If you have issues viewing or accessing this file contact us at NCJRS.gov. ------~------

CHAPTER 4 Treatment for Survival Prior to Death and Interpretation of Postmortem 'Toxicologic Findings

Eric G. Comstock, M.D,

The protocol for postmortem examination not detectable at postmortem examination. in the medical examiner's or coroner's office Substances detected may be found to have should provide for a minimum toxicologic been administered medicinally and to have no examination in every death. Specimens to be causative role whatsoever. Concentrations of collected for t0xicologic evaluation should drugs for which tolerance develops may be so include: (a) gastric contents with notation of high as to be considered an unequivocal cause the total volume, (b) heart blood, (c) urine, of death in a pharmacologically naive individ­ (d) bile, and (e) selected tissues, such as liver, ual, while they may have played no role what­ lung, and kidney. soever in a chronic drug user. The minimum toxicologic examination The purpose of this discussion is to direct should provide for qualitative screening with attention to the circumstances which influ­ quantitation when the qualitative procedures ence the interpretation of toxicologic findings are positive. Minimum routine screening pro­ at postmortem examination. cedures should include a test for volatile organics and screening procedures for detec­ tion of a variety of groups of drugs. Circum­ CIRCUMSTANCES INFLUENCING stances of death may dictate a more elaborate INTERPRETATION protocol or suggest specific substances or groups of substances that should be assessed.1 Statistical parameters, such as "the lethal The only significance that routinely can be dose 50 percent" or "the lethal concentration attached to positive toxicologic findings is 50 percent," permit the determination of the that a detected substance is present. It is ex­ relative toxicity of a substance for various tremely rare that causal significance can be species or for subgroups within a single attributed to a substance on the basis of analy­ species. The relative toxicity of various sub­ tical data alone. More commonly, the results stances may be compared using these con­ of toxicologic findings must be interpreted cepts. They are, however, not applicable to with consideration given to investigations of single individuals within a population except the scene, activities of the decedent inunedi­ for approximation of the order of magnitude ately prior to death, first aid or treatment of susceptibility of the individual to the sub­ efforts provided by laymen or by medical stance under consideration. personnel, and long-term drug use history. When discussions of susceptibility are limited to single individuals, statistical con­ These investigations may result in the Cause of cepts lose validity. It becomes necessary to death being attributed to a su?stance which is examine the factors that influence variation in susceptibility of individuals within the The author acknowledges the support of the population. While many of these variables National Institute 011 Drug Abuse (grant #aH81 DA 01466·0 lSI) for part of the research underlying the have not 'been defined, some have been the discussion in this chapter. subject of investigation. Individual differences in susceptibility to 1For further discussion of topics treated here, see also chapter 3, "Postmortem Examination," and toxic substances are determined in part by chapter 5, "Forensic Toxicology in Death Investiga­ genetic factors. Differences in enzymatic tion." armamentaria which determine efficacy of 23 24 COMSTOCK detoxification are slow and fast acetylation, drug which would unequivocally be fatal for glucose-6-phosphate dehydrogenase deficien­ the phalmaC,)logically naive individual. cies, acetylcholinesterase deficiencies, and Interpretation of ihe toxicologic findings in metabolic correlates with the hemoglobin­ postmortem examination requires consider­ opathies, such as sickle cell disease. Defects ation of the genetic variable in susceptibility, in amino acid metabolism also may alter sus­ appraisal of preexisting pathology, and assess­ ceptibility to some toxic substances. The ment of the phalmacologic experience of the occurrence of these genetically determined decedent. variations in metabolism may place the indi­ vidual significantly outside the normal curve of susceptibility, influencing interpretation of TREATMENT PRIOR TO DEATH postmortem findings. An individual may be made more suscep­ The phrase "treatment prior to death" is tible to some substances by preexisting path­ used to describe occurrences during the inter­ ology. Susceptibility to carbon monoxide val between exposure and death. This includes may be increased by coexisting pathological first aid given by laymen as well as treat­ processes limiting exchange of oxygen in the ment administered by the medical community. lung or in a target organ, such as brain or Implicit is a survival interval between the heart. Acquired end-organ susceptibility is exposure and the occurrence of death. During illustrated by chronic exposure to anticholi­ this interval, the pharmacodynamics of redis­ nesterase insecticides. Reduction of choli­ tribution or disposition influence the interpre­ nesterase levels results in significant increase