TOXICOLOGY AND APPLIED PHARMACOLOGY 6, 316-320 (1964)
 
 

        Paraldehyde was introduced into medical practice about eighty years ago. Its rapid action and relative safety frequently made it the drug of choice in combating acute excitement, insomnia, delirium, or convulsions. It is still used for these purposes. A search of the literature reveals a few reports on the toxicity of paraldehyde in human but no reference to its action in the presence of alcohol (Burnstein, 1943; Kotz et al., 1938; MacIntosh, 1939; Shor, 1941). Weatherby and Clements (1960) studied the effects of combinations of the two drugs in mice.

        Paraldehyde alone may produce death when the oral dose exceeds 120 ml but the developing depression (coma) usually precedes death by approximately 12 or more hours (see cases 11 and 12 below). Paraldehyde is similar to alcohol in its pharmacologic behavior, but it is a more powerful sedative. Toxic doses of either depress the respiratory center. It is generally agreed that under most conditions paraldehyde is a relatively innocuous drug, and it has been called one of the safest of the hypnotics. Because of the supposed wide margin of safety of this drug, it may be subject to abuse. The usual oral therapeutic dose for sedation as suggested by the U.S. Pharmacopeia is 8 ml, but in practice this dose is often exceeded, sometimes to 30 ml or higher, in the management of alcohol intoxication.

        Toxicity of ethyl alcohol has been investigated extensively and probably requires no further comment except a reminder that alcohol alone may produce death, but always following a period of coma. Kaye and Haag (1957) reported that the shorter the period of coma, the higher the terminal blood-alcohol level; the longer the period of coma, the lower the blood-alcohol level. Alcohol is metabolized and eliminated from the blood at a rate of approximately 0.02 g% per hour. Death from acute alcohol intoxication most often does not occur until 6-18 hours after onset of coma. If it does occur (on rare occasions) within several hours following onset of coma, then the terminal blood-alcohol level would be in excess of 0.50%.

        During the past several years, we have had occasion to study the following 9 cases in which the individuals died suddenly and unexpectedly following paraldehyde therapy for acute alcohol intoxication. Apparently these patients were in good health except for the signs due to alcohol. Each was ambulatory and in these instances abusive.

¹ Present address: School of Medicine, University of Puerto Rico, San Juan, Puerto Rico.
² Deceased.
 
 

Death occurred from ½ and 4 hours after the administration of paraldehyde (30-60 ml) and autopsy revealed no morphologic cause of death.

Case 1

Blood alcohol: 0.30%
Paraldehyde: 0.07%
Received at least 30 ml of paraldehyde
Death in 4 hours after paraldehyde

Case 2

Blood alcohol: 0.18%
Paraldehyde: 0.09%
Drank an undetermined amount of paraldehyde (at least 30 ml at home)
Death in 3 hours

Case 3

Blood alcohol: 0.03%
Paraldehyde: 0.07%
Received 30 ml of paraldehyde
Death in 3 hours

Case 4

Blood alcohol: 0.03%
Paraldehyde: 0.10%
Received 60 ml of paraldehyde, 3-hour interval
Death 2 hours after last dose
Autopsy revealed mild fatty change in liver, but in the pathologist’s opinion this was not of sufficient degree to account for death in itself. In this case perhaps consideration should be given to the fact that some slight evidence of liver damage was found at autopsy and paraldehyde is contraindicated in this condition.

Case 5

Blood alcohol: 0.07%
Paraldehyde: 0.08%
Received 45 ml paraldehyde at home
Death in 3 hours

Case 6

Blood alcohol: 0.15% ethyl; 0.06 methyl
Paraldehyde: 0.08%
Received 45 ml paraldehyde
Death in 2½ hours

Case 7

Blood alcohol: 0.26%
Paraldehyde: 0.05%
Received 2 x 10 ml paraldehyde intramuscularly
Death in 2 hours

Case 8

Blood alcohol: 0.27%
Paraldehyde: 0.06%
Received at least 15 ml of paraldehyde
Death in several hours

Case 9

Blood alcohol: 0.08%
Paraldehyde: 0.10%
Took at least 90 ml in one dose
Death in 30 minutes
 
 

Case 10

Blood: 0.18% paraldehyde (negative for ethyl alcohol)
Accidentally was given 120 ml orally: 8 hours later 120 ml more rectally; died 4 hours after second dose (total dose 240 ml).

