Pathophysiology: Concepts of Altered Health States, Eighth Edition: International Edition

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PATHOPHYSIOLOGY Concepts of Altered Health States EIGHTH EDITION

Carol Mattson Porth, RN, MSN, PhD (Physiology) Professor Emerita College of Nursing University of Wisconsin—Milwaukee Milwaukee, Wisconsin Glenn Matfin, BSc (Hons), MB ChB, DGM, FFPM, FACE, FACP, FRCP Clinical Associate Professor of Medicine, Department of Endocrinology School of Medicine New York University New York, New York

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Senior Acquisitions Editor: Hilarie Surrena Senior Managing Editor: Helen Kogut Editorial Assistant: Brandi Spade Senior Production Editor: Debra Schiff Director of Nursing Production: Helen Ewan Senior Managing Editor/Production: Erika Kors Senior Designer: Joan Wendt Senior Designer, Illustration: Brett MacNaughton Manufacturing Coordinator: Karin Duffield Indexer: Cassar Technical Services Compositor: Circle Graphics

8th Edition Copyright © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. Copyright © 2005, 2002 by Lippincott Williams & Wilkins. Copyright © 1998 by Lippincott-Raven Publishers. Copyright © 1994 by J. B. Lippincott Company. All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Lippincott Williams & Wilkins at 530 Walnut Street, Philadelphia PA 19106, via email at [email protected] or via website at lww.com (products and services). 9 8 7 6 5 4 3 2 1 Printed in China ISBN 10: 0-7817-6616-8 ISBN 13: 978-16054-7390-1 Not authorized for sale in North America. Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication. Application of this information in a particular situation remains the professional responsibility of the practitioner; the clinical treatments described and recommended may not be considered absolute and universal recommendations. The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with the current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new or infrequently employed drug. Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings. It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in his or her clinical practice. LWW.COM

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This book is dedicated to My family: Rick, Susan, Tom, Cody, and Noah —CAROL MATTSON PORTH

To my wife Marcia and my parents, Enid and Sid I also dedicate it to my mentor, Professor Harold Adelman, Tampa, Florida —GLENN MATFIN

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Consultants Kathryn J. Gaspard, PhD Clinical Associate Professor Emerita College of Nursing University of Wisconsin—Milwaukee Milwaukee, Wisconsin

Kim Litwack, RN, PhD, FAAN, APNP Associate Professor College of Nursing University of Wisconsin—Milwaukee Milwaukee, Wisconsin

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Contributors Judith A. Aberg, MD

Jason Faulhaber, MD, Fellow

Principal Investigator, AIDS Clinical Trials Unit Director of HIV, Bellevue Hospital Center Associate Professor of Medicine New York University School of Medicine (Chapter 20)

Division of Infectious Diseases and Immunology New York University School of Medicine New York, New York (Chapter 20)

Susan A. Fontana, PhD, APRN-BC Toni Balistrieri, RN, MSN, CCNS Clinical Nurse Specialist, Critical Care Zablocki Veterans Affairs Medical Center Milwaukee, Wisconsin (Chapter 24)

Associate Professor and Family Nurse Practitioner College of Nursing University of Wisconsin-Milwaukee Milwaukee, Wisconsin (Chapter 55)

Anna Barkman, RN, BN, MN

Kathryn J. Gaspard, PhD

Mount Royal College School of Nursing Faculty of Health & Community Studies Calgary, Alberta, Canada (Chapter 26)

Clinical Associate Professor Emerita College of Nursing University of Wisconsin-Milwaukee Milwaukee, Wisconsin (Chapters 12, 13, 14)

Diane S. Book, MD

Kathleen E. Gunta, MSN, RN, OCNS-C

Assistant Professor of Neurology Medical College of Wisconsin Milwaukee, Wisconsin (Chapter 51)

Clinical Nurse Specialist Aurora St. Luke’s Medical Center Milwaukee, Wisconsin (Chapters 57, 58)

Edward W. Carroll, MS, PhD

Safak Guven, MD, MBA, FACE, FACP

Clinical Assistant Professor Department of Biomedical Sciences, College of Health Sciences Marquette University Milwaukee, Wisconsin (Chapters 4, 6, 48, 54)

Las Vegas, Nevada (Chapter 42)

Robin Curtis, PhD Professor, Retired Department of Cellular Biology, Neurobiology, and Anatomy Medical College of Wisconsin Milwaukee, Wisconsin (Chapters 48, 54)

W. Michael Dunne Jr., PhD Professor of Pathology, Immunology, and Molecular Microbiology Washington University School of Medicine Medical Director of Microbiology Barnes-Jewish Hospital St. Louis, Missouri (Chapter 16)

Serena W. Hung, MD Assistant Professor, Department of Neurology Medical College of Wisconsin Milwaukee, Wisconsin (Chapter 50)

Scott A. Jens, OD, FAAO Doctor of Optometry Isthmus Eye Care, SC Middleton, Wisconsin (Chapter 54)

Mary Kay Jiricka, RN, MSN, CCRN, APN-BC Staff Nurse, Cardiac Intensive Care Unit Aurora St. Luke’s Medical Center Milwaukee, Wisconsin (Chapter 11)

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Contributors

Julie A. Kuenzi, RN, MSN, CDE

Sandra Kawczynski Pasch, RN, MS, MA

Manager–Diabetes and Endocrine Center Froedtert Hospital and Medical College of Wisconsin Milwaukee, Wisconsin (Chapter 42)

Assistant Professor Columbia College of Nursing Milwaukee, Wisconsin (Chapter 53)

Mary Pat Kunert, RN, PhD

Janice Kuiper Pikna, RN, MSN, CS

Associate Professor College of Nursing University of Wisconsin-Milwaukee Milwaukee, Wisconsin (Chapters 9, 10)

Clinical Nurse Specialist–Gerontology Froedtert Hospital Milwaukee, Wisconsin (Chapter 3)

Joan Pleuss, RD, MS, CDE, CD Nathan A. Ledeboer, PhD Assistant Professor of Pathology Medical College of Wisconsin Director, Clinical Microbiology DynaCare Laboratories Milwaukee, Wisconsin (Chapter 16)

Kim Litwack, RN, PhD, FAAN, APNP Associate Professor College of Nursing University of Wisconsin-Milwaukee Milwaukee, Wisconsin (Chapters 27, 32, 49)

Program Manager/Bionutrition Core General Clinical Research Center (GCRC) Medical College of Wisconsin Milwaukee, Wisconsin (Chapter 39)

Charlotte Pooler, RN, BScN, MN, PhD (Nursing), CNCC(C), CNC(C) Director, Baccalaureate Nursing Program Faculty of Health and Community Studies Grant MacEwan College Edmonton, Alberta, Canada (Chapters 26, 29)

Debra Bancroft Rizzo, RN, MSN, FNP-C Judy Wright Lott, RNC, DSN, FAAN Dean and Professor of Nursing Louise Herrington School of Nursing Baylor University Waco, Texas (Chapter 2)

Patricia McCowen Mehring, RNC, MSN, WHNP Nurse Practitioner, Department of OB-GYN Medical College of Wisconsin Milwaukee, Wisconsin (Chapters 45, 46, 47)

Carrie J. Merkle, RN, PhD, FAAN Associate Professor College of Nursing University of Arizona Tucson, Arizona (Chapters 5, 8)

Kathleen Mussatto, RN, PhD(C) Research Manager Herma Heart Center Children’s Hospital of Wisconsin Milwaukee, Wisconsin (Chapter 24)

Nurse Practitioner Rheumatic Disease Center Glendale, Wisconsin (Chapter 59)

Gladys Simandl, RN, PhD Professor Columbia College of Nursing Milwaukee, Wisconsin (Chapters 60, 61)

Cynthia Sommer, PhD, MT (ASCP) Associate Professor Emerita, Department of Biological Sciences University of Wisconsin-Milwaukee Milwaukee, Wisconsin (Chapters 17, 18)

Jill Winters, RN, PhD Director of Research and Scholarship; Associate Professor Marquette University College of Nursing Milwaukee, Wisconsin (Chapter 25)

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Reviewers Sally Aboelela, PhD

Jackie Carnegie, PhD, MEd

Jamie Flower, RN, MS

Assistant Professor Columbia University New York, New York

Assistant Professor, Department of Cellular and Molecular Medicine University of Ottawa Ottawa, Ontario, Canada

Assistant Professor University of Arkansas-Fort Smith Fort Smith, Arkansas

Joann Acierno, RN, BSN, MSN Assistant Professor Clarkson College Omaha, Nebraska

Joyce S. Fontana, RN, PhD Margaret Christensen, RN, PhD Associate Professor Northeastern University Boston, Massachusetts

Karen Bailey, RN, MSN, BC-FNP

Assistant Professor of Nursing St. Joseph College-W. Hartford West Hartford, Connecticut

Dorothy Ann Fraser, MSN, FNP-C

Assistant Professor; Family Nurse Practitioner Marshall University; Valley Health Huntington, West Virginia

Elizabeth Cohn, RN, NP, ACNP, DNSc

Joseph Balatbat, MD

Christine Colella, MSN, CS, CNP

Vice President of Academic Affairs Sanford-Brown Institute NYC New York, New York

Associate Professor of Clinical Nursing; Adult Nurse Practitioner University of Cincinnati Cincinnati, Ohio

Assistant Professor Adelphi University Garden City, New York

Lecturer University of California-Davis Davis, California

Susan K. Frazier, RN, PhD

Susan Blakey, RN, MS Assistant Professor Georgia Baptist College of Nursing Atlanta, Georgia

Cathleen A. Collins, RN, MSN Assistant Professor Texas Tech University Lubbock, Texas

Carey Bosold, RN, MSN, APN, FNP Assistant Professor Arkansas Tech University Russellville, Arkansas

Assistant Clinical Professor University of Florida Gainesville, Florida

Wanda Emberley Burke, RN, BN, MEd, PCNP

Professor Mercer University-Atlanta Atlanta, Georgia

Professor and Coordinator College Boreal Sudbury, Ontario, Canada

Professor Medical College of Ohio Toledo, Ohio

Sharon R. Haymaker, PhD, CRNP Crystal Donlevy, EdD Professor Cincinnati State Technical and Community College Cincinnati, Ohio

Faculty (Nurse Practitioner Program) Centre for Nursing Studies St. John’s, Newfoundland and Labrador, Canada

Margaret Fink, RN, EdD, BC

Connie Lorette Calvin, CRNA, ARNP, MS, Doctoral Fellow

Cindy Fitzgerald, RN, PhD(c), ARNP

Associate Clinical Coordinator Northeastern University Boston, Massachusetts

Assistant Professor Michigan State University College of Nursing Lansing, Michigan

James Hampton, PhD Dare Domico, RN, DSN

Carolyn M. Burger, RN, MSN, BC, AOCN Associate Professor Miami University Middletown Middletown, Ohio

Laura M. Freidhoff, MD

Louise Glover, RN, BA, A-EMCA David Derrico, RN, MSN

Donna Bowles, RN, MSN, EdD Associate Professor of Nursing Indiana University Southeast New Albany, Indiana

Associate Professor University of Kentucky Lexington, Kentucky

Assistant Professor Dominican University of California San Rafael, California

Assistant Professor and Coordinator, Family Nurse Practitioner Program Gonzaga University Spokane, Washington

Associate Professor Bloomsburg University Bloomsburg, Pennsylvania

Judy Hembd, RN, MSN Assistant Professor Montana State University Northern Havre, Montana

Lori Hendrickx, RN, EdD, CCRN Associate Professor South Dakota State University Brookings, South Dakota

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Reviewers

Leslie Higgins, PhD, APRN, BC

Brian Kipp, PhD

Eve Main, ARNP

Associate Professor and Director, Graduate Nursing Program Belmont University Nashville, Tennessee

Assistant Professor Grand Valley State University Allendale, Michigan

Assistant Professor Western Kentucky University Bowling Green, Kentucky

Lori Knight, CCHRA(c)

Maria E. Main, MSN, ARNP, MSN

Associate Professor, Biology Baptist Memorial College of Health Sciences Memphis, Tennessee

Instructor, Health Information Management Program SIAST Wascana Campus Regina, Saskatchewan, Canada

Assistant Professor Western Kentucky University Bowling Green, Kentucky

Kathleen J. Holbrook, BS

Therese M. Lahnstein, RN, MSN, CCRN

Vice President and Director Andrews and Holbrook Training Corporation Latham, New York

Assistant Professor Columbus State University Columbus, Georgia

Patricia C. Hunt, DO, MHA

Brigitte Lalonde, ACP

Adjunct Professor Pace University New York, New York

Coordinator/Professor La Cite Collegiale Ottawa, Ontario, Canada

Joanne Itano, RN, PhD, OCN

Gemme Langor, BN, Med

Interim Vice Chancellor; Director of Academic Plan and Policy University of Hawaii Honolulu, Hawaii

Professor Centre for Nursing Studies St. John’s, Newfoundland and Labrador, Canada

Frances Jackson, RN, PhD

Ramona Lazenby, EdD, CRNP

Associate Professor of Nursing Oakland University Rochester, Michigan

Assistant Dean and Associate Professor of Nursing Auburn University-Montgomery Montgomery, Alabama

Lisa Hight, EdD

Brenda Mason, MSN, APRN, FNP-BC Assistant Professor of Nursing Alderson-Broadus College Philippi, West Virginia

Timothy Maze, PhD Assistant Professor Lander University Greenwood, South Carolina

Sharon McCleave, BS, MEd

Nadine T. James, RN, BSN, MSN, PhD Assistant Professor University of Southern Mississippi Hattiesburg, Mississippi

Judy Jezierski, RN, MSN Chair, Department of Nursing Saint Joseph’s College West Hartford, Connecticut

Ritamarie John, DrNP, CPNP PNP/NNP Program Director Columbia University School of Nursing New York, New York

Brenda P. Johnson, RN, PhD Associate Professor Southeast Missouri State University Cape Girardeau, Missouri

Jennifer Johnson, MSN Assistant Professor, Department of Nursing University of NC-Pembroke Pembroke, North Carolina

Edna Johnson Lewis, MS, RN, CCRN, CS Clinical Assistant Professor Downstate Medical Center, College of Nursing Brooklyn, New York

Linda Linc, RN, PhD, CNS Professor University of Akron Akron, Ohio

Anne Lincoln, DVM Associate Professor, Biology North Country Community College Saranac Lake, New York

Suzanne E. Lindley, PhD, MS Associate Professor, Biology Limestone College Gaffney, South Carolina

Wendy B. Loren, MS, LMT Faculty Lane Community College Eugene, Oregon

Professor Seneca College Toronto, Ontario, Canada

Leigh Ann McInnis, PhD, APRN, BC, FNP Instructor Belmont University Nashville, Tennessee

Rhonda M. McLain, RN, DSN Assistant Professor Clayton College and State University Atlanta, Georgia

Thomas McNeilis, PhD, DO Associate Professor, Biology Dixie State College St. George, Utah

James A. Metcalf, PhD Professor George Mason University Fairfax, Virginia

Anita Mills, RN, MSN 4th Semester Lead Faculty Butler County Community College-El Dorado El Dorado, Kansas

Robert Moldenhauer, MS Professor St. Clair County Community College Port Huron, Michigan

Donna Moralejo, RN, PhD Memorial University School of Nursing St. John’s, New Foundland and Labrador, Canada

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Reviewers Mary Moran

Harry Plummer, RN, PhD

Frederick Slone, MD

Clinical Instructor Columbia University New York, New York

Professor University of Calgary Calgary, Alberta, Canada

Mary Morehouse, DO

Deborah Pool, RN, MS, CCRN

Faculty Drury University Springfield, Missouri

Instructor, Department of Nursing Glendale Community College Glendale, Arizona

Visiting Assistant Professor; Program Director for Basic Disaster Life Support University of South Florida College of Nursing Tampa, Florida

Marguerite Murphy, MS, RN

Debbie Pringnitz, PhD

Assistant Professor Medical College of Georgia Augusta, Georgia

Professor, Biology University of Maine-Fort Kent Fort Kent, Maine

Joan Nelson, DNP

Heidi Putman, RN, DNSc

Assistant Professor University of Colorado Denver Health Sciences Center Denver, Colorado

Assistant Professor West Virginia University Morgantown, West Virginia

Micki S. Raber, MSN, FNP-BC, PNP-BC Janet Nieveen, RN, PhD Assistant Professor University of Nebraska Medical Center Omaha, Nebraska

Assistant Clinical Professor University of Southern Alabama Mobile, Alabama

Shirlee Rankin, RMT, BA Amy Obringer, PhD Assistant Professor, Biology University of St. Frances-Ft. Wayne Fort Wayne, Indiana

Lead Instructor, Massage Therapy Programme CDI College Ottawa, Ontario, Canada

Thomas Lon Owen, PhD

Carl A. Ross, RN, PhD, CRNP, BC, CNE

Professor Northern Arizona University Flagstaff, Arizona

Professor of Nursing Robert Morris University School of Nursing and Allied Health Moon Township, Pennsylvania

Frank Paladino, BA, MA, PhD Professor Indiana Purdue University, Ft. Wayne Fort Wayne, Indiana

Christine Ruff, RN, MS, WHNP Assistant Professor University of Arkansas at Monticello Monticello, Arkansas

Davonya J. Person, MS Instructor/Laboratory Coordinator Auburn University Auburn, Alabama

Jo-Ann Sawatzky, RN, MN, PhD Assistant Professor University of Manitoba Winnipeg, Manitoba, Canada

Paul Pillitteri, PhD Assistant Professor of Biology Southern Utah University Cedar City, Utah

Lori Ploutz-Snyder, PhD Associate Professor and Chair of Exercise Science Syracuse University Syracuse, New York

Claire Schuster, RN, MSN, CNS, ARNP, CWS

Rachel Smetanka, PhD Assistant Professor, Biology Southern Utah University Cedar City, Utah

Melissa Smith, RN, MSN, FNP Clinical Instructor University of Missouri-Kansas City Kansas City, Missouri

Nan Smith-Blair, RN, PhD Assistant Professor University of Arkansas-Fayetteville Fayetteville, Arkansas

Janet Squires, RN, BN, MNC Memorial University School of Nursing St. John’s, Newfoundland and Labrador, Canada

Mary Stanley, RN, MA Assistant Professor University of Nebraska Medical Center College of Nursing Omaha, Nebraska

Gail Starich, BS, MS, PhD Dean, School of Health Sciences Brenau University Decatur, Georgia

Elaine E. Steinke, RN, PhD Professor Wichita State University Wichita, Kansas

Barbara Steuble, RN, MS Assistant Professor Samuel Merritt College Oakland, California

Professor; Family Nurse Practitioner; Clinical and Wound Care Specialist Berea College Berea, Kentucky

Jill Steuer, RN, PhD

Jane Shelby, RN, MSN

Lachel Story, RN, MSN

Director of Undergraduate Studies Belmont University Nashville, Tennessee

Instructor University of Southern Mississippi Hattiesburg, Mississippi

Associate Professor Capital University Columbus, Ohio

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Reviewers

Cheryl Swallow, RN, MSN

Laura Jean Waight, RN, MSN

Keeta Wilborn, RN, PhD

Professor St. Louis Community College-Forest Park Forest Park, Missouri

Instructor of Nursing West Texas A&M University Canyon, Texas

Department of Nursing Chair Brenau University Decatur, Georgia

Costellia Talley, BSN, MSN, PhD

Annette Ward, RN, MSN

Linda Wilson, MSN, PhD

Assistant Professor Michigan State University East Lansing, Michigan

Instructor Lower Columbia College Longview, Washington

Professor Middle Tennessee State University Murfreesboro, Tennessee

Stephenie Thibodeaux, MSN

A. Denyce Watties-Daniels, MS, RN

Sheryl Winn, BSN, MSN

Instructor Lamar State College-Orange Orange, Texas

Assistant Professor Coppin State University Baltimore, Maryland

Assistant Professor Macon State College Macon, Georgia

Donna Thompson, RN, MSN

Dorie Weaver, RN, MSN, FNP, APRN, BC

K. Mark Wooden, BS, PhD

Professor Salt Lake Community College Salt Lake City, Utah

Instructor DeSales University Center Valley, Pennsylvania

Associate Dean, CLAS; Department Chair, Math and Science Grand Canyon University Phoenix, Arizona

Karen S. Webber, RN, MN

Nicholas P. Ziats, PhD

Associate Professor Memorial University of Newfoundland St. John’s, Newfoundland and Labrador, Canada

Associate Professor of Pathology Case Western Reserve University Cleveland, Ohio

Ann Tritak, RN, BS, MA, EdD Associate Director RN-BSN Program; Associate Professor of Nursing Farleigh Dickinson University-Teaneck Teaneck, New Jersey

Jo Voss, RN, PhD, CNS Associate Professor South Dakota State University Brookings, South Dakota

Astatkie Zikarge, BS, MS, MD, MPH Michelina Eva Weicker, MD, MBA Professor Alvernia College Reading, Pennsylvania

Associate Professor of Environmental Health and Toxicology Texas Southern University Houston, Texas

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Preface The preparation of this edition has been both challenging and humbling. Challenging to incorporate the myriad of new information; humbling to realize that despite the advances in science and technology, illness and disease continue to occur and take their toll in terms of the physiologic as well as the social, psychological, and economic well-being of individuals, their families and communities, and the world. As the others before it, the eighth edition has been carefully reviewed and critiqued, reorganized, updated, and revised. Careful attention has been given to the incorporation of the most recent advances from the fields of genetics, immunity, and molecular biology. This edition maintains many of the features of the previous edition, including chapters on health and disease, sleep and sleep disorders, and neurobiology of thought and mood disorders. In addition there is added content on obesity and the metabolic syndrome. This edition, as no other, typifies a saying among scientists that “you can’t pick a flower without jiggling a star.” The forging of communications, travel and migration, and trade on a global scale has established links that have forever changed the understanding and application of scientific information and health care practices. The isolation of peoples and information is no longer possible or beneficial. As the borders and boundaries of individuals, countries, and continents have become more permeable, there has been an increased focus on exploring issues and incorporating practices relative to the world community. Within this text, the efforts of the world community in the expansion of scientific knowledge and the advances in health care technology are presented through the inclusion of international studies, WHO guidelines, and the health variants of diverse populations. In line with the greater international focus, this edition has added Dr. Glenn Matfin, who has roots in the United Kingdom, as coauthor and has also added two new contributing authors from Canada, Charlotte Pooler, RN, PhD, and Anna Barkman, RN, MN. The integration of full color into the design and illustrations has continued. Over 200 of the illustrations that appear in this edition are new or have been extensively modified. The illustrations have been carefully chosen to support the concepts that are presented in the text, while maintaining a balance between line drawings of anatomic structures and pathophysiologic processes, flow charts, and photographic illustrations of disease states. This offers not only visual appeal but also enhances conceptual learning, linking text content to illustration content. Two new features have heightened the synergism of text and illustration. The first, a feature called “Understanding,” focuses on the key physiologic processes and phenomena of a disorder. A process is broken down into its consecutive parts, which are presented in a sequential manner, to provide an insight

into the many opportunities for disease processes to disrupt the sequence. The second new element, the “clinical feature,” uses illustration to depict the clinical manifestations of selected disease states. This edition also retains the list of suffixes and prefixes, the glossary, and the table of normal laboratory values that were in the seventh edition. The table of laboratory values includes both conventional and SI units, as well as Internet addresses for conversion resources. Objectives continue to appear at the beginning of each major section in a chapter, and summary statements appear at the end. The key concept boxes have been retained within each chapter. They are intended to help the reader retain and use text information by providing a mechanism to incorporate the information into a larger conceptual unit as opposed to merely memorizing a string of related and unrelated facts. Review exercises appear at the end of each chapter and assist the reader in using the conceptual approach to solving problems related to chapter content. Despite the extensive changes and revision, every attempt has been made to present content in a manner that is logical, understandable, and that inspires reader interest. The content has been arranged so that concepts build on one another. Words are defined as content is presented. Concepts from physiology, biochemistry, physics, and other sciences are reviewed as deemed appropriate. A conceptual model that integrates the developmental and preventative aspects of health has been used. Selection of content was based on common health problems, including the special needs of children and elderly persons. Although intended as a course textbook, it also is designed to serve as a reference book that students can take with them and use in their practice once the course is finished. And finally, as a nurse-physiologist, my major emphasis with each revision has been to relate normal body functioning to the physiologic changes that participate in disease production and occur as a result of disease, as well as the body’s remarkable ability to compensate for these changes. The beauty of physiology is that it integrates all of the aspects of human genetics, molecular and cellular biology, and organ anatomy and physiology into a functional whole that can be used to explain both the physical and psychological aspects of altered health. Indeed, it has been my philosophy to share the beauty of the human body and to emphasize that in disease as in health, there is more “going right” in the body than is “going wrong.” This book is an extension of my career and, as such, of my philosophy. It is my hope that readers will learn to appreciate the marvelous potential of the body, incorporating it into their own philosophy and ultimately sharing it with their clients. Carol Mattson Porth xi

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To the Reader This book was written with the intent of making the subject of pathophysiology an exciting exploration that relates normal body functioning to the physiologic changes that occur as a result of disease, as well as the body’s remarkable ability to compensate for these changes. Indeed, it is these changes that represent the signs and symptoms of disease. Using a book such as this can be simplified by taking time out to find what is in the book and how to locate information when it is needed. The table of contents at the beginning of the book provides an overall view of the organization and content of the book. It also provides clues as to the relationships among areas of content. For example, the location of the chapter on neoplasia within the unit on cell function and growth indicates that neoplasms are products of altered cell growth. The index, which appears at the end of the book, can be viewed as a road map for locating content. It can be used to quickly locate related content in different chapters of the book or to answer questions that come up in other courses.

ORGANIZATION The book is organized into units and chapters. The units identify broad areas of content, such as alterations in the circulatory system. Many of the units have an introductory chapter that contains essential information about the structure and function of the body systems that are being discussed in the unit. These chapters provide the foundation for understanding the pathophysiology content presented in the subsequent chapters. The chapters focus on specific areas of content, such as heart failure and circulatory shock. The chapter outline that appears at the beginning of each chapter provides an overall view of the chapter content and organization. Icons identify specific content related to infants and children , pregnant women , and older adults .

READING AND LEARNING AIDS In an ever-expanding world of information you will not be able to read, let alone remember, everything that is in this book, or in any book, for that matter. With this in mind, we have developed a number of special features that will help you focus on and master the essential content for your current as well as future needs. The objectives that appear at the beginning of each major area of content provide a focus for your study. After you have finished each of these areas of content, you may want to go back and make sure that you have met each of the objectives.

After completing this section of the chapter, you should be able to meet the following objectives: ■ ■

Define the term orthostatic hypotension. Describe the cardiovascular, neurohumoral, and muscular responses that serve to maintain blood pressure when moving from the supine to standing position.

It is essential for any professional to use and understand the vocabulary of his or her profession. Throughout the text, you will encounter terms in italics. This is a signal that a word and the ideas associated with it are important to learn. In addition, two aids are provided to help you expand your vocabulary and improve your comprehension of what you are reading: the glossary and the list of prefixes and suffixes. The glossary contains concise definitions of frequently encountered terms. If you are unsure of the meaning of a term you encounter in your reading, check the glossary in the back of the book before proceeding. The list of prefixes and suffixes is a tool to help you derive the meaning of words you may be unfamiliar with and increase your vocabulary. Many disciplines establish a vocabulary by affixing one or more letters to the beginning or end of a word or base to form a derivative word. Prefixes are added to the beginning of a word or base, and suffixes are added to the end. If you know the meanings of common prefixes and suffixes, you can usually derive the meaning of a word, even if you have never encountered it before. A list of prefixes and suffixes can be found on the inside back cover.

BOXES Boxes are used throughout the text to summarize and highlight key information. You will frequently encounter two types of boxes: Key Concept Boxes and Summary Boxes. One of the ways to approach learning is to focus on the major ideas or concepts rather than trying to memorize a list of related and unrelated bits of information. As you have probably already discovered, it is impossible to memorize everything that is in a particular section or chapter of the book. Not only does your brain have a difficult time trying to figure out where to store all the different bits of information, your brain doesn’t know how to retrieve the information when you need it. Most important of all, memorized lists of content can seldom, if ever, be applied directly to an actual clinical situation. The Key Concept Boxes guide you in identifying the major ideas or concepts that form the foundation for truly understanding the major areas of content. When you understand the concepts in the Key Concept Boxes, you will have a framework for remembering and using the facts given in the text. xiii

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To the Reader

ILLUSTRATIONS AND PHOTOS

PRIMARY IMMUNODEFICIENCY DISORDERS ■

■

Primary immunodeficiency disorders are congenital or inherited abnormalities of immune function that render a person susceptible to diseases normally prevented by an intact immune system. Disorders of B-cell function impair the ability to produce antibodies and defend against microorganisms and toxins that circulate in body fluids (IgM and IgG) or enter the body through the mucosal surface of the respiratory or gastrointestinal tract (IgA). Persons with primary B-cell immunodeficiency are particularly prone to pyogenic infections due to encapsulated organisms.

The Summary Boxes at the end of each section provide a review and a reinforcement of the main content that has been covered. Use the summaries to assure that you have covered and understand what you have read.

The full-color illustrations will help you to build your own mental image of the content that is being presented. Each drawing has been developed to fully support and build upon the ideas in the text. Some illustrations are used to help you picture the complex interactions of the multiple phenomena that are involved in the development of a particular disease; others can help you to visualize normal function or understand the mechanisms whereby the disease processes exert their effects. In addition, photographs of pathologic processes and lesions provide a realistic view of selected pathologic processes and lesions.

Glutamate

Ca2+

NMDA receptor

IN SUMMARY,

CKD results from the destructive effects of many forms of renal disease. Regardless of the cause, the consequences of nephron destruction in CKD are alterations in the filtration, reabsorption, and endocrine functions of the kidneys. Chronic disease is defined as either diagnosed kidney damage or GFR of less than 60 mL/min/1.73 m2 for 3 months or more, and kidney failure as a GFR of less than 15 mL/min/1.73 m2, usually accompanied by most of the signs and symptoms of uremia, or a need to start renal replacement therapy. CKD affects almost every body system. It causes an accumulation of nitrogenous wastes (i.e., azotemia), alters sodium and water excretion, and alters regulation of body levels of potassium, phosphate, calcium, and magnesium. It also causes skeletal disorders, anemia, cardiovascular disorders, neurologic disturbances, gastrointestinal dysfunction, and discomforting skin changes.

Increase in intracellular calcium

Calcium cascade

• Release of intracellular enzymes • Protein breakdown • Free radical formation • Lipid peroxidation • Fragmentation of DNA • Nuclear breakdown

Brain cell injury and death

FIGURE 51-2 • The role of the glutamate-NMDA receptor in brain

TABLES AND CHARTS

cell injury.

Tables and charts are designed to present complex information in a format that makes it more meaningful and easier to remember. Tables have two or more columns, and are often used for the purpose of comparing or contrasting information. Charts have one column and are used to summarize information.

CLINICAL FEATURES New to this edition is a new type of illustration that depicts the clinical features of persons with selected diseases. This feature is designed to help you visualize the entire spectrum of clinical manifestations that are associated with these disease states.

TABLE 31-2 Sources

of Body Water Gains and Losses in the Adult

GAINS

LOSSES

Oral intake As water In food Water of oxidation Total

Urine Insensible losses Lungs Skin Feces Total

1000 mL 1300 mL 200 mL 2500 mL

1500 mL 300 mL 500 mL 200 mL 2500 mL

Epicanthal folds, slanted eyes, and flat facial profile Malformed ears

Congenital heart disease

CHART 22-1

Growth failure Mental retardation Flat occiput Big, protruding, wrinkled tongue

Intestinal malformations

RISK FACTORS IN CORONARY HEART DISEASE OTHER THAN LOW-DENSITY LIPOPROTEINS

Positive Risk Factors Age Men: ≥45 years Women: ≥55 years or premature menopause without estrogen replacement therapy Family history of premature coronary heart disease (definite myocardial infarction or sudden death before 55 years of age in father or other male first-degree relative, or before 65 years of age in mother or other female first-degree relative) Current cigarette smoking Hypertension (≥140/90 mm Hg* or on antihypertensive medication)

Acute lymphoblastic leukemia

Short, broad hands with simian crease

Wide gap between 1st and 2nd toes

FIGURE 7-9 • Clinical features of a child with Down syndrome.

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To the Reader

UNDERSTANDING PHYSIOLOGIC PROCESSES

APPENDICES

Also new to this edition is a feature called “Understanding” that focuses on the physiologic processes and phenomenon that form the basis for understanding disorders presented in the text. This feature breaks a process or phenomena down into its component parts and presents them in a sequential manner, providing an insight into the many opportunities for disease processes to disrupt the sequence.

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Your book contains two appendices. Appendix A, Lab Values, provides rapid access to normal values for many laboratory tests, as well as a description of the prefixes, symbols, and factors (e.g., micro, µ, 10−6) used for describing these values. Knowledge of normal values can help you to put abnormal values in context. Appendix B contains tables of dietary reference for carbohydrates, fats, proteins, fiber, vitamins, and minerals. We hope that this guide has given you a clear picture of how to use this book. Good luck and enjoy the journey!

Unit VIII Wording of Unit Title

Understanding • Myocardial Blood Flow Blood flow in the coronary vessels that supply the myocardium is influenced by (1) the aortic pressure, (2) autoregulatory mechanisms, and (3) compression of the intramyocardial vessels by the contracting heart muscle.

❶

Aortic Pressure

The two main coronary arteries that supply blood flow to the myocardium arise in the sinuses behind the two cusps of the aortic valve. Because of their location, the pressure and flow of blood in the coronary arteries reflects that of the aorta. During systole, when the aortic valve is open, the velocity of blood flow and position of the valve cusps cause the blood to move rapidly past the coronary artery inlets, and during diastole, when the aortic valve is closed, blood flow and the aortic pressure is transmitted directly into the coronary arteries.

❷

A variety of ancillary materials are available to support students and instructors alike.

Blood flow

Coronary artery

Autoregulatory Mechanisms

The heart normally extracts 60% to 80% of the oxygen in the blood delivered to it, leaving little in reserve. Accordingly, oxygen delivery during periods of increased metabolic demand depends on autoregulatory mechanisms that regulate blood flow through a change in vessel tone and diameter. During increased metabolic demand, vasodilation produces an increase in blood flow; during decreased demand, vasoconstriction or return of vessel tone to normal produces a reduction in flow. The mechanisms that link the metabolic activity of the heart to changes in vessel tone result from vasoactive mediators released from myocardial cells and the vascular endothelium.

STUDENT AND INSTRUCTOR RESOURCES

Aortic valve cusps

Resources for Students To heart muscle (myocardium) Systole

To heart muscle (myocardium)

■

Diastole

Endothelial cell

Myocardial metabolism and need for blood flow

■ Release of vasoactive mediators Vasoconstricting factors

Vasodilating factors

■ Vasoconstriction

Vasodilation

MATERIAL FOR REVIEW An important feature has been built into the text to help you verify your understanding of the material presented. After you have finished reading and studying the chapter, work on answering the review exercises at the end of the chapter. They are designed to help you integrate and synthesize material. If you are unable to answer a question, reread the relevant section in the chapter.

Resources for Instructors Instructor’s Resource DVD. This comprehensive resource includes the following: ■ ■

Review Exercises 1. A 34-year-old woman with diabetes is admitted to the emergency department in a stuporous state. Her skin is flushed and warm, her breath has a sweet odor, her pulse is rapid and weak, and her respirations are rapid and deep. Her initial laboratory tests indicate a blood sugar of 320 mg/dL, serum HCO3− of 12 mEq/L (normal, 24 to 27 mEq/L), and a pH of 7.1 (normal, 7.35 to 7.45). A. What is the most likely cause of her lowered pH and bicarbonate levels? B. How would you account for her rapid and deep respirations? C. Using the Henderson-Hasselbalch equation and the solubility coefficient for CO2 given in this chapter, what would you expect her PCO2 to be? D. How would you explain her warm, flushed skin and stuporous mental state?

Student Resource CD-ROM. This free CD-ROM is found in the front of the book, and contains ■ Animations of selected pathophysiologic processes ■ Links to relevant journal articles *. Even more animations are available online at thePoint.LWW.com along with Student Review Questions for every chapter. Study Guide for Porth’s Pathophysiology: Concepts of Altered Health States. This study guide reinforces and complements the text by helping you assess and apply your knowledge through case studies and a variety of questions styles, including multiple choice, fill-in-theblank, matching, short answer, and figure-labeling exercises that will help you practice for the NCLEX.

■ ■

■

■ ■

A Test Generator, containing more than 800 multiplechoice questions. Guided Lecture Notes that walk you though the chapter learning objective by learning objective with integrated references to the PowerPoint presentations. PowerPoint presentations. Student Assignments (written, group, clinical, and web) and Discussion Topics that can be implemented in the classroom or online. An Image Bank, containing approximately 300 images from the text in formats suitable for printing, projecting, and incorporating into web sites. WebCT- and Blackboard-ready materials, for use with your institution’s Learning Management system. Case Studies with critical-thinking/discussion questions.

*thePoint is a trademark of Wolters Kluwer Health.

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Acknowledgments As in past editions, many persons participated in the creation of this work. The contributing authors deserve a special mention, for they worked long hours preparing the content for the eighth edition of Pathophysiology: Concepts of Altered Health States. This edition is particularly meaningful since it marks over a quarter of a century since the first edition was published in 1982, and many of these authors have been with the book during this time and have played an essential role in the development of this edition. I would also like to acknowledge Dr. Glenn Matfin, who joined me as coauthor for this edition. His expertise contributed greatly to the development of this edition. I would also like to acknowledge Dr. Kathryn Gaspard and Dr. Kim Litwack for their consultation. Kathryn spent endless hours proofreading manuscripts and page proofs and tirelessly assisted in the development and modification of illustrations. Several other persons deserve special recognition. Georgianne Heymann assisted in editing the manuscript. As with previous editions, she provided not only excellent editorial assistance, but also encouragement and support when the tasks associated with manuscript preparation became most frustrating.

Sara Krause deserves recognition for her work in coordinating the development and modification of illustrations in the book. Sarah, along with Wendy Beth Jackelow and Anne Rains, are acknowledged for their talent in creating the many new illustrations and modifying the old illustrations for the book. I would also like to recognize the efforts of the editorial and production staff at Lippincott Williams & Wilkins that were directed by Margaret Zuccarini and Hilarie Surrena, Senior Acquisitions Editors. I particularly want to thank Helen Kogut, who served as Managing Editor; and Debra Schiff for her dedication as Production Editor. The students in the classes I have taught also deserve a special salute, for they provided the inspiration upon which this book is founded. They provided the questions, suggestions, and contact with the “real world” of patient care that have directed the organization and selection of content for the book. And last, but not least, I would like to acknowledge my family, my friends, and my colleagues for their patience, their understanding, and their encouragement throughout the entire process.

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Child

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Index of Specified Content , Pregnancy , Elderly

Chapter 2

Concepts of Altered Health in Children

Chapter 3

Concepts of Altered Health in Older Adults

Chapter 7

Genetic and Congenital Disorders

Genetic and Chromosomal Disorders Disorders Due to Environmental Influences Prenatal Diagnosis and Counseling Chapter 8

Neoplasia

Childhood Cancers Chapter 10

Alterations in Temperature Regulation

Fever in Children Fever in the Elderly Neonatal Hypothermia Chapter 11

Activity Tolerance and Fatigue

Exercise and Activity Tolerance in the Elderly Chapter 14

Disorders of Red Blood Cells

Chapter 19

Disorders of the Immune Response

Transient Hypogammaglobulinemia of Infancy Primary Immunodeficiency Disorders Chapter 20

Acquired Immunodeficiency Syndrome

HIV Infection in Pregnancy and in Infants and Children Chapter 23

Disorders of Blood Pressure Regulation

Hypertension During Pregnancy Hypertension in Children Hypertension in the Elderly Chapter 24

Disorders of Cardiac Function

Heart Disease in Infants and Children Chapter 26

Heart Failure and Circulatory Shock

Heart Failure in Infants and Children Heart Failure in the Elderly Chapter 28

Respiratory Tract Infections, Neoplasms, and Childhood Disorders

Sickle Cell Disease Red Cell Changes in the Neonate Red Cell Changes in the Elderly Chapter 15

Disorders of White Blood Cells and Lymphoid Tissues

Congenital Neutropenia Chapter 17

Innate and Adaptive Immunity

Transfer of Immunity From Mother to Infant Immune Response in the Elderly Chapter 18

Inflammation, Tissue Repair, and Wound Healing

Management of Lung Cancer in the Elderly Respiratory Disorders in Children Chapter 29

Disorders of Ventilation and Gas Exchange

Bronchial Asthma in Children Cystic Fibrosis Chapter 33

Disorders of Renal Function

Congenital Disorders of the Kidney Polycystic Kidney Disease Urinary Tract Infections in Children Urinary Tract Infections in Pregnant Women

Wound Healing in Neonate and Children

Urinary Tract Infections in the Elderly

Wound Healing in Aged Persons

Wilms Tumor xix

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Index of Specified Content

Chapter 34

Acute Renal Failure and Chronic Kidney Disease

Chronic Kidney Disease in Children Chronic Kidney Disease in the Elderly Chapter 35

Disorders of the Bladder and Lower Urinary Tract

Continence in Children Incontinence in the Elderly Chapter 37

Disorders of Gastrointestinal Function

Congenital Anomalies Gastroesophageal Reflux in Children Rotavirus and Acute Diarrheal Disease in Children

Chapter 48

Organization and Control of Neural Function

Neural Tube Defects Chapter 49

Somatosensory Function, Pain, and Headache

Pain in Children Pain in Older Adults Chapter 50

Disorders of Motor Function

Muscular Dystrophy Chapter 52

Sleep and Sleep Disorders

Sleep and Sleep Disorders in Children Sleep and Sleep Disorders in the Elderly

Chapter 39

Alterations in Nutritional Status

Childhood Obesity Malnutrition and Eating Disorders Chapter 41

Disorders of Endocrine Control of Growth and Metabolism

Chapter 53

Disorders of Thought, Mood, and Memory

Normal Cognitive Aging and Dementia Chapter 54

Disorders of Visual Function

Short Stature and Growth Hormone Deficiency in Children

Ophthalmia Neonatorum

Tall Stature and Growth Hormone Excess in Children

Senile Cataract

Isosexual Precocious Puberty

Congenital Cataract Retinoblastoma Strabismus and Amblyopia

Congenital Hypothyroidism Congenital Adrenal Hyperplasia Chapter 42

Diabetes Mellitus and the Metabolic Syndrome

Chapter 55

Disorders of Hearing and Vestibular Function

Otitis Media Hearing Loss in Infants and Children

Gestational Diabetes Chapter 43

Structure and Function of the Male Genitourinary System

Embryonic Development Aging Changes Chapter 44

Disorders of the Male Genitourinary System

Hypospadias and Epispadias Cryptorchidism Chapter 45

Structure and Function of the Female Reproductive System

Menopause and Aging Changes

Hearing Loss in the Elderly Chapter 58

Disorders of Musculoskeletal Function: Developmental and Metabolic Disorders

Alterations in Skeletal Growth and Remodeling Hereditary and Congenital Deformities Juvenile Osteochondroses Osteoporosis Rickets Chapter 59

Disorders of Musculoskeletal Function: Rheumatic Disorders

Rheumatic Disorders in Children Rheumatic Disorders in the Elderly

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Index of Specified Content

Chapter 61

Disorders of Skin Integrity and Function

Skin Disorders of Infancy Skin Manifestations of Common Infectious Diseases Normal Age-Related Changes Skin Lesions Common Among the Elderly

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Contents CHAPTER 3

UNIT•I

Concepts of Altered Health 36 in Older Adults

CONCEPTS OF HEALTH AND DISEASE 1

Janice Kuiper Pikna THE ELDERLY AND THEORIES OF AGING Who Are the Elderly? 36 Theories of Aging 38

CHAPTER 1

Concepts of Health and Disease

2

PHYSIOLOGIC CHANGES OF AGING 39 Integumentary Changes 39 Stature and Musculoskeletal Function Cardiovascular Function 41 Respiratory Function 42 Neurologic Function 42 Special Sensory Function 42 Immune Function 43 Gastrointestinal Function 44 Renal Function 44 Genitourinary Function 45

Carol M. Porth CONCEPTS OF HEALTH AND DISEASE Health 2 Disease 3

2

HEALTH AND DISEASE IN POPULATIONS 5 Epidemiology and Patterns of Disease 5 Determination of Risk Factors 6 Natural History 7 Levels of Prevention 8 Evidence-Based Practice and Practice Guidelines

CHAPTER 2

Concepts of Altered Health 10 in Children Judy Wright Lott 11 GROWTH AND DEVELOPMENT Prenatal Growth and Development Birth Weight and Gestational Age

INFANCY 15 Growth and Development 16 Health Problems of the Neonate Health Problems of the Infant EARLY CHILDHOOD 27 Growth and Development Common Health Problems

8

FUNCTIONAL PROBLEMS ASSOCIATED WITH AGING 45 Functional Assessment 46 Urinary Incontinence 46 Instability and Falls 47 Sensory Impairment 49 Depression and Cognitive Impairment DRUG THERAPY IN THE OLDER ADULT

11 13

19

36

40

49 52

U N I T • II CELL FUNCTION AND GROWTH

57

25

CHAPTER 4 27 28

MIDDLE TO LATE CHILDHOOD Growth and Development Common Health Problems

29 30

ADOLESCENCE 31 Growth and Development Common Health Problems

32 33

28

Cell and Tissue Characteristics

58

Edward W. Carroll FUNCTIONAL COMPONENTS OF THE CELL Protoplasm 58 The Nucleus 60 The Cytoplasm and Its Organelles 60 The Cytoskeleton 63 The Cell (Plasma) Membrane 65

58

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INTEGRATION OF CELL FUNCTION AND REPLICATION 66 Cell Communication 67 Cell Receptors 67 The Cell Cycle and Cell Division 69 Cell Metabolism and Energy Sources

CHROMOSOMES 121 Cell Division 122 Chromosome Structure

70

MOVEMENT ACROSS THE CELL MEMBRANE AND MEMBRANE POTENTIALS 73 Movement of Substances Across the Cell Membrane 74 Membrane Potentials 76 BODY TISSUES 80 Cell Differentiation 81 Embryonic Origin of Tissue Types Epithelial Tissue 81 Connective or Supportive Tissue Muscle Tissue 87 Nervous Tissue 90 Extracellular Tissue Components

PATTERNS OF INHERITANCE Definitions 125 Genetic Imprinting 125 Mendel’s Laws 126 Pedigree 127

124

GENE TECHNOLOGY 127 Genetic Mapping 127 Recombinant DNA Technology RNA Interference Technology

129 131

81

CHAPTER 7 86

Genetic and Congenital Disorders

133

Carol M. Porth 91

GENETIC AND CHROMOSOMAL DISORDERS Single-Gene Disorders 134 Multifactorial Inheritance Disorders 139 Chromosomal Disorders 140 Mitochondrial Gene Disorders 145

CHAPTER 5

Cellular Adaptation, Injury, 94 and Death

DISORDERS DUE TO ENVIRONMENTAL INFLUENCES Period of Vulnerability 147 Teratogenic Agents 147

Carrie J. Merkle 94 CELLULAR ADAPTATION Atrophy 95 Hypertrophy 95 Hyperplasia 96 Metaplasia 97 Dysplasia 97 Intracellular Accumulations Pathologic Calcifications 98

123

133

147

DIAGNOSIS AND COUNSELING 151 Genetic Assessment 151 Prenatal Screening and Diagnosis

151

97

CELL INJURY AND DEATH 99 Causes of Cell Injury 99 Mechanisms of Cell Injury 103 Reversible Cell Injury and Cell Death Cellular Aging 109

CHAPTER 8

Neoplasia 105

CHAPTER 6

Genetic Control of Cell Function 112 and Inheritance Edward W. Carroll GENETIC CONTROL OF CELL FUNCTION DNA Structure and Function 113 From Genes to Proteins 116

156

Carrie J. Merkle

112

CONCEPTS OF CELL DIFFERENTIATION AND GROWTH 156 The Cell Cycle 157 Cell Proliferation 160 Cell Differentiation 160 CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS Terminology 162 Benign Neoplasms 162 Malignant Neoplasms 163

162

ETIOLOGY OF CANCER 169 Genetic and Molecular Basis of Cancer Host and Environmental Factors 173

169

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CLINICAL MANIFESTATIONS Tissue Integrity 177 Systemic Manifestations Anemia 179 Paraneoplastic Syndromes

INCREASED BODY TEMPERATURE Fever 218 Hyperthermia 223

177 178

SCREENING, DIAGNOSIS, AND TREATMENT Screening 181 Diagnostic Methods 181 Cancer Treatment 183 CHILDHOOD CANCERS 190 Incidence and Types 190 Biology of Childhood Cancers Diagnosis and Treatment 192 Adult Survivors of Childhood and Adolescent Cancer 192

CHAPTER 11

Activity Tolerance and Fatigue

231 EXERCISE AND ACTIVITY TOLERANCE Types of Exercise 232 Physiologic and Psychological Responses 233 Assessment of Activity and Exercise Tolerance 237 Exercise and Activity Tolerance in the Elderly 238

191

ACTIVITY INTOLERANCE AND FATIGUE Mechanisms of Fatigue 239 Acute Physical Fatigue 240 Chronic Fatigue 240

198

Mary Pat Kunert 199 HOMEOSTASIS Constancy of the Internal Environment Control Systems 199

248

U N I T • IV

199

DISORDERS OF THE HEMATOPOIETIC SYSTEM

253

205

DISORDERS OF THE STRESS RESPONSE 208 Effects of Acute Stress 208 Effects of Chronic Stress 208 Post-traumatic Stress Disorder 209 Treatment and Research of Stress Disorders

CHAPTER 10

214

Mary Pat Kunert BODY TEMPERATURE REGULATION Mechanisms of Heat Production Mechanisms of Heat Loss 216

239

BED REST AND IMMOBILITY 243 Physiologic Effects of Bed Rest 244 Psychosocial Responses 248 Time Course of Physiologic Responses Interventions 249

CHAPTER 9

Alterations in Temperature Regulation

231

Mary Kay Jiricka

DISORDERS OF INTEGRATIVE FUNCTION 197

STRESS AND ADAPTATION 200 The Stress Response 200 Coping and Adaptation to Stress

226

180

U N I T • III

Stress and Adaptation

218

DECREASED BODY TEMPERATURE Hypothermia 227

179

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214 216

CHAPTER 12

Blood Cells and the Hematopoietic System 210

254

Kathryn J. Gaspard COMPOSITION OF BLOOD AND FORMATION 254 OF BLOOD CELLS Plasma 255 Blood Cells 255 Formation of Blood Cells (Hematopoiesis) DIAGNOSTIC TESTS 260 Blood Count 260 Erythrocyte Sedimentation Rate 261 Bone Marrow Aspiration and Biopsy

261

258

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CHAPTER 13

CHAPTER 15

Disorders of Hemostasis

Disorders of White Blood Cells 301 and Lymphoid Tissues

262

Kathryn J. Gaspard MECHANISMS OF HEMOSTASIS Vessel Spasm 262 Formation of the Platelet Plug Blood Coagulation 264 Clot Retraction 265 Clot Dissolution 268

Carol M. Porth

262

HEMATOPOIETIC AND LYMPHOID TISSUES Leukocytes (White Blood Cells) 301 Bone Marrow and Hematopoiesis 302 Lymphoid Tissues 303

263

NON-NEOPLASTIC DISORDERS OF WHITE BLOOD CELLS 304 Neutropenia (Agranulocytosis) Infectious Mononucleosis 306

HYPERCOAGULABILITY STATES 268 Hypercoagulability Associated With Increased Platelet Function 269 Hypercoagulability Associated With Increased Clotting Activity 269 BLEEDING DISORDERS 270 Bleeding Associated With Platelet Disorders 271 Bleeding Associated With Coagulation Factor Deficiencies 273 Bleeding Associated With Vascular Disorders 275 Disseminated Intravascular Coagulation 275

304

NEOPLASTIC DISORDERS OF HEMATOPOIETIC AND LYMPHOID ORIGIN 308 Malignant Lymphomas 308 Leukemias 313 Plasma Cell Dyscrasias 318

UNIT•V INFECTION, INFLAMMATION, AND IMMUNITY 323

CHAPTER 14

Disorders of Red Blood Cells

278

Kathryn J. Gaspard

CHAPTER 16

THE RED BLOOD CELL 278 Hemoglobin Synthesis 280 Red Cell Production 280 Red Cell Destruction 281 Red Cell Metabolism and Hemoglobin Oxidation 282 Laboratory Tests 282 ANEMIA 284 Blood Loss Anemia 284 Hemolytic Anemias 285 Anemias of Deficient Red Cell Production TRANSFUSION THERAPY 293 ABO Blood Groups 293 Rh Types 294 Blood Transfusion Reactions POLYCYTHEMIA

301

Mechanisms of Infectious Disease W. Michael Dunne, Jr., and Nathan A. Ledeboer INFECTIOUS DISEASES 324 Terminology 324 Agents of Infectious Disease

289

295

295

AGE-RELATED CHANGES IN RED BLOOD CELLS Red Cell Changes in the Neonate 296 Red Cell Changes With Aging 298

296

325

MECHANISMS OF INFECTION 332 Epidemiology of Infectious Diseases Portal of Entry 333 Source 334 Symptomatology 334 Disease Course 335 Site of Infection 335 Virulence Factors 336 DIAGNOSIS AND TREATMENT 338 OF INFECTIOUS DISEASES Diagnosis 338 Treatment 341 BIOTERRORISM AND EMERGING GLOBAL INFECTIOUS DISEASES 344 Bioterrorism 344 Global Infectious Diseases 345

333

324

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CHAPTER 17

Innate and Adaptive Immunity

Combined T-Cell and B-Cell Immunodeficiencies 406 Disorders of the Complement System Disorders of Phagocytosis 408 Stem Cell Transplantation 409