tation of the chemical findings at p0stmortem in response to administration of succinyl examination. choline. Impairment of liver function in­ Attempts at first aid may include the creases the relative susceptibility to sub­ mechanical induction of vomiting with conse­ stances dependent upon hepatic enzymes for quent aspiration asphyxia resulting in death detoxification. Significantly impaired renal unrelated to the concentration of toxic sub­ function increases susceptibility to sub­ stances present in the body. Efforts to induce stances normally excreted by the kidneY in a vomiting with sodium chloride are not un­ pharmacologically active form. common, and where vomiting has failed to Tolerance may develop to make an individ­ occur, death from hypernatrernia has occurred ual less susceptible to the lethal effects of in the presence of drugs of no toxicologic certain drugs. Dispositional tolerance is ex­ significance. Utilization of street treatment emplified by hepatic microsomal enzyme in­ folklore may result in intravenous injections duction. Experience with a toxic substance of milk or intravenous injections of table salt. over a period of time may result in increasing Other drugs that may be used in a treatment the rate of detoxification by increasing the effort include administration of ampheta­ activity of enzymes that effect the biotrans­ mines for barbiturate overdose and adminis­ formation of the substance to a nontoxic tration of chlorpromazine for amphetamine metabolite. Dispositional tolerance does not overdose. increase the concentration of toxic substance Once a patient finds his way to medical that can be tolerated at the target end organ. care, interpretation of subsequent postmortem Comparison of a tolerant individual with a findings may become very complicated. pharmacologically naive individual after a Administration of supportive care for pul­ similar survival interval shows lower tissue monary or cardiovascular failure may result concentrations of the substance in the toler­ in survival after the time that the original ant individual. "End-organ tolerance" des­ offending substance has been cleared from the cribes the adaptive procedure by which the body, with death due to injury incurred while target organ becomes less responsive to the the toxic substance was present. The per­ phalmacologic efhct of the substance. Devel­ formance of gastric lavage alters the interpre­ opment of end-organ tolerance permits an tation of postmortem examination of gastric individual to survive tissue concentrations of a contents and may add the complications of TREATMENT PRIOR TO DEATH AND POSTMORTEM TOXICOLOGIC FINDINGS 25 aspiration asphyxia or aspiration pneumonitis variety of complicating circumstances, any of of chemical or of infectious origin. In the which could be contributing factors in delayed treatment effort a variety of other drugs death. such as central nervous system and respiratory stimulants and pressor amines may be admin­ istered. Not only do these substances compli­ PHARMACODYNAMICS OF HOST­ cate interpretation of postmortem findings, SUBSTANCE RELATIONSHIPS but they may contribute to the lethality of the situation by adding the hazard of over­ Understanding the pharmacodynamics oc­ dose with these therapeutic agents. Other cm'ring with exposure to a toxic substance is possible complications that may occur during essential to interpretation of postmortem the treatment process include protracted findings. Figure 1 presents a schematic model hyperventilation; overcompensation of acid/ of the major ev~nts in absorption, redistribu­ base disturbances; dehydration and over­ tion, biotransformation, and excretion of· hydration in attempts at forced diuresis; toxic substances in the body. The substances obstruction of a main stem bronchus causing are absorbed through mucous membranes of collapse of the lung, arteriovenous shunting, the lung or the gastrointestinal tract i11to the and hypoxemia; and rupture of an emphyse­ systemic circulation. Water-soluble substances matous bleb with tension pneumothorax. may be excreted directly by the kidney. Monitoring of central venous pressure by way Lipid-soluble substances may be excreted by of a subclavian puncture has an attendant the liver through the bile. Gases may reenter hazard of hemothorax from the subclavian the lung and be exhaled, Lipid-soluble sub­ puncture. Also, retroperitoneal hemorrhage stances accumulate in fat depots from which secondary to extracorporeal dialysis has they are gradually released to be excreted or occurred. to be further metabolized, Within the various The investigation of treatment prior to tissues biotransformation may occur, resulting death and careful review of any clinical in a darivative which is less toxic or more records assist in the interpretation of post­ water soluble and more easily excreted by the mortem toxicologic findings. Treatment may kidney. In some instances, biotransformation permit a survival interval sufficient to remove may result in products that are as toxic or the originally involved substances from the more toxic than the original compound. body, may add one or more drugs not involved Quantitative data on blood levels of metha­ in the primary toxic episode, and may add a qualone and its metabolites, for example, sug-

