Blood and Tissue Concentrations of Drugs Associated with Fatalities

Symposium on Individualization of Drug Therapy

Blood and Tissue Concentrations of Drugs Associated with Fatalities MD., F.A.C.P.* Nelson S. Irey, M.D.,

The drug explosion of the past few decades has produced a large number of new drugs and chemical agents. The nonmedical use of these many substances in our modern "drug culture," produced not only by legitimate drug manufacturers but also by clandestine manufacture of legal drugs and the adulteration of legal and illegal drugs at street level, has complicated the investigation of drug overdose deaths. Now, more than ever, the clinician, the pathologist, and the toxicologist are called upon to interpret the significance of reported levels of drugs in body fluids and tissues. The purpose of this discussion is to present the findings in a series of 300 deaths from drug overdose: selected demographic features, toxicologic highlights, and a few cases chosen to emphasize some of the problems in analyzing and in validating the relationship between the drug and death. This experience of course is not necessarily representative of the overall picture in the country at large. Two thirds of the 300 cases were in the suicidal category; the maleto-female ratio was one-to-one in the suicidal group, but the males dominated three-to-one in the accidental deaths. The route of administration was mainly oral, only 15 per cent being by way of the needle and syringe. As to the age distribution, there were two peaks in the accidental deaths, the first being in the first decade. The second peak occurred in the third decade, corresponding with the solitary peak for the suicidal group. In this series of 300 cases, there was a total of 45 drugs and agents related to the deaths. However, seven of these drugs accounted for about half the fatalities, and most of our discussion will focus on this group (Table 1). "Chief, ':'Chief, Registry of Tissue Reactions to Drugs, Armed Forces Institute of Pathology, Washington, D.C. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army, the Department of Defense, or the sponsoring agency. The Registry of Tissue Reactions to Drugs is sponsored in part by the Food and Drug Administration (under contract FDA 67-53) and is under the auspices of Universities Associated for Research and Education in Pathology.

Vol. 58, No. 5, September 1974 Medical Clinics of North America- Vo!.

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Table 1.

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Overdose Deaths: Specific Drugs CASES

Barbiturates Morphine Propoxyphene Salicylates Methadone Chloroquine Glutethimide Total

28 28 27 18 17 15 14 147

As in the distant past, the barbiturates lead the list. As to categories, the analgesics and the sedatives are the most frequently related to overdose deaths (Table 2). For an overall picture of the comparative blood levels, Table 3 gives the mean levels. Note that the salicylate levels are the highest, that lethal levels of morphine and methadone are extremely low, and that the remaining four drugs lie between these extremes. Table 4 repeats the mean blood levels, but also includes the visceral levels (liver, kidney, and brain) and, in the column on the far right, the bile levels. There are several things to note in this table: 1. With the exception of the salicylates, the blood levels are all lower than those found in the liver and kidney, and the liver is the site of the highest levels. 2. There is a consistent drop in levels in going from the liver to the kidney to the brain (except for glutethimide, where the levels in the kidney and the brain are essentially equal). 3. The bile levels are conspicuously higher than those found in other sites in the morphine and methadone group, and to a lesser degree this is also true for propoxyphene and the barbiturates. Table 5 illustrates the wide range in lethal levels of these drugs. The middle column repeats the mean levels seen in Table 4; the left-hand columns list the minimum and maximum lethal figures; and the right-hand column the ratio of the low to the high levels. The greatest range is seen with glutethimide; there are large ranges with the barbiturates, methadone, and morphine, and the smallest range is seen in the salicylates. Table 2.

Overdose Deaths: Categories of Drugs CASES

Analgesics Sedatives Narcotics Antimalarials Total

62

42 28 15 147

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BLOOD AND TISSUE CONCENTRATIONS OF DRUGS WITH FATALITIES

Table 3.

