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Office of the Chief Medical Examiner, State of Maryland, 111 Penn Street, Baltimore, Maryland 21201. Abstract. Two cases are presented in which haloperidol ...
Journal of Analytical Toxicology, Vol. 15, September/October 1991

I Case Report

Two Fatalities Involving Haloperidol B a r r y S. L e v i n e , S z e - C h u n g W u , B r u c e A. G o l d b e r g e r , and Y a l e H. C a p l a n *

Office of the Chief Medical Examiner, State of Maryland, 111 Penn Street, Baltimore, Maryland 21201

Abstract Two cases are presented in which haloperidol was identified in postmortem toxicological analysis. One case was a suicidal overdose of the drug; the blood concentrations of haloperidol and reduced haloperidol were 1.9 and 1.4 mg/L, respectively9 Bile, liver, and urine concentrations were 3.4 mg/L, 44 mg/Kg and 69 mg/L for haloperidol and 1.6 mg/L, 43 mg/Kg, and 5.7 mg/L for reduced haloperidol, respectively. The second case was believed to be a natural cardiac death with a blood haloperidol concentration of 0.6 mg/L. The distribution of haloperidol and reduced haloperidol in this case was bile, 0.4 and 0.5 mg/L; kidney, 0.7 and 2.3 mg/Kg; liver, 5.0 and 13 mg/Kg; and urine, 0.4 and 2.3 mg/L.

Introduction

Haloperidol is a butyrophenone used in the treatment of psychotic disorders, Tourette's Syndrome, and behavioral problems in hyperactive children. Its mechanism of action, blocking dopamine receptors in the central nervous system, is similar to the phenothiazines. The toxic effects of the drug are related to this blockade. Extrapyramidal effects, such as rigidity, tremor, and akathisia are side effects observed with haloperidol usage. Tardive dyskinesia, characterized by involuntary movements of the face and extremities, is a late-appearing syndrome of haloperidol use. Peripheral side effects include dry mouth, constipation, faintness, and orthostatic hypotension (1). Haloperidol is extensively metabolized in humans, with less than 1% of an administered dose appearing in the urine as parent drug (2). One route of metabolism is the oxidative cleavage of the hydrocarbon chain, forming inactive fluorophenyl and piperidine metabolites (3). An additional metabolic pathway involves reduction of the keto group on the side chain to an alcohol, forming a compound known as reduced haloperidol. Reduced haloperidol has approximately 25% of the antipsychotic activity of the parent drug (4). The half-life of haloperidol after oral administration is about 18 hours (5,6). Numerous studies have been performed attempting to establish a therapeutic range for 9Author to whom requesls for repdnts or information should be addressed.

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haloperidol in plasma or blood; many of these studies were reviewed by Volavka and Cooper (7). Some studies failed to demonstrate a correlation between plasma concentration and effect, while other studies gave subranges between 5 and 50 ng/mL. The following two cases were presented to the Office of the Chief Medical Examiner, State of Maryland, where subsequent toxicological analysis revealed the presence of haloperidol. Limited data appear in the literature on tissue distribution of haloperidol in postmortem cases. Therefore, tissue distribution of haloperidol and reduced haloperidol in available specimens from two cases is provided.

Case Reports Case 1. A 35-year-old black male was found dead on the floor in a bedroom of a half-way house. Invesligation revealed a history of schizophrenia and alcohol abuse. A recent hospital admission following an attempted suicide by acetaminophen ingestion was reported by the half-way house staff. An empty container of a haloperidol prescription ( 120 tablets) filled the day before was found at the scene. Upon external examination, no signs of trauma or other injury were noted. Upon internal examination, findings included congested dark red-purple pulmonary parenchyma exuding moderate to ample amounts of blood and frothy fluid. Specimens including blood, vitreous humor, urine, liver, kidney, and stomach contents were submitted to the toxicology laboratory for comprehensive drug testing. Case 2. A 35-year-old white male was found dead in the backyard outside his home. Investigation revealed a history of depression and mild retardation. Medications noted included haloperidol, fluoxetine, and benztropine. In addition, the family reported that their son had complained of recent dizzy spells; however, he did not seek medical treatment and continued with his regular activities. Upon external examination, no signs of trauma or other injury were noted. Upon intemal examination, no abnormal findings were observed with the exception of the pulmonary parenchyma which was dark red-purple, exuding large amounts of blood and frothy fluid. Blood, vitreous humor, urine, liver, kidney and stomach contents were submitted to the Toxicology Laboratory for comprehensive drug testing.