FIGURE 1

PHARMACODYNAMICS OF HOST-SUBSTANCE RELA TIONSHIPS

Air Absorption Red istribution Blood Tissue GI contents

Exhaled Air Lung Excretion Bile Liver Biotra nsformation Urine Kidney l 233-583 0 -77 - 3 26 COMSTOCK gest, in the author's experience, that the de­ biotransformation. Tolerance to carbon mon­ gree of central nervous system depression oxide is not increased significantly by pre­ following acute overdose correlates better vious experience with the substance. The with the blood levels of a metabolite than it pathophysiology of carbon monoxide consists does with the blood concentration of metha­ of carboxyhemoglobin formation producing qualone. an oxygen transport deficiency tissue anoxia. Prior to death, all the processes illustrated When respiration ceases, no further change in in figure 1 are actively occurring. With the carboxyhemoglobin concentration occurs. advent of death, the arrest of circulation, and Continuous exposure of a healthy young the subsequent occurrence of tissue death, adult to an excess of carbon monoxide results these processes are arrested to yield the toxic­ in accumulation of carboxyhemoglobin to a ologic findings at postmortem examination. concentration in the order of 60 percent For interpretation of postmortem findings, saturation or higher. At these levels; cerebral the simplest situation prevails when there has anoxia results in respiratory arrest with no been a continuous excess of a toxic substance further change in carboxyhemoglobin concen­ available for absorption up until the moment tration. Postmortem examination reveals of death. The postmortem toxicologic exam­ carboxyhemoglobin concentrations in excess ination then reveals blood and tissue concen­ of 60 percent with no other toxicologic trations that were present at the time some findings. vital function was fatally impaired. Carbon monoxide exposure frequently in­ Once the toxic substance becomes limiting, duces nausea with subsequent vomiting. The the events diagramed in figure 1 no longer are presence of gastric contents in the respiratory driven by continuing absorption. When tract suggests aspiration asphyxia as a con­ absorption ceases, blood levels become a tributing factor to the hypoxia and death function of the rate of redistribution and might ensue with a carboxyhemoglobin con­ metabolism. When redistribution is controlled centration of 40-60 percent. primarily by physical factors such as storage Susceptibility to carbon monoxide-induced in lipid depots where the substance has no hypoxia is increased by the presence of any pharmacologic activity, the rapid decrease in defect in oxygen transport at the tissue level blood levels may have no relation to toxiCity. such as myocardial or cerebral arteriosclerosis. During this redistribution phase, the value of Such preexisting disease would increase the quantitative assessment of substances in the degree of impairment from any level uf carbo­ blood is substantially reduced. When non­ xyhemoglobin saturation and might result in a reversible toxic injUlY occurs in the presence postmortem finding of 30-60 percent carbo­ of a toxic substance that subsequently is xyhemoglobin concentration, depending upon removed from the body by continuing the severity of preexisting myocardial or metabolic processes, death may occur with no cerebral injury. detectable drug in the body. Had the decedent been a black with sickle It is important to determine whether the cell disease, then increased sensitivity to the processes in figure 1 were driven by a con­ effects of carbon monoxide would be antici­ tinuous excess of the toxic substance up until pated. The factors involved would be anemia the moment of death or whether the toxic with a decrease in total oxygen transport substance, for any reason, became limiting capability and the precipitation of sickling plior to the occurrence of death. with consequent microcapillary obstruction contributing to tissue anoxia. In all the above examples, continuous Carbon Monoxide excess of carbon monoxide until the time of Because of the simplicity of host-substance death was presumed. Had the site investiga­ interactions, carbon monoxide provides a use­ tion revealed the decedent had been removed ful example to explore principles discussed from exposure prior to death, then the phar­ above. Carbon monoxide is absorbed across macodynamics of excess substance no longer the respiratory mucosa and excreted across would prevail, and interpretation becomes the