AMERICAN ACADEMY OF PEDIATRICS Use of Chloral Hydrate For Sedation in Children Committee on Drugs and Committee on Environmental Health Publicity about the possible carcinogenicity of ceived 166 mg/kg chloral hydrate daily for 2 years. chloral hydrate along with the suggestion that alter- The incidence of hepatic tumors in the treated mice native sedatives should be used in children has gen- was 71 %,whereas the rate in controls was 15%. Of erated concern among physicians, dentists, and their the chloral hydrate-treated animals, 75% also had patients.1’2 Replacement of chloral hydrate with other hepatocellular pathologic changes including other sedatives would represent a major change in cytoplasmic alteration, hepatocellular necrosis, hepa- practice because it is one of the drugs most widely tocellular hyperplasia, chronic inflammation, and cy- employed to sedate young children undergoing den- tomegaly. tal and medical procedures and imaging studies. Chloral hydrate damages chromosomes in selected This statement will assist the practitioner in making mammalian test systems under certain experimental an informed decision regarding the use of chloral conditions. At high in vitro concentrations, chloral hydrate by summarizing (1) information pertaining hydrate produced nondisjunction in mouse sperma- to the potential for carcinogenesis associated with tocytes and Chinese hamster cells resulting in use of chloral hydrate, (2) the risk/benefit consider- aneuploidy.15-15 In one study, orally administered ations of available sedatives, and (3) risks associated chloral hydrate increased single-strand breaks in he- with prolonged sedation with chioral hydrate. patic DNA of male B6C3FI mice and Sprague-Daw- ley rats.16 However, these observations have not been EVIDENCE FOR CARCINOGENESIS OF corroborated by others, and a recent study showed CHLORAL HYDRATE that chloral hydrate does not produce DNA strand Some of the concern regarding potential carcino- breaks in the liver tissue of mice or rats, in primary genicity of chioral hydrate is based on the assump- cultures of rat or mouse hepatocytes, or in a cul- tion that chloral hydrate is a reactive metabolite of tured lymphoblastoid cell line.17 Aneuploidy18 and trichloroethylene, an industrial solvent, and is re- sister-chromatid exchanges19 were observed in hu- sponsible for the carcinogenicity of trichloroethyl- man lymphocytes exposed for 24 hours in vitro to ene.1’2 However, the validity of this assumption is concentrations of chloral hydrate ranging from 211 open to question. Although chloral hydrate is a me- to 1000 mg/L. tabolite of trichioroethylene, there is evidence that Because toxicity data in humans are difficult to the carcinogenicity of trichloroethylene is due to a obtain and frequently are limited, laboratory studies reactive intermediate epoxide metabolite rather than are usually the basis for the regulation of environ- chloral hydrate.3 As is the case for most chemical mental chemicals, food additives, and chemicals en- carcinogens, trichloroethylene is carcinogenic in countered in the work place. In general, chemicals some laboratory animal species but not in others.4 found to be carcinogenic in animals are regulated Multiple epidemiologic studies in humans have very strictly or, in some cases, banned. Laboratory failed to document an increase in cancer incidence studies also provide a basis for evaluating the risk to associated with trichloroethylene exposure,5-1#{176} al- humans from therapeutic agents, and such testing is though the ability of these studies to detect small in- required for new drugs. However, drugs, in contrast creases in risk of cancer is limited. to environmental residue chemicals, offer some ben- There are no studies pertaining to chloral hydrate- efit, and there are many situations in which the ben- associated carcinogenicity in humans. The evidence efit to the patient outweighs any potential risk. that chloral hydrate is carcinogenic comes from Therefore, therapeutically useful drugs that cause two studies in male B6C3F1 mice. Rijhsinghani and cancer in animals are sometimes used in the treat- colleagues reported hepatic adenomas or carcinomas ment of patients when the benefit from the drug in 6 of 8 mice 48 to 92 weeks after they received outweighs the potential risk. a single 10 mg/kg dose of chloral hydrate orally as weanlings, whereas 2 of 19 control mice developed USE OF CHLORAL HYDRATE COMPARED WITH tumorsY’ In another study conducted by the Envi- OTHER SEDATIVE/HYPNOTIC DRUGS ronmental Protection Agency,12 24 juvenile mice re- Sedative/hypnotic agents allow important diag- nostic and therapeutic procedures to be performed The recommendations in this publication do not indicate an exclusive safely and