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 psy-
chotic 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, con-
stipation, 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 piperi-
dine 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.
282 Reproduction (photocopying) of editorial content of this journal is prohibited without publisher's permission.
haloperidol in plasma or blood; many of these studies were re-
viewed 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. Lim-
ited 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 his-
tory of schizophrenia and alcohol abuse. A recent hospital ad-
mission following an attempted suicide by acetaminophen in-
gestion 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 ex-
amination, findings included congested dark red-purple pul-
monary parenchyma exuding moderate to ample amounts of
blood and frothy fluid. Specimens including blood, vitreous
humor, urine, liver, kidney, and stomach contents were sub-
mitted to the toxicology laboratory for comprehensive drug
testing.
Case 2. A 35-year-old white male was found dead in the back-
yard outside his home. Investigation revealed a history of de-
pression 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 pul-
monary 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 Toxi-
cology Laboratory for comprehensive drug testing.
Journal of Analytical Toxicology, Vol. 15, September/October 1991

Experimental
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
Materials are given in Table 1. Haloperidol and reduced haloperidol were
Haloperidol and reduced haloperidol were obtained from the identified by GC and confirmed by full scan electron impact
R.W. Johnson Pharmaceutical Research Institute and 100-mg/L GC/MS (Figure 1).
solutions as the free base in methanol were prepared. Ethylmor- There have been several reported fatalities resulting from
phine was donated by Merck and Co., and a 100-mg/L solution haloperidol. Ketai et al. (8) reported the case of a woman treated
in methanol served as the internal standard for analysis. Sulfuric in a hospital for psychotic behavior. She was administered 50 mg
acid (H2SO4), sodium hydroxide (NaOH), ammonium hydroxide of haloperidol on Day 1 and 70 mg on Day 2 of hospitalization.
(NH4OH), and isopropanol were Baker ACS grade. Methylene Because she failed to respond to the treatment, the dose was in-
chloride and n-butyl chloride were Burdick and Jackson high creased to 140 mg over the next 12 hours. Mild toxic reactions
purity grade. were treated with benztropine. On the fourth day of hospitaliza-
tion, she took 20 mg each hour for four hours and went to sleep.
Instrumentation Two hours later, she became cyanotic, resuscitation efforts failed,
Haloperidol and reduced haloperidol analyses were performed and she died. The authors had no explanation for the death, but
on a Hewlett-Packard 5880 gas chromatograph equipped with a hypothesized a possible idiosyncratic response to haloperidol. No
nitrogen-phosphorus detector and a Hewlett-Packard 7673A antemortem or postmortem blood concentrations of haloperidol
automatic sampler. The column used was an HP-5 cross-linked were reported. Modestin etal. (9) also encountered a case of
5% phenylmethylsilicone fused-silica capillary column (25 m x sudden death in a patient receiving a total of 230 mg of halo-
0.32 mm i.d. x 0.174am film thickness). Helium was the carrier peridol over a two-day period. Heavy breathing, cyanosis, a dis-
gas, flowing at 1 mL/min. The injector temperature was 250~ torted mouth, and an otherwise relaxed body were then ob-
and the detector temperature was 310~ The oven temperature served. Resuscitation was unsuccessful and death ensued. A
began at 100~ for 1 min, increased at 30~ to 200~ then in- drug-induced laryngeal spasm leading to cardiac arrest via vagal
creased at 10~ to 260~ and finally increased at 20~ to reflexes was postulated as the mechanism of death in this case.
300~ where it was held for 8 min. Splitless injection mode was Again, no blood or tissue concentrations of haloperidol were
utilized. The relative retention times of haloperidol and reduced
haloperidol to the internal standard were 1.43 and 1.47, respec- Table I. Toxicology Results from Two Cases
tively.
Confirmation of haloperidol and reduced haloperidol in each Heart blood
case was performed on a Hewlett Packard 5890A gas chro- Urine concentration
matograph interfaced to a Hewlett-Packard 5970 mass selective Case No. Drug result (mg/L)
detector. Gas chromatographic conditions similar to that above 1 haloperidol positive 1.9
were employed. reduced haloperidol positive 1.4
verapamil positive 0.5
Extraction verapamil metabotites positive N.Q.
To 5 mL standard, fluid, or tissue homogenate (l part tissue
plus 4 parts water) were added 2 mL 0.1N NaOH, 100 pL in- haloperidol positive 0.6
reduced haloperidol positive N.D.
ternal standard solution, and 21 mL n-butyl chloride. After
fluoxetine positive 0.6
mechanical rotation and centrifugation, the n-butyl chloride layer norfluoxetine positive 0.7
was separated and extracted with 3 mL of 1N H2SO4. The acid benztropine positive 0.09
layer was removed, alkalinized with 0.5 mL NHaOH and ex-
N.D.: none detected
tracted with 5 mL methylene chloride. The methylene chloride N.Q.: not quantified.
was transferred to a conical centrifuge tube and 200 pL of iso-
propanol was added. The methylene chloride was evaporated to
the isopropanol layer at 40~ and the isopropanol was trans- ~(636) Scan 12,739 rain. o# DATA:]217A2OA.D

ferred 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 Ge-t "-.. 206
four fortified standards. Appropriate dilution of specimens with
~c 20" 281 // \
distilled water was performed to ensure quantification within the
limits of the standard curve. 50 180 150 200 250 900 358
M&s~/Charge
s(667) s 19,238 mln. Of DATR:1217A28A.D
S 1007R[DUCEDHALOPERIDOL [',.
~ 801 I 924
gO
Results a n d D i s c u s s i o n ~c
~
Ja
4B 1
~ 56 97 13~
286
"\ iJ 349 377
a~ / ~ /~ i U 2oi ". ,J
In accordance with the standard laboratory procedures, a com- oh_,L .... l,Z ,. ,,-,, . . . . L ILL I, . . . / "~ ,k
50 1OO 150 200 250 300 350
prehensive test for alcohol and drugs was performed. This in- Ha~/Charge
cluded (1) a volatile screen for methanol, ethanol, acetone, and Figure 1. Mass spectrum of (A) haloperidoland (B) reduced halopeddol.
isopropanol by headspace gas chromatography; (2) a basic drug

