Forensic Pathology Reviews, Volume 6

Forensic Pathology Reviews, Volume 6

Forensic Pathology Reviews, Volume 6 Michael Tsokos, md, Series Editor Volume 1 (2004) • Hardcover: ISBN 1-58829-414-5 Full Text Download: E-ISBN 1-59259-786-6 Volume 2 (2005) • Hardcover: ISBN 1-58829-414-3 Full Text Download: E-ISBN 1-59259-872-2 Volume 3 (2005) • Hardcover: ISBN 1-58829-416-1 Full Text Download: E-ISBN 1-59259-910-9 Volume 4 (2006) • Hardcover: ISBN 1-58829-601-6 Full Text Download: E-ISBN 1-59259-921-4 Volume 5 (2008) • Hardcover: ISBN 978-1-58829-832-4 Full Text Download: E-ISBN 978-1-59745-110-9 Volume 6 (2011) • Hardcover: ISBN 978-1-61779-248-9 Full Text Download: E-ISBN 978-1-61779-249-6

Forensic Pathology Reviews Volume 6

by

Elisabeth E. Turk, MD Medizinische Abteilung, Asklepios Klinik Harburg, Hamburg, Germany

Editor Elisabeth E. Turk Medizinische Abteilung Asklepios Klinik Harburg Eißendorfer Pferdeweg 52 21075 Hamburg Germany [email protected]

ISSN 1556-5661 ISBN 978-1-61779-248-9 e-ISBN 978-1-61779-249-6 DOI 10.1007/978-1-61779-249-6 Springer New York Dordrecht Heidelberg London © Springer Science+Business Media, LLC 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Humana Press is part of Springer Science+Business Media (www.springer.com)

Preface

The field of forensic pathology is continuing to expand. Advances in research open up new fields of forensic expertise and exciting possibilities for national and international cooperation with a large variety of disciplines in medicine and other sciences. Autopsy and laboratory techniques are evolving rapidly, and existing techniques yield more and more accurate results. In Forensic Pathology Reviews, Volume 6, leading national and international authors provide cutting-edge reviews of key recent advances in the fields of traumatic death, sudden natural death and death time estimation. The new volume now features many color illustrations. The reviews are aimed at forensic experts across the world, serving as a guide to practical aspects as well as recent advances in forensic science and medicine. I wholeheartedly thank all authors who contributed to this volume. Their hard work and constant support has been a great inspiration. Hamburg, Germany

Elisabeth E. Turk

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Contents

  1 Sudden Natural Deaths in Infancy and Childhood.............................. Neil E.I. Langlois and Roger W. Byard   2 Post-mortem Investigation of Sudden Unexpected Death in Infancy: Role of Autopsy in Classification of Death........................ Martin A. Weber and Neil J. Sebire   3 Sudden Death from Pulmonary Causes................................................ Kris S. Cunningham and Michael S. Pollanen   4 Sectioning of the Heart, Searching for Pathology Under the Microscope, and the Cardiac Proteomics Approach in the Study of Sudden Cardiac Death Cases....................................... Vittorio Fineschi, M.S.B. Othman, and Emanuela Turillazzi   5 Endocrine Disorders with Potentially Fatal Outcome......................... Lars Hecht

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  6 Sudden Death from Infectious Disease................................................. 121 James A. Morris, Linda M. Harrison, and Robert M. Lauder   7 Aviation Deaths....................................................................................... 145 S. Anthony Cullen   8 Fatalities in General Aviation: From Balloons to Helicopters............ 169 Alex de Voogt   9 The 9/11 Attacks: The Medicolegal Investigation of the World Trade Center Fatalities.................................................... 181 James R. Gill, Mark Desire, T. Dickerson, and Bradley J. Adams 10 Injuries and Fatalities in All-Terrain Vehicle Crashes........................ 197 Richard J. Mullins and J.H. Mullins

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11 Advances in Entomological Methods for Death Time Estimation..................................................................... 213 Martin H. Villet and Jens Amendt 12 Tissue Fluorescence Spectroscopy in Death Time Estimation............ 239 Éverton S. Estracanholli, Cristina Kurachi, and Vanderlei S. Bagnato 13 Heat-Flow Finite-Element Models in Death Time Estimation............ 259 Holger Muggenthaler, Michael Hubig, and Gitta Mall 14 The Use of Protein Markers for the Estimation of the Postmortem Interval.................................................................... 277 Yekaterina Poloz and Danton H. O’Day 15 Alcohol and Drug Fatalities in Transportation: Forensic-Toxicological Implications...................................................... 295 F. Mußhoff Index................................................................................................................. 331

Contributors

Bradley J. Adams, PhD  Office of Chief Medical Examiner, 520 First Avenue, New York, NY 10016, USA [email protected] Jens Amendt, PhD  Institute of Forensic Medicine, University of Frankfurt, Kennedyallee 104, 60596 Frankfurt/Main, Germany [email protected] Vanderlei S. Bagnato, PhD  Instituto de Física de São Carlos, Universidade de São Paulo, Av. Trabalhador São-Carlense 400, São Carlos, SP 13566-590, Brazil [email protected] Roger W. Byard, MBBS, MD, FRCPC  Discipline of Pathology, The University of Adelaide, Level 3 Medical School North Building, Frome Road, Adelaide 5005, SA, Australia [email protected] S. Anthony Cullen, MD (R.I.P.)  Lately Consultant Pathologist, RAF Centre of Aviation Medicine, RAF Henlow, Bedfordshire, SG16 6DN, UK Kris S. Cunningham, MD, PhD  Provincial Forensic Pathology Unit, Ontario Forensic Pathology Service, Centre for Forensic Science and Medicine, University of Toronto, 26 Grenville Street, 2nd Floor, Toronto, ON, Canada M7A 2G9 [email protected] Mark Desire, MS, JD  Office of Chief Medical Examiner, 520 First Avenue, New York, NY 10016, USA [email protected] T. Dickerson, MS  Office of Chief Medical Examiner, 520 First Avenue, New York, NY 10016, USA [email protected] ix

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Contributors

Éverton S. Estracanholli, MS  Instituto de Física de São Carlos, Universidade de São Paulo, Av. Trabalhador São-Carlense 400, São Carlos, SP 13566-590, Brazil [email protected] Vittorio Fineschi, MD, PhD  Department of Forensic Pathology, University of Foggia, Ospedale Colonnello D’Avanzo, Via degli Aviatori 1, 71100 Foggia, Italy [email protected] James R. Gill, MD  Office of Chief Medical Examiner, 520 First Avenue, New York, NY 10016, USA [email protected] Linda M. Harrison, MD  Department of Pathology, University Hospitals of Morecambe Bay NHS Trust, Royal Lancaster Infirmary, Lancaster, UK [email protected] Lars Hecht, MD  Institut für Pathologie, HELIOS Klinikum Bad Saarow, Pieskower Street 33, 15526 Bad Saarow, Germany [email protected] Michael Hubig, PhD  Institut für Rechtsmedizin, Universitätsklinikum Jena, 07740 Jena, Germany [email protected] Cristina Kurachi, MD  Instituto de Física de São Carlos, Universidade de São Paulo, Av. Trabalhador São-Carlense 400, São Carlos, SP 13566-590, Brazil [email protected] Neil E.I. Langlois, MD  Forensic Science SA and University of Adelaide, 21 Divett Place, Adelaide, SA 5000, Australia [email protected] Robert M. Lauder, PhD  Division of Biomedical and Life Sciences, School of Health and Medicine, Lancaster University, Lancaster, UK [email protected] Gitta Mall, MD  Institut für Rechtsmedizin, Universitätsklinikum Jena, 07740 Jena, Germany [email protected] James A. Morris, MD, FRCPath  Department of Pathology, University Hospitals of Morecambe Bay NHS Trust, Royal Lancaster Infirmary, Lancaster, UK [email protected] Holger Muggenthaler, PhD  Institut für Rechtsmedizin, Universitätsklinikum Jena, Jena 07743, Germany [email protected] J.H. Mullins, BA  Nursing School, University of Minnesota, Minneapolis, MN, USA [email protected]

Contributors

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Richard J. Mullins, MD  Department of Surgery, Trauma/Critical Care Section L611, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA [email protected] F. Mußhoff, PhD  Department of Toxicology, Institute of Legal Medicine, Universitätsklinikum Bonn, Stiftsplatz 12, 53111 Bonn, Germany [email protected] Danton H. O’Day, BSc, MSc, PhD  Department of Cell and Systems Biology, University of Toronto, M5S 3G5 Toronto, ON, Canada Department of Biology, University of Toronto, L5L 1C6, Mississauga, ON, Canada [email protected] M.S.B. Othman,  Jabatan Perubatan Forensik Hospital Ipoh, Perak Darul Ridzuan, Malaysia, [email protected] Michael S. Pollanen, BSc, MD, PhD, FRCPC, DMJ (Path), MRCPath  Provincial Forensic Pathology Unit, Ontario Forensic Pathology Service, Centre for Forensic Science and Medicine, University of Toronto, 26 Grenville Street, 2nd Floor, Toronto, ON, Canada M7A 2G9 [email protected] Yekaterina Poloz, PhD  Department of Cell and Systems Biology, University of Toronto, M5S 3G5 Toronto, ON, Canada [email protected] Neil J. Sebire, MD, DRCOG, FRCPath  Department of Histopathology, Camelia Botnar Laboratories, Great Ormond Street Hospital, London WC1N 3JH, UK [email protected] Emanuela Turillazzi, MD, PhD  Department of Forensic Pathology, University of Foggia, Ospedale Colonnello D’Avanzo, Via degli Aviatori 1, 71100 Foggia, Italy [email protected] Martin H. Villet, MSc, PhD, PGDHE  Department of Zoology and Entomology, Rhodes University, Grahamstown 6140, South Africa [email protected] Alex de Voogt, MD  Division of Anthropology, American Museum of Natural History, 200 Central Park West, New York, NY 10024, USA [email protected] Martin A. Weber, DCH(SA), FRCPath  Department of Histopathology, Camelia Botnar Laboratories, Great Ormond Street Hospital, London WC1N 3JH, UK [email protected]

Chapter 1

Sudden Natural Deaths in Infancy and Childhood Neil E.I. Langlois and Roger W. Byard

Abstract  Nontraumatic sudden and unexpected death in the young is an ­uncommon event, but it is one that has tremendous impact on families and communities. Autopsy assessments may be difficult, as many entities are rare and have quite ­subtle manifestations. In the following chapter, a range of lethal (mostly) ­natural diseases that may be encountered in pediatric forensic practice are described ­involving central nervous system, respiratory, cardiovascular, gastrointestinal, hematopoetic, genitourinary, infectious, endocrine, metabolic, and miscellaneous conditions, the latter including connective tissue and chromosomal disorders. These are listed in Table 1.1. The issue of the “negative autopsy” is also discussed with the potential role of genetic screening. Given the broad nature of the subject matter, the chapter is not intended to be exhaustive, but covers a range of conditions that should be considered during the process of the postmortem examination process. Keywords  Sudden unexpected death • Childhood • Sudden infant death syndrome

Introduction The postmortem examination process in all cases of sudden death in the young begins with consideration of the history and circumstances surrounding the death [1]. A scene visit may be beneficial. Certain aspects may have to be deliberately sought. For example, symptoms of presyncope, syncope, and palpitations preceding

R.W. Byard (*) Discipline of Pathology, The University of Adelaide, Level 3 Medical School North Building, Frome Road, Adelaide 5005, SA, Australia e-mail: [email protected] E.E. Turk (ed.), Forensic Pathology Reviews, Volume 6, Forensic Pathology Reviews 6, DOI 10.1007/978-1-61779-249-6_1, © Springer Science+Business Media, LLC 2011

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death may not have been considered important and therefore not have been ­volunteered [2], or a history of circumstances that may have resulted in commotio cordis may not be forthcoming without direct questioning [3–5]. Certain medical conditions, such as myotonic or muscular dystrophies may not be immediately apparent on examination, but these conditions can be associated with sudden death due to cardiac arrhythmias [6–9] and obtaining a personal or family history may be revealing. Following on from the review of the history and circumstances of death, an external examination may reveal features suggestive of congenital abnormalities that may indicate an underlying syndrome and a possible cause for sudden death. Examples include William [10], Downs [11], and Marfan [12] syndromes. It is also possible to search databases for possible syndromes linked to a constellation of abnormal morphologic findings (http:ncbi.nlm.nih.gov/sites/entrez?db = omim). Photography is important for documentation of dysmorphic features, and extensive use of photography should be considered in pediatric autopsy cases for recording normal, as well as abnormal findings. Preautopsy radiography may also be informative in identifying abnormalities that may be linked to sudden death, such as the presence of a pneumothorax [13]. Consideration should be given to performing computerized tomographic (CT) scanning or magnetic resonance imaging (MRI) [14–17]. Progressing from the external examination to the internal examination may reveal an apparent cause of death. This will be reviewed using a systematic approach, while recognizing that the autopsy in practice is performed on a regional, cavity basis and that some causes of death are not isolated to a particular organ or system (summarized in Table 1.1).

Central Nervous System Examination of the head and cranial cavity should be performed in all cases to exclude trauma. Subarachnoid hemorrhage in children and young adults is more often due to arteriovenous malformation [18] than a berry aneurysm [19]. Subdural hemorrhage may result from blunt head trauma; however, microscopic hemorrhages in the dura may be due to an artifact caused in removing the dura [20]. There may be a history of epilepsy that is a recognized cause of sudden death at all ages. Sudden death in epilepsy (SUDEP) has been defined as “sudden, unexpected, witnessed or unwitnessed, nontraumatic, and nondrowning death in patients with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus where necropsy examination does not reveal a toxicological or anatomical cause for death” [21]. Death tends to occur in poorly controlled patients, frequently occurring at night in bed [22–28]. It has been suggested that electrical discharges within the brain occurring during a seizure result in a lethal cardiac arrhythmia or fatal autonomic disturbance [29–34]; alternatively, apnea during the tonic phase of a fit may be a mechanism of death [21, 35]. Examination of the brain

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Table 1.1  Causes of sudden death in childhood Central nervous system Infections Epilepsy Hemorrhage Tumors Metabolic disorders Structural abnormalities Miscellaneous

Respiratory Infections Upper airway obstruction Asthma Bronchopulmonary dysplasia Miscellaneous Cardiovascular Infections Congenital cardiac defects (before and after surgery) Cardiomyopathies Subaortic stenosis Valvular abnormalities Aortic abnormalities Coronary artery abnormalities

Venous abnormalities Vascular malformations Pulmonary hypertension Tumors Conduction defects Miscellaneous

Gastrointestinal Infections Intestinal obstruction Intestinal perforation Mesenteric defects Gastroesophageal reflux/aspiration Late-presentingcongenital diaphragmatic hernia Gastrointestinal hemorrhage Miscellaneous

Bleeding diatheses, vascular malformations

Moyamoya disease, fibromuscular dysplasia, Friedreich ataxia, tuberous sclerosis, von Recklinghausen disease, Guillain–Barre syndrome

Massive pulmonary hemorrhage, idiopathic pulmonary hemosiderosis, tension pneumothorax

Aortic stenosis, mitral valve prolapse syndrome, tricuspid valve prolapse Supravalvular stenosis, coarctation, William syndrome, DiGeorge syndrome Anomalous coronary arteries, aplasia/hypoplasia, idiopathic arterial calcinosis, coronary arteritis (Kawasaki disease) Total anomalous pulmonary venous drainage

Endocardial fibroelastosis, fibromuscular dysplasia, aortic cystic medial necrosis, Budd–Chiari syndrome, thromboembolism Gastroenteritis Intussusception, volvulus

Cystic fibrosis, pancreatitis, anorexia nervosa/malnutrition (continued)

N.E.I. Langlois and R.W. Byard

4 Table 1.1  (continued) Hematological Hemoglobinopathies Malignancies Bleeding diatheses Anemia Miscellaneous Genitourinary Primary renal disease Urinary tract obstruction Wilms tumor Complications of sexual maturity Miscellaneous Infectious Cardiovascular Respiratory Central nervous system Hematologic Gastrointestinal Genitourinary Generalized

Sickle cell disease Lymphoma, leukemia

Infections, polycythemia, splenic disorders Pyelonephritis, glomerulonephritis

Ruptured ectopic pregnancy, amniotic fluid embolism Hemolytic-uremic syndrome Myocarditis, endocarditis, rheumatic fever, aortitis Acute epiglottitis, acute bronchopneumonia Meningitis, encephalitis, poliomyelitis Malaria, infectious mononucleosis Gastroenteritis, botulism Pyelonephritis Septicemia, endotoxemia

Endocrine Congenital adrenal hyperplasia Diabetes mellitus Thyroid disease Metabolic Reye syndrome Fatty acid oxidation defects Carbohydrate disorders Amino acid disorders Urea cycle disorders Organic acid disorders

Acyl-CoA dehydrogenase deficiencies (MCAD, LCAD) Galactosemia, glycogen storage diseases Homocystinuria

Miscellaneous Connective tissue disorders Marfan syndrome, Ehlers–Danlos syndrome type IV Chromosomal disorders Trisomy 21 Skeletal disorders Achondroplasia Dermatological disorders Hypohydrotic ectodermal dysplasia Muscular conditions Malignant hyperthermia Immunological conditions Anaphylaxis (Adapted from Byard RW, Sudden Death in the Young, Cambridge University Press, 2010)

by a neuropathologist is useful in epilepsy-related deaths [36] as an underlying cerebral lesion responsible for seizures may be found in up to 60% of cases [37]. For this reason, retention of the brain for formal examination should be discussed with family members at the earliest available opportunity.

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Occasionally, sudden death may be the first presentation of a central nervous system tumor, possibly associated with hemorrhage [38, 39]. Sudden death may also occur due to obstruction of cerebrospinal fluid flow in children with Chiari malformation or from centrally placed lesions such as colloid cysts [40]. Ventriculoatrial shunts have been associated with recurrent and lethal pulmonary thromboemboli [41] and ventriculoperitoneal shunts may result in lethal sepsis if the tip of a catheter perforates the intestine [42]. Function of the shunt can usually be tested during the postmortem examination by injection or manual operation of the reservoir. Although certain syndromic disorders may present with central nervous systemrelated manifestations, the final cause of death may not be due to cerebral disease. An example of this is tuberous sclerosis where there may be epilepsy associated with cortical tubers, with sudden death being due instead to the effects of cardiac rhabdomyomas. Lethal episodes involve outflow obstruction and arrhythmias [43]. Vascular malformations may be associated with lethal intracranial hemorrhage or seizures, the latter also occurring with a range of developmental abnormalities and metabolic conditions such as Lafora, Leigh, and Rett syndromes. The heritable nature of many of these conditions makes accurate diagnosis at autopsy imperative [44–48]. Causes of death in neurofibromatosis may involve vascular disease and the effects of tumors [49, 50].