347

Cynthia Sommer IMMUNITY AND THE IMMUNE SYSTEM 347 Innate and Adaptive Immunity 348 Cells of the Immune System 348 Cytokines That Mediate and Regulate Immunity INNATE IMMUNITY 354 Epithelial Barriers 354 Cells of Innate Immunity 355 Pathogen Recognition 355 Soluble Mediators of Innate Immunity The Complement System 358 ADAPTIVE IMMUNITY 359 Antigens 361 Cells of Adaptive Immunity 362 B Lymphocytes and Humoral Immunity T Lymphocytes and Cellular Immunity Lymphoid Organs 370 Active Versus Passive Immunity 373 Regulation of the Immune Response

351

357

HYPERSENSITIVITY DISORDERS 410 Type I, Immediate Hypersensitivity Disorders Type II, Antibody-Mediated Disorders 414 Type III, Immune Complex–Mediated Disorders 415 Type IV, Cell-Mediated Hypersensitivity Disorders 416 Latex Allergy 418

410

419

AUTOIMMUNE DISEASE 421 Immunologic Tolerance 421 Mechanisms of Autoimmune Disease 422 Diagnosis and Treatment of Autoimmune Disease 424

373

CHAPTER 20

374

Acquired Immunodeficiency 427 Syndrome Jason Faulhaber and Judith A. Aberg THE AIDS EPIDEMIC AND TRANSMISSION OF HIV INFECTION 427 Emergence of the AIDS Epidemic 428 Transmission of HIV Infection 428

CHAPTER 18

Inflammation, Tissue Repair, 377 and Wound Healing

PATHOPHYSIOLOGY AND CLINICAL COURSE Molecular and Biologic Features of HIV Classification and Phases of HIV Infection Clinical Course 433

Carol M. Porth and Cynthia Sommer THE INFLAMMATORY RESPONSE 377 Acute Inflammation 378 Chronic Inflammation 388 Systemic Manifestations of Inflammation TISSUE REPAIR AND WOUND HEALING Tissue Repair 390 Wound Healing 392

408

TRANSPLANTATION IMMUNOPATHOLOGY 419 Mechanisms Involved in Transplant Rejection

365 368

DEVELOPMENTAL ASPECTS OF THE IMMUNE SYSTEM 374 Transfer of Immunity From Mother to Infant Immune Response in the Elderly 375

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389 390

430 432

PREVENTION, DIAGNOSIS, AND TREATMENT Prevention 439 Diagnostic Methods 440 Early Management 441 Treatment 441 Psychosocial Issues 443 HIV INFECTION IN PREGNANCY AND IN INFANTS AND CHILDREN 443

CHAPTER 19

Disorders of the Immune 400 Response Carol M. Porth IMMUNODEFICIENCY DISORDERS 400 Humoral (B-Cell) Immunodeficiencies 402 Cell-Mediated (T-Cell) Immunodeficiencies

430

405

439

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U N I T • VI DISORDERS OF CARDIOVASCULAR FUNCTION 449

DISORDERS OF THE ARTERIAL CIRCULATION Hyperlipidemia 479 Atherosclerosis 485 Vasculitis 489 Arterial Disease of the Extremities 491 Aneurysms and Dissection 494

479

DISORDERS OF THE VENOUS CIRCULATION Venous Circulation of the Lower Extremities Disorders of the Venous Circulation of the Lower Extremities 498

CHAPTER 21

Structure and Function of the Cardiovascular System

497 497

450

Carol M. Porth and Glenn Matfin ORGANIZATION OF THE CIRCULATORY SYSTEM Pulmonary and Systemic Circulations 451 Volume and Pressure Distribution 452

450

Disorders of Blood Pressure 505 Regulation

PRINCIPLES OF BLOOD FLOW 453 Relationships Between Blood Flow, Pressure, and Resistance 453 Wall Tension, Radius, and Pressure 456 Distention and Compliance 456 THE HEART AS A PUMP 457 Functional Anatomy of the Heart Cardiac Cycle 460 Regulation of Cardiac Performance

THE MICROCIRCULATION AND LYMPHATIC SYSTEM 470 Structure and Function 470 of the Microcirculation Capillary–Interstitial Fluid Exchange The Lymphatic System 473

Carol M. Porth 505 THE ARTERIAL BLOOD PRESSURE Mechanisms of Blood Pressure Regulation Blood Pressure Measurement 511

HYPERTENSION 512 Essential Hypertension 512 Secondary Hypertension 519 Malignant Hypertension 521 High Blood Pressure in Pregnancy High Blood Pressure in Children and Adolescents 523 High Blood Pressure in the Elderly

457 463

THE SYSTEMIC CIRCULATION AND CONTROL OF BLOOD FLOW 465 Blood Vessels 465 Arterial System 466 Venous System 467 Local and Humoral Control of Blood Flow

CHAPTER 23

468

506

521

525

ORTHOSTATIC HYPOTENSION 526 Pathophysiology and Causative Factors Diagnosis and Treatment 528

526

CHAPTER 24

Disorders of Cardiac Function

472

532

Toni Balistrieri and Kathy Mussatto

NEURAL CONTROL OF CIRCULATORY FUNCTION 474 Autonomic Nervous System Regulation 475 Central Nervous System Responses 475

532 DISORDERS OF THE PERICARDIUM Acute Pericarditis 533 Pericardial Effusion and Cardiac Tamponade Constrictive Pericarditis 535

CHAPTER 22

CORONARY ARTERY DISEASE 536 Coronary Circulation 536 Acute Coronary Syndrome 543 Chronic Ischemic Heart Disease

Disorders of Blood Flow in the Systemic Circulation

CARDIOMYOPATHIES 553 Primary Cardiomyopathies Secondary Cardiomyopathies

477

Glenn Matfin BLOOD VESSEL STRUCTURE AND FUNCTION Endothelial Cells 478 Vascular Smooth Muscle Cells 478

477

551

554 558

534

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INFECTIOUS AND IMMUNOLOGIC DISORDERS Infective Endocarditis 559 Rheumatic Heart Disease 560 VALVULAR HEART DISEASE 562 Hemodynamic Derangements Mitral Valve Disorders 564 Aortic Valve Disorders 566

559

CHAPTER 27 568

Structure and Function of the Respiratory System

STRUCTURAL ORGANIZATION OF THE RESPIRATORY SYSTEM 640 Conducting Airways 641 Lungs and Respiratory Airways 644 Pulmonary Vasculature and Lymphatic Supply Innervation 647 Pleura 648

Disorders of Cardiac Conduction 584 and Rhythm Jill Winters

DISORDERS OF CARDIAC RHYTHM AND CONDUCTION 591 Mechanisms of Arrhythmias 591 and Conduction Disorders Types of Arrhythmias and Conduction Disorders Diagnostic Methods 600 Treatment 601

593

CHAPTER 26

Heart Failure and Circulatory Shock

647

EXCHANGE OF GASES BETWEEN THE ATMOSPHERE AND THE LUNGS 648 Basic Properties of Gases 649 Ventilation and the Mechanics of Breathing 649 Lung Volumes 654 Pulmonary Function Studies 655 Efficiency and the Work of Breathing 655

584

606

Anna Barkman and Charlotte Pooler 607 616 616

CIRCULATORY FAILURE (SHOCK) 621 Pathophysiology of Circulatory Shock Cardiogenic Shock 623 Hypovolemic Shock 625 Distributive Shock 627 Obstructive Shock 630 Complications of Shock 630

640

Carol M. Porth and Kim Litwack

CHAPTER 25

HEART FAILURE 606 Pathophysiology of Heart Failure Acute Heart Failure Syndromes Manifestations of Heart Failure Diagnosis and Treatment 618

U N I T • VII DISORDERS OF RESPIRATORY FUNCTION 639

563

HEART DISEASE IN INFANTS AND CHILDREN Embryonic Development of the Heart 569 Fetal and Perinatal Circulation 570 Congenital Heart Defects 571 Kawasaki Disease 579

CARDIAC CONDUCTION SYSTEM Action Potentials 586 Electrocardiography 589

xxix

EXCHANGE AND TRANSPORT OF GASES Ventilation 657 Perfusion 658 Mismatching of Ventilation and Perfusion Diffusion 659 Oxygen and Carbon Dioxide Transport CONTROL OF BREATHING Respiratory Center 665 Regulation of Breathing Cough Reflex 667 Dyspnea 667

657

659 660

665 665

CHAPTER 28

Respiratory Tract Infections, Neoplasms, 670 and Childhood Disorders

622

HEART FAILURE IN CHILDREN AND THE ELDERLY Heart Failure in Infants and Children 632 Heart Failure in the Elderly 633

Carol M. Porth

632

RESPIRATORY TRACT INFECTIONS The Common Cold 671 Rhinosinusitis 672 Influenza 674 Pneumonias 676 Tuberculosis 681 Fungal Infections 685

670

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CANCER OF THE LUNG 687 Histologic Subtypes and Pathogenesis Clinical Features 689

U N I T • VIII

687

DISORDERS OF RENAL FUNCTION AND FLUIDS AND ELECTROLYTES 739

RESPIRATORY DISORDERS IN CHILDREN 690 Lung Development 690 Alterations in Breathing 693 Respiratory Disorders in the Neonate 693 Respiratory Infections in Children 695

CHAPTER 30

Structure and Function 740 of the Kidney

CHAPTER 29

Disorders of Ventilation 701 and Gas Exchange

Carol M. Porth KIDNEY STRUCTURE AND FUNCTION 740 Gross Structure and Location 741 Renal Blood Supply 741 The Nephron 741 Urine Formation 745 Regulation of Renal Blood Flow 749 Elimination Functions of the Kidney 751 Drug Elimination 753 Endocrine Functions of the Kidney 754 Action of Diuretics 754

Charlotte Pooler PHYSIOLOGIC EFFECTS OF VENTILATION 701 AND DIFFUSION DISORDERS Hypoxemia 702 Hypercapnia 703 DISORDERS OF LUNG INFLATION Disorders of the Pleura 704 Atelectasis 708

704

OBSTRUCTIVE AIRWAY DISORDERS 709 Physiology of Airway Disease 709 Bronchial Asthma 709 Chronic Obstructive Pulmonary Disease Bronchiectasis 721 Cystic Fibrosis 722

716

CHRONIC INTERSTITIAL (RESTRICTIVE) LUNG DISEASES 724 Etiology and Pathogenesis of Interstitial Lung Diseases 724 Occupational Lung Disease 725 Drug- and Radiation-Induced Lung Diseases Sarcoidosis 726 DISORDERS OF THE PULMONARY CIRCULATION Pulmonary Embolism 728 Pulmonary Hypertension 729 Cor Pulmonale 731 ACUTE RESPIRATORY DISORDERS 732 Acute Lung Injury/Acute Respiratory Distress Syndrome 732 Acute Respiratory Failure 733

TESTS OF RENAL FUNCTION 756 Urine Tests 756 Glomerular Filtration Rate 757 Blood Tests 757 Cystoscopy 758 Ultrasonography 758 Radiologic and Other Imaging Studies

758

CHAPTER 31

726

Disorders of Fluid and Electrolyte Balance

761

Glenn Matfin and Carol M. Porth 727

COMPOSITION AND COMPARTMENTAL DISTRIBUTION 761 OF BODY FLUIDS Introductory Concepts 762 Compartmental Distribution of Body Fluids 765 Capillary–Interstitial Fluid Exchange 765 SODIUM AND WATER BALANCE 770 Body Water Balance 770 Sodium Balance 771 Mechanisms of Regulation 772 Disorders of Thirst and Antidiuretic Hormone 772 Disorders of Sodium and Water Balance

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POTASSIUM BALANCE 783 Regulation of Potassium Balance Disorders of Potassium Balance

DISORDERS OF GLOMERULAR FUNCTION Etiology and Pathogenesis of Glomerular Injury 841 Types of Glomerular Disease 842 Glomerular Lesions Associated With Systemic Disease 846

783 785

CALCIUM, PHOSPHORUS, AND MAGNESIUM BALANCE 790 Mechanisms Regulating Calcium, Phosphorus, and Magnesium Balance 790 Disorders of Calcium Balance 792 Disorders of Phosphorus Balance 797 Disorders of Magnesium Balance 800

TUBULOINTERSTITIAL DISORDERS Renal Tubular Acidosis 848 Pyelonephritis 849 Drug-Related Nephropathies

Disorders of Acid-Base Balance

840

848

849

MALIGNANT TUMORS OF THE KIDNEY Wilms Tumor 851 Renal Cell Carcinoma 851

CHAPTER 32

xxxi

851

805

Carol M. Porth and Kim Litwack

CHAPTER 34

805 MECHANISMS OF ACID-BASE BALANCE Acid-Base Chemistry 806 Metabolic Acid and Bicarbonate Production Calculation of pH 807 Regulation of pH 807 Laboratory Tests 813

DISORDERS OF ACID-BASE BALANCE Metabolic Versus Respiratory Acid-Base Disorders 814 Compensatory Mechanisms 814 Metabolic Acidosis 815 Metabolic Alkalosis 819 Respiratory Acidosis 821 Respiratory Alkalosis 823

814

806

Acute Renal Failure and Chronic Kidney Disease

855

Carol M. Porth ACUTE RENAL FAILURE 855 Types of Acute Renal Failure Diagnosis and Treatment

856 858

CHRONIC KIDNEY DISEASE 859 Definition and Classification 859 Assessment of Glomerular Filtration Rate and Other Indicators of Renal Function Clinical Manifestations 862 Treatment 867

CHAPTER 33

Disorders of Renal Function

826

CHRONIC KIDNEY DISEASE IN CHILDREN AND ELDERLY PERSONS 870 Chronic Kidney Disease in Children 871 Chronic Kidney Disease in Elderly Persons

860

871

Carol M. Porth CONGENITAL AND INHERITED DISORDERS OF THE KIDNEYS 826 Congenital Disorders of the Kidneys 827 Inherited Cystic Kidney Diseases 828 Simple and Acquired Renal Cysts 830

CHAPTER 35

OBSTRUCTIVE DISORDERS 830 Mechanisms of Renal Damage Renal Calculi 832

CONTROL OF URINE ELIMINATION Bladder Structure 875 Neural Control of Bladder Function Diagnostic Methods of Evaluating Bladder Function 879

URINARY TRACT INFECTIONS 835 Etiologic Factors 836 Clinical Features 838 Diagnosis and Treatment 838 Infections in Special Populations

831

839

Disorders of the Bladder and Lower Urinary Tract

875

Carol M. Porth 875 876

ALTERATIONS IN BLADDER FUNCTION 880 Lower Urinary Tract Obstruction and Stasis Neurogenic Bladder Disorders 882 Urinary Incontinence 885

881

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CANCER OF THE BLADDER 890 Etiology and Pathophysiology Manifestations 890 Diagnosis and Treatment 890

CHAPTER 37 890

Disorders of Gastrointestinal 916 Function Carol M. Porth

U N I T • IX

DISORDERS OF THE ESOPHAGUS Congenital Anomalies 917 Dysphagia 917 Esophageal Diverticulum 918 Tears (Mallory-Weiss Syndrome) Hiatal Hernia 918 Gastroesophageal Reflux 919 Cancer of the Esophagus 920

DISORDERS OF GASTROINTESTINAL FUNCTION 893 CHAPTER 36

Structure and Function of the Gastrointestinal System

894

Carol M. Porth STRUCTURE AND ORGANIZATION OF THE GASTROINTESTINAL TRACT 894 Upper Gastrointestinal Tract 895 Middle Gastrointestinal Tract 896 Lower Gastrointestinal Tract 896 Gastrointestinal Wall Structure 897 MOTILITY 899 Control of Gastrointestinal Motility 899 Swallowing and Esophageal Motility 901 Gastric Motility 902 Small Intestine Motility 903 Colonic Motility and Defecation 904 HORMONAL, SECRETORY, AND DIGESTIVE FUNCTIONS Gastrointestinal Hormones Gastrointestinal Secretions Intestinal Flora 909 DIGESTION AND ABSORPTION Carbohydrate Absorption Fat Absorption 911 Protein Absorption 912

DISORDERS OF THE STOMACH Gastric Mucosal Barrier 922 Gastritis 922 Peptic Ulcer Disease 924 Cancer of the Stomach 927

916

918

921

DISORDERS OF THE SMALL AND LARGE INTESTINES 927 Irritable Bowel Syndrome 928 Inflammatory Bowel Disease 928 Infectious Enterocolitis 932 Diverticular Disease 934 Appendicitis 935 Alterations in Intestinal Motility 935 Alterations in Intestinal Absorption 941 Neoplasms 943

CHAPTER 38 905

Disorders of Hepatobiliary and Exocrine 949 Pancreas Function

905 906

Carol M. Porth THE LIVER AND HEPATOBILIARY SYSTEM Metabolic Functions of the Liver 952 Bile Production and Cholestasis 954 Bilirubin Elimination and Jaundice 954 Tests of Hepatobiliary Function 956

909 910

ANOREXIA, NAUSEA, AND VOMITING Anorexia 913 Nausea 913 Retching and Vomiting 913

913

949

DISORDERS OF HEPATIC AND BILIARY FUNCTION Hepatotoxic Disorders 957 Viral Hepatitis 959 Autoimmune Hepatitis 964 Intrahepatic Biliary Disorders 964 Alcohol-Induced Liver Disease 965 Cirrhosis, Portal Hypertension, and Liver Failure Cancer of the Liver 972

957

967

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DISORDERS OF THE GALLBLADDER AND EXOCRINE PANCREAS 974 Disorders of the Gallbladder and Extrahepatic Bile Ducts 974 Disorders of the Exocrine Pancreas 977

Disorders of Endocrine Control 1021 of Growth and Metabolism Glenn Matfin GENERAL ASPECTS OF ALTERED ENDOCRINE FUNCTION 1021 Hypofunction and Hyperfunction 1021 Primary, Secondary, and Tertiary Disorders

CHAPTER 39

Alterations in Nutritional Status

982

Joan Pleuss and Glenn Matfin NUTRITIONAL STATUS Energy Metabolism Energy Expenditure Energy Storage 984

983 983

THYROID DISORDERS 1030 Control of Thyroid Function Hypothyroidism 1034 Hyperthyroidism 1036

985

OVERWEIGHT AND OBESITY 992 Causes of Obesity 993 Types of Obesity 993 Health Risks Associated With Obesity Prevention and Treatment of Obesity Childhood Obesity 996

CHAPTER 42

UNIT•X

HORMONAL CONTROL OF GLUCOSE, FAT, AND PROTEIN METABOLISM 1047 Glucose, Fat, and Protein Metabolism Glucose-Regulating Hormones 1049

CHAPTER 40

1008 1014

1047

Safak Guven, Glenn Matfin, and Julie A. Kuenzi

DISORDERS OF ENDOCRINE FUNCTION 1007

THE ENDOCRINE SYSTEM Hormones 1009 Control of Hormone Levels Diagnostic Tests 1017

1037

998

Diabetes Mellitus and the Metabolic Syndrome

Mechanisms of Endocrine Control

1030

DISORDERS OF ADRENAL CORTICAL FUNCTION Control of Adrenal Cortical Function 1038 Congenital Adrenal Hyperplasia 1040 Adrenal Cortical Insufficiency 1041 Glucocorticoid Hormone Excess (Cushing Syndrome) 1043 Incidental Adrenal Mass 1044

994 995

UNDERNUTRITION AND EATING DISORDERS Malnutrition and Starvation 999 Eating Disorders 1001

Glenn Matfin

1022

PITUITARY AND GROWTH DISORDERS 1022 Pituitary Tumors 1022 Hypopituitarism 1022 Assessment of Hypothalamic-Pituitary Function 1023 Growth and Growth Hormone Disorders 1023 Isosexual Precocious Puberty 1029

982

NUTRITIONAL NEEDS 985 Recommended Dietary Allowances and Dietary Reference Intakes Nutritional Needs 986 Regulation of Food Intake and Energy Storage 989 Nutritional Assessment 990

xxxiii

1008

1047

DIABETES MELLITUS 1053 Classification and Etiology 1054 Clinical Manifestations of Diabetes 1059 Diagnostic Tests 1060 Diabetes Management 1061 Acute Complications 1067 Counter-regulatory Mechanisms and the Somogyi Effect and Dawn Phenomenon Chronic Complications 1070 Infections 1075

1069

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U N I T • XI DISORDERS OF GENITOURINARY AND REPRODUCTIVE FUNCTION 1079 CHAPTER 43

Structure and Function of the Male Genitourinary System

1080

Glenn Matfin STRUCTURE OF THE MALE REPRODUCTIVE SYSTEM 1080 Embryonic Development 1080 Testes and Scrotum 1081 Genital Duct System 1082 Accessory Organs 1083 Penis 1084

1092

1092

DISORDERS OF THE SCROTUM AND TESTES Congenital and Acquired Disorders 1098 Infection and Inflammation 1101 Neoplasms 1102 1104 1104 1105

MENSTRUAL CYCLE 1117 Hormonal Control 1118 Ovarian Follicle Development and Ovulation Endometrial Changes 1122 Cervical Mucus Changes 1122 Menopause 1122 1126

Disorders of the Female 1129 Reproductive System Patricia McCowen Mehring DISORDERS OF THE EXTERNAL GENITALIA AND VAGINA 1129 Disorders of the External Genitalia 1130 Disorders of the Vagina 1132

DISORDERS OF THE FALLOPIAN TUBES 1142 AND OVARIES Pelvic Inflammatory Disease 1142 Ectopic Pregnancy 1142 Cancer of the Fallopian Tube 1144 Ovarian Cysts and Tumors 1144

Glenn Matfin

DISORDERS OF THE PROSTATE Infection and Inflammation Hyperplasia and Neoplasms

1113

DISORDERS OF THE CERVIX AND UTERUS Disorders of the Uterine Cervix 1134 Disorders of the Uterus 1137

CHAPTER 44

DISORDERS OF THE PENIS 1092 Congenital and Acquired Disorders Disorders of Erectile Function 1094 Cancer of the Penis 1097

REPRODUCTIVE STRUCTURES External Genitalia 1113 Internal Genitalia 1115

CHAPTER 46

NEURAL CONTROL OF SEXUAL FUNCTION AND AGING CHANGES 1088 Neural Control 1089 Aging Changes 1089

1098

1113

Patricia McCowen Mehring

BREASTS 1126 Structure and Function

SPERMATOGENESIS AND HORMONAL CONTROL OF MALE REPRODUCTIVE FUNCTION 1084 Spermatogenesis 1085 Hormonal Control of Male Reproductive Function 1086

Disorders of the Male Genitourinary System

Structure and Function of the Female Reproductive System

DISORDERS OF PELVIC SUPPORT AND UTERINE POSITION 1148 Disorders of Pelvic Support 1148 Variations in Uterine Position 1151 MENSTRUAL DISORDERS 1151 Dysfunctional Menstrual Cycles Amenorrhea 1152 Dysmenorrhea 1153 Premenstrual Symptom Disorders DISORDERS OF THE BREAST Galactorrhea 1155 Mastitis 1155

1155

1151

1153

1133

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Ductal Disorders 1156 Fibroadenoma and Fibrocystic Changes Breast Cancer 1156

DEVELOPMENTAL ORGANIZATION OF THE NERVOUS SYSTEM 1192 Embryonic Development 1192 Segmental Organization 1196

1156

INFERTILITY 1160 Male Factors 1160 Female Factors 1160 Assisted Reproductive Technologies (ART)

1162

CHAPTER 47

Sexually Transmitted Infections

1166

Patricia McCowen Mehring INFECTIONS OF THE EXTERNAL GENITALIA Condylomata Acuminata (Genital Warts) Genital Herpes 1169 Molluscum Contagiosum 1171 Chancroid 1171 Granuloma Inguinale 1171 Lymphogranuloma Venereum 1171

1166

CHAPTER 49

Somatosensory Function, Pain, 1225 and Headache Kim Litwack

1174

DISORDERS OF NEURAL FUNCTION 1181

1234 1238

ALTERATIONS IN PAIN SENSITIVITY AND SPECIAL TYPES OF PAIN 1247 Alterations in Pain Sensitivity 1247 Special Types of Pain 1248

CHAPTER 48

Organization and Control 1182 of Neural Function

HEADACHE AND ASSOCIATED PAIN Headache 1251 Temporomandibular Joint Pain

Edward W. Carroll and Robin Curtis

NEUROPHYSIOLOGY 1187 Action Potentials 1187 Synaptic Transmission 1188 Messenger Molecules 1189

ORGANIZATION AND CONTROL 1225 OF SOMATOSENSORY FUNCTION Sensory Systems 1226 Sensory Modalities 1230 Clinical Assessment of Somatosensory Function 1232 PAIN 1233 Pain Theories 1234 Pain Mechanisms and Pathways Pain Threshold and Tolerance Types of Pain 1238 Assessment of Pain 1242 Management of Pain 1242

U N I T • XII

NERVOUS TISSUE CELLS 1182 Neurons 1183 Supporting Cells 1184 Metabolic Requirements of Nervous Tissue

THE AUTONOMIC NERVOUS SYSTEM 1215 Autonomic Efferent Pathways 1216 Central Integrative Pathways 1220 Autonomic Neurotransmission 1220

1167

VAGINAL INFECTIONS 1172 Candidiasis 1172 Trichomoniasis 1173 Bacterial Vaginosis 1173 VAGINAL-UROGENITAL-SYSTEMIC INFECTIONS Chlamydial Infections 1175 Gonorrhea 1176 Syphilis 1178

STRUCTURE AND FUNCTION OF THE SPINAL CORD AND BRAIN 1202 Spinal Cord 1202 Spinal Nerves 1204 The Brain 1205

1187

1251 1254

PAIN IN CHILDREN AND OLDER ADULTS Pain in Children 1255 Pain in Older Adults 1256

1254

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CHAPTER 50

CHAPTER 52

Disorders of Motor Function

Sleep and Sleep Disorders

1260

Serena W. Hung ORGANIZATION AND CONTROL OF MOTOR FUNCTION 1260 Organization of Movement The Motor Unit 1263 Spinal Reflexes 1264 Motor Pathways 1265 Assessment of Motor Function

Carol M. Porth NEUROBIOLOGY OF SLEEP 1338 Neural Structures and Pathways The Sleep–Wake Cycle 1339 Circadian Rhythms 1342 Melatonin 1342

1261

1265

DISORDERS OF THE MOTOR UNIT 1269 Skeletal Muscle Disorders 1269 Disorders of the Neuromuscular Junction Lower Motor Neuron Disorders 1273 Peripheral Nerve Disorders 1273 DISORDERS OF THE CEREBELLUM AND BASAL GANGLIA 1278 Disorders of the Cerebellum Disorders of the Basal Ganglia

1338

1270

1339

SLEEP DISORDERS 1343 Diagnostic Methods 1344 Circadian Rhythm Disorders 1345 Insomnia 1346 Narcolepsy 1348 Sleep-Related Movement Disorders Sleep Apnea 1349 Parasomnias 1351

1349

SLEEP AND SLEEP DISORDERS IN CHILDREN AND THE ELDERLY 1352 Sleep and Sleep Disorders in Children Sleep and Sleep Disorders in the Elderly

1278 1279

UPPER MOTOR NEURON DISORDERS 1284 Amyotrophic Lateral Sclerosis 1284 Demyelinating Disorder of the CNS 1285 Vertebral and Spinal Cord Injury 1287

1352 1353

CHAPTER 53

Disorders of Thought, Mood, 1357 and Memory

CHAPTER 51

Sandra Kawczynski Pasch

Disorders of Brain Function

1299

EVOLUTION IN UNDERSTANDING OF MENTAL ILLNESS 1357 Historical Perspectives 1357 The Role of Heredity in Mental Illness

Diane S. Book MECHANISMS AND MANIFESTATIONS OF BRAIN INJURY 1299 Mechanisms of Injury 1300 Head Injury 1308 Manifestations of Global Brain Injury CEREBROVASCULAR DISEASE Cerebral Circulation 1316 Stroke (Brain Attack) 1318 INFECTIONS AND NEOPLASMS Infections 1326 Brain Tumors 1328

ANATOMIC AND NEUROCHEMICAL BASIS OF BEHAVIOR 1360 Behavioral Anatomy of the Brain 1360 Physiology of Perception, Thought, and Memory 1362 Disorders of Perception 1363 Role of Neuromediators 1364 Neuroimaging 1365

1312

1316

1326

SEIZURE DISORDERS 1331 Etiology: Provoked and Unprovoked Seizures Classification 1332 Diagnosis and Treatment 1333 Generalized Convulsive Status Epilepticus

1359

DISORDERS OF THOUGHT AND VOLITION Schizophrenia 1367 1331

1334

DISORDERS OF MOOD Depressive Disorders

1369 1370

ANXIETY DISORDERS 1373 Panic Disorder 1374 Generalized Anxiety Disorder Obsessive-Compulsive Disorder Social Phobia 1375

1374 1374

1366

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DISORDERS OF ABUSE AND ADDICTION

CHAPTER 55

1375

DISORDERS OF MEMORY AND COGNITION Normal Cognitive Aging 1377 Dementia 1378

xxxvii

1376

Disorders of Hearing and Vestibular Function

1427

Susan A. Fontana and Carol M. Porth

U N I T • XIII

DISORDERS OF THE AUDITORY SYSTEM 1427 Disorders of the External Ear 1428 Disorders of the Middle Ear and Eustachian Tube 1429 Disorders of the Inner Ear 1434 Disorders of the Central Auditory Pathways Hearing Loss 1437

DISORDERS OF SPECIAL SENSORY FUNCTION 1387 CHAPTER 54

Disorders of Visual Function

DISORDERS OF VESTIBULAR FUNCTION 1442 The Vestibular System and Vestibular Reflexes 1442 Vertigo 1445 Motion Sickness 1445 Disorders of Peripheral Vestibular Function 1446 Disorders of Central Vestibular Function 1447 Diagnosis and Treatment of Vestibular Disorders 1448

1388

Edward W. Carroll, Scott A. Jens, and Robin Curtis DISORDERS OF THE ACCESSORY STRUCTURES OF THE EYE 1388 Disorders of the Eyelids 1390 Disorders of the Lacrimal System 1391 DISORDERS OF THE CONJUNCTIVA, CORNEA, AND UVEAL TRACT 1392 Disorders of the Conjunctiva 1392 Disorders of the Cornea 1394 Disorders of the Uveal Tract 1397 The Pupil and Pupillary Reflexes 1397

U N I T • XIV

INTRAOCULAR PRESSURE AND GLAUCOMA Control of Intraocular Pressure 1399 Glaucoma 1400

1398

DISORDERS OF THE LENS AND LENS FUNCTION Disorders of Refraction and Accommodation Cataracts 1403 DISORDERS OF THE VITREOUS AND RETINA Disorders of the Vitreous 1405 Disorders of the Retina 1405

1402 1402

1405

DISORDERS OF MUSCULOSKELETAL AND INTEGUMENTARY FUNCTION 1453 CHAPTER 56

Structure and Function of the 1454 Musculoskeletal System Carol M. Porth BONY STRUCTURES OF THE SKELETAL SYSTEM Bone Structures 1455 Bone Tissue 1456 Cartilage 1458 Hormonal Control of Bone Formation and Metabolism 1459

DISORDERS OF NEURAL PATHWAYS AND CORTICAL CENTERS 1416 Optic Pathways 1416 Visual Cortex 1417 Visual Fields 1417 DISORDERS OF EYE MOVEMENT 1419 Extraocular Eye Muscles and Their Innervation 1420 Strabismus 1422 Amblyopia 1423 Eye Examination in Infants and Children

1437

ARTICULATIONS AND JOINTS Tendons and Ligaments Types of Joints 1462

1424

1461 1461

1454

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CHAPTER 57

CHAPTER 59

Disorders of Musculoskeletal Function: 1465 Trauma, Infection, and Neoplasms

Disorders of Musculoskeletal Function: 1519 Rheumatic Disorders

Kathleen E. Gunta

Debra Bancroft Rizzo

INJURY AND TRAUMA OF MUSCULOSKELETAL STRUCTURES 1465 Athletic Injuries 1466 Soft Tissue Injuries 1466 Joint (Musculotendinous) Injuries 1467 Fractures 1471 Complications of Fractures and Other Musculoskeletal Injuries 1479 BONE INFECTIONS 1482 Osteomyelitis 1482 Tuberculosis of the Bone or Joint OSTEONECROSIS

1486

CRYSTAL-INDUCED ARTHROPATHIES Gout 1536 RHEUMATIC DISEASES IN CHILDREN AND THE ELDERLY 1538 Rheumatic Diseases in Children Rheumatic Diseases in the Elderly

CHAPTER 58

Disorders of Musculoskeletal Function: Developmental 1493 and Metabolic Disorders

1528

1536

1538 1539

CHAPTER 60

Structure and Function of the Skin

Kathleen E. Gunta ALTERATIONS IN SKELETAL GROWTH AND DEVELOPMENT 1493 Bone Growth and Remodeling 1494 Alterations During Normal Growth Periods Hereditary and Congenital Deformities Juvenile Osteochondroses 1502 Scoliosis 1504 METABOLIC BONE DISEASE Osteopenia 1509 Osteoporosis 1509 Osteomalacia and Rickets Paget Disease 1515

SERONEGATIVE SPONDYLOARTHROPATHIES Ankylosing Spondylitis 1528 Reactive Arthropathies 1530 Psoriatic Arthritis 1531

1506

1513

1519

OSTEOARTHRITIS SYNDROME 1531 Epidemiology and Risk Factors 1532 Pathogenesis 1532 Clinical Manifestations 1534 Diagnosis and Treatment 1535

1484

1485

NEOPLASMS 1486 Characteristics of Bone Tumors Benign Neoplasms 1487 Malignant Bone Tumors 1487 Metastatic Bone Disease 1490

SYSTEMIC AUTOIMMUNE RHEUMATIC DISEASES Rheumatoid Arthritis 1520 Systemic Lupus Erythematosus 1524 Systemic Sclerosis/Scleroderma 1527 Polymyositis and Dermatomyositis 1527

1544

Gladys Simandl

1494 1499

STRUCTURE AND FUNCTION OF THE SKIN Functions of the Skin 1544 Skin Structures 1545 Epidermis 1545 Basement Membrane 1549 Dermis 1549 Subcutaneous Tissue 1550 Skin Appendages 1551 MANIFESTATIONS OF SKIN DISORDERS Lesions and Rashes 1552 Pruritus 1553 Dry Skin 1554 Variations in Dark-Skinned People

1544

1552

1555

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NEVI AND SKIN CANCERS Nevi 1590 Skin Cancer 1590

Disorders of Skin Integrity 1557 and Function PRIMARY DISORDERS OF THE SKIN 1557 Pigmentary Skin Disorders 1558 Infectious Processes 1559 Acne and Rosacea 1568 Allergic and Hypersensitivity Dermatoses Papulosquamous Dermatoses 1575 Arthropod Infestations 1579 ULTRAVIOLET RADIATION, THERMAL, AND PRESSURE INJURY 1582 Skin Damage Caused by Ultraviolet Radiation Thermal Injury 1584 Pressure Ulcers 1587

1589

AGE-RELATED SKIN MANIFESTATIONS 1594 Skin Manifestations of Infancy and Childhood Skin Manifestations and Disorders in the Elderly 1598

Gladys Simandl

1571

APPENDIX A: LAB VALUES

1603

APPENDIX B: DIETARY REFERENCE INTAKES (DRIs) 1605 GLOSSARY 1582

INDEX

1621

1611

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Quick Table of Contents UNIT•I CONCEPTS OF HEALTH AND DISEASE 1

U N I T • IX DISORDERS OF GASTROINTESTINAL FUNCTION 893

1 Concepts of Health and Disease 2 2 Concepts of Altered Health in Children 10 3 Concepts of Altered Health in Older Adults 36

36 Structure and Function of the Gastrointestinal System 37 Disorders of Gastrointestinal Function 916 38 Disorders of Hepatobiliary and Exocrine Pancreas Function 949 39 Alterations in Nutritional Status 982

U N I T • II CELL FUNCTION AND GROWTH 57 4 5 6 7 8

Cell and Tissue Characteristics 58 Cellular Adaptation, Injury, and Death 94 Genetic Control of Cell Function and Inheritance Genetic and Congenital Disorders 133 Neoplasia 156

UNIT•X DISORDERS OF ENDOCRINE FUNCTION 1007

112

40 Mechanisms of Endocrine Control 1008 41 Disorders of Endocrine Control of Growth and Metabolism 1021 42 Diabetes Mellitus and the Metabolic Syndrome

U N I T • III DISORDERS OF INTEGRATIVE FUNCTION 197 9 Stress and Adaptation 198 10 Alterations in Temperature Regulation 11 Activity Tolerance and Fatigue 231

214

Blood Cells and the Hematopoietic System 254 Disorders of Hemostasis 262 Disorders of Red Blood Cells 278 Disorders of White Blood Cells and Lymphoid Tissues

301

UNIT•V INFECTION, INFLAMMATION, AND IMMUNITY 323 16 17 18 19 20

Mechanisms of Infectious Disease 324 Innate and Adaptive Immunity 347 Inflammation, Tissue Repair, and Wound Healing Disorders of the Immune Response 400 Acquired Immunodeficiency Syndrome 427

377

U N I T • VI DISORDERS OF CARDIOVASCULAR FUNCTION 449 21 22 23 24 25 26

Structure and Function of the Cardiovascular System 450 Disorders of Blood Flow in the Systemic Circulation 477 Disorders of Blood Pressure Regulation 505 Disorders of Cardiac Function 532 Disorders of Cardiac Conduction and Rhythm 584 Heart Failure and Circulatory Shock 606

U N I T • VII DISORDERS OF RESPIRATORY FUNCTION 639 27 Structure and Function of the Respiratory System 640 28 Respiratory Tract Infections, Neoplasms, and Childhood Disorders 670 29 Disorders of Ventilation and Gas Exchange 701

U N I T • VIII DISORDERS OF RENAL FUNCTION AND FLUIDS AND ELECTROLYTES 739 30 31 32 33 34 35

1047

U N I T • XI DISORDERS OF GENITOURINARY AND REPRODUCTIVE FUNCTION 1079

U N I T • IV DISORDERS OF THE HEMATOPOIETIC SYSTEM 253 12 13 14 15

894

Structure and Function of the Kidney 740 Disorders of Fluid and Electrolyte Balance 761 Disorders of Acid-Base Balance 805 Disorders of Renal Function 826 Acute Renal Failure and Chronic Kidney Disease 855 Disorders of the Bladder and Lower Urinary Tract 875

43 Structure and Function of the Male Genitourinary System 1080 44 Disorders of the Male Genitourinary System 1092 45 Structure and Function of the Female Reproductive System 1113 46 Disorders of the Female Reproductive System 1129 47 Sexually Transmitted Infections 1166

U N I T • XII DISORDERS OF NEURAL FUNCTION 1181 48 49 50 51 52 53

Organization and Control of Neural Function 1182 Somatosensory Function, Pain, and Headache 1225 Disorders of Motor Function 1260 Disorders of Brain Function 1299 Sleep and Sleep Disorders 1338 Disorders of Thought, Mood, and Memory 1357

U N I T • XIII DISORDERS OF SPECIAL SENSORY FUNCTION 1387 54 Disorders of Visual Function 1388 55 Disorders of Hearing and Vestibular Function

U N I T • XIV DISORDERS OF MUSCULOSKELETAL AND INTEGUMENTARY FUNCTION 1453 56 Structure and Function of the Musculoskeletal System 1454 57 Disorders of Musculoskeletal Function: Trauma, Infection, and Neoplasms 1465 58 Disorders of Musculoskeletal Function: Developmental and Metabolic Disorders 1493 59 Disorders of Musculoskeletal Function: Rheumatic Disorders 1519 60 Structure and Function of the Skin 1544 61 Disorders of Skin Integrity and Function 1557 Appendix A: Lab Values

1603

Appendix B: Dietary Reference Intakes (DRIs) Glossary

1611

Index 1621

1605

1427

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PREFIXES a-, an- without, lack of apnea (without breath) anemia (lack of blood) ab- separation, away from abductor (leading away from) aberrant (away from the usual course) ad- to, toward, near to adductor (leading toward) adrenal (near the kidney) ana- up, again, excessive anapnea (to breathe again) anasarca (severe edema) ante- before, in front of antecubital (in front of the elbow) antenatal (occurring before birth) anti- against, counter anticoagulant (opposing coagulation) antisepsis (against infection) ap-, apo- separation, derivation from apocrine (type of glandular secretion that contains cast-off parts of the secretory cell) aut-, auto- self autoimmune (immunity to self) autologous (pertaining to self graft or blood transfusion) bi- two, twice, double biarticulate (pertaining to two joints) bifurcation (two branches) brady- slow bradyesthesia (slowness or dullness of perception) cata- down, under, lower, negative, against catabolism (breaking down) catalepsy (diminished movement) circum- around, about circumflex (winding around) circumference (surrounding) contra- against, counter contraindicated (not indicated) contralateral (opposite side) de- away from, down from, remove dehydrate (remove water) deaminate (remove an amino group) dia- through, apart, across, completely diapedesis (ooze through) diagnosis (complete knowledge) dis- apart, reversal, separation discrete (made up of separated parts) disruptive (bursting apart) dys- difficulty, faulty, painful dysmenorrhea (painful menstruation) dyspnea (difficulty breathing)

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e-, ex- out from, out of enucleate (remove from) exostosis (outgrowth of bone) ec- out from eccentric (away from center) ectopic (out of place) ecto- outside, situated on ectoderm (outer skin) ectoretina (outer layer of retina) em-, en- in, on empyema (pus in) encephalon (in the brain) endo- within, inside endocardium (within heart) endometrium (within uterus) epi- upon, after, in addition epidermis (on skin) epidural (upon dura) eu- well, easily, good eupnea (easy or normal respiration) euthyroid (normal thyroid function) exo- outside exocolitis (inflammation of outer coat of colon) exogenous (originating outside) extra- outside of, beyond extracellular (outside cell) extrapleural (outside pleura) hemi- half hemialgia (pain affecting only one side of the body) hemilingual (affecting one side of the tongue) hyper- extreme, above, beyond hyperemia (excessive blood) hypertrophy (overgrowth) hypo- under, below hypotension (low blood pressure) hypothyroidism (underfunction of thyroid) im-, in- in, into, on immersion (act of dipping in) injection (act of forcing fluid into) im-, in- not immature (not mature) inability (not able) infra- beneath infraclavicular (below the clavicle) infraorbital (below the eye) inter- among, between intercostal (between the ribs) intervene (come between) intra- within, inside intraocular (within the eye) intraventricular (within the ventricles) intro- into, within introversion (turning inward) introduce (lead into) iso- equal, same isotonia (equal tone, tension, or activity) isotypical (of the same type)

juxta- near, close by juxtaglomerular (near an adjoining glomerulus in the kidney) juxtaspinal (near the spinal column) macro- large, long, excess macrocephaly (excessive head size) macrodystrophia (overgrowth of a part) mal- bad, abnormal maldevelopment (abnormal growth or development) malfunction (to function imperfectly or badly) mega- large, enlarged, abnormally large size megaprosopous (having a large face) megasoma (great size and stature) meso- middle, intermediate, moderate mesoderm (middle germ layer of embryo) mesocephalic (pertaining to a skull with an average breadth–length index) meta- beyond, after, accompanying metacarpal (beyond the wrist) metamorphosis (change of form) micro- small size or amount microbe (a minute living organism) microtiter (a titer of minute quantity) neo- new, young, recent neoformation (a new growth) neonate (newborn) oligo- few, scanty, less than normal oligogenic (produced by a few genes) oligospermia (abnormally low number of spermatozoa in the semen) para- beside, beyond paracardiac (beside the heart) paraurethral (near the urethra) per- through perforate (bore through) permeate (pass through) peri- around peribronchia (around the bronchus) periosteum (around bone) poly- many, much polyphagia (excessive eating) polytrauma (occurrence of multiple injuries) post- after, behind in time or place postoperative (after operation) postpartum (after childbirth) pre-, pro- in front of, before in time or place premaxillary (in front of the maxilla) prognosis (foreknowledge) pseud-, pseudo- false, spurious pseudocartilaginous (made up of a substance resembling cartilage) pseudopregnancy (false pregnancy) retro- backward, located behind retrocervical (located behind cervix) retrograde (going backward)

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semi- half, partly semiflexion (a limb midway between flexion and extension) semimembranous (composed in part of membrane) steno- narrow compressed, contracted stenocoriasis (contraction of the pupil of the eye) stenopeic (having a narrow slit or opening) sub-, sup- under, below subarachnoid (under arachnoid) subcutaneous (under skin) super- above, beyond, extreme supermedial (above the middle) supernumerary (an extreme number) supra- above, upon suprarenal (above kidney) suprascapular (on upper part of the scapula) sym-, syn- together, with symphysis (growing together) synapsis (joining together) tachy- swift, rapid tachycardia (rapid action of the heart) tachytrophism (rapid metabolism) trans- across, through, beyond transection (cut across) transduodenal (through the duodenum) ultra- beyond, in excess ultraligation (ligation of vessel beyond point of origin) ultrasonic (sound waves above the human ear’s audibility limit)

SUFFIXES -able, -ible ability to, capable of viable (capable of living) -al, -ar pertaining to labial (pertaining to the lip or lips) ocular (pertaining to the eye) -algia a painful condition neuralgia (pain that affects nerves) -ary pertaining to, connected with ciliary (resembling a hairlike structure) ovary (connected with the ovum) -ate action or state degenerate (to decline in condition) hemolysate (product of hemolysis) -cle, -cula, -cule, -culum, -culus diminutive cerebellum (little brain) molecule (small physical unit) pedicle (small footlike part)

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-ectasia, -ectasis a dilated or distended state bronchiectasis (dilatation of the bronchi) lymphectasia (distention with lymph) -ectomy cutting out appendectomy (excision of the appendix) -esthesia condition of sensation somatesthesia (somatic sense) -form shape, structure multiform (occurring in many shapes) ossiform (resembling the structure of bones) -fugal moving away from, driving away centrifugal (moving away from a center) febrifugal (relieving fever) -gen, -genic producing, produced by allergen (allergy producing) carcinogenic (cancer-producing agent) -gram a record, writing electrocardiogram (the graphic record of an electrocardiograph) mammogram (an x-ray film of breast tissue) -ia state, condition amblyopia (dimness of vision) septicemia (poisoning of the blood) -ic pertaining to manic (affected with madness) orchidic (pertaining to the testes) -ile pertaining to, characteristics of febrile (pertaining to fever) infantile (characteristic of infants) -ion process, action flexion (act of bending) hydration (the act of combining with water) -ism condition, state astigmatism (defect of vision due to corneal irregularity) rheumatism (inflammation, typically of muscles and joints) -itis inflammation appendicitis (inflammation of the appendix) carditis (inflammation of the heart muscles) -ity state disparity (inequality) hyperacidity (state characterized by the presence of excess acid) -logy a collected body of knowledge biology (the branch of knowledge that deals with living organisms) pathology (the study of characteristics, causes, and effects of disease)

-lysis disintegration, dissolution cytolysis (cell destruction) hemolysis (the dissolution of red blood cells) -odyne, -odynia pain, referring to/location of pain gastrodynia (stomach pain) odontodynia (toothache) -oid resembling, like epidermoid (resembling epidermis) thyroid (shaped like a shield) -ole, -olus diminutive centriole (a small center) malleolus (a small hammer) -or agent donor (one who donates) levator (an agent that elevates) -penia a deficiency leukopenia (deficiency of white blood cells) thrombocytopenia (deficiency of thrombocytes) -phagia, -phagy ingestion of, consumption of, practice of eating of a substance geophagy (eating earthy substances) lipophagia (ingestion of fat by cells) -plegia a paralyzed state esophagoplegia (paralysis of the esophagus) hemiplegia (paralysis of one side of the body) -poiesis formation of, production of cholanopoieses (production of bile acids) hematopoiesis (formation of red blood cells) -ptosis downward displacement, prolapse enteroptosis (downward displacement of the intestine) hepatoptosis (displacement of the liver) -rrhagia a breaking forth, bursting, fluid discharge lymphorrhagia (a flow of lymph) tracheorrhagia (bleeding from the trachea) -rrhaphy a suturing in place cysticorrhaphy (suturing the bladder) gastrorrhaphy (surgical suture of the stomach) -rrhea flow diarrhea (abnormally frequent intestinal evacuations) laryngorrhea (excessive mucus flow whenever the voice is used) -tomy cut into, incision into phlebotomy (incision of a vein) tracheotomy (cutting into the trachea) -sis (-asis, -esis, -osis) state or process dermatosis (a skin disease) hematemesis (vomiting blood)

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UNIT•I

Concepts of Health and Disease Early peoples were considered long-lived if they reached 30 years of age—that is, if they survived infancy. For many centuries, infant mortality was so great that large families became the tradition; many children in a family ensured that at least some would survive. Life expectancy has increased over the centuries, and today an individual in a developed country can expect to live about 71 to 79 years. Although life expectancy has increased radically since ancient times, human longevity has remained fundamentally unchanged. The quest to solve the mystery of human longevity, which appears to be genetically programmed, began with Gregor Mendel (1822–1884), an Augustinian monk. Mendel laid the foundation of modern genetics with the pea experiments he performed in a monastery garden. Today, geneticists search for the determinant, or determinants, of the human life span. Up to this time, scientists have failed to identify an aging gene that would account for a limited life span. However, they have found that cells have a finite reproductive capacity. As they age, genes are increasingly unable to perform their functions. The cells become poorer and poorer at making the substances they need for their own special tasks or even for their own maintenance. Free radicals, mutation in a cell’s DNA, and the process of programmed cell death are some of the factors that work together to affect a cell’s functioning.

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Chapter

Concepts of Health and Disease CAROL M. PORTH

CONCEPTS OF HEALTH AND DISEASE Health Disease Etiology Pathogenesis Morphology Clinical Manifestations Diagnosis Clinical Course HEALTH AND DISEASE IN POPULATIONS Epidemiology and Patterns of Disease Prevalence and Incidence Morbidity and Mortality Determination of Risk Factors Cross-Sectional and Case-Control Studies Cohort Studies Natural History Levels of Prevention Evidence-Based Practice and Practice Guidelines

➤ The term pathophysiology, which is the focus of this book, may be defined as the physiology of altered health. The term combines the words pathology and physiology. Pathology (from the Greek pathos, meaning “disease”) deals with the study of the structural and functional changes in cells, tissues, and organs of the body that cause or are caused by disease. Physiology deals with the functions of the human body. Thus, pathophysiology deals not only with the cellular and organ changes that occur with disease, but with the effects that these changes have on total body function. Pathophysiology also focuses on the mechanisms of the underlying disease and provides the background for preventive as well as therapeutic health care measures and practices. This chapter is intended to orient the reader to the concepts of health and disease, various terms that are used throughout the book, the sources of data and what they mean, and the broader aspects of pathophysiology in terms of the health and well-being of populations.

CONCEPTS OF HEALTH AND DISEASE After completing this section of the chapter, you should be able to meet the following objectives: ■ ■ ■

■

State the World Health Organization definition of health. State a definition of pathophysiology. Characterize the disease process in terms of etiology, pathogenesis, morphology, clinical manifestations, and prognosis. Explain the meaning of reliability, validity, sensitivity, specificity, and predictive value as it relates to observations and tests used in the diagnosis of disease.

What constitutes health and disease often is difficult to determine because of the way different people view the topic. What is defined as health is determined by many factors, including heredity, age and sex, cultural and ethnic differences, as well as individual, group, and governmental expectations.

Health In 1948, the Preamble to the Constitution of the World Health Organization (WHO) defined health as a “state of complete 2

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physical, mental, and social well-being and not merely the absence of disease and infirmity,” a definition that has not been amended since that time.1 Although ideal for many people, this was an unrealistic goal. At the World Health Assembly in 1977, representatives of the member governments of WHO agreed that their goal was to have all citizens of the world reach a level of health by the year 2000 that allows them to live a socially and economically productive life.1 The U.S. Department of Health and Human Services in Healthy People 2010 described the determinants of health as an interaction between an individual’s biology and behavior, physical and social environments, government policies and interventions, and access to quality health care.2

Disease A disease has been defined as an interruption, cessation, or disorder of a body system or organ structure that is characterized usually by a recognized etiologic agent or agents, an identifiable group of signs and symptoms, or consistent anatomic alterations.3 The aspects of the disease process include etiology, pathogenesis, morphologic changes, clinical manifestations, diagnosis, and clinical course.

Etiology The causes of disease are known as etiologic factors. Among the recognized etiologic agents are biologic agents (e.g., bacteria, viruses), physical forces (e.g., trauma, burns, radiation), chemical agents (e.g., poisons, alcohol), and nutritional excesses or deficits. At the molecular level, it is important to distinguish between abnormal molecules and molecules that cause disease.4 This is true of diseases such as cystic fibrosis, sickle cell anemia, and familial hypercholesterolemia, in which the genetic abnormality of a single amino acid, transporter molecule, or receptor protein produces widespread effects on health. Most disease-causing agents are nonspecific, and many different agents can cause disease of a single organ. On the other hand, a single agent or traumatic event can lead to disease of a number of organs or systems. Although a disease agent can affect more than a single organ and a number of disease agents can affect the same organ, most disease states do not have a single cause. Instead, the majority of diseases are multifactorial in origin. This is particularly true of diseases such as cancer, heart disease, and diabetes. The multiple factors that predispose to a particular disease often are referred to as risk factors. One way to view the factors that cause disease is to group them into categories according to whether they were present at birth or acquired later in life. Congenital conditions are defects that are present at birth, although they may not be evident until later in life. Congenital conditions may be caused by genetic influences, environmental factors (e.g., viral infections in the mother, maternal drug use, irradiation, or intrauterine crowding), or a combination of genetic and environmental factors. Acquired defects are those that are caused by events that occur after birth. These include injury, exposure to infectious agents, inadequate nutrition, lack of oxygen, inappropriate immune

3

responses, and neoplasia. Many diseases are thought to be the result of a genetic predisposition and an environmental event or events that serve as a trigger to initiate disease development.

