Postmortem toxicology Goldfrank

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Editors: Flomenbaum, Neal E.; Goldfrank, Lewis R.; Hoffman, Robert S.; Howland, Mary Ann; Lewin, Neal A.; Nelson, Lewis S.
Title: Goldfrank's Toxicologic Emergencies, 8th Edition
Copyright ©2006 McGraw-Hill
> Table of Contents > Part B - The Fundamental Principles of Medical Toxicology > Section III - Special Populations > Chapter 33 - Postmortem Toxicology
Chapter 33
Postmortem Toxicology
Rama B. Rao
Mark Flomenbaum
Intravenous phenytoin is administered to a 25-year-old man with a history of seizures, who is maintained on phenytoin in order to achieve a therapeutic concentration. Eight minutes after the beginning of the infusion, the man experiences a bradydysrhythmia followed by asystole. The infusion is immediately discontinued and resuscitation is attempted, but is unsuccessful.
Postmortem toxicology is the study of the presence, distribution, and quantification of a xenobiotic after death. This information is used to account for physiologic effects of a xenobiotic at the time of death, through its quantification and distribution in the body at the time of autopsy. Several variables may cause changes in xenobiotic concentrations during the interval between the time of death and subsequent autopsy. Toxicologists and forensic pathologists are frequently asked to interpret postmortem xenobiotic concentrations and decide whether these substances were incidental or contributory to the cause of death.
The development of the field of forensic toxicology, and the improvement of laboratory technology, now permits more refined identification and quantification of xenobiotics. The interpretation of postmortem xenobiotic concentrations and their significance, however, continues to evolve.
This chapter reviews factors affecting xenobiotic concentrations identified on autopsy and discusses an approach for interpreting postmortem toxicologic reports as they relate to cause and manner of death.37,39,45,46 and 47,53,61,71,89
History and Role of Medical Examiners
The relationship between antemortem xenobiotic exposures and death has been a subject of investigation for centuries. In 12th century England, an appointee of the royal court, eventually named the “coroner,”� was designated to record and identify causes of death.65 In suspicious circumstances coroners investigated poisonings, but scientific methods were primitive and conclusions regarding such deaths were conjecture, at best.
By the mid-19th century, however, techniques for detecting certain compounds in postmortem tissue were developed and focused generally on identifying heavy metals as a cause of death in homicides.40,65,69,86,91 At this time, coroners were still elected or appointed individuals with little or no medical training. However, with better laboratory techniques and autopsies performed by trained pathologists, the specialty of forensic medicine continued to develop. In late 19th century Massachusetts, trained pathologists, referred to as medical examiners, ultimately replaced the coroner system and were empowered by the state to investigate deaths (medicolegal autopsies).65 Currently in the United States, legal jurisdiction of death investigations is the responsibility of either a coroner or a medical examiner, depending on the state and/or county, with 19 states using medical examiner systems almost exclusively.44
The medicolegal autopsy is performed by a forensic pathologist who attempts to establish cause and manner of death (Table 33-1). “Cause of death”� is the physiologic agent or event necessary for death to occur. For example, the presence of cyanide in the toxicologic evaluation may be sufficient to establish cardiorespiratory arrest from cyanide poisoning. “Manner of death”� is an explanation of how the death occurred and broadly distinguishes natural from nonnatural (or violent) deaths. Nonnatural deaths, depending on the jurisdiction, can be divided into several categories (Table 33-2). With the identification of cyanide, the manner of death cannot be considered natural, because a poisoning is a “chemically traumatic”� (violent) event. The medical examiner must make the best determination of the manner of death based on available evidence.91,98 An unintentional exposure may be classified as an “accident”� (a legal term for some unintentional nonnatural deaths), and intentional self-exposure may be classified as a “suicide.”� If the circumstances indicate an exposure as a consequence of the acts of another person, the manner of death is classified as a “homicide.”�
Determination of manner of death has important consequences. Homicide necessitates involvement of law enforcement officials for further investigation. Cases deemed suicide not only impact survivors psychologically, but also may nullify life-insurance payments; conversely, a case deemed an “accident”� may have a double-indemnity insurance clause. Assignment of financial responsibility for workplace disasters may be similarly affected when illicit drugs are identified in the postmortem specimens of involved workers.
Recognition of xenobiotic-related deaths also has significant public health consequences. The forensic pathologist may be the first to identify and report critical information regarding fatal drug reactions, medication errors, or rapidly fatal epidemics associated with illicit drug use. In cases of occupational and environmental xenobiotic-related fatalities, interventions can be implemented to prevent subsequent morbidity and mortality. In addition, the pathologist describes gross and microscopic autopsy findings that may elucidate mechanisms of xenobiotic toxicity.
	TABLE 33-1. Information Used by Forensic Pathologists
	Autopsy
Evidence from scene
Laboratory investigations
Medical consultants
Available history
   Medical records
   Police reports
   Interviews with contacts
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Postmortem toxicologic techniques also can be used in other types of investigations. For example, when carboxyhemoglobin is identified in the burned human remains of an airplane crash, a cabin fire before descent is more probable than a fire on impact. This type of postmortem analysis is useful in reconstruction of events leading to the crash.8,51,57
The Toxicologic Investigation
Ordinarily, toxicologic samples are collected as part of a complete autopsy. In the hospital, when a death is assumed to be from natural causes, the hospital pathologist may perform an autopsy with consent of the family. In the medicolegal investigation, however, the forensic pathologist determines the need for a complete or partial autopsy and has the jurisdiction to act on that determination with or without familial consent. Occasionally, only fluid samples need be obtained if a complete autopsy is either unnecessary or the family has legal or religious grounds for objection. The precise list of xenobiotics screened in postmortem samples varies greatly by jurisdiction. Large cities may routinely screen for hundreds of illicit, therapeutic, and environmental xenobiotics. Occasionally the suspicions of the medical examiner warrant special assays that are performed only upon request.
The sampling of fluid and tissue may be obtained minutes to years after death. The “postmortem interval,”� defined by the degree of bodily decomposition, can vary, depending on environmental conditions, such as ambient temperature, humidity, and immersion under water.58 Samples may be collected from a body during advanced stages of decomposition, after exhumation from a grave, or after embalming.7,41,70 Knowing the condition of the body at the time of sampling assists in interpreting toxicologic findings. These postmortem changes are reviewed below.
Decomposition and Postmortem Biochemical Changes
The first stage of decomposition is autolysis where endogenous enzymes are released and normal mechanisms maintaining cellular integrity fail.52 Chemicals move across leaky cellular membranes down relative concentration gradients. Glycolysiscontinues in red blood cells until intracellular glucose is depleted, and then lactate is produced. Ultimately, intracellular ions and proteins are released into the blood, and tissue and blood acidemia develops (Table 33-3).91
	TABLE 33-2. Categories of Manner of Death
	Natural
Nonnatural
   Homicide
   Suicide
   Accident
   Therapeutic complicationa
   Undetermined
a Not all jurisdictions recognize therapeutic complication as a manner of death.
	TABLE 33-3. Postmortem Biochemical Changes Over First 3 Daysa
	Increased
Decreased
Stable
Variable
Amino acids
Cl-
BUN/creatinine (vitreous)
Lipids
Ammonia
Glucose
Cholinesterases
T3
Ca2+
Na-
Cortisol(serum)
 