Overdose Deaths: Mean Lethal Blood Levels (mg/100 ml) Salicylates Barbiturates Chloroquine Glutethimide Propoxyphene Morphine Methadone

Table 4. BLOOD

Barbiturates (28 cases) Chloroquine (15 cases) Glutethimide (14 cases) Propoxyphene (27 cases) Methadone (17 cases) Morphine (28 cases) Salicylates (18 cases)

81.2 8l.2 4.7 4.7 3.1 1.1 l.1 0.09 0.08

Drug Distribution-Blood and Viscera (Mean Levels, mg/100 ml) LIVER

KIDNEY

BRAIN

BILE

4.7

20.4

7.8

4.7

4.7

30.8

20.6

2.0

3.1

8.3

2.3

2.4

1.1

9.5

2.8

2.0

7.5

0.08

0.62

0.49

0.37

0.87

0.09

0.32

0.26

0.09

3.2

81.2

Table 5.

43.6

37.4

13.1

(mg/l 00 ml) Range of Lethal Levels (mg/100 BLOOD LEVEL (RANGE)

Barbiturates Chloroquine Glutethimide Propoxyphene Methadone Morphine Salicylates

3.25

0.7-15.7 1.1-10.3 0.19-7.7 0.3-2.0 0.02-0.45 0.01-0.2 54.5-138.0

RATIO MEAN

4.7 4.7 3.1 1.1 l.1 0.08 0.09 81.2

(LOW/HIGH)

1:22 1:9 1:40 1:6 1:22 1:20 1/2 1 :2 :2'/2

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This demonstrated latitude in the lethal range values takes us into a major area of this discussion: an analysis of the reasons for this extreme variability in levels from case to case in relation to the same drug. The higher blood and tissue levels are no doubt related to the fact that anyone person may take enough drug to kill five or ten persons. It is with the lower levels that we are mainly concerned. The first reason for low levels is that the case may actually not be a drug death, and that the presence of the drug is coincidental only. A few specific cases will illustrate this point: The first case, illustrating the part concomitant disease may play, is that of a young black male who ingested propoxyphene with suicidal intent. The hypoxia from his comatose state required the use of an intratracheal tube and a respirator. He died in a few hours. Autopsy revealed the presence of sickled red blood cells in the visceral vessels, including the brain. Noted also were the perifollicular hemorrhages in the spleen, considered to be almost pathognomonic for the presence of a sickle cell crisis. Toxicologic analysis revealed a level of propoxyphene of 1.5 mg per cent in his liver. This level is only one sixth the mean level found in 18 validated cases of propoxyphene deaths. Without the autopsy findings, this case might have been included in a series of propoxyphene deaths, with the resultant inclusion of a non-pure drug death, and would have meant falsely lowering the mean level in such a series, and resulted in an invalid minimum lethal level. A second case, also one with a concomitant basic disease, is that of a young addict found dead in bed. Propoxyphene levels were determined. Was this a drug death? Autopsy revealed severe coronary artery disease, associated with thrombosis. The propoxyphene levels in the liver and kidney in this case were only one twenty-fifth and one seventh, respectively, of the levels found in the 18 validated cases of propoxyphene overdose deaths. Again, the autopsy demonstrated an anatomic cause of death, and the presence of the drug was considered to be coincidental. The third case illustrating a non-pure drug death is that of a middleaged white male who attempted suicide with glutethimide. Prior to death a tracheostomy was performed. Autopsy revealed air embolism in the heart and in the pulmonary and cerebral circulations (probably introduced during the tracheostomy). Again, the drug levels were considerably below the mean levels in the blood, liver, and kidney, being only one third, one third, and one half, respectively, of the levels found in nine validated cases of glutethimide deaths. A fourth case pointing up the need for broadening the data base to include morphologic findings in the interpretation of alleged drug deaths is that of a 17 year old drug addict who died while using methamphetamine. Autopsy showed intracerebral and intraventricular hemorrhages. His blood level was only one fortieth the lethal level as cited by Winek. 66 In this case, it is thought that the drug induced a hypertensive state, with the consequent cerebrovascular accident. No doubt the drug caused the death, but it was not a pure toxicity death, but related to a side reaction of the drug, and the figures on this case do not belong in a listing of lethal levels that might be used as a reference point for practicing clinicians and pathologists.