283
 Journal of Analytical Toxicology, Vol. 15, September/October1991

provided. In another case of sudden death with therapeutic was likely an acute death because the ratio in blood was greater
haloperidol usage (10), gross pulmonary edema unexplained by than l. Additional analytical data is needed to facilitate more
other pathophysiologic conditions was observed. As in the pre- complete interpretation of postmortem haloperidol and reduced
vious cases, no monitoring was performed. haloperidol concentrations.
Case 1 is different than those previously reported deaths in-
volving 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 References
was an incidental finding. Haloperidol intoxication was the cause
of death. Case 2 is less clear and appears to be similar to the pre- 1. A. Gilman, L. Goodman, T. Rail, and F. Murad. The Pharmaco-
viously reported cases. Although the patient bad a history of logical Basis of Therapeutics, 7th ed., MacMillan, New York,
1985, pp. 400-408.
depression, there was no evidence to suggest suicide. The blood
2. A. Forsman, G. Folsch, M Larrson, and R. Ohman. On the
haloperidol concentration is higher than the reported therapeutic
metabolism of haloperidol in man. Curr. Ther. Res. 21:606-16
range, but in two non-overdose fatalities, blood haloperidol con-
(1977).
centrations of 1.2 and 0.2 mg/L were reported (11,12). The other 3. E.R. Korpi, B.H. Phelps, H. Granger, W. Chang, M. Linnoila, J.L.
drugs found in this case were present in therapeutic concentra- Meek, and R.J. Wyatt. Simultaneous determination of haloperidol
tions. Therefore, the medical examiner ruled that the death re- and its reduced metabolite in serum and plasma by isocratic
sulted from a cardiac arrhythmia, with the manner of death being liquid chromatography with electrochemical detection. Clin.
natural. Chem. 29:624-28 (1983).
It was anticipated that the tissue distribution of haloperidol and 4. M. Hariharan, E.K. Kindt, T. VanNoord, and R. Tandon. An im-
reduced haloperidol might provide a means of differentiating proved sensitive assay for simultaneous determination of plasma
overdose and natural deaths involving haloperidol. The fluid haloperidol and reduced hatoperidol levels by liquid chromatog-
and tissue concentrations in the two cases are provided in Table raphy using a coulometric detector. Ther. Drug Monit. 11:
II. The amount of haloperidol detected in liver in each case is ap- 701-707 (1989).
proximately one order of magnitude higher than the blood con- 5. Y.R Cheng, L.K. Paalzow, U. Bondesson, B. Ekblom, K. Eriksson,
S.O. Eriksson, A. Lindberg, and L. Lindstrom, Pharmacokinetics
centration. In a previously reported death (11), a similar liver-to-
of haloperidol in psychotic patients. Psychopharmacol. 91:
blood ratio of haloperidol was found. This distribution pattern is
410-14 (1987).
also similar to reported liver-to-blood ratios for chlorpromazine
6. R.L. Kunka and J.M. Perel. Haloperidol pharmacokinetics in
and thioridazine (13). From this limited data, it appears that the healthy volunteers. Cuff. Ther. Res. 45:1088-96 (1989).
amount of haloperidol in blood or liver and not the liver to blood 7. J. Vo[avka and T.B. Cooper. Review of haloperidol blood level and
ratio would he the indicator of overdosage. In addition, the ctinical response: Looking through the window. J. C/in. Psy-
haloperidol to reduced haloperido] ratio suggests that Case 1 chopharmacol. 7:25-30 (1987).
8. R. Ketai, J. Matthews and J.J. Mozdzen, Jr. Sudden death in a
Table II. Distribution of Haloperidol (H) and Reduced patient taking haloperidol. Am. J. Psychiatry. 136:112-13
Haloperidol (RH) in Two Cases (1979).
9. J. Modestin, R. Krapf, and W. Boker. A fatality during haloperidol
Case 1 Case 2 treatment: Mechanism of sudden death. Am. J. Psychiatry 138:
1616-17 (1981).
Specimen (units) H RH H RH 10. C.K. Mahutte, SK. Nakasato, and R.W. Light. Haloperidol and
sudden death due to pulmonary edema. Arch. Intem. Med. 142:
Bile (mg/L) 3.4 1.6 0.4 0.5 1951-52 (1982).
Blood (mg/L) 1.9 1.4 0.6 ND. 11. G.R. Johnson. High haloperidol concentrations in a traffic suicide.
Kidney (mg/Kg) N.S. N.S. 0.7 2.3 J. Forens. Sci. 33:823-25 (1988).
Liver (mg/Kg) 44 43 5.0 13 12. E. Korpi, J. Kleinman, D. Costakos, M. Linnoila, and R. Wyatt.
Stomach contents (total mg) 67 N.D. 5.0 N.D. Reduced haloperidol in the post-mortem brains of haloperidol-
Urine (rag/L) 6.6 5.7 0.4 2.3 treated patients. Psychiatry Res. 11:259-69 (1984).
13. R.C. Baselt and R.H Cravey. Disposition of Toxic Drugs and
N D none detected
NS: specimen not submitted. Chemicals in Man, 3rd ed., Year Book Medical, Chicago, 1989,
pp. 388-91.

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