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Journal of Analytical Toxicology, Vol. 15, September/October 1991

Experimental

Materials Haloperidol and reduced haloperidol were obtained from the R.W. Johnson Pharmaceutical Research Institute and 100-mg/L solutions as the free base in methanol were prepared. Ethylmorphine was donated by Merck and Co., and a 100-mg/L solution in methanol served as the internal standard for analysis. Sulfuric acid (H2SO4), sodium hydroxide (NaOH), ammonium hydroxide (NH4OH), and isopropanol were Baker ACS grade. Methylene chloride and n-butyl chloride were Burdick and Jackson high purity grade. Instrumentation Haloperidol and reduced haloperidol analyses were performed on a Hewlett-Packard 5880 gas chromatograph equipped with a nitrogen-phosphorus detector and a Hewlett-Packard 7673A automatic sampler. The column used was an HP-5 cross-linked 5% phenylmethylsilicone fused-silica capillary column (25 m x 0.32 mm i.d. x 0.174am film thickness). Helium was the carrier gas, flowing at 1 mL/min. The injector temperature was 250~ and the detector temperature was 310~ The oven temperature began at 100~ for 1 min, increased at 30~ to 200~ then increased at 10~ to 260~ and finally increased at 20~ to 300~ where it was held for 8 min. Splitless injection mode was utilized. The relative retention times of haloperidol and reduced haloperidol to the internal standard were 1.43 and 1.47, respectively. Confirmation of haloperidol and reduced haloperidol in each case was performed on a Hewlett Packard 5890A gas chromatograph interfaced to a Hewlett-Packard 5970 mass selective detector. Gas chromatographic conditions similar to that above were employed. Extraction To 5 mL standard, fluid, or tissue homogenate (l part tissue plus 4 parts water) were added 2 mL 0.1N NaOH, 100 pL internal standard solution, and 21 mL n-butyl chloride. After mechanical rotation and centrifugation, the n-butyl chloride layer was separated and extracted with 3 mL of 1N H2SO4. The acid layer was removed, alkalinized with 0.5 mL NHaOH and extracted with 5 mL methylene chloride. The methylene chloride was transferred to a conical centrifuge tube and 200 pL of isopropanol was added. The methylene chloride was evaporated to the isopropanol layer at 40~ and the isopropanol was transferred to an autosampler vial. The final isopropanol extract (2 !uL) was injected into the GC. Quantification was based on the area ratio of each compound to the internal standard in comparison to four fortified standards. Appropriate dilution of specimens with distilled water was performed to ensure quantification within the limits of the standard curve.

screen by GC-NPD; (3) an acid drug screen by GC-NPD; (4) color tests for salicylate, acetaminophen, and ethchlorvynol; and (5) morphine by radioimmunoassay. The results from each case are given in Table 1. Haloperidol and reduced haloperidol were identified by GC and confirmed by full scan electron impact GC/MS (Figure 1). There have been several reported fatalities resulting from haloperidol. Ketai et al. (8) reported the case of a woman treated in a hospital for psychotic behavior. She was administered 50 mg of haloperidol on Day 1 and 70 mg on Day 2 of hospitalization. Because she failed to respond to the treatment, the dose was increased to 140 mg over the next 12 hours. Mild toxic reactions were treated with benztropine. On the fourth day of hospitalization, she took 20 mg each hour for four hours and went to sleep. Two hours later, she became cyanotic, resuscitation efforts failed, and she died. The authors had no explanation for the death, but hypothesized a possible idiosyncratic response to haloperidol. No antemortem or postmortem blood concentrations of haloperidol were reported. Modestin etal. (9) also encountered a case of sudden death in a patient receiving a total of 230 mg of haloperidol over a two-day period. Heavy breathing, cyanosis, a distorted mouth, and an otherwise relaxed body were then observed. Resuscitation was unsuccessful and death ensued. A drug-induced laryngeal spasm leading to cardiac arrest via vagal reflexes was postulated as the mechanism of death in this case. Again, no blood or tissue concentrations of haloperidol were

Table I. Toxicology Results from Two Cases

Case No.

Drug

1

haloperidol reduced haloperidol verapamil verapamil metabotites

positive positive positive positive

1.9 1.4 0.5 N.Q.

haloperidol reduced haloperidol fluoxetine norfluoxetine benztropine

positive positive positive positive positive

0.6 N.D. 0.6 0.7 0.09

N.D.: none detected N.Q.: not quantified.

~(636)

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180

150

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19,238

200

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4B

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900

DATR:1217A28A.D

I 924

1

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250

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801 gO

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In accordance with the standard laboratory procedures, a comprehensive test for alcohol and drugs was performed. This included (1) a volatile screen for methanol, ethanol, acetone, and isopropanol by headspace gas chromatography; (2) a basic drug

Scan

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S

Results a n d D i s c u s s i o n

Heart blood concentration (mg/L)

Urine result

286

56

97

13~

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350

Figure 1. Mass spectrum of (A) haloperidoland (B) reduced halopeddol.