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BLOOD AND TISSUE CONCENTRATIONS OF DRUGS WITH FATALITIES

Another circumstance under which unusually low drug levels might be found is that related to the existence of a drug combination that has not been brought to light. In this day of polypharmacy, this should not be unexpected. It has long been known that alcohol and barbiturates, and that alcohol and chloral hydrate, can cause death in these combinations, with levels of these drugs (when in combination) being below their individual lethal levels. In the Drug Registry we have a number of cases of pure propoxyphene and pure meprobamate deaths, and we also have a group of cases in which these drugs have been in combination with ethyl alcohol, as shown in Table 6. The point of these data is that it takes considerably less of these drugs to kill if alcohol is also present. The ethanol level in the propoxyphene cases averaged 125 mg/lOO ml; in the meprobamate cases mg/ 1 00 m!. ml. Parenthetically, the lethal level of alcohol alone it was only 85 mg/lOO is usually above 400 mg/lOO m!. ml. It is evident that death occurred in these cases in the face of sublethal levels of the individual agents. Another example of the need for keeping in mind the presence of more than the initially suspected drug is that of a child hospitalized for acute salicylism. The history mentioned the use of ipecac for emesis. It was found that she had received both the syrup (10 ml) and later the fluid extract (also 10 ml). Since the adult dose of the fluid extract is 0.5 to 1.0 ml, this child received 10 to 20 times the adult dose on top of an already existing salicylate toxicity, and the case was signed out as that of a combined salicylate-ipecac toxicity. The previous examples have been cited to illustrate the need for including the clinical, toxicologic, and morphologic findings in drugrelated cases in order to separate the pure drug deaths from those complicated by a variety of other factors. Most of these illustrations emphasized the need for inclusion of the autopsy findings. On the other side of the coin, the next case points out the need for including toxicologic information, which is really a variation of the same theme: the need for integration of information from as many sources as possible in evaluating drug-related cases. As an illustration, a young soldier in Vietnam was brought to a medical facility in extreme dyspnea. While he could still talk, he claimed hypersensitivity to chloroquine, and said that he had taken one tablet of Table 6. Comparison of Mean Levels of Propoxyphene and Meprobamate in 46 Cases of Death from Single and Multiple Drugs mg/lOO ml or gm) (Level in mg/100 BLOOD

Propoxyphene Propoxyphene (+ ethanol) Meprobamate Meprobamate (+ ethanol)

1.0 0.78 25.5 8.5

KIDNEY

BRAIN

10.3 4.9

2.3 1.6

2.3 l.3 1.3

45.6 19.3

97.0 14.7

33.5 6.8

LIVER

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Table 7.

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Chloroquine Toxicity (mg/100 ml) Blood Brain Kidney Liver Lung

6.5 2.5 24.0 23.0 23.0

Gastric contents: 12.5 mg in total sample 240 ml

chloroquine~ chloroquine. Autopsy

revealed pulmonary edema and congestion. These nonspecific findings, plus generalized visceral congestion, are the usual morphologic findings in pure drug deaths. With the available history and the nondistinctive morphologic findings, this case was consistent with that of a hypersensitivity reaction. Fortunately, however, the autopsy prosecutor had submitted blood and visceral samples for toxicologic examination, with the findings as listed in Table 7. The quantities of chloroquine as listed here could not have been derived from only one chloroquine tablet, and are within lethal ranges as reported elsewhere. The case was ultimately signed out as one of chloroquine toxicity, and not as a chloroquine hypersensitivity. To return now to our earlier problem of accounting for the large range in lethal levels, the preceding cases have illustrated how very low levels could be invalidly related to death if autopsy information had not been included. Elimination of the previously described cases that were not pure drug toxicity cases, however, does not eliminate the rather wide variation in lethal levels that are found in the validated group of presumably pure drug-overdose cases. There are a number of reasons for this latitude, and some of them are listed in Table 8. As to the age factor, incomplete or undeveloped enzyme systems in the young may account for variations in blood and tissue levels and for the drug effects and consequences. Sex predisposes to variability in drug response, as illustrated by the relatively high incidence in females of blood dyscrasias related to amidopyrine, phenylbutazone, and chloramphenicol. chloramphenicoL As previously pointed out, variations in blood and tissue levels on the high side are related to the massive doses that some individuals may take. Table 8. Variations in Drug Levels in Overdose Deaths 1. 2. 3. 4. 5. 6. 7. 8.