Epinephrine
pH
Proteins (serum)
 
Hepatic enzymes
T4
Sulfates
 
Insulin (especially right-heart blood)
 
 
 
K+
 
 
 
Mg2+
 
 
 
a In refrigerated bodies.
The next stage of decomposition is putrefaction. This involves digestion of tissue by bacterial organisms that typically originate in the bowel or respiratory system. Later, other organisms may be introduced by insects or other external sources. As the putrefactive process advances, skin and organ colors change, epithelial blebs may form and separate from the underlying dermis, and gases may accumulate, forming foul odors and bloating.91
If death occurs in a very warm, dry climate, such as a desert or a comparably arid environment, the body may desiccate so rapidly that putrefactive changes may not occur. This results in mummification, and produces a lightweight cadaver with a tight, dry skin enveloping a prominent bony skeleton.91
If the environment is very cold and devoid of oxygen, such as at great depths under water, putrefaction will be slowed. Anoxic decomposition of fatty tissues occurs, forming a white cheesy material known as adipocere.
Another phase of decomposition, anthropophagia, occurs in unprotected postmortem environments where insects or other animals feed on the remains.91
Most postmortem changes are temperature dependent with increased temperatures accelerating the process, and cooler temperatures retarding it. In general, morgue refrigerators achieve low enough temperatures (40°F; 22°C) to prevent further gross decomposition and associated postmortem changes.
Another process that alters natural decomposition is embalming, a process of chemically preserving tissues that can be performed in a variety of ways.42,43 Typically, blood is drained through large vessel pumps, and an embalming fluid is injected intravascularly to perfuse and preserve the face and/or other tissues. Intracavitary spaces may be injected with the preserving substances, and solid organs may or may not be removed.
Samples used for Toxicologic Analysis
Unless the medical examiner is suspicious about a death, only standard autopsy samples will be taken from an otherwise intact body.23,36,49,54,74,89 These typically include samples of blood, gastric 
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contents, bile, urine, and, occasionally, solid organs such as the liver or brain. Less commonly, vitreous humor is obtained for analysis (Table 33-4). If the decedent was hospitalized prior to death, antemortem specimens may also be available for evaluation and comparison. These specimen analyses are reviewed in greater detail below.
	TABLE 33-4. Sampling Sites 16,21,24,36,49,91
	Routine
Infrequent
Uncommon
Bile
Bone
Antemortem blood
Blood
CSF
Extravasated blood
Brain
Fat
Extravasated fluid
Liver
Hair
Casket fluid
Gastric contents
Kidneys
Insect larvae
Urine
Lungs
Pupae casings
Vitreous humor
Muscle
Soil
 