Respiratory The oropharyngeal and laryngeal region should be carefully examined in all cases of unexpected death for causes of obstruction, including local infections such as acute epiglottitis (Fig. 1.1), congenital anomalies such as broncho-laryngomalacia [51, 52], laryngeal cysts [53], lingual thyroglossal cysts (Fig.  1.2) [54], hemangiomas [55], and aspirated foreign bodies [56, 57]. Infants with syndromes associated with mandibular hypoplasia are also at risk of acute airway obstruction [58]. Care should be taken to avoid over interpreting artifactual injuries caused by intubation [59]. However, medical procedures such as nasogastric tube insertion or inflicted injury may result in retropharyngeal abscess [60]. Individuals with tracheostomies may die unexpectedly if airway obstruction occurs from mucus plugging, or if an indwelling tube erodes into a major blood vessel [61]. Before opening the chest, the presence of a pneumothorax should be sought. This may be assessed by radiology [13], or at autopsy, by puncturing the chest wall beneath a level of water to look for escaping air [62]. Primary pneumothorax typically occurs in young, thin, tall males and is nonlethal; however, a tension pneumothorax may be rapidly fatal by causing midline shift of mediastinal structures [63]. Distended lungs with covering of the anterior surface of the heart with rib ­markings on the pleural surfaces raise the possibility of acute asthma. Other signs, such as plugging of bronchi, eosinophils, Charcot–Leyden crystals, bronchial wall thickening with edema, and basement membrane thickening [64–66] should be

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Fig. 1.1  Edema of the epiglottis with narrowing of the glottic inlet in a child with acute bacterial epiglottitis [1]

sought. However, these findings may not be present in up to 50% of cases [67], particularly if there has been attempted resuscitation [68], and a predominance of neutrophils rather than eosinophils has been described in acute deaths [69]. Primary diaphragmatic pathology may also result in a lethal outcome [70].

Cardiovascular Examination of the cardiovascular system begins with a general assessment of the anatomy, with particular regard to congenital abnormalities. Congenital abnorma­lities of the heart and great vessels may be unsuspected and can present with sudden death [1, 71–73]; death can occur following surgical correction, even late [71, 74–76]. Conditions include tetralogy of Fallot, transposition of the great vessels, left ventricular­ hypoplasia, and valvular stenoses (Fig. 1.3). Venous abnormalities are not usually associated with sudden death unless there is anomalous pulmonary venous drainage. In this condition, there is complete or partial drainage of pulmonary venous blood into the right side of the heart. In cases of compete anomalous drainage, there has to be a mechanism to enable shunting of

1  Sudden Natural Deaths in Infancy and Childhood Fig. 1.2  View of the posterior portion of the tongue showing a small lingual thyroglossal duct cyst at the foramen cecum. Enlargement would result in pressure on the epiglottis with posterior displacement and airway compromise

Fig. 1.3  Dysplasia of the aortic valve with significant stenosis

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Fig. 1.4  Thickening of the wall of a coronary artery due to vasculitis associated with Kawasaki disease (arrow)

oxygenated blood through a patent ductus arteriosus or a septal defect for survival to be possible [77–79]. Certain congenital anomalies of the coronary arteries, such as origin from the pulmonary trunk and left main origin from the right aortic sinus with the artery passing between the pulmonary artery and aorta, are associated with sudden death, particularly during exercise [80–83]. However, sudden death has been associated with all types of aberrantly sited arteries, and also in cases of arterial hypoplasia or aplasia [84–88]. Critical reduction of blood flow may occur with an acute angle of take off (>45°) or intimal ridges [89]. Rarely coronary artery thromboembolism may occur in childhood, usually in association with rheumatic fever or a congenital cardiac defect [90]. Atherosclerotic coronary artery disease is uncommon in childhood unless a hereditary hyperlipidemic syndrome is present. Coronary flow can also become compromised as a consequence of other conditions that cause arterial narrowing such as Kawasaki disease (Figs.  1.4 and 1.5) [91–93], fibromuscular ­dysplasia [94], and idiopathic arterial calcinosis (Fig. 1.6) [95]. The pulmonary arteries should be inspected, as pulmonary thromboembolism, although uncommon in the young does occur and has similar predisposing factors to older individuals, including conditions such as sepsis and malignancy [96, 97]. In  cases where there is no obvious initiating condition, the possibility of a ­thrombophilia such as mutations in the factor V Leiden and prothrombin genes (G20210A), or deficiencies in anti-thrombin III, plasminogen, and proteins C and S, or antiphospholipid syndrome should be considered [1]. Cerebral embolism may occur paradoxically if there is a septal defect present, or if the source of embolic material is cardiac, and may involve tumor, as in Wilms tumor [98], or infective material, as in cardiac ecchinococcosis [99].

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Fig. 1.5  Obliteration of the lumen of a coronary artery following Kawasaki disease

Fig. 1.6  Concentric calcification of the media with fibrointimal proliferation in a case of ­idiopathic arterial calcinosis

Pulmonary hypertension may be idiopathic or caused by a variety of ­mechanisms including increased vascular flow from shunting, embolism, and chronic hypoxia. Sudden death may occur due to arrhythmias from right ventricular hypertrophy (Fig. 1.7) [1]. Aortic dissection may be associated with Marfan syndrome [100], in which case genetic counseling of family members may be required. However, the identification

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Fig. 1.7  Right ventricular and atrial hypertrophy and dilation in a case of sudden death from ­pulmonary hypertension

of over 500 mutations in the fibrillin gene, the lack of association between ­phenotype and genotype, and the fact that 25–30% of cases are sporadic, makes attempts at determining clinical prognosis difficult [12]. Cardiac hypertrophy is a risk factor for arrhythmia and for sudden death, and may be associated with ventricular septal defects [101, 102]. Coarctation of the aorta may also result in cardiac hypertrophy [103] and has been associated with aortitis [104]. Hypertrophic cardiomyopathy may be apparent if a markedly increased heart weight is found when compared to standard tables, and there may be asymmetrical thickening of the septum [105]. Endocardial thickening may be present over the septum beneath the aortic valve due to impact from the anterior mitral valve cusp [106]. Myocardial fiber disarray is considered a characteristic feature of this ­disorder, but this may be focal, necessitating adequate sampling [106]. Caution is also required, as disorganized myocytes can be found in the normal heart (particularly around the junction of the septum with the anterior and posterior walls [105, 107]), such that a significant amount of disarray must be observed to diagnose the ­condition (around 20% in two histological blocks has been recommended [106]). Nuclear changes, fibrosis, and abnormalities of small intramyocardial vessels may be also observed. Cardiac hypertrophy may also occur due to dilated cardiomyopathy [108], which has nonspecific histological features, with fibrosis being common [109]. It is also recognized that acute cardiac death may be a late complication of ­chemotherapy, for example, following anthracycline [110, 111]. Oncocytic cardiomyopathy refers to a condition of uncertain etiology where ­cardiomegaly is associated with subendocardial or epicardial tan-white nodules

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with thickening of valves. The nodules are composed of aggregates of round to ­polygonal cells with granular cytoplasm. Sudden and unexpected death may occur in 20% of cases [112]. Myocardial noncompaction is a rare genetically heterogeneous cardiomyopathy where there is abnormal left ventricular development with failure of compaction of loose fetal myocardial fibers giving the left ventricle a spongy appearance with prominent trabeculation [113–117]. Involvement of the heart by tumor has been reported in association with sudden death [118], as has lipomatous hypertrophy of the interatrial septum, although this tends to occur in older individuals [119]. Floppy mitral valve is a recognized association with sudden death [120–123]. Although the mechanism is not understood, it is likely to be due to arrhythmia [124]. There is a reported association with Marfan’s syndrome, Ehlers–Danlos, osteogenesis imperfecta, and pseudoxanthoma elasticum [12, 121] and a familial element is present in some cases [120]. The valves should also be examined for the possibility of endocarditis [125]. Rheumatic heart disease may present acutely and a valvulitis of the mitral valve may be recognized [126]. Histological changes may be confined to the atria, or characteristic Ashoff bodies may be found throughout the heart [126, 127]. A method of sampling of the heart has been described by the TRAGADY group [128]. As part of this protocol, sampling of the right ventricle is advocated to ­identify or exclude right ventricular arrhythmogenic dysplasia (right ventricular cardiomyopathy), which may be associated with death during exertion [129, 130]. It has been proposed that there should be a separation between pure fatty replacement (that may also be related to Uhl anomaly when extensive), which may be regarded a ­congenital disorder, and fibrofatty replacement of the right ventricular myocardium (with or without inflammation), which is considered to be an acquired abnormality resulting from myocarditis with loss of myocytes [131–136]. It has been proposed that only the fibrofatty form should be regarded as true arrhythmogenic right ventricular ­dysplasia (cardiomyopathy) [137]. The changes are most marked in the right ventricular inflow, apex, and infundibular regions (the so-called triangle of dysplasia) [130, 134, 137]. However, involvement of the left ventricle has also been reported [138–140]. Sampling of the heart may also reveal evidence of myocarditis. Nonetheless, care must be taken not to over diagnose myocarditis as a cause of death as collections of lymphocytes without myocytolysis are a not uncommon incidental finding [141]. However, if changes meeting the Dallas criteria are present [142] in the absence of an alternative cause of death, then it is probably reasonable to attribute death to myocarditis [143]. The histological changes may be focal and sampling 8–10 histological blocks has been suggested [144, 145]. It has also been suggested that with advances in molecular biological techniques, it may be possible to make the diagnosis on the basis of PCR (polymerase chain reaction) demonstration of viral infection of the heart in the presence of a suggestive clinical history [146, 147]. Giant cell myocarditis may occur in children that may be an autoimmune disorder dependent on CD-4 positive T-lymphocytes [1].

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Gastrointestinal Gastrointestinal causes of sudden death in the young range from intestinal ­obstruction due to volvulus and intussusception, to gastric perforation with peritonitis, which should be apparent upon opening the abdomen [148, 149]. Malrotation of the gut may result in ischemia [150] and herniation of the intestine through congenital defects in the mesentery may also result in lethal obstruction with gangrene (Fig. 1.8) [151]. There may be underlying pathologies that should be sought, for example, gastric perforation is more common in children with severe developmental delay who may swallow air due to neuromuscular incoordination and who may have abnormally deep chest cavities predisposing to gastric torsion [152]. In addition, care must be taken as intussusception may also be a terminal event when death has resulted from other means [149, 153]. Rectal bleeding from an ischemic intestine in early childhood has been mistakenly attributed to trauma from sexual assault [154]. Late presenting congenital diaphragmatic hernia can be a cause of sudden death [155–157].

Fig. 1.8  Small intestinal infarction following herniation through a mesenteric defect (arrow)

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Hematologic Inspection of the spleen may reveal enlargement, which, with or without the presence of lymphadenopathy, may suggest underlying hematological abnormalities. Abnormalities such as leukemia and sickle cell disease may be present [84, 158]. Sickle cell disease should be considered as a cause of sudden death in African and Mediterranean populations [159], which may follow exertion or minor infection and result in sickle cell sequestration crisis [160]. The diagnosis can be made from histological sections; however, sickling may be a postmortem phenomenon. Electrophoresis will display the presence of abnormal hemoglobin [161]. Leukemia may present with fatal intracerebral hemorrhage following a short period of nonspecific malaise.

Genitourinary Genitourinary causes of sudden death such as Wilms tumor hemorrhage or ­embolism occur rarely [98]. Pathologists may check for vesico-ureteric reflux during the course of the autopsy, due to its association with pyelonephritis. If pyelonephritis is present it may be recognized by the presence of punctate yellow collections of pus in the renal parenchyma, often with surrounding erythema. The diagnosis can be ­confirmed by microscopic examination. Hemolytic-uremic syndrome is caused by a systemic thrombotic microangiopathy that may follow an infection such as gastrointestinal infection with verotoxinproducing Escherichia coli or Shigella dysenteriae type 1. It has also been linked to drugs, tumors, other infectious agents, and possibly to immunization. An acute onset of microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency may occur with sudden death from myocarditis or intracerebral hemorrhage [162]. Complications of pregnancy such as a ruptured ectopic pregnancy or amniotic fluid embolism should be suspected in any sexually mature female.

Infectious The examining pathologist must consider potential causes of death that are not ­system or body cavity specific, but which can be generalized in their manifestation and effects. Globally, fulminant infections remain major causes of rapid death in the young, with complications of acute gastroenteritis and malaria accounting for many deaths. Meningococcal sepsis and other types of bacterial meningitis (Fig. 1.9) are probably the best recognized infections causing rapid demise in previously well children in developed countries. Infection should always be considered a possibility at autopsy requiring the consideration of taking of additional samples for histology

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Fig. 1.9  Purulent exudate adherent to the base of the brain in a case of fatal bacterial meningitis

and other tests. Cerebrospinal fluid (CSF) can be taken by posterior spinal puncture before the body is opened, or by anterior puncture after evisceration of the organs. If CSF cannot be obtained by these routes, a swab of the basal region of the brain immediately after the skull is opened is a reasonable alternative. This can be supplemented by obtaining a sterile sample of brain tissue immediately following reflection of the dura. Once the chest is opened, the pericardial sac can be incised to allow a sterile puncture of the right atrium of the heart to obtain heart blood for culture. Samples from other organs, such as the heart, lungs, and spleen, should be taken as early as possible into the postmortem examination, before there has been significant handling of the organs. The surfaces of can be sterilized by searing or by washing by alcohol. Isopropyl alcohol should be used rather than ethanol to avoid contamination if samples are also being taken for toxicology. Testing of the heart for enteroviruses can be supplemented by taking of small bowel content. The use of the polymerase chain reaction (PCR) to search for molecular evidence of infecting organisms supplements viral culture, but has the advantage that it can be applied to formalin-fixed paraffin-embedded tissues [163]. Microscopic examination of tissues can prove a vital component of this ­assessment as entities such as pneumonia in the very young may result in sudden death following no specific, or only minimal, clinical signs [1]. While there may be a large difference in weight between the two lungs, with the involved lung being

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firm and airless, in certain cases the changes may only been apparent on histological examination. Microbiological studies may again be contributory with polymerase chain reaction (PCR) analysis of samples supplementing bacterial and viral culture for identification of infectious agents such as influenza [164]. Local infection of the upper airway may produce critical reduction in lumenal diameter and thus compromise oxygenation. This used to occur with acute ­epipiglottitis due to Hemophilus influenzae type B infection, but this has declined dramatically since the introduction of vaccinations in the early 1990s. Viral infections such as infectious mononucleosis due to Ebstein–Barr virus may cause lethal acute upper airway obstruction due to tonsillar enlargement [165]. Lethal obstruction may also occur if there is infection of the lingual tonsils [166]. Tonsillitis may also cause lethal hemorrhage [167]. Bacterial endocarditis may complicate ­congenital cardiac malformations and cause death from a variety of mechanisms [168]. Lemierre syndrome is a necrotizing infection of the head due to Fusobacterium necrophorum that causes septic thrombophlebitis of the internal jugular vein, meningitis and descending necrotizing mediastinitis [169]. Sudden death in childhood may be associated with infection such as parvovirus B19 [170] and rare infections include those due to hydatid disease where sudden death may result from cyst rupture with anaphylaxis or embolization of the contents [99, 171]. In some cases, the etiological agent of infectious syndromes may not be ­identified, such as in cases of hemorrhagic shock and encephalopathy. This condition was first described in 1983; the pathogenesis is unclear, but the condition affects previously healthy infants and children. In approximately half of the cases there is a short ­prodroma of respiratory infection or gastrointestinal upset followed by a rapid onset of shock, encephalopathy, hemorrhage, diarrhea, and oliguria. The pathological findings­are nonspecific. Features of disseminated intravascular coagulation may be present. Softening, edema, and infarction have been described in the brain [172].

Endocrine Endocrine causes of sudden death should be considered in the absence of a cause of death in other systems. Adrenocortical insufficiency may arise spontaneously, as part of congenital adrenal hypoplasia, in the context of sepsis, or as a result of ­exogenous steroid therapy, and result in death [173, 174]. Abnormal pigmentation of the gingival membranes and skin creases may be apparent in Addison’s disease [173]. Serum cortisol can be measured in these cases [175]. The vitreous humor from the eye may be used to obtain an indication of the antemortem electrolyte levels; however, after death, changes in electrolyte levels occur due to necrosis of retinal cells [176–178]. Poorly controlled diabetes mellitus may be a cause of sudden death in ­childhood, but the mechanism may not be clear, particularly when death occurs when the ­victim is unattended in bed [179, 180]. Testing of urine using a clinical “dipstick”

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is not a perfect tool for detecting unsuspected diabetes [181] and vitreous ­biochemical ­analysis should be performed. In addition to testing the vitreous for glucose, further relevant information may be obtained by testing the vitreous for the ketone b-hydroxbutyrate [182] and by measuring blood HbA1c levels (with elevated levels ­indicating the presence of diabetes mellitus [183–185]); as well as analyzing for insulin and c-peptide [186, 187]. Basal vacuolization of renal tubular epithelial cells may be seen in the kidneys following ketoacidosis [188]. After death, glucose levels in the blood and ­vitreous tend to fall as cells anerobically metabolize any sugars present [177]; hence, hypoglycemia cannot be reliably diagnosed after death [189, 190]. However, measurement of ­lactate has been proposed as a means of identifying antemortem hypoglycemia [191].

Metabolic A wide variety of metabolic disorders may result in sudden and unexpected death in infancy and childhood, the features of which have been described in detail elsewhere [192]. One of the most common is medium-chain acyl-CoA dehydrogenase deficiency where abnormal b-oxidation of fatty acids causes episodic hypoglycemia, lethargy, vomiting, seizures, coma, respiratory depression/apnea, and sudden death. MCAD deficiency has an autosomal recessive inheritance and the gene for MCAD has been fully characterized on chromosome 1p31. The estimated ­frequency is between one in 9,000–22,000 with a higher incidence among ­northern Europeans [1]. Reye’s syndrome [193] has now largely disappeared as a cause of death following viral infection due to the avoidance of the use of aspirin, and the more precise identification of specific disorders that had been included under this diagnostic umbrella.

Miscellaneous A variety of other conditions may be associated with sudden death, including ­connective tissue disorders such as Marfan and Ehlers–Danlos syndromes. Sudden death in Marfan syndrome may result from aortic dissection, and vessel rupture is a feature of Type IV Ehlers–Danlos syndrome associated with absence type III ­collagen. These events may manifest early in life, including during infancy [194, 195]. Infants with any one of the three common trisomies, 21, 18, and 13, are predisposed to early death; for example, children with Down syndrome are at higher risk of death from congenital cardiovascular abnormalities and infections, in addition to a wide range of other less common conditions [11]. Anaphylaxis may result in rapid death, sometimes with minimal findings at autopsy. Sampling of postmortem serum for tryptase and specific immunoglobulin E levels will be required to establish the diagnosis [196].