Pathogenesis Pathogenesis is the sequence of cellular and tissue events that take place from the time of initial contact with an etiologic agent until the ultimate expression of a disease. Etiology describes what sets the disease process in motion, and pathogenesis, how the disease process evolves. Although the two terms often are used interchangeably, their meanings are quite different. For example, atherosclerosis often is cited as the cause or etiology of coronary heart disease. In reality, the progression from fatty streak to the occlusive vessel lesion seen in persons with coronary heart disease represents the pathogenesis of the disorder. The true etiology of atherosclerosis remains largely uncertain.

Morphology Morphology refers to the fundamental structure or form of cells or tissues. Morphologic changes are concerned with both the gross anatomic and microscopic changes that are characteristic of a disease. Histology deals with the study of the cells and extracellular matrix of body tissues. The most common method used in the study of tissues is the preparation of histologic sections— thin, translucent sections of human tissues and organs—that can be examined with the aid of a microscope. Histologic sections play an important role in the diagnosis of many types of cancer. A lesion represents a pathologic or traumatic discontinuity of a body organ or tissue. Descriptions of lesion size and characteristics often can be obtained through the use of radiographs, ultrasonography, and other imaging methods. Lesions also may be sampled by biopsy and the tissue samples subjected to histologic study.

Clinical Manifestations Diseases can manifest in a number of ways. Sometimes the condition produces manifestations, such as fever, that make it evident that the person is sick. In other cases, the condition is silent at the onset and is detected during examination for other purposes or after the disease is far advanced. Signs and symptoms are terms used to describe the structural and functional changes that accompany a disease. A symptom is a subjective complaint that is noted by the person with a disorder, whereas a sign is a manifestation that is noted by an observer. Pain, difficulty in breathing, and dizziness are symptoms of a disease. An elevated temperature, a swollen extremity, and changes in pupil size are objective signs that can be observed by someone other than the person with the disease. Signs and symptoms may be related to the primary disorder or they may represent the body’s attempt to compensate for the altered function caused by the pathologic condition. Many pathologic states are not observed directly—one cannot see a sick heart or a failing kidney. Instead, what can be observed is the body’s attempt to compensate for changes in function brought about by the disease,

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such as the tachycardia that accompanies blood loss or the increased respiratory rate that occurs with pneumonia. A syndrome is a compilation of signs and symptoms (e.g., chronic fatigue syndrome) that are characteristic of a specific disease state. Complications are possible adverse extensions of a disease or outcomes from treatment. Sequelae are lesions or impairments that follow or are caused by a disease.

Diagnosis A diagnosis is the designation as to the nature or cause of a health problem (e.g., bacterial pneumonia or hemorrhagic stroke). The diagnostic process usually requires a careful history and physical examination. The history is used to obtain a person’s account of his or her symptoms and their progression, and the factors that contribute to a diagnosis. The physical examination is done to observe for signs of altered body structure or function. The development of a diagnosis involves weighing competing possibilities and selecting the most likely one from among the conditions that might be responsible for the person’s clinical presentation. The clinical probability of a given disease in a person of a given age, sex, race, lifestyle, and locality often is influential in arrival at a presumptive diagnosis. Laboratory tests, radiologic studies, computed tomography (CT) scans, and other tests often are used to confirm a diagnosis. An important factor when interpreting diagnostic test results is the determination of whether they are normal or abnormal. Is a blood count above normal, within the normal range, or below normal? What is termed a normal value for a laboratory test is established statistically from test results obtained from a selected sample of people. The normal values refer to the 95% distribution (mean plus or minus two standard deviations [mean ± 2 SD]) of test results for the reference population.5,6 Thus, the normal levels for serum sodium (136 to 145 mEq/L) represent the mean serum level for the reference population ± 2 SD. The normal values for some laboratory tests are adjusted for sex or age. For example, the normal hemoglobin range for women is 12.0 to 16.0 g/dL, and for men, 14.0 to 17.4 g/dL.7 Serum creatinine level often is adjusted for age in the elderly, and normal values for serum phosphate differ between adults and children. The quality of data on which a diagnosis is based may be judged for their validity, reliability, sensitivity, specificity, and predictive value.8,9 Validity refers to the extent to which a measurement tool measures what it is intended to measure. This often is assessed by comparing a measurement method with the best possible method of measure that is available. For example, the validity of blood pressure measurements obtained by a sphygmomanometer might be compared with those obtained by intra-arterial measurements. Reliability refers to the extent to which an observation, if repeated, gives the same result. A poorly calibrated blood pressure machine may give inconsistent measurements of blood pressure, particularly of pressures in either the high or low range. Reliability also depends on the persons making the measurements. For example, blood pressure measurements may vary from one observer to another because of the technique that is used (e.g., different observers may deflate the cuff at a different rate, thus obtaining different

values), the way the numbers on the manometer are read, or differences in hearing acuity. In the field of clinical laboratory measurements, standardization is aimed at increasing the trueness and reliability of measured values. Standardization relies on the use of written standards, reference measurement procedures, and reference materials.10 In the United States, the Food and Drug Administration (FDA) regulates in vitro diagnostic devices, including clinical laboratory instruments, test kits, and reagents. Manufacturers who propose to market new diagnostic devices must submit information on their instrument, test kit, or reagent to the FDA, as required by existing statutes and regulations. The FDA reviews this information to decide whether the product may be marketed in the United States. Measures of sensitivity and specificity are concerned with determining how likely or how well the test or observation will identify people with the disease and people without the disease11 (Fig. 1-1). Sensitivity refers to the proportion of people with a disease who are positive for that disease on a given test or observation (called a true-positive result). If the result of a very sensitive test is negative, it tells us the person does not have the disease and the disease has been excluded or “ruled out.” Specificity refers to the proportion of people without the disease who are negative on a given test or observation (called a true-negative result). Specificity can be calculated only from among people who do not have the disease. A test that is 95% specific correctly identifies 95 of 100 normal people. The other 5% are falsepositive results. A false-positive test result can be unduly stressful for the person being tested, whereas a false-negative test result can delay diagnosis and jeopardize the outcome of treatment. Predictive value is the extent to which an observation or test result is able to predict the presence of a given disease or condition.11,12 A positive predictive value refers to the proportion of true-positive results that occurs in a given population. In a group of women found to have “suspect breast nodules” in a cancer screening program, the proportion later determined to have breast cancer would constitute the positive predictive value. A negative predictive value refers to the true-negative

DISEASE

Positive

Present

Absent

True positive

False positive a b

TEST

c d Negative

False negative

True negative

FIGURE 1-1 • The relationship between a diagnostic test result and the occurrence of disease. There are two possibilities for the test result to be correct (true positive and true negative) and two possibilities for the result to be incorrect (false positive and false negative). (From Fletcher R. H., Fletcher S. W. [2005]. Clinical epidemiology: The essentials [4th ed., p. 36]. Philadelphia: Lippincott Williams & Wilkins.)

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observations in a population. In a screening test for breast cancer, the negative predictive value represents the proportion of women without suspect nodules who do not have breast cancer. Although predictive values rely in part on sensitivity and specificity, they depend more heavily on the prevalence of the condition in the population. Despite unchanging sensitivity and specificity, the positive predictive value of an observation rises with prevalence, whereas the negative predictive value falls.

Clinical Course The clinical course describes the evolution of a disease. A disease can have an acute, subacute, or chronic course. An acute disorder is one that is relatively severe, but self-limiting. Chronic disease implies a continuous, long-term process. A chronic disease can run a continuous course or can present with exacerbations (aggravation of symptoms and severity of the disease) and remissions (a period during which there is a decrease in severity and symptoms). Subacute disease is intermediate or between acute and chronic: it is not as severe as an acute disease and not as prolonged as a chronic disease. The spectrum of disease severity for infectious diseases, such as hepatitis B, can range from preclinical to persistent chronic infection. During the preclinical stage, the disease is not clinically evident but is destined to progress to clinical disease. As with hepatitis B, it is possible to transmit a virus during the preclinical stage. Subclinical disease is not clinically apparent and is not destined to become clinically apparent. It is diagnosed with antibody or culture tests. Most cases of tuberculosis are not clinically apparent, and evidence of their presence is established by skin tests. Clinical disease is manifested by signs and symptoms. A persistent chronic infectious disease persists for years, sometimes for life. Carrier status refers to an individual who harbors an organism but is not infected, as evidenced by antibody response or clinical manifestations. This person still can infect others. Carrier status may be of limited duration or it may be chronic, lasting for months or years.

IN SUMMARY,

the term pathophysiology, which is the focus of this book, may be defined as the physiology of altered health. A disease has been defined as any deviation from or interruption of the normal structure or function of any part, organ, or system of the body that is manifested by a characteristic set of symptoms or signs and whose etiology, pathology, and prognosis may be known or unknown. The causes of disease are known as etiologic factors. Pathogenesis describes how the disease process evolves. Morphology refers to the structure or form of cells or tissues; morphologic changes are changes in structure or form that are characteristic of a disease. A disease can manifest in a number ways. A symptom is a subjective complaint, such as pain or dizziness, whereas a sign is an observable manifestation, such as an elevated temperature or a reddened, sore throat. A syndrome is a compilation of signs and symptoms that are characteristic of a specific disease state.

5

A diagnosis is the designation as to the nature and cause of a health problem. The diagnostic process requires a careful history and physical examination. Laboratory tests, radiologic studies (e.g., CT scans), and other tests are used to confirm a diagnosis. The value of many tests is based on their reliability and validity, as well as their sensitivity and specificity. The clinical course of a disease describes its evolution. It can be acute (relatively severe, but self-limiting), chronic (continuous or episodic, but taking place over a long period), or subacute (not as severe as acute or as prolonged as chronic). Within the disease spectrum, a disease can be designated preclinical, or not clinically evident; subclinical, not clinically apparent and not destined to become clinically apparent; or clinical, characterized by signs and symptoms. ■

HEALTH AND DISEASE IN POPULATIONS After completing this section of the chapter, you should be able to meet the following objectives: ■ ■ ■ ■ ■ ■

Define the term epidemiology. Compare the meaning of the terms incidence and prevalence as they relate to measures of disease frequency. Compare the sources of information and limitations of mortality and morbidity statistics. Characterize the natural history of a disease. Differentiate primary, secondary, and tertiary levels of prevention. Propose ways in which practice guidelines can be used to improve health care.

The health of individuals is closely linked to the health of the community and to the population it encompasses. The ability to traverse continents in a matter of hours has opened the world to issues of populations at a global level. Diseases that once were confined to local areas of the world now pose a threat to populations throughout the world. As we move through the 21st century, we are continually reminded that the health care system and the services it delivers are targeted to particular populations. Managed care systems are focused on a population-based approach to planning, delivering, providing, and evaluating health care. The focus of health care also has begun to emerge as a partnership in which individuals are asked to assume greater responsibility for their own health.

Epidemiology and Patterns of Disease Epidemiology is the study of disease occurrence in human populations.11 It was initially developed to explain the spread of infectious diseases during epidemics and has emerged as a

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science to study risk factors for multifactorial diseases, such as heart disease and cancer. Epidemiology looks for patterns of persons affected with a particular disorder, such as age, race, dietary habits, lifestyle, or geographic location. In contrast to biomedical researchers, who seek to elucidate the mechanisms of disease production, epidemiologists are more concerned with whether something happens than how it happens. For example, the epidemiologist is more concerned with whether smoking itself is related to cardiovascular disease and whether the risk of heart disease decreases when smoking ceases. On the other hand, the biomedical researcher is more concerned about the causative agent in cigarette smoke and the pathway by which it contributes to heart disease. Much of our knowledge about disease comes from epidemiologic studies. Epidemiologic methods are used to determine how a disease is spread, how to control it, how to prevent it, and how to eliminate it. Epidemiologic methods also are used to study the natural history of disease, to evaluate new preventative and treatment strategies, to explore the impact of different patterns of health care delivery, and to predict future health care needs. As such, epidemiologic studies serve as a basis for clinical decision making, allocation of health care dollars, and development of policies related to public health issues.

Prevalence and Incidence Measures of disease frequency are an important aspect of epidemiology. They establish a means for predicting what diseases are present in a population and provide an indication of the rate at which they are increasing or decreasing. A disease case can be either an existing case or the number of new episodes of a particular illness that is diagnosed within a given period. Incidence reflects the number of new cases arising in a population at risk during a specified time. The population at risk is considered to be persons without the disease but who are at risk for developing it. It is determined by dividing the number of new cases of a disease by the population at risk for development of the disease during the same period (e.g., new cases per 1000 or 100,000 persons in the population who are at risk). The cumulative incidence estimates the risk of developing the disease during that period of time. Prevalence is a measure of existing disease in a population at a given point in time (e.g., number of existing cases divided by the current population).11 The prevalence is not an estimate of risk of developing a disease because it is a function of both new cases and how long the cases remain in the population. Incidence and prevalence are always reported as rates (e.g., cases per 100 or cases per 100,000).

Mortality statistics provide information about the causes of death in a given population. In most countries, people are legally required to record certain facts such as age, sex, and cause of death on a death certificate. Internationally agreed on classification procedures (the International Classification of Diseases [ICD] by the WHO) are used for coding the cause of death, and the data are expressed as death rates.1 Crude mortality rates (i.e., number of deaths in a given period) do not account for age, sex, race, socioeconomic status, and other factors. For this reason, mortality often is expressed as death rates for a specific population, such as the infant mortality rate. Mortality also can be described in terms of the leading causes of death according to age, sex, race, and ethnicity. Among all persons 65 years of age and older, the five leading causes of death in the United States are heart disease, malignant disease, cerebrovascular disease, chronic lower respiratory disease, and Alzheimer disease.13 Morbidity describes the effects an illness has on a person’s life. Many diseases, such as arthritis, have low death rates but a significant impact on a person’s life. Morbidity is concerned not only with the occurrence or incidence of a disease but with persistence and the long-term consequences of the disease.

Determination of Risk Factors Conditions suspected of contributing to the development of a disease are called risk factors. They may be inherent to the person (high blood pressure or overweight) or external (smoking or drinking alcohol). There are different types of studies used to determine risk factors, including cross-sectional studies, case-control studies, and cohort studies.

Cross-Sectional and Case-Control Studies Cross-sectional studies use the simultaneous collection of information necessary for classification of exposure and outcome status. They can be used to compare the prevalence of a disease in those with the factor (or exposure) with the prevalence of a disease in those who are unexposed to the factor, such as the prevalence of coronary heart disease in smokers and nonsmokers. Case-control studies are designed to compare persons known to have the outcome of interest (cases) and those known not to have the outcome of interest (controls).11 Information on exposures or characteristics of interest is then collected from persons in both groups. For example, the characteristics of maternal alcohol consumption in infants born with fetal alcohol syndrome (cases) can be compared with those in infants born without the syndrome (controls).

Morbidity and Mortality Morbidity and mortality statistics provide information about the functional effects (morbidity) and death-producing (mortality) characteristics of a disease. These statistics are useful in terms of anticipating health care needs, planning of public education programs, directing health research efforts, and allocating health care dollars.

Cohort Studies A cohort is a group of persons who were born at approximately the same time or share some characteristics of interest.11 Persons enrolled in a cohort study (also called a longitudinal study) are followed over a period of time to observe a specific health outcome. A cohort may consist of a single group of persons chosen

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because they have or have not been exposed to suspected risk factors; two groups specifically selected because one has been exposed and the other has not; or a single exposed group in which the results are compared with the general population. Framingham Study. One of the best-known examples of a cohort study is the Framingham Study, which was carried out in Framingham, Massachusetts.14 Framingham was selected because of the size of the population, the relative ease with which the people could be contacted, and the stability of the population in terms of moving into and out of the area. This longitudinal study, which began in 1950, was set up by the U.S. Public Health Service to study the characteristics of people who would later develop coronary heart disease. The study consisted of 5000 persons, aged 30 to 59 years, selected at random and followed for an initial period of 20 years, during which time it was predicted that 1500 of them would develop coronary heart disease. The advantage of such a study is that it can explore a number of risk factors at the same time and determine the relative importance of each. Another advantage is that the risk factors can be related later to other diseases such as stroke. Chart 1-1 describes some of the significant milestones from the Framingham Study.

CHART 1-1

FRAMINGHAM STUDY: SIGNIFICANT MILESTONES

• 1960—Cigarette smoking found to increase risk of heart disease • 1961—Cholesterol level, blood pressure, and electrocardiogram abnormalities found to increase risk of heart disease • 1967—Physical activity found to reduce risk of heart disease and obesity to increase risk of heart disease • 1970—High blood pressure found to increase risk of stroke • 1976—Menopause found to increase risk of heart disease • 1977—Effects of triglycerides and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol noted • 1978—Psychosocial factors found to affect heart disease • 1986—First report on dementia • 1988—High levels of HDL cholesterol found to reduce risk of death • 1994—Enlarged left ventricle shown to increase risk of stroke • 1996—Progression from hypertension to heart failure described • 1997—Report of cumulative effects of smoking and high cholesterol on the risk of atherosclerosis (Abstracted from Framingham Heart Study. [2001]. Research milestones. [Online.] Available: http://www.nhlbi.nih.gov/about/framingham.)

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Nurses’ Health Study. A second well-known cohort study is the Nurses’ Health Study, which was developed by Harvard University and Brigham and Women’s Hospital. The study began in 1976 with a cohort of 121,700 female nurses, 30 to 55 years of age, living in the United States.15 Initially designed to explore the relationship between oral contraceptives and breast cancer, nurses in the study have provided answers to detailed questions about their menstrual cycle, smoking habits, diet, weight and waist measurements, activity patterns, health problems, and medication use. They have collected urine and blood samples, and even provided researchers with their toenail clippings. In selecting the cohort, it was reasoned that nurses would be well organized, accurate, and observant in their responses, and that physiologically they would be no different from other groups of women. It also was anticipated that their childbearing, eating, and smoking patterns would be similar to those of other working women.

Natural History The natural history of a disease refers to the progression and projected outcome of the disease without medical intervention. By studying the patterns of a disease over time in populations, epidemiologists can better understand its natural history. Knowledge of the natural history can be used to determine disease outcome, establish priorities for health care services, determine the effects of screening and early detection programs on disease outcome, and compare the results of new treatments with the expected outcome without treatment. There are some diseases for which there are no effective treatment methods available, or the current treatment measures are effective only in certain people. In this case, the natural history of the disease can be used as a predictor of outcome. For example, the natural history of hepatitis C indicates that 80% of people who become infected with the virus fail to clear the virus and progress to chronic infection.16 Information about the natural history of a disease and the availability of effective treatment methods provides directions for preventive measures. In the case of hepatitis C, careful screening of blood donations and education of intravenous drug abusers can be used to prevent transfer of the virus. At the same time, scientists are striving to develop a vaccine that will prevent infection in persons exposed to the virus. The development of vaccines to prevent the spread of infectious diseases such as polio and hepatitis B undoubtedly has been motivated by knowledge about the natural history of these diseases and the lack of effective intervention measures. With other diseases, such as breast cancer, early detection through use of breast self-examination and mammography increases the chances for a cure. Prognosis refers to the probable outcome and prospect of recovery from a disease. It can be designated as chances for full recovery, possibility of complications, or anticipated survival time. Prognosis often is presented in relation to treatment options—that is, the expected outcomes or chances for survival with or without a certain type of treatment. The prognosis asso-

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ciated with a given type of treatment usually is presented along with the risk associated with the treatment.

Levels of Prevention Basically, leading a healthy life contributes to the prevention of disease. There are three fundamental types of prevention: primary prevention, secondary prevention, and tertiary prevention11,17 (Fig. 1-2). It is important to note that all three levels are aimed at prevention. Primary prevention is directed at keeping disease from occurring by removing all risk factors. Examples of primary prevention include the administration of folic acid to pregnant women and women who may become pregnant to prevent fetal neural tube defects, giving immunizations to children to prevent communicable disease, and counseling people to adopt healthy lifestyles as a means of preventing heart disease.11 Primary prevention is often accomplished outside the health care system at the community level. Some primary prevention measures are mandated by law (e.g., wearing seat belts in automobiles and helmet use on motorcycles). Other primary prevention activities (e.g., use of ear plugs or dust masks) occur in specific occupations. Secondary prevention detects disease early when it is still asymptomatic and treatment measures can effect a cure or stop it from progressing. The use of a Papanicolaou (Pap) smear for early detection of cervical cancer is an example of secondary prevention. Screening also includes history taking (asking if a person smokes), physical examination (blood pressure measurement), laboratory tests (cholesterol level determination), and other procedures (colonoscopy) that can be “applied reasonably rapidly to asymptomatic people.”11 Most secondary prevention is done in clinical settings. All types of health care professionals (e.g., physicians, nurses, dentists, audiologists, optometrists) participate in secondary prevention. Tertiary prevention is directed at clinical interventions that prevent further deterioration or reduce the complications of a disease once it has been diagnosed. An example is the use of β-adrenergic drugs to reduce the risk of death in persons

Clinical diagnosis

Onset

NO DISEASE

ASYMPTOMATIC DISEASE

CLINICAL COURSE

Primary

Secondary

Tertiary

Remove risk factors

Early detection and treatment

Reduce complications

FIGURE 1-2 • Levels of prevention. Primary prevention prevents disease from occurring. Secondary prevention detects and cures disease in the asymptomatic phase. Tertiary prevention reduces complications of disease. (From Fletcher R. H., Fletcher S. W. [2005]. Clinical epidemiology: The essentials [4th ed., p. 149]. Philadelphia: Lippincott Williams & Wilkins.)

who have had a heart attack. The boundaries of tertiary prevention go beyond treating the problem with which the person presents. In persons with diabetes, for example, tertiary prevention requires more than good glucose control—it includes provision for regular ophthalmologic examinations for early detection of retinopathy, education for good foot care, and treatment for other cardiovascular risk factors such as hyperlipidemia.11 Tertiary prevention measures also include measures to limit physical impairment and the social consequences of an illness. Most tertiary prevention programs are located within health care systems and involve the services of a number of different types of health care professionals.

Evidence-Based Practice and Practice Guidelines Evidence-based practice and evidence-based practice guidelines have recently gained popularity with clinicians, public health practitioners, health care organizations, and the public as a means of improving the quality and efficiency of health care.18 Their development has been prompted, at least in part, by the enormous amount of published information about diagnostic and treatment measures for various disease conditions, as well as demands for better and more cost-effective health care. Evidence-based practice has been defined as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.”18 It is based on the integration of the individual expertise of the practitioner with the best external clinical evidence from systematic research.18 The term clinical expertise implies the proficiency and judgment that individual clinicians gain through clinical experience and clinical practice. The best external clinical evidence relies on the identification of clinically relevant research, often from the basic sciences, but especially from patientcentered clinical studies that focus on the accuracy and precision of diagnostic tests and methods, the power of prognostic indicators, and the effectiveness and safety of therapeutic, rehabilitative, and preventive regimens. Clinical practice guidelines are systematically developed statements intended to inform practitioners and clients in making decisions about health care for specific clinical circumstances.19,20 They not only should review but must weigh various outcomes, both positive and negative, and make recommendations. Guidelines are different from systematic reviews. They can take the form of algorithms, which are step-by-step methods for solving a problem, written directives for care, or a combination thereof. The development of evidence-based practice guidelines often uses methods such as meta-analysis to combine evidence from different studies to produce a more precise estimate of the accuracy of a diagnostic method or the effects of an intervention method.21 It also requires review: by practitioners with expertise in clinical content, who can verify the completeness of the literature review and ensure clinical sensibility; from experts in guideline development who can examine the method

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by which the guideline was developed; and by potential users of the guideline.19 Once developed, practice guidelines must be continually reviewed and changed to keep pace with new research findings and new diagnostic and treatment methods. For example, the Guidelines for the Prevention, Evaluation, and Treatment of High Blood Pressure (see Chapter 23), first developed in 1972 by the Joint National Committee, have been revised seven times, and the Guidelines for the Diagnosis and Management of Asthma (see Chapter 29), first developed in 1991 by the Expert Panel, have undergone three revisions. Evidence-based practice guidelines, which are intended to direct client care, are also important in directing research into the best methods of diagnosing and treating specific health problems. This is because health care providers use the same criteria for diagnosing the extent and severity of a particular condition such as hypertension, and because they use the same protocols for treatment.

IN SUMMARY, epidemiology refers to the study of disease in populations. It looks for patterns such as age, race, and dietary habits of persons who are affected with a particular disorder to determine under what circumstances the particular disorder will occur. Incidence is the number of new cases arising in a given population during a specified time. Prevalence is the number of people in a population who have a particular disease at a given point in time or period. Incidence and prevalence are reported as proportions or rates (e.g., cases per 100 or 100,000 population). Mortality or death statistics provide information about the trends in the health of a population, whereas morbidity describes the effects an illness has on a person’s life. It is concerned with the incidence of disease as well as its persistence and long-term consequences. Conditions suspected of contributing to the development of a disease are called risk factors. Studies used to determine risk factors include cross-sectional studies, case-control studies, and cohort studies. The natural history refers to the progression and projected outcome of a disease without medical intervention. Prognosis is the term used to designate the probable outcome and prospect of recovery from a disease. The three fundamental types of prevention are primary prevention, secondary prevention, and tertiary prevention. Primary prevention, such as immunizations, is directed at removing risk factors so disease does not occur. Secondary prevention, such as a Pap smear, detects disease when it still is asymptomatic and curable with treatment. Tertiary prevention, such as use of β-adrenergic drugs to reduce the risk of death in persons who have had a heart attack, focuses on clinical interventions that prevent further deterioration or reduce the complications of a disease. Evidence-based practice and evidence-based practice guidelines are mechanisms that use the current best evidence to make decisions about the health care of individuals. They are based on the expertise of the individual practitioner integrated with the best clinical evidence from systematic review of cred-

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ible research studies. Practice guidelines may take the form of algorithms, which are step-by-step methods for solving a problem, written directives, or a combination thereof. ■

References 1. World Health Organization. (2007). About WHO: Definition of health; disease eradication/elimination goals. [Online.] Available: www.who.int/ about/definition/en/. Accessed September 16, 2007. 2. U.S. Department Health and Human Services. (2000). Healthy people 2010. National Health Information Center. [Online.] Available: www. healthypeople.gov. Accessed September 16, 2007. 3. Stedman’s medical dictionary. (2006). (28th ed., p. 855). Philadelphia: Lippincott Williams & Wilkins. 4. Waldenstrom J. (1989). Sick molecules and our concepts of illness. Journal of Internal Medicine 225, 221–227. 5. Brigden M. L., Heathcote J. C. (2000). Problems with interpreting laboratory tests. Postgraduate Medicine 107(7), 145–162. 6. Mayer D. (2004). Essentials of evidence-based medicine. New York: Cambridge University Press. 7. Fischbach F. (2004). A manual of laboratory and diagnostic tests (7th ed., p. 74, 964). Philadelphia: Lippincott Williams & Wilkins. 8. Bickley L. (2003). Bates’ guide to physical assessment and history taking (6th ed., pp. 641–642). Philadelphia: J. B. Lippincott. 9. Dawson B., Trapp R. G., Trapp R. (2004). Basic and clinical biostatistics. New York: Lange Medical Books/McGraw-Hill. 10. Michaud G. Y. (2005). The role of standards in the development and implementation of clinical laboratory tests: A domestic and global perspective. Cancer Biomarkers 1, 209–216. 11. Fletcher R. H., Fletcher S. W. (2005). Clinical epidemiology: The essentials (4th ed.). Philadelphia: Lippincott Williams & Wilkins. 12. Montori V. M., Wyer P., Newman T. B., et al. (2005). Tips for learning of evidence-based medicine: 5. The effect of spectrum of disease on performance of diagnostic tests. Canadian Medical Association Journal 173, 385–390. 13. Centers for Disease Control and Prevention. (2003). Death, percent of deaths, and death rates for 15 leading causes of death in selected age groups by race and sex: United States 1999. [Online]. Available: www.cdc.gov/ nchs/data/hestat/preliminarydeaths05_tables.pdf#C. Accessed September 16, 2007. 14. Framingham Heart Study. (2001). Framingham Heart Study: Design, rationale, objectives, and research milestones. [Online]. Available: www.nhlbi. nih.gov/about/framingham/design.htm. Accessed September 16, 2007. 15. Channing Laboratory. (2007). Nurses’ Health Study. [Online]. Available: www.channing.harvard.edu/nhs/publications/2005.shtml. Accessed September 16, 2007. 16. Liang J., Reherman B., Seeff L. B., et al. (2000). Pathogenesis, natural history, treatment, and prevention of hepatitis C. Annals of Internal Medicine 132, 296–305. 17. Stanhope M., Lancaster J. (2000). Community and public health nursing (5th ed., p. 43). St. Louis: Mosby. 18. Sackett D. L. (1996). Evidence based medicine: What it is and what it isn’t. British Medical Journal 312, 71–72. 19. Shekelle P. G., Woolff S. H., Eccles M., et al. (1999). Developing guidelines. British Medical Journal 318, 593–596. 20. Natsch S., van der Meer J. W. M. (2003). The role of clinical guidelines, policies, and stewardship. Journal of Hospital Infection 53, 172–176. 21. Acton G. J. (2001). Meta-analysis: A tool for evidence-based practice. AACN Clinical Issues 12, 539–545.

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Concepts of Altered Health in Children JUDY WRIGHT LOTT

GROWTH AND DEVELOPMENT Prenatal Growth and Development Embryonic Development Fetal Development Birth Weight and Gestational Age Abnormal Intrauterine Growth Assessment Methods INFANCY Growth and Development Organ Systems Health Problems of the Neonate Distress at Birth and the Apgar Score Neonatal Hypoglycemia Neonatal Jaundice Birth Injuries Health Problems of the Premature Infant Health Problems of the Infant Nutrition Irritable Infant Syndrome or Colic Failure to Thrive Sudden Infant Death Syndrome Injuries Infectious Diseases EARLY CHILDHOOD Growth and Development Common Health Problems MIDDLE TO LATE CHILDHOOD Growth and Development Common Health Problems Overweight and Obesity ADOLESCENCE Growth and Development Common Health Problems

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➤ Children are not miniature adults. Physical and psychological maturation and development strongly influence the type of illnesses children experience and their responses to these illnesses. Although many signs and symptoms are the same in persons of all ages, some diseases and complications are more likely to occur in the child. This chapter provides an overview of the developmental stages of childhood and the related health care needs of children. Specific diseases are presented in the different chapters throughout the book. At the beginning of the 20th century the infant mortality rate was 200 deaths per 1000 live births.1 Infectious diseases were rampant, and children, with their immature and inexperienced immune systems and their frequent exposure to other infected children, were especially vulnerable. With the introduction of antimicrobial agents, infectious disease control, and nutritional and technologic advances, infant mortality decreased dramatically. Although infant mortality in the United States has declined over past decades, the record low of 6.8 infant deaths per 1000 live births in 2004 was higher than that of many other industrialized countries in the world.2 Also of concern is the difference in mortality rates for white and nonwhite infants. Black non-Hispanic and American Indian/Alaska Native infants have consistently had a higher mortality rate than those of other racial or ethnic groups. The greatest disparity exists for black non-Hispanics, whose infant death rate was 13.6 per 1000 in 2004.2 One of the more perplexing causes of infant mortality is the incidence of preterm birth among women of all races and classes. Despite continued, gradual declines in the overall infant mortality rate during the latter part of the 20th century, the incidence of premature births continues to present a challenge to reducing the racial disparities in infant mortality rates, as well as the overall incidence of infant mortality. The percentage of infants born with very low birth weight (500

AIDS defining clinical category

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Category 3 1 month’s duration) Cytomegalovirus disease (other than liver, spleen, or nodes) Cytomegalovirus retinitis (with loss of vision) Encephalopathy, HIV-related Herpes simplex: chronic ulcer(s) (>1 month’s duration) or bronchitis, pneumonitis, or esophagitis Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (>1 month’s duration) Kaposi sarcoma Lymphoma, Burkitt (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium-intracellulare complex or M. kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site (pulmonary* or extrapulmonary) Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis jiroveci pneumonia Pneumonia, recurrent* Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of the brain Wasting syndrome due to HIV *Added to the 1993 expansion of the AIDS surveillance case definition. (Centers for Disease Control and Prevention. [1992]. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and Mortality Weekly Report 41 [RR-17], 19.)

tect the functioning of HIV-infected CD4+ T cells and cytotoxic T cells. Finally, early treatment could potentially help maintain a homogeneous viral population that will be better controlled by antiretroviral therapy and the immune system. The primary phase is followed by a latent period during which the person has no signs or symptoms of illness. The median time of the latent period is about 10 years. During this time, the CD4+ T-cell count falls gradually from the normal range of 800 to 1000 cells/µL to 200 cells/µL or lower. More recent data suggest that the CD4+ T-cell decline may not fall in an even slope based on level of HIV RNA levels, and the factors related to variability in the decline in CD4+ cells are under investigation.25 Lymphadenopathy develops in some persons with HIV infection

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during this phase.26 Persistent generalized lymphadenopathy usually is defined as lymph nodes that are chronically swollen for more than 3 months in at least two locations, not including the groin. The lymph nodes may be sore or visible externally. The third phase, overt AIDS, occurs when a person has a CD4+ cell count of less than 200 cells/µL or an AIDS-defining illness.22 Without antiretroviral therapy, this phase can lead to death within 2 to 3 years. The risk of opportunistic infections and death increases significantly when the CD4+ cell count falls below 200 cells/µL.

Clinical Course The clinical course of HIV varies from person to person. Most— 60% to 70%—of those infected with HIV develop AIDS 10 to 11 years after infection. These people are the typical progressors.22 Another 10% to 20% of those infected progress rapidly, with development of AIDS in less than 5 years, and are called rapid progressors. The final 5% to 15% are slow progressors, who do not progress to AIDS for more than 15 years. There is a subset of slow progressors, called long-term nonprogressors, who account for 1% of all HIV infections. These people have been infected for at least 8 years, are antiretroviral naive, have high CD4+ cell counts, and usually have very low viral loads. Among this group, the elite controllers consist of individuals who have spontaneous and sustained virologic suppression without the use of antiretroviral medications. This group of HIV-infected individuals is currently being investigated to assist in determining the immunologic and virologic interactions that allow those individuals to maintain virologic suppression of HIV.27

Opportunistic Infections Opportunistic infections begin to occur as the immune system becomes severely compromised. The number of CD4+ T cells directly correlates with the risk of development of opportunistic infections. In addition, the baseline HIV RNA level contributes and serves as an independent risk factor.28 Opportunistic infections involve common organisms that do not produce infection unless there is impaired immune function. Although a person with AIDS may live for many years after the first serious illness, as the immune system fails, these opportunistic illnesses become progressively more severe and difficult to treat. Opportunistic infections are most often categorized by the type of organism (e.g., fungal, protozoal, bacterial and mycobacterial, viral). Bacterial and mycobacterial opportunistic infections include bacterial pneumonia, salmonellosis, bartonellosis, Mycobacterium tuberculosis (TB), and Mycobacterium avium-intracellulare complex (MAC). Fungal opportunistic infections include candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, penicilliosis, and pneumocystosis. Protozoal opportunistic infections include cryptosporidiosis, microsporidiosis, isosporiasis, and toxoplasmosis. Viral infections include those caused by cytomegalovirus (CMV), herpes simplex and zoster viruses, human papillomavirus,

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viral load CD4 + T lymphocyte count

HIV-1 exposure

2–4 weeks Acute clinical syndrome

8–10 years Latency

2–3 years Overt AIDS

FIGURE 20-3 • Viral load and CD4+ cell count during the phases of HIV infection.

and JC virus, the causative agent of progressive multifocal leukoencephalopathy (PML). In the United States, the most common opportunistic infections are bacterial pneumonia, Pneumocystis jiroveci pneumonia, oropharyngeal (thrush) or esophageal candidiasis, CMV retinitis, and infections caused by MAC.29

Respiratory Manifestations The most common causes of respiratory disease in persons with HIV infection are bacterial pneumonia, P. jiroveci pneumonia, and pulmonary TB. Other organisms that cause opportunistic pulmonary infections in persons with AIDS include CMV, MAC, Toxoplasma gondii, and Cryptococcus neoformans. Pneumonia also may occur because of more common bacterial pulmonary pathogens, including Streptococcus pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenzae.30 Some persons may become infected with multiple organisms, and it is not uncommon to find more than one pathogen present. Kaposi sarcoma (to be discussed) also can occur in the lungs. P. jiroveci Pneumonia. P. jiroveci (formerly known as Pneumocystis carinii) pneumonia (PCP) was the most common presenting manifestation of AIDS during the first decade of the

CHART 20-2

• • • • • •

SIGNS AND SYMPTOMS OF ACUTE HIV INFECTION

Fever Fatigue Rash Headache Lymphadenopathy Pharyngitis

• • • • • •

Arthralgia Myalgia Night sweats Gastrointestinal problems Aseptic meningitis Oral or genital ulcers

epidemic. PCP is caused by P. jiroveci, an organism that is common in soil, houses, and many other places in the environment. In persons with healthy immune systems, P. jiroveci does not cause infection or disease. In persons with HIV infection, P. jiroveci can multiply quickly in the lungs and cause pneumonia. As the disease progresses, the alveoli become filled with a foamy, protein-rich fluid that impairs gas exchange (Fig. 20-4). Since HAART and prophylaxis for PCP were instituted, the incidence has decreased.29 PCP still is common in people unaware of their HIV-positive status, in those who choose not to treat their HIV infection or take prophylaxis, and in those with poor access to health care. The best predictor of PCP is a CD4+ cell count below 200 cells/µL,29 and it is at this point that prophylaxis with trimethoprim-sulfamethoxazole (or an alternative agent in the case of adverse reactions to sulfa compounds) is strongly recommended.27 The symptoms of PCP may be acute or gradually progressive. Patients may present with complaints of a mild cough, fever, shortness of breath, and weight loss. Physical examination may demonstrate only fever and tachypnea, and breath sounds may be normal. The chest x-ray film may show interstitial infiltrates, but may be reported negative in up to 30% of cases.31 Diagnosis of PCP is made on recognition of the organism in pulmonary secretions. This can be done through examination of induced sputum, bronchoalveolar lavage, transbronchial biopsy, and, rarely, open lung biopsy. Mycobacterium Tuberculosis. Tuberculosis is the leading cause of death for people with HIV infection worldwide, and is often the first manifestation of HIV infection. At least one third of the 40 million people estimated to be living with HIV are likely to be infected with TB (UNAIDS press release, March 20, 2007). TB cases in the United States decreased from the 1950s to 1985; then, in 1986, the number of TB cases began to increase (see Chapter 28).32 A number of factors contributed to this increase, including changes in immigration patterns and increased numbers of people living in group settings like prisons,

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A

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B

FIGURE 20-4 • Pneumocystis jiroveci pneumonia. (A) The alveoli are filled with a foamy exudate, and the interstitium is thickened and contains a chronic inflammatory infiltrate. (B) A centrifuged bronchoalveolar lavage specimen impregnated with silver shows a cluster of P. jiroveci cysts. (From Rubin E., Farber J. L. [Eds.]. [1994]. Pathology [2nd ed.]. Philadelphia: Lippincott Williams & Wilkins.)

shelters, and nursing homes, but the most profound factor was HIV infection. The lungs are the most common site of M. tuberculosis infection, but extrapulmonary infection of the kidney, bone marrow, and other organs also occurs in people with HIV infection. Whether a person has pulmonary or extrapulmonary TB, most persons present with fever, night sweats, cough, and weight loss. Persons infected with M. tuberculosis (i.e., those with positive tuberculin skin test results) are more likely to develop reactivated TB if they become infected with HIV. Coinfected individuals (i.e., those with both HIV and TB infection) are also more likely to have a rapidly progressive form of TB. Equally important, HIV-infected persons with TB coinfection usually have an increase in viral load, which decreases the success of TB therapy. They also have an increased number of other opportunistic infections and an increased mortality rate. Since the late 1960s, most persons with TB have responded well to therapy. However, in 1991, there were outbreaks of multidrug-resistant (MDR) TB. To be classified as MDR TB, the tubercle bacilli must be resistant to at least isoniazid and rifampin. The tubercle bacilli have recently developed more extensive resistance to include fluoroquinolones and other second-line agents, including capreomycin and kanamycin. These tuberculous strains are called extensively drug-resistant (XDR) TB.33 Since the original outbreak of MDR TB in the early 1990s, new cases of MDR TB have declined, largely because of improved infection control practices and the expansion of directly observed therapy programs.

people with HIV infection.34 Aphthous ulcers presumed secondary to HIV are also common. Persons experiencing these infections usually complain of painful swallowing or retrosternal pain. The clinical presentation can range from asymptomatic to a complete inability to swallow and resulting dehydration. Endoscopy or barium esophagography is required for definitive diagnosis. Diarrhea or gastroenteritis is a common complaint in persons with HIV infection. Patients should be evaluated for the same common causes of diarrhea as in the general population. The most common protozoal opportunistic infection that causes diarrhea is due to Cryptosporidium parvum. The clinical features of cryptosporidiosis can range from mild diarrhea to severe, watery diarrhea with a loss of up to several liters of water per day. The most severe form usually occurs in persons with a CD4+ cell count of less than 50 cells/µL, and also can include malabsorption, electrolyte disturbances, dehydration, and weight loss.20 Other organisms that cause gastroenteritis and diarrhea are Salmonella, CMV, Clostridium difficile, Escherichia coli, Shigella, Giardia, and microsporidia.31 These organisms are identified by examination of stool cultures or endoscopy.

Nervous System Manifestations

Gastrointestinal Manifestations

HIV infection, particularly in its late stages of severe immunocompromise, leaves the nervous system vulnerable to an array of neurologic disorders, including HIV-associated neurocognitive disorders (HAND), toxoplasmosis, and PML. These disorders can affect the peripheral nervous system or CNS and contribute to the morbidity and mortality of persons with HIV infection.

Diseases of the gastrointestinal tract are some of the most frequent complications of HIV infection and AIDS. Esophageal candidiasis, CMV infection, and herpes simplex virus infection are common opportunistic infections that cause esophagitis in

HIV-Associated Neurocognitive Disorders. In 2007, the National Institute of Mental Health and National Institute of Neurologic Diseases and Stroke developed a new classification

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with standardized diagnostic criteria. The three conditions comprising HAND are HIV-associated asymptomatic neurocognitive impairment (ANI); HIV-associated mild neurocognitive disorder (MND); and HIV-associated dementia (HAD, formerly AIDS dementia complex).35 HAND is a syndrome of cognitive impairment with motor dysfunction or behavioral/psychosocial symptoms associated with HIV infection itself.35 HAD is usually a late complication of HIV infection. The clinical features of HAD are impairment of attention and concentration, slowing of mental speed and agility, slowing of motor speed, and apathetic behavior. The diagnosis of HAD is one of exclusion, and all other potential etiologies need to be excluded. Treatment of HAD consists of HAART to decrease symptoms and may result in significant improvement of both motor and cognitive skills. Toxoplasmosis. Toxoplasmosis is a common opportunistic infection in persons with AIDS. The organism responsible, T. gondii, is a parasite that most often affects the CNS.36 Toxoplasmosis usually is a reactivation of a latent T. gondii infection that has been dormant in the CNS. The typical presentation includes fever, headaches, and neurologic dysfunction, including confusion and lethargy, visual disturbances, and seizures. Computed tomography scans or, preferably, magnetic resonance imaging (MRI) should be performed immediately to detect the presence of neurologic lesions. Prophylactic treatment with trimethoprim-sulfamethoxazole, dapsone-pyrimethamine, or atovaquone is effective against T. gondii when the CD4+ cell count falls below 100 cells/µL. Given that these medications are also used for prevention of PCP, almost all persons under care with a CD4+ count lower than 200 cells/µL will be receiving effective toxoplasmosis prophylaxis. Since the use of trimethoprim-sulfamethoxazole and HAART began, the incidence of toxoplasmosis has decreased.36 Progressive Multifocal Leukoencephalopathy. Progressive multifocal leukoencephalopathy is a demyelinating disease of the white matter of the brain caused by the JC virus, a DNA papovavirus that attacks the oligodendrocytes.37 PML advances slowly, and it can be weeks to months before the patient seeks medical care. PML is characterized by progressive limb weakness, sensory loss, difficulty controlling the digits, visual disturbances, subtle alterations in mental status, hemiparesis, ataxia, diplopia, and seizures.37 The mortality rate is high, and the average survival time is 2 to 4 months. Diagnosis is based on clinical findings and an MRI, and confirmed by the presence of the JC virus.37 There is no proven cure for PML, but improvement can occur after starting effective HAART. In patients who develop PML while on HAART, however, the outcome may be worse secondary to immune reconstitution syndrome.38

Cancers and Malignancies Persons with AIDS have a high incidence of certain malignancies, especially Kaposi sarcoma (KS), non-Hodgkin lymphoma, and noninvasive cervical carcinoma. The increased incidence of

malignancies probably is a function of impaired cell-mediated immunity. As persons with HIV infection are living longer, there have been reports of the increasing incidence of age- and gender-specific malignancies.39 Persons with HIV infection appear to have an increased risk of lung cancer even after adjusting for tobacco history. Non–AIDS-defining malignancies account for more morbidity and mortality than AIDS-defining malignancies in the antiretroviral therapy era. Traditional risk factors play a significant role in the increased risk of non–AIDSdefining malignancies for HIV-infected individuals, but do not entirely explain the excess cancer risk.39 Increased incidences of lip cancer, penile cancer, and breast cancer have also been demonstrated in the post-HAART era.40 Kaposi Sarcoma. Kaposi sarcoma is a malignancy of the endothelial cells that line small blood vessels.41 An opportunistic cancer, KS occurs in immunosuppressed persons (e.g., transplant recipients or persons with AIDS). KS was one of the first opportunistic cancers associated with AIDS, and still is the most frequent malignancy related to HIV infection. It is 2000 times more common in people infected with HIV than in the rest of the population.41 Before 1981, most cases of KS were found in North America among elderly men of Mediterranean or Eastern European Jewish descent and in Africa among young black adults and children.41 There is evidence linking KS to a herpesvirus (herpesvirus 8, also called KS-associated herpes virus [KSHV]).41 Over 95% of KS lesions, regardless of the source or clinical subtype, have reportedly been found to be infected with KSHV. The virus is readily transmitted through homosexual and heterosexual activities; however, there is a disproportionately higher incidence of KS in men who have sex with men compared with women and other men. Maternal–infant transmission also can occur. The virus has been detected in saliva from infected persons, and other modes of transmission are suspected. The lesions of KS can be found on the skin and in the oral cavity, gastrointestinal tract, and the lungs. More than 50% of people with skin lesions also have gastrointestinal lesions. The disease usually begins as one or more macules, papules, or violet skin lesions that enlarge and become darker (Fig. 20-5). They may enlarge to form raised plaques or tumors. These irregularly shaped tumors can range from 0.8 to 1.5 inches in size. Tumor nodules frequently are located on the trunk, neck, and head, especially the tip of the nose. They usually are painless in the early stages, but discomfort may develop as the tumor develops. Invasion of internal organs, including the lungs, gastrointestinal tract, and lymphatic system, commonly occurs. Gastrointestinal tract KS is often asymptomatic, but can cause pain, bleeding, or obstruction.41 Pulmonary KS usually is a late development of the disease and causes dyspnea, cough, and hemoptysis.41 The tumors may obstruct organ function or rupture and cause internal bleeding. The progression of KS may be slow or rapid. A presumptive diagnosis of KS usually is made based on visual identification of red or violet skin or oral lesions.41 Biopsy of at least one lesion should be done to establish the diagnosis

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Because the manifestations of non-Hodgkin lymphoma are similar to those of other opportunistic infections, diagnosis often is difficult. Diagnosis can be made by biopsy of the affected tissue. Treatment consists of aggressive combination chemotherapy that may include intrathecal chemotherapy. In the post-HAART era, outcomes of patients with non-Hodgkin lymphoma have significantly improved, with a 57% complete remission rate and median survival rates of 50% to 64% at 3 years, depending on the lymphoma subtype and tumor burden.42,43 A

Noninvasive Cervical and Anal Carcinoma. The human papillomavirus (HPV) has been linked to the development of cervical carcinoma and anal carcinoma in both HIV-positive men and women.44 Women with HIV infection experience a higher incidence of cervical intraepithelial neoplasia (CIN) than non–HIV-infected women.45 HIV-infected women often experience persistent and recurrent HPV-associated anogenital disease but may not be at a higher risk for development of invasive cervical cancer.45 Occurrence of cervical dysplasia is detected by Papanicolaou smear and cervical colposcopy. Routine screening for anal intraepithelial neoplasia should be encouraged in all HIV-positive patients regardless of history of receptive anal intercourse.46 In 2007, a quadrivalent vaccine to prevent HPV infection was FDA approved.47 The safety and immunogenicity of this vaccine among HIV-infected men and women are being studied.

Wasting Syndrome

B FIGURE 20-5 • Kaposi sarcoma. (A) Intraoral Kaposi sarcoma of the hard palate secondary to HIV infection. (B) Cutaneous brown Kaposi sarcoma lesions located over the maximal left ankle and foot. (From Centers for Disease Control and Prevention Public Image Library. [Online.] Available: http://phil.cdc.gov/phil/ details.asp.)

and to distinguish KS from other skin lesions that may resemble it. Diagnosis of solitary gastrointestinal or pulmonary KS is more difficult because endoscopy and bronchoscopy are needed for diagnosis and biopsy of such lesions is contraindicated because of the risk of severe bleeding. Effective HAART is the treatment of choice for localized KS. Local therapy with liquid nitrogen or vinblastine, chemotherapy, radiation, and interferon injections are the most common therapies for those with extensive or systemic disease.41 Non-Hodgkin Lymphoma. Non-Hodgkin lymphoma (see Chapter 15) develops in 3% to 4% of people with HIV infection. The clinical features are fever, night sweats, and weight loss.

In 1997, wasting became an AIDS-defining illness. The syndrome is common in persons with HIV infection or AIDS. Wasting is characterized by involuntary weight loss of at least 10% of baseline body weight in the presence of diarrhea, more than two stools per day, or chronic weakness and a fever.48 This diagnosis is made when no other opportunistic infections or neoplasms can be identified as causing these symptoms. Factors that contribute to wasting are anorexia, metabolic abnormalities, endocrine dysfunction, malabsorption, and cytokine dysregulation. Treatment for wasting includes nutritional interventions like oral supplements or enteral or parenteral nutrition. There also are numerous pharmacologic agents used to treat wasting, including appetite stimulants, cannabinoids, and megestrol acetate.

Metabolic and Morphologic Disorders A wide range of metabolic and morphologic disorders is associated with HIV infection, including lipoatrophy and mitochondrial disorders, lipohypertrophy, hypercholesterolemia, hypertriglyceridemia, insulin resistance, and impaired glucose tolerance. The term lipodystrophy is frequently used to describe the body composition changes with or without the other metabolic derangements. Metabolic complications among people with HIV infection on HAART have been increasing since the introduction of potent HAART.49 Insulin resistance and diabetes

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appear to be higher among those with HIV infection compared with the general population, although traditional risk factors contribute significantly.50,51 Insulin resistance and diabetes also appear to be more associated with the use of specific nucleosides in combination with protease inhibitors rather than just the protease inhibitors, as initially thought. The one protease inhibitor exception is indinavir, which does alter the GLUT-4 transport system.52,53 It is still not known why insulin resistance occurs in people with HIV infection, and most experts believe it is secondary to dysregulation of metabolic pathways or to indirect effects through mitochondrial toxicity linked to adipocyte toxicity. Treatment of insulin resistance is the same as for people without HIV infection—a healthy, balanced diet; exercise; and weight loss, if needed (see Chapter 42). HIV and its therapies have been associated with dyslipidemia independent of HAART.54 The severity of the dyslipidemia and the typical pattern of the lipid profile differ among the classes and within the classes of antiretroviral agents.55 The class of protease inhibitors is generally associated with elevated total cholesterol and triglyceride levels. The antiretroviral class of NNRTIs has been associated with elevated high-density lipoprotein (HDL) cholesterol and total cholesterol levels. NRTIs are a heterogeneous class in regard to lipids. Stavudine is more commonly associated with dyslipidemia with elevated total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels. Before beginning antiretroviral therapy, a fasting lipid panel should be drawn, repeated in 3 to 6 months, and then repeated yearly. Currently, treatment of these lipid abnormalities is based on a modified version of the National Cholesterol Education Program (NCEP) endorsed by the HIV Medicine Association.56 One strategy in attempting to correct or reverse these abnormalities is to switch the HAART regimen to an equally suppressive one that contains medications less likely to cause dyslipidemia. It is important to carefully weigh the risks of potential loss of virologic suppression when alterations in HAART are made. One study compared the benefits of switching from a protease inhibitor to an NNRTI (efavirenz or nevirapine) with those of adding a lipid-lowering drug (pravastatin or bezafibrate), and found that lipid-lowering therapy was more effective than switching.57 The statins (e.g., atorvastatin, fluvastatin, pravastatin, simvastatin; discussed in Chapter 22) are the recommended medications to manage elevated LDL cholesterol. However, caution must be used because there can be serious drug-metabolizing interactions between the protease inhibitors, NNRTIs, and statins. Because increased triglycerides can lead to pancreatitis and may be an independent risk factor for coronary heart disease, the fibric acid derivatives (e.g., fenofibrate), niacin, or fish oil may be prescribed as a means of decreasing triglyceride levels.56 Lipodystrophy. Lipodystrophy related to HIV infection includes symptoms that fall into two categories: changes in body composition and metabolic changes.58 The alterations in body appearance are an increase in abdominal girth, buffalo hump

development (abnormal distribution of fat in the supraclavicular area), wasting of fat from the face and extremities, and breast enlargement in men and women. Most individuals experience either lipohypertrophy or lipoatrophy. Mixed patterns of fat changes are less common.59 The metabolic changes include elevated serum cholesterol, low HDL cholesterol, elevated triglyceride levels, and insulin resistance. Originally attributed to the use of protease inhibitors, the pathogenesis of these metabolic derangements is complex and there may be multiple confounding factors.60 Diagnosis of lipodystrophy is difficult because it may depend on subjective measures of reports of alteration in body shape and also because the term has not been standardized. The Lipodystrophy Case Definition Study Group developed a definition that incorporated 10 clinical, metabolic, and body composition variables that can diagnose lipodystrophy with 80% accuracy.61 The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) also developed a model to define lipodystrophy.62 However, neither study’s definitions have gained wide acceptance, and most clinicians prefer to describe the spectrum of signs and symptoms their patients experience. Therefore, it is critical when interpreting the vast number of clinical trials that one note the definition used for that particular study. There is no consensus on the best treatment for lipohypertrophy or lipoatrophy.63 Some preliminary data are available on the use of recombinant human growth hormone to decrease visceral adipose tissue and subcutaneous adipose tissue. Metformin and thiazolidinedione, oral antidiabetic drugs, have also been studied; results have been inconsistent. Some experts recommend switching to a non–protease inhibitor-based HAART regimen for treatment of lipohypertrophy, although this has not resulted in consistent results either. There is some evidence that switching from a thymidine analog to a nonthymidine analog may improve lipoatrophy. Surgical intervention (e.g., liposuction, implantation or injection of synthetic substances) has been used with some success. Mitochondrial Disorders. The mitochondria control many of the oxidative chemical reactions that release energy from glucose and other organic molecules. The mitochondria transform this newly released energy into adenosine triphosphate (ATP), which cells use as an energy source. In the absence of normal mitochondrial function, cells revert to anaerobic metabolism with generation of lactic acid. The mitochondrial disorders seen in persons with HIV infection are attributed to NRTIs, particularly the thymidine analogs.64 The most common presentations are lipoatrophy and peripheral neuropathy, although patients may not experience both. Patients may also present with nonspecific gastrointestinal symptoms, including nausea, vomiting, and abdominal pain. They may develop altered liver function and lactic acidosis. Since the recognition of the ascending polyneuropathy syndrome and reports of hepatic failure due to combination therapy with stavudine and didanosine, reports of life-threatening events due to mitochondrial toxicities have dramatically decreased.