Nails
 
 
Skin
 
Blood
Postmortem cell lysis prevents the reporting of plasma concentrations, and “blood”� concentrations are reported instead. Intravascular blood from the subclavian or femoral vessels is a common source for toxicologic examination. In patients with a prolonged postmortem interval, or in cases where intravascular blood is coagulated, right-heart blood may serve as a sample site. Usually just 1 site is sampled unless an unusual xenobiotic with nonuniform distribution is suspected of causing the death.
Other sources of blood are sometimes available to the forensic pathologist. These other sources include antemortem samples and, occasionally, extravasated blood, which is unlikely to undergo extensive metabolism. Intracranial clots, in particular, serve as useful comparative samples in patients with a prolonged survival period following exposure to a xenobiotic.
In advanced states of decomposition blood from the abdominal or thoracic cavities is less useful, as it can be contaminated by bacteria or other substances that may affect xenobiotic recovery and/or analysis.
Vitreous Humor
Because of the relatively avascular and acellular nature of the fluid, the vitreous humor is well protected from the early decompositional changes that typically occur in blood.16,21,24 When bodies are immediately refrigerated, creatinine, blood urea nitrogen, and sodium can be reliably approximated from vitreous humor samples for up to 3 or 4 days. Potassium concentrations are less reliable, as cell lysis causes intracellular release. When vitreous glucose is elevated, hyperglycemia at the time of death can be assumed. A low vitreous glucose is inconclusive with regard to the antemortem serum glucose concentration. A low vitreous glucose may be a result of either antemortem hypoglycemia or postmortem glycolysis, even in the relatively avascular vitreous.
The aqueous content of the vitreous is normally higher than that of blood and may affect partitioning of certain water-soluble xenobiotics.
Urine
Urine may be available at autopsy and can reveal renally eliminated substances or their metabolites. Because the bladder serves as a reservoir in which metabolism is unlikely to occur, the concentrations of xenobiotics obtained at autopsy reflect antemortem urine concentrations. An isolated urine sample is of limited quantitative value, but may be useful when compared to other sample sites.
Gastric Contents
The gross contents of the stomach are inspected for color, odor, and the presence or absence of pill fragments, food particles, activated charcoal, and other foreign materials.89 Typically, gastric concentrations of xenobiotics are reported as milligrams of substance per gram of total gastric contents. Xenobiotic-induced pylorospasm, diminished intestinal motility, or decreased splanchnic blood flow all may decrease gastric emptying and affect the quantitative values obtained from sampling different parts of the GI tract.
Solid Organs and Other Sources
Xenobiotic concentrations in solid organs such as liver or brain are usually reported as milligrams of substance per kilogram of tissue. Other tissue samples, including hair and nails, are used for thiol-avid agents such as metals. Rarely, tracheal aspirates of gases can be analyzed to confirm inhalational exposures. Pleural fluid analysis of postmortem xenobiotics typically yields qualitative results in decomposed bodies, as redistribution of xenobiotics from the stomach and intestines may occur.30,81
Other Sampling Sources
In an embalmed body, either the organs that remain, such as muscle tissue, or the embalming fluid can be used for analysis. Some countries regulate the contents of embalming fluid to specifically avoid confounding postmortem analysis. Most embalming fluid in the United States consists of formaldehyde, sodium borate, sodium nitrate, glycerin, and water. When a body is disinterred, soil samples are usually obtained from above and below the coffin site to permit identification of chemicals that may have leeched into or out of the body.
On rare occasion, cremated remains, often referred to as cremains, will be the only source of sampling available. Most metallic implants such as pacemakers are removed prior to cremation, and only dental remains, particulate matter, and, occasionally, calcifiedblood vessels are available for analysis.4,97 In most cremations performed in the United States, the incineration process is followed by grinding remains to form a fine particulate matter.97 The ability to extract xenobiotics from such samples is markedly limited at best, and there are few published data on the subject. A new technique to identify such heavy metals as lead from cremains has been described but is not routinely used at present.4,97