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The “Negative” Autopsy Despite meticulous examination considering potential anatomical (gross and ­microscopic), biochemical, microbiological, and metabolic causes of death, no apparent cause of death may be found in around 4–10% of postmortem examinations [145, 197–200]. There has been recent interest in molecular causes of sudden death as an explanation in such cases. One particular group of such disorders is associated with prolongation of the QT interval. The QT interval is the duration of the phase from ventricular depolarization (onset of ventricular contraction) to the end of ventricular repolarization (resetting of the electrical potential in the cardiac myocytes) [201, 202]. The QT interval varies with heart rate, but using Bazett’s formula [201, 203], a corrected QT interval (QTc) can be calculated that is independent of the rate. An individual with a QTc greater than 440 ms may have a 2.3 times increased risk of sudden death compared to controls [204]. Research into the long QT syndrome has revealed a number of genetic defects in components of the ion channels in cardiac myocytes [202, 205]; ion channels are essential for the control of muscular depolarization and depolarization. Mutations in the potassium channel genes KCNQ1 (LQT1) and KCHN2 (LQT2) and the sodium channel gene SCH5A (LQT3) are the most common causes of the long QT ­syndrome [206, 207]. The phenotypes associated with mutations vary, such that LQT1 and LQT2 are associated with death at times of emotional or physical stress and exercise (particularly swimming with LQT1); loud noise may cause arrhythmias in LQT2, but LQT3 is associated with death during sleep (and is one cause of Brugada ­syndrome [205, 208]) [202, 207]. Although the heritable nature of long QT has been known for many years, several mutations are known and the implications to ­families of finding polymorphisms may be uncertain [209–211]. It has been suggested that genetic screening should be performed in all cases of sudden death with negative postmortem examinations [212]. However, in the future it may also be shown that molecular abnormalities provide an explanation as to why sudden death occurs in some patients with chronic disease states such as epilepsy [213], asthma [214], and diabetes [215–217], but not others.

Conclusion Given the wide range of disorders and conditions that may result in sudden and/or unexpected deaths in the young [1], autopsies must be comprehensive and involve careful review of clinical and family histories, full dissections with specialized ­evaluations where necessary, and use of ancillary testing, such as microbiologic, metabolic, and genetic screening; in some cases, a scene visit may be beneficial. The complex and rare nature of many of these diseases also means that early involvement of additional specialists such as medical geneticists and pediatric ­cardiologists, radiologists, and microbiologists may provide invaluable information

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and guidance in the assessment of such cases. As always, determining what an ­individual has died from, and not with, may be the ultimate challenge.

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128. Skinner JR, Duflou JA, Semsarian C (2008) Reducing sudden death in young people in Australia and New Zealand: the TRAGADY initiative. Med J Australia 10:539–540 129. Gallagher PJ (1994) The investigation of cardiac death. In: Anthony PP, MacSween RNM (eds) Recent advances in histopathology. Longman, Edinburgh, pp 123–146 130. McRae TA, Chung MK, Asher CR (2001) Arrhythmogenic right ventricular cardiomyopathy: a cause of sudden death in young people. Clev Clin J Med 68:459–467 131. Burke AP, Farb A, Tashko G, Virmani R (1998) Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium. Are they different diseases? Circulation 97:1571–1580 132. Calabrese F, Basso C, Carturan E, Valente M, Thiene G (2006) Arrhythmogenic right ventricular cardiomyopathy/dysplasia: is there a role for viruses? Cardiovasc Pathol 15: 11–17 133. Corrado D, Basso C, Thiene G (2000) Arrhythmogenic right ventricular cardiomyopathy: diagnosis, prognosis and treatment. Heart 83:588–595 134. D’Amati G, Leone O, Di Gioia CRT, Magelli C, Arpesella G, Grillo P et  al (2001) Arrhythmogenic right ventricular cardiomyopathy: clinicopathologic correlation based on a revised definition of pathologic patterns. Hum Pathol 32:1078–1086 135. Sheppard MN (1998) Arrhythmogenic right ventricular dysplasia and arrhythmogenic right ventricular cardiomyopathy: do these entities exist and are they the same disease? Curr Diagn Pathol 5:150–156 136. Tabib A, Liore R, Chalabreysse L, Meyronnet D, Miras A, Malicier D et  al (2003) Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia. Circulation 108:3000–3005 137. Fornes P, Ratel S, Lecomte D (1998) Pathology of arrhythmogenic right ventricular cardiomyopathy/dysplasia – an autopsy study of 20 forensic cases. J For Sci 43:777–783 138. Gemayel C, Pelliccia A, Thompson PD (2001) Arrhythmogenic right ventricular cardiomyopathy. J Am Col Cardiol 38:1773–1781 139. Michalodimitrakis M, Papadomanolakis A, Stiakakis J, Kanaki K (2002) Left side right ventricular dysplasia. Med Sci Law 42:313–317 140. Shrapnel M, Gilbert JD, Byard RW (2001) “Arrhythmogenic left ventricular dysplasia” and sudden death. Med Sci Law 41:159–162 141. Davies MJ (1981) Pathological view of sudden cardiac death. Brit Heart J 45:88–96 142. Aretz HT (1987) Myocarditis: The Dallas criteria. Hum Pathol 18:619–624 143. Smith NM, Bourne AJ, Clapton WC, Byard RW (1992) The spectrum of presentation at autopsy of myocarditis in infancy and childhood. Pathology 24:129–131 144. Corby C (1960) Isolated myocarditis as a cause of sudden death. Med Sci Law 1:23–31 145. Cohle SD, Sampson BA (2001) The negative autopsy: sudden cardiac death or other? Cardiovasc Pathol 10:219–222 146. Dettmeyer R, Kandolf R, Schmidt P, Schlamann M, Madea B (2001) Lympho-monocytic enteroviral myocarditis: traditional, immunohistological and molecular pathological methods for diagnosis in a case of suspected sudden infant death syndrome (SIDS). Forensic Sci Int 119:141–144 147. Baughman KL (2006) Diagnosis of myocarditis. Death of Dallas criteria. Circulation 113:593–595 148. Byard RW (2000) Sudden infant death, large intestinal volvulus and a duplication cyst of the terminal ileum. Am J Forensic Med Pathol 21:62–64 149. Byard RW, Simpson A (2001) Sudden death and intussusception in infancy and childhood autopsy considerations. Med Sci Law 41:41–45 150. Levin TL, Liebling MS, Ruzal-Shapiro C, Berdon WE, Stolar CJ (1995) Midgut malfixation in patients with congenital diaphragmatic hernia: what is the risk of midgut volvulus? Pediatr Radiol 25:259–261 151. Byard RW, Wick R (2008) Congenital mesenteric anomalies and unexpected death. Ped Develop Pathol 15:205–209

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152. Byard RW, Couper RTL, Cohle S (2001) Gastric distension, cerebral palsy and unexpected death. J Clin Forensic Med 8:81–85 153. Cox DE (1997) Intussusception: agonal phenomenon or cause of death? Med Sci Law 37:355–358 154. Byard RW, Donald TG, Rutty G (2008) Non-traumatic causes of perianal hemorrhage and excoriation in the young. Forensic Sci Med Pathol 4:159–163 155. Byard RW, Bohn DJ, Wilson G, Smith CR, Ein SH (1990) Unsuspected diaphragmatic hernia: a potential cause of sudden and unexpected death in infancy and early childhood. J Pediatr Surg 25:1166–1168 156. Byard RW, Bourne AJ, Cockington RA (1991) Fatal gastric perforation in a 4-year-old child with a late-presenting congenital diaphragmatic hernia. Pediatr Surg Int 6:44–46 157. Vandy FC, Landrum JE, Gerig NR, Prahlow JA (2008) Death due to late-presenting congenital diaphragmatic hernia in a 2-year-old child. Am J Forensic Med Pathol 29:75–79 158. Whybourne A, Zillman MA, Miliauskas J, Byard RW (2001) Sudden and unexpected infant death due to occult lymphoblastic leukaemia. J Clin Forensic Med 8:160 159. Graham JK, Mosunjac M, Hanzlick RL, Mosunjac M (2007) Sickle cell lung disease and sudden death. A retrospective/prospective study of 21 autospy cases and literature review. Am J Forensic Med Pathol 28:168–172 160. Wirthwein DP, Spotswood SD, Barnard SD, Barnard JJ, Prahlow JA (2001) Death due to microvascular occlusion in sickle-cell trait following physical exertion. J For Sci 46:399–401 161. Thogmartin JR, Wilson CI, Palma NA, Ignacio SS, Pellan WA (2009) Histological diagnosis of sickle cell trait. A blinded analysis. Am J Forensic Med Pathol 30:36–39 162. Manton N, Smith NM, Byard RW (2000) Unexpected childhood deaths due to hemolytic uremic syndrome. Am J Forensic Med Pathol 21:90–92 163. Bonin S, Petrera F, Niccolini B, Stanta G (2003) PCR analysis in archival postmortem tissues. J Clin Pathol Mol Pathol 56:184–186 164. Landi KK, Coleman AT (2008) Sudden death in toddlers caused by influenza B infection: a report of two cases and a review of the literature. J For Sci 53:213–215 165. Byard RW (2002) Unexpected death due to infectious mononucleosis. J Forensic Sci 47:202–204 166. Byard RW, Silver MM (1993) Sudden infant death and acute posterior lingual inflammation. Int J Pediatr Otorhinolaryngol 28:77–81 167. Byard RW (2008) Tonsillitis and sudden childhood death. J Forensic Legal Med 15:516–518 168. Byramji A, Gilbert JD, Byard R. Sudden death as a complication of bacterial endocarditis. Am J Forensic Med Pathol 32:140–142 169. Gilbert JD, Warner M, Byard RW (2009) Lemierre syndrome and unexpected death in childhood. Am J Forensic Med Pathol 16:478–481 170. Zack F, Kilngel K, Kandolf R, Wegener R (2995) Sudden cardiac death in a 5-year-old girl associated with parvovirus B19 infection. Forensic Sci Int 155:13–17 171. Byard RW (2009) An analysis of possible mechanisms of unexpected death occurring in hydatid disease (echinococcosis). J For Sci 54:919–922 172. Little D, Wilkins B (1997) Haemorrhagic shock and encephalopathy syndrome. An unusual cause of sudden death in children. Am J Forensic Med Pathol 18:79–83 173. Burke MP, Opeskin K (1999) Adrenocortical insufficiency. Am J Forensic Med Pathol 20:60–65 174. Tough SC, Green FH, Paul JE, Wigle DT, Butt JC (1996) Sudden death from asthma in 108 children and young adults. J Asthma 33:179–188 175. Clapper A, Nashelsky MB, Dailey M (2008) Evaluation of serum cortisol in the postmortem diagnosis of acute adrenal insufficiency. Am J Forensic Med Pathol 29:181–184 176. Balasooriya BAW, St Hill CA, Williams AR (1984) The biochemistry of vitreous humour. A comparative study of the potassium, sodium and urate concentrations in the eyes at identical time intervals after death. Forensic Sci Int 26:85–91 177. Coe JI (1972) Use of chemical determinants on vitreous humor in forensic pathology. J For Sci 17:541–546

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1 78. Coe I (1993) Postmortem Chemistry Update. Am J Forensic Med Pathol 14:91–117 179. Irwin J, Cohle SD (1988) Sudden death due to diabetic ketoacidosis. Am J Forensic Med Pathol 9:119–121 180. Tattersall RB, Gill GV (1990) Unexplained deaths of type I diabetic patients. Diabetic Med 8:49–58 181. Wei OY, Teece S (2006) Urine dipsticks in screening for diabetes mellitus. Emerg Med J 23:138 182. Osuna E, Vivero G, Conejero J, Abenza JM, Martínez P, Luna A et al (2005) Postmortem vitreous humor b-hydroxybutyrate: its utility for the postmortem interpretation of diabetes mellitus. Forensic Sci Int 153:189–195 183. Goullé J-P, Lacroix C, Bouige D (2002) Glycated hemoglobin: a useful post-mortem reference marker in determining diabetes. Forensic Sci Int 128:44–49 184. Khuu HM, Robinson AC, Brissie RM, Konrad RJ (1999) Postmortem diagnosis of unsuspected diabetes mellitus established by determination of decedent’s hemoglobin A1c level. J For Sci 44:643–646 185. Winecker RE, Hammett-Stabler C, Chapman JF, Ropero-Miller JD (2002) HbA1c as a postmortem tool to identify glycemic control. J For Sci 47:1373–1379 186. Batalis NI, Prahlow JA (2004) Accidental insulin overdose. J For Sci 49:1117–1120 187. Haibach H, Shah JH (1987) Homicide by insulin administration. J For Sci 32:208–216 188. Kock KF, Vestergaard V (1994) Armanni-Ebstein lesions of the kidney: diagnostic of death in diabetic coma? Forensic Sci Int 67:169–174 189. Gama R, Teale JD, Marks V (2003) Best Practice No 173. Clinical and laboratory investigation of adult spontaneous hypoglycaemia. J Clin Pathol 56:641–646 190. Patel F (1994) Diabetic death bed: post-mortem determination of hypoglycemia. Med Sci Law 34:84–87 191. Kernbach-Wighton G, Sprung R, Püschel K (2001) On the diagnosis of hypoglycemia in car drivers - including a review of the literature. Forensic Sci Int 115:89–94 192. Gilbert-Barness E, Barness L (2000) Metabolic diseases: foundations of clinical management, genetics and pathology. Eaton press. Natick, Mass 193. Young TW (1992) Reye’s syndrome. A diagnosis occasionally made first at medicolegal autopsy. Am J Forensic Med Pathol 13:21–27 194. Byard RW (2006) Sudden death in Marfan syndrome. In: Tsokos M (ed) Forensic pathology reviews. Humana Press, pp 93–106 195. Byard RW, Keeley FW, Smith CR (1990) Type IV Ehlers-Danlos syndrome presenting as sudden infant death. Am J Clin Pathol 93:579–582 196. Riches KJ, Byard RW (2004) The detection of fatal anaphylaxis at autopsy – an overview. Scand J Forensic Sci 10:61–63 197. Langlois NEI (2006) The use of histology in 638 coronial post-mortem examinations of adults: an audit. Med Sci Law 46:310–320 198. Langlois NEI (2009) Sudden adult death: a review. Forensic Sci Med Pathol 5:210–232 199. Lawler W (1990) The negative coroner’s necropsy: a personal approach and consideration of difficulties. J Clin Pathol 43:977–980 200. Thomas AC, Knapman PA, Krikler DM, Davies MJ (1988) Community study of the causes of “natural” sudden death. Br Med J 297:1453–1456 201. Meek S, Morris F (2002) ABC of clinical electrocardiography. Introduction. II-Basic terminology. Br Med J 324:470–473 202. Morita H, Wu J, Zipes DP (2008) The QT syndromes: long and short. Lancet 372:750–763 203. Gupta A, Lawrence A, Krishnan K, Kavinsky CJ, Trohman RG (2007) Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes. Am Heart J 153:891–899 204. Algra A, Tijssen JGP, Roelandt JRTC, Pool J, Lubsen J (1991) QTc prolongation measured by standard 12-lead electrocardiology is an independent risk factor for sudden death due to ­cardiac arrest. Circulation 83:1888–1894 205. Towbin JA (2004) Molecular genetic basis of sudden cardiac death. In: Berger S (ed) Pediatric clinics of North America. Saunders, Philadelphia, pp 1229–1253

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206. Priori S, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M et  al (2003) Risk ­stratification in the long-QT syndrome. N Engl J Med 348:1866–1874 207. Roden DM (2008) Long-QT syndrome. N Engl J Med 358:169–176 208. Brugada P, Brugada J (1992) Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicentre report. J Am Col Cardiol 20:1391–1396 209. Doolan A, Langlois NEI, Chiu C, Ingles J, Lind J, Semsarian C (2008) Postmortem molecular analysis of KCNQ1 and SCN5A genes in sudden unexplained death in young Australians. Int J Cardiol 23:138–141 210. Oliva A, Pascali VL, Hong K, Brugada R (2005) Molecular autopsy of sudden cardiac death (SCD). The challenge of forensic pathologist to the complexity of genomics. Am J Forensic Med Pathol 26:369–370 211. Priori SG, Napolitano C (2006) Molecular underpinning of “Good Luck”. Circulation 114:360–362 212. Di Paolo M, Luchini D, Bloise R, Priori SG (2004) Postmortem molecular analysis in victims of sudden unexplained death. Am J Forensic Med Pathol 25:182–184 213. Johnson JN, Hofman N, Haglund CM, Cascino GD, Wilde AAM, Ackerman MJ (2009) Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy. Neurology 72:224–231 214. Rosero SZ, Zareba W, Moss AJ, Robinson JL, Ali RH, Locati EH et al (1999) Asthma and the risk of cardiac events in the long QT syndrome. Am J Cardiol 84:1406–1411 215. Start RD, Barber C, Kaschula ROC, Robinson RTCE (2007) The “dead in bed syndrome” – cause of sudden death in Type 1 diabetes mellitus. Histopathology 51:843–845 216. Tu E, Twigg SM, Duflou J, Semsarian C (2008) Causes of death in young Australians with type 1 diabetes: a review of coronial postmortems. Med J Aust 188:699–702 217. Veglio M, Chinaglia A, Cavallo-Perin P (2004) QT interval, cardiovascular risk factors and risk of sudden death in diabetes. J Endocrinol Invest 27:175–181

Chapter 2

Post-mortem Investigation of Sudden Unexpected Death in Infancy: Role of Autopsy in Classification of Death Martin A. Weber and Neil J. Sebire

