite what some deem as the inferior outcomes of extended criteria transplantation, the unacceptable sequelae of end-stage disease will compel continuous redefinition of the extended criteria.

Determination of Brain Death As with most cadaveric donors, the evaluation of the geriatric donor begins with the declaration of brain death. A review of the Scientific Registry of Transplant Recipients (SRTR)

data shows that most brain deaths occur secondary to stroke, with the second most prevalent diagnosis occurring with trauma (41.9 and 38.1%, respectively) [13]. When a braininjured patient presents with coma and evidence of irreversible structural brain injury, the screening process for organ donation is begun. In general, the physician or medical team taking care of this individual is responsible for notifying the area organ procurement organization (OPO) to start the process. Once the process is initiated, the OPO will dispatch field coordinators who are then responsible for facilitating declaration of brain death, family counseling, and consent for donation, as well as completing the screening process with review of medical and social histories, and the completion of laboratory and serologic tests. Once all information is acquired, communication with the transplant center and transplant center physician will lead to an appropriately matched recipient with arrangements made for eventual procurement of the organs. The declaration of brain death is mandatory prior to proceeding with evaluation for procurement. The current brain death criteria in the USA is outlined in a set of guidelines published in 1981 entitled the President’s Commission for the Study of Ethical Problems and adopted under the Uniform Determination of Death Act. This act states that death has occurred once there is irreversible cessation of brain function including the brainstem. Each state government has adopted these guidelines in legislating local criteria for determining brain death. Usually there are variations in the necessity and type of confirmative testing required, how many examinations are required to determine brain death, and how many physicians are required to make that determination. Most hospitals will then establish their own protocols for determining brain death for potential donors under their care.

97  Elderly Donors in Transplantation

Symptoms that support the diagnosis of brain death include the absence of brainstem reflexes, cortical activity, and demonstration of irreversibility of the injury. All reversible causes of a coma must then be ruled out, including hypothermia, hypoxia, hypoglycemia, hyperglycemia, uremia, hepatic failure, Reye’s syndrome, hyponatremia, hypercalcemia, myxedema, adrenal failure, and CNS depressants. When reversible causes are ruled out and symptoms of brain death exist, then brain death is initially confirmed with apnea testing. The patient should be warm, maintaining a blood pressure greater than 90 mmHg, preoxygenated with 100% FiO2 for 10 min, and eucapnia must be confirmed with initial pretest blood gas. The test is commenced by disconnecting the patient from the ventilator. During this time, high-flow oxygen is delivered into the trachea via catheter at the level of the carina. The patient is monitored for respiratory activity; if any is present, the patient is immediately reconnected to the ventilator. A standard waiting time of 8 min is instituted if the patient remains apneic and hemodynamically stable. If a repeat blood gas yields a PaCO2 of 60 mmHg or greater then brain death is declared. The test can be repeated with 10-min duration if 60 mmHg is not attained. Confirmatory tests include the EEG, and tests that confirm lack of cerebral blood flow (cerebral angiography, duplex ultrasound, radionuclide cerebral blood flow scanning).

Donor Management The physiology of brain death has been delineated over the years by animal models and observations in human case series. Brain death proceeds as ischemia in a rostral-caudal fashion. This progression causes initially an increased vagal activation followed by the Cushing reflex due to a mixed vagal/sympathetic stimulation. Continued progression of ischemia down the brainstem produces an autonomic surge causing extreme elevation of heart rate and blood pressure, followed by sympathetic deactivation as the spinal cord is eventually affected. In general, this results in a hemodynamically unstable patient. The initial goal of donor management, therefore, is an assessment and maintenance of hemodynamic stability. This is achieved via echocardiography and resuscitation via crystalloid, colloid, and blood product infusions. Vasoactive support could be added via use of dopamine and dobutamine infusions. Finally, hormone replacement therapy (i.e., thyroxine, methylprednisolone, insulin, and vasopressin) may be instituted in a donor with persistent hemodynamic lability. The goal is maintenance of blood pressure above 100  mmHg, CVP around 10  mmHg, and urine output above 40  mL/h. There may be benefit in maintaining urine outputs greater than 100  mL/h, however detriment in outputs greater than 300  mL/h. When donors