successfully in children. For decades chlo- course of treatment or serve as a standard of medical care. Variations, taking ral hydrate has been widely used for short-term Se- into account individual circumstances, may be appropriate. PEDIATRICS (ISSN 0031 4005). Copyright © 1993 by the American Acad- dation of children.2#{176}22 The acute toxicity of chloral emy of Pediatrics. hydrate when used in recommended single doses Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Vol. 92 No. 3 September 1993 471 for sedation is low. The lethal to therapeutic dose longer; in one study its concentration did not decline ratio is much higher than with the barbiturates.23 in infants for 6 days after a single 50 mg/kg dose of However, acute overdoses may cause cardiorespira- chloral hydrate.34 The long half-lives of these metab- tory depression.23 On rare occasions, excessive or olites lead to their accumulation during repetitive repetitive doses have been associated with cardiac dosing with chloral hydrate.32’34 Although the accu- arrhythmias.24-26 mulation of active metabolites is of concern, pub- Alternatives to chloral hydrate for short-term se- lished documentation of clinical toxicity is limited. dation of children include the barbiturates, phenothi- There is evidence that chloral hydrate and/or trichlo- azines, and benzodiazepines. Although the opiates roethanol may increase the risk of both direct and produce sedation, they usually are reserved for situ- indirect hyperbilirubinemia in newborns.32’35 Fur- ations in which some degree of analgesia in addition thermore, trichloroacetic acid is highly protein- to sedation is desired and are not considered compa- bound36 and theoretically could compete with biliru- rable to the nonanalgesic sedative/hypnotics. bin for albumin binding sites. It also has been Chloral hydrate is not the only sedative that is a suggested that high concentrations of trichioroacetic carcinogen in experimental animals. Some of the ben- acid may contribute to metabolic acidosis.37 Toxicity zodiazepine and barbiturate sedatives also have been characterized by respiratory depression and hypoto- shown to be carcinogenic in animal studies.2729 In nia associated with a trichloroethanol plasma con- addition, the barbiturates have been associated with centration seven times that associated with sedation a possible increased incidence in malignant tumors in adults was reported in an infant receiving multiple in humans.3#{176} doses of chloral hydrate while on mechanical venti- Each of the sedative/hypnotics has advantages lation.38 The infant recovered 7 days after discontin- and disadvantages that should be considered when uation of chloral hydrate administration. selecting one for inducing short-term sedation. Ad- ministration of any sedative entails some degree of CONCLUSIONS AND RECOMMENDATIONS risk and requires proper monitoring of the patient to I . Chloral hydrate is an effective sedative with a low minimize that risk.31 Drugs from each of the classes incidence of acute toxicity when administered of sedatives may be administered safely and effec- orally in the recommended dosage for short-term tively by physicians and dentists who are experi- sedation. There is a great deal of experience with enced in their use and who exercise proper monitor- chioral hydrate and most practitioners are familiar ing procedures. Currently, sufficient data are not with its use. available in infants and children to establish any of 2. Repetitive dosing of chloral hydrate is of concern the available sedatives as superior with respect to because of accumulation of the metabolites, either efficacy or safety. Furthermore, available infor- trichloroethanol and trichloroacetic acid, which mation regarding long-term theoretical risk of carci- may produce excessive central nervous system de- nogenicity does not provide a basis at this time for pression, predispose newborns to conjugated and sufficient concern to warrant selection of an alterna- nonconjugated hyperbilirubinemia, decrease al- tive sedative to chloral hydrate. Therefore, physi- bumin binding of bilirubin, and contribute to met- cians and dentists should select a sedative based on abolic acidosis. the type and degree of sedation required and their 3. Although available information regarding theoret- knowledge and experience with the respective seda- ical long-term risk of carcinogenicity is of concern, tives. A sudden switch by physicians and dentists it does not provide a basis for sufficient concern to from a sedative with which they are familiar to one warrant selection of an alternative sedative rather with which they have less experience and for which than chloral hydrate. there are not sufficient safety and pharmacologic 4. Sufficient data are