Entomotoxicology
In putrefied bodies and in bodies that have undergone anthropophagy, fluids and insect parts can be analyzed. Forensic entomologists collect samples of these insects from the remains and after taking into account the stage of insect life, environmental conditions, and season, can extrapolate the approximate time of death. The species Calliphoridae, or bluebottle fly, is attracted to unprotected remains by a very fine scent that develops in the body 
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within hours of death. The adult fly lays eggs on mucosal surfaces or in open wounds. Once the eggs hatch, the larvae feed on the decomposing tissue. Larval samples can be examined for the presence of toxins. To achieve accurate analysis, these samples must be collected and preserved immediately, because living larvae can continue to metabolize certain xenobiotics. In another phase of their life cycle, the larvae undergo pupation, secreting a substance that encloses them into pupal casings until they hatch as adults. These casings are often found in the soil beneath the body. Some toxins have been identified in the casings even after the adult fly has emerged (Table 33-5).79 A variety of other anthropophagic insect species may demonstrate the presence of xenobiotics;1,38,56 this process of analysis is termed entomotoxicology.
	TABLE 33-5. Xenobiotics Reported from Larvae and Pupae Casings38,56,79,91
	Benzoylecognine
Cocaine
Heroin
Malathion
Mercury
Methamphetamine
Morphine
Nortriptyline
Oxazepam
Phenobarbital
Triazolam
	TABLE 33-6. Considerations in Interpreting Postmortem Xenobiotic Concentrations
	Xenobiotic dependent
   Pharmacokinetic considerations
      State of absorption/distribution at time of death
      Postmortem redistribution
      Postmortem metabolism
   Pharmacodynamic considerations
      Expected clinical effects
      Synergistic interactions
   Postmortem xenobiotic stability during
         Putrefaction
         Preservation
Decedent dependent
   Comorbid conditions
   Tolerance
   Pharmacogenetic variability
Autopsy dependent
   Postmortem interval: state of preservation/decomposition
   Previously undiagnosed conditions
   Specimens sampled
   Sample sites
   Handling and preservation
Other
   Laboratory techniques
   Evidence at scene
   Previously published tissue concentrations
Interpretation of Postmortem Toxicologic Results
Once fluid and tissue samples are collected and analyzed for the presence of xenobiotics, the process of interpreting the results begins. This complex task attempts to account for the clinical effects of a xenobiotic at the time of death by integrating medical history, autopsy findings, and toxicologic reports. Multiple confounding variables can affect the sample concentrations of xenobiotics from the time of death to that of the autopsy. Variables include the nature, metabolism, and distribution of the xenobiotic, the state of health of the decedent, and the techniques and findings of the autopsy (Tables 33-6 and 33-7).
Variables Relating to the Xenobiotic
Postmortem Redistribution
Xenobiotic blood concentration may be higher at autopsy than at the time of death if the agent undergoes significant postmortem redistribution.50,73,96,103 Most often, redistribution occurs with substances that have large volumes of distribution and when decomposition results in release of intracellular xenobiotic into the extracellular compartment.77 For example, amitriptyline may be released from tissue into the blood as autolysis progresses, resulting in a higher blood concentration at autopsy than at the time of death. If postmortem redistribution is not considered, xenobiotic concentrations obtained at autopsy may be misinterpreted as supratherapeutic or toxic, and the cause of death may be inappropriately attributed to this agent.
	TABLE 33-7. Xenobiotic Stability and Laboratory Recovery10,12,22,27,73,79,80,87
	Quantitative recovery affected by preservatives
As, Pb, Hg, Cu, Ag
Cyanide
Carbon monoxide
Ethchlorvynol
Nortriptyline (converted to amitriptyline in fixatives) 
Chemical stability in formalin 
Stable
Labile
Succinylcholine
Desipramine
Phenobarbital
 