1323

develop diabetes insipidus, hypotonic replacement to keep up with hypotonic urine loss becomes necessary combined with desmopressin. When urine output drops below 40 mL/h the addition of diuretics and mannitol may be helpful in donor management. Previous studies have shown shortened time to graft failure in donors with terminal serum creatinine levels greater than 1.5 mg/dL. In a separate analysis of donor factors that predispose to decreased graft survival, it has been reported that the goal in donor management of keeping serum creatinine levels under 2 mL/dL seems to exert favorable effect on graft function in recipients [14]. The likelihood of impaired renal function in the older donor mandates donor management that is aimed to optimize serum creatinine levels. Much consideration has been given to renal biopsy and correlation with function and level of glomerulosclerosis (GS). However, there have been mixed results, and no consistent correlation has been observed between increased GS and graft survival and function. In general, worse outcomes were demonstrated with GS greater than 20% [15]. In theory, the transfer of more nephron mass via transplanting two same donor ECD allografts may improve posttransplant glomerular filtration rate (GFR) [16]. Further improvements may be achieved by using pulsatile perfusion to improve ECD outcomes. Ex vivo perfusion of ECD kidneys did not show definite survival advantage; however, there are indications that pumped kidneys have increased final use of ECD kidneys as well as decreased DGF [17]. In the elderly donor, advanced age impairs regenerative capacity of the liver and therefore injury due to ischemia and subsequent recovery from injury could be exaggerated. Occasionally, a liver biopsy can be used to assess other variables that may increase the rate of primary nonfunction; the presence of steatosis > 30% is considered as extremely highrisk, as is periportal fibrosis [18]. A short cold ischemia CIT (55 years has increased from 1,133 in 1996 to 1,491 in 2004 [30]. This observational cohort study using data from OPTN/ UNOS compared the outcomes of LDRT in recipients older than 60 years receiving either kidney from old donors (>55 years) or young donors (£55 years). Similar graft and patient survival rates were found after 4 years in both groups: 78 and 82% in the old donor group and 81 and 84% in the young donor group, respectively. Thus, LDRT from the older donor appears to be a suitable option to decrease time on the waiting list, especially in elderly recipients. Living donor liver transplantation (LDLT) was first performed in 1989 with transplantation of a left hepatic lobe of an adult into a child [31]. Ten years later, adult-to-adult LDLT was introduced attempting left-hepatic lobe transplantation, but dismal results due to small-to-size graft syndrome discouraged this approach [32]. Consequently, the larger right-hepatic lobe grafts have replaced them in routine use at many centers. Recently, the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) investigated the rate and severity of complications in right-lobe living donors [33]. A 38% complication rate was reported, with infection (12.5%), biliary leak (9.2%), and incisional hernias (6%) being the most common ones; overall mortality was 0.8%. Certain donor characteristics were associated to significant higher risk of postoperative complications. Intraoperative transfusion of more than 1 unit of blood and alkaline phosphatase ³86 IU/L were associated to increased risk of developing complications after LDLT. Patel et  al. reported an overall complication rate after left- and rightlobe LDLT of 29% [34]. Interestingly, they described donors older than 50 years as a risk factor for major complications. Decreased capacity of regeneration in older donors has been hypothesized as possible explanation for this finding [35]. In other studies, diminished early graft regeneration from older donors was shown to affect graft survival as well [36, 37]. It is well established that donors can experience

97  Elderly Donors in Transplantation

severe ­psychiatric complications [38]. In an A2ALL retrospective study including 392 patients, one or multiple psychiatric complications were presented in 4% of the patients including three severe psychiatric complications like suicide, accidental drug overdose, and suicide attempt. These tragic events may be prevented with careful psychiatric assessment and monitoring of liver donors. Presumably, quality of life should be affected after LDLT, but a recent meta-analysis evaluating adult LDLT outcomes reported that the donors rated higher on quality-of-life scales than the general population and one study even reported some improvements in their psychosocial measures [39].

Organ Allocation Policies UNOS is a private not-for-profit organization created in 1987 that nucleates all transplant hospitals’ waiting lists and links all OPOs. In order to optimize the distribution and allocation of organs, different organ allocation systems were created to assure maximal utility, justice, and transparency of this scarce resource. The efficacy of any organ allocation system is measured by patient and graft survival rates and patient survival rates can be divided into survival on the waiting list and survival after transplantation. Liver allocation is now based on the Model for End-Stage Liver Disease (MELD) that predicts 3-month mortality on the waiting list and benefit from transplantation. MELD is based on logarithmic transformation of the recipient’s bilirubin, creatinine, and international normalized ratio (INR) into a validated mathematical model. After 1 year of introducing the MELD score, a 3.5% reduction in waiting list mortality, a 12% reduction of new candidates to the liver transplant waiting list, and identical posttransplant survival were reported [40]. Despite the positive effect the MELD score had on organ allocation, there is still potential room for improvement such as incorporation of new parameters (i.e., sodium) and donor factors, which are now not taken into consideration. The kidney allocation system has evolved over the past 20 years. Currently, patients are ranked according to an allocation algorithm based on their waiting time, degree of HLA matching, pediatric candidates, and panel-reactive antibodies. However, the waiting time on the kidney transplant list continues to increase, largely due to the increase of the number of new registrants aged 50 years or older. Consequently, the criteria for accepting kidneys for transplantation were extended and organs from donors ³ 55 years of age are used with increasing frequency. An Italian group reported similar long-term graft survival in those recipients who received a kidney from donors older than 60 years when compared with donors £ 60 years [41]. In order to improve the distribution of