respiratory mucosa. There is no significant considerably more difficult. With removal TREATMENT PRIOR TO DEATH AND POSTMORTEM TOXICOLOGIC FINDINGS 27 from exposure to carbon monoxide, the Single doses of barbiturates may be expected blood would be in negative equilibrium with to achieve peak levels in the blood in approxi­ the environment with carbon monoxide being mately 2 hours. excreted v~a the lungs. The longer the survival After reaching the blood, a very small interval after removal from exposure, the fraction of the barbiturates is excreted by the lower will be the concentration of carbon kidney unchanged. The major proportion is monoxide found in the blood at postmortem redistributed to the tissues with a large share examination. Persisting spontaneous ventila­ going initially to lipid depots. Biotransfonna­ tion or provision of passive respiratory sup­ tion occurs primarily in the liver where the port with 100 percent oxygen could result in barbiturates are metabolized to inactive dissipation of all carbon monoxide from the de11vatives that are excreted by the lddney. body prior to the occurrence of death. In Quantitative determination of barbiturates such an instance, the postmortem toxicologic in the blood is of the greatest value when the examination might reveal carboxyhemoglobin barbiturates have been talmn in excess and concentrations down to zero. In contrast, a absorption has been continuous up until chain smoker whose death was due to trau­ death has occurred. With secobarbital, con­ matic injury could manifest 10 percent centrations in the order of 2-4 mg/IOO ml carboxyhemoglobin saturation, though car­ should be anticipated. Since death is due to bon monoxide played no role whatever as a anoxia secondary to respiratory depression, cause of death. the occurrence of respiratory compromise In the relatively simple example of carbon induced by vomiting and aspiration will result monoxide, it is shown that the substance may in death at slightly lower blood levels. Pre­ be present at postmortem toxicologic exami· existing disease such as hepatic cirrhosis with nation without any causative role. Where a reduction in the rate at which barbiturates are causative relation exists, the interpretation of metabolized to nontoxic derivatives will not postmortem findings may be influenced by significantly influence the quantitative rela­ the genetic pattern, by preexisting disease, by tionships in the blood so long as the dose interculTent complications, by postexposure administered was in large excess. Preexisting survival, and by treatment between exposure disease which reduces oxygen transport, such and death. as anemia, acute or chronic pUlmonary disease, and arteriosclerosis, will reduce the Barb itu rates blood level required to account for death. Acquired end-organ tolerance resulting from The barbiturates are selected as an example long-term excessive use of the barbiturates because they are commonly available, widely increases the blood level required to cause used drugs; they are encountered fraquently apnea. Acquired dispositional tolerance by in the toxicologic postmortem examination, way of hepatic microsomal enzyme induction and they illustrate most of the pharmaco­ does not influence the quantitative relation­ dynamic relationships illustrated in figure 1. ship between blood level and apnea. Con­ The primary lethal effect of the barbiturates ditions which change the rate of absol'ption of is anoxia as a result of respiratory alTest barbiturates from the gastrointestinal tract do following central nervous system depression. not alter the quantitative relationship between Phenobarbital is omitted from this discussion blood level and apnea but decrease the time because its pharmacodynamics are very differ­ necessary to achieve a fatal concentration. ent from the short- and intennediate-acting The absence of food, the presence of ade­ barbiturates. quate fluid volume in the gastrointestinal Barbiturates taken orally in excess so that tract, or the simultaneous ingestion of alco­ absorption is the rate-limiting factor result in hol, all increase the rate at which the barbitu­ coma in 1-6 hours depending upon the pres­ rates are absorbed. The simultaneous ingestion ence of food in the gastrointestinal tract. of other substances having sedative/hypnotic Simultaneous ingestion of alcohol facilitates properties decreases the blood level of bar­ absorption of the barbiturates because of the biturates required to induce