THERAPEUTIC ASSESSMENT of CHLORAL HYDRATE PREMEDICATION for PEDIATRIC DENTISTRY Paul A

Home , Chloral betaine, Chloral hydrate, Dichloralphenazone, Flurazepam, Methaqualone, Triclofos

BRIEF REVIEWS

THERAPEUTIC ASSESSMENT OF CHLORAL HYDRATE PREMEDICATION FOR PEDIATRIC DENTISTRY Paul A. Moore, D.M.D., Ph.D. Forsyth Dental Center, Boston, MA

First introduced by Liebrich in 1968, chloral administration of an aqueous solution of chloral hydrate is one of the oldest sedative-hypnotic hydrate, peak plasma concentrations of TCE are drugs used in medicine.1 Its continued popularity reached in 20 to 60 minutes.8 Plasma half life today demonstrates its generally perceived utility. of TCE is estimated to be eight hours.68 Plasma A recent survey of 26,294 medical patients found levels of chloral hydrate are undetectable even 21% received chloral hydrate during their hospi- immediately after administration. talization. The drug was prescribed primarily for The elimination half-life of the second meta- insomnia.2 In dental practice, chloral hydrate is bolite, TCA, is about four days.9 Substantial ac- commonly administered to children as an oral cumulation of TCA is observed with repeated daily sedative. In a 1981 survey, the majority of pedo- administration. Both TCA and TCE are eliminated dontists who premedicated patients had used chlo- as conjugates of glucuronide.6 Absorption is sig- ral hydrate.3 Considering present concerns and nificantly delayed when chloral hydrate is formu- restrictions regarding parenteral sedation tech- lated in capsules.10 Rectal absorption of prepara- niques, the utilization of oral sedative agents such tions using polyethylene glycol vehicles is nearly as chloral hydrate is likely to increase. This re- as rapid as oral absorption although somewhat less view will evaluate the pharmacology, efficacy and complete.9.11 safety of chloral hydrate as an oral premedicant Although definitive studies, particularly in chil- in dentistry. dren, are sparse, it is generally assumed that therapeutic doses of chloral hydrate have minimal PHARMACOLOGY effects on respiratory and cardiovascular function.12 In adults, a 20 mg/kg dose causes no sig- Chloral is a halogenated derivative of acetal- nificant change in arterial blood pressure or heart dehyde. The addition of three chloride atoms in- rate. Changes in respiratory function (pCO2, res- creases the lipid solubility and CNS depressant piratory rate, tidal volume) are comparable to natur- properties of acetaldehyde. To improve stability, al sleep. Asthmatic patients may be somewhat chloral is formulated as a hydrate by adding one more sensitive to chloral hydrate's minimal respira- molecule of water to the carbonyl groups (Figure 1). tory depressive properties.13 Chloral betaine, dichloralphenazone and sodium The primary pharmacologic effect of chloral hy- trichloroethyl phosphate (triciofos) are alternative drate is central nervous system (CNS) depression. formulation ofs chloral. Because of tissue irritation, Signs and symptoms of ingesting increasing doses formulations of chloral are administered orally and of chloral hydrate progress from relaxation, lethar- rectally only. gy, drowsiness and hypnosis to loss of conscious- The sedative-hypnotic activity of these chloral ness and coma. derivatives is due to the common metabolite tri- Chloral hydrate is most commonly prescribed as chloroethanol (Figure 1).4.5 Following absorption, a hypnotic for older adults. Fixed doses of 500 or chloral hydrate is rapidly metabolized primarily 1000 mg are commonly prescribed one half to one to trichloroethanol (TCE) and to a lesser extent hour prior to bedtime. Although both doses have to trichloroacetic acid Following oral been suggested to be equally effective,2 clinical (TCA).4.6,7 impressions and experimental trials favor the higher dose.1415.16 Changes in rapid eye move- ment (REM) sleep parameters are minimal with chloral hydrate.1517 The hypnotic efficacy of chloral hydrate appears to decrease with repeated use on Accepted for publication August 17, 1984. Address reprint requests to Dr. Paul Moore, Department of consecutive nights.18 Although other hypnotic Pharmacology, Forsyth Dental Center, 140 Fenway, Boston, agents may be equal or superior to chloral hy- MA 02115 drate,1419 the perceived safety of chloral hydrate