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the scarce resource of cadaveric kidneys the current allocation policy is being reviewed by UNOS Kidney Transplant Committee. Since May 2005, the order of candidates on the waiting list for lung transplantation has been based on the Lung Allocation Score (LAS). LAS is defined as the transplant benefit measure minus the waiting list urgency measure, which are calculated using a statistical model and candidate’s clinical and physiological characteristics. The factors used in calculating each factor are described elsewhere [42]. LAS is represented by a continuous scale from 0 to 100, higher scores represent higher urgency and greater potential transplant benefit. Since LAS was implemented, waiting time has decreased from 681 to 446 days (p  65 years to recipients > 65 years), with the goal of kidney grafts outliving the recipients. HLA matching is ­disregarded, kidneys are allocated to local transplant candidates to decrease the CIT as much as possible, and only

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n­ onimmunized (panel reactive antibodies 55 years, nonheart beating donor, CIT > 36 h, and donor hypertension or diabetes) compared favorably with the waiting list dialysis cohort that did not undergo transplantation was 5 years [5]. To deterTable  97.3  Patient survival for expanded criteria donor kidney transplants Years posttransplantation Age (years) at Tx 3 Months 1 Year 3 Years 5 Years 18–34 98.4% 96.9% 35– 49 98.5% 95.4% 50– 64 95.4% 89.5% ³65 93.8% 85.8% Source: Adapted from Metzger et  al. [2], with Blackwell

93.1% 87.6% 86.3% 77.8% 76.7% 63.5% 63.8% 55.5% permission of Wiley-

Table  97.4  Patient survival for nonexpanded criteria donor kidney transplants Years posttransplantation Age (years) at Tx 3 Months 1 Year 3 Years 5 Years 18–34 35– 49 50– 64 ³65 Source: Adapted Blackwell

99.2% 97.9% 96.3% 90.4% 98.5% 96.6% 92.5% 84.8% 96.4% 92.3% 86.2% 74.7% 94.6% 88.7% 77.6% 59.0% from Metzger et  al. [2], with permission of Wiley-

mine whether accepting an ECD kidney is the right choice for an individual recipient, the critical issue is how much longer the patient would have to wait before the poorer outcomes and increased costs of waiting on dialysis therapy would outweigh the benefits of receiving an SCD kidney [48]. Interestingly, Merion et al. compared the relative risk of mortality for ECD kidney recipients versus those receiving standard therapy [49]. Because of the increased ECD recipient mortality in the perioperative period, cumulative survival did not equal that of standard dialysis therapy patients until 3.5 years of kidney transplantation. Consequently, recipient ­survival longer than 3.5 years justifies ECD kidney ­transplantation. The subgroups with significant ECD survival benefit included both sexes, patients > 40 years, nonHispanics, unsensitized patients, and those with diabetes or hypertension. Importantly, survival benefits are demonstrated in centers with long median waiting times, where ECD recipients had a 27% lower risk of death when compared to staying on dialysis (p 50 years of age) with low disease

severity [model for end-stage liver disease (MELD) score of 10–14] and without HCV. The reason why high-DRI grafts were allocated to candidates with lower MELD scores can be explained by the concept that most ill patients may have disproportionately poorer outcomes with high-risk grafts. However, several studies demonstrated that patients with a MELD score ³ 20 experienced significant survival benefits even when they received a high-DRI organ [55–57]. The unpredictable underlying course of the liver disease makes timing of liver transplantation a more complex problem; therefore, ECD should be proposed for patients with higher risks of dying such as those with MELD scores ³ 20. The survival benefit of high-DRI organ allocation to older candidates requires further assessment.

Old Organ Function In kidney transplantation, the goal of the special allocation procedure is to reduce the time associated with placement by matching ECD grafts with patients previously designated as