283

Journal of Analytical Toxicology, Vol. 15, September/October1991

provided. In another case of sudden death with therapeutic haloperidol usage (10), gross pulmonary edema unexplained by other pathophysiologic conditions was observed. As in the previous cases, no monitoring was performed. Case 1 is different than those previously reported deaths involving haloperidol. This was a known suicidal ingestion of the drug. The blood concentration of haloperido[ was at least an order of magnitude higher than the reported upper limits of the therapeutic range for haloperidol. The presence of verapamil was an incidental finding. Haloperidol intoxication was the cause of death. Case 2 is less clear and appears to be similar to the previously reported cases. Although the patient bad a history of depression, there was no evidence to suggest suicide. The blood haloperidol concentration is higher than the reported therapeutic range, but in two non-overdose fatalities, blood haloperidol concentrations of 1.2 and 0.2 mg/L were reported (11,12). The other drugs found in this case were present in therapeutic concentrations. Therefore, the medical examiner ruled that the death resulted from a cardiac arrhythmia, with the manner of death being natural. It was anticipated that the tissue distribution of haloperidol and reduced haloperidol might provide a means of differentiating overdose and natural deaths involving haloperidol. The fluid and tissue concentrations in the two cases are provided in Table II. The amount of haloperidol detected in liver in each case is approximately one order of magnitude higher than the blood concentration. In a previously reported death (11), a similar liver-toblood ratio of haloperidol was found. This distribution pattern is also similar to reported liver-to-blood ratios for chlorpromazine and thioridazine (13). From this limited data, it appears that the amount of haloperidol in blood or liver and not the liver to blood ratio would he the indicator of overdosage. In addition, the haloperidol to reduced haloperido] ratio suggests that Case 1

was likely an acute death because the ratio in blood was greater than l. Additional analytical data is needed to facilitate more complete interpretation of postmortem haloperidol and reduced haloperidol concentrations.

References 1.

2.

3.

4.

5.

6. 7.

8.

Table II. Distribution of Haloperidol (H) and Reduced Haloperidol (RH) in Two Cases 9.

Case 1 Specimen (units) Bile (mg/L) Blood (mg/L) Kidney (mg/Kg) Liver (mg/Kg) Stomach contents (total mg) Urine (rag/L) N D none detected NS: specimen not submitted.

284

Case 2

H

RH

H

RH

3.4 1.9 N.S. 44 67 6.6

1.6 1.4 N.S. 43 N.D. 5.7

0.4 0.6 0.7 5.0 5.0 0.4

0.5 ND. 2.3 13 N.D. 2.3

10.

11. 12.

13.

A. Gilman, L. Goodman, T. Rail, and F. Murad. The Pharmacological Basis of Therapeutics, 7th ed., MacMillan, New York, 1985, pp. 400-408. A. Forsman, G. Folsch, M Larrson, and R. Ohman. On the metabolism of haloperidol in man. Curr. Ther. Res. 21:606-16 (1977). E.R. Korpi, B.H. Phelps, H. Granger, W. Chang, M. Linnoila, J.L. Meek, and R.J. Wyatt. Simultaneous determination of haloperidol and its reduced metabolite in serum and plasma by isocratic liquid chromatography with electrochemical detection. Clin. Chem. 29:624-28 (1983). M. Hariharan, E.K. Kindt, T. VanNoord, and R. Tandon. An improved sensitive assay for simultaneous determination of plasma haloperidol and reduced hatoperidol levels by liquid chromatography using a coulometric detector. Ther. Drug Monit. 11: 701-707 (1989). Y.R Cheng, L.K. Paalzow, U. Bondesson, B. Ekblom, K. Eriksson, S.O. Eriksson, A. Lindberg, and L. Lindstrom, Pharmacokinetics of haloperidol in psychotic patients. Psychopharmacol. 91: 410-14 (1987). R.L. Kunka and J.M. Perel. Haloperidol pharmacokinetics in healthy volunteers. Cuff. Ther. Res. 45:1088-96 (1989). J. Vo[avka and T.B. Cooper. Review of haloperidol blood level and ctinical response: Looking through the window. J. C/in. Psychopharmacol. 7:25-30 (1987). R. Ketai, J. Matthews and J.J. Mozdzen, Jr. Sudden death in a patient taking haloperidol. Am. J. Psychiatry. 136:112-13 (1979). J. Modestin, R. Krapf, and W. Boker. A fatality during haloperidol treatment: Mechanism of sudden death. Am. J. Psychiatry 138: 1616-17 (1981). C.K. Mahutte, SK. Nakasato, and R.W. Light. Haloperidol and sudden death due to pulmonary edema. Arch. Intem. Med. 142: 1951-52 (1982). G.R. Johnson. High haloperidol concentrations in a traffic suicide. J. Forens. Sci. 33:823-25 (1988). E. Korpi, J. Kleinman, D. Costakos, M. Linnoila, and R. Wyatt. Reduced haloperidol in the post-mortem brains of haloperidoltreated patients. Psychiatry Res. 11:259-69 (1984). R.C. Baselt and R.H Cravey. Disposition of Toxic Drugs and Chemicals in Man, 3rd ed., Year Book Medical, Chicago, 1989, pp. 388-91.