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Chloral hydrate disposition following single-dose administration to critically ill neonates and children
D J Mayers1, K W Hindmarsh, K Sankaran
1Perinatal Research Laboratory, Neonatal Services, College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.
Insights
Chloral hydrate (CH) metabolism and pharmacokinetics differ significantly in neonates and infants compared to adults. The active metabolite, trichloroethanol (TCE), has a prolonged half-life in younger patients, necessitating careful consideration for clinical use.
Area of Science:
- Pharmacology
- Pediatric Medicine
- Drug Metabolism
Background:
- Limited data exists on chloral hydrate (CH) metabolism and pharmacokinetics in neonates and infants.
- Physiological immaturity in pediatric populations can significantly alter drug disposition.
Purpose of the Study:
- To investigate the metabolism and pharmacokinetics of chloral hydrate (CH) in preterm infants, full-term infants, and toddler-child patients.
- To compare CH disposition in pediatric groups with adult data.
Main Methods:
- Oral administration of a single 50 mg/kg dose of chloral hydrate (CH).
- Analysis of parent drug and metabolites (trichloroethanol and trichloroacetic acid) using gas chromatography with an electron capture detector.
- Categorization of 22 patients into three groups based on postconceptual age.
Main Results:
- Chloral hydrate (CH) was detectable for several hours in all pediatric groups.
- The half-life (t1/2) and area-under-the-curve of trichloroethanol (TCE) were significantly longer in preterm and full-term infants compared to toddler-children and adults.
- Trichloroacetic acid exhibited a prolonged residence time, with concentrations declining slowly even after 6 days.
Conclusions:
- Pediatric age significantly impacts chloral hydrate (CH) pharmacokinetics, particularly the elimination of its active metabolite, trichloroethanol (TCE).
- The prolonged half-life of TCE in neonates and infants requires careful dosing considerations.
- Trichloroacetic acid's long persistence warrants further investigation regarding potential accumulation and clinical implications.
Abstract:
Although the metabolism and pharmacokinetics of chloral hydrate (CH) have been studied in healthy adults, no comprehensive studies have been done in neonates and young infants. Major physiological differences between these groups could greatly affect drug disposition. In this study the patient population (22 patients) was divided into three groups according to postconceptual age: group 1 = preterm infants (31-37 weeks), group 2 = fullterm infants (38-42 weeks) and group 3 = toddler-child patients (57-708 weeks). After receiving one 50 mg/kg oral dose of CH, the parent drug and its metabolites were determined by gas chromatography utilizing an electron capture detector. CH, contrary to what has been reported in the adult, was detectable for several hours after oral administration to patients in all three groups. A highly significant negative correlation was observed amongst the three groups for the half-life (t1/2) and area-under-the-curve for 0 to infinity values for trichloroethanol (TCE), the active metabolite responsible for the sedation effect. The t1/2 value for TCE in group 3 (9.67 h) was similar to that reported for the adult population, but in the less mature subjects it was approximately three (group 2: 27.8 h) to four times (group 1: 39.8 h) greater. Trichloroacetic acid had a remarkably long residence time in the study population after a single dose of CH. The concentration of this metabolite failed to decline even 6 days after dose. These issues should be carefully considered when CH administration is contemplated for clinical use in neonates, infants and children.