SEPTEMBER/OCTOBER 1984 191 CI N Cl H DENTAL THERAPY conjugated Cl-C-C-OH Cl-C-C-OH , I product Chloral hydrate is frequently employed in oph- Cl OH CI H thalmology, neurology, anesthesiology and den- chloral hydrate (ClH) trichloroethanol (TCE tistry as a sedative premedicant for disruptive, anxious and uncooperative pediatric patients who can- not be managed adequately by psychological or physical means.3.26.67.68 Pharmacologic manage- CI 0 I// ment of uncooperative preschool children is one of Cl-C-C conjugated the most complicated and controversial of \ CI OH dental therapeutics. To provide adequate care to trichloroacetic acid (TCA extremely uncooperative children, practitioners must often choose between general anesthesia Fig. 1-Metabolic pathway of chloral hydrat[e. that can require costly and inconvenient hospitali- zation, and deep conscious sedation that may be only marginally effective.29 The use of an oral premedicant is a reasonably effective and safe al- explains its popularity. Disorientatiion, confusion, ternative to general anesthesia for the moderately irritability, delusions and hallucinati ons have been anxious patient. reported among some elderly patienits who receive Reports from uncontrolled evaluations of chloral even low doses of chloral hydrate.2:0.21 hydrate as a pedodontic premedicant are frequent- Chloral hydrate has been recc)mmended for ly superlative.31 .32 As shown in Table 1, controlled treatment of cerebral irritability in riewborns. Fre- studies have provided less consistent findings. quent reports of its value for mana!ging childhood Differences in patient characteristics (age, weight, convulsions have been published.22.23.24 Kuzemko health status) and study design (efficacy criteria, and Hartley found diazepam as effective as chloral timing of drug administration and dental procedure) hydrate for managing convulsions irn the newborn.- make comparisons between individual studies Because repeated dosing with chlor'al hydrate was difficult. However, there appears to be a threshold found to restrict newborn weight glain, diazepam dose, below which chloral hydrate efficacy as a was the recommended treatment.25 ~~i ~ pedodontic sedative premedicant has not been

TABLE 1. Clinical Evaluation of Chloral Hydrate Sample Ineffective Effective Investigator Size Dose Dose Comments Smith27 14 30-75 mg/kg handicapped 4-16 yr. olds, double blind, placebo controlled Robbins28 58 60 mg/kg* 2-6 yr. olds, double blind, placebo controlled Evans et al.30 75 33 mg/kg 3-8 yr. olds, double blind, placebo controlled with methampyrone 500 mg Chambers et al.33 15 39.6 mg/kg 39.6 mg/kg 4-13 yr. olds Koenigsberg et al.34 19 75 mg/kg 1-4 yr. olds, double blind with N2O Moore et al.35 60 20, 40 mg/kg 60 mg/kg 2-5 yr. olds, double blind, placebo controlled *estimated weight from Documenta Geigy Scientific Tables, Ed. 6, Geigy Pharmaceuticals, Ardsley, NY 1962.