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IN SUMMARY,

HIV is a retrovirus that infects the body’s CD4+ T cells and macrophages. HIV genetic material becomes integrated into the host cell DNA, so new HIV can be made. Manifestations of infection, such as acute mononucleosislike symptoms, may occur shortly after infection, and this is followed by a latent phase that may last for many years. The end of the latent period is marked by the onset of opportunistic infections and cancers as the person is diagnosed with AIDS. The complications of these infections can manifest throughout the respiratory, gastrointestinal, and nervous systems, and can include pneumonia, esophagitis, diarrhea, gastroenteritis, tumors, wasting syndrome, altered mental status, seizures, motor deficits, and metabolic disorders. ■

PREVENTION, DIAGNOSIS, AND TREATMENT After completing this section of the chapter, you should be able to meet the following objectives: ■ ■ ■ ■

■ ■

■

Discuss the transmission of HIV. Describe preventive strategies to decrease the transmission of HIV. Explain the possible significance of a positive antibody test for HIV infection. Differentiate between the enzyme immunoassay (enzyme-linked immunosorbent assay) and Western blot antibody detection tests for HIV infection. Describe the methods used in the early management of HIV infection. Compare the actions of the reverse transcriptase inhibitors (e.g., nucleoside/nucleotide analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors), protease inhibitors, and fusion inhibitors in terms of controlling HIV replication. Enumerate some of the psychosocial issues associated with HIV infection/AIDS.

Since the first description of AIDS, considerable strides have been made in understanding the pathophysiology of the disease. The virus and its mechanism of action, HIV antibody screening tests, and some treatment methods were discovered within a few years after the recognition of the first cases. Further progress in understanding the pathophysiology of AIDS and the development of more powerful treatments continues to be made.

Prevention Because there is no cure for HIV infection or AIDS, adopting risk-free or low-risk behavior is the best protection against the disease. Abstinence or long-term, mutually monogamous sexual relationships between two uninfected partners are the best ways

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to avoid HIV infection and other STDs. Correct and consistent use of latex condoms can provide protection from HIV by not allowing contact with semen or vaginal secretions during intercourse.10 Natural or lambskin condoms do not provide the same protection from HIV as latex because of the larger pores in the material. Only water-based lubricants should be used with condoms; petroleum (oil-based) products weaken the structure of the latex. Injection of drugs provides another opportunity for HIV transmission. Avoiding recreational drug use and particularly avoiding the practice of using syringes that may have been used by another person are important to HIV prevention. Medical and public health authorities recommend that persons who inject drugs use a new sterile syringe for each injection, or if this is not possible, clean their syringes thoroughly with a household bleach mixture. Other substances that alter inhibitions can lead to risky sexual behavior and increase the risk of exposure to HIV. For example, smoking cocaine (i.e., “crack”) heightens the perception of sexual arousal, and this can influence the user to practice unsafe sexual behavior.65 The addictive nature of many recreational drugs can lead to an increase in the frequency of unsafe sexual behavior and the number of partners as the user engages in sex in exchange for money or drugs. Persons concerned about their risk should be encouraged to get information and counseling and be tested to find out their infection status. Public health programs in the United States have been profoundly affected by the HIV epidemic. Although standard methods for disease intervention and statistical analysis are applied to HIV infection, public health programs have become more responsive to community concerns, confidentiality, and longterm follow-up of clients as a direct result of the HIV epidemic. In 2006, the CDC issued an update on the recommendations for testing for HIV.66 The CDC now recommends that all individuals 13 to 64 years of age should be routinely screened for HIV. Anyone who is at continued risk for HIV infection should be tested at least annually; those who are at high risk—injection drug users and their partners, persons who exchange sex for money or drugs, anyone who has had more than one sex partner since the last HIV test—should be tested more frequently. Whenever HIV testing is performed, pretest and post-test counseling should be offered. HIV prevention counseling should be culturally competent, sensitive to issues of sexual identity, developmentally appropriate, and linguistically relevant.12 The essential elements of any HIV prevention/counseling interaction include a personalized risk assessment and prevention plan.66 Education and behavioral intervention continue to be the mainstays of HIV prevention programs. Individual risk assessment and education regarding HIV transmission and possible prevention techniques or skills are delivered to persons in clinical settings and to those at high risk of infection in community settings. Community-wide education is provided in schools, the workplace, and the media. Training for professionals can have an impact on the spread of HIV and is an important element of prevention. The constant addition of new information on HIV makes prevention an ever-changing and challenging endeavor.

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Diagnostic Methods The diagnostic methods used for HIV infection include laboratory methods to determine infection and clinical methods to evaluate the progression of the disease. The most accurate and inexpensive method for identifying HIV infection is the HIV antibody test. The first commercial assays for HIV were introduced in 1985 to screen donated blood. Since then, use of antibody detection tests has been expanded to include evaluating persons at increased risk for HIV infection. The HIV antibody test procedure consists of screening with an enzyme immunoassay (EIA), also known as enzyme-linked immunosorbent assay (ELISA), followed by a confirmatory test, the Western blot assay, which is performed if the EIA is positive.67 In light of the psychosocial issues related to HIV infection and AIDS, sensitivity and confidentiality must be maintained whenever testing is implemented. Counseling before and after testing to allay fears, provide accurate information, ensure appropriate follow-up testing, and provide referral to needed medical and psychosocial services is essential. The EIA detects antibodies produced in response to HIV infection.21 In an EIA, when blood is added, antibodies to HIV bind to HIV antigens. The antigen–antibody complex is then detected using an anti–human immunoglobulin G (IgG) antibody conjugated to an enzyme such as alkaline phosphatase. A substrate is then added from which the enzyme produces a color reaction. Color development, indicating the amount of HIV antibodies found, is measured. The test is considered reactive, or positive, if color is produced, and negative, or nonreactive, if there is no color. EIA tests have high false-positive rates, so samples that are repeatedly reactive are tested by a confirmatory test such as the Western blot. The Western blot test is more specific than the EIA, and in the case of a false-positive EIA result, the Western blot test can identify the person as uninfected. The Western blot is a more sensitive assay that looks for the presence of antibodies to specific viral antigens.21 For the test, HIV antigens are separated by electrophoresis based on their weight, and then transferred to nitrocellulose paper and arranged in strips, with larger proteins at the top and smaller proteins at the bottom. The serum sample is then added. If HIV antibodies are present, they bind with the specific viral antigen on the paper. An enzyme and substrate then are added to produce a color reaction as in the EIA. If there are no colored bands present, the test is negative. A test is positive when certain combinations of bands are present. A test can be indeterminate if there are bands present but they do not meet the criteria for a positive test result. An indeterminate or falsepositive test result can occur during the window period before seroconversion. When a serum antibody test result is reactive or borderline by EIA and positive by Western blot, the person is considered to be infected with HIV. When an EIA is reactive and the Western blot is negative, the person in not infected with HIV. Both tests are important because, in some situations, misinformation can be generated by EIA testing alone because there are many situations that can produce a false-positive (Chart 20-3) or a false-negative EIA result. The Western blot test therefore is essential to determine which persons with positive EIA results are truly infected.

CHART 20-3

CAUSES OF FALSE-POSITIVE OR FALSE-NEGATIVE HIV ELISA TEST RESULTS

False-Positive Results • Hematologic malignant disorders (e.g., malignant melanoma) • DNA viral infections (e.g., infectious mononucleosis [Epstein-Barr virus]) • Autoimmune disorders • Primary biliary cirrhosis • Immunizations (e.g., influenza, hepatitis) • Passive transfer of HIV antibodies (mother to infant) • Antibodies to class II leukocytes • Chronic renal failure/renal transplant • Stevens-Johnson syndrome • Positive rapid plasma reagin test False-Negative Results • “Window” period after infection • Immunosuppression therapy • Replacement transfusion • B-cell dysfunction • Bone marrow transplant • Contamination of specimen with starch powder from gloves • Use of kits that detect primary antibody to the p24 viral core protein

Millions of HIV antibody tests are performed in the United States each year. New technology has led to new forms of testing, like the oral test, home testing kits, and the new rapid blood test. Oral fluids contain antibodies to HIV. In the late 1990s, the FDA approved the OraSure test.20 The OraSure uses a cotton swab, which is inserted into the mouth for 2 minutes, placed in a transport container with preservative, and then sent to a laboratory for EIA and Western blot testing. Home HIV testing kits can be bought over the counter. The kits, approved by the FDA, allow persons to collect their own blood sample through a finger-stick process, mail the specimen to a laboratory for EIA and confirmatory Western blot tests, and receive results by telephone in 3 to 7 days. In November 2002, the FDA approved the Ora Quick Rapid HIV-1 Antibody Test.68 The Ora Quick uses a whole-blood specimen from a finger stick and can provide results in about 20 minutes. Reactive, or positive, test results require confirmation using Western blot testing. A person with a reactive result needs to be told that the preliminary test was positive, but he or she needs a confirmatory test. The use of a rapid test should facilitate people receiving the results of their HIV test more regularly because they do not need to return for their test results 2 weeks later unless it is positive or there is concern that the person may be in the window period before seroconversion. Polymerase chain reaction (PCR) is a technique for detecting HIV DNA (see Chapter 16). PCR detects the presence of the virus rather than the antibody to the virus, which the EIA and

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Western blot tests detect. PCR is useful in diagnosing HIV infection in infants born to infected mothers because these infants have their mothers’ HIV antibody regardless of whether the children are infected. Because the amount of viral DNA in the HIVinfected cell is small compared with the amount of human DNA, direct detection of viral genetic material is difficult. PCR is a method for amplifying the viral DNA up to 1 million times or more to increase the probability of detection.

Early Management The management of HIV infection has changed dramatically since the mid-1990s. This change is due to a better understanding of the pathogenesis of HIV, the emergence of viral load testing, and the increased number of medications available to fight the virus. After HIV infection is confirmed, a baseline evaluation should be done.67 This evaluation should include a complete history and physical examination and baseline laboratory tests. Routine follow-up care of a stable, asymptomatic HIVinfected patient should include a history and physical examination along with CD4+ cell count and viral load testing every 3 to 4 months. Persons who are symptomatic may need to be seen more frequently. Therapeutic interventions are determined by the level of disease activity based on the viral load, the degree of immunodeficiency based on the CD4+ cell count, and the appearance of specific opportunistic infections. The U.S. Department of Health and Human Services (DHHS) guidelines released in October 2006 recommend the initiation of antiretroviral therapy based on symptomatic disease and CD4+ cell counts.69 According to these guidelines, all symptomatic patients should be treated with antiretroviral therapy. If the individual is asymptomatic, therapy is recommended when the person’s CD4+ cell counts are 200/µL or less. For those who have a CD4+ cell count greater than 350/µL, antiretroviral therapy is generally not recommended. For those whose CD4+ cell count is 200 to 350/µL, antiretroviral therapy should be considered and a decision individualized to the patient should be made.69 Because recent studies suggest that non–HIVrelated conditions such as renal, liver, and heart disease may occur more frequently among those not on HAART, some experts are reverting back to previous recommendations to start therapy when the CD4+ count is higher.70,71 In addition, patients are more likely to experience toxicities due to HAART at lower CD4+ counts compared with those who begin HAART at higher CD4+ counts.72 As HIV infection progresses, prophylaxis and treatment of opportunistic infections are critical.73,74 Prophylaxis may differ based on geographic and environmental exposures and tolerability of medications, as well as the person’s CD4+ cell count. Early recognition of HIV infection is becoming more common, and medical intervention in the early stages may delay lifethreatening symptoms and slow the progression of the disease. Because of frequent advances in the management of HIV infection, primary care providers must be prepared to update their knowledge of diagnosis, testing, evaluation, and medical intervention. The Infectious Diseases Society of America/HIV Medicine Association, the CDC, the DHHS, and the U.S. Public Health Service regularly issue guidelines to assist clinicians in caring for persons with HIV infection.

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Treatment There is no cure for HIV infection. The medications that are currently available to treat HIV infection decrease the amount of virus in the body, but they do not eradicate HIV. The treatment of HIV infection is one of the most rapidly evolving fields in medicine. Because different drugs act on different stages of the replication cycle, optimal treatment includes a combination of at least two to three drugs, often referred to as HAART.69 The goal of HAART is sustained suppression of HIV replication, resulting in an undetectable viral load and an increasing CD4+ cell count. In general, antiretroviral therapies are prescribed to slow the progression to AIDS and improve the overall survival time of persons with HIV infection. The first drug that was approved by the FDA for the treatment of HIV was zidovudine in 1987. Since then, an increasing number of therapeutics has been approved by the FDA for treatment of HIV infection. There currently are five classes of HIV antiretroviral medications: nucleoside and nucleotide analog reverse transcriptase inhibitors; non-nucleoside reverse transcriptase inhibitors; protease inhibitors; entry inhibitors; and the newest class, integrase inhibitors (Table 20-2). Each type of agent attempts to interrupt viral replication at a different point. Reverse transcriptase inhibitors inhibit HIV replication by acting on the enzyme reverse transcriptase. There are three types of HIV medications that work on this enzyme, nucleoside analog reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Nucleoside analog reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors act by blocking the elongation of the DNA chain by stopping more nucleosides from being added. Non-nucleoside reverse transcriptase inhibitors work by binding to the reverse transcriptase enzyme so it cannot copy the virus’s RNA into DNA (see Fig. 20-1). Protease inhibitors bind to the protease enzyme and inhibit its action. This inhibition prevents the cleavage of the polyprotein chain into individual proteins, which would be used to construct the new virus. Because the information inside the nucleus is not put together properly, the new viruses that are released into the body are immature and noninfectious (see Fig. 20-1). The two newest classes of antiretroviral therapy are the entry inhibitors and integrase inhibitors. The entry inhibitors prevent HIV from entering or fusing with the CD4+ cell, thus blocking the virus from inserting its genetic information into the CD4+ T cell75 (see Fig. 20-1). There are two types of entry inhibitors: fusion inhibitors and CCR5 antagonists. The FDA approved the first fusion inhibitor, enfuvirtide, in March 2003. It is a subcutaneous injection given twice daily. In September 2007, the FDA approved the first CCR5 antagonist, maraviroc. Integrase inhibitors block the integration step of the viral cycle, thus preventing the HIV genome from integrating into the host’s genome.76 This is the newest class of inhibitors; the FDA approved the first drug in this class, raltegravir, in October 2007. Preventive and therapeutic vaccines for HIV are also being investigated.77 The preventive vaccine would be given to someone who is HIV negative, with the goal of preventing infection if exposed to HIV. These vaccines have focused mainly on

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Unit V Infection, Inflammation, and Immunity TABLE 20-2 Antiviral

Medications Used in Treatment of HIV Infection

MEDICATION (GENERIC NAME AND INITIALS) BY CLASSIFICATION

MEDICATION TRADE NAME

DOSING SCHEDULE

Retrovir Videx Videx EC Epivir Zerit Ziagen Hivid Emtriva

Twice daily Twice daily Once daily Once or twice daily Twice daily Once or twice daily Every 8 hours Once daily

Viread

Once daily

Viramune Sustiva Rescriptor Intelence

Once or twice daily Once daily Three times daily Twice daily

Norvir Invirase Crixivan Viracept Lexiva Kaletra Reyataz Aptivus Prezista

Varies Every 12 or 24 hours Every 8 or 12 hours Every 12 hours Every 12 or 24 hours Every 12 or 24 hours Every 24 hours Every 12 hours Every 12 hours

Fuzeon Selzentry

Every 12 hours Every 12 hours

Isentress

Every 12 hours

Combivir Epzicom Trizivir Truvada Atripla

Twice daily Once daily Twice daily Once daily Once daily

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Zidovudine (AZT) Didanosine (ddl) Didanosine (ddl) enteric coated Lamivudine (3TC) Stavudine (d4T) Abacavir (ABC) Zalcitabine (ddC) Emtricitabine (FTC) Nucleotide Reverse Transcriptase Inhibitor (NRTI)

Tenofovir (TDFNV) Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Nevirapine (NVP) Efavirenz (EFV) Delavirdine (DLV) Etravirine Protease Inhibitors (PIs)

Ritonavir (RTV) Saquinavir (SQV)* Indinavir (IDV)* Nelfinavir (NLF) Fosamprenavir (fAPV)* Lopinavir/ritonavir (LPV/r) Atazanavir (ATV)* Tipranavir (TPV)* Darunavir (DRV)* Entry Inhibitors

Enfuvirtide (T-20) Maraviroc Integrase Inhibitor

Raltegravir Combination Medications

AZT + 3TC ABC + 3TC AZT + 3TC + ABC TDFNV + FTC TDFNV + FTC + EFV *Recommended to be boosted with ritonavir.

inducing neutralizing antibodies to prevent infections. The second type of vaccine would be used in people who are already infected with HIV as a therapeutic strategy to control HIV replication. The goal of these vaccines would be to better control the HIV viremia by lowering the viral load set point, changing the viral load trajectories, and preserving immune function for longer periods of time. These vaccines have focused on bringing about cellular immune responses and preparing the immune system for the lysis of infected cells. To date, these strategies have proved disappointing.

Opportunistic infections occur as a consequence of immunodeficiency, which is caused by the progressive loss of CD4+ T cells. Drugs and vaccines commonly are used for the prevention and treatment of opportunistic infections and conditions, including PCP, toxoplasmosis, MAC infection, candidiasis, CMV infection, influenza, hepatitis B, and S. pneumoniae infection.73,74 Prophylactic medications are used once an individual’s CD4+ cell count has dropped below a certain level that indicates his or her immune system is no longer able to fight off opportunistic infections.73,74

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Persons with HIV infection should be advised to avoid infections as much as possible and seek evaluation promptly when they occur. Immunization is important because persons infected with HIV are at risk for contracting other infectious diseases. Some of these diseases can be avoided by vaccination while the immune system’s responsiveness is relatively intact. Persons with asymptomatic HIV infection and CD4+ cell counts greater than 200 cells/µL should be vaccinated against measles, mumps, and rubella. Pneumococcal vaccine should be given once, as soon as possible after HIV infection is diagnosed, and then every 10 years, and influenza vaccine should be given yearly.67 Hepatitis A and B vaccines appear to be more immunogenic when the HIV viral load is suppressed.78,79 Live-virus vaccines should not be given to persons with HIV infection; however, there is much interest in the possibility of vaccinating those HIV-infected persons with varicella-zoster virus (VZV) vaccine to decrease the risk of VZV disease recurrences, or shingles. A study conducted among children with HIV infection demonstrated virus-specific lymphocyte proliferative responses in all subjects by 4 weeks and in 90% by 1 year after VZV vaccination.80 All subjects tolerated the vaccination without adverse reactions or rises in HIV viral load.

Psychosocial Issues HIV infection and AIDS affect all spheres of life.81 The psychological effects of HIV infection or AIDS may be just as significant as the physical effects. The dramatic impact of this illness is compounded by complex reactions on the part of the person with HIV or AIDS; his or her partner, friends, and family; members of the health care team; and the community. These reactions may be influenced by inadequate information, fear of contagion, shame, prejudices, and condemnation of risk behaviors.82 Acknowledging a diagnosis of HIV infection or AIDS may be the first indication to family and colleagues of an otherwise hidden lifestyle (i.e., homosexuality or drug use). This increases the strain on relationships with important support persons. Shock is a common reaction people have when they are diagnosed with HIV infection, often followed by anger at themselves or others and denial or guilt. In addition to the fear and grief associated with death, the person with HIV infection or AIDS also may experience uncertainty and may feel helpless, hopeless, stigmatized, and out of control.81 Many people with HIV infection have preexisting mental health conditions such as depression or anxiety disorders as well as alcohol and other drug abuse (AODA). Appropriate diagnosis and treatment should be made available when mental health problems or AODA are evident. Diagnosis and treatment of cognitive and affective disorders are essential parts of ongoing care for the HIV-infected person.81 The emotional stress, feelings of isolation, and sadness experienced by the person with HIV infection or AIDS can be overwhelming. Most persons, however, manage to learn to cope and live with their HIV infection. Persons with the disease must have as much information and control as possible. They should be encouraged to direct their energies in a positive manner and continue with their social and group activities as long as such activities are helpful. Appropri-

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ate social support systems (e.g., AIDS service organizations, community groups, religious organizations) should be called on to assist whenever possible. When they learn they can live with HIV infection, many persons acquire a positive outlook based on living their lives to the fullest. To deal with these complex issues, the health care team must recognize and accept their own fears, prejudices, and emotions concerning those with HIV infection or AIDS. Personal feelings must not prevent caregivers from acknowledging the intrinsic human worth of all persons and their right to be treated with dignity and respect. Members of the health care team should have adequate support for their own emotional needs generated from working with persons with HIV infection. Grief, anxiety, and concern over stigmatization are normal feelings and should be acknowledged and dealt with through peer support or professional counseling to reduce burnout and emotional strain among members of the health care provider team.

IN SUMMARY,

because there is no cure for HIV infection, risk-free or low-risk behavior is the best protection against it. Abstinence or long-term, mutually monogamous sexual relationships between two uninfected partners, use of condoms, avoiding drug use, and the use of sterile syringes if drug use cannot be avoided are essential to halting the transmission of HIV. HIV infection is diagnosed using the EIA or rapid test together with the Western blot assay, both of which are antibody detection tests. The emotional stress, feelings of isolation, and sadness experienced by the person with HIV infection or AIDS can be overwhelming, but most persons adjust to living with HIV infection. Diagnosis and treatment of cognitive and affective disorders are an essential part of ongoing care for the HIV-infected person. Appropriate treatment should be made available when alcohol or other drug dependence is noted. The management of HIV infection/AIDS incorporates the use of HAART; early recognition and treatment of opportunistic infections and other clinical disorders; as well as acknowledgment and support of the psychosocial issues that are an ongoing concern for those who are infected with the virus. ■

HIV INFECTION IN PREGNANCY AND IN INFANTS AND CHILDREN After completing this section of the chapter, you should be able to meet the following objectives: ■ ■ ■

Discuss the vertical transmission of HIV from mother to child and recommended prevention measures. Cite problems with the diagnosis of HIV infection in the infant. Compare the progress of HIV infection in infants and children with HIV infection in adults.

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Early in the epidemic, children who acquired HIV could have become infected through blood products or perinatally. Now, almost all of the children who become infected with HIV at a young age in the United States get the infection perinatally. Fortunately, the incidence of perinatally infected children in the United States has markedly decreased and, as of 2006, only about 300 infants have been infected.83 Infected women may transmit the virus to their offspring in utero, during labor and delivery, or through breast milk.84 The risk of transmission is increased if the mother has advanced HIV disease as evidenced by low CD4+ cell counts or high levels of HIV in the blood (high viral load); if there was prolonged time from rupture of membranes to delivery; if the mother breast-feeds the child; or if there is increased exposure of the fetus to maternal blood.84

HIV INFECTION IN PREGNANCY AND IN INFANTS AND CHILDREN ■

■

HIV can be passed from mother to infant during labor and delivery or through breast-feeding. The course of HIV infection is different for children than adults.

Diagnosis of HIV infection in children born to HIVinfected mothers is complicated by the presence of maternal anti-HIV IgG antibody, which crosses the placenta to the fetus.11 Consequently, infants born to HIV-infected women can be HIV antibody positive by ELISA for up to 18 months of age even though they are not infected with HIV. PCR testing for HIV DNA is used most often to diagnose HIV infection in infants younger than 18 months of age. Two positive PCR tests for HIV DNA are needed to diagnose a child with HIV infection. Children born to mothers with HIV infection are considered uninfected if they become HIV antibody negative after 6 months of age, have no other laboratory evidence of HIV infection, and have not met the surveillance case definition criteria for AIDS in children. The landmark Pediatric AIDS Clinical Trials Group (PACTG) 076 trial reported that perinatal transmission could be lowered by two thirds, from 26% to 8%, by administering zidovudine to the mother during pregnancy and labor and delivery and to the infant when it is born.10 The U.S. Public Health Service therefore recommends that HIV counseling and testing should be offered to all pregnant women.66 The recommendations also stress that women who test positive for HIV antibodies should be informed of the perinatal prevention benefits of zidovudine therapy and offered HAART, which often includes zidovudine. This is done because it has now been found that women receiving antiretroviral therapy who also have a viral load less than 1000 copies/mL have very low rates of perinatal transmission. One caveat to antiretroviral therapy in pregnancy is that efavirenz cannot be used during the first trimester because it is a teratogen, causing neural tube defects. Benefits of volun-

tary testing for mothers and newborns include reduced morbidity because of intensive treatment and supportive health care, the opportunity for early antiretroviral therapy for mother and child, and information regarding the risk of transmission from breast milk. Because pregnant women in less developed countries do not always have access to zidovudine, studies are being conducted in Africa to determine if other, simpler and less expensive antiretroviral regimens can be used to decrease transmission from mother to infant. One such study, HIVNET 012, evaluated single-dose nevirapine compared with zidovudine and found that nevirapine lowered the risk of HIV transmission by almost 50%.85 However, this strategy could lead to nevirapine resistance, and other studies evaluating drug combinations and strategies are being conducted. Children may have a different clinical presentation of HIV infection than adults. Failure to thrive, CNS abnormalities, and developmental delays are the most prominent primary manifestations of HIV infection in children.10 Children born with HIV infection usually weigh less and are shorter than noninfected infants. A major cause of early mortality for HIV-infected children is PCP, which may also be transmitted vertically. As opposed to adults, in whom PCP occurs in the late stages, PCP occurs early in children, with the peak age of onset at 3 to 6 months. For this reason, prophylaxis with trimethoprimsulfamethoxazole is started by 4 to 6 weeks for all infants born to HIV-infected mothers, regardless of their CD4+ cell count or infection status.

IN SUMMARY,

infected women may transmit the virus to their offspring in utero, during labor and delivery, or through breast milk. It is recommended that all pregnant women be tested for HIV at the time of diagnosis of pregnancy and again at the time of labor and delivery. Diagnosis of HIV infection in children born to HIV-infected mothers is complicated by the presence of maternal HIV antibody, which crosses the placenta to the fetus. This antibody usually disappears within 18 months in uninfected children. Administration of antiretroviral therapy to the mother during pregnancy and labor and delivery and to the infant when it is born decreases perinatal transmission. ■

Review Exercises 1. A 29-year-old woman presents to the clinic for her initial obstetrics visit, about 10 weeks into her pregnancy. A. This woman is in a monogamous relationship. Should an HIV test be a part of her initial blood work? Why? B. The woman’s HIV test comes back positive. What should be done to decrease the risk of her passing on HIV to her infant?

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C. The infant is born, and its initial antibody test is positive. Does this mean the infant is infected? How is the diagnosis of HIV infection in an infant younger than 18 months made, and why is this different than the diagnosis for adults? 2. A 40-year-old man presents to the clinic very short of breath, and based on radiography and examination, he is diagnosed with Pneumocystis jiroveci pneumonia (PCP). His provider does an HIV test, which is positive. On further testing, the man’s CD4+ count is found to be 100 cells/µL and his viral load is 250,000 copies/mL. A. Why did the provider do an HIV test after the man was diagnosed with PCP? B. Is there a way to prevent PCP? C. What CDC classification does this man fall into based on his CD4+ count and symptomatology? Why?

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15. Stramer S. L., Glynn S. A., Kleinman S. H., et al. (2004). Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing. New England Journal of Medicine 351, 760–768. 16. Abbas A. K. (2005). Diseases of immunity. In Kumar V., Abbas A. K., Fausto N. (Eds.), Robbins and Cotran pathologic basis of disease (7th ed., pp. 245–258). Philadelphia: Elsevier Saunders. 17. Warren J. S., Bennett D. P., Pomerantz R. J. (2008). Immunopathology. In Rubin R., Strayer D. E. (Eds.), Rubin’s pathology: Clinicopathologic foundations of medicine (5th ed., pp. 131–136). Philadelphia: Lippincott Williams & Wilkins. 18. Trecarichi E. M., Tumbarello M., de Gaetano Donati K., et al. (2006). Partial protective effect of CCR5-delta 32 heterozygosity in a cohort of heterosexual Italian HIV-1 exposed uninfected individuals. AIDS Research and Therapy 3, 22. 19. Fauci A. S. (1988). The human immunodeficiency virus: Infectivity and mechanisms of pathogenesis. Science 239, 617–622. 20. Holodniy M. (1999). Establishing the diagnosis of HIV infection. In Dolin R., Masur H., Saag M. S. (Eds.), AIDS therapy (pp. 3–14). Philadelphia: Churchill Livingstone. 21. Centers for Disease Control and Prevention. (1992). 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and Mortality Weekly Report 41(RR-17), 1–23. 22. Rizzardi G. P., Pantaleo G. (1999). The immunopathogenesis of HIV-1 infection. In Armstrong D., Cohen J. (Eds.), Infectious diseases (Section 5, Chapter 6, pp. 1–12). London: Harcourt. 23. Hecht F. M., Busch M. P., Rawal B., et al. (2002). Use of laboratory tests and clinical symptoms for identification of primary HIV infections AIDS 16, 1119–1129. 24. Hecht F. M., Wang L., Collier A. (2006). A multicenter observational study of potential benefits of initiating combination antiretroviral therapy during acute infection. Journal of Infectious Disease 194, 725–733. 25. Rodriguez B., Sethi A. K., Cheruvu V. K. (2006). Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. Journal of the American Medical Association 296, 1498–1506. 26. Pantaleo G., Graziosi C., Fauci A. S. (1993). The immunopathogenesis of human immunodeficiency virus infection. New England Journal of Medicine 328, 327–335. 27. Walker B. (2007). Elite control of HIV infection: Implications for vaccine and treatment. Top HIV MED 15(4), 134–136. Review. 28. Kaplan J. E., Hanson D. L., Jones J. L., et al. (2001).Viral load as an independent risk factor for opportunistic infections in HIV-infected adults and adolescents. AIDS 15, 1831–1836. 29. Kaplan J. E., Hanson D., Dworkin M. S., et al. (2000). Epidemiology of HIV associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clinical Infectious Diseases 30(Suppl. 1), S5–S14. 30. Afessa B., Green B. (2000). Bacterial pneumonia in hospitalized patients with HIV. Chest 117, 1017–1022. 31. Huang L., Stansell J., Osmond D. (1999). Performance of an algorithm to detect Pneumocystis carinii pneumonia in symptomatic HIV-infected persons. Chest 115, 1025–1032. 32. UNAIDS. (2006). Frequently asked questions about tuberculosis. [Online.] Avaliable: http://data.unaids.org/pub/factsheet/2006/tb_hiv_qa.pdf. Accessed March 28, 2008. 33. Shah N. S., Wright A., Bai G. H., et al. (2007). Worldwide emergence of extensively drug-resistant tuberculosis. Emerging Infectious Diseases 13(3), 380–387. 34. Wilcox C. M. (2004). Gastrointestinal manifestations of AIDS. Nutrition in Clinical Practice 19, 356–364. 35. Antinori A., Arendt G., Becker J. T. (2007). Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69, 1789–1799. 36. Dedicoat M., Livesley N. (2006). Management of toxoplasmic encephalitis in HIV-infected adults (with an emphasis on resource-poor settings). Cochrane Database of Systematic Reviews, July 19, 3, CD005420. 37. Berger J. R., Houff S. (2006). Progressive multifocal leukoencephalopathy: Lessons from AIDS and natalizumab. Neurological Research 28, 299–305.

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38. Roberts M. T. (2005). AIDS-associated progressive multifocal leukoencephalopathy: Current management strategies. CNS Drugs 19, 671–682. 39. Silverberg M. J., Abrams D. I. (2007). AIDS-defining and non-AIDSdefining malignancies: Cancer occurrence in the antiretroviral therapy era. Current Opinion in Oncology 19, 446–451. 40. Frisch M., Biggar R. J., Engels E. A. (2001). Association of cancer with AIDS-related immunosuppression in adults. Journal of the American Medical Association 285, 1736–1745. 41. Antman K., Chang Y. (2000). Kaposi’s sarcoma. New England Journal of Medicine 342, 1027–1038. 42. Lim S. T., Karim R., Nathwani B. N., et al. (2005). AIDS-related Burkitt’s lymphoma versus diffuse large-cell lymphoma in the pre-highly active antiretroviral therapy (HAART) and HAART eras: Significant differences in survival with standard chemotherapy. Journal of Clinical Oncology 23, 4430–4438. 43. Mounier N., Spina M., Gisselbrecht C. (2007). Modern management of non-Hodgkin lymphoma in HIV-infected patients. British Journal of Haematology 136, 685–698. 44. Einstein M. H., Kadish A. S. (2004). Anogenital neoplasia in AIDS. Current Opinion in Oncology 16, 455–462. 45. Massad L. S., Fazzari M. J., Anastos K., et al. (2007). Outcomes after treatment of cervical intraepithelial neoplasia among women with HIV. Journal of Lower Genital Tract Disease 11, 90–97. 46. Abramowitz L., Benabderrahmane D., Ravaud P., et al. (2007). Anal squamous intraepithelial lesions and condyloma in HIV-infected heterosexual men, homosexual men and women: Prevalence and associated factors. AIDS 21, 1457–1465. 47. De Vuyst H., Franceschi S. (2007). Human papillomavirus vaccines in HIV-positive men and women. Current Opinion in Oncology 19, 470–475. 48. Polsky B., Kotler D., Steinhart C. (2004). Treatment guidelines for HIVassociated wasting. HIV Clinical Trials 5, 50–61. 49. Umeh O. C., Currier J. S. (2005). Lipids, metabolic syndrome, and risk factors for future cardiovascular disease among HIV-infected patients. Current HIV/AIDS Reports 2, 132–139. 50. Brown T. T., Cole S. R., Li X., et al. (2005). Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Archives of Internal Medicine 165, 1179–1184. 51. Howard A. A., Floris-Moore M., Arnsten J. H., et al. (2005). Disorders of glucose metabolism among HIV-infected women. Clinical Infectious Diseases 40, 1492–1499. 52. Hertel J., Struthers H., Horj C. B., et al. (2004). A structural basis for the acute effects of HIV protease inhibitors on GLUT4 intrinsic activity. Journal of Biological Chemistry 279, 55147–55152. 53. Koster J. C., Remedi M. S., Qiu H., et al. (2003). HIV protease inhibitors acutely impair glucose-stimulated insulin release. Diabetes 52, 1695–1700. 54. Riddler S. A., Smit E., Cole S. R., et al. (2003). Impact of HIV infection and HAART on serum lipids in men. Journal of the American Medical Association 289, 2978–2982. 55. Tungsiripat M., Aberg J. A. (2005). Dyslipidemia in HIV-infected individuals [invited review]. Cleveland Clinic Journal of Medicine 72, 1113–1120. 56. Dubé M. P., Stein J. H., Aberg J. A., et al. (2003). Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV) infected adults receiving antiretroviral therapy: Recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clinical Infectious Diseases 37, 613–627. 57. Calza L., Manfredi R., Colangeli V., et al. (2005). Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia. AIDS 19, 1051–1058. 58. Tershakovec A. M., Frank I., Rader D. (2004). HIV-related lipodystrophy and related factors. Atherosclerosis 174, 1–10. 59. Mulligan K., Parker R. A., Komarow L., et al. (2006). Mixed patterns of changes in central and peripheral fat following initiation of antiretroviral therapy in a randomized trial. Journal of Acquired Immune Deficiency Syndromes 41, 590–597.

60. Grinspoon S., Carr A. (2005). Cardiovascular risk and body-fat abnormalities in HIV-infected adults. New England Journal of Medicine 352, 48–62. 61. Carr A., Law M. (2003). HIV Lipodystrophy Case Definition Study Group: An objective lipodystrophy severity grading scale derived from the lipodystrophy case definition score. Journal of Acquired Immune Deficiency Syndromes 33, 571–576. 62. Tien P. C., Benson C., Zolopa A. R., et al. (2006). The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM): Methods, design, and sample characteristics. American Journal of Epidemiology 163, 860–869. 63. Wohl D. A. (2004). Diagnosis and management of body morphology changes and lipid abnormalities associated with HIV Infection and its therapies. Topics in HIV Medicine 12(3), 89–93. 64. McComsey G., Lonergan J. T. (2004). Mitochondrial dysfunction: Patient monitoring and toxicity management. Journal of Acquired Immune Deficiency Syndromes 37(Suppl. 1), S30–S35. 65. Edlin B. R., Irwin K. L., Faruque S., et al., and the Multicenter Crack Cocaine and HIV Infection Study Team. (1994). Intersecting epidemics: Crack cocaine use and HIV infection among inner-city young adults. New England Journal of Medicine 331, 1422–1427. 66. Centers for Disease Control and Prevention. (2006). Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. Morbidity and Mortality Weekly Report 55(RR14), 1–17. 67. Aberg J. A., Gallant J. E., Anderson J., et al. (2004). Primary care guidelines for the management of persons infected with human immunodeficiency virus: Recommendations of the HIV Medicine Association of the Infectious Disease Society of America. Clinical Infectious Diseases 39, 609–629. 68. Centers for Disease Control and Prevention. (2002). Notice to readers: Approval of a new rapid test for HIV antibody. Morbidity and Mortality Weekly Report 51(46), 1051–1052. 69. Panel on Antiretroviral Guidelines for Adult and Adolescents. (2008). Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services. [Online.] Available: www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed March 30, 2008. 70. El-Sadr W. M., Lundgren J. D., Neaton J. D., et al. (2006). Strategies for Management of Antiretroviral Therapy (SMART) Study Group: CD4+ count-guided interruption of antiretroviral treatment. New England Journal of Medicine 355, 2283–2296. 71. Palella F. J. Jr., Deloria-Knoll M., Chmiel J. S., et al., HIV Outpatient Study (HOPS) Investigators. (2003). Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata. Annals of Internal Medicine 138, 620–626. 72. Lichtenstein K., Armon C., Moorman A., et al. (2007). Initiation of antiretroviral therapy at higher CD4+ T cell counts ≥ 350 cells/mm3 does not increase incidence or risk of peripheral neuropathy, anemia, or renal insufficiency. Journal of Acquired Immune Deficiency Syndromes 247(1), 27–35. 73. Masur H., Kaplan J. E., Holmes K. K., U.S. Public Health Service; Infectious Diseases Society of America. (2002). Guidelines for preventing opportunistic infections among HIV-infected persons—2002: Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Annals of Internal Medicine 137, 435–478. 74. Benson C. A., Kaplan J. E., Masur H., et al. (2004). Treating opportunistic infections among HIV-infected adults and adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. Morbidity and Mortality Weekly Report Recommended Reports 53(RR-15), 1–112 [erratum in Morbidity and Mortality Weekly Report 2005, 54(12), 311]. 75. Rusconi S., Scozzafava A., Mastrolorenzo A., et al. (2007). An update in the development of HIV entry inhibitors. Current Topics in Medical Chemistry 7, 1273–1289.

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81. O’Brien A. M., Oerlemans-Bunn M., Blachfield J. C. (1987). Nursing the AIDS patient at home. AIDS Patient Care 1, 21. 82. Lippman S. W., James W. A., Frierson R. L. (1993). AIDS and the family: Implications for counseling. AIDS Care 5, 71–78. 83. AIDSinfo. (2006). Perinatal guidelines from the AETC National Resource Center. [Online.] Available: www.aidsinfo.nih.gov/Guidelines/Guideline Detail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=9. 84. Boyer P., Dillon M., Navaie M., et al. (1994). Factors predictive of maternal-fetal transmission of HIV-1. Journal of the American Medical Association 271, 1925–1930. 85. Guay L., Muskoe P., Fleming T., et. al. (1999). Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354, 795–802.

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U N I T • VI

Disorders of Cardiovascular Function Of all body systems, the heart and circulation presented the most difficult puzzle to solve. From the fifth century bc, theories about blood and its movement were linked to the concept of the four elements (fire, earth, air, and water) and the pneuma, or life force. According to the Greek physician Galen (ad 130–200), the starting point of the circulatory system was the gut, where food was made into “chyle” and then carried to the liver where it was converted into blood. From the liver, which was believed to be the center of the circulation, a small amount of blood was sent to the heart and lungs where heat from the heart and pneuma from the air were added, producing an ultimate concoction of “vital spirits” that was carried in the arteries to all parts of the body. It was not until the work of the English physician William Harvey (1578–1657) that answers to the mysteries of the circulation began to emerge. It was he who first proposed that blood traveled in a circuitous route through the body, being pumped by the active phase of the heart’s contraction, not relaxation as had previously been believed. In his studies, Harvey showed that a cut artery in an animal spurts during the heart’s contraction. He also demonstrated that the atria of the heart had the same relationship to the ventricles as the ventricles do to the arteries and that blood from the heart was circulated through the lungs, where it was oxygenated. As strange as it may seem today, these concepts were so revolutionary to Harvey’s contemporaries that the world’s basic understanding of how the body functions was thrown into turmoil.

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Structure and Function of the Cardiovascular System CAROL M. PORTH AND GLENN MATFIN

ORGANIZATION OF THE CIRCULATORY SYSTEM Pulmonary and Systemic Circulations Volume and Pressure Distribution PRINCIPLES OF BLOOD FLOW Relationships Between Blood Flow, Pressure, and Resistance Resistance to Flow Velocity and Cross-Sectional Area Laminar Versus Turbulent Flow Wall Tension, Radius, and Pressure Distention and Compliance THE HEART AS A PUMP Functional Anatomy of the Heart Pericardium Myocardium Endocardium Heart Valves and Fibrous Skeleton Cardiac Cycle Ventricular Systole and Diastole Atrial Filling and Contraction Regulation of Cardiac Performance Preload Afterload Cardiac Contractility Heart Rate THE SYSTEMIC CIRCULATION AND CONTROL OF BLOOD FLOW Blood Vessels Vascular Smooth Muscle Arterial System Arterial Pressure Pulsations Venous System Local and Humoral Control of Blood Flow Short-Term Autoregulation Long-Term Regulation of Blood Flow Humoral Control of Vascular Function THE MICROCIRCULATION AND LYMPHATIC SYSTEM Structure and Function of the Microcirculation Capillary Structure and Function Control of Blood Flow in the Microcirculation 450

Capillary–Interstitial Fluid Exchange Hydrostatic Forces Osmotic Forces Balance of Hydrostatic and Osmotic Forces The Lymphatic System NEURAL CONTROL OF CIRCULATORY FUNCTION Autonomic Nervous System Regulation Autonomic Regulation of Cardiac Function Autonomic Regulation of Vascular Function Autonomic Neurotransmitters Central Nervous System Responses

➤ The main function of the circulatory system, which consists of the heart and blood vessels, is that of transport. The circulatory system delivers oxygen and nutrients needed for metabolic processes to the tissues; carries waste products from the tissues to the kidneys and other excretory organs for elimination; and circulates electrolytes and hormones needed to regulate body function. It also plays an important role in body temperature regulation, which relies on the circulatory system for transport of core heat to the periphery, where it can be dissipated into the external environment.

ORGANIZATION OF THE CIRCULATORY SYSTEM After completing this section of the chapter, you should be able to meet the following objectives: ■

■

Compare the function and distribution of blood flow and blood pressure in the systemic and pulmonary circulations. State the relation between blood volume and blood pressure in arteries, veins, and capillaries of the circulatory system.

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Pulmonary and Systemic Circulations The circulatory system can be divided into two parts: the pulmonary circulation, which moves blood through the lungs and creates a link with the gas-exchange function of the respiratory system, and the systemic circulation, which supplies all the other tissues of the body (Fig. 21-1). The blood that is in the heart and pulmonary circulation is sometimes referred to as the central circulation and that outside the central circulation as the peripheral circulation. The pulmonary circulation consists of the right heart, the pulmonary artery, the pulmonary capillaries, and the pulmonary veins. The large pulmonary vessels are unique in that the pulmonary artery is the only artery that carries venous blood and the pulmonary veins, the only veins that carry arterial blood. The systemic circulation consists of the left heart, the aorta and its branches, the capillaries that supply the brain and peripheral tissues, and the systemic venous system and the vena cava. The veins from the lower portion of the body merge to form the inferior vena cava and those from the head and upper extremities merge to form the superior vena cava, both of which empty into the right heart.

Head and upper limbs Systemic circuit Lungs

Pulmonary circuit

Heart

Systemic circuit

Digestive tract

Kidneys

Trunk and lower limbs

FIGURE 21-1 • Systemic and pulmonary circulations. The right side of the heart pumps blood to the lungs, and the left side of the heart pumps blood to the systemic circulation.

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FUNCTIONAL ORGANIZATION OF THE CIRCULATORY SYSTEM ■

■

■

■

The circulatory system consists of the heart, which pumps blood; the arterial system, which distributes oxygenated blood to the tissues; the venous system, which collects deoxygenated blood from the tissues and returns it to the heart; and the capillaries, where exchange of gases, nutrients, and wastes takes place. The circulatory system is divided into two parts: the low-pressure pulmonary circulation, linking circulation and gas exchange in the lungs, and the highpressure systemic circulation, providing oxygen and nutrients to the tissues. Blood flows down a pressure gradient from the highpressure arterial circulation to the low-pressure venous circulation. The circulation is a closed system, so the output of the right and left heart must be equal over time for effective functioning of the circulation.

Although the pulmonary and systemic circulations function similarly, they have some important differences. The pulmonary circulation, which is located in the chest and near the heart, is the smaller of the two circulations and functions as a low-pressure system with a mean arterial pressure of approximately 12 mm Hg. The low pressure of the pulmonary circulation allows blood to move through the lungs more slowly, which is important for gas exchange. In contrast, the systemic circulation, which must transport blood to distant parts of the body, often against the effects of gravity, functions as a high-pressure system, with a mean arterial pressure of 90 to 100 mm Hg. The heart, which propels blood through the circulatory system, consists of two pumps in series—the right heart, which propels blood through the gas-exchange vessels in the lungs, and the left heart, which propels blood through the vessels that supply all the other tissues in the body. Both sides of the heart are further divided into two chambers, an atrium and a ventricle. The atria function as collection chambers for blood returning to the heart and as auxiliary pumps that assist in filling the ventricles. The ventricles are the main pumping chambers of the heart. The right ventricle pumps blood through the pulmonary artery to the lungs and the left ventricle pumps blood through the aorta into the systemic circulation. The ventricular chambers of the right and left heart have inlet valves and outlet valves that act reciprocally (i.e., one set of valves is open while the other is closed) to control the direction of blood flow through the cardiac chambers. Because it is a closed system, the effective function of the circulatory system requires that the outputs of both sides of the

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heart must pump the same amount of blood over time. If the output of the left heart were to fall below that of the right heart, blood would accumulate in the pulmonary circulation. Likewise, if the right heart were to pump less effectively than the left heart, blood would accumulate in the systemic circulation. However, the left and right heart seldom ejects exactly the same amount of blood with each beat. This is because blood return to the heart is affected by activities of daily living such as taking a deep breath or moving from the seated to standing position. These beat-by-beat variations in cardiac output are accommodated by the large storage capabilities of the venous system that allow for temporary changes in blood volume. The accumulation of blood occurs only when the storage capacity of the venous system has been exceeded.

Volume and Pressure Distribution Blood flow in the circulatory system depends on a blood volume that is sufficient to fill the blood vessels and a pressure difference across the system that provides the force to move blood forward. The total blood volume is a function of age and body weight, ranging from 85 to 90 mL/kg in the neonate and from 70 to 75 mL/kg in the adult. As shown in Figure 21-2, approximately 4% of the blood at any given time is in the left heart, 16% is in the arteries and arterioles, 4% is in the capillaries, 64% is in the venules and veins, and 4% is in the right heart. The arteries and arterioles, which have thick, elastic walls and function as a distribution system, have the highest pressure. The capillaries are small, thin-walled vessels that link the arterial and venous sides of the circulation. Because of their small size and large surface area, the capillaries contain the smallest amount of blood. The venules and veins, which contain the largest amount of blood, are thin-walled, distensible vessels that function as a reservoir to collect blood from the capillaries and return it to the right heart.

Blood moves from the arterial to the venous side of the circulation along a pressure gradient, moving from an area of higher pressure to one of lower pressure. The pressure distribution in the different parts of the circulation is almost an inverse of the volume distribution (see Fig. 21-2). Thus, the pressure in the arterial side of the systemic circulation, which contains only approximately one sixth of the blood volume, is much greater than the pressure on the venous side of the circulation, which contains approximately two thirds of the blood. This pressure and volume distribution is due in large part to the structure and relative elasticity of the arteries and veins. It is the pressure difference between the arterial and venous sides of the circulation (approximately 84 mm Hg) that provides the driving force for flow of blood in the systemic circulation. The pulmonary circulation has a similar arterial–venous pressure difference, albeit of a lesser magnitude, that facilitates blood flow. Because the pulmonary and systemic circulations are connected and function as a closed system, blood can be shifted from one circulation to the other. In the pulmonary circulation, the blood volume, which approximates 450 mL in the average-size adult, can vary from as low as 50% of normal to as high as 200% of normal. An increase in intrathoracic pressure, which impedes venous return to the right heart, can produce a transient shift from the pulmonary to the systemic circulation of as much as 250 mL of blood. Body position also affects the distribution of blood volume. In the recumbent position, approximately 25% to 30% of the total blood volume is in the central circulation. On standing, this blood is rapidly displaced to the lower part of the body due to the forces of gravity. Because the volume of the systemic circulation is approximately seven times that of the pulmonary circulation, a shift of blood from one system to the other has a much greater effect in the pulmonary than in the systemic circulation.

Pressure (mm Hg)

120 100 80 60 40 20 0

Lt. Aorta vent.

Lg. art.

Sm. art.

Arterioles

Caps.

Rt. Pul. vent. art.

64%

60 Total blood volume (%)

Veins

FIGURE 21-2 • Pressure and volume dis-

40 20

16% 4%

0

4%

4%

tribution in the systemic circulation. The graphs show the inverse relation between internal pressure and volume in different portions of the circulatory system. (From Smith J. J., Kampine J. P. [1990]. Circulatory physiology: The essentials [3rd ed.]. Baltimore: Williams & Wilkins.)

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IN SUMMARY,

the circulatory system functions as a transport system that circulates nutrients and other materials to the tissues and removes waste products. The circulatory system can be divided into two parts: the pulmonary circulation and the systemic circulation. The heart pumps blood throughout the system, and the blood vessels serve as tubes through which blood flows. The arterial system carries blood from the heart to the tissues and the veins carry it back to the heart. The cardiovascular system is a closed system with a right and left heart connected in series. The systemic circulation, which is served by the left heart, provides blood flow for all the tissues except the lungs, which are served by the right heart and the pulmonary circulation. Blood moves throughout the circulation along a pressure gradient, moving from the high-pressure arterial system to the low-pressure venous system. In the circulatory system, pressure is inversely related to volume. The pressure on the arterial side of the circulation, which contains only approximately one sixth of the blood volume, is much greater than the pressure on the venous side of the circulation, which contains approximately two thirds of the blood. ■

PRINCIPLES OF BLOOD FLOW After completing this section of the chapter, you should be able to meet the following objectives: ■

■ ■

Define the term hemodynamics and describe the effects of blood pressure, vessel radius, vessel length, vessel cross-sectional area, and blood viscosity on blood flow. Use the law of Laplace to explain the effect of radius size on the pressure and wall tension in a vessel. Use the term compliance to describe the characteristics of arterial and venous blood vessels.

The term hemodynamics refers to the principles that govern blood flow in the circulatory system. These basic principles of physics are the same as those applied to the movement of fluid in general. The concepts of flow, pressure, resistance, and capacitance as applied to blood flow in the cardiovascular system will be used in subsequent chapters to describe the hemodynamic changes that occur with disorders of the cardiovascular system.

Relationships Between Blood Flow, Pressure, and Resistance The most important factors governing the flow of blood in the cardiovascular system are pressure, resistance, and flow. Blood flow (F) through a vessel or series of blood vessels is determined by the pressure difference (ΔP) between the two ends of a vessel (the inlet and the outlet) and the resistance (R) that

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blood must overcome as it moves through the vessel (F = ΔP/R). In the cardiovascular system, blood flow is represented by the cardiac output. Resistance is the opposition to flow caused by friction between the moving blood and the stationary vessel wall. In the peripheral circulation, the collective resistance of all the vessels in that part of the circulation is referred to as the peripheral vascular resistance (PVR) or, sometimes, as the systemic vascular resistance. The flow, pressure, and resistance relationships also can be applied on a smaller scale to determine the blood flow and resistance to flow of a single organ.

