Neonatal Deaths Associated With Use Of Benzyl Alcohol -- United States

Sixteen neonatal deaths thought to be caused by the benzyl alcohol preservative used in some intravascular solutions have been reported to the Food and Drug Administration (FDA) by 2 medical centers (1,2). The deaths occurred in pre-term neonates weighing 2500 gms who had central intravascular catheters flushed periodically each day with bacteriostatic normal saline containing 9 mg/ml benzyl alcohol. Ten deaths occurred in 1 institution over a 6-month period and 6 deaths occurred in the other institution over a 16-month period. Investigators in the 2 hospitals have reported that similar deaths have not occurred since flush solutions without preservatives have been substituted for those with the benzyl alcohol.

Onset of toxic illness in the infants occurred between several days and a few weeks of age with a characteristic clinical picture that included metabolic acidosis progressing to respiratory distress and gasping respirations. Many infants also had central-nervous-system dysfunction, including convulsions and intracranial hemorrhage; hypotension leading to cardiovascular collapse was a late finding usually presaging death.

Gas chromatographic analysis demonstrated benzyl alcohol or its metabolites in blood and urine samples from infants in 1 hospital. Retrospective analysis of urine samples from 5 infants in the other hospital for organic acid profile by gas-liquid chromatography showed urine benzoate levels of 4.4-16.1 mg/mg creatinine and hippurate levels of 7.4-33.3 mg/mg creatinine (normal values = 0-trace); serum benzoic acid levels were 8.4-28.7 mEq/L (normal = 0). Review of the medical records of the affected infants resulted in estimates of daily intake of benzyl alcohol ranging from 99 to 405 mg/kg/day.

Based on these reports, the FDA has recommended that intravascular flush solutions containing benzyl alcohol not be used for newborns and that diluents with this preservative not be used as medications for these infants.

Illness suspected of having been caused by use of benzyl alcohol should be reported promptly to the FDA, Division of Drug Experience, Attn: Judith K. Jones, M.D., Ph.D., Room 15-B-07, HFD-210, 5600 Fishers Lane, Rockville, Maryland 20857; telephone (301)443-4580. Reported by JJ Gershanik, B Beecher, W George, A Sole, M Leither, C Kapadious, Southern Baptist Hospital, New Orleans, Louisiana; WJ Brown, NRM Buist, HTC Gipson, RK Huston, NG Kennaway, Oregon Health Sciences University, Portland; Div of Drug Experience, Office of Biometrics and Epidemiology, Bureau of Drugs and Biologics, FDA; Chronic Disease Div, Center for Environmental Health, Hospital Infections Program, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: Benzyl alcohol is an aromatic alcohol usually used in a concentration of 0.9% as a bacteriostatic preservative in multiple-dose vials of solutions or drugs for parenteral therapy. Bacteriostatic sodium chloride, USP, is frequently used in the management of critically ill patients to flush intravascular catheters after the addition of medications or the withdrawal of blood; and sterile bacteriostatic water for injection, USP, is used to dilute or reconstitute medications for intravenous use. In addition, medications, such as some formulations of sodium heparin, USP, that are frequently used for infants and other critically ill patients may be preserved with benzyl alcohol.

Toxic effects of benzyl alcohol, including respiratory failure, vasodilation, hypotension, convulsions, and paralysis have been known for years (3-5). However, little is known about the toxic effects or levels of benzyl alcohol in neonates, especially in sick premature infants. Animal toxicity studies (6) show an LD((50)) of approximately 33 ml/kg (300 mg/kg) in rats treated by rapid intravenous infusion with 0.9% benzyl alcohol, although 40 ml/kg (360 mg/kg) by slow intravenous infusion was tolerated without mortality. Adult dogs were killed by doses of 88-113 ml/kg (830-1060 mg/kg) of 0.9% benzyl alcohol intravenously, but tolerated smaller infusions without signs of toxicity. The serum half-life of benzyl alcohol in adult dogs is estimated at 1.5 hours. On the basis of the animal studies, it has been estimated that rapid intravenous infusion of adult humans with as much as 30 ml of 0.9% benzyl alcohol (approximately 4.5 mg/kg) in saline should be safe (6).

Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid. However, this metabolic pathway may not be well developed in premature infants. The benzyl alcohol may therefore have been metabolized to benzoic acid, which could not be conjugated by the immature liver but accumulated, causing metabolic acidosis (2).

These reports of neonatal toxicity from benzyl alcohol are highly noteworthy. However, caution must be exercised in attributing individual illness to benzyl alcohol since many of the described clinical features commonly occur in neonates seriously ill from other causes. Newborns most likely to receive large volumes of flush solutions, relative to body weight, are the very small, sick premature infants who already have a high risk of mortality. Thus, mortality potentially attributable to benzyl alcohol should also be assessed by a careful comparison of neonatal mortality in newborns receiving large amounts of non-bacteriostatic flush solutions and medications with comparable newborns receiving large amounts of bacteriostatic solutions and medications. Retrospective analyses of newborns who received saline flushes with benzyl alcohol and survived are also needed to establish whether a dose-response relationship exists between clinical and laboratory findings and the intensity of exposures to benzyl alcohol, and to identify more completely the pathologic and clinical features of toxicity in newborns.

References

1. Gershanik JJ, Beecher B, George W, Sole A, Leither M, Kapadious C. Gasping syndrome: benzyl alcohol poisoning. Clin Res 1981;29:895a.

2. Brown WJ, Buist NRM, Gipson HTC, Huston RK, Kennaway NG. Benzyl alcohol poisoning: a cause of metabolic acidosis and death in neonatal infants. Lancet (In press).

3. Macht DI. A pharmacological and therapeutic study of some benzyl esters.J Pharmacol 1918;II:419-46.

4. Gruber CM. The pharmacology of benzyl alcohol and its esters. J Lab Clin Med 1923;9:15.

5. WHO Drug Information Bulletin 1981 (Jan-Jun), pp 29, 31.

6. Kimura ET, Darby TD, Krause RA, Brondyk HD. Parenteral toxicity studies with benzyl alcohol. Toxicol Appl Pharmacol 1971;18:60.

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