192 ANESTHESIA PROGRESS demonstrated. Given alone, chloral hydrate pro- TABLE 2. Drug Interactions with Chloral Hydrate vided measurable sedation at doses above 40 mg/kg. When administered in combination with Agent Interaction other CNS depressants, a lower dose of chloral hy- CNS depressants Additive sedative and drate may be effectively prescribed.28.34.35 barbiturates hypnotic effects with For most of these clinical evaluations, moder- benzodiazepines possible prolonged ately or extremely uncooperative patients were nitrous oxide sedation and loss of studied. One might speculate that chloral hydrate promethazine consciousness could effectively sedate mildly anxious patients at doses in the 20-40 mg/kg range. However, mildly Ethyl alcohol Supra-additives CNS anxious children can usually be managed by depressant response due to increased plasma methods which do not require sedative drugs. levels of chloral hydrate and alcohol. ADVERSE REACTIONS TO Anticoagulants CHLORAL HYDRATE bishydroxycoumarin Possible reduction of hypoprothrombinemia. Adverse effects to chloral hydrate administration sodium warfarin Possible enhancement of are rare. When used as a hypnotic, untoward reac- hypoprothrombinemia. tions occur in about 2% of the cases. Overt CNS depression, characterized by disorientation, Furosemide Transient diaphoresis, prolonged drowsiness, lethargy or coma, account flushing, hypertension for half of these reactions.2 In order of decreasing and tachycardia. occurrence, the following reactions were also reported: sensitivity reactions, gastrointestinal disturbances, CNS excitation, headache, hepatic decompensation and coagulation disturbances. The reports of reactions in dental premedication depression to such an extent that the child's pro- are generally similar although dose related reac- tective reflexes are compromised.35 tions such as prolonged CNS depression and The combination of chloral hydrate with alcohol vomiting appear to be more frequent in younger (a "Mickey Finn" or "knock-out drops") is thought ambulating populations.2528 With extremely high to produce a supra-additive drug interaction. The doses of chloral hydrate (75 mg/kg), a 48% inci- degree of CNS depression appears significantly dence of vomiting in a pedodontic population has greater than simply the addition of each agent's been reported.34 The nraximum recommended activity.38 The explanation for this supra-additive dose in children, irrespective of body weight is effect is that alcohol promotes the conversion of 1000-1500 mg.2771 chloral hydrate to the active metabolite trichloro- Cutaneous reactions to chloral hydrate, although ethanol (TCE). Additionally, TCE inhibits alcohol described frequently in textbooks, seldom occur. metabolism by competing with alcohol dehydrog- Skin eruptions are usually erythematous, eczema- enase.39 The consequences of these metabolic tous and scarlatiniform.21.36 Fixed eruptions, skin actions is elevation and prolongation of TCE and lesions occurring at the same site upon repeated alcohol levels when chloral hydrate is coad- administration, have also been reported.37 ministered with alcohol.40.41 Chloral hydrate has been implicated in modifying responses to the oral anticoagulants (bis-hydroxy- DRUG INTERACTIONS coumarin) Dicumarol® and (sodium warfarin) Coumadin®.42 Dicumarol levels are decreased Chloral hydrate has been implicated in a variety when patients receive repeated doses of chloral hy- of drug interactions (Table 2). As one might expect, drate.43 Excessive hypothrombinemia has been chloral hydrate will produce additive depression reported when Coumadin is administered with chlo- when administered with other sedatives and CNS ral hydrate.4445 Although precaution is indicated, depressants. This additive drug interaction permits these interactions may be clinically insignificant, one to decrease the dose of both depressants, particularly with single dose therapy of chloral hy- thereby limiting individual drug side effects. The drate.46.47 reduced dosages when chloral hydrate is com- An unusual interaction has also been reported bined with promethazine has been shown to ap- between chloral hydrate and furosemide (Lasix®). preciably decrease the incidence of nausea and The reaction, characterized by transient diaphor- vomiting.2834 The use of N20/O2 in combination esis, hot flashes, variable blood pressure, tachy- with 40 mg/kg chloral hydrate will deepen the level cardia and hypertension, occurs when an intra- of sedation. N20/O2 in combination with 60 mg/kg venous bolus of furosemide is preceded 8 to 24 chloral hydrate may increase the level of CNS hours by chloral hydrate. It has been suggested

