Pharmacokinetics and analgesic effects of intravenous propacetamol vs rectal paracetamol in children after major craniofacial surgery.
BACKGROUND
The pharmacokinetics and analgesic effects of intravenous and rectal paracetamol were compared in nonventilated infants after craniofacial surgery in a double-blind placebo controlled study.


METHODS
During surgery all infants (6 months-2 years) received a rectal loading dose of 40 mg.kg(-1) paracetamol 2 h before anticipated extubation. On admittance to the pediatric surgical ICU, the children were randomized to receive either a 15 min intravenous infusion of 40 mg.kg(-1) propacetamol, a prodrug of paracetamol, or 20 mg.kg(-1) paracetamol rectally every 6 h. A population pharmacokinetic analysis of the paracetamol plasma concentration time-profiles was undertaken using nonlinear mixed effects models. The visual analogue scale (VAS) (score 0-10 cm) and COMFORT Behavior scale (score 6-30) were used to monitor analgesia in the 24-h period following surgery.


RESULTS
Twelve infants received intravenous propacetamol and 14 paracetamol suppositories. Paracetamol pharmacokinetics were described according to a two-compartmental model with linear disposition. Pharmacokinetic parameters were standardized to a 70 kg person using allometric '1/4 power' models. Parameter estimates were: absorption half-life from the rectum 4.6 h, propacetamol hydrolysis half-life 0.028 h, clearance 12 l.h(-1).70 kg(-1), intercompartmental clearance 116 l.h(-1).70 kg(-1), central and peripheral volume of distribution 7.9 and 44 l.70 kg(-1), respectively. During the 24-h study period 22 infants exhibited VAS scores <4 cm, which was considered a cutoff point. On single occasions four patients, two in each group, exhibited a VAS score >/=4 cm. Nine patients in the rectal treatment group and three patients in the intravenous treatment group received midazolam for COMFORT-B scores exceeding 17 (P < 0.05).


CONCLUSIONS
Intravenous propacetamol proved to be more effective than rectal paracetamol in infants after craniofacial surgery. Midazolam was more frequently administered to patients receiving paracetamol suppositories, indicating that these children experienced more distress, possibly caused by pain.
Prins
Sandra A
SA
Department of Pediatric Surgery, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
Van Dijk
Monique
M
Van Leeuwen
Pim
P
Searle
Susan
S
Anderson
Brian J
BJ
Tibboel
Dick
D
Mathot
Ron A A
RA
D000082:Acetaminophen / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000285:Administration, Rectal; D000698:Analgesia / Q000379:methods*; D000700:Analgesics / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018686:Anesthetics, Intravenous / Q000008:administration & dosage; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000601:surgery*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage; D010147:Pain Measurement / Q000379:methods / Q000706:statistics & numerical data; D010149:Postoperative Pain / Q000188:drug therapy*; D010919:Placebos / Q000008:administration & dosage; D016896:Treatment Outcome
D000700:Analgesics; D018686:Anesthetics, Intravenous; D010919:Placebos; D000082:Acetaminophen; C063776:propacetamol; D008874:Midazolam