Resistance to Flow The blood vessels and the blood itself constitute resistance to flow. A helpful equation for understanding the relationship between resistance, blood vessel diameter (radius), and blood viscosity factors that affect blood flow was derived by the French physician Poiseuille more than a century ago. The equation F = ΔP (pressure) × π × r (radius)4/8 × L (length) × η (viscosity) expands on the previous equation, F = ΔP/R, by relating flow to several determinants of resistance—vessel radius and blood viscosity. The length of vessels does not usually change and 8 is a constant that does not change. Because flow is directly related to the fourth power of the radius, small changes in vessel radius can produce large changes in flow to an organ or tissue. For example, if the pressure remains constant, the rate of flow is 16 times greater in a vessel with a radius of 2 mm (2 × 2 × 2 × 2) than in a vessel with a radius of 1 mm. The total resistance offered by a set of blood vessels also depends on whether the vessels are arranged in series, in which blood flows sequentially from one vessel to another, or arranged in parallel, in which the total blood flow is distributed simultaneously among parallel vessels. Viscosity is the resistance to flow caused by the friction of molecules in a fluid. The viscosity of a fluid is largely related to its thickness. The more particles that are present in a solution, the greater the frictional forces that develop between the molecules. Unlike water that flows through plumbing pipes, blood is a nonhomogeneous liquid. It contains blood cells, platelets, fat globules, and plasma proteins that increase its viscosity. The red blood cells, which constitute 40% to 45% of the formed elements of the blood, largely determine the viscosity of the blood. Under special conditions, temperature may affect viscosity. There is a 2% rise in viscosity for each 1°C decrease in body temperature, a fact that helps explain the sluggish blood flow seen in persons with hypothermia.

Velocity and Cross-Sectional Area Velocity is a distance measurement; it refers to the rate of displacement of a particle of fluid with respect to time (centimeters per second). Flow is a volume measurement. It refers to the displacement of a volume of fluid with respect to time (mL/second); it is determined by the cross-sectional area of a vessel and the velocity of flow. When the flow through a given segment of the circulatory system is constant—as it must be for continuous flow—the velocity is inversely proportional to the cross-sectional area of the vessel (i.e., the smaller the cross-sectional area, the

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Unit VIII Wording of Unit Title

Understanding • The Hemodynamics of Blood Flow The term hemodynamics is used to describe factors such as (1) pressure and resistance, (2) vessel radius, (3) cross-sectional area and velocity of flow, and (4) laminar versus turbulent flow that affect blood flow through the blood vessels in the body.

❶

Pressure difference

Pressure, Resistance, and Flow

The flow (F) of fluid through a tube, such as blood through a blood vessel, is directly related to a pressure difference (P1 – P2) between the two ends of the tube and inversely proportional to the resistance (R) that the fluid encounters as it moves through the tube. The resistance to flow, in peripheral resistance units (PRU), is determined by the blood viscosity, vessel radius, and whether the vessels are aligned in series or in parallel. In vessels aligned in series, blood travels sequentially from one vessel to another such that the resistance becomes additive (e.g., 2 + 2 + 2 = 6 PRU). In vessels aligned in parallel, such as capillaries, the blood is not confined to a single channel but can travel through each of several parallel channels such that the resistance becomes the reciprocal of the total resistance (i.e., 1/R). As a result, there is no loss of pressure, and the total resistance (e.g., 1/2 + 1/2 +1/2 = 3/2 PRU) is less than the resistance of any of the channels (i.e., 2) taken separately.

Flow

P1

P2

Resistance

P1 Flow

P2

Pi

Po

R1

R2

R3

Series

R1

Pi

R2

Po

Flow R3

Parallel

Pi, pressure in; Po, pressure out.

❷

1 mm

Vessel Radius

In addition to pressure and resistance, the rate of blood flow through a vessel is affected by the fourth power of its radius (the radius multiplied by itself four times). Thus, blood flow in vessel B with a radius of 2 mm will be 16 times greater than in vessel A with a radius of 1 mm.

1 mL/min Vessel A 2 mm 16 mL/min

Vessel B

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❸

Cross-sectional Area and Velocity of Flow

The velocity or rate of forward movement of the blood is affected by the cross-sectional area of a blood vessel. As the cross-sectional area of a vessel increases (sections 1 and 3), blood must flow laterally as well as forward to fill the increased area. As a result, the mean forward velocity decreases. In contrast, when the cross-sectional area is decreased (section 2), the lateral flow decreases and the mean forward velocity is increased.

❹

Laminar and Turbulent Flow

Blood flow is normally laminar, with platelets and blood cells remaining in the center or axis of the bloodstream. Laminar blood flow can be described as layered flow in which a thin layer of plasma adheres to the vessel wall, while the inner layers of blood cells and platelets shear against this motionless layer. This allows each layer to move at a slightly faster velocity, with the greatest velocity occurring in the central part of the bloodstream. Turbulent blood flow is flow in which the blood elements do not remain confined to a definite lamina or layer, but develop vortices (i.e., a whirlpool effect) that push blood cells and platelets against the wall of the vessel. More pressure is required to force a given flow of blood through the same vessel (or heart valve) when the flow is turbulent rather than laminar. Turbulence can result from an increase in velocity of flow, a decrease in vessel diameter, or low blood viscosity. Turbulence is usually accompanied by vibrations of the fluid and surrounding structures. Some of these vibrations in the cardiovascular system are in the audible frequency range and may be detected as murmurs or bruits.

greater the velocity of flow). This phenomenon can be compared with cars moving from a two-lane to a single-lane section of a highway. To keep traffic moving at its original pace, cars would have to double their speed in the single-lane section of the highway. So it is with blood flow in the circulatory system. The linear velocity of blood flow in the circulatory system varies widely from 30 to 35 cm/second in the aorta to 0.2 to 0.3 mm/second in the capillaries. This is because even though each individual capillary is very small, the total cross-sectional area of all the systemic capillaries greatly exceeds the crosssectional area of other parts of the circulation. As a result of this large surface area, the slower movement of blood allows ample time for exchange of nutrients, gases, and metabolites between the tissues and the blood.

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Velocity

Crosssectional area

1

2

3

Laminar flow

Turbulent flow

Laminar Versus Turbulent Flow Ideally, blood flow is laminar or streamlined, with the blood components arranged in layers so that the plasma is adjacent to the smooth, slippery endothelial surface of the blood vessel, and the blood elements, including the platelets, are in the center or axis of the bloodstream. This arrangement reduces friction by allowing the blood layers to slide smoothly over one another, with the axial layer having the most rapid rate of flow. Under certain conditions, blood flow switches from laminar to turbulent flow. In turbulent flow, the laminar stream is disrupted and the fluid particles become mixed radially (crosswise) and axially (lengthwise). Because energy is wasted in propelling blood both radially and axially, more energy (pressure) is required to drive turbulent flow than laminar flow.

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Turbulent flow can be caused by a number of factors, including high velocity of flow, change in vessel diameter, and low blood viscosity. The tendency for turbulence to occur is increased in direct proportion to the velocity of flow. Low blood viscosity allows the blood to move faster and accounts for the transient occurrence of heart murmurs in some persons who are severely anemic. Turbulence is often accompanied by vibrations of the blood and surrounding structures. Some of these vibrations are in the audible range and can be heard using a stethoscope. For example, a heart murmur results from turbulent flow through a diseased heart valve. Turbulent flow may also predispose to clot formation as platelets and other coagulation factors come in contact with the endothelial lining of the vessel.

Wall Tension, Radius, and Pressure In a blood vessel, wall tension is the force in the vessel wall that opposes the distending pressure inside the vessel. The French astronomer and mathematician Pierre de Laplace described the relationship between wall tension, pressure, and the radius of a vessel or sphere more than 200 years ago. This relationship, which has come to be known as the law of Laplace, can be expressed by the equation, P = T/r, in which T is wall tension, P is the intraluminal pressure, and r is vessel radius (Fig. 21-3A). Accordingly, the internal pressure expands the vessel until it is exactly balanced by the tension in the vessel wall. The smaller the radius, the greater the pressure needed to balance the wall tension. The law of Laplace can also be used to express the effect of the radius on wall tension (T = P × r). This correlation can be

P

T

P

T

A

compared with a partially inflated balloon (see Fig. 21-3B). Because the pressure in the balloon is equal throughout, the tension in the section with the smaller radius is less than the tension in the section with the larger radius. The same principle holds true for an arterial aneurysm, in which the tension and risk of rupture increase as the aneurysm grows (see Chapter 22). The law of Laplace was later expanded to include wall thickness (T = P × r/wall thickness). Thus, wall tension is inversely related to wall thickness, such that the thicker the vessel wall, the lower the tension, and vice versa. In hypertension, arterial vessel walls hypertrophy and become thicker, thereby reducing the tension and minimizing wall stress. The law of Laplace can also be applied to the pressure required to maintain the patency of small blood vessels. Providing that the thickness of a vessel wall remains constant, it takes more pressure to overcome wall tension and keep a vessel open as its radius decreases in size. The critical closing pressure refers to the point at which blood vessels collapse so that blood can no longer flow through them. For example, in circulatory shock there is a decrease in blood volume and vessel radii, along with a drop in blood pressure. As a result, many of the small blood vessels collapse as blood pressure drops to the point where it can no longer overcome the wall tension. The collapse of peripheral veins often makes it difficult to insert venous lines that are needed for fluid and blood replacement.

Distention and Compliance Compliance refers to the total quantity of blood that can be stored in a given portion of the circulation for each millimeter of mercury (mm Hg) rise in pressure. Compliance reflects the distensibility of the blood vessel. The distensibility of the aorta and large arteries allows them to accommodate the pulsatile output of the heart. The most distensible of all vessels are the veins, which can increase their volume with only slight changes in pressure, allowing them to function as a reservoir for storing large quantities of blood that can be returned to the circulation when it is needed. The compliance of a vein is approximately 24 times that of its corresponding artery because it is 8 times as distensible and has a volume 3 times as great.

Radius

IN SUMMARY,

Tension = Pressure × radius

B FIGURE 21-3 • The law of Laplace relates pressure (P), tension (T), and radius in a cylindrical blood vessel. (A) The pressure expanding the vessel is equal to the wall tension divided by the vessel radius. (B) Effect of the radius of a cylindrical balloon on tension. In a balloon, the tension in the wall is proportional to the radius because the pressure is the same everywhere inside the balloon. The tension is lower in the portion of the balloon with the smaller radius. (From Rhoades R. A., Tanner G. A. [1996]. Medical physiology [p. 627]. Boston: Little, Brown.)

blood flow is influenced by the pressure difference between the two ends of the vessel, the vessel length, its radius and cross-sectional area, the viscosity of the blood, and tension of the vessel wall. The rate of flow is directly related to the pressure difference between the two ends of the vessel and the vessel radius and inversely related to vessel length and blood viscosity. The cross-sectional area of a vessel influences the velocity of flow; as the cross-sectional area decreases, the velocity is increased, and vice versa. Laminar blood flow is flow in which there is layering of blood components in the center of the bloodstream. This reduces frictional forces and prevents clotting factors from coming in contact with the vessel wall. In contrast to laminar flow, turbulent flow is disordered flow, in which the blood moves crosswise and lengthwise in blood ves-

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Chapter 21 Structure and Function of the Cardiovascular System sels. The relation between wall tension, transmural pressure, and radius is described by the law of Laplace, which states that the pressure needed to overcome wall tension becomes greater as the radius decreases. Wall tension is also affected by wall thickness; it increases as the wall becomes thinner and decreases as the wall becomes thicker. Compliance, which reflects the distensibility of blood vessels, refers to the total quantity of blood that can be stored in a given part of the circulatory system for each mm Hg rise in pressure. ■

THE HEART ■

■

THE HEART AS A PUMP After completing this section of the chapter, you should be able to meet the following objectives: ■

■

■ ■

■

Describe the structural components and function of the pericardium, myocardium, endocardium, and the heart valves and fibrous skeleton. Draw a figure of the cardiac cycle, incorporating the volume, pressure, phonocardiographic, and electrocardiographic changes that occur during atrial and ventricular systole and diastole. Define the terms preload and afterload. State the formula for calculating the cardiac output and explain the effects that venous return, cardiac contractility, and heart rate have on cardiac output. Describe the cardiac reserve and relate it to the FrankStarling mechanism.

The heart is a four-chambered muscular pump approximately the size of a man’s fist that beats an average of 70 times each minute, 24 hours each day, 365 days each year for a lifetime. In 1 day, this pump moves more than 1800 gallons of blood throughout the body, and the work performed by the heart over a lifetime would lift 30 tons to a height of 30,000 feet.

Functional Anatomy of the Heart The heart is located between the lungs in the mediastinal space of the intrathoracic cavity in a loose-fitting sac called the pericardium. It is suspended by the great vessels, with its broader side (i.e., base) facing upward and its tip (i.e., apex) pointing downward, forward, and to the left. The heart is positioned obliquely, so that the right side of the heart is almost fully in front of the left side of the heart, with only a small portion of the lateral left ventricle on the frontal plane of the heart (Fig. 21-4). When the hand is placed on the thorax, the main impact of the heart’s contraction is felt against the chest wall at a point between the fifth and sixth ribs, a little below the nipple and approximately 3 inches to the left of the midline. This is called the point of maximum impulse. The wall of the heart is composed of an outer epicardium, which lines the pericardial cavity; the myocardium or muscle

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■

■

■

■

The heart is a four-chambered pump consisting of two atria (the right atrium, which receives blood returning to the heart from the systemic circulation, and the left atrium, which receives oxygenated blood from the lungs) and two ventricles (a right ventricle, which pumps blood to the lungs, and a left ventricle, which pumps blood into the systemic circulation). Heart valves control the direction of blood flow from the atria to the ventricles (the atrioventricular valves), from the right side of the heart to the lungs (pulmonic valve), and from the left side of the heart to the systemic circulation (aortic valve). The myocardium, or muscle layer of the atria and ventricles, produces the pumping action of the heart. Intercalated disks between cardiac muscle cells contain gap junctions that allow for immediate communication of electrical signals from one cell to another so the cardiac muscle acts as a single unit, or syncytium. The cardiac cycle is divided into two major periods: systole, when the ventricles are contracting, and diastole, when the ventricles are relaxed and filling. The cardiac output or amount of blood that the heart pumps each minute is determined by the amount of blood pumped with each beat (stroke volume) and the number of times the heart beats each minute (heart rate). Cardiac reserve refers to the maximum percentage of increase in cardiac output that can be achieved above the normal resting level. The work of the heart is determined by the volume of blood it pumps out (preload) and the pressure that it must generate to pump the blood out of the heart (afterload).

layer; and the smooth endocardium, which lines the chambers of the heart (Fig. 21-5). A fibrous skeleton supports the valvular structures of the heart. The interatrial and interventricular septa divide the heart into a right and a left pump, each composed of two muscular chambers: a thin-walled atrium, which serves as a reservoir for blood coming into the heart, and a thick-walled ventricle, which pumps blood out of the heart. The increased thickness of the left ventricular wall results from the additional work this ventricle is required to perform.

Pericardium The pericardium forms a fibrous covering around the heart, holding it in a fixed position in the thorax and providing physical protection and a barrier to infection. The pericardium consists of a tough, outer fibrous layer and a thin, inner serous layer. The outer fibrous layer is attached to the great vessels

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External jugular vein

Internal jugular vein

Subclavian vein

B Superior vena cava

Aortic arch

Right atrium

Left atrium

Left coronary artery

Right ventricle Pleura

Right coronary artery

Pericardium

Left ventricle

Posterior

A

Left ventricle

Right ventricle Interventricular septum

C

Anterior

FIGURE 21-4 • (A) Anterior view of the heart, lungs, and great vessels (note that the lungs, which normally fold over part of the heart’s anterior, have been pulled back). (B) The heart in relation to the sternum, ribs, and lungs. (C) Cross-section of the heart showing the increased thickness of the left ventricle compared with the right.

that enter and leave the heart, the sternum, and the diaphragm. The fibrous pericardium is highly resistant to distention; it prevents acute dilation of the heart chambers and exerts a restraining effect on the left ventricle. The inner serous layer consists of a visceral layer and a parietal layer. The visceral layer, also known as the epicardium, covers the entire heart and great vessels and then folds over to form the parietal layer that lines the fibrous pericardium (see Fig. 21-5). Between the visceral and parietal layers is the pericardial cavity, a potential space that

contains 30 to 50 mL of serous fluid. This fluid acts as a lubricant to minimize friction as the heart contracts and relaxes.

Myocardium The myocardium, or muscular portion of the heart, forms the wall of the atria and ventricles. Cardiac muscle cells, like skeletal muscle, are striated and composed of sarcomeres that contain actin and myosin filaments (see Chapter 4). They are smaller and

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Chapter 21 Structure and Function of the Cardiovascular System Pericardial cavity

Fibrous pericardium

Muscle fiber

459

Nucleus

Myocardium Striations

Endocardium

Intercalated disk

A

Parietal pericardium Visceral pericardium (epicardium)

FIGURE 21-5 • Layers of the heart, showing the visceral pericardium, pericardial cavity, parietal pericardium, fibrous pericardium, myocardium, and endocardium.

more compact than skeletal muscle cells and contain many large mitochondria, reflecting their continuous energy needs. The contractile properties of cardiac muscle are similar to those of skeletal muscle, except the contractions are involuntary and the duration of contraction is much longer. Unlike the orderly longitudinal arrangement of skeletal muscle fibers, cardiac muscle cells are arranged as an interconnecting latticework, with their fibers dividing, recombining, and then dividing again (Fig. 21-6A). The fibers are separated from neighboring cardiac muscle cells by dense structures called intercalated disks. The intercalated disks, which are unique to cardiac muscle, contain gap junctions that serve as low-resistance pathways for passage of ions and electrical impulses from one cardiac cell to another (see Fig. 21-6B). Thus, the myocardium behaves as a single unit, or syncytium, rather than as a group of isolated units, as does skeletal muscle. When one myocardial cell becomes excited, the impulse travels rapidly so the heart can beat as a unit. As in skeletal muscle, cardiac muscle contraction involves actin and myosin filaments, which interact and slide along one another during muscle contraction. A number of important proteins regulate actin–myosin binding. These include tropomyosin and the troponin complex (see Chapter 4, Fig. 4-22). The troponin complex consists of three subunits (troponin T, troponin I, and troponin C) that regulate calcium-mediated contraction in striated muscle. In clinical practice, the measurement of serum levels of the cardiac forms of troponin T and troponin I are used in the diagnosis of myocardial infarction (see Chapter 24). Although cardiac muscle cells require calcium for contraction, they have a less well-defined sarcoplasmic reticulum for storing calcium than skeletal muscle cells. Thus, cardiac muscle relies more heavily than skeletal muscle on an influx of extracellular calcium ions for contraction. The cardiac glycosides (e.g., digoxin) are inotropic drugs that increase cardiac

B Longitudinal portion (contains large gap junctions)

FIGURE 21-6 • (A) Cardiac muscle fibers, showing their branching structure. (B) Area indicated where cell junctions lie in the intercalated disks.

contractility by increasing the free calcium concentration in the vicinity of the actin and myosin filaments.

Endocardium The endocardium is a thin, three-layered membrane that lines the heart. The innermost layer consists of smooth endothelial cells supported by a thin layer of connective tissue. The endothelial lining of the endocardium is continuous with the lining of the blood vessels that enter and leave the heart. The middle layer consists of dense connective tissue with elastic fibers. The outer layer, composed of irregularly arranged connective tissue cells, contains blood vessels and branches of the conduction system and is continuous with the myocardium.

Heart Valves and Fibrous Skeleton An important structural feature of the heart is its fibrous skeleton, which consists of four interconnecting valve rings and surrounding connective tissue. It separates the atria and ventricles and forms a rigid support for attachment of the valves and insertion of the cardiac muscle (Fig. 21-7). The tops of the valve rings are attached to the muscle tissue of the atria, pulmonary trunks, and aorta. The bottoms are attached to the ventricular walls. For the heart to function effectively, blood flow must occur in a one-way direction, moving in a forward (antegrade) manner through the chambers of the right heart to the lungs and then through the chambers of the left heart to the systemic

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Tricuspid valve

Mitral valve

valve, located between the left ventricle and the aorta, controls the flow of blood into the systemic circulation. Because their flaps are shaped like half-moons, they are often referred to as the semilunar valves. The semilunar valves have three cuplike cusps that are attached to the valve rings (Fig. 21-10B). These cuplike structures collect the retrograde, or backward, flow of blood that occurs toward the end of systole, enhancing closure. For the development of a perfect seal along the free edges of the semilunar valves, each valve cusp must have a triangular shape, which is facilitated by a nodular thickening at the apex of each leaflet (see Fig. 21-10A). Behind the semilunar valves are the sinuses of Valsalva. In these sinuses, eddy currents develop that tend to keep the valve cusps away from the vessel walls. The openings for the coronary arteries are located behind the right and left cusps, respectively, of the aortic valve. Were it not for the presence of the sinuses of Valsalva and the eddy currents, the coronary artery openings would be blocked by the valve cusps. There are no valves at the atrial sites (i.e., venae cavae and pulmonary veins) where blood enters the heart. This means that excess blood is pushed back into the veins when the atria become distended. For example, the jugular veins typically become prominent in severe right-sided heart failure when they normally should be flat or collapsed. Likewise, the pulmonary venous system becomes congested when outflow from the left atrium is impeded.

Cardiac Cycle Aortic valve

Coronary arteries

Pulmonic valve

FIGURE 21-7 • Fibrous skeleton of the heart, which forms the four interconnecting valve rings and support for attachment of the valves and insertion of cardiac muscle.

circulation (Fig. 21-8). This unidirectional flow is provided by the heart’s two atrioventricular (i.e., tricuspid and mitral) valves and two semilunar (i.e., pulmonary and aortic) valves. The atrioventricular (AV) valves control the flow of blood between the atria and the ventricles. The thin edges of the AV valves form cusps, two on the left side of the heart (i.e., bicuspid valve) and three on the right side (i.e., tricuspid valve). The bicuspid valve is also known as the mitral valve. The AV valves are supported by the papillary muscles, which project from the wall of the ventricles, and the chordae tendineae, which attach to the valve (Fig. 21-9). Contraction of the papillary muscles at the onset of systole ensures closure by producing tension on the leaflets of the AV valves before the full force of ventricular contraction pushes against them. The chordae tendineae are cordlike structures that support the AV valves and prevent them from everting into the atria during systole. The aortic and pulmonic valves control the movement of blood out of the ventricles. The pulmonic valve, which is located between the right ventricle and the pulmonary artery, controls the flow of blood into the pulmonary circulation, and the aortic

The term cardiac cycle is used to describe the rhythmic pumping action of the heart. The cardiac cycle is divided into two parts: systole, the period during which the ventricles are contracting, and diastole, the period during which the ventricles are relaxed and filling with blood. Simultaneous changes occur in left atrial pressure, left ventricular pressure, aortic pressure, ventricular volume, the electrocardiogram (ECG), and heart sounds during the cardiac cycle (Fig. 21-11). The electrical activity, recorded on the ECG, precedes the mechanical events of the cardiac cycle. The small, rounded P wave of the ECG represents depolarization of the sinoatrial node (i.e., pacemaker of the heart), the atrial conduction tissue, and the atrial muscle mass. The QRS complex registers the depolarization of the ventricular conduction system and the ventricular muscle mass. The T wave on the ECG occurs during the last half of systole and represents repolarization of the ventricles. The cardiac conduction system and the ECG are discussed in detail in Chapter 25.

Ventricular Systole and Diastole Ventricular systole is divided into two periods: the isovolumetric contraction period and the ejection period. The isovolumetric contraction period, which begins with closure of the AV valves and occurrence of the first heart sound, heralds the onset of systole. Immediately after closure of the AV valves, there is an additional 0.02 to 0.03 second during which the semilunar (pulmonary and aortic) valves remain closed. During

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Superior vena cava

Right pulmonary artery

Left pulmonary artery

Pulmonic valve Pulmonary veins Pulmonary veins

Left atrium Aortic valve

Right atrium

Mitral valve Chordae tendineae

Tricuspid valve

FIGURE 21-8 • Valvular structures of the heart. Arrows show the course of blood flow through the heart chambers. The atrioventricular valves are in an open position, and the semilunar valves are closed. There are no valves to control the flow of blood at the inflow channels (i.e., vena cava and pulmonary veins) to the heart. (Modified from Smeltzer S. C., Bare B. G. [2004]. Brunner and Suddarth’s textbook of medical-surgical nursing [10th ed., p. 648]. Philadelphia: Lippincott Williams & Wilkins.)

Left ventricle Right ventricle Inferior vena cava Papillary muscles

Mitral valve cusps Open Closed

Chordae tendineae Slack Taut

Papillary muscle Relaxed Contracted

A Mitral valve open

Papillary muscles

B Mitral valve closed

FIGURE 21-9 • The mitral (atrioventricular) valve showing the papillary muscles and chordae tendineae. (A) The open mitral valve with relaxed papillary muscles and slack chordae tendineae. (B) The closed mitral valve with contracted papillary muscles and taut chordae tendineae that prevent the valve cusps from everting into the atria.

Descending aorta

this period (see Fig. 21-11), the ventricular pressures rise abruptly because both the AV and semilunar valves are closed and no blood is leaving the ventricles. The ventricles continue to contract until left ventricular pressure is slightly higher than aortic pressure and right ventricular pressure is higher than pulmonary artery pressure. At this point, the semilunar valves open, signaling the onset of the ejection period. Approximately 60% of the stroke volume is ejected during the first quarter of systole, and the remaining 40% is ejected during the next two quarters of systole. Little blood is ejected from the heart during the last quarter of systole, although the ventricle remains contracted. At the end of systole, the ventricles relax, causing a precipitous fall in intraventricular pressures. As this occurs, blood from the large arteries flows back toward the ventricles, causing the aortic and pulmonic valves to snap shut—an event that is marked by the second heart sound. The aortic pressure reflects changes in the ejection of blood from the left ventricle. There is a rise in pressure and stretching of the elastic fibers in the aorta as blood is ejected into the aorta at the onset of systole. The aortic pressure continues to rise and then begins to fall during the last quarter of systole as blood flows out of the aorta into the peripheral vessels. The incisura, or notch, in the aortic pressure tracing represents closure of the aortic valve. The aorta is highly elastic and as such stretches during systole to accommodate the blood that is being ejected from the left heart. During diastole, recoil of the elastic fibers in the aorta serves to maintain the aortic pressure. Diastole is marked by ventricular relaxation and filling. After closure of the semilunar valves, the ventricles continue to

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Wall of aorta Orifices of coronary arteries

Nodule at apex Line of thickening Valve leaflet

A

Left ventricle

B

relax for another 0.03 to 0.06 second. During this time, which is referred to as the isovolumetric relaxation period, both the semilunar and AV valves remain closed and the ventricular volume remains the same, as the ventricular pressure drops until it becomes less than the atrial pressure (see Fig. 21-11). As this occurs, the AV valves open and blood that has been accumulating in the atria during systole moves into the ventricles. Most of ventricular filling occurs during the first third of diastole, which is called the rapid filling period. During the middle third of diastole, inflow into the ventricles is almost at a standstill. The last third of diastole is marked by atrial contraction, which gives an additional thrust to ventricular filling. When audible, the third heart sound is heard during the rapid filling period of diastole as blood flows into a distended or noncompliant ventricle. The fourth heart sound occurs during the last third of diastole as the atria contract. During diastole, the ventricles increase their volume to approximately 120 mL (i.e., the end-diastolic volume), and at the end of systole, approximately 50 mL of blood (i.e., the endsystolic volume) remains in the ventricles (see Fig. 21-11). The difference between the end-diastolic and end-systolic volumes (approximately 70 mL) is called the stroke volume. The ejection fraction, which is the stroke volume divided by the end-diastolic volume, represents the fraction or percentage of the end-diastolic volume that is ejected from the heart during systole. The left ventricular ejection fraction (normally about 55% to 75% when determined by echocardiography or angiocardiography) is frequently used to evaluate the prognosis of persons with a variety of heart diseases.

Atrial Filling and Contraction There are three main atrial pressure waves that occur during the cardiac cycle—the a, c, and v waves. The a wave occurs during the last part of diastole and is caused by atrial contraction. The c wave occurs as the ventricles begin to contract and their

FIGURE 21-10 • Diagram of the aortic valve. (A) The position of the aortic valve at the base of the ascending aorta is indicated. (B) The appearance of the three leaflets of the aortic valve when the aorta is cut open and spread out, flat. (From Cormack D. H. [1987]. Ham’s histology [9th ed.]. Philadelphia: J. B. Lippincott.)

increased pressure causes the AV valves to bulge into the atria. The v wave occurs toward the end of systole when the AV valves are still closed and results from a slow buildup of blood in the atria. The right atrial pressure waves are transmitted to the internal jugular veins as pulsations. These pulsations can be observed visually and may be used to assess cardiac function. For example, exaggerated a waves occur when the volume of the right atrium is increased because of impaired emptying into the right ventricle. Because there are no valves between the junctions of the central veins (i.e., venae cavae and pulmonary veins) and the atria, atrial filling occurs during both systole and diastole. During normal quiet breathing, right atrial pressure usually varies between −2 and +2 mm Hg. It is this low atrial pressure that maintains the movement of blood from the systemic circulation into the right atrium and from the pulmonary veins into the left atrium. Right atrial pressure is regulated by a balance between the ability of the heart to move blood out of the right heart and through the left heart into the systemic circulation and the tendency of blood to flow from the peripheral circulation into the right atrium. When the heart pumps strongly, right atrial pressure is decreased and atrial filling is enhanced. Right atrial pressure is also affected by changes in intrathoracic pressure. It is decreased during inspiration when intrathoracic pressure becomes more negative, and it is increased during coughing or forced expiration when intrathoracic pressure becomes more positive. Venous return is a reflection of the amount of blood in the systemic circulation that is available for return to the right heart and the force that moves blood back to the right side of the heart. Venous return is increased when the blood volume is expanded or when right atrial pressure falls, and it is decreased in hypovolemic shock or when right atrial pressure rises. Although the main function of the atria is to store blood as it enters the heart, these chambers also act as pumps that aid in ventricular filling. This function becomes more important

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Isovolumetric relaxation period

120 Aortic valve closes

100 80

Aortic pressure 60 Aortic valve opens

40

Left ventricular pressure

20

Atrial pressure

100

Atrial contraction

Ventricular volume (mL)

80 40 R

R

P

T

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ECG Q 1st Heart sounds

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2nd 3rd

Systole

Diastole Time (sec)

Left atrium Right atrium

Left ventricle

Right ventricle Isovolumetric

A contraction

Ventricular ejection

B

Isovolumetric relaxation

Ventricular filling

C

Atrial contraction

FIGURE 21-11 • (Top) Events in the left side of the heart, showing changes in aortic pressure, left ventricular pressure, atrial pressure, left ventricular volume, the electrocardiogram (ECG), and heart sounds during the cardiac cycle. (Bottom) Position of the atrioventricular and semilunar valves during (A) isovolumetric contraction and ventricular ejection, (B) isovolumetric relaxation and ventricular filling, and (C) atrial contraction.

during periods of increased activity when the diastolic filling time is decreased because of an increase in heart rate or when heart disease impairs ventricular filling. In these two situations, the cardiac output would fall drastically were it not for the action of the atria. It has been estimated that atrial contraction can contribute as much as 30% to cardiac reserve during periods of increased need, while having little or no effect on cardiac output during rest.

Regulation of Cardiac Performance The efficiency of the heart as a pump often is measured in terms of cardiac output or the amount of blood the heart pumps each minute. The cardiac output (CO) is the product of the stroke volume (SV) and the heart rate (HR) and can be expressed by the equation: CO = SV × HR. The cardiac output varies with body size and the metabolic needs of the tissues. It increases

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with physical activity and decreases during rest and sleep. The average cardiac output in normal adults ranges from 3.5 to 8.0 L/minute. In the highly trained athlete, this value can increase to levels as high as 32 L/minute during maximum exercise. The cardiac reserve refers to the maximum percentage of increase in cardiac output that can be achieved above the normal resting level. The normal young adult has a cardiac reserve of approximately 300% to 400%. Cardiac performance is influenced by the work demands of the heart and the ability of the coronary circulation to meet its metabolic needs. The heart’s ability to increase its output according to body needs mainly depends on four factors: the preload, or ventricular filling; the afterload, or resistance to ejection of blood from the heart; cardiac contractility; and the heart rate. Heart rate and cardiac contractility are strictly cardiac factors, meaning they originate in the heart, although they are controlled by various neural and humoral mechanisms. Preload and afterload, on the other hand, are mutually dependent on the behavior of the heart and the vasculature. Not only do they determine the cardiac output, they are themselves determined by the cardiac output and certain vascular characteristics.

LVED pressure (mm Hg) 0

10

20

30

40

50

A

10 Cardiac output (L/min)

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B

6

4

2

Overlap

Optimal

Overstretched

Preload The preload represents the volume work of the heart. It is called the preload because it is the work or load imposed on the heart before the contraction begins. Preload represents the amount of blood that the heart must pump with each beat and is largely determined by the venous return to the heart and the accompanying stretch of the cardiac muscle fibers. The increased force of contraction that accompanies an increase in ventricular end-diastolic volume is referred to as the Frank-Starling mechanism or Starling law of the heart (Fig. 21-12). The anatomic arrangement of the actin and myosin filaments in the myocardial muscle fibers is such that the tension or force of contraction depends on the degree to which the muscle fibers are stretched just before the ventricles begin to contract. The maximum force of contraction and cardiac output is achieved when venous return produces an increase in left ventricular end-diastolic filling (i.e., preload) such that the muscle fibers are stretched about two and one-half times their normal resting length. When the muscle fibers are stretched to this degree, there is optimal overlap of the actin and myosin filaments needed for maximal contraction. The Frank-Starling mechanism allows the heart to adjust its pumping ability to accommodate various levels of venous return. Cardiac output is less when decreased filling causes excessive overlap of the actin and myosin filaments or when excessive filling causes the filaments to be pulled too far apart.

Afterload The afterload is the pressure or tension work of the heart. It is the pressure that the heart must generate to move blood into the aorta. It is called the afterload because it is the work presented to the heart after the contraction has commenced. The systemic arterial

FIGURE 21-12 • The Frank-Starling ventricular function curve in a normal heart. (Top) An increase in left ventricular end-diastolic (LVED) pressure produces an increase in cardiac output (curve B) by means of the Frank-Starling mechanism. The maximum force of contraction and increased stroke volume are achieved when diastolic filling causes the muscle fibers to be stretched about two and one-half times their resting length. In curve A, an increase in cardiac contractility produces an increase in cardiac output without a change in LVED volume and pressure. (Bottom) Stretching of the actin and myosin filaments at the different LVED filling pressures.

blood pressure is the main source of afterload work on the left heart and the pulmonary arterial pressure is the main source of afterload work on the right heart. The afterload work of the left ventricle is also increased with narrowing (i.e., stenosis) of the aortic valve. For example, in the late stages of aortic stenosis, the left ventricle may need to generate systolic pressures up to 300 mm Hg to move blood through the diseased valve.

Cardiac Contractility Cardiac contractility refers to the ability of the heart to change its force of contraction without changing its resting (i.e., diastolic) length. The contractile state of the myocardial muscle is determined by biochemical and biophysical properties that govern the actin and myosin interactions in the myocardial cells. It is strongly influenced by the number of calcium ions that are available to participate in the contractile process. An inotropic influence is one that modifies the contractile state of the myocardium independent of the Frank-Starling mechanism (see Fig. 21-12, top curve). For example, sympathetic stimulation produces a positive inotropic effect by increasing the calcium that is available for interaction between the actin

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and myosin filaments. Hypoxia exerts a negative inotropic effect by interfering with the generation of adenosine triphosphate (ATP), which is needed for muscle contraction.

Heart Rate The heart rate determines the frequency with which blood is ejected from the heart. Therefore, as the heart rate increases, cardiac output tends to increase. As the heart rate increases, the time spent in diastole is reduced, and there is less time for the ventricles to fill. At a heart rate of 75 beats per minute, one cardiac cycle lasts 0.8 second, of which approximately 0.3 second is spent in systole and approximately 0.5 second in diastole. As the heart rate increases, the time spent in systole remains approximately the same, whereas that spent in diastole decreases. This leads to a decrease in stroke volume and, at high heart rates, a decrease in cardiac output. One of the dangers of ventricular tachycardia is a reduction in cardiac output because the heart does not have time to fill adequately.

IN SUMMARY,

the heart is a four-chambered muscular pump that lies in the pericardial sac within the mediastinal space of the intrathoracic cavity. The wall of the heart is composed of an outer epicardium, which lines the pericardial cavity; a fibrous skeleton; the myocardium, or muscle layer; and the smooth endocardium, which lines the chambers of the heart. The four heart valves control the direction of blood flow. The cardiac cycle describes the pumping action of the heart. It is divided into two parts: systole, during which the ventricles contract and blood is ejected from the heart, and diastole, during which the ventricles are relaxed and blood is filling the heart. The stroke volume (approximately 70 mL) represents the difference between the end-diastolic volume (approximately 120 mL) and the end-systolic volume (approximately 50 mL). The electrical activity of the heart, as represented on the ECG, precedes the mechanical events of the cardiac cycle. The heart sounds signal the closing of the heart valves during the cardiac cycle. Atrial contraction occurs during the last third of diastole. Although the main function of the atria is to store blood as it enters the heart, atrial contraction acts to increase cardiac output during periods of increased activity when the filling time is reduced or in disease conditions in which ventricular filling is impaired. The heart’s ability to increase its output according to body needs depends on the preload, or filling of the ventricles (i.e., enddiastolic volume); the afterload, or resistance to ejection of blood from the heart; cardiac contractility, which determines the force of contraction; and the heart rate, which determines the frequency with which blood is ejected from the heart. The maximum force of cardiac contraction occurs when an increase in preload stretches muscle fibers of the heart to approximately two and one-half times their resting length (i.e., Frank-Starling mechanism). A rapid heart rate decreases the time spent in diastolic filling of the ventricles, with a resultant decrease in stroke volume. ■

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THE SYSTEMIC CIRCULATION AND CONTROL OF BLOOD FLOW After completing this section of the chapter, you should be able to meet the following objectives: ■ ■ ■

■

■

Compare the structure and function of arteries and veins. Describe the structure and function of vascular smooth muscle. Use the equation blood pressure = cardiac output × peripheral vascular resistance to explain the regulation of arterial blood pressure. Define autoregulation and characterize mechanisms responsible for short-term and long-term regulation of blood flow. Describe mechanisms involved in the humoral control of blood flow.

The vascular system functions in the delivery of oxygen and nutrients and removal of waste products from the tissues. It consists of the arteries and arterioles, the capillaries, and the venules and veins. Although blood vessels of the vascular system are often compared with a system of rigid pipes and tubes, this analogy serves only as a starting point. Blood vessels are dynamic structures that constrict and relax to adjust blood pressure and flow to meet the varying needs of the many different tissue types and organ systems. Structures such as the heart, brain, liver, and kidneys require a large and continuous flow to carry out their vital functions. In other tissues such as the skin and skeletal muscle, the need for blood flow varies with the level of function. For example, there is a need for increased blood flow to the skin during fever and for increased skeletal muscle blood flow during exercise.

Blood Vessels All blood vessels, except the capillaries, have walls composed of three layers, or coats, called tunicae (Fig. 21-13). The outermost layer of a vessel, called the tunica externa or tunica adventitia, is composed primarily of loosely woven collagen fibers that protect the blood vessel and anchor it to the surrounding structures. The middle layer, the tunica media, is largely a smooth muscle layer that constricts to regulate and control the diameter of the vessel. Larger arteries have an external elastic lamina that separates the tunica media from the tunica externa. The innermost layer, the tunica intima, consists of a single layer of flattened endothelial cells with minimal underlying subendothelial connective tissue. The endothelial layer provides a smooth and slippery inner surface for the vessel. This smooth inner lining, as long as it remains intact, prevents platelet adherence and blood clotting. The layers of the different types of blood vessels vary with vessel function. The walls of the arterioles, which control blood pressure, have large amounts of smooth muscle. Veins

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Artery

oxide (formerly known as the endothelial relaxing factor) acts locally to produce smooth muscle relaxation and regulate blood flow. These factors are discussed more fully in the section on Local and Humoral Control of Blood Flow.

Vein Tunica intima

THE VASCULAR SYSTEM AND CONTROL OF BLOOD FLOW ■

■

Tunica media

Tunica externa

Tunica media

Tunica externa

■

FIGURE 21-13 • Medium-sized artery and vein, showing the relative thicknesses of the three layers.

are thin-walled, distensible, and collapsible vessels. Capillaries are single-cell–thick vessels designed for the exchange of gases, nutrients, and waste materials.

■

Vascular Smooth Muscle Vascular smooth muscle cells, which form the predominant cellular layer in the tunica media, produce vasoconstriction or dilation of blood vessels. Smooth muscle contracts slowly and generates high forces for long periods with low energy requirements; it uses only 1/10 to 1/300 the energy of skeletal muscle. These characteristics are important in structures, such as blood vessels, that must maintain their tone day in and day out. Compared with skeletal and cardiac muscles, smooth muscle has less well-developed sarcoplasmic reticulum for storing intracellular calcium, and it has very few fast sodium channels. Depolarization of smooth muscle instead relies largely on extracellular calcium, which enters through calcium channels in the muscle membrane. Sympathetic nervous system control of vascular smooth muscle tone occurs through receptoractivated opening and closing of the calcium channels. In general, α-adrenergic receptors are excitatory in that they cause the channels to open and produce vasoconstriction, and β-adrenergic receptors are inhibitory in that they cause the channels to close and produce vasodilation. Calcium channel blocking drugs cause vasodilation by blocking calcium entry through the calcium channels. Smooth muscle contraction and relaxation also occur in response to local tissue factors such as lack of oxygen, increased hydrogen ion concentrations, and excess carbon dioxide. Nitric

■

The vascular system, which consists of the arterial system, the venous system, and the capillaries, functions in the delivery of oxygen and nutrients and in the removal of wastes from the tissues. The arterial system is a high-pressure system that delivers blood to the tissues. It relies on the intermittent ejection of blood from the left ventricle and the generation of arterial pressure pulsations or waves that move blood toward the capillaries where the exchange of gases, nutrients, and wastes occur. The venous system is a low-pressure system that collects blood from the capillaries. It relies on the presence of valves in the veins of the extremities to prevent retrograde flow and on the milking action of the skeletal muscles that surround the veins to return blood to the right heart. Local control of blood flow is regulated by mechanisms that match blood flow to the metabolic needs of the tissue. Over the short term, the tissues autoregulate flow through the synthesis of vasodilators and vasoconstrictors derived from the tissue, smooth muscle, or endothelial cells; over the long term, blood flow is regulated by creation of a collateral circulation. Neural control of circulatory function occurs through the sympathetic and parasympathetic divisions of the autonomic nervous system. Sympathetic stimulation increases heart rate, cardiac contractility, and vessel tone (vascular resistance), whereas parasympathetic stimulation decreases heart rate.

Arterial System The arterial system consists of the large and medium-sized arteries and the arterioles. Arteries are thick-walled vessels with large amounts of elastic fibers. The elasticity of these vessels allows them to stretch during systole, when the heart contracts and blood enters the circulation, and to recoil during diastole, when the heart relaxes. The arterioles, which are predominantly smooth muscle, serve as resistance vessels for the circulatory system. They act as control valves through which blood is released as it moves into the capillaries. Changes in the activity of sympathetic fibers that innervate these vessels cause them to constrict or to relax as needed to maintain blood pressure.

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Arterial Pressure Pulsations

Thoracic aorta Abdominal aorta Dorsalis pedis

Pressure (mm Hg)

The delivery of blood to the tissues of the body depends on pressure pulsations or waves of pressure that are generated by the intermittent ejection of blood from the left ventricle into the distensible aorta and large arteries of the arterial system. The arterial pressure pulse represents the energy that is transmitted from molecule to molecule along the length of the vessel (Fig. 21-14). In the aorta, this pressure pulse is transmitted at a velocity of 4 to 6 m/second, which is approximately 20 times faster than the flow of blood. Therefore, the pressure pulse has no direct relation to blood flow and could occur if there was no flow at all. When taking a pulse, it is the pressure pulses that are felt, and it is the pressure pulses that produce the Korotkoff sounds heard during blood pressure measurement. The tip or maximum deflection of the pressure pulsation coincides with the systolic blood pressure, and the minimum point of deflection coincides with the diastolic pressure. The pulse pressure is the difference between systolic and diastolic pressure. If all other factors are equal, the magnitude of the pulse pressure reflects the volume of blood ejected from the left ventricle in a single beat. Both the pressure values and the conformation of the pressure wave change as it moves though the peripheral arteries, such that pulsations in the large arteries are even greater than those in the aorta (see Fig. 21-14). In other words, systolic pressure and pulse pressure are higher in large arteries than in the aorta. The increase in pulse pressure in the “downstream” arteries is due to the fact that immediately after ejection from the left ventricle, the pressure wave travels at a higher velocity than the

Time (sec)

FIGURE 21-14 • Amplification of the arterial pressure wave as it moves forward in the peripheral arteries. This amplification occurs as a forward-moving pressure wave merges with a backward-moving reflected pressure wave. (Inset) The amplitude of the pressure pulse increases in the thoracic aorta, abdominal aorta, and dorsalis pedis.

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blood itself, augmenting the downhill pressure. Furthermore, at branch points of arteries, pressure points are reflected backward, which also tends to augment pressure at those sites. With peripheral arterial disease, there is a delay in the transmission of the reflected wave so that the pulse decreases rather than increases in amplitude. After its initial amplification, the pressure pulse becomes smaller and smaller as it moves through the smaller arteries and arterioles, until it disappears almost entirely in the capillaries. This damping of the pressure pulse is caused by the resistance and distensibility characteristics of these vessels. The increased resistance of these small vessels impedes the transmission of the pressure waves, whereas their distensibility is great enough that any small change in flow does not cause a pressure change. Although the pressure pulses usually are not transmitted to the capillaries, there are situations in which this does occur. For example, injury to a finger or other area of the body often results in a throbbing sensation. In this case, extreme dilation of the small vessels in the injured area produces a reduction in the dampening of the pressure pulse. Capillary pulsations also occur in conditions that cause exaggeration of aortic pressure pulses, such as aortic regurgitation or patent ductus arteriosus (see Chapter 24).

Venous System The venous system is a low-pressure system that returns blood to the heart. The venules collect blood from the capillaries, and the veins transport blood back to the right heart. Blood from the systemic veins flows into the right atrium of the heart; therefore, the pressure in the right atrium is called the central venous pressure. Right atrial pressure is regulated by the ability of the right ventricle to pump blood into the lungs and the tendency of blood to flow from the peripheral veins into the right atrium. The normal right atrial pressure is about 0 mm Hg, which is equal to atmospheric pressure. It can increase to 20 to 30 mm Hg in conditions such as right heart failure and the rapid transfusion of blood at a rate that greatly increases total blood volume and causes excessive quantities of blood to attempt to flow into the heart from the systemic veins. The veins and venules are thin-walled, distensible, and collapsible vessels. The veins are capable of enlarging and storing large quantities of blood, which can be made available to the circulation as needed. Even though the veins are thin walled, they are muscular. This allows them to contract or expand to accommodate varying amounts of blood. Veins are innervated by the sympathetic nervous system. When blood is lost from the circulation, the veins constrict as a means of maintaining intravascular volume. Valves in the veins of extremities prevent retrograde flow (Fig. 21-15) and with the help of skeletal muscles that surround and intermittently compress the leg veins in a milking manner, blood is moved forward to the heart. This pumping action is known as the venous or muscle pump. There are no valves in the abdominal or thoracic veins, and blood flow in these veins is heavily influenced by the pressure in the abdominal and thoracic cavities, respectively.

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Open valve

Blood flow (times normal)

Toward heart

Acute

2

1

0

Long term

0

50 100 150 200 250 Arterial pressure (mm Hg)

FIGURE 21-16 • Effect of increasing arterial pressure on blood flow

Closed valve

FIGURE 21-15 • Portion of a femoral vein opened, to show the valves. The direction of flow is upward. Backward flow closes the valve.

Because the venous system is a low-pressure system, blood flow must oppose the effects of gravity. In a person in the standing position, the weight of the blood in the vascular column causes an increase of 1 mm Hg in pressure for every 13.6 mm of distance below the level of the heart. Were it not for the valves in the veins and the action of the skeletal muscles, the venous pressure in the feet would be about +90 mm Hg in the standing adult. Gravity has no effect on the venous pressure in a person in the recumbent position because the blood in the veins is then at the level of the heart.

Local and Humoral Control of Blood Flow Tissue blood flow is regulated on a minute-to-minute basis in relation to tissue needs and on a longer-term basis through the development of collateral circulation. Neural mechanisms regulate the cardiac output and blood pressure needed to support these local mechanisms.

Short-Term Autoregulation Local control of blood flow is governed largely by the nutritional needs of the tissue. For example, blood flow to organs such as the heart, brain, and kidneys remains relatively constant, although blood pressure may vary over a range of 60 to 180 mm Hg (Fig. 21-16). The ability of the tissues to regulate

through a muscle. The solid curve shows the effect if pressure is raised over a few minutes. The dashed curve shows the effect if the arterial pressure is raised slowly over many weeks. (From Guyton A. C., Hall J. E. [1996]. Textbook of medical physiology [9th ed., p. 203]. Philadelphia: W. B. Saunders.)

their own blood flow over a wide range of pressures is called autoregulation. Autoregulation of blood flow is mediated by changes in blood vessel tone due to changes in flow through the vessel or by local tissue factors, such as lack of oxygen or accumulation of tissue metabolites (i.e., potassium, lactic acid, or adenosine, which is a breakdown product of ATP). Local control is particularly important in tissues such as skeletal muscle, which has blood flow requirements that vary according to the level of activity. Reactive Hyperemia. An increase in local blood flow is called hyperemia. The ability of tissues to increase blood flow in situations of increased activity, such as exercise, is called functional hyperemia. When the blood supply to an area has been occluded and then restored, local blood flow through the tissues increases within seconds to restore the metabolic equilibrium of the tissues. This increased flow is called reactive hyperemia. The transient redness seen on an arm after leaning on a hard surface is an example of reactive hyperemia. Local control mechanisms rely on a continuous flow from the main arteries; therefore, hyperemia cannot occur when the arteries that supply the capillary beds are narrowed. For example, if a major coronary artery becomes occluded, the opening of channels supplied by that vessel cannot restore blood flow. Endothelial Control of Vascular Function. One of the important functions of the endothelial cells lining the arterioles and small arteries is the synthesis and release of factors that control vessel dilation. Of particular importance was the discovery, first reported in the early 1980s, that the intact endothelium was able to produce a factor that caused relaxation of vascular smooth muscle. This factor was originally named endothelium-derived relaxing factor and is now known to be nitric oxide. The normal

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endothelium maintains a continuous release of nitric oxide, which is formed from L-arginine through the action of an enzyme called nitric oxide synthase (Fig. 21-17). The production of nitric oxide can be stimulated by a variety of endothelial agonists, including acetylcholine, bradykinin, histamine, and thrombin. Shear stress on the endothelium resulting from an increase in blood flow or blood pressure also stimulates nitric oxide production and vessel relaxation. Nitric oxide also inhibits platelet aggregation and secretion of platelet contents, many of which cause vasoconstriction. The fact that nitric oxide is released into the vessel lumen (to inactivate platelets) and away from the lumen (to relax smooth muscle) suggests that it protects against both thrombosis and vasoconstriction. Nitroglycerin, which is used in the treatment of angina, produces its effects by causing the release of nitric oxide in vascular smooth muscle of the target tissues. The endothelium also produces a number of vasoconstrictor substances, including angiotensin II, vasoconstrictor prostaglandins, and a family of peptides called endothelins. There are at least three endothelins. Endothelin-1, made by human endothelial cells, is the most potent endogenous vasoconstrictor known. Receptors for endothelins also have been identified.

Long-Term Regulation of Blood Flow Collateral circulation is a mechanism for the long-term regulation of local blood flow. In the heart and other vital structures, anastomotic channels exist between some of the smaller arteries. These channels permit perfusion of an area by more than one artery. When one artery becomes occluded, these anastomotic channels increase in size, allowing blood from a patent artery to perfuse the area supplied by the occluded vessel. For example,

Endothelium

Nitric oxide (NO) synthase L-arginine + O2

NO

NO Vascular smooth muscle Smooth muscle relaxation

Vessel dilation

FIGURE 21-17 • Function of nitric oxide in smooth muscle relaxation.

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persons with extensive obstruction of a coronary blood vessel may rely on collateral circulation to meet the oxygen needs of the myocardial tissue normally supplied by that vessel. As with other long-term compensatory mechanisms, the recruitment of collateral circulation is most efficient when obstruction to flow is gradual rather than sudden.