SEPTEMBER/OCTOBER 1984 193 that the response is due to competition of tri- low therapeutic indices, primarily because the chloroacetic acid, furosemide and possibly thyroxin mechanism for their therapeutic usefulness is simi- for common serum albumin binding sites. lar to their toxicity. For chloral hydrate, a doubling of the therapeutic dose is likely to significantly increase the incidence of vomiting and/or loss of consciousness. It should be noted that the clinical ACUTE TOXICITY setting may determine what is a toxic effect. For ex- ample, loss of consciousness may be a life- The majority of acute toxic reactions to chloral threatening situation in a pedodontic office while hydrate have occurred following suicide attempts unconsciousness is the therapeutic endpoint in in adults.48-53 Frequently other CNS depressants operating room anesthesiology. The safety of ther- were taken simultaneously.61 A typical case report apy is obviously not only based on a drug's inher- describes a patient who is comatose, hypotensive ent safety but the practitioner's competence. Addi- and hypoventilating upon arrival to an emergency tionally, reactions unrelated to dose such as room. Supraventricular and ventricular arrhythmias anaphylaxis are not measured by a therapeutic are frequently noted. Severe esophageal and gas- index. tric irritation with necrosis have also been re- Risk-benefit assessment of chloral hydrate seda- ported.59.60 Symptomatic treatment and hemo- tion provides another modulus of acceptability. dialysis have been used successfully and are When doses in the 40-60 mg/kg range are used, recommended treatments.54.55 Because arrhyth- chloral hydrate appears relatively safe and effec- mias are commonly reported, an EKG monitor tive. Obviously, it is a practitioner's responsibility should be applied and, when indicated, an antiar- to attempt to maximize the benefits and minimize rhythmic agent such as lidocaine or a beta blocker the risks of any therapy. It should be noted that the may prove useful.56-58 benefits-a relaxed and cooperative patient-do Few overdose reactions have been reported in not occur 1000/% of the time. For conscious sedation pediatric dentistry. Life threatening hypotension to be effective, good nonpharmacologic patient and respiratory arrest have occurred with esti- management techniques and profound local mated doses of 86 mg/kg and 118 mg/kg.62.63 anesthesia are essential. Even with optimal dose Three inadvertent overdose reactions have been and ideal patient management techniques, some recently described by Hayden.64 These were due to patients will be unmanageable and may require either incorrect calculation of dose or lack of com- alternative techniques, such as general anes- munication among dentists, staff and patients.64 A thesia. relatively low dose (250 mg) has reportedly induced The risks of using recommended doses of chloral laryngospasm and cardiac arrest when chloral hydrate are apparently minimal and are related hydrate elixir, a known irritant to mucosa tissue, primarily to tissue irritability, gastric upset and over was rapidly introduced into the oral pharynx with a sedation. Some factors seem to increase the risk of syringe.65 As with adults, children lose conscious- using chloral hydrate as a pediatric premedicant. ness, become hypotensive, hypoventilate and de- velop cardiac arrhythmias. 1) Age and weight: When dosing on a mg/kg Overdose with chloral hydrate may be self- basis, children under the age of 2 or weighing less limiting. Because vomiting is frequent with doses than 35 lbs. appear to have an increased risk of above 60 mg/kg, absorption of the total dose is being rendered unconscious.35.6768 often prevented. In children, hypotension and 2) Dose: Doses above the accepted range of cardiac arrhythmias commonly occur with over- 40-60 mg are more likely to induce vomiting or dose. These symptoms are distinctly different from cause loss of consciousness.28.34 local anesthetic or narcotic overdose where con- 3) Drug combinations: The concomitant use of vulsions and respiratory depression are usually chloral hydrate with barbiturates, alcohol, N20 or reported. benzodiazepines increases the reported incidence of toxicity.267.69 4) Physical status: Patients with marked renal, hepatic or cardiac impairment are likely to be less CONCLUSIONS tolerant of larger doses of chloral hydrate. In pediatric dentistry the use of chloral hydrate A number of criteria can be used to judge the has been more thoroughly evaluated than most acceptability of a given therapy. Drug therapy can pharmacologic sedation techniques. When precau- never be considered completely without liability. tion is taken for age, weight, dose, concomitant The Therapeutic Index, which compares the effec- drugs, and physical status, chloral hydrate appears tive dose of a given drug to its toxic dose, is one to be an acceptable adjunctive means for man- way of assessing the usefulness of a particular aging moderately uncooperative pediatric dental agent. Anesthetics and sedatives have relatively patients.