apnea. AlcoilOi increased solubility of barbiturates in alcohol. ingested simultaneously increases the rate of 28 COMSTOCK absorption and decreases the blood levels re­ In order to be considered for titration, quired to induce apnea. patients must have a history of sedative drug When the dose of barbiturates is limit­ use consisting of a minimum daily average ing, or when absorption is interrupted by dose of three times the usual therapeutic emptying the stomach or the administration amount for a period of time exceeding 3 of activated charcoal, the survival may occur weeks. Pre-titration assessment includes a during an interval when the blood is not in complete medical and social history, a physi­ positive balance with respect to the barbitu­ cal examination, a psychiat~ic diagnostic rates in the gastrointestinal tract. Interpreta­ interview, clinical laboratory procedures, tion of quantitative blood levels of barbitu­ including a routine urine, CBC, SMA-12, rates is extremely difficult when the blood VDRL, and chest x-ray, and blood and urine concentration is decreasing. The concentra­ analyses for drugs. If there are no significant tion observed becomes a function of the rate medical findings, the patient is considered a of metabolism or rate of excretion. Abnor­ candidate for titration. malities of either may increase or decrease the The purpose of the titration is to achieve a ratc~ at which the barbiturate concentration in gradually increasing blood level of a sedative the blood is reduced. The ingestion of a single drug to reach the clinical manifestations con­ dose of 3,000 mg of secobarbital by a phar­ sistent with early intoxication. The titration macologically naive individual may result in protocol is discontinued when the patient coma for up to 48 hours or death. In contrast, manifests ataxia, slurred speech, drowsiness, ingestion of 3,000 mg of barbiturate by an and horizontal and vertical nystagmus. From individual who is a chronic heavy user of bar­ the beginning of the titration until the clinical biturates may induce coma for a period of end point is reached, an oral dose of sedative only 8-12 hours. The longer the period of drug is administered hourly with assessment coma, the greater is the influence of second­ and recording of vital signs and other clinical ary complications such as dehydration, aspira­ signs and symptoms before the administration tion pneumonia, and secondary infections. of each dose. Titration is initiated at 9 :00 a.m. Administration of medical care introduces If the patient is free of any signs or symptoms the possibility of complications secondary to of toxicity, the following dosage schedule is diagnostic and treatment procedures as out­ observed: In the first hour, two therapeutic lined above under the section Carbon Mon­ doses are administered. On the second and oxide. The toxicologic examination further is third hours, a single therapeutic dose is complicated by drugs used therapeutically administered. If the patient manifests no signs during the l?eriod of medical care. or symptoms of intoxication, on the fourth hour a dosage of two times the therapeutic dose is resumed and is continued each hour DETERMINATION OF TOLERANCE until the predetermined clinical manifesta­ TO SEDATIVE DRUGS tions are observed. Blood is drawn every 2 hours during the administration phase of titra­ Clinical and laboratory assessment of toler­ tion and each hour after the administration of ance to sedative drugs among chronic drug the last dose until the next dose of medication users has been possible in the Polydrug Abuse is required. Ordinarily this time interval is of Research and Treatment Program of the the order of 6-8 hours. A therapeutic dose of Institute of Clinical Toxicology in Houston, short-acting to intermediate-acting barbitu­ Texas. 2 Detoxification of potentially addicted rates is 100 mg, and a therapeutic dose of individuals requires determination of the methaqualone is 300 mg. dosage level of sedative drugs from which the Table 1 summarizes the data on total dose individual shoulLl be withdrawn. Tolerance is of sedative drug required to reach clinical end determined by a clinical titration technique. point with the administration of four com­ monly used sedative dmgs: secobarbital, Tuinal (a combination of equal parts of seco­ 2S\lpported by the National Institute on Drug barbital and amobarbital), amobarbital, and Abuse, grant #H81 DA 01466 01S1. methaqualone. Data on 18 patients titrated

