CHLORAL HYDRATE DISPOSITION IN CRITICALLY ILL PAEDIATRIC PATIENTS
Date
1992-07
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Degree Level
Doctoral
Abstract
Chloral hydrate (CH), the oldest sedative-hypnotic
used today, has largely been replaced in general medicine
by newer drugs (benzodiazepines) but it still enjoys
extensive use in paediatrics. However, few studies have
investigated CH in that patient group. Chloral hydrate is
rapidly metabolized to trichloroethanol (TCE),
trichloroethanol-glucuronide (TCE-G) and trichloroacetic
acid (TCA). The metabolites are excreted renally. Chloral
hydrate is an irritant and has been linked to cardio-
pulmonary and central nervous system toxicity in cases of
intoxication. Drug interactions with CH have also been
reported.
The objective of this study was to examine the
disposition of CH within a critically ill paediatric
patient population and to determine if routine use of CH
has the potential to result in toxicity. The present
investigation examined pharmacokinetic parameters of CH and
its metabolites, plasma protein binding of TCA as a
mechanism of the furosemide/CH drug interaction and the
respective roles CH and TCE play in sedation.
Gas chromatography with electron capture detection was
used to determine levels of CH and its metabolites in
plasma and urine. The plasma protein binding of TCA was
determined both in vitro and ex vivo using micropartition
ultrafiltration.
Because of the paucity of information on routine
dosages and dosing intervals in paediatric patients a small
pilot study (n=7) was undertaken to determine if the
potential for CH intoxication existed. The elimination of
TCE, TCE-G and TCA were much slower in the study group than
in adults. Trichloroacetic acid was especially persistent.
Its plasma concentrations showed no signs of decline in
four patients 14 days after the final CH administration.
Dosing intervals were variable but, without exception, much
shorter than the elimination half-life values (ty,) of the
metabolites. In two cases TCE concentrations were in the
toxic range (>100 µg/mL), however no signs of intoxication
were noted.
In the single dose study, patients were from three age
groups: preterm neonates (n=9), term neonates (n=8) and
PICU patients (n=5). The clearance of CH was equivalent
among the groups. TCE t% and area-under-the-curve (AUC)
values were negatively correlated with age. The tm value
for TCE in PICU patients was similar to that reported for
adults, but in the less mature subjects it was
approximately three (term) to four (preterm) times greater.
Renal clearance for TCE was higher in PICU patients than in
neonates. The AUC0_G4 for TCA was also higher in PICU
patients than in the neonatal groups but the renal
clearance in the same time period was not significantly
different. Plasma protein binding of TCA was studied in vitro in
adult, neonatal cord and neonatal exchange transfusion
plasma. Trichloroacetic acid binding was highest in adult
plasma followed by cord plasma and exchange transfusion
plasma. Affinity (ka) appeared to be lower in the neonatal
plasma. Furosemide concentrations of 2 and 20 µg/mL did
not affect the plasma protein binding of TCA. Only the
furosemide concentration which is well above that
encountered clinically (200 µg/mL) resulted in
significantly decreased binding. In neonates the decreased
binding appeared to be due to decreased binding affinity
for TCA. This could not be confirmed in adult plasma.
Ex vivo binding was lower in preterm samples than in
the in vitro studies. Term neonates and adult samples more
closely resembled their respective in vitro data.
The sedative-hypnotic effects of CH have, in the past,
been solely ascribed to TCE. However the t% of TCE is much
longer than the dosing intervals normally used for CH.
Therefore the relationship between plasma levels of TCE and
the sedation status of infants was examined. A numerical
scale was developed to assess the state of sedation and/or
agitation of preverbal patients and used to quantitate the
relative level of consciousness of infants following CH
administration. There did not appear to be any correlation
between the sedation scores and TCE plasma levels.
However, when the sedation scores were plotted against CH
plasma concentrations a regular, cyclical pattern was
detected. Levels of CH rather than TCE appeared to
correlate with the sedation scores.
Description
Keywords
Toxicology, Paediatrics, Chloral Hydrate
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Biochemistry
Program
Toxicology