Diazepam
 
Phenytoin (30 days)
 
Chemical stability in putrefying liver 
Stable
Labile
Acetaminophen
o,p-Aminophenols
Amitriptyline
Chlordiazepoxide
Barbiturates
Chlorpromazine
Chloroform
Clonazepam
Clemastine
Malathion
Dextropropoxyphene
Metronidazole
Diazepam
Nitrofurazone
Doxepin
Nitrazepam
Flurazepam
p-Nitrophenol
Glutethemide
Obidoxime
Hydrochlorothiazide
Perphenazine
Imipramine
Trifluoperazine
Lorazepam
Methaqualone
Morphine
Nicotine
Paraquat
Pentachlorophenol
Quinine
Strychnine
Vegetable alkaloids
 
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Postmortem Metabolism
Less commonly, xenobiotic concentration may fall secondary to postmortem metabolism. For example after death, cocaine continues to be degraded by blood cholinesterases, which are stable in postmortem tissue. Unless blood is collected immediately after the time of death in tubes containing enzyme inhibitors such as sodium fluoride, the concentration of cocaine will continue to fall and the analysis will not accurately reflect the concentration of the drug at the time of death.55,63,94 Specific information that is available regarding postmortem redistribution or metabolism should be considered and the toxicologic results interpreted accordingly.
State of Absorption and Distribution
Both in the living and deceased, the state of absorption, distribution, and other toxicokinetic principles affect the sampling concentration of a xenobiotic. For a xenobiotic with minimal postmortem metabolism or redistribution, the phase of absorption is suggested by the relative quantity of the agent in different fluids and solid organs. For example, a high concentration of xenobiotic pill fragments in the gastric contents, with progressively lower concentrations in the liver, blood, vitreous, and brain, suggests an early phase of absorption at the time of death. When an agent is orally administered and the tissue concentration is highest in the liver, the relationship suggests a postabsorption phase but a predistribution concentration. A concentration found to be highest in the urine suggests that the xenobiotic was in an elimination phase at the time of death. Although this approach has limitations, it may be important for correlating the state of absorption and the expected clinical course of the xenobiotic. Unfortunately, multiple samples may not always be available at the time of autopsy or the interpretation of reports, and opportunities for subsequent sampling are often limited.
Xenobiotic Stability
Xenobiotic stability refers to the ability of an agent to maintain its molecular integrity despite changes during decomposition of the body, storage conditions, or the addition of preservatives.5,13,15,84,92,100,101 and 102 Postmortem xenobiotic stability was assessed in homogenized liver tissue infused with various concentrations of xenobiotics.92 The samples were allowed to putrefy outdoors, and sequential sampling of xenobiotic concentrations was performed. The xenobiotics that decreased in concentration as putrefaction progressed were considered “labile,”� whereas samples with a constant concentration were considered stable. The authors proposed that the chemical moieties of a xenobiotic determine its stability. For example, labile agents share the molecular configurationof an oxygen-nitrogen bond, thiono groups, or aminophenols. Conversely, chemical structures that enhance stability include single-bonded sulfur groups, carbon-oxygen and carbon-nitrogen bonds, as well as sulfur-oxygen and hydrogen-nitrogen bonds. Although not explicitly studied in otherwise intact, putrefying bodies, logically, a less-stable xenobiotic may be recovered in a lower concentration than the actual concentration at the time of death. This must be considered when information regarding stability is available and the body of the decedent is in an advanced stage of decomposition.
Xenobiotic Chemical Interactions
An artifact may result from a chemical interaction with a xenobiotic added during the postmortem period, such as embalming fluid.35 In a study of xenobiotic-spiked blood and formalin in test tubes, amitriptyline was formed through methylation of nortriptyline.26 Identification of amitriptyline, which was not present at the time of death, could confuse the interpretation of toxicologic analyses.
Expected Clinical Effects of the Xenobiotic
For a fatality to be attributed to a xenobiotic, the expected clinical course of the exposure should be consistent with the autopsy findings. For example, what are the implications if a person is found dead 90 minutes after having been seen ingesting pills and a large concentration of acetaminophen is identified in both the gastric contents and blood, but not in other tissues of a person? Although suicidal intent (manner) may be supported by this finding, the onset of death within minutes is inconsistent with a fatality from an acetaminophen overdose. Thus, another cause of death must be sought. Interpretation of postmortem toxicology must also incorporate clinically relevant consequences of xenobiotic interactions. For example, the combined ingestion of phenobarbital and ethanol can cause fatal respiratory depression. Although neither may be fatal alone, their clinical synergy must be acknowledged during toxicologic interpretation.
Variables Related to the Decedent
Comorbid Conditions
The clinical response to a xenobiotic may be affected by acquired and inherited physiologic conditions that are not always identified on autopsy. A thorough medical history is important, and may assist in interpreting the clinical effects of a xenobiotic exposure. Similarly, certain clinical conditions may produce substances that interfere with postmortmen laboratory assays. For example, an individual with a critical illness may produce digoxin-like immunoreactive substances (DLIS) which can cross-react with the postmortem digoxin assay.6 Without knowledge of DLIS production, the results may confound toxicologic analysis.