Age Sex Amount of drug taken Drug combinations Presence of disease states Hypersensitivity to drug(s) or diluent(s) Incomplete toxicologic examination Laboratory error

BLOOD AND TISSUE CONCENTRATIONS OF DRUGS WITH FATALITIES

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Drug combinations have already been mentioned. Disease states include a number of abnormalities discussed elsewhere in this volume: pharmacogenetic, idiosyncratic, and pharmacokinetic factors, and enzyme induction and inhibition that produce unusual reactive states with associated variations from the usual in blood and tissue levels. Included also are concurrent liver and kidney diseases. Another reason for inordinately low levels of drugs may be that the mechanism of death was not toxicity, but was related to a hypersensitivity state, either to the major drug involved, or to its excipient or diluent. Also to be mentioned in the differential diagnosis at this point is the cardiotoxicity that may exist to certain diluents. Quinine, for example, which is used as a filler in certain street drug formulations, has been found experimentally in rats to cause bradycardia and asystole. In addition to failure to pick up more than one drug (in multiple deaths), another type of incomplete toxicologic examination is the failure to identify a poison such as cyanide or strychnine that has been purposely and secretly included in the drug formulation, as has been done at times for homicidal purposes. Lastly, among the reasons for extremes of drug levels, we must mention laboratory error, including mislabeling of specimens and faulty pro~ cedural techniques. It is evident from the discussion to this point that the lower drug levels in alleged drug deaths may include non-pure drug fatalities unless careful validation is carried out, and that after careful validation is accomplished there still remains a wide latitude in lethal levels for many drugs - as much as a 1 :40 ratio of minimum to maximum (as in the case of glutethimide). It is interesting to note, however, that this range is of the same magnitude as described by Dr. Koch-Weser with regard to variations in dosage of guanethidine that were necessary to achieve a satisfactory control of hypertension cases, and by Dr. Atkinson in his article on therapy with Dilantin, in which the same dosage of this agent had a variation of 11::50 50 in achieved blood levels in a group of patients he studied. This similarity of minimum-maximum latitude or range should not be too surprising, though, since whether we are dealing with therapeutic regimens in the living or with lethal levels in the dead, the same fundamental processes are involved: pharmacogenetics, pharmacokinetics, individual idiosyncrasies, and enzyme induction and inhibition-all of which are mechanisms and factors that result in wide variations in drug effects and levels from person to person. Some of the complications of drug abuse are listed in Table 9. We have not seen examples to date of the first five listed complications in our series of cases. Bronchopneumonia is not unusual in those .who who survive for a time with aggressive therapeutic measures. Necrotizing angiitis indistinguishable from periarteritis nodosa was described several years ago by Citron and associates. Also included is the complication of renal failure, which was noted in 15 per cent of one reported series of drug overdose deaths, this renal failure being related to renal shutdown secondary to shock and hypoxia after the central depression by the drug.

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Table 9.

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Complications of Narcotism 1. 2. 3. 4. 5. 6. 7. 8. 9.

Hepatitis Malaria Endocarditis Transverse myelitis Tetanus Bronchopneumonia Cor pulmonale Necrotizing angiitis Renal failure

Another vascular complication is the development of multiple angiothromboses. These were associated with cor pulmonale in a young addict who died with an overdose of methadone. Similar birefringent material was found in the antecubital fossa, along with venous thrombosis of the basilic vein. Similar foreign body materials (from diluent material such as talc or starch) are not infrequently found in the liver and lungs of addicts. It is not surprising that some of the inflammatory and infectious complications should occur under the conditions in which street drugs are produced. It is also not surprising that there should be chemical contamination and mislabeling of street drugs. As an illustration of street-drug mislabeling, by laboratory analysis seven samples of street drugs that were sold with the label of "barbiturates" actually consisted of the following compounds: Methapyrilene, protein product, amphetamine, quinine, Fiorinal, caffeine, and Dilantin. , We have discussed the findings in a series of drug-overdose cases, with particular emphasis on body fluid and tissue levels, and have pointed out some of the reasons for the wide range in lethal levels that occur in drug deaths. Table 10 summarizes the causes of death in drug-related cases, going beyond the pure toxicity deaths. On the first point, while the term drug drug as it appears in item 1 is in the singular, it is important to keep in mind that illicit street drug formulations are frequently multiple, and that the problem may be one of combined drugs. This multiplicity is not, of course, limited to street drug combinations, but also includes legitimate circumstances. On the second point, death may be associated with low levels because of a hypersensitivity or idiosyncratic reaction. These may be related not Table 10. 1. Direct toxicity of the drug 2. Hypersensitivity reaction a. Drug of abuse b. Cutting agent c. Contaminants 3. Poisons 4. Contributory accidents