L-~~~ ___~~_~ ______~ TREATMENT PRIOR TO DEATH AND POSTMORTEM TOXICOLOGIC FINDINGS 29

TABLE 1. Total dose of sedative drug required to reach mild toxicity by clinical signs and symptoms

DOSE OF BARBITURATES TOTAL DURING TITRATION (mg x 10-2 )

0 1>., A 0- 00 0 '"o I I !

0 0 0 0 0 0 0 0 0 0 o Secoborbital N-=18 8 0 8

0 o o Tuinal N=6

Amobarbital N= 3

.. :. I • • • Methaqualone N=20 • " " : o

DOSE OF METHAQUALONE TOT Al DURING TITRATION (mg X 10-2 )

with secobarblt;a[ reveal the minimum dose to qualone, secobarbital, Tuinal, and amobar­ reach toxicity to be 100 mg, and the maxi­ bital. These data reveal the variability in mum dose required to be 1,500 mg. Fifteen bloud level among patients who manifest of the 18 patients required 500-800 mg to similar degrees of clinical impairment. reach the clinical end point. Six patients were titrated with Tuinal. The data shown repre­ sent total combined barbiturate in mg, and CONCLUSIONS the range to reach toxicity was 600-2,000 mg. Three patients were titrated on amobarbital, The only unequivocal conclusion to be revealing a range of 700-1,400 mg. Twenty drawn from postmortem toxicology exami­ patients were titrated with methaqualone, nation is that the drugs identified are present revealing a range of 300-4,950 mg with 17 in the body. Toxicological data alone are not patients falling within the range of 900-3,000 sufficient to establish the cause of death. mg. The data from clini(;al titration, consider­ Drugs or other toxic substances present may ing the total amount of drug tolerated, have no etiologic significance. In contrast, a reveal that in a population with a history of fatal illness may be precipitated by a toxic chronic drug misuse, the amount of drug substance which has been cleared to below tolerated to reach a well-defined state of the limit of detection at the time death clinical intoxication varies in the order of occurs. The investigation required for inter­ tenfold. pretation of the toxicologic findings should The concentration of the drug in blood was include the following considerations: determined hourly after the patient reached 1. Was the toxic substance present in ex­ the clinical end point of toxicity. The highest cess so that the blood concentration was concentration of the administered drug increasing at the time of death? occurred ordinarily 2-3 hours after the last 2. If the toxic substance was not present dose. Table 2 displays the maximum concen­ in excess and the blood concentration was tration encountered with four drugs: Metha- decreasing at the time of death, what was the 80 COMSTOCK

TABLE 2. Peak blood levels found in chronic drug-using patients after titration to mild toxicity with the drug indicated. Clinical findings are ataxia, slurred speech, drowsiness, nystagmus.

DRUG CONCENTRATION (mg /100ml BLOOD) o

_Me ...... ,,' • 0 . .. M~thaqualone N= 30

... N= ...... • • ..o Secobarbital 21

Tuinal N= 7 total barbiturate

Amobarbital N= 3

duration of time between ma.,'(imum blood 8. Is the decedent pharmacologically naive concentration and the time that death oc­ 01' has there been long-term use of the sub­ curred? stanl~e(s) involved acutely or other substances 3. What secondary events occurred, such to which cross-tolerance might exist? as aspiration, which would compromise vital 9. Are the substances involved ones which function? induce end-organ or dispositional tolerance? 4. What disease conditions pre-existed 10. If first aid or other treatment was ad­ which could increase sensitivity to the effects ministered prior to death, what diagnostic and of the toxic substance? therapeutic procedures were performed, what 5. Were multiple substances identified, drugs were administered, and what complica­ and what was their relative contribution to tions might have these procedures or drugs the terminal event? induced? 6. What drugs 01' other toxic substances 11. What gem'tic factors exist that might was the decedent using or exposed to in his influence susceptibility to the toxic substance current everyday activities including occupa­ involved? tional exposure? 12. How comprehensive was the post­ 7. What chronic drug use or occupational mortem toxicology examination, and what exposure to toxic substances has the decedent substances or groups of substances might not sustained? have been detected?

------.