Abstract  Sudden unexpected deaths in infancy (SUDI) represent the commonest group of post-neonatal childhood deaths. Pathologists in the UK are currently recommended to follow the “Kennedy protocol” when performing such autopsies. This suggested protocol is primarily based on practice from expert opinion and the approach to the post-mortem examination has changed little over recent decades. The identification of specific medical causes of death at autopsy in SUDI has slightly improved in recent years, but around two-thirds of cases remain unexplained, being classified as SIDS or SUDI according to local protocols and circumstances. Current protocols include the autopsy with macroscopic examination of organs, but in the majority of cases in which a cause of death is identified, the diagnosis is based on a combination of ancillary investigations including histological examination and microbiological findings, which are mandatory studies in these infant deaths. However, with increasing evidence regarding the relative frequency with which the various components of the autopsy provide information regarding the cause of death, and recognition that immunological responses and/or bacterial products may be of increasing importance, alternative and/or additional diagnostic techniques are required which may result in modified evidence-based autopsy protocols. The aim of this article is to review the current evidence for protocols of post-mortem investigations of SUDI, with particular emphasis on features which may distinguish natural from unnatural deaths, and to evaluate the approach to investigations which maximise the likelihood of identifying natural causes of death. The article will not discuss issues related to non-accidental or inflicted injury, which remain complex and beyond the scope of this review. Keywords  Sudden infant death • SIDS • Autopsy • Microbiology • Rib fractures • Pulmonary haemosiderin-laden macrophages N.J. Sebire (*) Department of Histopathology, Camelia Botnar Laboratories, Great Ormond Street Hospital, London WC1N 3JH, UK e-mail: [email protected] E.E. Turk (ed.), Forensic Pathology Reviews, Volume 6, Forensic Pathology Reviews 6, DOI 10.1007/978-1-61779-249-6_2, © Springer Science+Business Media, LLC 2011

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Terminology and Classification of Sudden Infant Deaths Sudden unexpected death in infancy (SUDI) of an apparently healthy child has been reported for thousands of years, and became commonly known as “cot-/ crib-death.” This term is potentially misleading, as it implies that death invariably occurs in the cot [1] and the term was superseded by the definition of sudden infant death ­syndrome (SIDS) in 1969 [2]. However, “cot-death” is still widely used, particularly by the lay public, sometimes synonymously with SIDS, while others apply it to any sudden unexpected infant death, even when a cause of death is determined. SIDS was initially defined as, “the sudden death of an infant or young child, which is unexpected by history, and in which a thorough post-mortem examination fails to demonstrate an adequate cause of death” [2], and in 1971 SIDS became a registrable cause of death in England and Wales [3]. Decades later, in 1989, the National Institute of Child Health and Human Development (NICHD) proposed further ­modification of the definition, restricting the term to infants less than 1 year of age, and emphasising the importance of a thorough death scene investigation and review of the clinical history [4]. This was subsequently further modified into “typical” (Category I SIDS) and “atypical” deaths (Category II SIDS), as well as a third ­category (Category III SIDS) intended solely for epidemiological purposes to accommodate countries where autopsies were not routinely performed [5, 6], although this failed to gain wide acceptance. In 2004, an international panel [7] proposed a further classification, widely referred to as the “San Diego definition,” defined as, “the sudden unexpected death of an infant less than 1 year of age, with onset of the fatal episode apparently occurring during sleep, that remains unexplained after a thorough investigation, including performance of a complete autopsy and review of the circumstances of death and the c­ linical history” (Table 2.1). This current definition restricts the diagnosis of SIDS to cases where death is associated with sleep and makes it compulsory to investigate the circumstances surrounding death [7]. It is noteworthy that according to this classification, co-sleeping and prone sleeping-associated deaths are to be classified as SIDS (either as Category I or Category II deaths depending on other findings) if there is no convincing ­evidence of accidental asphyxia based on the review of the death scene and/or autopsy findings, a contentious issue for many pathologists, there being an ongoing debate as to whether sudden infant deaths in the presence of such clearly established risk factors constitute SIDS, accidents or neglect [3, 9]. Several variables intrinsic to the definition also remain poorly defined. For example, what criteria constitute “sudden” and what exactly is meant by “unexpected?” Equally, there is variation in pathologists’ interpretation of the potential significance of pathological changes and whether these may represent an adequate explanation of death or whether the death would better be classified as SIDS [1, 10, 11]. Furthermore, a “complete autopsy” according to this protocol requires toxicology and vitreous chemistry, neither of which is routinely performed in many centres in the UK (vide infra). Finally, the term “SIDS” remains controversial in view of its

(continued)

•

• As above

Category IB SIDS: (classic features of SIDS present but incompletely documented)

One or more not performed: –  Radiology –  Microbiology –  Vitreous chemistry –  Metabolic studies –  Toxicology

Death unexplained by autopsy findings, including –  Radiology –  Microbiology –  Vitreous chemistry –  Metabolic studies –  Toxicology No lethal pathological findings Minor respiratory system inflammatory infiltrates are acceptable • Intrathoracic petechiae supportive but not obligatory or diagnostic • No evidence of unexplained trauma, abuse, neglect, or unintentional injury • No significant thymic stress*

• Death unexplained >21 days and 0.1‰: 29.1% >0.8‰: 48.1% 28.5% Drugs 26.7% 24.7% 6.1% 21.9% Spain [14] 1996–1998 33 Blood and urine

0.6% 5.2% 2.2% 3.4%

1.2%

58.9% 43.8% >0.8‰: 48.1% Illicit: 8.8% 10.0% Licit: 4.7% 5.6% 7.0%

Spain [13] 1991–2000 5,745 Blood

36.36%

Glasgow

UK [16] 1998–2002 22 Blood

0.9% 0.5% 3.9% 7.6%

5.2% 0.8%

4.9%

17.0%

35%

>0.1‰: 44.0%

USA [17, 18] 2001–2002 370 Blood and serum

3.5% 12./% Diazepam 4.1% 4.6% (continued)

b

b

4.6%b

Illicit: 8.1% 13.6% Licit: 19.4% >0.2‰: 4.9%

>0.2‰: 22.2%

Sweden [15] 2000–2002 855 Blood and urine

1.0% 0.5% 0.5%

MOR morphine, HC hydrocodon a Includes Methamphetamine, MDMA, cocaine, (pseudo)ephedrin, phentermine b Including methamphetamine, MDMA

3.1%

2.3%

Barbiturates Phencyclidine Ephedrine Ketamine Propyphenazone Antidepr Phenytoin Pain killers Others

0.4% 0.5%

3.9%

Methadone

1.9%

0.8% 1.7%

3.4%

1.3%

Opiates

4.9%

Italy [12]

Table 15.5  (continued) Australia [7] Canada [8] France [9] Hong Kong [10] Italy [11]

0.5%

0.6%

0.3%

3.2%

Spain [13]

0.6%

0.1%

USA [17, 18]

1.9%

4.6% 1.6% (MOR) (MOR) 1.9% (HC)

Spain [14] Sweden [15] UK [16]

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These factors can influence the outcome of epidemiological studies and make it nearly impossible to compare results. Thus, there is need for methodological guidelines. Recently, a consensus report was published defining guidelines, standards, core data variables and other controls that could be basis for future research [20].

Alcohol, Drugs or Medicines and Driving In the following, basic information is given about alcohol, drugs and medicines, especially concerning effects in driving based on various sources [2, 3, 21–24].

Effects of Alcohol on Driving It is well known that alcohol has a profound effect on driving skills. Because of its depressant effects, drivers can misjudge their capabilities. The effects of alcohol are determined by body weight and time. Some of the effects of alcohol that affect driving include the following: • Reaction time – slow reflexes can decrease the ability to react swiftly to situations. • Vision – eye muscles function more slowly; eye movement and perception are altered, possibly resulting in blurred vision; night vision and colour perception are also impaired. • Tracking – the ability to judge the car’s position on the road, the location of other vehicles, centre line, road signs, etc. can be affected adversely. • Concentration – attention to driving may decrease and/or drowsiness may occur. • Comprehension – the depressant effect of alcohol hinders the ability to make rational decisions. • Coordination – the mechanics of driving can be affected by reduced eye/hand/ foot coordination. If alcohol is used in combination with other drugs (legal or illegal) the effects of both substances can increase. In case of prescribed drugs health professionals must educate patients about the danger of combining alcohol with medication: • • • • • •

Impaired vision. Reduced reaction times. Reduced concentration and vigilance. Feeling more relaxed and drowsy, the driver may fall asleep at the wheel. Difficulties in interpreting complex sensory information. Difficulties with multiple tasks such as a person’s ability to keep a vehicle within the lane limits and keep the correct direction while paying attention to other important things during driving.

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F. Mußhoff

• Drivers might ignore traffic rules. • Drivers may feel more confident which may lead to increased risk tolerance. Hangover effects of alcohol the day after can also affect a person’s ability to concentrate and to drive safely and might let him fall asleep while driving. Someone who drinks alcohol may think that he is able to alter his driving to counteract any impairment of his driving ability; however, it is a well-known effect of alcohol that drivers have an altered view and experience of reality. This means that actions and responses may be quite different to what is actually required and drivers may be unaware of how much their driving skills are affected by alcohol. In general, blood alcohol concentrations (BACs) of 0.5  g/l or lower lead to driving impairments. Reduced capacity, for example demonstrated in tunnel vision (impairment of peripheral vision caused by reduced performance of the retinal neurones and of the corresponding areas of the cerebral cortex) already occurs at a BAC of 0.3 g/l [25]. As of 0.3 g/l, driving up close to another car, misperceptions of speed and incorrect passing may be caused by impaired depth of visual acuity [26]. Examining eye movements and reactions of drunken drivers with a BAC of 0.7 g/l revealed that the average length of visually fixing an object was significantly longer for intoxicated drivers. With regard to reaction behaviour it was ascertained that inebriated drivers obtained significantly poorer results than sober drivers. For example, inebriated drivers had more problems to react appropriately to sudden appearing objects. Moreover, sober drivers remembered more observation exercises (cyclists, pedestrians, traffic signs) along a test road than intoxicated drivers. Responsiveness, endurance and visual structuring capacity decrease under the influence of alcohol. Furthermore, a significant increase of the readiness for taking risks can be observed. According to Bartl et  al. [27], an intoxication of 0.5  g/l up to 0.84 g/l lead to a decrease of relevant driving capacities (ability to observe, to react and to concentrate as well as mental capacity). In particular, it is interesting that the most reduced capacities are seen in test situations with highest correlation to the number of traffic accidents. In general, effects become more apparent as BAC increases. BACs of 1.0–1.5  g/l will lead to a marked loss of coordination and perception. 1.5–2.0 g/l will be evident as drunkenness and at 2.0 g/l the “passing out” stage occurs. 3.0 g/l will greatly heighten the risk of poisoning. Concentrations higher than 4.5/5.0 g/l are probably fatal due to respiratory paralysis. The causal effects of alcohol on impaired driving are well established, to the extent where it has been possible to enact legislation for the use of alcohol by drivers based on a valid classification system (BAC 0.5–0.8‰ = risk curve begins to ascend; BAC > 0.8‰ = considerable risk increase for most drivers; BAC 1.0‰ = definite increase of crash risk for all drivers [28]). The so-called Grand-Rapids Study by Borkenstein et  al. [29] proved the correlation between alcohol intoxication and accident risk by comparing more than 12,000 accidents of inebriated and sober drivers (Fig. 15.1). The probabilities of causing an accident could be attributed to the different BACs indicated in Table 15.6.

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Fig. 15.1  Correlation between blood alcohol concentration (BAC) and accident risk according to Borkenstein [29]

Table 15.6  Probabilities of causing an accident for different BACs (according to [29])

g/l BAC 0.0 0.6 1.0 1.2

Probability   0×   2×   6× 25×

Effects of Cannabis on Driving Cannabis terms the preparation of the Cannabis sativa plant. Used products are marihuana (dried parts of the plant), hashish (resin of female flowering tops) and hashish oil (extract from resin). Further data are summarized in Table  15.7. Depressant THC effects slow down brain activity and other areas of the central

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F. Mußhoff

Table 15.7  Data sheet concerning cannabinoids Cannabinoids Active agent

Metabolites

Intoxication

Effects on driving

Tetrahydrocannabinol (THC) Effective dose by inhalation at approx. 15 mg of THC (cannabis 0.1–0.2 g hashish) with maximum plasma concentration after 15–20 min Half-life approx. 45 min in absorption phase, 3.5 h in distribution phase and up to 24 h in the terminal elimination phase Window of detection in plasma 4–6 h (after singular consumption) 11-OH-THC (psychotropic substance) Half-life 12–18 h in the terminal elimination phase Window of detection in plasma 4–6 h (after singular consumption) THC-COOH (inactive) Half-life 25–37 h, in the terminal elimination phase up to 6 days Window of detection 2–3 days in plasma after singular consumption, approx. 3 weeks after regular consumption and in urine samples 2–3 d after singular consumption and up to 3 m after regular consumption Acute phase (1–2 h): central sedating effects with dysfunction in motor activity/speech; reddened glassy eyes; mydriasis; in general slowing down and maybe slow-witted Subacute phase (approx. 4–6 h after consumption): drowsiness gone, more exuberant, unconcerned basic mood with euphoria, serenity and internal calmness, under elimination of negative environmental factors; lowered criticism ability; over-confidence of capacity Postacute phase (approx. 12–24 h): decreased impulse, passivity, dizziness Sedation; severe fatigue, motor disturbances, concentration and attention weaknesses; extensions of reaction time; sensitivity to light; accumulation of false, inadequate reactions; disorders of entrenched automatisms (changing speeds, deviations or drift from the lane, violation of right of way signs and red lights; inadequate reactions to perceptions on the edge of the visual field)

nervous system (CNS) while the minor hallucinogenic effects can distort a person’s perception of the world. The effects of cannabis can be different for each person and are influenced by factors such as: • Dose (ingested and also dependent on the THC content of the preparation). • Ingestions route: when cannabis is smoked the effects are experienced very quickly and may last up to 5 or 8 h; after oral consumption the onset of effects can be delayed by about 60–90 min and can last up to 24 h. • Consumer’s psychological and physical attributes; general factors such as mental or emotional state and physical health can influence the effects of a drug. Therefore, it is difficult to prognose exactly in which way and how long cannabis will affect a person’s ability to drive safely. As a general guideline some of the effects of cannabis that can affect a person’s driving ability include the following: • Reduced coordination and slower reaction times • Slower information processing ability, confusion and impaired thinking • Changes in visual, auditory, time and space perception

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The “hangover” effects of cannabis which can last for several hours can also impair the driving ability. The following studies concerning cannabis and driving constitute only an excerpt of studies recently evaluated by Raes et al. [3]. Ramaekers et al. [30] defined performance impairment (in terms of motor control, motor impulsivity and executive function) as a function of THC concentration in serum. It was concluded that 2 and 5  ng/ml are the lower and upper ranges of a serum THC limit for impairment. Binomial tests showed an initial and significant shift towards impairment in the critical tracking task for serum THC concentrations between 2 and 5  ng/ml. At concentrations between 5 and 10 ng/ml approximately 75–90% of the observations were indicative of significant impairment in every performance test. At THC concentrations above 30  ng/ml 100% of observations in every performance test were indicative of significant impairment. Some deleterious effects of cannabis appear to be additive or even synergistic with those of alcohol; combination of both substances results in prolongation as well as enhancement of their effects [31]. Driving studies showed that drivers under the influence of alcohol and cannabis are less attentive to traffic approaching from side streets while the use of either cannabis or alcohol had no effect [32]. Furthermore, the combination of cannabis and alcohol generates an additional decrement in lateral control on top of the decrement caused by either cannabis or alcohol [31]. Few epidemiological studies investigated the risk of being involved in traffic accidents while driving under the influence of cannabis. A Canadian case–control study of driving under the influence of cannabis alone was associated with an odds ratio (OR) of 2.2 (95% CI: 1.5–3.4), while taking all cannabis cases into account, an OR of 4.6 (95% CI: 3.4–6.2) was found [33]. Driving under the influence of alcohol (BAC > 0.8‰) and cannabis was associated with an increased accident risk of 80.5 (OR, 95% CI: 28.2–230.2). Another French study with drivers below the age of 27 years who were driving under the influence of cannabis alone was associated with an increased accident risk of 2.5 (OR, 95% CI: 1.5–4.2); alcohol (BAC > 0.5‰) and cannabis led to an increased risk of 4.6 (OR, 95% CI: 2.0–10.7) [34]. A Dutch and Norwegian study showed an increased (statistically insignificant) accident risk for driving under the influence of cannabis alone [16]. Another study realized in Australia found an OR of 2.7 (95% CI: 1.02–7.0) for being responsible for an accident while driving under the influence of cannabis alone [7]. For drivers with blood THC concentrations ³5  ng/ml, the OR was greater and statistically more significant (OR 6.6, 95% CI: 1.5–28.0). A significantly stronger positive association with accident responsibility was also seen in drivers who were positive for cannabis and had a BAC ³ 0.5‰ compared with drivers having a BAC ³ 0.5‰ with no cannabis consumption (OR 2.9, 95% CI: 1.1–7.7). Drivers in France involved in fatal crashes with positive cannabis detection were associated with decreased sense of responsibility (OR 3.3, 95% CI: 2.6–4.2) [35]. Moreover, a significant dose effect was identified with OR increasing from 1.6 (95% CI: 0.8–3.0) for THC concentrations in blood of 0–1 ng/ml to 2.1 (95% CI: 1.3–3.4) for THC concentrations above 5 ng/ml. For driving under the influence of alcohol combined with cannabis an OR of 14 (95% CI: 8.0–24.7) was calculated.

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In a recent review, Ramaekers et al. [36] concluded that a person who consumed cannabis may think that he can alter his driving to counteract any impairment to his driving ability; however, the effects of cannabis may mean lead to an altered view and experience of reality. This means that actions and responses may be quite different to what is actually required and drivers may be unaware of how much their driving skills are affected by cannabis. THC has been shown to impair cognition, psychomotor function and actual driving performance in a doserelated manner. Detrimental effects appear more prominent in highly automated driving behaviour, compared to more complex driving tasks that require conscious control.

Effects of Heroin and Other Opioids on Driving Opium is the dried milky exudation from the unripe capsules of Papaver somniferum, containing morphine (4–21%) as well as noscapine (2–8%), codeine (0.7–3%), papaverine (0.5–1.3%) and the baine (0.2–1%) which are combined under the term “opiate.” After further extraction heroin (=diacetylmorphine) is synthesized from morphine by double acetylation. Heroin is more lipophilic and reaches the brain more rapidly than morphine and euphoric effects are more intense. Heroin can be inhaled (by smoking or inhaling the vapors of heated powder), snorted or injected intravenously (usual dose 10–15 mg). Further information is summarized in Table 15.8. Morphine is a potent analgesic, therapeutically used for the relief of moderate to severe pain. Abuse is rare in Europe. Codeine is a licit opiate with antitussive and analgesic properties. Other so-called opioids include synthetic drugs such as pethidine, oxy- or hydrocodone, tramadol, tilidine, methadone or buprenorphine which are used for the relief of moderate to severe pain (e.g. palliative care), the latter in substitution programs. Heroin and other opioids are depressant drugs. They slow down the activity of the brain and other parts of the CNS. Sedation induces sleepiness, apathy and indifference to external stimuli and a decrease of reaction time. In combination with alcohol sedation is enhanced. Miosis has a negative influence on the accommodation of the eyes to darkness (entering a tunnel, driving at night). The effects of opioids are influenced by a range of factors such as: • The type of opioid and its strength. • The dose because larger amounts can produce different effects (e.g. heroin can vary in strength and purity, thus it can be difficult to predict the extent to which a person’s driving skills will be impaired after using heroin). • The ingestion route (injected > swallowed or smoked). • The consumer’s psychological and physical attributes.