Tolerance
Tolerance is an acquired condition in which higher and higher xenobiotic concentrations are required to produce a given clinical effect. It is an important consideration for deaths in the presence of opioids, ethanol, and sedative-hypnotic agents. For example, respiratory depression and death from methadone is easily diagnosed in an opioid-naive individual with a history of methadone exposure and methadone-positive postmortem samples. However, the same methadone concentrations in a patient on chronic methadone maintenace therapy will not produce the same outcome. Unfortunately, there are no biochemical or histologic markers on autopsy that can be used to predict clinically dangerous xenobiotic concentrations in tolerant individuals. Complex postmortem assays analyzing opioid receptors are not routinely used.34 Postmortem assessment of tolerance ultimately depends on knowledge of the patient, pharmacokinetics of the agent, and the best judgment of the investigator.
Pharmacogenetics
There is genetic variability in the expression of certain metabolic enzymes. For example, pharmacogenetic differences in metabolic enzymes such as CYP2D6 predispose some individuals to fatal hypotension from the inability to metabolize debrisoquine. Such distinctions are not routinely identifiable on autopsy.28
Variables Relating to the Autopsy
State of Decomposition
In decedents with advanced stages of decomposition, xenobiotics can diffuse from depot compartments such as the stomach or bladder into adjacent tissues and blood vessels, or secondarily affecting their sample concentrations.22,67,68,76,77 and 78
During putrefaction, bacteria cause fermentation of endogenous carbohydrates, resulting in ethanol formation. In decedents 
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without gross evidence of putrefaction, especially those in cool, dry environments, endogenous ethanol production is minimal.17,18 With a longer postmortem interval or in an environment more conducive to ethanol production, the distinction between endogenous and exogenous sources of ethanol becomes more difficult. Multiple sample sites are often useful in making the distinction.93
Handling of the Body
Inappropriate handling of the body can result in artifacts.83,85 In one reported case, methanol was detected in the vitreous humor of a decedent, postembalming.12 The methanol was subsequently traced to a spray cleanser that likely settled on the surface of open eyes during washing of the body.
In the United States, preservatives containing metals are currently banned for use in embalming because they can contaminate subsequent evaluation for metal poisoning. Formalin may also affect stability or quantitative identification of some xenobiotics. When necessary, an analysis of embalming fluid used by the mortician, or soil sampling around disinterred bodies, can facilitate the toxicological investigation.19
Autopsy Findings
In many xenobiotic-related deaths, the anatomic findings are nonspecific.99 In some cases, the autopsy reveals confirmatory or supportive findings. A large quantity of undigested pills in the stomach is consistent with an intentional overdose, and suicide can be considered. Centrilobular hepatic necrosis may be found in decedents with a history of acetaminophen overdose. The autopsy may reveal other findings such as coronary artery narrowing, chronic hypertension, renal abnormalities, or a clinically silent myocardial injury. Such information may be useful to assess the potential effects of a xenobiotic in a patient with previously undiagnosed conditions. In other cases, the absence of a chronic condition may be strongly suggestive of a xenobiotic-related death. For example, a decedent with an autopsy finding of aortic dissection, in the absence of chronic hypertensive findings or other predisposing conditions, may suggest a xenobiotic-induced hypertensive crisis, as may occur from use of cocaine or other sympathomimetics.
Artifacts Related to Sampling Sites
Site-specific differences in postmortem xenobiotic blood concentrations are common.33 For example, blood drawn from femoral vessels may have a low glucose because of postmortem glycolysis, but the glucose concentration of blood removed from the right-heart chambers may be high as a result of the release of liver glycogen stores. Hyperglycemic states are more reliably assessed from sampling of the vitreous humor. An elevated vitreous glucose concentration suggests antemortem hyperglycemia. The individual interpreting the toxicologic report must know the exact site sampled.20,54
Ideally, more than one site is available for comparison. Multiple blood samples are not often routinely obtained. The comparison of concentrations from different sites may reveal important information regarding the state of xenobiotic absorption at the time of death, and acute versus chronic exposure.9,10 and 11,20,25,29,48,59,63,72,74,76,77,80,81 and 82,87,88,93,95
Other Considerations
Published therapeutic, toxic, and fatal postmortem xenobiotic concentrations are available to aid in interpretation of postmortem specimens.3,62 However, the conditions associated with reported concentrations do not necessarily permit comparisons with those concentrations in a particular case under investigation. Thus, these resourcesare valuable, but should be used mainly as guidelines and not accepted as absolute values that define fatal toxic concentrations. Similarly, formulas available for assessing xenobiotic doses or concentrations in the living, are not usually applicable when analyzing postmortem samples.