Case 11

Blood: 0.10% paraldehyde (negative for ethyl alcohol)
Received 60 ml in 20 hours; accidentally received additional 90 ml orally in one dose; died 11 hours later (total dose 150 ml).
 

Case 12

Blood: 0.13% paraldehyde (negative for ethyl alcohol)
Drank 120 ml to relieve pain in leg. Deep coma. Slept for approximately 16 hours.
Awakened with no undue aftereffects.

Cases 10 and 11 are included to indicate the higher blood paraldehyde levels, and the longer intervals between exposure and death in uncomplicated paraldehyde poisoning.

Case 12 indicates that in the absence of alcohol, quite large quantities of paraldehyde may be tolerated.

The blood-paraldehyde levels in this study were determined by a modification of the method of Stotz (1943). The blood-alcohol levels were determined by modification of Bogen’s method as described by Kaye and Haag (1954).
 
 

In an attempt to evaluate the relative hazard of the administration of paraldehyde to animals already intoxicated with alcohol, studies on mice were performed. Male albino mice weighing 20-30 g were used. These mice were deprived of food overnight and were then given alcohol and or paraldehyde orally. Room temperature was regulated at about 25⁰C. The acute oral LD₅₀ for alcohol in mice was reported by Ramsey and Haag (1946) to be 11.1 ml of 95% alcohol per kilogram. This is confirmed in Table 1. The LD₅₀ for paraldehyde in mice was found to be 1.79 ml/kg (see Table 1). This is in line with the finding of Weatherby and Clements (1960).

of an intraperitoneal LD₅₀ of 1.77 g/kg. See Table 2 for the combined action of oral paraldehyde after intake of alcohol.

From Table 2, it appears that there may be an additive synergism between alcohol and paraldehyde in mice that becomes more pronounced when the interval between the alcohol and paraldehyde administration is increased to several hours. However, when these data were

when these data were examined statistically using chi-square to compare the mortality rate of mice at zero hour with the mortality at 2, 3, 4, 5, and 6 hours, synergism was demonstrated only at 5 hours (P=0.05).

        Weatherby and Clements (1960) in a study with mice reported similar findings of an additive action of ethyl alcohol and paraldehyde, but in their study this was most evident at zero hours between the drugs, and progressively decreased as the time interval lengthned. Perhaps the differences may be related to the route. They used the intraperitoneal route and we used the oral.

        Since there appears to be a strong possibility of an additive synergistic action between those two drugs, further studies with larger numbers and various species of animals are in order.
 
 

        The present study indicates that there is a combined action of alcohol and paraldehyde that may lead to death in some cases. Caution against overdosage should be exercised in their combined use.

        During the past several years, we have had the occasion to study nine cases in which the individual died suddenly and unexpectedly following paraldehyde therapy for acute alcoholism. Apparently these patients were in good health, other than for symptoms of alcoholism. Death occurred from ½ hour to 4 hour after administration of paraldehyde (30-60 ml), and autopsy revealed no morphologic cause of death.

        Paraldehyde alone may produce death when the dose excceds 120 ml, but the developing depression (coma) usually precedes death by at least 12 hours.

        Experiments with mice appear to confirm this combined action of alcohol and paraldehyde.
 
 

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KAYE, S., and HAAG, H.B. (1954). Determinatin of ethyl alcohol in blood. J. Forensic Med. 1, 373-381.

KAYE, S., and HAAG, H.B. (1957). Terminal blood alcohol concentration in 94 fatal human cases of acute alcoholism. J. Am. Med. Assoc.
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KOTZ, J., ROTH, G.B., and RYON, W.A. (1938). Idiosyncrasy to paraldehyde. J. Am. Med. Assoc. 110 (part 2), 2145-2148.

McDOUGAL, J., and WYLLIE, A.N. (1932). A fatal case of paraldehyde poisoning. J. Mental Sci. 78, 374.

MACINTOSH, R.B. (1939). Paraldehyde poisoning treated in a respirator. Brit. Med. J. 1, 827- 829.

RAMSEY, H., and HAAG, H.B. (1946). The synergism between the barbiturates and ethyl alcohol. J. Pharmacol. Exptl. Therap. 88, 313-322.

SHOR, M. (1941). Paraldehyde poisoning. Report of a fatally. J. Am. Med. Assoc. 117, 1534-1535.

STOTZ, E.J. (1943). Colorimetric determination of acetaldehyde in blood. J. Biol. Chem. 148, 585-591.

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