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Table 15.8  Data sheet concerning opioids Opioids Application form Heroin Effective dose parenteral approx. 50–250 mg “street heroine” Half-life 2–9 min Intermediate 6-Monoacetylmorphine with a half-life of approx. 38 min Active agent Morphine (Analgetic effective single dose 5–20 mg) Half-life 1.1–3.1 h Window of detection in plasma several hours (dose-dependent), in urine approx. 2–3 days Codeine Oral single dose 10–60 mg Half-life 1.9–3.9 h Window of detection in plasma several hours up to a few days (dosedependent), in urine approx. 2–3 days Dihydrocodeine Oral single dose 10–30 (60) mg Half-life 3.3–4.5 h Window of detection in plasma several hours up to a few days (dosedependent), in urine approx. 2–3 days Intoxication Acute phase: in the primal phase incapacity for minutes after i.v. application; in the second phase mild euphoria; indifference; euphoric as well as dysphoric moods; fluent transition to deprivation syndrome with merely physical insufficiencies as well as a decrease in attention and perception; in general an uncontrolled additional consumption of CNS-depressant substances (benzodiazepine, cannabinoids, methadone, codeine, dihydrocodeine, alcohol) but also centrally stimulating substances (amphetamine, ecstasy, cocaine), so synergetic as well as antagonistic effects are possible Effects on driving CNS depression and sedation, apathy, drowsiness, and dizziness with concentration weakness; motoric reduction; extended time of reaction; miosis (hell-dark-adaptation); short after application/during detoxification: slow, “shaky” way of driving including drift from the lane/ collisions; as the strong hypnotic effect wears off, perhaps aggressive, unrestrained way of driving (aggressive driving, inadequate, risky over-taking; violation of right of way signs, etc.)

So it is difficult to say exactly in which way and how long opioids will affect a person’s ability to drive safely. As a general guideline, some of the effects of heroin and the misuse of some opioids that may affect a person’s driving ability include the following: • Slow reaction time • Taking longer to respond to events or situations and possibly choosing an inappropriate response • Reduced coordination

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• • • • •

F. Mußhoff

Reduced ability to think clearly Changes to visual acuity such as blurred vision Drowsiness or starting to “nod off” Miosis Nausea and vomiting

When the effects of heroin or opioid diminish some people may experience withdrawal symptoms like cravings or “hanging out,” cramps and flu-like symptoms which may also affect a person’s driving ability. As summarized by Raes et al. [3], a French case–control study demonstrated that morphine consumption is associated with increased accident risk (OR 8.2, 95% CI: 2.5–27.3) [35]. A Dutch study revealed that use of codeine is not associated with increased accident risk (RR 3.0, 95% CI: 0.7–14.2) while heroin and morphine (not combined) are associated with increased accident risk of 32.4 (OR, 95% CI: 1.8–592.0) [16]. Furthermore, a study of Norway showed that driving under the influence of opiates alone (morphine, heroin or codeine) is associated with an increased accident risk of 13.8 (OR, 95% CI: 1.2–154.2). A meta-analysis of data from the Dutch and Norwegian studies indicates that drivers under the influence of opiates only have an increased risk of being involved in an accident, as indicated by RR of 3.2 (95% CI: 1.4–6.9) and an OR of 3.7 (95% CI: 1.4–10.0). The question is whether patients under opioid therapy, for example palliative care patients, are able to drive. A structured evidence-based review by Fishbain et al. [37] evaluated 48 studies to determine what kind of evidences exists for and against opioid-related impairment of driving skills in opioid-dependent/tolerant patients. Fishbain concluded that the majority of studies indicated that opioids apparently do not impair driving-related skills in opioid-dependent patients and that – under certain conditions – patients stabilized on long-term opioid therapy are able to drive. Thus, physicians should not necessarily take the position that being on opioids precludes driving. It was recommended that patients on long-term opioid treatment should be advised of the current status of this research. It should be the patient’s decision whether he does or does not drive but the following rules should be respected: 1. After starting the opioid treatment or after increase in dosage patients should not drive for at least 4–5 days. 2. They should not drive if they feel sedated. 3. They should report sedation/unsteadiness/cognitive decline immediately to the physician so that reduction in dosage can be initiated. 4. Under no circumstances they should consume alcohol or other illicit drugs such as cannabinoids and drive. 5. They should avoid taking further medication, especially if it causes sleepiness, like for example antihistamines or fever medicines prescribed by a doctor or bought over-the-counter. 6. They should change their way of taking the medication without visiting the physician.

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In summary – as pointed out by Raes et al. [3] – opioids cause cognitive and psychomotor impairment highly dependent on the type of opioid and the administered dose. Morphine tends to slow users’ responses although accuracy is not diminished. Fentanyl produces cognitive impairment in doses used in out-patient surgical procedures but shows little impairment effect when used for long-term pain management. Heroin users show clear impairment of psychomotor and cognitive skills, some of which can last for more than a year after the last drug use. Some of the impairments are related to severity of dependence and duration of use. Acute effects of methadone can be avoided by dividing the daily dose. Methadone maintenance treatment does cause impairment, including additional impairment higher than impairment associated with heroin dependence although the latter can be better explained by other associated risk factors in some cases. Buprenorphine users do not generally show impairment but at high doses. Patients on long-term opioid therapy develop some impairment of psychomotor and cognitive performance. However, the effect of the opioid drug itself concerning the impairment of patients under opioid maintenance therapy is unclear. Other factors like diseases and pain seem to be of greater importance than opioid effects.

Effects of Cocaine on Driving Cocaine is extracted from leaves of the coca plant Erythroxylon coca. The leaves can be chewed. Cocaine base (“free base” or “crack”) is smoked while the hydrochloride is snorted (25–100  mg) or injected. Further information is given in Table 15.9. Cocaine is a stimulant drug and speeds up the activity of the brain and other parts of the CNS. It can vary in purity and strength which makes it difficult to predict the extent to which a person’s driving ability will be impaired after using the drug. As a general guideline, some of the effects of cocaine that can affect a person’s driving are as follows: • Impaired ability to react appropriately • Poor concentration and judgement • Over-confidence in driving skills, not necessarily supported by an actual improvement in driving ability • Feelings of increased confidence which may increase the risk that the person will take unnecessary risks • Feelings of aggression which may lead to dangerous driving • Drowsiness as the cocaine wears off which may increase the risk that the driver suddenly falls asleep It has to be taken into consideration that the “come down” effects (e.g. exhaustion, mood swings and depression) after cocaine consumption may also impair a person’s driving ability.

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Table 15.9  Data sheet concerning cocaine Cocaine Active agent:

Metabolites:

Intoxication:

Effects on driving:

Cocaine Single dose of approx. 10 mg pure cocaine-HCl i.v., 20–50 mg i.n., max. 100 mg Half-life 42–90 min Window of detection in plasma 4–6 h (instable!), in urine 6–8 h Benzoylecgonine Half-life 4.5–7 h Window of detection in plasma a few days (dose-dependent), in urine 3–6 days Ecgoninmethylester Half-life 3.1–5 h Window of detection in plasma a few days (dose-dependent), in urine 3–6 days Euphoric phase: feeling high with euphoric moods, strong positive sensations, bravery, increasing risk-taking, increase of impetus without getting exhausted or tired, decrease of inhibitions, over-confidence, lowered criticism ability Inebriation phase: often negative and anxious misperception of environment (possibly. hallucinatory state with paranoia) Depressive phase: loss of impetus; tiredness and exhaustion; irritability and depression Unrestrained and risky way of driving with inadequate high speed and over-confidence in driving skills; restlessness; poor concentration; nervousness; sensitivity to light (dilation of the pupils); irritability and aggressiveness; decreasing concentration and attention but also: due to physical exhaustion, tiredness and depressive alienation (possibly disorientation, confusion, paranoia) with slow or changing speed, drift from the lane, etc.; frequently, due to paranoia, hit and run incl. car chases

Because of a low number of positive cases in most studies it was impossible to calculate the risks concerning traffic accidents after cocaine abuse [3]. A study in Canada revealed that driving under the influence of cocaine is associated with an increased accident risk of 12.2 (OR, 95% CI: 7.2–20.6) [33, 38]. Driving under the influence of either cocaine or a combination of cocaine and cannabis, of cocaine and alcohol (BAC > 0.8‰) or cocaine, cannabis and alcohol (BAC > 0.8‰) was associated with an increased accident risk of 4.9 (OR, 95% CI: 1.4–17.4), 8.0 (OR, 95% CI: 3.1–20.7), 170.5 (OR, 95% CI: 21.2–1,371.2) and 85.3 (OR, 95% CI: 9.5–767.0), respectively.

Effects of Amphetamine, Methamphetamine and “Ecstasy” on Driving As well as cocaine, amphetamines are central stimulants. They belong to the group of drugs that include prescription medicines and illegally produced amphetamines

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Table 15.10  Data sheet concerning amphetamines Amphetamines Active agents:

Intoxication:

Effects on driving:

Amphetamine, methamphetamine, MDMA, MDA, and MDEA Effective doses approx. 10–50 mg amphetamine/methamphetamine and approx. up to 100 mg MDMA/MDEA/MDA Half-life 4–12 (34) h for amphetamine, approx. 9 h for methamphetamine and approx. 7–25 h for MDMA/MDA/MDEA Window of detection in plasma for each 6–24 h, in urine 1–3 days With short-term application: stimulating, sleep- and tiredness-restraining, mood-lightening effect with feeling of increased concentration ability, talkativeness, etc. With long-term application: disturbance, anxiety and depression as well as restlessness, agitation and confusion or even violent behaviour Detectable from the outside: nervousness; motor disturbances, inability to concentrate; dilated, fixed pupils; trembling; insomnia respectively tiredness and later loss of impetus, fatigue and exhaustion,; irritability; depression Acute phase: unrestrained and risky driving with inadequate high speed increased sense of capacity (Over-confidence, misjudgement, disturbance, fidgetiness, nervousness, sensitivity to light (mydriasis), irritability and aggressiveness), sometimes dramatic capacity decrease when subsiding with physical exhaustion, tiredness and depressive alienation (reduced concentration and attention, disorientation, confusion, loss of reality, etc.) with typical driving features due to fatigue (slow/changing speed, drift from the lane, etc.)

and methamphetamine (sometimes known as “speed,” “base” or “paste”; crystal methamphetamine is sometimes called “ice” or “crystal meth”). Ecstasy is the term for a range of drugs that are structurally similar to 3,4-methylenedioxymethamphetamine (MDMA) and shows effects like amphetamines (stimulants) and hallucinogens. Amphetamines suppress feelings like tiredness and hunger and increase mental alertness and physical energy. In addition, they enhance the mood and increase self-confidence. Therapeutic applications of amphetamines are the treatment of narcolepsy, obesity and hyperactive behaviour in children. Amphetamines are used by truckers and students to stay awake for long periods. MDMA and analogues are stimulants (“dance-pills”) and entactogens (leading to emotional disinhibition and increased social communication abilities). As the substances loose their effects it comes to negative feelings like fatigue, anxiety, emptiness and depression. Later, “hangovers” associated with headaches, muscle aches, exhaustion, apathy, sweating, nausea and further effects are experienced. Further data are given in Table 15.10. It is considered that the effects of amphetamines/ecstasy are influenced by a range of factors, thus each person can show different reactions. Things to consider include the following: • Quality and dose (there is no quality control on illegally manufactured drugs so that manufacturers may substitute a wide range of substances) • Consumer’s psychological and physical attributes

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As a general guideline, some of the effects of amphetamines that can affect a person’s driving ability include the following: • • • • •

Attention difficulties and a tendency to fidget Feeling of disorientation Lack of coordination Impaired ability to react appropriately and safely control a vehicle Aggressive and dangerous driving and increased chance of taking unnecessary risks • Over-confidence in driving skills which is not necessarily supported by actual improvement of driving ability • Drowsiness as the effects of amphetamine wears off and the driver possibly falls asleep (rebound fatigue) Similar to cocaine, the “come down” effects after amphetamines consumption (exhaustion, concentration difficulties, irritability and depression) may impair a person’s driving ability, too. Raes et  al. [3] summarized several studies concerning amphetamines and driving. Driving simulation showed that the intake of dexamphetamine (0.42 mg/kg) causes a decrease of all driving performances that were simulated by inducing problems like incorrect signalling, failing to stop at red lights and slow response time [39]. Brookhuis et al. [40] performed driving simulator tests on a group of young people who had admitted to take MDMA regularly. They were tested shortly after MDMA consumption as well as before they were intend to go to a party and again during a control night at a corresponding time when they were sober. Under the influence of MDMA subjects drove faster only in residential areas with speed limit of 50 km/h. Speed variance increased in the city as well as on the motorway. Lateral control and gap acceptance was not affected. Crashes occurred during two of the 20 control rides and four times while under the influence of MDMA which is a 100% increase. In Norway, Gustavsen et al. [41] analyzed the concentration– effect relationship between blood amphetamine concentrations and impairment in selected cases with amphetamine or methamphetamine as the only drug present in blood samples from impaired drivers. According to the police physician, 27% were judged to be not impaired while 73% were judged to be impaired. A positive relationship was found between blood amphetamine concentration and impairment but it showed a limit at concentrations of 270–530 ng/ml. In the Canadian study, it was demonstrated that driving under the influence of amphetamines is associated with increased accident risk of 12.8 (OR, 95% CI: 3.0–54.0) [33]. In the responsibility analysis of Drummer et  al. [7] the amphetamine-associated risk was not calculated but was calculated for a group of substances acting as stimulants, namely amphetamine, methamphetamine, MDMA, ephedrine, pseudoephedrine, phentermine and cocaine. There was no significant association between stimulant use and crash responsibility. However, when truckers were considered as “discrete driver type” the OR increased to 8.8 and was of borderline statistical significance (95% CI: 1.0–77.8).

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Effects of Hallucinogens on Driving Hallucinogens like ketamine, LSD (lysergic acid diethylamide), magic mushrooms (psilocybin), mescaline (peyote cactus), and PCP (phencyclidine) distort a person’s perception of reality. The effects of hallucinogens vary greatly and combination of hallucinogenic drugs with other hallucinogens might have unpredictable effects on a person’s ability to drive safely. Some of the effects of hallucinogenic drugs that can affect a person’s driving include the following: • • • •

Distorted perception of reality Impaired thinking Blurred vision Reduced coordination

Effects of Medicines on Driving In general, the highest risk of driving impairment and having an accident due to pharmaceutical drug usage is thought to be during the first 2 weeks after a person began taking medication. In Table  15.11, relevant medicines with potential relevance to influence driving ability are summarized. The effects of medicines can be different for each person. Type of medicine, dosage and the consumer’s psychological and physical attributes are just some of many other factors that can influence the drug-induced effects on a person. Thus, it is difficult to prognose exactly in which way and how long specific medicines will affect a person’s ability to drive safely. In general, the health professional has to inform a patient about potential side-effects of new prescribed medication. The patient himself should read the package insert or the Consumer Medication Information sheet (CMI) before taking any medicine. It is highly important to check whether a new prescribed medicine or combination of medicines may have an impact on driving ability. It is possible that herbal remedies may also impair a person’s ability to drive safely. In contrast, a patient who is concerned about a prescription should not stop taking the medication but should not drive until he expressed his concerns to his health professional. The medical condition itself may impair a person’s ability to drive safely; in this case, the medication may rather assist than hinder safe driving. Extra care should be taken with medicines used to treat: • • • • • • •

Sleeping difficulties Anxiety, depression and stress Pain such as strong painkillers containing codeine and other opioids Allergies and hay fever Colds and flu Arthritis Blood pressure

Table 15.11  Short summary of medicaments relevant in traffic accidents according to Schubert [42] Pharmaceutical classes Examples for substances/agents Risk Analgetica Strong analgesic, sedation, perhaps withdrawal, change in Opioids Morphine derivatives mood and impulse, change of cognitive and sensory Morphine, codeine dihydrocodeine, substitutes capacity (methadone, buprenorphine), oxycodone, hydromorphone, tilidine, tramadol Uncritical mono-compounds (maybe. headache, nausea, Non-opioid analgetica Salicylates vertigo); danger due to mixing compounds, e. g. with Acetaminophene caffeine Propyphenazone Phenacetine Antidiabetica Insulin Hyper- and hypoglycemia, esp. in phases of re-/adjustment Sulfonylurea derivatives Impairment of CNS functions and sedating Antiepileptica Clonazepam Phenobarbital Phenytoine Primidone Due to substance class more or less sedating effect Antihistaminica Diphenhydramine Promethazine Ketotifene Partly sedating or impairing the cardiovascular system Antihypertensiva Clonidine (vertigo, tiredness, headache) Reserpine Guanethidine Prazosine, enalapril captopril, lisinopril, betablockers Narcotics Mixed compounds for ambulant short or local Partly differing half-times and due to this reduction of anaesthesia/e.g., lidocaine, nitrous oxide, etc. psychomotility Ophtalmica Anticholinergica, atropin, belladonna e.g. dysfunction of accomodation

++ + up to ++++

++ ++ up to ++

+ up to ++++

+ up to + +

+ + up to +++

++ up to +++

− up to +++

++ up to ++++

Level

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+ up to ++++ + up to ++++

Dullness, impulse reduction, dysfunction of coordination and psychomotility Increase or reduction of impulse, CNS accompanying symptoms, lowering of spasm threshold Soothing, sleep-inducing effect with reduction of performance and reaction Long half-times and cumulation; due to this effects on psychomotility Long-term reduced concentration and restlessness with cancelling tiredness for a short time

+ up to +++

++ + up to ++++

++ ++ up to ++

Level

Risk

− no effect, + little effect, ++ slight effect, +++ obvious effect, ++++ severe effect

Stimulants

Sedativa, Hypnotika

Examples for substances/agents

Neuroleptica e.g. chlorpromazine haloperidol thioridazin Antidepressiva e.g. amitriptyline, trimipramine Tranquilizer e.g. diazepam, flunitrazepam, oxazepam Barbiturates, benzodiazepines, bromureides, chloralhydrate, piperidin derivatives Caffeine Ephedrine norpseudoephedrine

Pharmaceutical classes

Psychopharmaceuticals

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Epilepsy Heart conditions Fluid retention Nausea Stomach problems Diabetes Several types of infections

As a general guideline some of the effects of medicines that can affect a person’s driving ability include the following • • • • • •

Drowsiness or tiredness Dizziness or feeling light-headed Difficulty to concentrate Feeling edgy, angry or aggressive Feeling nauseous or otherwise unwell Reduced coordination or feeling shaky and unstable

Using benzodiazepines and driving, for example may cause an increase in the risk of a person to have an accident [3]. People on higher doses or those who just began to take higher doses are the most at risk of impaired driving and to have a resulting accident which is due to some of the effects of benzodiazepines that may affect driving ability such as drowsiness and fatigue, blurred vision, lack of muscular coordination, slower reaction time, slower information processing, reduced concentration and impaired judgement.