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being willing to accept them. In assessing the potential impact of these allocation procedures, the sensitivity of ECD grafts to cold ischemia time became of great importance. ECD transplant recipients have a greater DGF prevalence than non-ECD kidney transplant recipients, in part related to CIT [58]. A European multicenter study described transplants performed with kidneys retrieved from elderly donors: CIT was associated with greater incidence of DGF and decreased graft survival when censored for death [59]. Most analyses suggest that ECD kidneys should be used locally to minimize any detrimental effect of CIT on graft function and survival. Currently, ESP and OTPN/UNOS organ allocation policy for ECD kidneys favors reducing CIT over HLA matching. A great concern has been raised about the effect of donor age on long-term outcome. A review from UNOS data confirms that cadaveric kidneys from donors older than 60 years are associated with a 50% survival at 5 years, compared with the graft survival rate of 70% in patients receiving cadaveric donor kidneys from donors aged 19–45 years [60]. Interestingly, living donors older than 55 years have been reported to represent a significant risk of allograft failure [61]. However, as it was mentioned earlier, a recent review from OTPN/UNOS database suggested that recipients older than 60 years might benefit from living donors aged 65 years or older. These data support that donor age has turned to be a powerful predictor of long-term renal allograft function. The main reason for kidney allograft loss in ECD recipients is death with a functioning kidney. Gill et  al. [30] described cardiovascular disease and infection as the most common identifiable causes of death in ECD recipients (28.6 and 19.8%, respectively). These are expected findings reflecting the current trend to allocate ECD grafts to older recipients. With conventional immunosuppressive regimens, the risk of infectious death in older recipients increases exponentially because of higher infectious vulnerability in the elderly population, and it can be decreased by lowering immunosuppression [60]. Reduction of immunosuppression may be better tolerated in the elderly population since the incidence and severity of acute rejections is lower than in younger recipients, possibly because of the immune impaired aging [62, 63]. Nevertheless, kidneys from older donors are more likely to undergo acute rejection episodes in the early posttransplantation period when compared with kidneys from younger donors [64, 65] and may be related to a more intense proinflammatory response, increased expression of HLA in epithelial and endothelial cells, and the recruitment of antigen-presenting cells [51]. Consequently, it has been suggested that immunosuppression individualization and adequate patient selection, together with better HLAmatching, tend to decrease infection and rejection risk in ECD kidney transplant recipients [46, 66]. In liver transplantation, immediate and long-term function of liver allograft procured from older donors is affected by the

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exposure to cold ischemia with an increased rate of primary and delayed nonfunction [53, 67, 68]. Grafts with more than 14  h of cold ischemia have been associated with a twofold increase in preservation damage resulting in prolonged postoperative course, biliary stricture, and decreased graft survival [67–69]. The European Liver Transplant Registry survey showed that 5-year recipient survival was 57% with CIT > 15 h versus 64% with CIT between 12 and 15  h and 67% with CIT  30  mg/m2) has been reported to increase the risk of postoperative complications after ECD liver transplantation, such as respiratory failure and infections [73]. Furthermore, transplantation of livers from donors older than 40 years of age is associated with increased severity of HCV recurrence and fibrosis rates [74]. It is debatable whether old livers should be allocated to recipients with HCV infection [75].

Ethics Ethical allocation priorities are a topic of ongoing discussion [76]. Disclosing the risk and benefits of solid-organ transplantation and obtaining inform consent from patients might occur at any moment of the transplant process, when the patients are placed on the waiting list and/or when an organ is offered. Candidates willing to accept an ECD organ should be specifically informed about the potential risks a marginal graft can carry. A distinction between the risk of disease transmission and graft failure should be emphasized as part of the informed consent process. In all cases, patients should be informed to whether declining ECD will delay their receipt of an organ, and provide reasonable assessment of the potential of death before SCD becomes available. Candidates, who did not consider ECD as an option, should be offered the chance to reassess their decision, especially when their clinical condition is changed. In such circumstances, transplant physicians’ clinical judgment plays a key role to establish risk and benefits of providing a particular organ to a particular patient. Transplant teams are therefore ethically obliged to look carefully into the principles, rules, or preferences they use to allocate ECD organs.

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Case Study A 69-year-old male with history of smoking, hypertension, coronary artery disease, and atrial fibrillation on coumadin presented to the ER with headache, nausea, and vomiting. Initial workup including head CT scan demonstrated large intracranial hemorrhage and significant brain edema. The patient continued to experience neurological deterioration with evidence of brain herniation and hemodynamic instability requiring multiple vasopressors. The family was notified and expressed interest in organ donation. 1. Determination of brain death: All reversible causes of a coma were ruled out (i.e., hypothermia, hypoxia, hypoglycemia, etc.). An apnea testing was consistent with brain death, and that was later confirmed by a radionuclide cerebral blood flow scan. 2. Donor management: Hemodynamic stability was achieved via resuscitation with crystalloids and vasoactive support. Hormone replacement therapy with thyroxine was instituted, helping to wean-off vasopressors. Blood pressure was maintained >100 mmHg, CVP > 10  mmHg, urine output > 40  mL/h. Finally, reversal of diabetes insipidus was achieved with desmopressin. 3. Procurement procedure: The presence of abdominal donor malignancies was excluded after an extensive abdominal exploration, and the thoracic and abdominal organs were evaluated for transplantation. • Heart and lung were discarded because of advanced donor age and comorbidities. • Liver allocation: liver function tests revealed a total bilirubin 1.2 mg/dL, AST 35 IU/mL, ALT 51 IU/ mL and viral hepatitis serologies were negative. In order to exclude fibrosis and steatosis, a liver biopsy was performed showing ­macrosteatosis