Humoral Control of Vascular Function Humoral control of blood flow involves the effect of vasodilator and vasoconstrictor substances in the blood. Some of these substances are formed by special glands and transported in the blood throughout the entire circulation. Others are formed in local tissues and aid in the local control of blood flow. Among the most important of the humoral factors are norepinephrine and epinephrine, angiotensin II, histamine, serotonin, bradykinin, and the prostaglandins. Norepinephrine and Epinephrine. Norepinephrine is an especially powerful vasoconstrictor hormone; epinephrine is less so and in some tissues (e.g., skeletal muscle) even causes mild vasodilation. Stimulation of the sympathetic nervous system during stress or exercise causes local constriction of veins and arterioles because of the release of norepinephrine from sympathetic nerve endings. In addition, sympathetic stimulation causes the adrenal medullae to secrete both norepinephrine and epinephrine into the blood. These hormones then circulate in the blood, causing direct sympathetic stimulation of blood vessels in all parts of the body. Angiotensin II. Angiotensin II is another powerful vasoconstrictor substance. Angiotensin II is produced as a part of the renin-angiotensin-aldosterone system and normally acts on many arterioles simultaneously to increase the peripheral vascular resistance, thereby increasing the arterial blood pressure (discussed in Chapter 23). Histamine. Histamine has a powerful vasodilator effect on arterioles and has the ability to increase capillary permeability, allowing leakage of both fluid and plasma proteins into the tissues. Histamine is largely derived from mast cells in injured tissues and basophils in the blood. In certain tissues, such as skeletal muscle, the activity of the mast cells is mediated by the sympathetic nervous system; when sympathetic control is withdrawn, the mast cells release histamine. Serotonin. Serotonin is liberated from aggregating platelets during the clotting process; it causes vasoconstriction and plays a major role in control of bleeding. Serotonin is found in brain and lung tissues, and there is some speculation that it may be involved in the vascular spasm associated with some allergic pulmonary reactions and migraine headaches. Bradykinin. The kinins (i.e., kallidins and bradykinin) are liberated from the globulin kininogen, which is present in body

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fluids. Bradykinin causes intense dilation of arterioles, increased capillary permeability, and constriction of venules. It is thought that the kinins play special roles in regulating blood flow and capillary leakage in inflamed tissues. It is also believed that bradykinin helps to regulate blood flow in the skin as well in the salivary and gastrointestinal glands. Prostaglandins. Prostaglandins are synthesized from constituents of the cell membrane (i.e., the long-chain fatty acid arachidonic acid). Tissue injury incites the release of arachidonic acid from the cell membrane, which initiates prostaglandin synthesis. There are several prostaglandins (e.g., E2, F2, D2), which are subgrouped according to their solubility; some produce vasoconstriction and some produce vasodilation. As a rule of thumb, those in the E group are vasodilators, and those in the F group are vasoconstrictors. The corticosteroid hormones produce an anti-inflammatory response by blocking the release of arachidonic acid, preventing prostaglandin synthesis.

IN SUMMARY,

the walls of all blood vessels, except the capillaries, are composed of three layers: the tunica externa, tunica media, and tunica intima. The layers of the vessel vary with its function. Arteries are thick-walled vessels with large amounts of elastic fibers. The walls of the arterioles, which control blood pressure, have large amounts of smooth muscle. Veins are thin-walled, distensible, and collapsible vessels. Venous flow is designed to return blood to the heart. It is a lowpressure system and relies on venous valves and the action of muscle pumps to offset the effects of gravity. The delivery of blood to the tissues of the body depends on pressure pulses that are generated by the intermittent ejection of blood from the left ventricle into the distensible aorta and large arteries of the arterial system. The combination of distensibility of the arteries and their resistance to flow reduces the pressure pulsations so that constant blood flow occurs by the time blood reaches the capillaries. The mechanisms that control local blood flow are designed to ensure adequate delivery of blood to the capillaries in the microcirculation, where the exchange of cellular nutrients and wastes occurs. Local control is governed largely by the needs of the tissues and is regulated by local tissue factors such as lack of oxygen and the accumulation of metabolites. Hyperemia is a local increase in blood flow that occurs after a temporary occlusion of blood flow. It is a compensatory mechanism that decreases the oxygen debt of the deprived tissues. Collateral circulation is a mechanism for long-term regulation of local blood flow that involves the development of collateral vessels. The endothelial relaxing factor (mainly nitric oxide) and humoral factors, such as norepinephrine and epinephrine, angiotensin II, histamine, serotonin, bradykinin, and the prostaglandins, contribute to the regulation of blood flow. ■

THE MICROCIRCULATION AND LYMPHATIC SYSTEM After completing this section of the chapter, you should be able to meet the following objectives: ■ ■ ■ ■

Define the term microcirculation. Describe the structure and function of the capillaries. Explain the forces that control the fluid exchange between the capillaries and the interstitial spaces. Describe the structures of the lymphatic system and relate them to the role of the lymphatics in controlling interstitial fluid volume.

The term microcirculation refers to the functions of the smallest blood vessels, the capillaries and the neighboring lymphatic vessels. The microcirculation is the site of exchange of gases, nutrients, and waste products in the tissues, as well as the site of vascular and interstitial fluid exchange.

Structure and Function of the Microcirculation The structures of the microcirculation include the arterioles, capillaries, and venules. Blood enters the microcirculation through an arteriole, passes through the capillaries, and leaves through a small venule. The metarterioles serve as thoroughfare channels that link arterioles and capillaries (Fig. 21-18). Small cuffs of smooth muscle, the precapillary sphincters, are positioned at the arterial end of the capillary. The smooth muscle tone of the arterioles, venules, and precapillary sphincters

Arteriole

Smooth muscles

Precapillary sphincters Arterial capillary

Thoroughfare channel Venous capillary Venule

FIGURE 21-18 • Capillary bed. Precapillary sphincters control the flow of blood through the capillary network. Thoroughfare channels (i.e., arteriovenous shunts) allow blood to move directly from the arteriole into the venule without moving through nutrient channels of the capillary.

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serves to control blood flow through the capillary bed. Depending on venous pressure, blood flows through the capillary channels when the precapillary sphincters are open.

Capillary Structure and Function Capillaries are microscopic vessels that connect the arterial and venous segments of the circulation. In each person, there are approximately 10 billion capillaries, with a total surface area of 500 to 700 m2. The capillary wall is composed of a single layer of endothelial cells and their basement membrane (Fig. 21-19). The endothelial cells form a tube just large enough to allow the passage of red blood cells, one at a time. Water-filled junctions, called the capillary pores, join the capillary endothelial cells and provide a pathway for passage of substances through the capillary wall. The size of the capillary pores varies with capillary function. In the brain, the endothelial cells are joined by tight junctions that form the bloodbrain barrier. This prevents substances that would alter neural excitability from leaving the capillary. In organs that process blood contents, such as the liver, capillaries have large pores so that substances can pass easily through the capillary wall. The glomerular capillaries in the kidney have small openings called fenestrations that pass directly through the middle of the endothelial cells, a property that is consistent with the filtration function of the glomerulus. Because of their thin walls and close proximity to the cells of metabolically active tissues, capillaries are particularly well suited for the exchange of gases and metabolites between cells

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and the bloodstream. This exchange of substances occurs through spaces between tissue cells called the interstitium (Fig. 21-20). The interstitium is supported by collagen and elastin fibers and filled with proteoglycan (sugar–protein) molecules that combine with water to form a tissue gel. The tissue gel acts like a sponge to entrap the interstitial fluid and provide for distribution of the fluid, even to those cells that are most distant from the capillary. Fluids, electrolytes, gases, and substances of small and large molecular weights move across the capillary endothelium by diffusion, filtration, and pinocytosis. The exchange of gases and fluids across the capillary wall occurs by simple diffusion. Lipid-soluble substances such as oxygen and carbon dioxide readily exchange across the endothelial cells by diffusion. Water flows through the capillary endothelial cell membranes through water-selective channels called aquaporins. Water and watersoluble substances such as electrolytes, glucose, and amino acids also diffuse between the endothelial cells in the capillary pores. Pinocytosis (discussed in Chapter 4) is responsible for the movement of white blood cells and large protein molecules.

Control of Blood Flow in the Microcirculation Blood flow through capillary channels, designed for exchange of nutrients and metabolites, is called nutrient flow. In some parts of the microcirculation, blood flow bypasses the capillary bed, moving through a connection called an arteriovenous shunt, which directly connects an arteriole and a venule. This type of blood flow is called non-nutrient flow because it does not allow for nutrient exchange. Non-nutrient channels are common in the

Cells Basal lamina (cut)

Nucleus of endothelial cell Lumen

Capillary pores

Red blood cell

Endothelial cell Intercellular junctions Capillary

Collagen fiber bundles

Free water vesicle

Proteoglycan filaments

FIGURE 21-20 • Structure of the interstitium. Proteoglycan fila-

FIGURE 21-19 • Endothelial cells and intercellular junctions in a section of capillary.

ments are everywhere in the spaces between the collagen fiber bundles. Free water vesicles and small amounts of free fluid in the form of rivulets occasionally may occur. (Adapted from Guyton A. C., Hall J. E. [2006]. Textbook of medical physiology [11th ed., p. 184]. Philadelphia: Elsevier Saunders.)

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skin and are important in terms of heat exchange and temperature regulation (discussed in Chapter 10).

Capillary–Interstitial Fluid Exchange The direction and magnitude of fluid movement across the capillary wall are largely controlled by the hydrostatic and osmotic pressures of the capillary and interstitial fluids, as well as the permeability of the capillary wall. The direction of fluid movement can either be into or out of the capillary. When net fluid movement is out of the capillary into the interstitial spaces, it is called filtration, and when net movement is from the interstitium into the capillary, it is called absorption (Fig. 21-21). The capillary hydrostatic pressure represents the fluid pressure that tends to push water and its dissolved substances through the capillary pores into the interstitium. The osmotic pressure caused by the plasma proteins in the blood tends to pull fluid from the interstitial spaces back into the capillary. This pressure is termed colloidal osmotic pressure to differentiate the osmotic effects of the plasma proteins, which are suspended colloids, from the osmotic effects of substances such as sodium and glucose, which are dissolved crystalloids. Capillary permeability controls the movement of water and substances, such as the plasma proteins that influence osmotic pressure, into the interstitial spaces. Also important to this exchange mechanism is the lymphatic system, which removes excess fluid and osmotically active proteins and large particles from the interstitial spaces and returns them to the circulation.

Capillary

Venous end

Arterial end

Filtration

Reabsorption

Interstitium

Lymph flow

To circulation

Lymphatic

FIGURE 21-21 • Capillary filtration and lymph flow. Fluid is filtered out of the capillary and into the interstitium at the arterial end of the capillary. Most of the fluid is reabsorbed at the venous end of the capillary, with the rest of the fluid entering the terminal lymphatics for return to the circulation.

Hydrostatic Forces The capillary hydrostatic pressure is the principal force in capillary filtration. The hydrostatic pressure (blood pressure) within the capillaries is determined by both the arterial and venous pressures (the capillaries being interspersed between the arteries and veins). An increase in small artery and arterial pressure elevates capillary hydrostatic pressure, whereas a reduction in each of these pressures has the opposite effect. A change in venous pressure has a greater effect on the capillary hydrostatic pressure than does the same change in arterial pressure. About 80% of increased venous pressure, such as that caused by venous thrombosis or congestive heart failure, is transmitted back to the capillary. Capillary hydrostatic pressure is also affected by the previously discussed effects of gravity on venous pressure. When a person stands, the hydrostatic pressure is greater in the legs and lower in the head. The interstitial hydrostatic pressure is the pressure exerted by the interstitial fluids outside the capillary. It can be positive or negative. A positive interstitial fluid pressure opposes capillary filtration and a negative interstitial fluid pressure increases the movement of fluid out of the capillary into the interstitium. In the normal nonedematous state, the interstitial hydrostatic pressure is close to zero or slightly negative (−1 to −4 mm Hg) and has very little effect on capillary filtration or outward movement of fluid.

Osmotic Forces The key factor that restrains fluid loss from the capillaries is the colloidal osmotic pressure (approximately 28 mm Hg) generated by the plasma proteins. The plasma proteins are large molecules that disperse in the blood and occasionally escape into the tissue spaces. Because the capillary membrane is almost impermeable to the plasma proteins, these particles exert an osmotic force that pulls fluid into the capillary and offsets the pushing force of the capillary filtration pressure. The plasma contains a mixture of plasma proteins, including albumin, globulins, and fibrinogen. Albumin, which is the smallest and most abundant of the plasma proteins, accounts for approximately 70% of the total osmotic pressure. It is the number, not the size, of the particles in solution that controls the osmotic pressure. One gram of albumin (molecular weight of 69,000) contains almost six times as many molecules as 1 g of fibrinogen (molecular weight of 400,000). (Normal values for the plasma proteins are albumin, 4.5 g/dL; globulins, 2.5 g/dL; and fibrinogen, 0.3 g/dL.) Although the size of the capillary pores prevents most plasma proteins from leaving the capillary, small amounts escape into the interstitial spaces and exert an osmotic force that tends to pull fluid from the capillary into the interstitium. This amount is increased in conditions such as inflammation in which an increase in capillary permeability allows plasma proteins to escape into the interstitium. The lymphatic system is responsible for removing proteins from the interstitium. In the absence of a functioning lymphatic system, interstitial colloidal osmotic pressure increases, causing fluid to accumulate.

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Normally, a few white blood cells, plasma proteins, and other large molecules enter the interstitial spaces; these cells and molecules, which are too large to reenter the capillary, rely on the loosely structured wall of the lymphatic vessels for return to the vascular compartment.

Balance of Hydrostatic and Osmotic Forces Normally, the movement of fluid between the capillary bed and the interstitial spaces is continuous. As E. H. Starling pointed out more than a century ago, a state of equilibrium exists as long as equal amounts of fluid enter and leave the interstitial spaces. The forces that contribute to the Starling equilibrium are illustrated in Figure 21-22. In the diagram, the hydrostatic pressure at the arterial end of the capillary is higher than at the venous end. The pushing force of the capillary hydrostatic pressure on the arterial end of the capillary, along with the pulling effects of the interstitial colloidal osmotic pressure, contribute to the net outward movement of fluid. The capillary colloidal osmotic pressure and opposing interstitial osmotic pressure determine the reabsorption of fluid at the venous end of the capillary. A slight imbalance in forces causes slightly more filtration of fluid into interstitial spaces than absorption back into the capillary; it is this fluid that is returned to the circulation by the lymphatic system. Disorders of capillary fluid exchange are discussed in Chapter 31.

The Lymphatic System

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tissues, however, have prelymphatic channels that eventually flow into areas supplied by the lymphatics. Lymph is derived from interstitial fluids that flow through the lymph channels. It contains plasma proteins and other osmotically active particles that rely on the lymphatics for movement back into the circulatory system. The lymphatic system is also the main route for absorption of nutrients, particularly fats, from the gastrointestinal tract. The lymphatic system also filters the fluid at the lymph nodes and removes foreign particles such as bacteria. When lymph flow is obstructed, a condition called lymphedema occurs. Involvement of lymphatic structures by malignant tumors and removal of lymph nodes at the time of cancer surgery are common causes of lymphedema. The lymphatic system is made up of vessels similar to those of the circulatory system. These vessels commonly travel along with an arteriole or venule or with its companion artery and vein. The terminal lymphatic vessels are made up of a single layer of connective tissue with an endothelial lining and resemble blood capillaries. The lymphatic vessels lack tight junctions and are loosely anchored to the surrounding tissues by fine filaments (Fig. 21-23). The loose junctions permit the entry of large particles, and the filaments hold the vessels open under conditions of edema, when the pressure of the surrounding tissues would otherwise cause them to collapse. The lymph capillaries drain into larger lymph vessels that ultimately empty into the right and left thoracic ducts (Fig. 21-24). The thoracic ducts empty into the circulation at the junctions of the subclavian and internal jugular veins.

The lymphatic system, commonly called the lymphatics, serves almost all body tissues, except cartilage, bone, epithelial tissue, and tissues of the central nervous system (CNS). Most of these

B Interstitial fluid Opening Tissue cell

Capillary hydrostatic pressure

Capillary colloidal osmotic pressure

Anchoring filament

28 mm Hg

Arterial end

28 mm Hg 10 mm Hg

Filtration

Venous end

Reabsorption

Venule Blood capillary Tissue cell Interstitial fluid

Interstitial fluid hydrostatic pressure –3 mm Hg

Interstitial colloidal osmotic pressure –8 mm Hg

FIGURE 21-22 • Capillary–interstitial fluid exchange equilibrium. Normally, the forces (capillary hydrostatic pressure, interstitial colloidal osmotic pressure, and the opposing interstitial fluid pressure) that control the outward movement of fluid from the capillary (filtration) are almost balanced by the forces (capillary colloidal osmotic pressure and interstitial colloidal osmotic pressure) that pull fluid back into the capillary (reabsorption).

Lymph Endothelium of lymphatic capillary

Arteriole Lymphatic capillary

A FIGURE 21-23 • (A) Location of the lymphatic capillary. Fluid from the arterial side of the capillary bed moves into the interstitial spaces and is reabsorbed in the venous side of the capillary bed. (B) Details of the lymphatic capillary with its anchoring filaments and overlapping edges that serve as valves and can be pushed open, allowing the inflow of interstitial fluid and its suspended particles.

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Right jugular trunk

Left jugular trunk

Right subclavian trunk Left subclavian trunk Right lymphatic duct

Thoracic (left lymphatic) duct

Right bronchomediastinal trunk Right lymphatic duct Right brachiocephalic vein Superior vena cava

Thoracic duct Inferior vena cava

Internal jugular vein Left lymphatic duct Subclavian vein

Intercostal trunks

Aorta

Although the divisions are not as distinct as in the circulatory system, the larger lymph vessels show evidence of having intimal, medial, and adventitial layers similar to blood vessels. The intima of these channels contains elastic tissue and an endothelial layer, and the larger collecting lymph channels contain smooth muscle in their medial layer. Contraction of this smooth muscle assists in propelling lymph toward the thorax. External compression of the lymph channels by pulsating blood vessels in the vicinity and active and passive movements of body parts also aid in forward propulsion of lymph. The rate of flow through the lymphatic system through all of the various lymph channels, approximately 120 mL/hour, is determined by the interstitial fluid pressure and the activity of lymph pumps.

IN SUMMARY, exchange of fluids between the vascular compartment and the interstitial spaces occurs at the capillary level. The capillary hydrostatic pressure pushes fluids out of the capillaries, and the colloidal osmotic pressure exerted by the plasma proteins pulls fluids back into the capillaries. Albumin, which is the smallest and most abundant of the plasma proteins, provides the major osmotic force for return of fluid to the vascular compartment. Normally, slightly more fluid leaves the capillary bed than can be reabsorbed. This excess fluid is returned to the circulation by way of the lymphatic channels. ■

FIGURE 21-24 • Lymphatic system, showing the thoracic duct and position of the left and right lymphatic ducts (inset).

NEURAL CONTROL OF CIRCULATORY FUNCTION After completing this section of the chapter, you should be able to meet the following objectives: ■

■ ■

■

Describe the roles of the medullary vasomotor and cardioinhibitory centers in controlling the function of the heart and blood vessels. Relate the performance of baroreceptors and chemoreceptors in the control of cardiovascular function. Describe the distribution of the sympathetic and parasympathetic nervous systems in the innervation of the circulatory system and their effects on heart rate and cardiac contractility. Relate the role of the central nervous system in terms of regulating circulatory function.

The neural control centers for the integration and modulation of cardiac function and blood pressure are located bilaterally in the medulla oblongata. The medullary cardiovascular neurons are grouped into three distinct pools that lead to sympathetic innervation of the heart and blood vessels and parasympathetic innervation of the heart. The first two, which control sympathetic-mediated acceleration of heart

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rate and blood vessel tone, are called the vasomotor center. The third, which controls parasympathetic-mediated slowing of heart rate, is called the cardioinhibitory center. These brain stem centers receive information from many areas of the nervous system, including the hypothalamus. The arterial baroreceptors and chemoreceptors provide the medullary cardiovascular center with continuous information regarding changes in blood pressure (see Chapter 23).

Autonomic Nervous System Regulation The neural control of the circulatory system occurs primarily through the sympathetic and parasympathetic divisions of the autonomic nervous system (ANS). The ANS contributes to the control of cardiovascular function through modulation of cardiac (i.e., heart rate and cardiac contractility) and vascular (i.e., peripheral vascular resistance) functions.

Autonomic Regulation of Cardiac Function The heart is innervated by the parasympathetic and sympathetic nervous systems. Parasympathetic innervation of the heart is achieved by means of the vagus nerve. The parasympathetic outflow to the heart originates from the vagal nucleus in the medulla. The axons of these neurons pass to the heart in the cardiac branches of the vagus nerve. The effect of vagal stimulation on heart function is largely limited to heart rate, with increased vagal activity producing a slowing of the pulse. Sympathetic outflow to the heart and blood vessels arises from neurons located in the reticular formation of the brain stem. The axons of these neurons exit the thoracic segments of the spinal cord to synapse with the postganglionic neurons that innervate the heart. Cardiac sympathetic fibers are widely distributed to the sinoatrial and AV nodes and the myocardium. Increased sympathetic activity produces an increase in the heart rate and the velocity and force of cardiac contraction.

Autonomic Regulation of Vascular Function The sympathetic nervous system serves as the final common pathway for controlling the smooth muscle tone of the blood vessels. Most of the sympathetic preganglionic fibers that control vessel function originate in the vasomotor center of the brain stem, travel down the spinal cord, and exit in the thoracic and lumbar (T1–L2) segments. The sympathetic neurons that supply the blood vessels maintain them in a state of tonic activity, so that even under resting conditions, the blood vessels are partially constricted. Vessel constriction and relaxation are accomplished by altering this basal input. Increasing sympathetic activity causes constriction of some vessels, such as those of the skin, the gastrointestinal tract, and the kidneys. Blood vessels in skeletal muscle are supplied by both vasoconstrictor and vasodilator fibers. Activation of sympathetic vasodilator fibers causes vessel relaxation and provides the muscles with increased blood flow during exercise. Although the parasympathetic nervous

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system contributes to the regulation of heart function, it has little or no control over blood vessels.

Autonomic Neurotransmitters The actions of the ANS are mediated by chemical neurotransmitters. Acetylcholine is the postganglionic neurotransmitter for parasympathetic neurons and norepinephrine is the main neurotransmitter for postganglionic sympathetic neurons. Sympathetic neurons also respond to epinephrine, which is released into the bloodstream by the adrenal medulla. The neurotransmitter dopamine can also act as a neurotransmitter for some sympathetic neurons. The synthesis, release, and inactivation of the autonomic neurotransmitters are discussed in Chapter 48.

Central Nervous System Responses It is not surprising that the CNS, which plays an essential role in regulating vasomotor tone and blood pressure, would have a mechanism for controlling the blood flow to the cardiovascular centers that control circulatory function. When the blood flow to the brain has been sufficiently interrupted to cause ischemia of the vasomotor center, these vasomotor neurons become strongly excited, causing massive vasoconstriction as a means of raising the blood pressure to levels as high as the heart can pump against. This response is called the CNS ischemic response, and it can raise the blood pressure to levels as high as 270 mm Hg for as long as 10 minutes. The CNS ischemic response is a lastditch stand to preserve the blood flow to vital brain centers; it does not become activated until blood pressure has fallen to at least 60 mm Hg, and it is most effective in the range of 15 to 20 mm Hg. If the cerebral circulation is not reestablished within 3 to 10 minutes, the neurons of the vasomotor center cease to function, so that the tonic impulses to the blood vessels stop and the blood pressure falls precipitously. The Cushing reflex is a special type of CNS reflex resulting from an increase in intracranial pressure. When the intracranial pressure rises to levels that equal intra-arterial pressure, blood vessels to the vasomotor center become compressed, initiating the CNS ischemic response. The purpose of this reflex is to produce a rise in arterial pressure to levels above intracranial pressure so that the blood flow to the vasomotor center can be reestablished. Should the intracranial pressure rise to the point that the blood supply to the vasomotor center becomes inadequate, vasoconstrictor tone is lost, and the blood pressure begins to fall. The elevation in blood pressure associated with the Cushing reflex is usually of short duration and should be considered a protective homeostatic mechanism. The brain and other cerebral structures are located within the rigid confines of the skull, with no room for expansion, and any increase in intracranial pressure tends to compress the blood vessels that supply the brain. IN SUMMARY,

the neural control centers for the regulation of cardiac function and blood pressure are located in the reticular formation of the lower pons and medulla of the brain stem, where the integration and modulation of ANS responses occur.

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These brain stem centers receive information from many areas of the nervous system, including the hypothalamus. Both the parasympathetic and sympathetic nervous systems innervate the heart. The parasympathetic nervous system functions in regulating heart rate through the vagus nerve, with increased vagal activity producing a slowing of heart rate. The sympathetic nervous system has an excitatory influence on heart rate and contractility, and it serves as the final common pathway for controlling the smooth muscle tone of the blood vessels. ■

B. What happens to cardiac output during increased expiratory effort in which a marked increase in intrathoracic pressure produces a decrease in venous return to the right heart? C. Given these changes in cardiac output that occur during increased respiratory effort, what would you propose as one of the functions of the FrankStarling curve?

Bibliography

Review Exercises 1. In persons with atherosclerosis of the coronary arteries, symptoms of myocardial ischemia do not usually occur until the vessel has been 75% occluded. A. Use the Poiseuille law to explain. 2. Once an arterial aneurysm has begun to form, it continues to enlarge as the result of the increased tension in its wall. A. Explain the continued increase in size using the law of Laplace. B. Using information related to cross-sectional area and velocity of flow, explain why there is stasis of blood flow with the tendency to form clots in aneurysms with a large cross-sectional area. 3. Use events in the cardiac cycle depicted in Figure 21-11 to explain: A. The effect of hypertension on the isovolumetric contraction period. B. The effect of an increase in heart rate on the time spent in diastole. C. The effect of an increase in the isovolumetric relaxation period on the diastolic filling of the ventricle 4. Use the Frank-Starling ventricular function curve depicted in Figure 21-12 to explain the changes in cardiac output that occur with changes in respiratory effort. A. What happens to cardiac output during increased inspiratory effort in which a marked decrease in intrathoracic pressure produces an increase in venous return to the right heart?

Aukland K., Reed R. K. (1993). Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiological Reviews 73, 1–78. Costano L. S. (2002). Physiology (2nd ed., pp. 101–166). Philadelphia: W. B. Saunders. Davis M. J., Hill M. A. (1999). Signaling mechanisms underlying the vascular myogenic response. Physiological Reviews 79, 387–423. Ellis C. G., Jagger J., Sharpe M. (2005). The microcirculation as a functional system. Critical Care 9(Suppl. 4), S3–S8. Feletou M., Vanhoutte P. M. (1999). The alternative: EDHF. Journal of Molecular and Cellular Cardiology 31, 15–22. Ganong W. F. (2005). Review of medical physiology (22nd ed., pp. 515–630). New York: Lange Medical Books/McGraw-Hill. Guyton A. C., Hall J. E. (2006). Medical physiology (11th ed., pp. 161–277). Philadelphia: Elsevier Saunders. Klabunde R. E. (2005). Cardiovascular physiology concepts. Philadelphia: Lippincott Williams & Wilkins. Levy M. N., Pappano A. J. (2007). Cardiovascular physiology (9th ed.). Philadelphia: Mosby Elsevier. Mifflin S. W. (2001). What does the brain know about blood pressure? News in Physiological Science 16, 266. Norton J. M. (2001). Toward consistent definitions for preload and afterload. Advances in Physiological Education 25(1), 53–61. Rhoades R. S., Tanner G. A. (2003). Medical physiology (2nd ed., pp. 191–308). Boston: Little, Brown. Ross M. H., Kaye G. L., Pawlina W. (2003). Histology: A text and atlas (4th ed., pp. 326–354). Philadelphia: Lippincott Williams & Wilkins. Segal S. S. (2005). Regulation of blood flow in the microcirculation. Microcirculation 12, 33–45. Smith J. J., Kampine J. P. (1989). Circulatory physiology: The essentials (3rd ed.). Baltimore: Williams & Wilkins. Toda N., Okamura T. (2003). The pharmacology of nitric oxide in the peripheral nervous system of blood vessels. Pharmacological Reviews 55, 271–324. Vanhoutte P. M. (1999). How to assess endothelial function in human blood vessels. Journal of Hypertension 17, 1047–1058.

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Chapter

22

GLENN MATFIN

BLOOD VESSEL STRUCTURE AND FUNCTION Endothelial Cells Endothelial Dysfunction Vascular Smooth Muscle Cells DISORDERS OF THE ARTERIAL CIRCULATION Hyperlipidemia Lipoproteins Hypercholesterolemia Atherosclerosis Risk Factors Mechanisms of Development Clinical Manifestations Vasculitis Polyarteritis Nodosa Giant Cell Temporal Arteritis Arterial Disease of the Extremities Acute Arterial Occlusion Atherosclerotic Occlusive Disease Thromboangiitis Obliterans Raynaud Disease and Phenomenon Aneurysms and Dissection Aortic Aneurysms Aortic Dissection DISORDERS OF THE VENOUS CIRCULATION Venous Circulation of the Lower Extremities Disorders of the Venous Circulation of the Lower Extremities Varicose Veins Chronic Venous Insufficiency Venous Thrombosis

➤ Blood flow in the arterial and venous systems depends on a system of patent blood vessels and adequate perfusion pressure. Unlike disorders of the respiratory system or central circulation that cause hypoxia and impair oxygenation of tissues throughout the body, the effects of blood vessel disease usually are limited to local tissues supplied by a particular vessel or group of vessels. With arterial disorders, there is decreased blood flow to the tissues along with impaired delivery of oxygen and nutrients, and with venous disorders there is interference with the outflow of blood and removal of waste products. Disturbances in blood flow can result from pathologic changes in the vessel wall (i.e., atherosclerosis and vasculitis), acute vessel obstruction due to thrombus or embolus, vasospasm (i.e., Raynaud phenomenon), or abnormal vessel dilation (i.e., arterial aneurysms or varicose veins).

BLOOD VESSEL STRUCTURE AND FUNCTION After completing this section of the chapter, you should be able to meet the following objectives: ■ ■

Describe the functions of the endothelial cells and define the term endothelial dysfunction. Describe the function of vascular smooth muscle and its role in vascular repair.

Although the heart is at the center of the cardiovascular system, it is the blood vessels that transport blood throughout the body. The walls of all blood vessels, except the very smallest, are composed of three distinct layers: an outer layer of loosely woven collagen tissue, the tunica externa, which is composed of loose connective tissue; a middle layer, the tunica media, which consists primarily of circumferentially arranged layers of smooth muscle cells; and an inner layer, the tunica intima, which consists of a single layer of endothelial cells that line the lumen of the vessel, and the underlying subendothelial connective tissue (Fig. 22-1). As the main cellular components of the blood vessel wall, the 477

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Smooth muscle cell

Endothelial Dysfunction

Internal elastic membrane Connective tissue Endothelial cells Lumen

Tunica externa (outer coat)

Tunica media (middle coat)

Tunica intima (inner coat)

FIGURE 22-1 • Diagram of a typical artery showing the tunica externa, tunica media, and tunica intima.

endothelial and smooth muscle cells play an important role in the pathogenesis of many disorders of the arterial circulation.

Endothelial Cells Endothelial cells form a continuous lining for the entire vascular system called the endothelium. Once thought to be nothing more than a lining for blood vessels, it is now known that the endothelium is a versatile, multifunctional tissue that plays an active role in controlling vascular function1,2 (Table 22-1). As a semipermeable membrane, the endothelium controls the transfer of molecules across the vascular wall. The endothelium also plays a role in the control of platelet adhesion and blood clotting; modulation of blood flow and vascular resistance; metabolism of hormones; regulation of immune and inflammatory reactions; and elaboration of factors that influence the growth of other cell types, particularly vascular smooth muscle cells.

TABLE 22-1 Endothelial

Structurally intact endothelial cells respond to various abnormal stimuli by adjusting their usual functions and by expressing newly acquired functions.1 The term endothelial dysfunction describes several types of potentially reversible changes in endothelial function that occur in response to environmental stimuli. Inducers of endothelial dysfunction include cytokines and bacterial and viral products that cause inflammation; hemodynamic stresses and lipid products that are critical to the pathogenesis of atherosclerosis; and hypoxia. Dysfunctional endothelial cells, in turn, produce other cytokines, growth factors, procoagulant or anticoagulant substances, and a variety of other biologically active products. They also influence the reactivity of underlying smooth muscle cells through production of both relaxing factors (e.g., nitric oxide) and contracting factors (e.g., endothelins; see Chapter 21).

Vascular Smooth Muscle Cells Vascular smooth muscle cells, which form the predominant cellular layer in the tunica media, produce vasoconstriction or dilation of blood vessels. A network of vasomotor nerves of the sympathetic component of the autonomic nervous system supplies the smooth muscle in the blood vessels. These nerves are responsible for vasoconstriction of the vessel walls. Because they do not enter the tunica media of the blood vessel, the nerves do not synapse directly on the smooth muscle cells. Instead, they release the neurotransmitter norepinephrine, which diffuses into the media and acts on the nearby smooth muscle cells. The resulting impulses are propagated along the smooth muscle cells through their gap junctions, causing contraction of the entire muscle cell layer and thus reducing the radius of the vessel lumen. Vascular smooth muscle cells also synthesize collagen, elastin, and other components of the extracellular matrix; elaborate growth factors and cytokines; and after vascular injury mi-

Cell Properties and Functions

MAJOR PROPERTIES

ASSOCIATED FUNCTIONS/FACTORS

Maintenance of a selective permeability barrier Regulation of thrombosis

Controls the transfer of small and large molecules across the vessel wall Elaboration of prothrombogenic molecules (von Willebrand factor, plasminogen activator) and antithrombotic molecules (prostacyclin, heparin-like molecules, plasminogen activator) Elaboration of vasodilators (nitric oxide, prostacyclin) and vasoconstrictors (endothelins, angiotensin-converting enzyme) Production of growth-stimulating factors (platelet-derived growth factor, hematopoietic colony-stimulating factor) and growth-inhibiting factors (heparin, transforming growth factor-β) Expression of adhesion molecules that regulate leukocyte migration and release of inflammatory and immune system mediators (e.g., interleukins, interferons) Synthesis of collagen, laminin, proteoglycans Oxidation of VLDL, LDL, cholesterol

Modulation of blood flow and vascular reactivity Regulation of cell growth, particularly smooth muscle cells Regulation of inflammatory/immune responses

Maintenance of the extracellular matrix Involvement in lipoprotein metabolism

Data from Schoen F. J. (2005). Blood vessels. In Kumar V., Abbas A. K., Fausto N. (Eds.), Robbins and Cotran pathologic basis of disease (7th ed., p. 514). Philadelphia: Elsevier Saunders; and Ross M. H., Kaye G. L., Pawlina W. (2003). Histology: A text and atlas (4th ed., p. 332). Philadelphia: Lippincott Williams & Wilkins.

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grate into the intima and proliferate.1 Thus, smooth muscle cells are important in both normal vascular repair as well as pathologic processes such as atherosclerosis. The migratory and proliferative activities of vascular smooth muscle cells are stimulated by growth promoters and inhibitors. Promoters include plateletderived growth factor, thrombin, fibroblast growth factor, and cytokines such as interferon gamma and interleukin-1. Growth inhibitors include nitric oxide. Other regulators include the reninangiotensin system (angiotensin II) and the catecholamines. IN SUMMARY,

the walls of blood vessels are composed of three layers: an outer layer of loosely woven collagen tissue, a middle layer of vascular smooth muscle, and an inner layer of endothelial cells. The endothelium controls the transfer of molecules across the vascular wall, plays a role in the control of platelet adhesion and blood clotting, modulation of blood flow and vascular resistance, metabolism of hormones, regulation of immune and inflammatory reactions, and elaboration of factors that influence the growth of other cell types, particularly the smooth muscle cells. The term endothelial dysfunction describes several types of potentially reversible changes in endothelial function that occur in response to environmental stimuli. Vascular smooth muscle cells not only control dilation and vasoconstriction of blood vessels, but elaborate growth factors and synthesize collagen, elastin, and other components of the extracellular matrix that are important in both normal vascular repair as well as pathologic processes such as atherosclerosis. ■

DISORDERS OF THE ARTERIAL CIRCULATION After completing this section of the chapter, you should be able to meet the following objectives: ■

■ ■ ■ ■ ■ ■ ■

■

■

List the five types of lipoproteins and state their function in terms of lipid transport and development of atherosclerosis. Describe the role of lipoprotein receptors in removal of cholesterol from the blood. Cite the criteria for diagnosis of hypercholesterolemia. Describe possible mechanisms involved in the development of atherosclerosis. List risk factors in atherosclerosis. List the vessels most commonly affected by atherosclerosis and describe the vessel changes that occur. State the signs and symptoms of acute arterial occlusion. Describe the pathology associated with the vasculitides and relate it to four disease conditions associated with vasculitis. Compare the mechanisms and manifestations of ischemia associated with atherosclerotic peripheral vascular disease, Raynaud phenomenon, and thromboangiitis obliterans (i.e., Buerger disease). Distinguish between the pathology and manifestations of aortic aneurysms and dissection of the aorta.

479

The arterial system distributes blood to all the tissues in the body. There are three types of arteries: large elastic arteries, including the aorta and its distal branches; medium-sized arteries, such as the coronary and renal arteries; and small arteries and arterioles that pass through the tissues. The large arteries function mainly in transport of blood. The medium-sized arteries are composed predominantly of circular and spirally arranged smooth muscle cells. Distribution of blood flow to the various organs and tissues of the body is controlled by contraction and relaxation of the smooth muscle of these vessels. The small arteries and arterioles regulate capillary blood flow. Each of these different types of arteries tends to be affected by different disease processes. Disease of the arterial system affects body function by impairing blood flow. The effect of impaired blood flow on the body depends on the structures involved and the extent of altered flow. The term ischemia (i.e., “holding back of blood”) denotes a reduction in arterial flow to a level that is insufficient to meet the oxygen demands of the tissues. Infarction refers to an area of ischemic necrosis in an organ produced by occlusion of its arterial blood supply or its venous drainage. The discussion in this section focuses on blood lipids and hypercholesterolemia, atherosclerosis, vasculitis, arterial disease of the extremities, and arterial aneurysms.

DISORDERS OF THE ARTERIAL CIRCULATION ■ ■

■

■

■

The arterial system delivers oxygen and nutrients to the tissues. Disorders of the arterial circulation produce ischemia owing to narrowing of blood vessels, thrombus formation associated with platelet adhesion, and weakening of the vessel wall. Atherosclerosis is a progressive disease characterized by the formation of fibrofatty plaques in the intima of large and medium-sized vessels, including the aorta, coronary arteries, and cerebral vessels. The major risk factors for atherosclerosis are hypercholesterolemia and inflammation. Vasculitis is an inflammation of the blood vessel wall resulting in vascular tissue injury and necrosis. Arteries, capillaries, and veins may be affected. The inflammatory process may be initiated by direct injury, infectious agents, or immune processes. Aneurysms represent an abnormal localized dilatation of an artery due to a weakness in the vessel wall. As the aneurysm increases in size, the tension in the wall of the vessel increases and it may rupture. The increased size of the vessel also may exert pressure on adjacent structures.

Hyperlipidemia Triglycerides, phospholipids, and cholesterol, which are classified as lipids, are a diverse group of compounds that have many key biological functions. Triglycerides, which are used in energy

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metabolism, are combinations of three fatty acids condensed with a single glycerol molecule. Phospholipids, which contain a phosphate group, are important structural constituents of lipoproteins, blood clotting components, the myelin sheath, and cell membranes. Although cholesterol is not composed of fatty acids, its steroid nucleus is synthesized from fatty acids and thus its chemical activity is similar to that of other lipid substances.3 Elevated levels of blood cholesterol (hypercholesterolemia) are implicated in the development of atherosclerosis with its attendant risk of heart attack and stroke. This is a major public health issue that is underscored by striking statistics released by the American Heart Association (AHA). An estimated 37.2 million Americans have high-risk serum cholesterol levels (240 mg/ dL or greater) that could contribute to a heart attack, stroke, or other cardiovascular event associated with atherosclerosis.4

Low density

VLDL 55% 65% triglycerides, 10% cholesterol, 5% 10% protein

LDL 10% triglycerides, 50% cholesterol, 25% protein

Lipoproteins Because cholesterol and triglyceride are insoluble in plasma, they are encapsulated by a stabilizing coat of water-soluble phospholipids and proteins (called apoproteins). These particles, which are called lipoproteins, transport cholesterol and triglyceride to various tissues for energy utilization, lipid deposition, steroid hormone production, and bile acid formation. There are five types of lipoproteins, classified according to their densities as measured by ultracentrifugation: chylomicrons, very– low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). VLDL carries large amounts of triglycerides that have a lower density than cholesterol. LDL is the main carrier of cholesterol, whereas HDL actually is 50% protein (Fig. 22-2). Each type of lipoprotein consists of a large molecular complex of lipids combined with apoproteins.5,6 The major lipid constituents are cholesterol esters, triglycerides, nonesterified (or free) cholesterol, and phospholipids. The insoluble cholesterol esters and triglycerides are located in the hydrophobic core of the lipoprotein macromolecule, surrounded by the soluble phospholipids, nonesterified cholesterol, and apoproteins (Fig. 22-3). Nonesterified cholesterol and phospholipids provide a negative charge that allows the lipoprotein to be soluble in plasma. There are four major classes of apoproteins: A (i.e., apoAI, apoA-II, and apoA-IV), B (i.e., apoB-48, apoB-100), C (i.e., apoC-I, apoC-II, and apoC-III), and apoE.4,5 The apoproteins control the interactions and ultimate metabolic fate of the lipoproteins. Some of the apoproteins activate the lipolytic enzymes that facilitate the removal of lipids from the lipoproteins; others serve as a reactive site that cellular receptors can recognize and use in the endocytosis and metabolism of the lipoproteins. The major apoprotein in LDL is apoB-100, whereas in HDL it is apoA-I. Research findings suggest that genetic defects in the apoproteins may be involved in hyperlipidemia and accelerated atherosclerosis.5–8 There are two sites of lipoprotein synthesis: the small intestine and the liver. The chylomicrons, which are the largest

Chylomicrons 80% 90% triglycerides, 2% protein

High density

HDL 5% triglycerides, 20% cholesterol, 50% protein

FIGURE 22-2 • Lipoproteins are named based on their protein content, which is measured in density. Because fats are less dense than proteins, as the proportion of triglycerides decreases, the density increases.

of the lipoprotein molecules, are synthesized in the wall of the small intestine. They are involved in the transport of dietary (exogenous pathway) triglycerides and cholesterol that have been absorbed from the gastrointestinal tract. Chylomicrons transfer their triglycerides to the cells of adipose and skeletal muscle tissue. The remnant chylomicron particles, which contain cholesterol, are then taken up by the liver and the cholesterol used in the synthesis of VLDL or excreted in the bile. Cholesterol esters

Triglycerides

Apoproteins

Phospholipids

FIGURE 22-3 • General structure of a lipoprotein. The cholesterol esters and triglycerides are located in the hydrophobic core of the macromolecule, surrounded by phospholipids and apoproteins.

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The liver synthesizes and releases VLDL and HDL. The VLDLs contain large amounts of triglycerides and lesser amounts of cholesterol esters.1 They provide the primary pathway for transport of the endogenous triglycerides produced in the liver, as opposed to those obtained from the diet. They are also the body’s main source of energy during prolonged fasting. Like chylomicrons, VLDLs carry their triglycerides to fat and muscle cells, where the triglycerides are removed. The resulting IDL fragments are reduced in triglyceride content and enriched in cholesterol. They are taken to the liver and recycled to form VLDL, or converted to LDL in the vascular compartment. IDLs are the main source of LDL. The exogenous and endogenous pathways for triglyceride and cholesterol transport are shown in Figure 22-4. LDL, sometimes called the bad cholesterol, is the main carrier of cholesterol. LDL is removed from the circulation by either LDL receptors or by scavenger cells such as monocytes or macrophages. Approximately 70% of LDL is removed through the LDL receptor-dependent pathway, and the rest is removed by the scavenger pathway.1 Although LDL receptors are widely distributed, approximately 75% are located on hepatocytes; thus,

481

the liver plays an extremely important role in LDL metabolism. LDL receptor-mediated removal involves binding of LDL to cell surface receptors, followed by endocytosis, a phagocytic process in which LDL is engulfed and moved into the cell in the form of a membrane-covered endocytic vesicle. Within the cell, the endocytic vesicles fuse with lysosomes, and the LDL molecule is enzymatically degraded, causing free cholesterol to be released into the cytoplasm. Other, nonhepatic tissues (i.e., adrenal glands, smooth muscle cells, endothelial cells, and lymphoid cells) also use the LDL receptor-dependent pathway to obtain cholesterol needed for membrane and hormone synthesis. These tissues can control their cholesterol intake by adding or removing LDL receptors. The scavenger pathway involves ingestion by phagocytic monocytes and macrophages. These scavenger cells have receptors that bind LDL that has been oxidized or chemically modified. The amount of LDL that is removed by the scavenger pathway is directly related to the plasma cholesterol level. When there is a decrease in LDL receptors or when LDL levels exceed receptor availability, the amount of LDL that is removed by scavenger cells is greatly increased. The uptake of

Endogenous pathway

Exogenous pathway

Reverse cholesterol transport HDL

Dietary triglycerides and cholesterol Bile acid and cholesterol

Receptordependent pathway

HDL

LDL receptor Intestine

Scavenger pathway

Extrahepatic tissue

Liver

LDL VLDL

Chylomicron Chylomicron fragments

Blood vessels

FIGURE 22-4 • Schematic representation of the exogenous and endogenous pathways for triglyceride and cholesterol transport.

Adipose and skeletal muscle tissue

Cholesterol Triglycerides IDL

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LDL by macrophages in the arterial wall can result in the accumulation of insoluble cholesterol esters, the formation of foam cells, and the development of atherosclerosis. HDL is synthesized in the liver and often is referred to as the good cholesterol. HDL participates in the reverse transport of cholesterol by carrying cholesterol from the peripheral tissues back to the liver. Epidemiologic studies have shown an inverse relation between HDL levels and the development of atherosclerosis.9,10 It is thought that HDL, which is low in cholesterol and rich in surface phospholipids, facilitates the clearance of cholesterol from the periphery (including atheromatous plaques) and transports it to the liver, where it may be excreted rather than reused in the formation of VLDL (reverse cholesterol transport). The mechanism whereby HDL promotes the movement of cholesterol from peripheral cells to lipid-poor HDL, involves a specialized lipid transporter called the ATP-binding cassette transporter A class 1 (ABCA1).11 Defects in this system (resulting from mutations in the ABCA1 transporter) are responsible for Tangier disease, which is characterized by accelerated atherosclerosis and little or no HDL. HDL is also believed to inhibit cellular uptake of LDL by reducing oxidation, thereby preventing uptake of oxidized LDL by the scavenger receptors on macrophages. It has been observed that regular exercise, moderate alcohol consumption, and certain lipid medications increase HDL levels. Smoking and the metabolic syndrome (see Chapter 42), which are in themselves risk factors for atherosclerosis, are also associated with decreased levels of HDL.1,10

Hypercholesterolemia The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults includes a classification system for hyperlipidemia that describes optimal to very high levels of LDL cholesterol, desirable to high levels of total cholesterol, and low and high levels of HDL cholesterol12 (Table 22-2). The NCEP recommends that all adults 20 years of age and older should have a fasting lipoprotein profile (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) measured once every 5 years. If testing is done in the nonfasting state, only the total cholesterol and HDL are considered useful. A follow-up lipoprotein profile should be done on persons with nonfasting total cholesterol levels of 200 mg/dL or more or HDL levels lower than 40 mg/dL. Lipoprotein measurements are particularly important in persons at high risk for developing coronary heart disease (CHD). Serum cholesterol levels may be elevated as a result of an increase in any of the lipoproteins—the chylomicrons, VLDL, IDL, LDL, or HDL. The commonly used classification system for hyperlipidemia is based on the type of lipoprotein involved (Table 22-3). Several factors, including nutrition, genetics, medications, comorbid conditions, and metabolic diseases, can raise blood lipid levels. Most cases of elevated levels of cholesterol are probably multifactorial. Some persons may have increased sensitivity to dietary cholesterol, others have a lack of LDL receptors, and still others have an altered synthesis of the apopro-

TABLE 22-2 NCEP

Adult Treatment Panel III Classification of LDL, Total, and HDL Cholesterol (mg/dL)

LDL Cholesterol

150 beats per minute); and the respiratory rate is increased (resting rate >50 breaths per minute).80 Diagnosis and Treatment. Diagnosis of heart failure in infants and children is based on symptomatology, chest radiographic films, electrocardiographic findings, echocardiographic techniques to assess cardiac structures and ventricular function

633

(i.e., end-systolic and end-diastolic diameters), arterial blood gases to determine intracardiac shunting and ventilationperfusion inequalities, and other laboratory studies to determine anemia and electrolyte imbalances. Treatment of heart failure in infants and children includes measures aimed at improving cardiac function and eliminating excess intravascular fluid. Oxygen delivery must be supported and oxygen demands controlled or minimized. Whenever possible, the cause of the disorder is corrected (e.g., medical treatment of sepsis and anemia, surgical correction of congenital heart defects). With congenital anomalies that are amenable to surgery, medical treatment often is needed for a time before surgery and usually is continued in the immediate postoperative period. For some children, only medical management can be provided. Medical management of heart failure in infants and children is similar to that in the adult, although it is tailored to the special developmental needs of the child. Inotropic agents such as digitalis often are used to increase cardiac contractility. Diuretics may be given to reduce preload and vasodilating medications used to manipulate the afterload. Medication doses must be carefully tailored to control for the child’s weight and conditions such as reduced renal function. Daily weighing and accurate measurement of intake and output are imperative during acute episodes of failure. Most children feel better in the semiupright position. An infant seat is useful for infants with chronic heart failure. Activity restrictions usually are designed to allow children to be as active as possible within the limitations of their heart disease. Infants with heart failure often have problems feeding. Small, frequent feedings usually are more successful than larger, less frequent feedings. Severely ill infants may lack sufficient strength to suck and may need to be tube fed. The treatment of heart failure in children should be designed to allow optimal physical and psychosocial development. It requires the full involvement of the parents, who often are the primary care providers; therefore, parent education and support are essential.

Heart Failure in the Elderly Heart failure is one of the most common causes of disability in the elderly and is the most frequent hospital discharge diagnosis for the elderly in the United States and Canada. An estimated 90% of people with heart failure are older than 60 years of age.3 Among the factors that have contributed to the increased numbers of older people with heart failure are the improved therapies for ischemic and hypertensive heart disease.84 Thus, persons who would have died from acute myocardial disease 20 years ago are now surviving, but with residual left ventricular dysfunction. Advances in treatment of other diseases have also contributed indirectly to the rising prevalence of heart failure in the older population. Coronary heart disease, hypertension, and valvular heart disease (particularly aortic stenosis and mitral regurgitation) are common causes of heart failure in older adults.85,86 In con-

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trast to the etiology in middle-aged persons with heart failure, factors other than systolic failure contribute to heart failure in the elderly. Preserved left ventricular function may be seen in 40% to 80% of older persons with heart failure.86 Aging is associated with impaired left ventricular filling due to changes in myocardial relaxation and compliance. These alterations lead to a shift in the left ventricular pressure–volume relationship, such that small increases in left ventricular volume lead to greater increases in left ventricular diastolic pressure. This increase in diastolic pressure further compromises left ventricular filling and leads to increases in left atrial, pulmonary venous, and pulmonary capillary pressures, and thus predisposes to pulmonary congestion and heart failure.85 Although diastolic heart failure accounts for less than 10% of heart failure cases in persons younger than 60 years of age, it accounts for greater than 50% of cases after age 75 years.85 There are a number of changes associated with aging that contribute to the development of heart failure in the elderly.84–86 First, reduced responsiveness to β-adrenergic stimulation limits the heart’s capacity to maximally increase heart rate and contractility. A second major effect of aging is increased vascular stiffness, which leads to a progressive increase in systolic blood pressure with advancing age, which in turn contributes to the development of left ventricular hypertrophy and altered diastolic filling. Third, in addition to increased vascular stiffness, the heart itself becomes stiffer and less compliant with age. The changes in diastolic stiffness result in important alterations in diastolic filling and atrial function. A reduction in ventricular filling not only affects cardiac output, but produces an elevation in diastolic pressure that is transmitted back to the left atrium, where it stretches the muscle wall and predisposes to atrial ectopic beats and atrial fibrillation. The fourth major effect of cardiovascular aging is altered myocardial metabolism at the level of the mitochondria. Although older mitochondria may be able to generate sufficient ATP to meet the normal energy needs of the heart, they may not be able to respond under stress.

CHART 26-3

MANIFESTATIONS OF HEART FAILURE IN THE ELDERLY

Symptoms Nocturia or nocturnal incontinence Fatigue Cognitive impairment (e.g., problem solving, decision making) Depression Restlessness/acute delirium Sleep disturbance History of falls Loss of appetite Signs Dependent edema (ankles when sitting up and sacral edema when supine) Pulmonary crackles (usually late sign)

Clinical Features

crackles, occur less commonly in the elderly, in part because of the increased incidence of diastolic failure, in which signs of right-sided heart failure are late manifestations and a third heart sound is typically absent.86 Instead, behavioral changes and altered cognition such as short-term memory loss and impaired problem solving are more common.2 With exacerbation of heart failure, the elderly often present with acute delirium and dementia.34 Depression is common in the elderly with heart failure and shares the symptoms of sleep disturbances, cognitive changes, and fatigue.2 The elderly also maintain a precarious balance between the managed symptom state and acute symptom exacerbation. During the managed symptom state, they are relatively symptom free while adhering to their treatment regimen. Acute symptom exacerbation, often requiring emergency medical treatment, can be precipitated by seemingly minor conditions such as poor adherence to sodium restriction, infection, or stress. Failure to promptly seek medical care is a common cause of progressive acceleration of symptoms.

Manifestations. The manifestations of heart failure in the elderly often are masked by other disease conditions.2 Nocturia and nocturnal incontinence is an early symptom but may be caused by other conditions such as prostatic hypertrophy. Lower extremity edema may reflect venous insufficiency. Impaired perfusion of the gastrointestinal tract is a common cause of anorexia and profound loss of lean body mass. Loss of lean body mass may be masked by edema. Exertional dyspnea, orthopnea, and impaired exercise tolerance are cardinal symptoms of heart failure in both younger and older persons with heart failure. However, with increasing age, which is often accompanied by a more sedentary lifestyle, exertional dyspnea becomes less prominent. Instead of dyspnea, the prominent sign may be restlessness. Chart 26-3 summarizes the manifestations of heart failure in the elderly. Physical signs of heart failure, such as elevated jugular venous pressure, hepatic congestion, S3 gallop, and pulmonary

Diagnosis and Treatment. The diagnosis of heart failure in the elderly is based on the history, physical examination, chest radiograph, and electrocardiographic findings.87 However, the presenting symptoms of heart failure often are difficult to evaluate. Symptoms of dyspnea on exertion are often interpreted as a sign of “getting older” or attributed to deconditioning from other diseases. Ankle edema is not unusual in the elderly because of decreased skin turgor and the tendency of the elderly to be more sedentary with the legs in a dependent position. Treatment of heart failure in the elderly involves many of the same methods as in younger persons, with medication dose adaptations to reduce age-related adverse and toxic events.2 ACE inhibitors may be particularly beneficial to preserve cognitive and functional capacities.2 Activities are restricted to a level that is commensurate with the cardiac reserve. Seldom is bed rest recommended or advised. Bed rest causes rapid deconditioning of skeletal muscles and increases the risk of complications such as

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orthostatic hypotension and thromboemboli. Instead, carefully prescribed exercise programs can help to maintain activity tolerance. Even walking around a room usually is preferable to continuous bed rest. Sodium restriction usually is indicated.