Effects of Mixing Drugs on Driving Taking more than one drug at the same time or taking one drug followed by another can have unpredictable results [21]. This includes mixing illegal drugs and legal drugs such as alcohol and medicines (prescribed and over-the-counter medication). If a person takes multiple drugs (including alcohol, medicines and illegal drugs) each drug could alter the effects of the other, often in an unpredictable way. The effects of mixing drugs are influenced by a range of factors and can be different for each person. Things to consider include the following: • • • •

Type of drugs Dose of each drug Intake of drugs (taken at the same time, at different times and in which order) Consumer’s psychological and physical attributes (person’s mental or emotional state and physical health)

The risk of a crash while someone is under the influence of two or more drugs (illicit, licit or pharmaceutical) may be even higher than under the influence of one drug.

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Combining drugs with similar effects such as alcohol and cannabis, alcohol and benzodiazepines, or amphetamines and ecstasy can increase the effects of each drug. Depressant drugs like alcohol, cannabis, heroin or other opioids, and benzodiazepines slow down brain activity and other parts of the central nervous system. Combining depressants can multiply the depressant effects (slowing down) in an additive as well as in an exponential way. Stimulant drugs like amphetamines, cocaine and ecstasy speed up brain activity and other parts of the CNS and combination of stimulants can multiply the stimulant effects. This lead to greater stress on the body, particularly on the heart and other vital organs, and can impair a person’s driving ability more than in the case that only one drug was consumed. Combining drugs with different effects like alcohol and ecstasy or cocaine and benzodiazepines seem to “cancel each other out.” This makes it difficult for someone to estimate how much his driving ability has been impaired. If a person has been drinking alcohol and using amphetamines, for example, he may not feel the depressant effects of the alcohol as they have been masked by the stimulant effects of amphetamines. The person may feel capable of driving when he might be drunk in fact. These combinations also put a lot of stress on the body since it tries to balance the different effects of the drugs which simultaneously exert their effects.

Forensic-Toxicological Analysis As described above, in the epidemiological aspect alcohol, drugs and medicines play an important role especially in (fatal) traffic accidents. Therefore, a chemicaltoxicological analysis should be performed in every case of traffic accident. Not only drivers responsible for the crash but also pedestrians or others persons who were recognized as victims can be affected. During the course of clarification drug-related mistakes of victims could be interpreted as jointly responsible for an event. After an accident without injuries or fatalities drug analysis is performed, as routinely done in every case that is suspicious of DUI using routine laboratory procedures. Analysis is complicated if injured or fatal persons have to be tested due to some specifics which have to be considered like potential influences of emergency medical aid (medication, infusions, loss of blood), a longer time period between event and sampling of material for analyses (also between the time of death and sampling) or no availability of definite sample material even in fatalities (e.g. blood).

Matrices In principle, various matrices are useful for chemical-toxicological analysis to investigate cases of drugged driving. Generally, urine is the sample of choice for screening and identification of unknown drugs because concentrations of substances

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are relatively high compared with other matrices such as blood, saliva or sweat. Saliva and sweat are potentially useful for on-site drug-testing procedures in living persons but not in fatalities. In urine, the window of detection for a preceding consumption of drugs is markedly enhanced compared to blood. Additionally, the sometimes active or inactive metabolites of drugs in urine samples can be identified in addition, or even exclusively. Otherwise, a positive result in a urine sample does not necessarily prove an actual impairment. The dose of a drug and as a general rule impairments due to drug consumption are most closely correlated with its concentration in blood. For this purpose, the relevant matrices that should be analyzed for quantification are whole blood or rather serum or plasma. In these matrices, the unchanged drug is detectable in most cases and the sample material is relatively homogenous because physiologic parameters vary only within narrow limits. In addition, blood or plasma samples are mandatory in cases of DUI in a relevant number of countries all over the world. Difficulties arise when only aged or haemolysed or post-mortem blood is available, even in cases of fatal traffic accidents.

Post-mortem Material for Toxicological Analysis in Traffic Fatalities In general, specimens available in post-mortem toxicology investigations can be numerous and variable and may be selected based on case history, requests, legal aspects and availability in a given case. Further information about post-mortem toxicology is given in some excellent reviews [43, 44].

Body Fluids Urine As described above, the accumulation of drugs and metabolites in urine usually results in high concentrations facilitating detection of drug use. Therefore, urine has a great potential to provide information on ante-mortem drug exposure and is frequently used as a screening specimen. However, there is no correlation between urine drug concentration and pharmacological effects and urine may not always be indicative for acute poisoning and impairment.

Bile Even in post-mortem cases in which urine is not available bile may be substituted. Bile represents a collection and storage depot for many drugs and corresponding metabolites that have a biliary excretion and are subject to enterohepatic circulation.

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Many drugs have been shown to accumulate in bile and the detection of drugs and/ or major metabolites in bile may indicate previous or chronic exposure to a drug. Cerebrospinal Fluid and Vitreous Humour Cerebrospinal fluid and vitreous humour are thought to be closer to the site of action of drugs than blood and are useful to screen for a variety of drugs. They are less subject to contamination and bacterial invasion by virtue of their protected environment inside the brain, the spinal column or the eye. Both cerebrospinal fluid and vitreous humour also contain very little enzymes and proteins. Therefore, drugs which are highly protein bound or those which are lipophilic tend to be found in lower concentrations in these fluids than in blood. Vitreous humour is also useful for alcohol analysis and has been used to distinguish ante-mortem alcohol ingestion from post-mortem alcohol formation. Gastric and Intestinal Contents Oral ingestion remains the most popular means of exposure, especially to medicines. Therefore, the gastrointestinal contents are essential for screening. Undigested pills and tablets are often present. Blood As described above, blood is the specimen of choice for quantifying and interpreting concentrations of drugs and corresponding metabolites. For further interpretation quantitation is usually performed on specimens from peripheral sites, for example from the femoral vein, because post-mortem drug concentration can vary from site to site. Caution has to be made concerning samples labelled as “heart blood.” Samples may not have been collected from the heart itself but drawn blind through the chest wall and may include pleural or chest fluid, pericardial fluid and even gastric content if the death was traumatic. Following severe injury or trauma, samples from defined sources are often not available and blood may be collected only from the thoracic or abdominal cavity. The composition of these specimens markedly differs from whole blood. Therefore, these “blood” samples only provide a qualitative documentation of the presence of a drug. Tables  15.12 and 15.13 summarize factors that should be taken into consideration when interpreting blood analysis results. Tissue Samples Tissues usually collected for post-mortem toxicological investigations include liver, kidney, lung, brain and skeletal muscle specimens, as well as adipose tissue. Drug

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Table 15.12  Special considerations in the interpretation of blood analysis results in post-mortem toxicology 1. Cardiac vs. peripheral blood: site dependence and distribution/redistribution phenomena •  Cardiac blood is usually more abundant than peripheral blood •  In contrast to concentrations derived from peripheral sources, reference data of cardiac blood drug concentrations (from living persons) are not available •  Important factors affecting the concentration ratio cardiac/peripheral blood are the type of drug, its volume of distribution, concentration range, protein binding, pKa-value and the post-mortem interval between death and autopsy (sampling) •  Site-dependent differences can also arise from an incomplete distribution of the drug at the time of death, and/or from post-mortem redistribution at the cellular level by passive diffusion or via the vascular pathway from the major organs; the vascular pathway may depend on the blood remaining fluid after death •  The ante-mortem interval may be of importance, as one of the main factors behind the redistribution phenomena: during the distribution phase, the arterial blood concentration can be appreciably higher than the venous blood concentration   To consider: •  Drug levels in heart blood are mainly higher than in femoral venous blood and often there is a wide range of ratios of drug concentrations in cardiac vs. peripheral blood (basic drugs with a large volume of distribution showed the greatest range) Heart blood is only useful for qualitative screening procedures! 2. Blood to serum/plasma ratios •  Blood is a complex mixture containing solubilized proteins, dissolved fats, solids, and suspended cells but drug concentrations provided in literature are usually determined in serum •  The water content and pH of a post-mortem blood sample may also differ significantly from physiological ranges; samples are often haemolysed, putrefied, and may be quite inhomogeneous mixtures   To consider: •  Literature data of serum/plasma concentrations cannot be absolutely used to classify the concentrations determined from post-mortem blood •  Blood to plasma concentration ratios for drugs of forensic interest has to be taken into consideration Be careful in interpretation of quantitative data with respect to the characteristics of the drug of interest! 3. Post-mortem instability of substances and metabolic production (Table 15.14) •  Bioconversion in situ after death as well as in collection vessels can occur •  Decomposition and bacterial production occur dependent on time intervals and temperature   To consider: •  Target analytes in living and deceased can vary •  Possible influences of storage conditions prior to sampling as well as between sampling and analysis has to be taken into consideration Special target analytes and artefacts due to storage have to be considered in post-mortem toxicology!

detection in tissue specimens may be considered whenever drugs are involved that are highly lipophilic in nature and are preferably bound to tissue. Tissue samples may also be useful in cases with extended post-mortem time period (time interval between accident and time of death) and whenever body fluids are not available or difficult to obtain.

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Table 15.13  Special mechanisms in post-mortem samples between time of death and sampling and during further storage, modified according to [42, 59] Mechanisms Example(s) Chemical instability • Hydrolysis • Heroin, cocaine, acetyl salicylic acid • Oxidation • Oxidation of sulphur containing drugs, morphine Metabolic instability • Hydrolysis of ester type drugs or prodrugs • Esterases (endogenous) • Enzyme activities derived from • Hydrolysis of glucuronides, e.g. morphine glucuronides • Reduction, e.g. nitrobenzodiazepines, THCCOOH bacteria • Oxidation, e.g. thioridazine Metabolic production Ethanol, GHB, carbon monoxide, cyanide

Kidney Even in cases without urine samples a kidney specimen can be useful for screening purposes since most drugs and metabolites are excreted into urine and will pass through the kidneys. Liver Liver is favoured as a specimen when blood is not available due to exsanguination, fire or decomposition. Since most drugs are metabolized in the liver, both the parent compound and its metabolites may be present in high concentrations. Analysis of a liver tissue specimen may also help to differentiate acute overdose from therapeutic use of drugs with a narrow dosing window.

Lungs Often high drug concentrations can be found in lung tissue, especially in cases of inhalation or intravenous poisoning.

Brain Brain is a useful specimen for the measurement of drugs because it is the principal site of action for many drugs. Additionally, lipophilic substances like, for example antidepressants, narcotics and halogenated hydrocarbons accumulate in central nervous tissue. According to Mura et al. [45], THC for example can be detected in brain regions that are influenced by its effects even if the substance is no longer detectable in blood. This could be of special interest in traffic fatalities.

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Skeletal Muscle Skeletal muscle as a post-mortem sample for analysis is used when blood is not available, for example due to exsanguination. It is present in large quantities and less affected by decomposition than the internal organs. However, the muscle to blood ratio is influenced by the time lapse between drug exposure and death as well as by the volume of distribution of the drug and drug analysis on skeletal muscle is rather qualitative than quantitative in nature. Muscle specimens had also been considered as an alternative sample for alcohol analysis but the muscle to blood ethanol concentration ratio was found to depend on the time course of ethanol absorption, distribution and elimination. Hair Samples Hair samples may provide retrospective information about drug (ab)use [46, 47]. The amounts deposited in hair are functions of both ingestion/exposure and of the metabolic regimen. There are various factors that influence drug concentrations in hair. However, hair analysis revealed information about previous drug consumption and tolerance.

Laboratory Approaches to Drug Testing in DUI Cases In cases with suspicion of driving while impaired by drugs and especially in traffic fatalities samples should be subjected to a broad screen for common drugs not only relevant to the patterns of recreational drug use in jurisdiction but also for common CNS-acting prescription and over-the-counter drugs [48]. Analysis starts with an immunoassay screening procedure in most cases. These assays are often class-specific rather than drug-specific and their value is to rule out the presence of certain drug classes in form of presumptive tests without further forensic relevance, especially at court. Positive immunoassay results should not be considered as proof of identification of a compound without complementary confirmatory analysis. Furthermore, it has to be taken into consideration that immunoassays will not detect all types of drugs that are present; it may produce different intensities of response to members of the same drug class and may fail to identify important members of drug classes completely. Due to cross-reactivity and considering interferences false-negative and false-positive immunoassay results can be revealed, especially in biological samples of road casualties (after medical treatment with various drugs and infusions or if sample material is available after a crash that is poorly defined). Especially in cases of fatal traffic injuries immunoassay tests should be supplemented by chromatographic tests to include as many of the relevant drugs as possible. Without this procedure there is significant possibility that the drug or the metabolite that has caused impairment is not identified.

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“Gold standard” for confirmatory identification of drugs in biological samples are gas chromatographic or liquid chromatographic procedures coupled with mass spectrometry (GC/MS or LC/MS(−MS)). Generally, a clean-up procedure is applied to the sample to separate drug(s) and metabolites from the sample matrix and to concentrate the analytes since then they can be detected and quantified more readily. Gas chromatographic – mass spectrometric (GC/MS) as well as liquid chromatographic – mass spectrometric (LC/MS) procedures for drugs of abuse monitoring in cases of DUI were recently reviewed and are not matter of the present article [49–52]. Each laboratory is free to perform chemical-toxicological analysis using home-made procedures. However, analytical methods should be validated and a linear range and limits of detection and quantification have to be established according to accepted guidelines [53]. Recently, the German speaking Society of Toxicological and Forensic Chemistry (GTFCh) published new guidelines and recommendations for forensic-toxicological analyses containing some more details and especially concerning the method validation in forensic-toxicological analytical techniques including pre-testing with immunoassays [54]. Recommendations for appropriate cut-offs for screening and confirmation in both blood and urine are provided for some of the most important analytes in DUI investigations (Table  15.14). As described by Farrell et  al. [48], too, thresholds were established to reflect the performance of both commercially screening technology and confirmatory techniques, both routinely used in forensic toxicology laboratories. These recommended cutoffs were based on analytical methodology rather than pharmacology or the probability of impairment. It has to be realized that in many cases laboratories use an immunoassay cut-off concentration that is lower than the manufacturer’s recommended cutoff, particularly if the assay is marketed towards clinical testing (intoxication with high drug concentrations). This is common practice as long as laboratories properly validate their procedures and establish in-house cut-off concentrations using appropriate matrix. In contrast to other groups, the German speaking Society of Toxicological and Forensic Chemistry (GTFCh) only recommended values for confirmatory chromatographic procedures. If an immunoassay is used as preliminary test the laboratory has to demonstrate the required sensitivity for the target substance. The list of drugs in Table  15.11, proposed according to statistical data of the USA, does not claim completeness and does not represent an exhaustive or comprehensive list of analytes or impairing substances. There is a substantial regional variability in patterns of illicit drug use and some drugs that are specific or unspecific to the laboratory’s demographic area can be in- or excluded. Because some drugs such as, for example, GHB are only analyzed in few cases at the request of local authorities or with special strong suspicion, probably the real number of cases DUI is underestimated. Recent studies demonstrated that the combination of an amphetaminebased drug with GHB could be very popular [55, 56]. Table 15.14 does not contain recommendations for hallucinogens and inhalants. However, hallucinogens such as LSD, peyote and psilocybin, as well as commonly abused inhalants such as butane, ether or other anaesthetics, freon, nitrous oxide, toluene and xylene will significantly impair the user’s ability to operate a motor vehicle safely. Currently, there

10 50 10

–a 50 –a

–d –d –d –d –d 50 –d 50 –d –e –e –e –e

CNS depressants Alprazolam Chlordiazepoxide Clonazepam 7-Aminoclonazepam Diazepam Nordiazepam Lorazepam Oxazepam Temazepam Trazodone Amitriptyline Nortriptyline Diphenhydramine

10 50 10 10 20 20 10 50 50 25 25 25 25

20 20 20 20

20 20 20 20

CNS stimulants Amphetamine Methamphetamine MDMA MDA MDEA Cocaine Benzoylecgonine Cocaethylene 25 25 25 25 25 10 30

–d –d –d –d –d 100 –d 100 –d –e –e –e –e

–a 300 –a

200 200 200 200

50 totalc 50 totalc 50 totalc 50 totalc 50 totalc 50 totalc 50 totalc 50 totalc 50 totalc 50 50 50 50

20 50 20

50 50 50 50

Table 15.14  Recommended scope and analytical cutoffs of toxicological analysis in DUI investigations Blood (ng/ml) Urine (ng/ml) Target analyte Screen Confirmation (Farrell et al. [47]) GTFCh [53] (Serum) Screen Confirmation (Farrell et al. [47]) Cannabis 2 1 –a 2 THC –a Carboxy-THC 10 5 10 20b 5 11-OH-THC –a 2 (1) –a 2

30

200 200 200 200 200

10 totalc

GTFCh [53]

324 F. Mußhoff

–f –f –f 50 20 freeg –f 50 –e

–e 10

Narcotic analgesics Codeine Hydrocodone Hydromorphone Methadone Morphine Oxycodone Propoxyphene Tramadol

Dissociative drugs Dextromethorphan Phencyclidine

20 10

10 10 10 10 10 10 50 20

500 500 20 100 100 100 500 500 1,000 5,000

50 10

10

GTFCh [53] (Serum)

–e 25

–f –f –f 300 200 –f 300 –e

–e –e –e –a –a 200 –e –e –e –e

50 10

50 50 50 50 50 totalc 50 50 20

500 500 20 100 100 100 5,000 5,000 1,000 10,000

Urine (ng/ml) Screen Confirmation (Farrell et al. [47])

200 25 totalc

25 totalc

GTFCh [53]

THC = Delta-9-tetrahydrocannabinol; Carboxy-THC = 11-nor-9-carboxy-delta-9-tetrahydrocannabinol; 11-OH-THC = 11-hydroxy-delta-9-tetrahydrocannabinol; MDMA = 3,4-methylenedioxymethamphetamine a  Immunoassay screening not targeted to this analyte b  Combination of free and conjugated analyte c  Immunoassay screening targeted to nordiazepam, oxazepam or both; not an effective tool for screening all drugs in this class d  Not routinely screened for by immunoassay e  Immunoassay screening targeted to morphine; not an effective tool for screening all drugs in this class f  Free drug, not conjugated

–e –e –e –a –a 100 –e –e –e –e

Blood (ng/ml) Screen Confirmation (Farrell et al. [47])

Carisoprodol Meprobamate Zolpidem Butalbital Phenobarbital Secobarbital Phenytoin Carbamazepin Topiramate Gamma-hydroxybutyrate

Target analyte

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exist limited techniques for routine screening of blood and urine for these compounds and usually target analysis is performed if case information suggest possible involvement of such substances.