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SEPTEMBER/OCTOBER 1984 195 46. Voall JA: Warfarin-chloral hydrate interaction: phar- 60. Vellar DA, Richardson JP, Doyle JC, Keating M: Gastric macological activity and clinical significance. Ann Intern necrosis: A rare complication of chloral hydrate intox- Med 81:341-344, 1974. ication. Br J Surg 59:317-319, 1972. 47. Rickles FR and Griner PF: Chloral hydrate and warfarin. 61. McBay AJ, Boling VR, Reynolds PC: Short communica- N Eng J Med 286:611-612, 1972. tions: Spectrophotometric determination of trichloro- 48. Henwood CR: A death involving phenazone and chloral ethanol in chloral hydrate poisoning. J Anal Toxicol hydrate. J Forensic Sci Soc 9:35-36, 1969. 4:99-101, 1980. 49. Wiseman HM and Hampel G: Cardiac arrhythmias due 62. Troutman KC: Misuse of chloral hydrate in sedating a to chloral hydrate poisoning. Br Med J 2:960, 1978. pediatric dental patient. ASDA Mortality and Morbidity 50. King K and England JF: Chloral hydrate (Noctec) over- Conference. ASDA Annual Meeting, Boston, 1984. dose. Med J Aust 2:260, 1983. 63. Nordenberg A, Delisle G, Izukawa T: Cardiac arrhythmia 51. Orwin JM and Schroeder HG: Safety of chloral. Br Med in a child due to chloral hydrate ingestion. Pediatrics J 3:187, 1968. 47:134-135, 1971. 52. Brown AM and Cade JF: Cardiac arrhythmias after chloral 64. Hayden Jr. J: Chloral hydrate as a sedative in dentistry. hydrate overdose. Med J Aust 1:28-29, 1980. J. Colorado Dent Assoc 61:3-4, 1982. 53. Marshall AJ: Cardiac arrhythmias caused by chloral 65. Granoff DM, McDaniel DB, Borkowf SP: Cardiorespiratory hydrate. Br Med J 2:994, 1977. arrest following aspiration of chloral hydrate. Am J Dis 54. Stalker NE, Gambertoglio JG, Fukumitsu CJ, Naughton JL, Child 122:170-171, 1971. Benet LZ: Acute massive chloral hydrate intoxication from chloral hy- treated with hemodialysis: a clinical pharmacokinetic anal- 66. Silver W and Stier M: Cardiac arrhythmias ysis. J Clin Pharmacol 18:136-142, 1978. drate. Pediatrics 48:332-333, 1971. 67. Mitchell AA, Louik C, LaCouture P, Stone D, Goldman P, 55. Vaziri ND, Kumar KP, Mirahmadi K, Rosen S: Hemodialysis Shapiro S: Risks to children from tomographic scan in treatment of acute chloral hydrate poisoning. South Med 1982. J 70:377-378, 1977. premedication. JAMA 247:2385-2388, 56. Gustafson A, Svensson S, Ugander L: Cardiac arrhythmias 68. Grimes JG: Oral premedication in children. Anesth Anaig in chloral hydrate poisoning. Acta Med Scand 201:227- 41:201-212, 1962. 230, 1977. 69. Berry DJ: Determination of trichloroethanol at therapeutic 57. Digiovanni AJ: Reversal of chloral hydrate-associated car- and overdose levels in blood and urine by electron cap- diac arrhythmia by a beta-adrenergic blocking agent. ture gas chromatography. J Chromatography Anesthesiology 31:93-97, 1969. 107:107-114. 1975. 58. Bowyer K and Glasser SP: Chloral hydrate overdose and 70. Malach M and Berman N: Furosemide and chloral hydrate cardiac arrhythmias. Chest 77:232-235, 1980. adverse drug interaction. JAMA 232:638-639, 1975. 59. Gleich GJ, Mongan ES, Vaules DW: Esophageal struc- 71. Ripa LW and Barenie JT: Sedative-hypnotics. Management ture following chloral hydrate poisoning. JAMA of Dental Behavior in Children. PSG PubI Co., Littleton, 201:120-121, 1967. MA, 1979.

196 ANESTHESIA PROGRESS