IN SUMMARY,

the mechanisms of heart failure in children and the elderly are similar to those in adults. However, the causes and manifestations may differ because of age. In children, heart failure is seen most commonly during infancy and immediately after heart surgery. It can be caused by congenital and acquired heart defects and is characterized by fatigue, effort intolerance, cough, anorexia, abdominal pain, and impaired growth. Treatment of heart failure in children includes correction of the underlying cause whenever possible. For congenital anomalies that are amenable to surgery, medical treatment often is needed for a time before surgery and usually is continued in the immediate postoperative period. For many children, only medical management can be provided. In the elderly, age-related changes in cardiovascular functioning contribute to heart failure but are not in themselves sufficient to cause heart failure. The manifestations of heart failure often are different and superimposed on other disease conditions; therefore, heart failure often is more difficult to diagnose in the elderly than in younger persons. Because the elderly are more susceptible to adverse and toxic medication reactions, medication doses need to be adapted and more closely monitored. ■

Review Exercises 1. A 75-year-old woman with long-standing hypertension and angina due to coronary heart disease presents with ankle edema, nocturia, increased shortness of breath with activity, and a chronic nonproductive cough. Her blood pressure is 170/80 and her heart rate 92. Electrocardiography and chest radiography indicate the presence of left ventricular hypertrophy. A. Relate the presence of uncontrolled hypertension and coronary artery disease to the development of heart failure in this woman. B. Explain the significance of left ventricular hypertrophy in terms of both a compensatory mechanism and as a pathologic mechanism in the progression of heart failure. C. Use Figure 26-2 to explain this woman’s symptoms, including shortness of breath and nonproductive cough. 2. A 26-year-old man is admitted to the emergency department after an automobile injury with excessive blood loss. He is alert and anxious, his skin is cool and moist, his heart rate is 135, and his blood pressure is

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100/85. He is receiving intravenous fluids, which were started at the scene of the accident by an emergency medical technician. He has been typed and crossmatched for blood transfusions and a urinary catheter has been inserted to monitor his urinary output. His urinary output has been less than 10 mL since admission and his blood pressure has dropped to 85/70. Efforts to control his bleeding have been unsuccessful and he is being prepared for emergency surgery. A. Use information regarding the compensatory mechanisms in circulatory shock to explain this man’s presenting symptoms, including urinary output. B. Use Figure 26-11 to hypothesize about this man’s blood loss and maintenance of blood pressure. C. The treatment of hypovolemic shock is usually directed at maintaining the circulatory volume through fluid resuscitation rather than maintaining the blood pressure through the use of vasoactive medications. Explain.

References 1. Hunt S. A., Abraham W. T., Chin M. H., et al. (2005). ACC/AHA 2005 guidelines for diagnosis and management of chronic heart failure in the adult. Circulation 112, e154–e235. 2. Arnold J. M. O., Liu P., Demers C., et al. (2006). Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: Diagnosis and management. Canadian Journal of Cardiology 22, 23–45. 3. American Heart Association. (2007). Heart disease and stroke statistics: 2007 update at a glance. [Online.] Available: www.americanheart.org/ downloadable/heart/1166711577754HS_StatsInsideText.pdf. Accessed March 4, 2007. 4. Chow C. M., Donovan L., Manuel D., et al. (2005) Regional variation in self-reported heart disease prevalence in Canada [abstract]. Canadian Journal of Cardiology 21, 1265–1271. 5. Guyton A. C., Hall J. E. (2006). Textbook of medical physiology (11th ed., pp. 103–115, 264, 278–288). Philadelphia: Elsevier Saunders. 6. Klabunde R. E. (2005). Cardiovascular physiology concepts. Philadelphia: Lippincott Williams & Wilkins. 7. Opie L. H. (2005). Mechanisms of cardiac contraction and relaxation. In Zipes D. P., Libbey P., Bonow R. O., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (7th ed., pp. 457–489). Philadelphia: Elsevier Saunders. 8. Carroll J. D., Hess O. M. (2005). Assessment of normal and abnormal cardiac function. In Zipes D. P., Libbey P., Bonow R. O., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (7th ed., pp. 491–507). Philadelphia: Elsevier Saunders. 9. Wu E. B., Yu C. M. (2005). Management of diastolic heart failure: A practical review of pathophysiology and treatment trial data. International Journal of Clinical Practice 59, 1239–1246. 10. Fletcher L., Thomas D. (2001). Congestive heart failure: Understanding the pathophysiology and management. Journal of the American Academy of Nurse Practitioners 13, 249–257. 11. Givertz M. M., Colucci W. S., Braunwald E. (2005). Clinical aspects of heart failure: Pulmonary edema, high-output failure. In Zipes D. P., Libbey P., Bonow R. O., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (7th ed., pp. 539–568). Philadelphia: Elsevier Saunders.

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12. Aurigemma G. P., Gaasch W. H. (2004). Diastolic heart failure. New England Journal of Medicine 351, 1095–1105. 13. Haney S., Sur D., Xu Z. (2005). Diastolic heart failure: A review and primary care perspective. Journal of the American Board of Family Practice 18, 189–195. 14. Colucci W. C. (2005). Pathophysiology of heart failure. In Zipes D. P., Libbey P., Bonow R. O., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (7th ed., pp. 509–568). Philadelphia: Elsevier Saunders. 15. Budev M. M., Arroliga A. C., Wiedemann H. P., et al. (2003). Cor pulmonale: An overview. Seminars in Respiratory Critical Care Medicine 23, 233–243. 16. Francis G. S., Tang W. H. W. (2003). Pathophysiology of congestive heart failure. Reviews in Cardiovascular Medicine 4(Suppl. 2), S14–S20. 17. Adams K. F. (2004). Pathophysiologic role of the renin-angiotensinaldosterone and sympathetic nervous system in HF. American Journal of Health-System Pharmacy 61(Suppl. 2), S4–S13. 18. Weber K. T. (2001). Aldosterone in congestive heart failure. New England Journal of Medicine 345, 1689–1697. 19. Struthers A. D. (2005). Pathophysiology of heart failure following myocardial infarction. Heart 91, 14–16. 20. Pitt B., Zannad F., Remme W. J., et al. (1999). The effect of spironolactone on morbidity and mortality in patients with severe heart failure. New England Journal of Medicine 341, 709–717. 21. Levin E. R., Gardner D. G., Samson W. K. (1998). Natriuretic peptides. New England Journal of Medicine 339, 321–328. 22. Baughman K. L. (2002). B-type natriuretic peptide: A window to the heart. New England Journal of Medicine 347, 158–159. 23. Nathisuwan S., Talbert R. L. (2002). A review of vasopeptidase inhibitors: A new modality in the treatment of hypertension and chronic heart failure. Pharmacotherapy 22, 27–42. 24. Spieker L. E., Lüscher T. F. (2003). Will endothelin receptor antagonists have a role in heart failure? Medical Clinics of North America 87, 459–474. 25. Ergul A. (2002). Endothelin-1 and endothelin receptor antagonists as potential cardiovascular therapeutic agents. Pharmacotherapy 22, 54–65. 26. Kardys I., Knetsch A. M., Bleumink G. S., et al. (2006). C-reactive protein and risk of heart failure: The Rotterdam Study. American Heart Journal 152, 514–520. 27. Estes N. A. M. III. (2006). Implantable cardioverter defibrillator and cardiac resynchronization therapy in patients with left ventricular dysfunction: Evidence based medicine, economics, and guidelines: CME. [Online.] Available:www.medscape.com/viewprogram/5242. Accessed February 24, 2007. 28. Hunter J. J., Chien K. R. (1999). Signaling pathways for cardiac hypertrophy and failure. New England Journal of Medicine 341, 1276–1284. 29. Gheorghiade M., Zannad F., Sopko G., et al. (2005). Acute heart failure syndrome: Current state and framework for future research. Circulation 112, 3958–3968. 30. Nieminen M. S., Harjola V.-P. (2005). Definition and epidemiology of acute heart failure syndrome. American Journal of Cardiology 95 (Suppl. G), 5G–10G. 31. Filippatos G., Zannad F. (2007). An introduction to acute heart failure syndromes: Definition and classification. Heart Failure Review 12, 87–90. 32. Brack T. (2003). Cheyne-Stokes respiration in patients with congestive heart failure. Swiss Medical Weekly 133, 605–610. 33. Crijns H. J., Tjeerdsma G., De Kam P. J., et al. (2000). Prognostic value of the presence and development of atrial fibrillation in patients with advanced chronic HF. European Heart Journal 21, 1238–1245. 34. Arnold J. M. O., Howlett J. G., Dorian P., et al. (2007). Canadian Cardiovascular Society consensus conference recommendations on heart failure update 2007: Prevention, management during intercurrent illness or acute decompensation, and use of biomarkers. Canadian Journal of Cardiology, 23, 21–45. [Online.] Available: www.ccs.ca/ consensus_conferences/cc_library_e.aspx. Accessed March 4, 2007. 35. Nolan P. E. (2004). Integrating traditional and emerging treatment options in heart failure. American Journal of Health-System Pharmacy 61(Suppl. 2), S14–S22.

36. Piña H. L. (Chair, Writing Group). (2003). Exercise and heart failure: A statement from the American Heart Association Committee on Exercise, Rehabilitation, and Prevention. Circulation 107, 1210–1225. 37. Bristow M. R., Linas S., Port J. D. (2005). Drugs in treatment of heart failure. In Zipes D. P., Libbey P., Bonow R. O., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (7th ed., pp. 569–601). Philadelphia: Elsevier Saunders. 38. MERIT-HF Study Group. (1999). Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353, 2001–2007. 39. Dee W. J. (2003). Digoxin remains useful in the management of chronic heart failure. Medical Clinics of North America 87, 317–337. 40. Hachey D. M., Smith T. (2003). Use of nesiritide to treat acute decompensated HF. Critical Care Nurse 23, 53–55. 41. Stoltzfus S. (2006). The role of noninvasive ventilation: CPAP and BiPAP in the treatment of congestive HF. Dimensions of Critical Care Nursing 25(2), 66–70. 42. Bendjelid K., Schutz N., Suter P. M., et al. (2005). Does continuous positive airway pressure by face mask improve patients with acute cardiogenic pulmonary edema due to left ventricular diastolic dysfunction? Chest 127, 1053–1056. 43. Albert N. M. (2003). Cardiac resynchronization therapy through biventricular pacing in patients with HF and ventricular dyssynchrony. Critical Care Nurse 23(June Suppl.), 2–13. 44. Wheeldon D. R. (2003). Mechanical circulatory support: State of the art and future perspectives. Perfusion 8, 233–243. 45. Hunt S. A., Kouretas P. C., Balsam L. B., et al. (2005). Heart transplantation. In Zipes D. P., Libbey P., Bonow R. W., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (7th ed., pp. 641–651). Philadelphia: Elsevier Saunders. 46. Vilquin J. T., Marolleau J. P. (2004). Cell transplantation in heart failure management [abstract]. Médecine Sciences 20(6–7), 651–662. 47. Giordano A., Galderisi U., Marino I. R. (2007). From the laboratory bench to the patient’s bedside: An update on clinical trials with mesenchymal stem cells [abstract]. Journal of Cell Physiology 211, 27–35. 48. Patel N. D., Barreiro C. J., Williams J. A., et al. (2005). Surgical ventricular remodeling for patients with clinically advanced congestive HF and severe left ventricular dysfunction. Journal of Heart and Lung Transplantation 24, 2202–2210. 49. Holmes C. L., Walley K. R. (2003). The evaluation and management of shock. Clinical Chest Medicine 24, 775–789. 50. Aymong E. D., Ramanathan K., Buller C. E. (2007). Pathophysiology of cardiogenic shock complicating acute myocardial infarction. Medical Clinics of North America 91, 701–712. 51. Antman E. M. (2005). Cardiogenic shock. In Zipes D. P., Libbey P., Bonow R. O., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (7th ed., pp. 1200–1202). Philadelphia: Elsevier Saunders. 52. Parrillo J. E. (1995). Pathogenic mechanisms of septic shock. New England Journal of Medicine 328, 1471–1477. 53. Hollenberg S. M., Kavinsky C. J., Parrillo J. E. (1999). Cardiogenic shock. Annals of Internal Medicine 131, 47–59. 54. Hochmann J. S. (2003). Cardiogenic shock complicating acute myocardial infarction: Expanding the paradigm. Circulation 107, 2998–3002. 55. Naka Y., Chen J. M., Rose E. A. (2005). Assisted circulation in the treatment of heart failure. In Zipes D. P., Libbey P., Bonow R. O., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (7th ed., pp. 625–640). Philadelphia: Elsevier Saunders. 56. Antman E. M., Anbe D. T., Armstrong P. W., et al. (2004). ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: Executive summary: A report of the ACC/AHA Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines on the Management of Patients with Acute Myocardial Infarction). Journal of the American College of Cardiology 44, 671–719. 57. Kelley D. M. (2005). Hypovolemic shock. Critical Care Nursing Quarterly 28(1), 2–19.

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Chapter 26 Heart Failure and Circulatory Shock 58. Dutton R. P. (2007). Current concepts in hemorrhagic shock. Anesthesiology Clinics 25, 23–34. 59. Landry D. W., Oliver J. A. (2001). The pathogenesis of vasodilatory shock. New England Journal of Medicine 345, 588–595. 60. Lieberman P. (2006). Anaphylaxis. Medical Clinics of North America 90, 77–95. 61. Brown S. G. A. (2007). The pathophysiology of shock in anaphylaxis. Immunology and Allergy Clinics of North America 27, 165–175. 62. Ellis A. K., Day J. H. (2003). Diagnosis and management of anaphylaxis. Canadian Medical Association Journal 169, 307–312. 63. Stankiewicz J., Ruta W., Gorski P. (1995). Latex allergy. International Journal of Occupational Medicine and Environmental Health 8, 139–148. 64. Levy M. M., Fink M. P., Marshall J. C., et al. (2003). SCCM/ESICM/ ACCP/ATS/SIS International sepsis definitions conference. Critical Care Medicine 31, 1250–1256. 65. Nguyen H. B., Rivers E. P., Abrahamian F. M. (2006). Severe sepsis and septic shock: Review of the literature and emergency department management guidelines. Annals of Emergency Medicine 48, 28–54. 66. Russell J. A. (2006). Management of sepsis. New England Journal of Medicine 355, 1699–1711. 67. Howell G., Tisherman S. A. (2006). Management of sepsis. Surgical Clinics of North America 86, 1523–1539. 68. Vincent J. L., Taccone F., Schmit X. (2007). Classification, incidence, and outcomes of sepsis and multiple organ failure. Contributions to Nephrology 156, 64–74. 69. Annane D., Bellissant I., Cavaillon J.-M. (2005). Septic shock. Lancet 365, 63–78. 70. Rivers E. P., McIntyre L., Morro D. C., et al. (2005). Early and innovative interventions for severe sepsis and septic shock: Taking advantage of the window of opportunity. Canadian Medical Association Journal 173, 1054–1065. 71. Gullo A., Bianco N., Berlot G. (2006). Management of severe sepsis and septic shock: Challenges and recommendations. Critical Care Clinics 22, 489–501. 72. Van den Berghe G., Woulters P., Weekers F., et al. (2001). Intensive insulin therapy in critically ill patients. New England Journal of Medicine 345, 1359–1367. 73. Smith J. J., Kampine J. P. (1980). Circulatory physiology (p. 298). Baltimore: Williams & Wilkins.

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74. Abraham, E. (2003). Neutrophils and acute lung injury. Critical Care Medicine 31, S195–S199. 75. Ausiello D. A., Benos D. J., Aboud F., et al. (2004). The acute respiratory distress syndrome. Annals of Internal Medicine 141, 460–470. 76. Rubenfeld, G. D., Herridge M. S. (2007). Epidemiology and outcomes of acute lung injury. Chest 131, 554–562. 77. Fink M. (1991). Gastrointestinal mucosal injury in experimental models of shock, trauma and sepsis. Critical Care Medicine 19, 627–641. 78. Levi M., Ten Cate H. T. (1999). Disseminated intravascular coagulation. New England Journal of Medicine 341, 586–592. 79. Balk R. A. (2000). Pathogenesis and management of multiple organ dysfunction or failure in acute sepsis and septic shock. Critical Care Clinics 16, 337–352. 80. Bernstein D. (2004). Heart failure. In Behrman R. E., Kliegman R. M., Nelson W., Jenson H. B. (Eds.), Nelson textbook of pediatrics (17th ed., pp. 1582–1587). Philadelphia: Elsevier Saunders. 81. Kay J. D., Colan S. D., Graham T. P. (2001). Congestive heart failure in pediatric patients. American Heart Journal 142, 923–928. 82. O’Laughlin M. P. (1999). Congestive heart failure in children. Pediatric Clinics of North America 46, 263–273. 83. Rosenthal D., Chrisant M., Edens E., et al. (2004). International Society for Heart and Lung Transplantation: Practice guidelines for management of heart failure in children. Journal of Heart and Lung Transplantation 23, 1313–1333. 84. Thomas S., Rich M. W. (2007). Epidemiology, pathophysiology, and prognosis of heart failure in the elderly. Clinics in Geriatric Medicine 23, 1–10. 85. Schwartz J. B., Zipes D. P. (2005). Cardiovascular disease in the elderly. In Zipes D. P., Libbey P., Bonow R. O., et al. (Eds.), Braunwald’s heart disease: A textbook of cardiovascular medicine (7th ed., pp. 1925–1949). Philadelphia: Elsevier Saunders. 86. Rich M. W. (2006). Heart failure in older adults. Medical Clinics of North America 90, 863–885. 87. Abdelhafiz A. H. (2002). Heart failure in older people: Causes, diagnosis, and treatment. Age and Aging 31, 29–36.

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U N I T • VII

Disorders of Respiratory Function In the early studies of the body, there is almost no mention of the lungs or respiratory passages. Although the pneuma, or “vital spirits,” of the body were closely related to the air and vapors of the universe, the lungs and air passages were almost disregarded. It was not until the circulation of blood had been charted that real progress in understanding the respiratory system took place. A major step in the understanding of respiration began with the work of Robert Boyle (1627–1691), an Irish scholar. Using an air pump, Boyle proved that a candle would not burn and a small bird or mouse could not live inside a jar from which the air had been removed. Scientists at this time believed that when something burned, air lost a mysterious substance called phlogiston. It was the British clergyman Joseph Priestley (1733–1804) who discovered that a gas made by heating oxide of mercury supported combustion. He called this gas, which later became known as oxygen, dephlogisticated air. Priestley showed that a mouse lived longer in a given volume of dephlogisticated air than it did in ordinary air. Antoine Lavoisier (1743–1794), a French chemist, confirmed that oxygen was present in inspired air and carbon dioxide in expired air and gave oxygen its name. In 1791, just 16 years after Priestley’s discovery of oxygen, it was shown that blood contained both oxygen and carbon dioxide. From this point on, a detailed understanding of the respiratory system and its function proceeded rapidly.

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Structure and Function of the Respiratory System CAROL M. PORTH AND KIM LITWACK

STRUCTURAL ORGANIZATION OF THE RESPIRATORY SYSTEM Conducting Airways Nasopharyngeal Airways Larynx Tracheobronchial Tree Lungs and Respiratory Airways Alveoli Pulmonary Vasculature and Lymphatic Supply Pulmonary and Bronchial Circulations Lymphatic Circulation Innervation Pleura EXCHANGE OF GASES BETWEEN THE ATMOSPHERE AND THE LUNGS Basic Properties of Gases Ventilation and the Mechanics of Breathing Respiratory Pressures Chest Cage and Respiratory Muscles Lung Compliance Airway Airflow Lung Volumes Pulmonary Function Studies Efficiency and the Work of Breathing EXCHANGE AND TRANSPORT OF GASES Ventilation Distribution of Ventilation Dead Air Space Perfusion Distribution of Blood Flow Hypoxia-Induced Vasoconstriction Shunt Mismatching of Ventilation and Perfusion Diffusion Oxygen and Carbon Dioxide Transport Oxygen Transport Carbon Dioxide Transport CONTROL OF BREATHING Respiratory Center Regulation of Breathing Chemoreceptors Lung Receptors Cough Reflex Dyspnea 640

➤ The primary function of the respiratory system, which consists of the airways and lungs, is gas exchange. Oxygen from the air is transferred to the blood and carbon dioxide from the blood is eliminated into the atmosphere. In addition to gas exchange, the lungs serve as a host defense by providing a barrier between the external environment and the inside of the body. Finally, the lung is also a metabolic organ that synthesizes and metabolizes different compounds. This chapter focuses on the structural organization of the respiratory system; exchange of gases between the atmosphere and the lungs; exchange of gases in the lungs and its transport in the blood; and control of breathing. The function of the red blood cell in the transport of oxygen is discussed in Chapter 14.

STRUCTURAL ORGANIZATION OF THE RESPIRATORY SYSTEM After completing this section of the chapter, you should be able to meet the following objectives: ■ ■

■ ■

■ ■

State the difference between the conducting and the respiratory airways. Trace the movement of air through the airways, beginning in the nose and oropharynx and moving into the respiratory tissues of the lung. Describe the function of the mucociliary blanket. Compare the supporting structures of the large and small airways in terms of cartilaginous and smooth muscle support. State the function of the two types of alveolar cells. Differentiate the function of the bronchial and pulmonary circulations that supply the lungs.

The respiratory system consists of the air passages, the two lungs and the blood vessels that supply them, and the structures that provide a ventilator mechanism, that is, the rib cage and the respiratory muscles, which includes the diaphragm—the

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principal respiratory muscle. Functionally, the respiratory system can be divided into two parts: the conducting airways, through which air moves as it passes between the atmosphere and the lungs, and the respiratory tissues of the lungs, where gas exchange takes place. The lungs are soft, spongy, cone-shaped organs located side by side in the chest cavity (Fig. 27-1). They are separated from each other by the mediastinum (i.e., the space between the lungs) and its contents—the heart, blood vessels, lymph nodes, nerve fibers, thymus gland, and esophagus. The upper part of the lung, which lies against the top of the thoracic cavity, is called the apex, and the lower part, which lies against the diaphragm, is called the base. The lungs are divided into lobes: three in the right lung and two in the left.

CONDUCTING AND RESPIRATORY AIRWAYS ■

■

■

Respiration requires ventilation, or movement of gases into and out of the lungs; perfusion, or movement of blood through the lungs; and diffusion of gases between the lungs and the blood. Ventilation depends on the conducting airways, including the nasopharynx and oropharynx, larynx, and tracheobronchial tree, which move air into and out of the lungs but do not participate in gas exchange. Gas exchange takes place in the respiratory airways of the lungs, where gases diffuse across the alveolarcapillary membrane as they are exchanged between the air in the lungs and the blood that flows through the pulmonary capillaries.

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Conducting Airways The conducting airways consist of the nasal passages, mouth and pharynx, larynx, trachea, bronchi, and bronchioles (see Fig. 27-1). Besides functioning as a conduit for airflow, the conducting airways serve to “condition” the inspired air. The air we breathe is warmed, filtered, and moistened as it moves through these structures. Heat is transferred to the air from the blood flowing through the walls of the respiratory passages; the mucociliary blanket removes foreign materials; and water from the mucous membranes is used to moisten the air. A combination of cartilage, elastic and collagen fibers, and smooth muscle provides the airways with the rigidity and flexibility needed to maintain airway patency and ensure an uninterrupted supply of air. Most of the conducting airways are lined with ciliated pseudostratified columnar epithelium, containing a mosaic of mucus-secreting glands, ciliated cells with hairlike projections, and serous glands that secrete a watery fluid containing antibacterial enzymes (Fig. 27-2). The epithelial layer gradually becomes thinner as it moves from the pseudostratified epithelium of the bronchi to cuboidal epithelium of the bronchioles and then to squamous epithelium of the alveoli. The mucus produced by the epithelial cells in the conducting airways forms a layer, called the mucociliary blanket, that protects the respiratory system by entrapping dust, bacteria, and other foreign particles that enter the airways. The cilia, which are in constant motion, move the mucociliary blanket with its entrapped particles in an escalator-like fashion toward the oropharynx, from which it is expectorated or swallowed. The function of cilia in clearing the lower airways is optimal at normal oxygen levels and is impaired when oxygen levels are higher or lower than normal. It is also impaired by drying conditions, such as breathing heated but unhumidified indoor air during the winter months. Cigarette smoking slows down or paralyzes the motility of the cilia. This slowing allows the

Nasopharynx Oropharynx

Rib

Epiglottis Trachea Intrapulmonary bronchus

Larynx

Intercostal muscle

Extrapulmonary bronchus Alveoli

Parietal pleura Pleural space Lung

Respiratory bronchiole

Diaphragm

FIGURE 27-1 • Structures of the respiratory system. The structures of the pleura are shown in the inset.

Esophagus

Visceral pleura

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Mucous blanket Cilia Goblet cell Pseudostratified epithelium

BRONCHIOLE

ALVEOLUS

Simple epithelium

FIGURE 27-2 • Airway wall structure: bronchus, bronchiole, and alveolus. The bronchial wall contains pseudostratified epithelium, smooth muscle cells, mucous glands, connective tissue, and cartilage. In smaller bronchioles, a simple epithelium is found, cartilage is absent, and the wall is thinner. The alveolar wall is designed for gas exchange, rather than structural support. (From Weibel E. R., Taylor R. C. [1988]. Design and structure of the human lung. In Fishman A. P. [Ed.], Pulmonary diseases and disorders [Vol. 1., p. 14]. New York: McGraw-Hill.)

Smooth muscle Mucous gland Submucosal connective tissue

Cartilage

residue from tobacco smoke, dust, and other particles to accumulate in the lungs, decreasing the efficiency of this pulmonary defense system. As discussed in Chapter 29, these changes are thought to contribute to the development of chronic bronchitis and emphysema. The conducting airways are kept moist by water contained in the mucous membranes of the upper airways and the tracheobronchial tree. The capacity of the air to contain moisture without condensation increases as the temperature rises. Thus, the air in the alveoli, which is maintained at body temperature, usually contains considerably more moisture than the atmospheretemperature air that we breathe. The difference between the moisture contained in the air we breathe and that found in the alveoli is drawn from the moist surface of the mucous membranes that line the conducting airways and is a source of insensible water loss. Under normal conditions, approximately 1 pint of water per day is lost in humidifying the air breathed. During fever, the water vapor in the lungs increases, causing more water to be lost from the respiratory mucosa. Also, fever usually is accompanied by an increase in respiratory rate so that more air needing to be moisturized passes through the airways. As a result, respiratory secretions thicken, preventing free movement of the cilia and impairing the protective function of the mucociliary defense system. This is particularly true in persons whose water intake is inadequate.

Nasopharyngeal Airways The nose is the preferred route for the entrance of air into the respiratory tract during normal breathing. As air passes through the nasal passages, it is filtered, warmed, and humidified. The outer nasal passages are lined with coarse hairs, which filter and trap dust and other large particles from the air. The upper portion of the nasal cavity is lined with a mucous membrane that contains a rich network of small blood vessels; this portion of the nasal cavity supplies warmth and moisture to the air we breathe. The mouth serves as an alternative airway when the nasal passages are plugged or when there is a need for the exchange of large amounts of air, as occurs during exercise. The oropharynx extends posteriorly from the soft palate to the epiglottis. The oropharynx is the only opening between the nose and mouth and

the lungs. Both swallowed food on its way to the esophagus and air on its way to the larynx pass through it. Obstruction of the oropharynx leads to immediate cessation of ventilation. Neural control of the tongue and pharyngeal muscles may be impaired in coma and other neurologic disorders. In these conditions, the tongue falls back into the pharynx and obstructs the airway, particularly if the person is lying on his or her back. Swelling of the pharyngeal structures caused by injury, infection, or severe allergic reaction also predisposes a person to airway obstruction, as does the presence of a foreign body.

Larynx The larynx connects the oropharynx with the trachea. The walls of the larynx are supported by firm cartilaginous structures that prevent collapse during inspiration. The functions of the larynx can be divided into two categories: those associated with speech and those associated with protecting the lungs from substances other than air. The larynx is located in a strategic position between the upper airways and the lungs and sometimes is referred to as the “watchdog of the lungs.” The cavity of the larynx is divided into two pairs of shelflike folds stretching from front to back with an opening in the midline (Fig. 27-3). The upper pair of folds, called the vestibular folds, has a protective function. The lower pair of folds, called the vocal folds, produces the vibrations required for making vocal sounds. The vocal folds and the elongated opening between them are called the glottis. A complex set of muscles controls the opening and closing of the glottis. The epiglottis, which is located above the larynx, is a large, leafshaped piece of cartilage that is covered with epithelium. When only air is flowing through the larynx, the inlet of the larynx is open and the free edges of the epiglottis point upward. During swallowing, the larynx is pulled superiorly and the free edges of the epiglottis move downward to cover the larynx, thus routing liquids and foods into the esophagus. In addition to opening and closing the glottis for speech, the vocal folds of the larynx can perform a sphincter function, closing off the airways. When confronted with substances other than air, the laryngeal muscles contract and close off the airway. At the same time, the cough reflex is initiated as a means of

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Epiglottis

Epiglottis Glottis

Vestibular folds (false vocal cords) Vocal folds (true vocal cords)

FIGURE 27-3 • (A) Coronal section showing the position of the epiglottis, the vestibular folds (true vocal cords), and vocal folds (false vocal cords), and glottis. (B) Vocal cords viewed from above with glottis closed and (C) with glottis open.

Trachea

A

removing a foreign substance from the airway. If the swallowing mechanism is partially or totally paralyzed, food and fluids can enter the airways instead of the esophagus when a person attempts to swallow. These substances are not easily removed; and when they are pulled into the lungs, they can cause a serious inflammatory condition called aspiration pneumonia.

Tracheobronchial Tree The tracheobronchial tree, which consists of the trachea, bronchi, and bronchioles, can be viewed as a system of branching tubes. It is similar to a tree whose branches become smaller and more numerous as they divide (Fig. 27-4A). There are approximately 23 levels of branching, beginning with the conducting airways and ending with the respiratory airways, where gas exchange takes place (see Fig. 27-4B). The trachea, or windpipe, is a continuous tube that connects the larynx and the major bronchi of the lungs. The walls of the trachea are supported by horseshoe- or C-shaped rings of hyaline cartilage, which prevent it from collapsing when the pressure in the thorax becomes negative (Fig. 27-5). The open part of the C ring, which abuts the esophagus, is connected by smooth muscle. Since this portion of the trachea is not rigid, the esophagus can expand anteriorly as swallowed food passes through it. The trachea extends to the superior border of the fifth thoracic vertebra, where it divides to form the right and left main or primary bronchi. Between the main bronchi is a keel-like ridge, called the carina (Fig. 27-6). The mucosa of the carina is highly sensitive; violent coughing is initiated when a foreign object (e.g., suction catheter) makes contact with it. The structure of the primary bronchi is similar to that of the trachea in

False vocal cord

B True vocal cord

Inner lining of trachea

C

that these airways are lined with a mucosal surface and supported by cartilaginous rings. Each primary bronchus, accompanied by the pulmonary arteries, veins, and lymph vessels, enters the lung through a slit called the hilum. On entering the lungs, each primary bronchus divides into secondary or lobular bronchi that supply each of the lobes of the lung—three in the right lung and two in the left (see Fig. 27-6). The right middle lobe bronchus is of relatively small diameter and length and sometimes bends sharply near its bifurcation. It is surrounded by a collar of lymph nodes that drain the middle and the lower lobe and is particularly subject to obstruction. The secondary bronchi, in turn, divide to form the segmental bronchi, which supply the bronchopulmonary segments of the lung. There are 10 segments on the right lung and 9 on the left (Fig. 27-7). These segments are identified according to their location in the lung (e.g., the apical segment of the right upper lobe) and are the smallest named units in the lung. Lung disorders such as atelectasis and pneumonia often are localized to a particular bronchopulmonary segment. The structure of the secondary and segmental bronchi is similar, for the most part, to that of the primary bronchi; however, the C-shaped cartilage rings are replaced by irregular plates of hyaline cartilage that completely surround the lumina of the bronchi, and there are two layers of smooth muscle spiraling in opposite directions (Fig. 27-8). The segmental bronchi continue to branch, forming smaller bronchi, until they become the terminal bronchioles, the smallest of the conducting airways. As these bronchi branch and become smaller, their wall structure changes. The cartilage gradually decreases and there is an increase in smooth muscle and elastic tissue (with respect to the thickness of the wall). By the time the bronchioles are reached, there is no cartilage present and their walls are composed mainly of smooth muscle and

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Z Trachea

Trachea

Conducting zone

0

Left primary bronchus Secondary bronchi

1

BR

2 3

BL

4

TBL Segmental bronchi Transit and respiratory zone

17

Terminal bronchioles

A

B

RBL

18 19

AD

20 21 22

AS

23

FIGURE 27-4 • (A) Conducting and respiratory air pathways inferior to the larynx. (From Anatomic Chart Company. Atlas of human anatomy [p. 175]. Springhouse, PA: Springhouse.) (B) Idealization of the human airways. The first 16 generations of branching (Z) make up the conducting airways, and the last 7 constitute the respiratory zone (or transitional and respiratory zone). BR, bronchus; BL, bronchiole; TBL, terminal bronchiole; RBL, respiratory bronchiole; AD, alveolar ducts; AS, alveolar sacs. (From Weibel E. R. [1962]. Morphometry of the human lung [p. 111]. Berlin: Springer-Verlag.)

Posterior Esophagus

elastic fibers. Bronchospasm, or contraction of these muscles, causes narrowing of the bronchioles and impairs air flow. The elastic fibers, which radiate from the outer layer of the bronchial wall and connect with elastic fibers arising from other parts of the bronchial tree, exert tension on the bronchial walls; by pulling uniformly in all directions, they help maintain airway patency.

Lungs and Respiratory Airways Trachealis muscle

Lumen of trachea

Hyaline cartilage

Ciliated epithelium Anterior

FIGURE 27-5 • Cross-section of the trachea, illustrating its relationship to the esophagus, the position of the supporting hyaline cartilage rings in its wall, and the trachealis muscle connecting the free ends of the cartilage rings.

The lungs are the functional structures of the respiratory system. In addition to their gas exchange function, they inactivate vasoactive substances such as bradykinin; they convert angiotensin I to angiotensin II; and they serve as a reservoir for blood storage. Heparin-producing cells are particularly abundant in the capillaries of the lung, where small clots may be trapped. The gas exchange function of the lung takes place in the lobules of the lungs. Each lobule, which is the smallest functional unit of the lung, is supplied by a branch of a terminal bronchiole, an arteriole, the pulmonary capillaries, and a venule (see Fig. 27-8). Gas exchange takes place in the terminal respiratory bronchioles and the alveolar ducts and sacs. Blood enters the lobules through a pulmonary artery and exits through a pulmonary vein. Lymphatic structures surround the lobule and aid in the removal of plasma proteins and other particles from the interstitial spaces.

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Carina Right main bronchus

B

Left mainstem bronchus

Left main bronchus

Left pulmonary artery

Right main bronchus Right superior lobe bronchus

Left pulmonary veins

Superior lobe Middle lobe Right middle lobe bronchus

Right inferior lobe bronchus Inferior lobe

A

Left

Right

FIGURE 27-6 • (A) Anterior view of respiratory structures, including the lobes of the lung, the larynx, trachea, and the main bronchi on the left and the main pulmonary artery and vein on the right. (B) The carina is located at the bifurcation of the right and left mainstem bronchi.

Air

Lymphatics

Bronchiole

1 1 2

Smooth muscle

2

3 3

Pulmonary vein

4

6

Pulmonary capillaries

5 10

9

6

5

4

Pulmonary artery

8

7

10

9 8

FIGURE 27-7 • Bronchopulmonary segments of the human lung. Left and right upper lobes: (1) apical, (2) posterior, (3) anterior, (4) superior lingular, and (5) inferior lingular segments. Right middle lobe: (4) lateral and (5) medial segments. Lower lobes: (6) superior (apical), (7) medial-basal, (8) anterior-basal, (9) lateralbasal, and (10) posterior-basal segments. The medial-basal segment (7 ) is absent in the left lung. (From Fishman A. P. [1980]. Assessment of pulmonary function [p. 19]. New York: McGraw-Hill.)

Pores of Kohn

Alveoli

FIGURE 27-8 • Lobule of the lung, showing the bronchial smooth muscle fibers, pulmonary blood vessels, and lymphatics.

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Unlike the larger bronchi, the respiratory bronchioles are lined with simple epithelium rather than ciliated pseudostratified epithelium (see Fig. 27-2). The respiratory bronchioles also lack the cartilaginous support of the larger airways. Instead, they are attached to the elastic spongelike tissue that contains the alveolar air spaces.

Macrophage Basal lamina Erythrocyte

Type I alveolar cell

Alveoli The alveoli are the terminal air spaces of the respiratory tract and the actual sites of gas exchange between the air and the blood. Each alveolus is a small outpouching of respiratory bronchioles, alveolar ducts, and alveolar sacs (see Fig. 27-8). The alveolar sacs are cup-shaped, thin-walled structures that are separated from each other by thin alveolar septa. A single network of capillaries occupies most of the septa, so blood is exposed to air on both sides. There are approximately 300 million alveoli in the adult lung, with a total surface area of approximately 50 to 100 m2. Unlike the bronchioles, which are tubes with their own separate walls, the alveoli are interconnecting spaces that have no separate walls (Fig. 27-9). As a result of this arrangement, there is a continual mixing of air in the alveolar structures. Small holes in the alveolar walls, the pores of Kohn, also contribute to the mixing of air.

Alveolar lumen

Type II alveolar cell Nucleus

Lamellar inclusion body Capillary lumen

Mitochondria

Surfactant

Endothelial cells

FIGURE 27-10 • Schematic illustration of type I and type II alveolar cells and their relationship to the alveoli and pulmonary capillaries. Type I alveolar cells comprise most of the alveolar surface. Type II alveolar cells, which produce surfactant, are located at the corners between adjacent alveoli. Also shown are the endothelial cells, which line the pulmonary capillaries, and an alveolar macrophage.

The alveolar epithelium is composed of two types of cells: type I and type II alveolar cells (Fig. 27-10). The alveoli also contain brush cells and macrophages. The brush cells, which are few in number, are thought to act as receptors that monitor the air quality of the lungs. The macrophages, which are present in both the alveolar lumen and the septum of the alveoli, function to remove offending material from the lung. Type I Alveolar Cells. The type I alveolar cells, also known as type I pneumocytes, are extremely thin squamous cells with a thin cytoplasm and flattened nucleus that occupy about 95% of the surface area of the alveoli. They are joined to one another and to other cells by occluding junctions. These junctions form an effective barrier between the air and the components of the alveolar wall. Type I alveolar cells are not capable of cell division.

FIGURE 27-9 • Close-up of a cross-section of a small bronchus and surrounding alveoli. (Courtesy of Janice A. Nowell, University of California, Santa Cruz.)

Type II Alveolar Cells. The type II alveolar cells, also called type II pneumocytes, are small cuboidal cells located at the corners of the alveoli. Type II cells are as numerous as type I cells, but because of their different shape, they cover only about 5% of the alveolar surface area. The type II cells synthesize pulmonary surfactant, a substance that decreases the surface tension in the alveoli and allows for greater ease of lung inflation. They are also the progenitor cells for type I cells. After lung injury, they proliferate and restore both type I and type II alveolar cells. Pulmonary surfactant is a complex mixture of phospholipids, neutral lipids, and proteins that is synthesized in the

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type II alveolar cells. Type II alveolar cells are rich in mitochondria and are metabolically active. Their apical cytoplasm contains stacks of parallel membrane sheets or lamellae, called the lamellar bodies. All of the components of surfactant are synthesized by the alveolar type II cells and stored as preformed units in the lamellar bodies. Secretion of surfactant occurs by exocytosis. The major route of clearance of surfactant within the lung is through reuptake by the type II cells. After reuptake, the phospholipids are either recycled or degraded and reused in the synthesis of new phospholipids. The surfactant molecules produced by the type II alveolar cells reduce the surface tension at the air–epithelium interface and modulate the immune functions of the lung. Recent research has revealed four types of surfactant, each with a different molecular structure: surfactant proteins A (SP-A), B (SP-B), C (SP-C), and D (SP-D). SP-B and SP-C reduce the surface tension at the air–epithelium interface and increase lung compliance and ease of lung inflation. SP-B is particularly important to the generation of the surface-reducing film that makes lung expansion possible (to be discussed). SP-A and SP-D do not reduce surface tension, but contribute to host defenses that protect against pathogens that have entered the lung. They are members of the collectin protein family that function as a part of the innate immune system (see Chapter 17). Collectively, they opsonize pathogens, including bacteria and viruses, to facilitate phagocytosis by macrophages. They also regulate the production of inflammatory mediators. Evidence also suggests that SP-A and SP-D are directly bactericidal, meaning they can kill bacteria in the absence of immune system effector cells. Alveolar Macrophages. The macrophages, which are present in both the connective tissue of the septum and in the air spaces of the alveolus, are responsible for the removal of offending substances from the alveoli. In the air spaces, they scavenge the surface to remove inhaled particulate matter, such as dust and pollen. Some macrophages pass up the bronchial tree in the mucus and are disposed of by swallowing or coughing when they reach the pharynx. Others enter the septal connective tissue, where, filled with phagocytosed materials, they remain for life. Thus, at autopsy, urban dwellers, as well as smokers, usually show many alveolar macrophages filled with carbon and other polluting particles from the environment. The alveolar macrophages also phagocytose insoluble infectious agents such as Mycobacterium tuberculosis. The activated macrophages then aggregate to form a fibrin-encapsulated granuloma, called a tubercle, to contain the infection. The tubercle bacillus can remain dormant in this stage or be reactivated years later, when the person’s immunologic tolerance wanes as the result of old age or immunosuppressive disease or therapy (see Chapter 28).

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from the pulmonary artery and provides for the gas exchange function of the lungs (see Fig. 27-8). Deoxygenated blood leaves the right heart through the pulmonary artery, which divides into a left pulmonary artery that enters the left lung and a right pulmonary artery that enters the right lung. Return of oxygenated blood to the heart occurs by way of the pulmonary veins, which empty into the left atrium. This is the only part of the circulation where arteries carry deoxygenated blood and veins carry oxygenated blood. The bronchial circulation distributes blood to the conducting airways and the supporting structures of the lung. The bronchial circulation has a secondary function of warming and humidifying incoming air as it moves through the conducting airways. The bronchial arteries arise from the thoracic aorta and enter the lungs with the major bronchi, dividing and subdividing along with the bronchi as they move out into the lung, supplying them and other lung structures with oxygen. The blood from the capillaries in the bronchial circulation drains into the bronchial veins, with the blood from the larger bronchial veins emptying into the vena cava. Blood from the smaller bronchial veins empties into the pulmonary veins. Because the bronchial circulation does not participate in gas exchange, this blood is deoxygenated. As a result, it dilutes the oxygenated blood returning to the left side of the heart through the pulmonary veins. The bronchial blood vessels are the only ones that can undergo angiogenesis (formation of new vessels) and develop collateral circulation when vessels in the pulmonary circulation are obstructed, as in pulmonary embolism. The development of new blood vessels helps to keep lung tissue alive until the pulmonary circulation can be restored.

Lymphatic Circulation The lungs are also supplied with lymphatic drainage that parallels that of their dual blood supply. One set of lymph vessels, the superficial vessels, drains the surface of the lung and travels in the connective tissue of the visceral pleura. A second set of the vessels, the deep lymphatic vessels, follows the pulmonary arteries, pulmonary veins, and bronchial tree down to the level of the respiratory bronchioles (see Fig. 27-8). Both of these systems have numerous interconnections and both form networks that drain into the hilar lymph nodes at the base of each lung. Particulate matter entering the lung is partly removed through these channels, as are the plasma proteins that have escaped from the pulmonary capillaries. The latter function is particularly important in keeping the lungs dry and in preventing the accumulation of fluid in the pleural cavity.

Innervation Pulmonary Vasculature and Lymphatic Supply Pulmonary and Bronchial Circulations The lungs are provided with a dual blood supply, the pulmonary and bronchial circulations. The pulmonary circulation arises

The lung is innervated by the sympathetic and parasympathetic divisions of the autonomic nervous system. It is parasympathetic stimulation, through the vagus nerve, that is responsible for the slightly constricted smooth muscle tone in the normal resting lung. There is no voluntary motor innervation of the lung, nor are there pain fibers. Pain fibers are found only in the pleura.

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Stimulation of the parasympathetic nervous system leads to airway constriction and increased glandular secretion. Parasympathetic innervation of the lung arises from the vagal nuclei in the medulla. Preganglionic fibers from the vagal nuclei descend in the vagus nerve to ganglia adjacent to the airways and blood vessels of the lung. Postganglionic fibers from the ganglia then complete the network that innervates smooth muscle, blood vessels, and epithelial cells, including the goblet and submucosal glands. Both the preganglionic and postganglionic fibers contain excitatory (cholinergic) motor neurons that respond to acetylcholine. Parasympathetic innervation is greater in the large airways and diminishes toward the smaller airways. Stimulation of the sympathetic nervous system causes airway relaxation, blood vessel constriction, and inhibition of glandular secretion. Sympathetic innervation arises from the cell bodies in paravertebral sympathetic ganglia. Neurotransmitters of the sympathetic nervous system include the catecholamines norepinephrine and epinephrine.

Pleura A thin, transparent, double-layered serous membrane, called the pleura, lines the thoracic cavity and encases the lungs (see Fig. 27-1). The outer parietal layer lines the pulmonary cavities and adheres to the thoracic wall, the mediastinum, and the diaphragm. The inner visceral pleura closely covers the lung and is adherent to all its surfaces. It is continuous with the parietal pleura at the hilum of the lung, where the major bronchus and pulmonary vessels enter and leave the lung. A thin film of serous fluid separates the two pleural layers, allowing the two layers to glide over each other and yet hold together, so there is no separation between the lungs and the chest wall. The pleural cavity is a potential space in which serous fluid or inflammatory exudate can accumulate. The term pleural effusion is used to describe an abnormal collection of fluid or exudate in the pleural cavity.

IN SUMMARY, the respiratory system consists of the air passages and the lungs, where gas exchange takes place. Functionally, the air passages of the respiratory system can be divided into two parts: the conducting airways, through which air moves as it passes into and out of the lungs, and the respiratory tissues, where gas exchange actually takes place. The conducting airways include the nasal passages, mouth and nasopharynx, larynx, and tracheobronchial tree. Air is warmed, filtered, and humidified as it passes through these structures. The lungs are the functional structures of the respiratory system. In addition to their gas exchange function, they inactivate vasoactive substances such as bradykinin; they convert angiotensin I to angiotensin II; and they serve as a reservoir for blood. The lobules, which are the functional units of the lung, consist of the respiratory bronchioles, alveoli, and pulmonary capillaries. It is here that gas exchange takes place. Oxygen from the alveoli diffuses across the alveolar capillary mem-

brane into the blood, and carbon dioxide from the blood diffuses into the alveoli. There are two types of alveolar cells: type I and type II. Type I cells, which provide the gas exchange function of the lung, are extremely thin squamous cells lining most of the surface of the alveoli. Type II cells, which produce surfactant and serve as progenitor cells for type I cells, are small cuboidal cells. There are four types of surfactant protein (SP): SP-A, SP-B, SP-C, and SP-D. SP-B and SP-C provide the critical surface tension–lowering properties necessary for ease of lung inflation. SP-A and SP-D modulate the immune response to foreign pathogens and participate in local inflammatory responses. The lungs are provided with a dual blood supply: the pulmonary circulation provides for the gas exchange function of the lungs and the bronchial circulation distributes blood to the conducting airways and supporting structures of the lung. The lungs are also supplied by a dual system of lymphatic vessels: a superficial system in the visceral pleura and a deep system that supplies deeper pulmonary structures, including the respiratory bronchioles. The respiratory system is innervated by the sympathetic and parasympathetic divisions of the autonomic nervous system. Parasympathetic innervation causes airway constriction and an increase in respiratory secretions, whereas sympathetic innervation causes bronchial dilation and a decrease in respiratory tract secretions. There is no voluntary motor innervation of the lung, nor are there pain fibers. Pain fibers are found only in the pleura. The lungs are encased in a thin, transparent, double-layered serous membrane called the pleura. A thin film of serous fluid separates the outer parietal and inner visceral pleural layers, allowing the two layers to glide over each other and yet hold together, so there is no separation between the lungs and the chest wall. The pleural cavity is a potential space in which serous fluid or inflammatory exudate can accumulate. ■

EXCHANGE OF GASES BETWEEN THE ATMOSPHERE AND THE LUNGS After completing this section of the chapter, you should be able to meet the following objectives: ■

■

■

Describe the basic properties of gases in relation to their partial pressures and their pressures in relation to volume and temperature. State the definition of intrathoracic, intrapleural, and intra-alveolar pressures, and state how each of these pressures changes in relation to atmospheric pressure during inspiration and expiration. Use the law of Laplace to explain the need for surfactant in maintaining the inflation of small alveoli.

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■

■

Differentiate between the determinants of airway resistance and lung compliance and their effect on the work of breathing. Define inspiratory reserve, expiratory reserve, vital capacity, residual lung volume, and FEV1.0.

Basic Properties of Gases The air we breathe is made up of a mixture of gases, mainly nitrogen and oxygen. These gases exert a combined pressure called the atmospheric or barometric pressure. The pressure at sea level, which is defined as 1 atmosphere, is 760 millimeters of mercury (mm Hg, or torr) or 14.7 pounds per square inch (PSI). When measuring respiratory pressures, atmospheric pressure is assigned a value of zero. A respiratory pressure of +15 mm Hg means that the pressure is 15 mm Hg above atmospheric pressure, and a respiratory pressure of −15 mm Hg is 15 mm Hg less than atmospheric pressure. Respiratory pressures often are expressed in centimeters of water (cm H2O) because of the small pressures involved (1 mm Hg = 1.35 cm H2O pressure). The pressure exerted by a single gas in a mixture is called the partial pressure. The capital letter “P” followed by the chemical symbol of the gas (PO2) is used to denote its partial pressure. The law of partial pressures states that the total pressure of a mixture of gases, as in the atmosphere, is equal to the sum of the partial pressures of the different gases in the mixture. If the concentration of oxygen at 760 mm Hg (1 atmosphere) is 20%, its partial pressure is 152 mm Hg (760 × 0.20). Water vapor is different from other types of gases in that its partial pressure is affected by temperature but not atmospheric pressure. The relative humidity refers to the percentage of moisture in the air compared with the amount that the air can hold without causing condensation (100% saturation). Warm air holds more moisture than cold air. This is the reason that precipitation in the form of rain or snow commonly occurs when the relative humidity is high and there is a sudden drop in atmospheric temperature. The air in the alveoli, which is 100% saturated at normal body temperature, has a water vapor pressure of 47 mm Hg. The water vapor pressure must be included in the sum of the total pressure of the gases in the alveoli (i.e., the total pressure of the other gases in the alveoli is 760 − 47 = 713 mm Hg). Air moves between the atmosphere and the lungs because of a pressure difference. According to the laws of physics, the pressure of a gas varies inversely with the volume of its container, provided the temperature remains constant. If equal amounts of a gas were placed in two different-sized containers, the pressure of the gas in the smaller container would be greater than the pressure in the larger container. The movement of gases is always from the container with the greater pressure to the one with the lesser pressure. The chest cavity can be viewed as a volume container. During inspiration, the size of the chest cavity increases and air moves into the lungs; during expiration, air moves out of the lungs as the size of the chest cavity decreases.

649

Ventilation and the Mechanics of Breathing Ventilation is concerned with the movement of gases into and out of the lungs. There is nothing complicated about ventilation. It is purely a mechanical event that obeys the laws of physics as they relate to the behavior of gases. It relies on a system of open airways and the respiratory pressures created as the movements of the respiratory muscles change the size of the chest cage. The degree to which the lungs inflate and deflate depends on the respiratory pressures inflating the lung, compliance of the lungs, and airway resistance.

VENTILATION AND GAS EXCHANGE ■

■

■

■

Ventilation refers to the movement of gases into and out of the lungs through a system of open airways and along a pressure gradient resulting from a change in chest volume. During inspiration, air is drawn into the lungs as the respiratory muscles expand the chest cavity; during expiration, air moves out of the lungs as the chest muscles recoil and the chest cavity becomes smaller. The ease with which air is moved into and out of the lung depends on the resistance of the airways, which is inversely related to the fourth power of the airway radius, and lung compliance, or the ease with which the lungs can be inflated. The minute volume, which is determined by the metabolic needs of the body, is the amount of air that is exchanged each minute. It is the product of the tidal volume or amount of air exchanged with each breath multiplied by the respiratory rate.

Respiratory Pressures The pressure inside the airways and alveoli of the lungs is called the intrapulmonary pressure or alveolar pressure. The gases in this area of the lungs are in communication with atmospheric pressure (Fig. 27-11). When the glottis is open and air is not moving into or out of the lungs, as occurs just before inspiration or expiration, the intrapulmonary pressure is zero or equal to atmospheric pressure. The pressure in the pleural cavity is called the intrapleural pressure. The intrapleural pressure of a normal inflated lung is always negative in relation to alveolar pressure, approximately −4 mm Hg between breaths when the glottis is open and the alveolar spaces are open to the atmosphere. The lungs and the chest wall have elastic properties, each pulling in the opposite direction. If removed from the chest, the lungs would contract to a smaller size, and the chest wall, if freed from the lungs, would expand. The opposing forces of the chest wall and lungs create a pull against the visceral and parietal layers of the

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return to the right atrium. The Valsalva maneuver is used to study the cardiovascular effects of increased intrathoracic pressure on peripheral venous pressures, cardiac filling, and cardiac output, as well as post-strain heart rate and blood pressure responses.