Interpretation of Post-mortem Toxicology Results in Traffic Fatalities Because in cases of fatal traffic fatalities the sampling of biological specimens for toxicological analysis takes place immediately post-mortem formation of alcohol is negligible for further interpretation. In contrast, it has been demonstrated that alcohol in stomach content may diffuse through the gastric wall and the diaphragm and eventually enters into the heart and central blood vessels [57, 58]. Severe trauma with rupture of the stomach and the diaphragm might lead to a passing of gastric content into the chest cavity which reveals in artefactual high chest blood alcohol concentrations. In addition, agonal or post-mortem movement of gastric contents into the trachea and the lungs can lead to elevated alcohol concentrations in the major central pulmonary and in cardiac vessels and may cause erroneous interpretation [59]. Interpretation of the concentration of other drugs in post-mortem specimens is complicated because many drugs are unstable in vivo and in vitro [60] (Table 15.14). For example, cocaine is hydrolyzed readily before and after death. It was demonstrated that serum cholinesterase is responsible for the hydrolysis to ecgonine methyl ester while the formation of benzoylecgonine may arise from spontaneous nonenzymatic hydrolysis [61]. Therefore, interpretation must not only be based on the measured concentration of cocaine but also on ecgonine methyl ester and benzoylecgonine. Some benzodiazepines (e.g. flunitrazepam, nitrazepam or clonazepam) are also known to be unstable in vitro and exact calculation of peri-mortem concentration is not practical [62, 63]. Many other drugs have poor stability in post-mortem blood, too (e.g. chlordiazepoxide, olanzapine, zopiclone). However, one of the most important factors to affect the interpretation of postmortem drug concentrations is post-mortem redistribution as described above. The use of reference tables of therapeutic and toxic drug concentrations should be treated with caution. Tables are useful in clinical toxicology but they are of limited value if it comes to interpretation of post-mortem concentrations. Inappropriate use of those tables can result in over- or underestimation of potential effects of the drug since they depend on the degree of tolerance, pre-existing diseases and if other substances are present. Tolerance as well as inter-individual variations in pharmacological response (e.g. pharmacogenetics), drug interactions and the presence of natural diseases always has to be taken into consideration [64]. Potential tolerance can be proven by hair analysis which gives information about recent substance use [46, 47]. Medical prescriptions of the last weeks or months should also be checked for further interpretation. In cases of injured or dead suspects in traffic accidents it is decisive that law enforcement officers perform broad investigation including crash reconstruction at the scene – perhaps with the help of technical experts – and recording of

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witness statements to document impairment. At court, influence of technical defects has to be excluded and responsibility or culpability of a suspect or contributory impairing effects due to alcohol or other drugs have to be demonstrated by forensic experts in individual cases. DUI investigations must be consistently, scientifically and objectively. Toxicologists help to establish the connection between driving behaviour and drug use [48].

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prevalence of alcohol, cannabis and other drugs between 900 injured drivers and 900 control subjects: results of a French collaborative study. Forensic Sci Int 133:79–85 35. Laumon B, Gadegbeku B, Martin JL, Biecheler MB (2005) Cannabis intoxication and fatal road crashes in France: population based case-control study. BMJ 331:1371 36. Ramaekers JG, Berghaus G, van Laar M, Drummer OH (2004) Dose related risk of motor vehicle crashes after cannabis use. Drug Alcohol Depend 73:109–119 37. Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS (2003) Are opioid-dependent/tolerant patients impaired in driving-related skills? A structured evidence-based review. J Pain Symptom Manag 25:559–577 38. Dussault C, Brault M, Lemire AM, Bouchard J (2001) The role of cocaine in fatal crashes: first results of the Quebec drug study. Annu Proc Assoc Adv Automot Med 45:125–137 39. Silber BY, Papafotiou K, Croft RJ, Ogden E, Swann P, Stough (2005) The effects of dexamphetamine on simulated driving performance. Psychopharmacology (Berl). 179:536–543 40. Brookhuis KA, de Waard D, Samyn N (2004) Effects of MDMA (ecstasy), and multiple drugs use on (simulated) driving performance and traffic safety. Psychopharmacology (Berl) 173:440–445 41. Gustavsen I, Morland J, Bramness JG (2006) Impairment related to blood amphetamine and/ or methamphetamine concentrations in suspected drugged drivers. Accid Anal Prev 38:490–495 42. Schubert W, Schneider W, Eisenmenger W, Stephan E (2005) Begutachtungsleitlinien zur Kraftfahrereignung, Kommentar. 2. Aufl., Kirschbaum Verlag, Bonn 43. Skopp G (2004) Preanalytic aspects in postmortem toxicology. Forensic Sci Int 142:75–100 44. Drummer OH (2004) Postmortem toxicology of drugs of abuse. Forensic Sci Int 142: 101–113 45. Mura P, Kintz P, Dumestre V, Raul S, Hauet T (2005) THC can be detected in brain while absent in blood. J Anal Toxicol 29:842–843 46. Musshoff F, Madea B (2007) New trends in hair analysis and scientific demands on validation and technical notes. Forensic Sci Int 165:204–215 47. Musshoff F, Madea B (2007) Analytical pitfalls in hair testing. Anal Bioanal Chem 388:1475–1494 48. Farrell LJ, Kerrigan S, Logan BK (2007) Recommendations for toxicological investigation of drug impaired driving. J Forensic Sci 52:1214–1218 49. Moeller MR, Kraemer T (2002) Drugs of abuse monitoring in blood for control of driving under the influence of drugs. Ther Drug Monit 24:210–221 50. Maurer HH (2009) Mass spectrometric approaches in impaired driving toxicology. Anal Bioanal Chem 393:97–107 51. Maurer HH (2005) Multi-analyte procedures for screening for and quantification of drugs in blood, plasma, or serum by liquid chromatography-single stage or tandem mass spectrometry (LC-MS or LC-MS/MS) relevant to clinical and forensic toxicology. Clin Biochem 38:310–318 52. Kraemer T, Paul LD (2007) Bioanalytical procedures for determination of drugs of abuse in blood. Anal Bioanal Chem 388:1415–1435 53. Peters FT, Drummer OH, Musshoff F (2007) Validation of new methods. Forensic Sci Int 165:216–224 5 4. Society of Toxicological and Forensic Chemistry (GTFCh) (2009) Richtlinie der GTFCh zur Qualitätssicherung bei forensisch-toxikologischen Untersuchungen und Anforderungen an die Validierung von Analysenmethoden. http://www.gtfch.org/cms/ index.php/guidelines?Itemid=126 55. Dresen S, Kempf J, Weinmann W (2007) Prevalence of gamma-hydroxybutyrate (GHB) in serum samples of amphetamine, metamphetamine and ecstasy impaired drivers. Forensic Sci Int 173:112–116 56. Verschraagen M, Maes A, Ruiter B, Bosman IJ, Smink BE, Lusthof KJ (2007) Post-mortem cases involving amphetamine-based drugs in The Netherlands. Comparison with driving under the influence cases. Forensic Sci Int 170:163–170

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Index

A Abdominal injury, 161 Accident investigation characteristics, 173 crash rate, 173 HFACS, 172 LOSA, 172 Swiss Cheese Model, 171 Acute (apparent) life threatening events (ALTEs), 130 Acute lung injury (ALI) surfactant deficiency, 49 and ventilator associated trauma, 50–52 Adult pulmonary pathology cancer, physiological derangements bronchogenic carcinomas, 63 metastatic carcinoma, 63 paraneoplastic syndromes, 63, 64 primary bronchogenic carcinoma, 62 primary malignancies and metastatic tumor deposits, 61 squamous cell carcinoma, 62 emphysema and asthma acute exacerbation, 69 COPD, 67 Langerhans cell histiocytosis, 68 long term smoking/chronic occupational exposures, 67 severe and acute respiratory distress, 69 systemic anaphylaxis, 69 infections acute, complications, 60 ancillary testing, tissues sampling, 60 aspiration, gastric contents, 59 community acquired and nosicomial pneumonia, 57, 58 histomorphological appearance, 59

host immunological defense, 57 lung involvement, 57, 58 pneumonia, 60 respiratory outbreaks, 60–61 risk factors, pneumonia, 58 interstitial lung disease acute conditions, 70 connective tissue stains, 71 diagnostic challenges, 71 end-stage chronic interstitial pneumonitis, 71 hypersensitivity pneumonitis, 71 pleural and interstitial nodules, 70 pneumonitis, 70 suspected aspiration, 61 systemic disease processes, 72 vascular and cardiovascular disease pulmonary hypertension, 65–67 pulmonary thromboembolism, 63–65 Air Accident Investigation Branch (AAIB), 148–150 Air balloons aviation accident, 175 crashes, 175–176 Aircraft accidents analysis, 168 in continental Europe, 150 disease, aircrew coronary artery, 154–155 post-mortem examination, 153–154 suicide, 155–156 injury mechanisms abdominal injury, 161 control, crash time, 162–164 deceleration effects, 157 head injury, 159 horizontal forces, 157–158

E.E. Turk (ed.), Forensic Pathology Reviews, Volume 6, Forensic Pathology Reviews 6, DOI 10.1007/978-1-61779-249-6, © Springer Science+Business Media, LLC 2011

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332 Aircraft accidents (cont.) human tolerance to deceleration, 157 lack, safety harness, 157 overhead lockers, 158 pattern, 161–162 perpendicular forces, 158 pulmonary fat and bone marrow embolism, 164 scoring systems, 158–159 thoracic injury, 159–161 investigation action, scene, 151–152 autopsy, 152–153 human, aircraft and operational factors, 151 “Human Factors Group”, 151 obligatory statutory investigations, 150 toxicology blood alcohol levels, 165 carbon monoxide and cyanide, 165–166 crop spraying accidents, 167–168 disruption and contamination, 164–165 therapeutic and “over-the-counter” drugs, 167 in UK Coroner’s and AAIB inquiries, 149 definition, Annex 13, 148 investigation, 148–149 Standards and Recommended Practices for Aircraft Accident Inquiries, 147 State of Occurrence, 148 in USA, 149–150 Alcohol and drug fatality, transportation amphetamine, methamphetamine and “ecstasy” effects data sheet, 315 described, 314–315 guideline, person’s driving ability, 316 MDMA consumption, 316 responsibility analysis, 316 therapeutic applications, 315 cannabis effects altered view and reality experiences, 310 data sheet, 308 deleterious, 309 epidemiological studies, 309 guideline, person’s driving ability, 308 performance impairment, 309 used products and factors, 307–308 cocaine effects altered view and reality experiences, 310 calculation, accident risk, 314 data sheet, 314 described, 313

Index guideline, person’s driving ability, 313 effects altered view and reality experiences, 306 BACs, 306–307 correlation, BAC and accident risk, 307 medication, 305–306 probabilities, accident cause, 307 problems, 305 epidemiological data classification, 302 drivers rate, 300 DUI and responsibility analysis, 300 fatal accidents, responsibility analysis, 300 fatally injured drivers, 301 median exposure rate, 300 “real” risk factors vs. other factors, 302 roadside surveys, drivers, 300 THC, responsibility rate, 301 traffic accidents, prevalence, 302–304 forensic-toxicological analysis body fluids, post-mortem material, 322–326 drug, 321 drug testing, 326–330 hair samples, post-mortem material, 326 matrices, 321–322 tissue samples, post-mortem material, 323–326 hallucinogens effects, 317 heroin and opioids effects codeine use, 312 data sheet, 307, 308 factors, 310 guideline, person’s driving ability, 311–312 morphine, methadone and buprenorphine, 313 opium and morphine, 310 rules, 312 structured evidence-based review, 312 symptoms, 312 medicines effects benzodiazepines use, 320 CMI and conditions, 317 guideline, person’s driving ability, 320 medications, 317, 318 mixing drugs effects alcohol and medicines, 320 depressant and stimulant, 321 factors, 320 motor vehicle crashes, 299 post-mortem toxicology alcohol formation, 330 cocaine, 330

Index tolerance and reference tables use, 330–331 ALI. See Acute lung injury All-terrain vehicles (ATV) crashes CPSC, 200–201 definition, 200 ICD, 201–202 injury pattern, 204–212 manufacture, 199 public health authorities response, 202–204 Anthropology Deutsche bank, 194–195 human remains discoveries, 193–194 and personal effects, 195 osteology, 194 phase II recovery, 194 role, 194 sifting process, 195–196 WTC recovery work, 196 9/11 Attacks anthropology, 193–196 autopsy, 184 events airplanes, 185 description, 184 twin towers, 184 fatalities investigation, 183–184 forensic biology, 189–193 investigation and remains recovery, 185–189 pathologist, 184 Autopsy blood culture, 139–140, 142–143 fundamental requirements, 76 good, medico-legal and complete, 75–76 haemorrhage, 132 pathology, 143 pneumonia, 60 primary lung carcinoma, 61 protocols, 90 pulmonary edema and congestion, 56 report, pulmonary hypertension, 65–67 respiratory distress syndrome (RDS), 50 role (see SUDI post-mortem investigation)severe BPD, 50 staff safety, 60 sudden death, role, 90 Aviation accidents and fatality, 178–179 investigation, 171–173 aircraft-specific studies

333 helicopter air taxi accident, 175 homebuilt airplanes and gyroplanes, 176 hot-air balloons, 175–176 epidemiological studies Aerospace Medical Association, 173 environment and operational factors, 174 fatal and non-fatal injury, 173 helicopters, 176–177 pathology distal tibial shaft, 177–178 drugs and alcohol, 178 neck trauma, 178 powerline collisions, 177 types, accident mid-air collisions, 174 pilot characteristics, 175 spatial disorientation, 174 Aviation deaths. See Aircraft accidents B Backscattered electron (BSE), 86 Blood alcohol concentrations (BACs) description, 306 probabilities, accident cause, 307 Body cooling, 261, 272 Bronchopulmonary dysplasia (BPD), 50 Brugada syndrome, 85 BSE. See Backscattered electron C Calmodulin calcium sensor and signal transducer, 281 calpain-mediated CnA cleavage, 290 PP2A degradation, 292–293 Calmodulin-binding proteins (CaMBPs) degradation, postmorterm calpain, 281, 289 CaMKII, 289–290 cellular process control, 281 CnA, 290–292 iNOS activity regulation, 290 MARCKS, 289 PP2A stabilization/translation, 292–293 tissue probing, 289 Calpain cleavage CaMKII, 289 CnA, 290–292 iNOS, 290 MARCKS, 289 PP2A, 292–293 proteolytic agent, 281

334 Cerebrospinal fluid (CSF) glucose and lactate levels, 139 PCR, 138 protein, 137–138 proteomics causes, 139 proteins, 138 white cell count meningitis, 136 neutrophils, 136 SIDS, 136, 137 Childhood, sudden death. See also Sudden natural deaths, infancy and childhoodcoronary artery thromboembolism, 6 diabetes mellitus, 14 metabolic disorders, 14–16 parvovirus B19 and hydatid disease, 13 rectal bleeding, 10 CLSM. See Confocal laser scanning microscopy Confocal laser scanning microscopy (CLSM) description, 87 FLIM-based analysis, 87 structure, 86 Consumer Product Safety Commission (CPSC) annual report, ATV deaths, 200, 201 estimation, 201 NEISS, 201 authorities and executives, 203 data base, 205 ICD-9-CM, 201 Coronary artery disease, 154–155 CPSC. See Consumer Product Safety Commission D Death time estimation cadaver, 241 ecological succession data analysis, 229–230 experimental design, 228–229 insect community structure changes, 228 entomology, 216–218 FEM software, 266–267 theory, 264–266 FE-model boundary conditions, 269–272 geometry, 267–268 initial conditions, 269 material properties, 268–269

Index fluorescence spectroscopy, 243–245 forensic entomology, 215 insects, 221–228 methods, 261 model curves approaches, 262 PMI, 242 post mortem cooling, 261, 262, 276 specimens identification cuticular hydrocarbons, 220–221 genetic techniques, 220 insects, 218 morphology, 219–220 spectra interrogation light source, Y-type probe and spectrometer, 246 rat skin, 247 spectral analysis fluorescence, PMI, 247–249 tissue degradation, 248 spectral processing intensity ratio analysis, 249–250 PCA, 250–258 standardising methods Daubert judgement, 230 forensic entomology, 230–231 ISO/IEC, 231 thermodynamics, 262–264 tissue changes, 242 validation body constitutions and environmental temperature levels, 272–274 measurement cases, 275 simulation results, 273, 275 thermal tissue properties, 268, 269 Degradation, CaMBPs. See Calmodulin-binding proteins degradation, postmorterm Deoxyribonucleic acid (DNA) analysis, 184 database, 192 human diploid cell, 132–133 identification family member, 187 reference samples, 190–191 techniques, 190 profiles, 191 recovery phases, 193 sources, 191 test types, 192 Dissection techniques inflow-outflow and “short-axis” method, 77 plane, 77, 79 requirements, 76 Driving under influence (DUI) drivers test, 300

Index drug testing, laboratory approaches (see Forensic-toxicological analysis)investigations, 331 DUI. See Driving under influence E EEM. See Excitation Emission Matrix Ehlers–Danlos syndrome, 17 Endocrinology adrenal crisis/Addison’s disease, 96 Conn’s syndrome, 96 hypoparathyroidism, 98 morphological and post-mortem biochemical findings adrenal gland, 101–104 diabetes mellitus/coma diabeticum, 110–112 endocrine pancreas, 108–110 parathyroid gland, 107–108 pituitary gland, 98–101 thyroid gland, 104–107 myxeodema coma, 97 parathyrotoxic crisis chronic hyperparathyroidism, 97 hypercalcaemia, 98 pituitary coma postpartum haemorrhage, 96 symptoms, hypopituitarism, 95 post-mortem biochemistry adrenocorticotropic hormone, 114 blood glucose metabolism, 114–115 catecholamines, 113 cortisol, 113 thyroid hormones, 112–113 thyrotoxicosis, 97 Entomology physiological time, 218 post mortem events and intervals ecological succession and oviposition, 217–218 PMImin and PMImax, 216–217 Excitation Emission Matrix (EEM), 259 F FAC. See Family Assistance Center Family Assistance Center (FAC) family member relationship, 191 objectives, 187 Fatalities alcohol and drug (see Alcohol and drug fatality, transportation)ATV (see All-terrain vehicles (ATV)