BLOOD AND TISSUE CONCENTRATIONS OF DRUGS WITH FATALITIES

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only to the major drug, but also with substances used to dilute or cut the drug, as listed under subitems band c. Hidden poisons such as cyanide or strychnine should also be kept in mind, as listed under item 3. As indicated in item 4, the immediate cause of death may be a consequence of poor judgment and/or incoordination while under the influence of sublethal levels of drugs. Complete examination toxicologically should include the following body tissues: subcutaneous tissue, vessel of injection, liver, kidney, lung, brain, and muscle and fat. Body fluids for examination should include the following: blood, urine, bile, gastric contents, intestinal contents, and nasal secretions. As previously demonstrated, the highest levels are to be found in the liver and bile, and samples from these sites particularly should be taken. Multiple samples for distribution studies are also important to avoid complete dependence on one specimen, since its container might be broken or lost, or the fluid spilled inadvertently. Also, adequate distribution studies may have important medicolegal inferences. The importance of an adequate and broad-based toxicologic examination is stressed, particularly in this day of polypharmacy, in order to avoid missing the drug combinations that are so common. So in the toxicologic drug search one must not be limited by the leads given in the history or by the circumstances surrounding the case, or even by the labels on the drug containers at the scene. An adequate toxicologic laboratory should be able to assist in this search by accomplishing a screening of the material submitted. Such a screening would encompass something over 100 of the more commonly used and available drugs and agents, under the seven categories as listed in Table 11. A few examples of these categories are included in the parentheses. In summary, adequate analysis of drug overdose cases is a multifactorial problem, and valid diagnoses can be made only if there is a broad information base, which must include an adequate knowledge of the history and the circumstances surrounding the case, an adequately broad toxicologic examination, and a complete autopsy. And finally, in line with the theme of this symposium, it is evident from the findings and analyses in this series of drug overdose deaths that there is considerable individualization in these fatalities as to their toxicologic findings, and the wide range in their fatal levels is a resultant of multiple factors and variables which may be active in the individual case.

Table 11. 1. 2. 3. 4. 5. 6. 7.

Toxicologic Screening

Gases (HCN, CO) Volatiles (CN, phenols, benzene) Acidic compounds (barbiturates, (barbiturates. salicylates) Basic compounds (alkaloids, tranquilizers) Metals and metalloids (Pb, Hg, As) Corrosives (strong acids and bases) Inorganic nonmetallic compounds (halides, borates)

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REFERENCES 1. Curry, A.: Poison Detection in Human Organs, 2nd ed. Springfield, Ill., Charles C Thomas, 1969. 16: 1992. Froede, R. C., and Stahl, C. J.: Fetal narcotism in military personnel. J. Forens. Sci., 16:199218, 1971. 3. Hennigar, G. R.: Drug and chemical injury. In Anderson's Pathology, 6th ed. St. Louis, C. V. Mosby Co., 1971. 4. Martin, E. W.: Hazards of Medication. Philadelphia, J. B. Lippincott Co., 1971. 5. Rehling, C. J.: Poison residues in human tissues. In Stolman, A. (ed.): Progress in Chemical Toxicology, Volume 3. New York, Academic Press, 1967. 6. Winek, C. L.: Drug and chemical blood levels. In Wecht, C. H. (ed.): Legal Medicine Annual. New York, Appleton-Century-Crofts, 1971. Armed Forces Institute of Pathology Washington, D.e. D.C. 20306