Intrapleural pressure Airway pressure

Chest Cage and Respiratory Muscles

Intra-alveolar pressure

Intrathoracic pressure

FIGURE 27-11 • Partitioning of respiratory pressures.

pleura, causing the pressure in the pleural cavity to become negative. During inspiration, the elastic recoil of the lungs increases, causing intrapleural pressure to become more negative than during expiration. Without the negative intrapleural pressure holding the lungs against the chest wall, their elastic recoil properties would cause them to collapse. Although intrapleural pressure is negative in relation to alveolar pressure, it may become positive in relation to atmospheric pressure (e.g., during forced expiration and coughing). The transpulmonary (trans = “across”) pressure is the difference between the alveolar and intrapleural pressures. As will be explained later, it is used in determining pulmonary compliance. The intrathoracic pressure is the pressure in the thoracic cavity. It is essentially equal to the intrapleural pressure and is the pressure to which the lungs, heart, and great vessels are exposed. Forced expiration against a closed glottis, such as occurs during defecation and the Valsalva maneuver, produces marked increases in intrathoracic pressure and impedes venous

Airflow in

The lungs and major airways share the chest cavity with the heart, great vessels, and esophagus. The chest cavity is a closed compartment bounded on the top by the neck muscles and at the bottom by the diaphragm. The outer walls of the chest cavity are formed by 12 pairs of ribs, the sternum, the thoracic vertebrae, and the intercostal muscles that lie between the ribs. Mechanically, the act of breathing depends on the fact that the chest cavity is a closed compartment whose only opening to the external atmosphere is through the trachea. Ventilation consists of inspiration and expiration. During inspiration, the size of the chest cavity increases, the intrathoracic pressure becomes more negative, and air is drawn into the lungs. Expiration occurs as the elastic components of the chest wall and lung structures that were stretched during inspiration recoil, causing the size of the chest cavity to decrease and the pressure in the chest cavity to increase. The diaphragm is the principal muscle of inspiration. When the diaphragm contracts, the abdominal contents are forced downward and the chest expands from top to bottom (Fig. 27-12). During normal levels of inspiration, the diaphragm moves approximately 1 cm, but this can be increased to 10 cm on forced inspiration. The diaphragm is innervated by the phrenic nerve roots, which arise from the cervical level of the spinal cord, mainly from C4 but also from C3 and C5. Persons who sustain spinal cord injury above C3 lose the function of the diaphragm and require mechanical ventilation (see Chapter 50). Paralysis of one side of the diaphragm causes the chest to move up on that side rather than down during inspiration because of the negative pressure in the chest. This is called paradoxical movement. The external intercostal muscles, which also aid in inspiration, connect to the adjacent ribs and slope downward and for-

Airflow out

FIGURE 27-12 • Movement of the dia-

Pressure

Inspiration

Pressure

Expiration

phragm and changes in chest volume and pressure during inspiration and expiration. During inspiration, contraction of the diaphragm and expansion of the chest cavity produce a decrease in intrathoracic pressure, causing air to move into the lungs. During expiration, relaxation of the diaphragm and chest cavity produces an increase in intrathoracic pressure, causing air to move out of the lungs.

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Chapter 27 Structure and Function of the Respiratory System Increased vertical diameter

Increased A-P diameter External intercostals contracted

Internal intercostals contracted Diaphragm relaxed

FIGURE 27-13 • Expansion and contraction of the chest cage during expiration and inspiration, demonstrating especially diaphragmatic contraction, elevation of the rib cage, and function of the (A) external and (B) internal intercostals.

651

Diaphragmatic contraction

A

ward (Fig. 27-13). When they contract, they raise the ribs and rotate them slightly so that the sternum is pushed forward; this enlarges the chest from side to side and from front to back. The intercostal muscles receive their innervation from nerves that exit the central nervous system at the thoracic level of the spinal cord. Paralysis of these muscles usually does not have a serious effect on respiration because of the effectiveness of the diaphragm. The accessory muscles of inspiration include the scalene muscles and the sternocleidomastoid muscles. The scalene muscles elevate the first two ribs, and the sternocleidomastoid muscles raise the sternum to increase the size of the chest cavity. These muscles contribute little to quiet breathing but contract vigorously during exercise. For the accessory muscles to assist in ventilation, they must be stabilized in some way. For example, persons with bronchial asthma often brace their arms against a firm object during an attack as a means of stabilizing their shoulders so that the attached accessory muscles can exert their full effect on ventilation. The head commonly is bent backward so that the scalene and sternocleidomastoid muscles can elevate the ribs more effectively. Other muscles that play a minor role in inspiration are the alae nasi, which produce flaring of the nostrils during obstructed breathing. Expiration is largely passive. It occurs as the elastic components of the chest wall and lung structures that were stretched during inspiration recoil, causing air to leave the lungs as the intrathoracic pressure increases. When needed, the abdominal and the internal intercostal muscles can be used to increase expiratory effort (see Fig. 27-13B). The increase in intra-abdominal pressure that accompanies the forceful contraction of the abdominal muscles pushes the diaphragm upward and results in an increase in intrathoracic pressure. The internal intercostal muscles move inward, which pulls the chest downward, increasing expiratory effort.

Lung Compliance Lung compliance refers to the ease with which the lungs can be inflated. Compliance can be appreciated by comparing the ease of blowing up a noncompliant new balloon that is stiff and resistant with a compliant one that has been previously blown up and is easy to inflate. Specifically, lung compliance (C) de-

Inspiration

Abdominals contracted

B

Expiration

scribes the change in lung volume (ΔV) that can be accomplished with a given change in respiratory pressure (ΔP); thus, C = ΔV/ΔP. It takes more pressure to move the same amount of air into a noncompliant lung than it does into a compliant one. Lung compliance is determined by the elastin and collagen fibers of the lung, its water content, and surface tension. It also depends on the compliance of the thoracic or chest cage. It is diminished by conditions that reduce the natural elasticity of the lung, block the bronchi or smaller airways, increase the surface tension in the alveoli, or impair the flexibility of the thoracic cage. Lung tissue is made up of elastin and collagen fibers. The elastin fibers are easily stretched and increase the ease of lung inflation, whereas the collagen fibers resist stretching and make lung inflation more difficult. In lung diseases such as interstitial lung disease and pulmonary fibrosis, the lungs become stiff and noncompliant as the elastin fibers are replaced with scar tissue. Pulmonary congestion and edema produce a reversible decrease in pulmonary compliance. Elastic recoil describes the ability of the elastic components of the lung to recoil to their original position after having been stretched. Overstretching lung tissues, as occurs with emphysema, causes the elastic components of the lung to lose their recoil, making the lung easier to inflate but more difficult to deflate because of its inability to recoil. Surface Tension. An important factor in lung compliance is the surface tension or attraction forces of the surface molecules in the alveoli. The alveoli are lined with a thin film of liquid, and it is at the interface between this liquid film and the alveolar air that surface tension develops. This is because the forces that hold the water molecules of the liquid film together are stronger than those that hold the air molecules in the alveoli together. In the alveoli, excess surface tension causes water molecules in the liquid film to contract, making lung inflation difficult. The units of surface tension are those of force per unit length. The relationship between the pressure within a sphere such as an alveolus and the tension in the wall can be described using the law of Laplace (pressure = 2 × surface tension/ radius). If the surface tension were equal throughout the lungs, the alveoli with the smallest radii would have the greatest

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pressure, and this would cause them to empty into the larger alveoli (Fig. 27-14A). The reason this does not occur is because of special surface tension-lowering molecules, called surfactant, that line the inner surface of the alveoli. Pulmonary surfactant is a complex mixture of phospholipids, neutral lipids, and proteins that is synthesized in the type II alveolar cells. Substances that are termed surfactants consist of two parts with opposing properties that are irreversibly bound to each other. One part is polar and seeks aqueous fluid or hydrophilic (water-attracting) surfaces; the other is nonpolar and seeks oil, air, or hydrophobic (water-repelling) surfaces (see Fig. 27-14B). Pulmonary surfactant forms a monolayer, with its hydrophilic surface binding to liquid film on the surface of the alveoli and its hydrophobic surface facing outward toward the gases in the alveolar air. It is this monolayer that interrupts the surface tension that develops at the air–liquid interface in the alveoli. Pulmonary surfactant, particularly SP-B, exerts several important effects on lung inflation: it lowers the surface tension and it increases lung compliance and ease of lung inflation. Without surfactant, lung inflation would be extremely difficult. In addition, it helps to keep the alveoli dry and prevent pulmonary edema. This is because water is pulled out of the pulmonary capillaries into the alveoli when increased surface tension causes the alveoli to contract. Surfactant also provides for stability and more even inflation of the alveoli. Alveoli, except those at the pleural surface, are surrounded by other alveoli. Thus, the tendency of one alveolus to collapse is opposed by the traction exerted by the surrounding alveolus. The surfactant molecules are also more densely packed in small alveoli than in large alveoli (see Fig. 27-14C). In surgical and bedridden patients, shallow and quiet breathing often impairs the spreading of surfactant. Encouraging these patients to cough and deep breathe enhances the spreading of surfactant. This allows for a more even distribution of ventilation and prevention of atelectasis. The type II alveolar cells that produce surfactant do not begin to mature until the 26th to 27th week of gestation; consequently, many premature infants have difficulty producing sufficient amounts of surfactant. This can lead to alveolar collapse and severe respiratory distress. This condition, called infant respiratory distress syndrome, is the single most common cause of respiratory disease in premature infants. Surfactant dysfunction also is possible in the adult. This usually occurs as the result of severe injury or infection and can contribute to the development of a condition called acute respiratory distress syndrome (see Chapter 29).

Airway Airflow The volume of air that moves into and out of the air exchange portion of the lungs is directly related to the pressure difference between the lungs and the atmosphere and inversely related to the resistance that the air encounters as it moves through the airways. Depending on the velocity and pattern of flow, airflow can be laminar or turbulent.

P = 2 T/r

Alveolus

Alveolus Airways

A

Radius = 1 Surface tension = T Radius = 2 Surface tension = T Surfactant molecule Palmitate Nonpolar part Air Liquid

Glycerol Polar part

Phosphate Choline

Air

B

Liquid

Surfactant film (thicker in small alveolus; thinner in larger alveolus)

C FIGURE 27-14 • (A) The effect of the surface tension (forces generated at the fluid–air interface) and radius on the pressure and movement of gases in the alveolar structures. According to the law of Laplace (P = 2 T/r, P = pressure, T = tension, r = radius), the pressure generated within the sphere is inversely proportional to the radius. Air moves from the alveolus with a small radius and higher pressure to the alveolus with the larger radius and lower pressure. (B) Surfactant molecules, showing their hydrophilic heads attached to the fluid lining of the alveolus and their hydrophobic tails oriented toward the air interface. (C) The surfactant molecules form a monolayer (shaded in blue) that disrupts the intermolecular forces and lowers the surface tension more in the smaller alveolus with its higher concentration of surfactant than in the larger alveolus with the lower concentration.

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Laminar or streamlined airflow occurs at low flow rates in which the air stream is parallel to the sides of the airway. With laminar flow, the air at the periphery must overcome the resistance to flow, and as a result, the air in the center of the airway moves faster. Turbulent airflow is disorganized flow in which the molecules of the gas move laterally, collide with one another, and change their velocities. Whether turbulence develops depends on the radius of the airways, the interaction of the gas molecules, and the velocity of airflow. It is most likely to occur when the radius of the airways is large and the velocity of flow is high. Turbulent flow occurs regularly in the trachea. Turbulence of airflow accounts for the respiratory sounds that are heard during chest auscultation (i.e., listening to chest sounds using a stethoscope). In the bronchial tree with its many branches, laminar airflow probably occurs only in the very small airways, where the velocity of flow is low. Because the small airways contribute little resistance to airflow, they constitute a silent zone (to be discussed). Airway Resistance. Airway resistance is the ratio of the pressure driving inspiration or expiration to airflow. The French physician Jean Léonard Marie Poiseuille first described the pressure–flow characteristics of laminar flow in a straight circular tube, a correlation that has become known as the Poiseuille law. According to the Poiseuille law, the resistance to flow is inversely related to the fourth power of the radius (R = 1/r4). If the radius is reduced by one half, the resistance increases 16-fold (2 × 2 × 2 × 2 = 16). Airway resistance differs in large (e.g., trachea and bronchi), medium-sized (e.g., segmental), and small (e.g., bronchioles) airways. Therefore, the total airway resistance is equal to the sum of the resistances in these three types of airways. The site of most of the resistance along the bronchial tree is the large bronchi, with the smallest airways contributing very little to the total airway resistance. This is because most of these airways are arranged in parallel and their resistances are added as reciprocals (i.e., total combined resistance = 1/R + 1/R, etc.). Although the resistance of each individual bronchiole may be relatively high, their great number results in a large total crosssectional area, causing their total resistance to be low. Many airway diseases, such as emphysema and chronic bronchitis, begin in the small airways. Early detection of these diseases is often difficult because a considerable amount of damage must be present before the usual measurements of airway resistance can detect them. Airway resistance is greatly affected by lung volumes, being less during inspiration than expiration. This is because elastic fibers connect the outside of the airways to the surrounding lung tissues. As a result, these airways are pulled open as the lungs expand during inspiration, and they become narrower as the lungs deflate during expiration (Fig. 27-15). This is one of the reasons why persons with conditions that increase airway resistance, such as bronchial asthma, usually have less difficulty during inspiration than during expiration. Airway resistance is also affected by the bronchial smooth tone that controls airway diameter. The smooth muscles in the

653

Low lung volume

High lung volume

FIGURE 27-15 • Interaction of tissue forces on airways during low and high lung volumes. At low lung volumes, the tissue forces tend to fold and place less tension on the airways and they become smaller; during high lung volumes, the tissue forces are stretched and pull the airways open.

airway, from the trachea down to the terminal bronchioles, are under autonomic nervous system control. Stimulation of the parasympathetic nervous system causes bronchial constriction as well as increased mucus secretion, whereas sympathetic stimulation has the opposite effect. Airway Compression During Forced Expiration. Airway resistance does not change much during normal quiet breathing; however, it is significantly increased during forced expiration, such as in vigorous exercise. Airflow through the collapsible airways in the lungs depends on the distending airway (intrapulmonary) pressures that hold the airways open and the external (intrapleural or intrathoracic) pressures that surround and compress the airways. The difference between these two pressures (intrathoracic pressure minus airway pressure) is called the transpulmonary pressure. For airflow to occur, the distending pressure inside the airways must be greater than the compressing pressure outside the airways. During forced expiration, the transpulmonary pressure is decreased because of a disproportionate increase in the intrathoracic pressure compared with airway pressure. The resistance that air encounters as it moves out of the lungs causes a further drop in airway pressure. If this drop in airway pressure is sufficiently great, the surrounding intrathoracic pressure will compress the collapsible airways (i.e., those that lack cartilaginous support),

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Oral airway pressure

Area of airway collapse Airway resistance

Forced expiration Intrapleural pressure

Nonrigid airways

B Airway pressure

A

causing airflow to be interrupted and air to be trapped in the terminal airways (Fig. 27-16). Although this type of airway compression usually is seen only during forced expiration in persons with normal respiratory function, it may occur during normal breathing in persons with lung diseases. For example, in conditions that increase airway resistance, such as emphysema, the pressure drop along the smaller airways is magnified, and an increase in intra-airway pressure is needed to maintain airway patency. Measures such as pursed-lip breathing increase airway pressure and improve expiratory flow rates in persons with chronic obstructive pulmonary disease (discussed in Chapter 29). This is also the basis for using positive end-expiratory pressure in persons who are being mechanically ventilated. Infants who are having trouble breathing often grunt to increase their expiratory airway pressures and keep their airways open.

FIGURE 27-16 • Mechanism that limits maximal expiratory flow rate. (A) Airway patency and airflow in the nonrigid airways of the lungs rely on a transpulmonary pressure gradient in which airway pressure is greater than intrapleural pressure. (B) Airway resistance normally produces a drop in airway pressure as air moves out of the lungs. The increased intrapleural pressure that occurs with forced expiration produces airway collapse in the nonrigid airways at the point where intrapleural pressure exceeds airway pressure.

Lung Volumes Lung volumes, or the amount of air exchanged during ventilation, can be subdivided into three components: (1) the tidal volume, (2) the inspiratory reserve volume, and (3) the expiratory reserve volume (Fig. 27-17). The tidal volume (TV) is the volume of air inspired (or exhaled) with each breath. It varies with age, gender, body position, and metabolic activity. It usually is about 500 mL in the average-sized adult and about 3 to 5 mL/kg in children. The maximum amount of air that can be inspired in excess of the normal TV is called the inspiratory reserve volume (IRV), and the maximum amount that can be exhaled in excess of the normal TV is the expiratory reserve volume (ERV). Approximately 1200 mL of air always remains in the lungs after forced expiration; this air is the residual volume (RV). The RV increases with age because there is more trapping of air in the

5000

Inspiratory reserve volume 3100 mL

4000 3000 2000 1000 0 mL

Tidal volume 500 mL Expiratory reserve volume 1200 mL Residual volume 1200 mL Lung volumes

Vital capacity 4800 mL

6000

FIGURE 27-17 • Tracings of respiratory volumes (left) Inspiratory capacity 3600 mL Total lung capacity 6000 mL Functional residual capacity 2400 mL

Lung capacities

and lung capacities (right) as they would appear if made using a spirometer. The tidal volume (yellow) represents the amount of air inhaled and exhaled during normal breathing; the inspiratory reserve volume (pink), the maximal amount of air in excess of the tidal volume that can be forcefully inhaled; the maximal expiratory reserve (blue), the maximal amount of air that can be exhaled in excess of the tidal volume; and the residual volume (green), the air that continues to remain in the lung after maximal expiratory effort. The inspiratory capacity represents the sum of the inspiratory reserve volume and the tidal volume; the functional residual capacity, the sum of the maximal expiratory reserve and residual volumes; and the total lung capacity, the sum of all the volumes.

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lungs at the end of expiration. These volumes can be measured using an instrument called a spirometer. Lung capacities include two or more lung volumes. The vital capacity equals the IRV plus the TV plus the ERV and is the amount of air that can be exhaled from the point of maximal inspiration. The inspiratory capacity equals the TV plus the IRV. It is the amount of air a person can breathe in beginning at the normal expiratory level and distending the lungs to the maximal amount. The functional residual capacity is the sum of the RV and ERV; it is the volume of air that remains in the lungs at the end of normal expiration. The total lung capacity is the sum of all the volumes in the lungs. The RV cannot be measured with the spirometer because this air cannot be expressed from the lungs. It is measured by indirect methods, such as the helium dilution method, nitrogen washout method, or body plethysmography. Lung volumes and capacities are summarized in Table 27-1.

Pulmonary Function Studies The previously described lung volumes and capacities are anatomic or static measures determined by lung volumes and measured without relation to time. The spirometer also is used to measure dynamic lung function (i.e., ventilation with respect to time); these tests often are used in assessing pulmonary function. Pulmonary function measures include maximum voluntary ventilation, forced vital capacity, forced expiratory volumes and flow rates, and forced inspiratory flow rates (Table 27-2). Pulmonary function is measured for various clinical purposes, including diagnosis of respiratory disease, preoperative surgical and anesthetic risk evaluation, and symptom and disability evaluation for legal or insurance purposes. The tests also are used for evaluat-

TABLE 27-1

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ing dyspnea, cough, wheezing, and abnormal radiologic or laboratory findings. The maximum voluntary ventilation measures the volume of air that a person can move into and out of the lungs during maximum effort lasting for 12 to 15 seconds. This measurement usually is converted to liters per minute. The forced vital capacity (FVC) involves full inspiration to total lung capacity followed by forceful maximal expiration. Obstruction of airways produces a FVC that is lower than that observed with more slowly performed vital capacity measurements. The forced expiratory volume (FEV) is the expiratory volume achieved in a given time period. The FEV1.0 is the FEV that can be exhaled in 1 second. The FEV1.0 frequently is expressed as a percentage of the FVC. The FEV1.0 and FVC are used in the diagnosis of obstructive lung disorders. The forced inspiratory vital flow (FIF) measures the respiratory response during rapid maximal inspiration. Calculation of airflow during the middle half of inspiration (FIF25%–75%) relative to the forced mid-expiratory flow rate (FEF25%–75%) is used as a measure of respiratory muscle dysfunction because inspiratory flow depends more on effort than does expiration.

Efficiency and the Work of Breathing The minute volume, or total ventilation, is the amount of air that is exchanged in 1 minute. It is determined by the metabolic needs of the body. The minute volume is equal to the TV multiplied by the respiratory rate, which is normally about 6000 mL (500 mL TV × respiratory rate of 12 breaths per minute) in the average-sized adult during normal activity. The efficiency of breathing is determined by matching the TV and respiratory

Lung Volumes and Capacities

VOLUME

SYMBOL

Tidal volume (about 500 mL at rest) Inspiratory reserve volume (about 3000 mL) Expiratory reserve volume (about 1100 mL) Residual volume (about 1200 mL)

TV IRV

Functional residual capacity (about 2300 mL) Inspiratory capacity (about 3500 mL) Vital capacity (about 4600 mL)

FRC

Total lung capacity (about 5800 mL)

TLC

ERV RV

IC VC

MEASUREMENT Amount of air that moves into and out of the lungs with each breath Maximum amount of air that can be inhaled from the point of maximal expiration Maximum volume of air that can be exhaled from the resting end-expiratory level Volume of air remaining in the lungs after maximal expiration. This volume cannot be measured with the spirometer; it is measured indirectly using methods such as the helium dilution method, the nitrogen washout technique, or body plethysmography. Volume of air remaining in the lungs at end-expiration (sum of RV and ERV) Sum of IRV and TV Maximal amount of air that can be forcibly exhaled from the point of maximal inspiration Total amount of air that the lungs can hold; it is the sum of all the volume components after maximal inspiration. This value is about 20% to 25% less in females than in males.

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TABLE 27-2

Pulmonary Function Tests

TEST

SYMBOL

MEASUREMENT*

Maximal voluntary ventilation Forced vital capacity

MVV FVC

Forced expiratory volume achieved in 1 second Percentage of forced vital capacity Forced midexpiratory flow rate

FEV1.0

Maximum amount of air that can be breathed in a given time Maximum amount of air that can be rapidly and forcefully exhaled from the lungs after full inspiration. The expired volume is plotted against time. Volume of air expired in the first second of FVC

FEV1.0 /FVC%

Volume of air expired in the first second, expressed as a percentage of FVC

FEF25%–75%

Forced inspiratory flow rate

FIF25%–75%

The forced midexpiratory flow rate determined by locating the points on the volume-time curve recording obtained during FVC corresponding to 25% and 75% of FVC and drawing a straight line through these points. The slope of this line represents the average midexpiratory flow rate. FIF is the volume inspired from RV at the point of measurement. FIF25%–75% is the slope of a line between the points on the volume pressure tracing corresponding to 25% and 75% of the inspired volume.

*By convention, all the lung volumes and rates of flow are expressed in terms of body temperature and pressure and saturated with water vapor (BTPS), which allows for a comparison of the pulmonary function data from laboratories with different ambient temperatures and altitudes.

rate in a manner that provides an optimal minute volume while minimizing the work of breathing. The work of breathing is determined by the amount of effort required to move air through the conducting airways and by the ease of lung expansion, or compliance. Expansion of the lungs is difficult for persons with stiff and noncompliant lungs; they usually find it easier to breathe if they keep their TV low and breathe at a more rapid rate (e.g., 300 × 20 = 6000 mL) to achieve their minute volume and meet their oxygen needs. In contrast, persons with obstructive airway disease usually find it less difficult to inflate their lungs but expend more energy in moving air through the airways. As a result, these persons take deeper breaths and breathe at a slower rate (e.g., 600 × 10 = 6000 mL) to achieve their oxygen needs.

IN SUMMARY, the movement of air between the atmosphere and the lungs follows the laws of physics as they relate to gases. The air in the alveoli contains a mixture of gases, including nitrogen, oxygen, carbon dioxide, and water vapor. With the exception of water vapor, each gas exerts a pressure that is determined by the atmospheric pressure and the concentration of the gas in the mixture. Water vapor pressure is affected by temperature but not atmospheric pressure. Air moves into the lungs along a pressure gradient. The pressure inside the airways and alveoli of the lungs is called intrapulmonary (or alveolar) pressure; the pressure in the pleural cavity is called pleural pressure; and the pressure in the thoracic cavity is called intrathoracic pressure. Breathing is the movement of gases between the atmosphere and the lungs. It requires a system of open airways and pressure changes resulting from the action of the respiratory mus-

cles in changing the volume of the chest cage. The diaphragm is the principal muscle of inspiration, assisted by the external intercostal muscles. The scalene and sternocleidomastoid muscles elevate the ribs and act as accessory muscles for inspiration. Expiration is largely passive, aided by the elastic recoil of the respiratory muscles that were stretched during inspiration. When needed, the abdominal and internal intercostal muscles can be used to increase expiratory effort. Lung compliance describes the ease with which the lungs can be inflated. It is determined by the elastic and collagen fibers of the lung, the water content, the surface tension of the alveoli, and the compliance of the chest cage. It also reflects the surface tension at the air–epithelium interface of the alveoli. Surfactant molecules, produced by type II alveolar cells, reduce the surface tension in the lungs and thereby increase lung compliance. The volume of air that moves into and out of the air exchange portion of the lungs is directly related to the pressure difference between the lungs and the atmosphere and inversely related to the resistance that the air encounters as it moves through the airways. Depending on the velocity and pattern of flow, airflow can be laminar or turbulent. Airway resistance refers to the impediment to flow that the air encounters as it moves through the airways. It differs with airway size, being greatest in the medium-sized bronchi and lowest in the smaller bronchioles. Lung volumes and lung capacities reflect the amount of air that is exchanged during normal and forced breathing. The tidal volume (TV) is the amount of air that moves into and out of the lungs during normal breathing; the inspiratory reserve volume (IRV) is the maximum amount of air that can be inspired in excess of the normal TV; and the expiratory reserve volume (ERV) is the maximum amount that can be exhaled in excess of

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the normal TV. The residual volume (RV) is the amount of air that remains in the lungs after forced expiration. Lung capacities include two or more lung volumes. The vital capacity equals the IRV plus the TV plus the ERV and is the amount of air that can be exhaled from the point of maximal inspiration. The minute volume, which is determined by the metabolic needs of the body, is the amount of air that is exchanged in 1 minute (i.e., respiratory rate and TV). ■

EXCHANGE AND TRANSPORT OF GASES After completing this section of the chapter, you should be able to meet the following objectives: ■ ■ ■ ■ ■ ■ ■

Trace the exchange of gases between the air in the alveoli and the blood in the pulmonary capillaries. Differentiate between pulmonary and alveolar ventilation. Explain why ventilation and perfusion must be matched. Cite the difference between dead air space and shunt. List four factors that affect the diffusion of gases in the alveoli. Explain the difference between PO2 and hemoglobinbound oxygen and O2 saturation, and oxygen content. Explain the significance of a shift to the right and a shift to the left in the oxygen–hemoglobin dissociation curve.

657

Distribution of Ventilation The distribution of ventilation between the apex and base of the lung varies with body position and the effects of gravity on intrapleural pressure (Fig. 27-18). In the seated or standing position, gravity exerts a downward pull on the lung, causing intrapleural pressure at the apex of the lung to become more negative than that at the base of the lung. As a result, the alveoli at the apex of the lung are more fully expanded than those at the base of the lung. The same holds true for dependent portions of the lung in the supine or lateral position. In the supine position, ventilation in the lowermost (posterior) parts of the lung exceeds that in the uppermost (anterior) parts. In the lateral position (i.e., lying on the side), the dependent lung is better ventilated. The distribution of ventilation also is affected by lung volumes. Compliance reflects the change in volume that occurs with a change in pressure. It is less in fully expanded alveoli, which have difficulty accommodating more air, and greater in alveoli that are less inflated. During full inspiration in the seated or standing position, the airways are pulled open and air moves into the more compliant portions of the lower lung. At low lung volumes, the opposite occurs. In this case, the pleural pressure at the base of the lung exceeds airway pressure compressing the airways so that ventilation is greatly reduced, while the airways in the upper part of the lung

• • • • • • • • •

The primary functions of the lungs are oxygenation of the blood and removal of carbon dioxide. Pulmonary gas exchange is conventionally divided into three processes: ventilation, or the flow of gases into and out of the alveoli of the lungs; perfusion, or flow of blood in the adjacent pulmonary capillaries; and diffusion, or transfer of gases between the alveoli and the pulmonary capillaries. The efficiency of gas exchange requires that alveolar ventilation occur adjacent to perfused pulmonary capillaries.

– 10 cm H 2 O Intrapleural pressure

– 2.5 cm H 2 O 100%

• 50%

Volume

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•

Ventilation Ventilation refers to the exchange of gases in the respiratory system. There are two types of ventilation: pulmonary and alveolar. Pulmonary ventilation refers to the total exchange of gases between the atmosphere and the lungs. Alveolar ventilation is the exchange of gases within the gas exchange portion of the lungs. Ventilation requires a system of open airways and a pressure difference that moves air into and out of the lungs. It is affected by body position and lung volume as well as by disease conditions that affect the heart and respiratory system.

0 +10

– 20 0 –10 Intrapleural pressure (cm H 2 O)

– 30

FIGURE 27-18 • Explanation of the regional differences in ventilation down the lung; the intrapleural pressure is less negative at the base than at the apex. As a consequence, the basal lung is relatively compressed in its resting state but expands more on inspiration than the apex. (From West J. B. [2001]. Pulmonary physiology and pathophysiology [p. 99]. Philadelphia: Lippincott Williams & Wilkins.)

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remain open so that the top of the lung is better ventilated than the bottom. Even at low lung volumes, some air remains in the alveoli of the lower portion of the lungs, preventing their collapse. According to the law of Laplace (discussed previously), the pressure needed to overcome the tension in the wall of a sphere or an elastic tube is inversely related to its radius; therefore, the small airways close first, trapping some gas in the alveoli. There may be increased trapping of air in the alveoli of the lower part of the lungs in older persons and in those with lung disease (e.g., emphysema). This condition is thought to result from a loss in the elastic recoil properties of the lungs, so that the intrapleural pressure, created by the elastic recoil of the lung and chest wall, becomes less negative. In these persons, airway closure occurs at the end of normal instead of low lung volumes, trapping larger amounts of air with a resultant increase in the residual lung volume.

Dead Air Space Dead space refers to the air that must be moved with each breath but does not participate in gas exchange. The movement of air through dead space contributes to the work of breathing but not to gas exchange. There are two types of dead space: that contained in the conducting airways, called the anatomic dead space, and that contained in the respiratory portion of the lung, called the alveolar dead space. The volume of anatomic airway dead space is fixed at approximately 150 to 200 mL, depending on body size. It constitutes air contained in the nose, pharynx, trachea, and bronchi. The creation of a tracheostomy (surgical opening in the trachea) decreases anatomic dead space ventilation because air does not have to move through the nasal and oral airways. Alveolar dead space, normally about 5 to 10 mL, constitutes alveolar air that does not participate in gas exchange. When alveoli are ventilated but deprived of blood flow, they do not contribute to gas exchange and thereby constitute alveolar dead space. The physiologic dead space includes the anatomic dead space plus alveolar dead space. In persons with normal respiratory function, physiologic dead space is about the same as anatomic dead space. Only in lung disease does physiologic dead space increase. Alveolar ventilation is equal to the minute ventilation minus the physiologic dead space ventilation.

Perfusion The primary functions of the pulmonary circulation are to perfuse or provide blood flow to the gas exchange portion of the lung and to facilitate gas exchange. The pulmonary circulation serves several important functions in addition to gas exchange. It filters all the blood that moves from the right to the left side of the circulation; it removes most of the thromboemboli that might form; and it serves as a reservoir of blood for the left side of the heart. The gas exchange function of the lungs requires a continuous flow of blood through the respiratory portion of the lungs. Deoxygenated blood enters the lung through the pulmonary

artery, which has its origin in the right side of the heart and enters the lung at the hilus, along with the primary bronchus. The pulmonary arteries branch in a manner similar to that of the airways. The small pulmonary arteries accompany the bronchi as they move down the lobules and branch to supply the capillary network that surrounds the alveoli (see Fig. 27-8). The oxygenated capillary blood is collected in the small pulmonary veins of the lobules, and then it moves to the larger veins to be collected in the four large pulmonary veins that empty into the left atrium. The pulmonary blood vessels are thinner, more compliant, and offer less resistance to flow than those in the systemic circulation, and the pressures in the pulmonary system are much lower (e.g., 22/8 mm Hg versus 120/70 mm Hg). The low pressure and low resistance of the pulmonary circulation accommodate the delivery of varying amounts of blood from the systemic circulation without producing signs and symptoms of congestion. The volume in the pulmonary circulation is approximately 500 mL, with approximately 100 mL of this volume located in the pulmonary capillary bed. When the input of blood from the right heart and output of blood to the left heart are equal, pulmonary blood flow remains constant. Small differences between input and output can result in large changes in pulmonary volume if the differences continue for many heart beats. The movement of blood through the pulmonary capillary bed requires that the mean pulmonary arterial pressure be greater than the mean pulmonary venous pressure. Pulmonary venous pressure increases in left-sided heart failure, allowing blood to accumulate in the pulmonary capillary bed and cause pulmonary edema (see Chapter 26).

Distribution of Blood Flow As with ventilation, the distribution of pulmonary blood flow is affected by body position and gravity. In the upright position, the distance of the upper apices of the lung above the level of the heart may exceed the perfusion capabilities of the mean pulmonary arterial pressure (approximately 12 mm Hg); therefore, blood flow in the upper part of the lungs is less than that in the base or bottom part of the lungs (Fig. 27-19). In the supine position, the lungs and the heart are at the same level, and blood flow to the apices and base of the lungs becomes more uniform. In this position, blood flow to the posterior or dependent portions (e.g., bottom of the lung when lying on the side) exceeds flow in the anterior or nondependent portions of the lungs.

Hypoxia-Induced Vasoconstriction The blood vessels in the pulmonary circulation are highly sensitive to alveolar oxygen levels and undergo marked vasoconstriction when exposed to hypoxia. The precise mechanism for this response is unclear. When alveolar oxygen levels drop below 60 mm Hg, marked vasoconstriction may occur, and at very low oxygen levels, the local flow may be almost abolished. In regional hypoxia, as occurs with atelectasis, vasoconstriction is localized to a specific region of the lung. In this case, vasoconstriction has the effect of directing blood flow

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659

Airways Venous blood

Zone 1 PA > Pa > PV

Alveolar Pa

PA

Arterial

Arterial blood

Zone 2 Pa > PA > PV PV

Venous

Distance

Zone 3 Pa > PV > PA Blood flow

FIGURE 27-19 • The uneven distribution of blood flow in the

Perfusion without ventilation

lung results from different pressures affecting the capillaries, which are affected by body position and gravity. (From West J. B. [2000]. Respiratory physiology: The essentials [p. 41]. Philadelphia: Lippincott Williams & Wilkins.)

Alveolus

Ventilation without perfusion

Normal

FIGURE 27-20 • Matching of ventilation and perfusion. (Center)

away from the hypoxic regions of the lungs. When alveolar hypoxia no longer exists, blood flow is restored. Generalized hypoxia, such as occurs at high altitudes and in persons with chronic hypoxia due to lung disease, causes vasoconstriction throughout the lung. Prolonged hypoxia can lead to pulmonary hypertension and increased workload on the right heart (discussed in Chapter 29). A low blood pH produces a similar effect, particularly when alveolar hypoxia is present (e.g., during circulatory shock).

Shunt Shunt refers to blood that moves from the right to the left side of the circulation without being oxygenated. As with dead air space, there are two types of shunts: physiologic and anatomic. In an anatomic shunt, blood moves from the venous to the arterial side of the circulation without moving through the lungs. Anatomic intracardiac shunting of blood due to congenital heart defects is discussed in Chapter 24. In a physiologic shunt, there is mismatching of ventilation and perfusion within the lung, resulting in insufficient ventilation to provide the oxygen needed to oxygenate the blood flowing through the alveolar capillaries. Physiologic shunting of blood usually results from destructive lung disease that impairs ventilation or from heart failure that interferes with movement of blood through sections of the lungs.

Mismatching of Ventilation and Perfusion The gas exchange properties of the lung depend on matching ventilation and perfusion, ensuring that equal amounts of air and blood are entering the respiratory portion of the lungs. Both dead air space and shunt produce a mismatching of ventilation and perfusion, as depicted in Figure 27-20. With shunt (depicted on the left), there is perfusion without ventilation,

Normal matching of ventilation and perfusion; (left) perfusion without ventilation (i.e., shunt); (right) ventilation without perfusion (i.e., dead air space).

resulting in a low ventilation–perfusion ratio. It occurs in conditions such as atelectasis in which there is airway obstruction (see Chapter 29). With dead air space (depicted on the right), there is ventilation without perfusion, resulting in a high ventilation– perfusion ratio. It occurs in conditions such as pulmonary embolism, which impairs blood flow to a part of the lung. The arterial blood leaving the pulmonary circulation reflects mixing of blood from normally ventilated and perfused areas of the lung as well as areas that are not ventilated (dead air space) or perfused (shunt). Many of the conditions that cause mismatching of ventilation and perfusion involve both dead air space and shunt. In chronic obstructive lung disease, for example, there may be impaired ventilation in one area of the lung and impaired perfusion in another area.

Diffusion Diffusion occurs in the respiratory portions of the lung and refers to the movement of gases across the alveolar–capillary membrane. Gas diffusion in the lung can be described by the Fick law . of diffusion. The Fick law states that the volume of a gas (Vgas) diffusing across the membrane per unit time is directly proportional to the partial pressure difference of the gas (P1 − P2), the surface area (SA) of the membrane, and the diffusion coefficient (D), and is inversely proportional to the thickness (T) of the membrane (Fig. 27-21). Several factors influence the diffusion of gases in the lung. The administration of high concentrations of oxygen increases the difference in partial pressure between the two sides of the membrane and increases the diffusion of the gas. Diseases that destroy lung tissue (i.e., surface area for diffusion) or increase the thickness of the alveolar–capillary membrane adversely influence the diffusing capacity of the lungs.

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MATCHING OF VENTILATION AND PERFUSION ■

■

■

■

Exchange of gases between the air in the alveoli and the blood in pulmonary capillaries requires a matching of ventilation and perfusion. Dead air space refers to the volume of air that is moved with each breath but does not participate in gas exchange. Anatomic dead space is that contained in the conducting airways that normally do not participate in gas exchange. Alveolar dead space results from alveoli that are ventilated but not perfused. Shunt refers to blood that moves from the right to the left side of the circulation without being oxygenated. With an anatomic shunt, blood moves from the venous to the arterial side of the circulation without going through the lungs. Physiologic shunting results from blood moving through unventilated parts of the lung. The blood oxygen level reflects the mixing of blood from alveolar dead space and physiologic shunting areas as it moves into the pulmonary veins.

The removal of one lung, for example, reduces the diffusing capacity by one half. The thickness of the alveolar–capillary membrane and the distance for diffusion are increased in persons with pulmonary edema or pneumonia. The characteristics of the gas and its molecular weight and solubility constitute the diffusion coefficient and determine how rapidly a gas diffuses through the respiratory membranes. For example, carbon dioxide diffuses 20 times more rapidly than oxygen because of its greater solubility in the respiratory membranes. The diffusing capacity provides a measure of the rate of gas transfer in the lungs per partial pressure gradient. Because the initial alveolar–capillary difference for oxygen cannot be measured, carbon monoxide is used to determine the diffusing capacity. Carbon monoxide has several advantages: (1) its uptake is not limited by diffusion or blood flow; (2) there is essentially no carbon monoxide in venous blood; and (3) its affinity for hemoglobin is 210 times that of oxygen, ensuring that its partial pressure will remain essentially zero in the pulmonary capillary. The most common technique for making this measurement is the single-breath test. This test involves the inhalation of a single breath of dilute carbon monoxide (CO), followed by a breath-hold of 10 seconds. The diffusing capacity can be calculated using the lung volume and the percentage of CO in the alveoli at the beginning and end of the 10-second breath-hold.

Oxygen and Carbon Dioxide Transport . SA x D (P1 – P2 ) Vgas = T

. Vgas = P1

P2

Surface area (SA)

Thickness (T)

FIGURE 27-21 • The Fick law of diffusion states that the diffusion . of a gas (Vgas) across a sheet of tissue is related to the surface area (SA) of the tissue, the diffusion constant (D) for the gas, and the partial pressure difference (P1 − P2) on either side of the tissue, and is inversely proportional to the thickness (T) of the tissue.

Although the lungs are responsible for the exchange of gases with the external environment, it is the blood that transports these gases between the lungs and body tissues. The blood carries oxygen and carbon dioxide in the physically dissolved state and in combination with hemoglobin. Carbon dioxide also is converted to bicarbonate and transported in that form. Dissolved oxygen and carbon dioxide exert a partial pressure that is designated in the same manner as the partial pressures in the gas state. In the clinical setting, blood gas measurements are used to determine the partial pressure of oxygen (PO2) and carbon dioxide (PCO2) in the blood. Arterial blood commonly is used for measuring blood gases. Venous blood is not used because venous levels of oxygen and carbon dioxide reflect the metabolic demands of the tissues rather than the gas exchange function of the lungs. The PO2 of arterial blood normally is above 80 mm Hg, and the PCO2 is in the range of 35 to 45 mm Hg. Normally, the arterial blood gases are the same or nearly the same as the partial pressure of the gases in the alveoli. The arterial PO2 often is written PaO2, and the alveolar PO2 as PAO2, with the same types of designations being used for PCO2. This text uses PO2 and PCO2 to designate both arterial and alveolar levels of the gases.

Oxygen Transport Oxygen is transported in two forms: (1) in chemical combination with hemoglobin, and (2) in the dissolved state. Hemoglo-

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bin carries about 98% to 99% of oxygen in the blood and is the main transporter of oxygen. The remaining 1% to 2% of the oxygen is carried in the dissolved state. Only the dissolved form of oxygen passes through the capillary wall, diffuses through the cell membrane, and makes itself available for use in cell metabolism. The oxygen content (measured in mL/100 mL) of the blood includes the oxygen carried by hemoglobin and in the dissolved state. Hemoglobin Transport. Hemoglobin is a highly efficient carrier of oxygen. Hemoglobin with bound oxygen is called oxyhemoglobin, and when oxygen is removed, it is called deoxygenated or reduced hemoglobin. Each gram of hemoglobin carries approximately 1.34 mL of oxygen when it is fully saturated. This means that a person with a hemoglobin level of 14 g/100 mL carries 18.8 mL of oxygen per 100 mL of blood. In the lungs, oxygen moves across the alveolar–capillary membrane, through the plasma, and into the red blood cell, where it forms a loose and reversible bond with the hemoglobin molecule. In normal lungs, this process is rapid, so that even with a fast heart rate the hemoglobin is almost completely saturated with oxygen during the short time it spends in the pulmonary capillaries. As the oxygen moves out of the capillaries in response to the needs of the tissues, the hemoglobin saturation, which usually is approximately 95% to 97% as the blood leaves the left side of the heart, drops to approximately 75% as the mixed venous blood returns to the right side of the heart. Dissolved Oxygen. The partial pressure of oxygen represents the level of dissolved oxygen in plasma. The amount of dissolved oxygen depends on its partial pressure and its solubility in the plasma. In the normal lung at 760 mm Hg atmospheric pressure, the PO2 of arterial blood is approximately 100 mm Hg. The solubility of oxygen in plasma is fixed and very small. For every 1 mm Hg of PO2 present, 0.003 mL of oxygen becomes dissolved in 100 mL of plasma. This means that at a normal arterial PO2 of 100 mm Hg, the blood carries only 0.3 mL of dissolved oxygen in each 100 mL of plasma. This amount (approximately 1%) is very small compared with the amount that can be carried in an equal amount of blood when oxygen is attached to hemoglobin. Although the amount of oxygen carried in plasma under normal conditions is small, it can become a lifesaving mode of transport in cases of carbon monoxide poisoning, when most of the hemoglobin sites are occupied by carbon monoxide and are unavailable for transport of oxygen. The use of a hyperbaric chamber, in which 100% oxygen can be administered at high atmospheric pressures, increases the amount of oxygen that can be carried in the dissolved state. Binding Affinity of Hemoglobin for Oxygen. The efficiency of the hemoglobin transport system depends on the ability of the hemoglobin molecule to bind oxygen in the lungs and release it as it is needed in the tissues. Oxygen that remains bound to hemoglobin cannot participate in tissue metabolism. The term affinity refers to hemoglobin’s ability to bind oxygen. Hemo-

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globin binds oxygen more readily when its affinity is increased and releases it more readily when its affinity is decreased. As described in Chapter 14, the hemoglobin molecule is composed of four polypeptide chains with an iron-containing heme group. Because oxygen binds to the iron atom, each hemoglobin molecule can bind four molecules of oxygen when it is fully saturated. Oxygen binds cooperatively with the heme groups on the hemoglobin molecule. After the first molecule of oxygen binds to hemoglobin, the molecule undergoes a change in shape. As a result, the second and third molecules bind more readily, and binding of the fourth molecule is even easier. In a like manner, the unloading of the first molecule of oxygen enhances the unloading of the next molecule and so on. Thus, the affinity of hemoglobin for oxygen changes with hemoglobin saturation. Hemoglobin’s affinity for oxygen is also influenced by pH, carbon dioxide concentration, and body temperature. It binds oxygen more readily under conditions of increased pH (alkalosis), decreased carbon dioxide concentration, and decreased body temperature and it releases it more readily under conditions of decreased pH (acidosis), increased carbon dioxide concentration, and fever. For example, increased tissue metabolism generates carbon dioxide and metabolic acids and thereby decreases the affinity of hemoglobin for oxygen. Heat also is a byproduct of tissue metabolism, explaining the effect of fever on oxygen binding. Red blood cells contain a metabolic intermediate called 2,3-diphosphoglycerate (2,3-DPG) that also affects the affinity of hemoglobin for oxygen. An increase in 2,3-DPG enhances unloading of oxygen from hemoglobin at the tissue level. Conditions that increase 2,3-DPG include exercise, hypoxia that occurs at high altitude, and chronic lung disease. The Oxygen Dissociation Curve. The relation between the oxygen carried in combination with hemoglobin and the PO2 of the blood is described by the oxygen–hemoglobin dissociation curve, which is shown in Figure 27-22. The x axis of the graph depicts the PO2 or dissolved oxygen. It reflects the partial pressure of the oxygen in the lungs (i.e., the PO2 is approximately 100 mm Hg when room air is being breathed, but can rise to 200 mm Hg or higher when oxygen-enriched air is breathed). The left y axis depicts hemoglobin saturation or the amount of oxygen that is carried by the hemoglobin. The right y axis depicts oxygen content or total amount of the oxygen content being carried in the blood. The S-shaped oxygen dissociation curve has a flat top portion representing binding of oxygen to hemoglobin in the lungs and a steep portion representing its release into the tissue capillaries (see Fig. 27-22A). The S shape of the curve reflects the effect that oxygen saturation has on the conformation of the hemoglobin molecule and its affinity for oxygen. At approximately 100 mm Hg PO2, a plateau occurs, at which point the hemoglobin is approximately 98% saturated. Increasing the alveolar PO2 above this level does not increase the hemoglobin saturation. Even at high altitudes, when the partial pressure of oxygen is considerably decreased, the hemoglobin remains

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Understanding • Oxygen Transport All body tissues rely on oxygen (O2) that is transported in the blood to meet their metabolic needs. Oxygen is carried in two forms: dissolved and bound to hemoglobin. About 98% of O2 is carried by hemoglobin and the remaining 2% is carried in the dissolved state. Dissolved oxygen is the only form that diffuses across cell membranes and produces a partial pressure (PO2), which, in turn, drives diffusion. The transport of O2 involves (1) transfer from the alveoli to the pulmonary capillaries in the lung; (2) hemoglobin binding and transport; and (3) the dissociation from hemoglobin in the tissue capillaries.

❶

Lung

Alveoli-to-Capillary Transfer

In the lung, O2 moves from the alveoli to the pulmonary capillaries as a dissolved gas. Its movement occurs along a concentration gradient, moving from the alveoli, where the partial pressure of PO2 is about 100 mm Hg, to the venous end of the pulmonary capillaries with their lesser O2 concentration and lower PO2. The dissolved O2 moves rapidly between the alveoli and the pulmonary capillaries, such that the PO2 at the arterial end of the capillary is almost if not the same as that in the alveoli.

Alveolus

O2

O2 Pulmonary capillary

Red blood cell

PO2

relatively well saturated. At 60 mm Hg PO2, for example, the hemoglobin is still approximately 89% saturated. The steep portion of the dissociation curve—between 60 and 40 mm Hg—represents the removal of oxygen from the hemoglobin as it moves through the tissue capillaries. This portion of the curve reflects the fact that there is considerable transfer of oxygen from hemoglobin to the tissues with only a small drop in PO2, thereby ensuring a gradient for oxygen to move into body cells. The tissues normally remove approximately 5 mL of oxygen per 100 mL of blood, and the hemoglobin of mixed venous blood is approximately 75% saturated as it returns to the right side of the heart. In this portion of the dissociation curve (saturation 2 times a week but 1 time a week

FEV1.0 or PEF >60%–30%

Frequent

FEV1.0 or PEF ≤60% predicted PEF variability >30%

FEV1.0, forced expiratory volume in 1 second; PEF, peak expiratory flow rate. Adapted from National Asthma Education and Prevention Program. (2003). Expert Panel report 2: Guidelines for the diagnosis and management of asthma: Update of selected topics—2002. National Institutes of Health publication no. 02-5074. Bethesda, MD: National Institutes of Health.

frequency and severity of disease symptoms.18 The medications used in the treatment of asthma include those with bronchodilator and anti-inflammatory actions. They are categorized into two general categories: quick-relief medications and longterm control medications. The quick-relief medications include the short-acting β2-adrenergic agonists, anticholinergic agents, and systemic corticosteroids. The short-acting β2-adrenergic agonists (e.g., albuterol, bitolterol, pirbuterol, terbutaline) relax bronchial smooth muscle and provide prompt relief of symptoms, usually within 30 minutes. They are administered by inhalation (i.e., metered-dose inhaler [MDI] or nebulizer), and their recommended use is in alleviating acute attacks of asthma because regular use does not produce beneficial effects.18 An increase in the use of short-acting β2-adrenergic agonists or use of more than one canisters in a month indicates progression or inadequate control of the disease. The anticholinergic medications (e.g., ipratropium) block the postganglionic efferent vagal pathways that cause bronchoconstriction. These medications, which are administered by inhalation, produce bronchodilation by direct action on the large airways and do not change the composition or viscosity of the bronchial mucus. It is thought that they may provide some additive benefit for treatment of asthma exacerbations when administered with inhaled β2-adrenergic agonists.17 A short course of systemic corticosteroids, administered orally or parenterally, may be used for treating the inflammatory reaction associated with the late-phase response. Although their onset of action is slow (>4 hours), systemic corticosteroids may be used in the treatment of moderate to severe exacerba-

tions because of their action in preventing the progression of the exacerbation, speeding recovery, and preventing early relapses.17 The long-term medications are taken on a daily basis to achieve and maintain control of persistent asthma symptoms. They include anti-inflammatory agents, long-acting bronchodilators, and leukotriene modifiers. The Expert Panel defines antiinflammatory medications as “those that cause a reduction in markers of airway inflammation in airway tissues and airway secretions (e.g., eosinophils, mast cells, activated lymphocytes, macrophages, cytokines, or inflammatory mediators) and thus decrease the intensity of airway hyperresponsiveness.”18 The corticosteroids are considered the most effective anti-inflammatory agents for use in long-term treatment of asthma. Inhaled corticosteroids administered by MDI usually are preferred because of minimal systemic absorption and degree of disruption in hypothalamic-pituitary-adrenal function. In severe cases, oral or parenterally administered corticosteroids may be necessary. The anti-inflammatory agents sodium cromolyn and nedocromil are also used to prevent an asthmatic attack. These agents act by stabilizing mast cells, thereby preventing release of the inflammatory mediators that cause an asthmatic attack. They are used prophylactically to prevent early and late responses but are of no benefit when taken during an attack. The long-acting β2-adrenergic agonists, which are available for administration in inhaled (e.g., salmeterol, formoterol) or oral (e.g., albuterol sustained release) routes, act by relaxing bronchial smooth muscle. They are used as an adjunct to antiinflammatory medications for providing long-term control of

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symptoms, especially nocturnal symptoms, and for preventing exercise-induced bronchospasm. The long-acting β2-adrenergic agonists have durations of action of at least 12 hours and should not be used to treat acute symptoms or exacerbations.18 Theophylline, a methylxanthine, is a bronchodilator that acts by relaxing bronchial smooth muscle. The sustainedrelease form of the drug is used as an adjuvant therapy and is particularly useful in relieving nighttime symptoms. It may be used as an alternative, but not preferred, medication in longterm preventative therapy when there are issues concerning adherence with regimens using inhaled medications or when cost is a factor. Because elimination of the drug varies widely among persons, blood levels are required to ensure that the therapeutic, but not toxic, dose is achieved.18 A group of medications called the leukotriene modifiers or anti-leukotrienes are available for use in the treatment of asthma.34 Leukotrienes are potent biochemical mediators released from mast cells that cause bronchoconstriction, increased mucus secretion, and attraction and activation of inflammatory cells in the airways. There are two types of leukotriene modifiers: (1) those that act by inhibiting 5-lipoxygenase (e.g., zileuton), an enzyme required for leukotriene synthesis; and (2) those that act by inhibiting the binding of leukotrienes to their receptor in the target tissues (e.g., zafirlukast and montelukast). A particular advantage of the leukotriene modifiers is that they are taken orally.

Severe Asthma Severe or refractory asthma represents a subgroup (probably