335 crashes)coronary artery disease prevalence, pilot, 154 GA (see Aviation)WTC anthropology, 193–196 events, 184–185 forensic biology, 189–193 investigation, 185–189 FEM. See Finite-element-method Finite-element-method (FEM) software, 266–267 theory discretisation and results, 264 explanatory scheme, 264, 265 functions values, locations, 264–265 heat transfer equation, 265, 266 partial differential equation and second order spatial derivatives, 265 shape functions, 266 Finite element (FE)-model boundary conditions conduction, 269 convection, 270 internal power, 271–272 radiation factors, 270–271 geometry 3D, 267 grey-scaled materials, 267, 268 initial conditions, 269 material properties, 268–269 Flavine adenine dinucleotide (FAD), 245 Forensic biology DNA phases, recovery, 193 identification, 193 reference samples direct, 190–191 family members, 191 test types, 192 WTC DNA database, 192 identification, 189–190 Forensic pathologist response, homicide, 184 role, 184, 197 Forensic-toxicological analysis body fluids, post-mortem material bile, 322–323 blood, 323 blood analysis results, interpretation, 324 brain, 325 cerebrospinal fluid and vitreous humor, 323 gastric and intestinal contents, 323 skeletal muscle, 326 urine, 321–322

336 Forensic-toxicological analysis (cont.) drug analysis, 321 drug testing, laboratory approaches cutoffs recommendations, 327–329 GC/MS and LC/MS procedures, 327 GHB, 327 “gold standard”, 327 GTFCh, 327 immunoassay screening procedure, 326 hair samples, post-mortem material, 326 matrices, 321–322 tissue samples, post-mortem material brain, 325 drug detection, 323–324 kidney and liver, 325 lungs, 325 skeletal muscle, 326 G General aviation (GA) accident and fatality, 178–179 investigation, 171–173 types, 174–175 aircraft-specific studies, 175–176 epidemiological studies, 173–174 helicopters, 176–177 pathology, 177–178 H Haemorrhagic shock and encephalopathy (HSE), 129 Haemosiderin-laden macrophages (HLMs) birth weight and gestational age, 39–40 comparison, NAI, 39 structure, and intra-alveolar haemorrhage, 39 Head injury, 159 Heart sectioning, SCD examination, 76–77 long axis method described, steps, 77, 80 structure, 77, 80 long vs. short-axis sections, 79, 81, 82 requirement, information, 76 “short-axis” methods described, steps, 80–81 inflow-outflow and, 77 structure, 80, 81 standard method described, steps, 77 plane dissections, 77, 79 structure, 77–79

Index tissue sampling histological and immunohistochemical examination, 81–82 structure, 82, 83 Heat flow mechanisms, 262–263 Helicopters air taxi accident, 175 crashworthy aircraft, 176 EMS crashes, 176 lap belt and shoulder harness, 176–177 sling-load operations, 177 Hemolytic-uremic syndrome, 12 Heparin-induced thrombocytopenia (HIT), 101 HIT. See Heparin-induced thrombocytopenia HLMs. See Haemosiderin-laden macrophages Human factors analysis and classification system (HFACS), 172 Hypoxic ischaemic encephalopathy (HIE) and ALTE, 131 brain damage, 131 counter argument, 132 NAHI, 132 non-accidental injury, 131 I ILAC. See International Laboratory Accreditation Cooperation Immunoglobulin G (IgG), 126, 142 Immunohistochemistry techniques Brugada syndrome, 85 description, 83 detection, TNFa, 84 DNA testing, 85 “final common pathway”, 85 high-resolution imaging, 85 LQTS and SNTA1, 85 markers, 84 sodium and potassium channel subunits, 85 Infection explained SUDI, 124–125 HSE age incidence, 129 IgG, 126 respiratory tract, 126, 130 role, 143 Injury mechanisms, aircraft accidents abdominal injury, 161 control, crash time, 162–164 deceleration effects, 157 head injury, 169 horizontal forces, 157–158 human tolerance to deceleration, 157

Index lack, safety harness, 157 overhead lockers, 158 pattern of injuries, 161–162 perpendicular forces, 158 pulmonary fat and bone marrow embolism, 164 scoring systems, 158–159 thoracic injury, 159–161 Injury pattern, ATV brain, 205 children, 204–205 CPSC database, 205 death rate, children, 205 driving safety course, 205 mechanism backward rollover, 209, 210 crushed right upper face, 207 drivers and passengers, 208 driving prohibition, 207 front-over-rear rollover, 208, 209 neck, wire slung, 210, 211 off-road vehicle injuries, 212 prehospital care providers, 212 riding rate, 210 risk factors, 206 rollovers, right hip, 208, 209 Safety Institute, 212 vs. truck on public road, 208 related crashes, 204 riding, 205–206 Insects adults age estimation NIRS, 226–227 ovarian development and wing wear, 227 pteridine accumulation and flies relationship, 226, 227 techniques, 226 cuticular hydrocarbons adult flies, 224 discriminant function analysis, 223 larvae, 223 puparia, 224 data analysis insect development, 227–228 linear regression model, 228 gene expression and RNA analysis, 222–223 hormone production, 223 measurement accuracy, precision and bias, 221–222 pupae developmental anatomy beetles and flies life cycles, 219 metamorphosis, 226

337 MSCT and MRI, 225 spatial and temoporal resolution, 225 International Classification of Disease, 9th revision, Clinical Modification (ICD-9-CM), 201–202 International Laboratory Accreditation Cooperation (ILAC), 231 Investigation and remains recovery, WTC fatality death certification asphyxia, 188 memorial park, 189 positive identifications, 188 FAC, 187 identification, 187–188 medical examiner examination area, 185–186 postmortem tissue samples, 186–187 triage, 186 K Kawasaki disease, 6–7 L Lemierre syndrome, 13 M Magnetic resonance imaging (MRI), 225 Marfan syndrome, 7–8, 16 Mass disaster forensic medicine response, 196 identification, 184 Metabolic crisis, 114 Microbiology, post-mortem group 1 and 2 pathogens, 40 positive culture result, 40–41 Staphylococcus aureus and Escherichia coli, 40 MRI. See Magnetic resonance imaging Multi-slice computed tomography (MSCT), 225 N National Electronic Injury Surveillance System (NEISS), 201 “Negative” autopsy, 17 Non-accidental head injury (NAHI), 131 Nuclear magnetic resonance (NMR), 242

338 O Off-road vehicles dirt bikes, 200 E Code 821.X, 201 injuries, 212 P PCA. See Principal component analysis Pediatric pulmonary pathology ALI and ventilator associated trauma chronic aspiration, 51 diffuse intravascular fat emboli, 51 mechanisms, alveolar damage, 52 mortality rate and causes, 50–51 ventilation associated injuries, 52 born alive/dead flotation/hydrostatic test, 52 gas producing bacteria, 52–53 stringent physical evidence, 53 hypoplasia co-existing systemic developmental abnormalities, 48 description, 48 lungs radiological examination, 49 severe, 48–49 respiratory distress syndrome and bronchopulmonary dysplasia BPD, 50 surfactant deficiency, 49–50 SUDI and SIDS acute epiglottitis, 54 acute viral pneumonitis, 53 bacterial tracheitis, 54 bacterial/viral infections, 53 Haemophilus influenzae and pneumococcus/parainfluenza viruses, 54 hematoxylin and eosin staining, 56 immunohistochemistry, respiratory syncytial virus, 55 interstitial and intra-alveolar hemosiderin and siderophages, 57 nasopharynx sampling, 53 occlusive laryngeal polyp, 55 protein rich fluid use, 56 RSV, 54–56 Period of insect activity (PIA), 216 PMI. See Post-mortem interval PMSI. See Post mortem submergence interval Polymerase chain reaction (PCR), 138 Post-mortem biochemistry adrenal gland adrenocortical atrophy, 101

Index chronic follicular lymphocytic infiltration, 104 congenital enzyme defect, 103 eosinophilic cytoplasmatic inclusions, 102–103 incidentalomas, 102 lymphocytic infiltration, 101 macroscopic appearance, adrenocortical adenoma, 102 phaeochromocytoma, 103 Waterhouse-Fridrichsen syndrome, 101 adrenocorticotropic hormone, 114 blood glucose metabolism haemoglobin A1c, 114 hormone and c-peptide levels, 115 ketoacidotic coma, 115 vitreous humour and CSF, 114 catecholamines, 113 cortisol, 113 diabetes mellitus/coma diabeticum lymphocytic infiltration, 110 nodular glomerulosclerosis, 111–112 nuclei, liver epithelia, 111 periodic acid Schiff staining, 111 endocrine pancreas blood glucose level regulation, 108 insulinoma, cellular arrangement, 108–109 islet amyloid polypeptide (IAPP), 109, 110 nesidioblastosis, 109 symptoms, hypoglycaemia, 108 parathyroid gland cellular atypia and infiltrative growth behaviour, 108 histologic appearance, 107, 108 hyperparathyroidism, 107 pituitary gland cicatrisation, 99 connatal ACTH cell aplasia, 101 high power micrograph, adenoma, 100 hypophysitis, 100 inflammatory lesions, 98 necroses, neurohypophysis, 98 necrosis, early stage, 99 thyroid gland acid mucopolysaccharides, mitral valve, 106 atrophic autoimmune thyroiditis, 105 autopsy appearance, 107 Grave’s disease, 105, 106 Hashimoto’s thyroiditis, 104 regressive change, 105–106 residual fibrosis, 105

Index thyroid hormones, 112–113 Post-mortem interval (PMI) adult flies, 224 CaMBPs degradation (see Calmodulinbinding proteins (CaMBPs) degradation, postmorterm) determination, 242, 243, 245 device development, protein markers, 294 environmental influences, 293–294 fluorescence spectroscopy, 243, 245, 259 forensic pathology, 279 markers, protein, 281, 282–288 membrane permeability, 280 metamorphosis process, 222–223 prediction, 243, 255, 257, 259 protein degradation assessment, 280–281 Post mortem submergence interval (PMSI), 216 Principal component analysis (PCA) angular coefficient temporal evolution, 258 animal probability, 257 autovetores determination, 254 correlation plots, real and estimated PMI, 258 data projection, 254 representation, matricial form, 253 EEM, 259 in vivo animal’s skin fluorescence spectra, 252 matrix transformation, 253 new base data representation, 255 optical technique, 259 PC1 vs. PC2, 258 PMI, representative regions, 255–256 spectrum processing, 249 validation, PMI determination, 257 Protein CaMBPs degradation, 281–293 markers, 281–288 PMI measurement, markers, 294 Public health authorities response, ATVs crashes, 203 financial burden, 204 hospitalized patients, 203–204 injuries, 202 manufactures, 203 National Inpatient Sample, 203 rider-related risk factor, 203 Pulmonary pathology adult (see Adult pulmonary pathology) identification, autopsy, 72–73 pediatric (see Pediatric pulmonary pathology)

339 R Reconstruction, injury patterns, 161–162 Rib fractures interpretationSee SUDI post-mortem investigation S Scanning electron microscopy (SEM), 86 SCDSee Sudden cardiac death Scoring systems, 158–159 SEMSee Scanning electron microscopy SIDSSee Sudden infant death syndrome Single nucleotide polymorphisms (SNPs), 143 Spectral processing, intensity ratio analysis distribution, PMI function, 250 emission spectrum, 249 real and estimated PMI correlation plots, 252, 256 Sudden and unexpected death in infancy (SUDI), 53–57 Sudden cardiac death (SCD) cases autopsy good, medico-legal and complete, 75–76 role and protocols, 90 described, 76, 89 heart sectioning examination, 76–77 inflow-outflow and “short-axis” methods, 77 long axis method, 77, 80 long vs. short-axis sections, 81, 82 requirement, information, 76 short axis method, 80–81 standard method, 77, 79 structure, 77–79 tissue sampling, 81–82 Janssen cautions, 91 laboratory technologies analytical proteomics, 89 cardiac hypertrophy, 88–89 defined, proteome, 88 DNA testing and extraction, 87 high-quality DNA extraction, 87 mass spectrometry, 89 “pre-PCR restoration process”, 87–88 proteomic investigations, 88 Western blot analysis, 89, 90 microscopic approach Brugada syndrome, 85 CLSM, 87–88 high-resolution imaging, 85 histological examination, 82, 83

340 Sudden cardiac death (SCD) cases (cont.) immunohistochemistry, 83–84 LQTS and SNTA1, 85 markers use, immunohistochemical, 84 myofibers structural changes, 86 significance, 82, 85 sodium and potassium channel, 85 TEM, SEM and BSE, 86 TNFa, immunohistochemical detection, 84 requirements, 76 Sudden death autopsy pathology, 143 infection role, 143 pulmonary causes (see Sudden death, pulmonary pathology)SNPs, 143 SUDA, 142–143 SUDC, 141–142 SUDI, 124–141 Sudden death in epilepsy (SUDEP), 2 Sudden death, pulmonary pathology adult cancer and physiological derangements, 61–63 emphysema and asthma, 67–69 infections, 57–61 interstitial lung disease, 70–71 suspected aspiration, 61 systemic disease processes, 72 vascular and cardiovascular disease, 63–67 pediatric ALI and ventilator associated trauma, 50–52 born alive/dead, 52–53 hypoplasia, 48–49 respiratory distress syndrome and bronchopulmonary dysplasia, 49–50 SUDI and SIDS, 53–57 Sudden infant death syndrome (see Sudden infant death syndrome)terminology and classification, 28–31 Sudden infant death syndrome (SIDS). See also Sudden natural deaths, infancy and childhood definition and categories, 28 diagnosis, 28 “dustbin diagnosis”, 31 explained infection, 124–125 mandibular hypoplasia, 3 metabolic disorders, 14–16 SUDI, 31, 53–57

Index trisomies, 17 unexplained, risk factors co-sleeping/bed-sharing, 32 pacifiers use, 32 rates, 31, 32 “triple-risk” hypothesis, 33 Sudden natural deaths, infancy and childhood anaphylaxis, 17 cardiovascular system cardiac hypertrophy, 8 congenital abnormalities, 4 coronary arteries, 6, 7 dysplasia, aortic valve, 5 floppy mitral valve, 9 hypertrophic cardiomyopathy, 8 Marfan syndrome, 7–8 myocardial noncompaction, 9 myocarditis, 9 oncocytic cardiomyopathy, 8–9 pulmonary arteries, 6 pulmonary hypertension, 7, 8 venous abnormalities, 4–6 central nervous system subarachnoid hemorrhage, 2 SUDEP, 2–3 tuberous sclerosis, 3 ventriculoatrial shunts, 3 Ehlers–Danlos syndrome, 17 endocrine, 14 gastrointestinal diaphragmatic defect, 11 gut malrotation, 10 small intestinal infarction, 10 genitourinary hemolytic-uremic syndrome, 12 pyelonephritis, 11–12 hematologic, 11 infectious causes Hemophilus influenzae type B infection, 13 Lemierre syndrome, 13 meningococcal sepsis and bacterial meningitis, 11, 12 pneumonia, 11–12 Marfan syndrome, 16 metabolic disorders, 14–16 “negative” autopsy, 17 preautopsy radiography, 2 respiratory acute asthma, 3–4 epiglottis edema, 4 lingual thyroglossal duct cyst, tongue, 5 oropharyngeal and laryngeal region, 3 pneumothorax, 3

Index Sudden unexpected death in childhood (SUDC) IgG, 142 LQTS, 141 SUDI, 141 Sudden unexpected death in infancy (SUDI) ALTEs, 130 blood culture bacteria, 139 post mortem isolation, 139 S. aureus and E. coli, 140 cerebrospinal fluid, 135–139 channelopathy mutations ion channels, 135 prolonged QT, 135 classification, 124 CSF, 135–139 death mode baby check scores, SIDS infants, 127–128 bacterial toxins, 128 classical concept, 128 transient bacteraemia, 128 deleterious mutations genetic networks, 134 zygotes, 134 explained SUDI–infection baby check scoring system, 125 case control study, 125 pneumonia, septicaemia and meningitis, 125 gastrointestinal tract flora, 140 gene/environmental Interactions base changes, 133 changes, genes regulatory control, 133 DNA, 132 neutral mutations, 133 HIE, 131–132 inclusion criteria, CESDI, 124 “Near Miss”, 129 respiratory tract bacterial flora, 140 SIDS, 124 unexplained epidemiological features, 128 impressive body, evidence, 127 respiratory tract infection, 126 urine, 140–141 Sudden unexpected early neonatal death (SUEND), 36 SUDI. See Sudden unexpected death in infancy SUDI post-mortem investigation autopsy protocol and cause of death ancillary, 34 component, 34, 35

341 macroscopic examination, 34 microbiological analyses, 34 multi-agency approach, 34 paediatric tertiary centre, 34 tandem mass spectrometry, 34–36 evidence-based protocol, 41–42 HLMs, pulmonary birth weight and gestational age, 39–40 comparison, NAI, 39 structure and intra-alveolar haemorrhage, 39 infection role bacterial toxin hypothesis, 33 pathogenesis, 33 Staphylococcus aureus, 33 neuropathology role, 41 post-mortem microbiology interpretation group 1 and 2 pathogens, 40 positive culture result, 40–41 Staphylococcus aureus and Escherichia coli, 40 rib fractures interpretation data, autopsy series, 37 healing, macroscopic appearances, 37, 38 NAI component, 36–37 pooled data, 38 resuscitation-related fractures, 38 sudden infant deaths classification, San Diego, 28–30 complete autopsy, 28 cot/crib death and SIDS, 28 described, SUDI, 31 diagnosis, 28 “dustbin diagnosis”, 31 San Diego definition, 28 SUEND description, 36 vs. SUDI, 36 toxicology role, 41 unexplained SUDI/SIDS, risk factors behaviour modification strategies, 31 co-sleeping/bed-sharing, 32 pacifiers use, 32 rates, 31, 32 “triple-risk” hypothesis, 33 SUEND. See Sudden unexpected early neonatal death Suicide, 155–156 T TEM. See Transmission electron microscopy Terrorism. See 9/11 Attacks

342 Thermodynamics, heat transfer equation, 263–264 mechanisms, 262–263 Thoracic injury, 159–161 Time of colonisation (TOC), 216 Tissue fluorescence spectroscopy absorption, 243 biomolecule, 244 energy levels and electrons states, 243 laser system, 245 phosphorescence, 244 photons interaction and groups, 244 PMI determination, 245 sensitive technique, 242

Index TOC. See Time of colonisation Toxicology, aircraft accidents blood alcohol levels, 165 carbon monoxide and cyanide, 165–166 crop spraying accidents, 167–168 disruption and contamination, 164–165 therapeutic and “over-the-counter” drugs, 167 Transmission electron microscopy (TEM), 86 Trauma, 153, 158, 159 W World Trade Center (WTC) See 9/11 Attacks