Other Limitations
Although there are generalized standards of practice in forensic investigations, specimen collection and laboratory methodology may vary.2,3 Some xenobiotic concentrations may be falsely elevated or depressed, depending on chosen methodology.30,64 Descriptions of specific laboratory toxicology techniques are beyond the scope of this chapter, but these variables must also be given consideration in postmortem toxicologic interpretations. Other limitations may include the lack of information relating to the circumstances of death, and possible compromises in specimen handling that affect the proper chain of custody, required in forensic autopsies.
Summary
To accurately interpret postmortem toxicologic reports, it is essential to understand potential biochemical changes and the artifacts that affect postmortem sampling. Unfortunately, because of the complexity and variety of mitigating circumstances, there is no single resource that can systematically correlate postmortem xenobiotic blood and tissue concentrations to those at the actual time of death. Postmortem toxicology is an evolving discipline that may only permit the most likely truths associated with the xenobiotic identified and the circumstances in question.14,31,66
Progress in this field depends on the continued collaboration between treating physicians, medical and forensic toxicologists, and forensic pathologists.
Case Discussion
A complete medical history was reported to the medical examiner including the details of his general health, why he presented to the hospital, and what transpired immediately prior to, and during the cardiac arrest. The tubing and all remaining fluid in the phenytoin infusion was saved for analysis, and the laboratory was informed to save all samples of antemortem and perimortem blood obtained during the hospitalization.
The postmortem blood from the right subclavian vein revealed lidocaine 8 µg/mL and phenytoin 16 µg/mL, but lidocaine is not commonly used during bradycardic arrests. The toxicologist therefore requested a complete medical record to determine whether this medication was administered during an attempt to restore circulation. If it was so used, lidocaine could be excluded as a cause of cardiac arrest and treated as a therapeutic artifact. Alternatively, lidocaine toxicity might have caused a bradydysrhythmia. The volume of distribution of lidocaine is between 1 and 2 L/kg and undergoes limited postmortem redistribution. If the toxicologist remains uncertain about causation, the remainder of the intravenous infusion can be analyzed for the presence of lidocaine and the possibility of a medication error. As it turned out, the resuscitation resulted in a transient episode of ventricular fibrillation that was treated with successive defibrillation and the administration of boluses of lidocaine. The remaining 40 mL of the original phenytoin infusion contained only phenytoin in a propylene glycol diluent. The conclusion was reached that the postmortem lidocaine concentration 
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was likely a result of resuscitative efforts and in the absence of any other autopsy findings, the bradycardic arrest was likely caused by rapid infusion of propylene glycol, as the diluent used with intravenous phenytoin.
Additional Case Discussions
Case A
A 72-year-old male with a history of atrial fibrillation is found dead 1 hour after his last dose of digoxin. The autopsy, performed the following day, demonstrated an enlarged heart and findings consistent with chronic hypertension. The postmortem right-heart blood digoxin concentration was 5.6 ng/mL. How should these results be interpreted?
This high blood concentration may reflect either the early state of absorption or postmortem redistribution of digoxin. Alternatively, the individual may have suffered death from chronic digoxin toxicity. Sampling another site, such as the vitreous humor, becomes important to make the distinction. The vitreous concentration will likely reflect the chronic concentration of digoxin as it equilibrates with blood over a period of hours after ingestion. If the vitreous humor concentration is 0.9 ng/mL and the vitreous creatinine is 0.8 mg/dL, it is unlikely that chronic digoxin toxicity was responsible for the patient's death.
Case B
A 50-year-old man with diabetes is found in an advanced stage of decomposition in his apartment during a warm summer month. The vitreous humor is cloudy and has a glucose concentration of 5 mg/dL. Right-heart ethanol concentration is 40 mg/dL. How do you interpret these values?
Unlike elevations in vitreous glucose, low vitreous glucose is inconclusive with regard to the glycemic state at the time of death. Thus, low vitreous glucose is inconclusive in establishing antemortem hypoglycemia even if the postmortem interval was relatively brief and the vitreous sample, clear. The ethanol could have been consumed prior to death, or it could have been generated during the postmortem interval, but usually does not rise above 50 mg/dL. An ethanol sample from the brain and bladder (if available) in which ethanol undergoes less fermentation would be useful to make the distinction. Regardless of the source of the ethanol, a level of 40 mg/dL is unlikely to have caused death alone, but may be useful if aspiration, unusual bodily position, or other sedative hypnotics were also identified at autopsy.
References
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