High-dose oral acetaminophen 30 mg/kg in pediatric anesthesia
high dose (40 mg/kg) oral acetaminophen for BMT
"All 60 min plasma concentrations were ≥ 70 μmol·l–1 (ED50 for adenotonsillectomy) and less than 800 μmol·l–1 (associated with toxicity)"
acetaminophen 60 mg/kg and 90 mg/kg paracetamol in fit young adult patients undergoing third molar extractions
"90 mg/kg dose, though safe, does not offer any advantages over 60 mg/kg dose"
High dose acetaminophen 40 mg/kg was better than 100 mg/kg
"acetaminophen (100 mg/kg) was no more effective than 40 mg/kg and was associated with increased nausea and vomiting. "
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Here are the above papers in more detail:
The analgesic efficacy of preoperative high dose (40 mg·kg–1) oral acetaminophen after bilateral myringotomy and tube insertion in children
PHILLIP BOLTON MBChB, HILARY S BRIDGE MBChB, CAROLYNE J MONTGOMERY MD and PAMELA M MERRICK BSN
Pediatric Anesthesia Pediatric Anesthesia Volume 12, Issue 1, pages 29–35, January 2002
Background: The purpose of this study was to measure the plasma levels and analgesic effectiveness of a dose of 40 mg·kg–1 of preoperative oral acetaminophen.
Methods: Thirty children aged 55 (17–72) months undergoing bilateral myringotomy and tube insertion (BMT) received acetaminophen 40 mg·kg–1 p.o. preoperatively. Plasma levels were measured, at 29 (10–51) min and at 60 min in the postanaesthesia care unit (PACU). Children's Hospital of Eastern Ontario Pain Scale (CHEOPS), for all subjects and the Poker Chip Tool (PCT) a self-report scale for subjects aged > 4 years, were used. After discharge, 24-h analgesic efficacy was evaluated using an observer Visual Analogue Scale (VAS) score and further acetaminophen use was recorded.
Results: Plasma concentrations were 259 (60–391) μmol·l–1 and 250 (135–450) μmol·l–1, respectively. All 60 min plasma concentrations were ≥ 70 μmol·l–1 (ED50 for adenotonsillectomy) and less than 800 μmol·l–1 (associated with toxicity). Twenty-six subjects (87%) had adequate analgesia (CHEOPS ≤ 8). The PCT was only understood in the PACU by 13 of the 21 children > 4 years (62%). The median worst 24-h observer VAS was 0.5 (0–5.5) (27 subjects). No further analgesic was required after discharge in 16/28 (57%). A higher plasma level was associated with fewer doses of acetaminophen after discharge (r=–0.36, P=0.05).
Conclusions: No relationship was evident between age, the 60 min plasma acetaminophen level and the CHEOPS carried out at the same time. Acetaminophen 40 mg·kg–1 p.o. results in 60 min plasma levels of 250 (135–450) μmol·l–1. The in-hospital analgesic efficacy was 87% (CHEOPS < 9, no further analgesics) and the 24-h efficacy was 57% (need for further acetaminophen).
Affiliation
Comparative safety and efficacy of two high dose regimens of oral paracetamol in healthy adults undergoing third molar surgery under local anaesthesia.
Zacharias M1, De Silva RK, Hickling J, Medlicott NJ, Reith DM.
Journal Anaesth Intensive Care. 2007 Aug;35(4):544-9.
This study compared the efficacy and safety of single oral doses of 60 mg/kg and 90 mg/kg paracetamol in fit young adult patients undergoing third molar extractions. The study was a randomised, blinded, crossover design on 20 young, fit adults. Paracetamol was administered 30 minutes prior to the surgical extraction of the teeth, which was done under intravenous sedation and local anaesthesia. There were no clinically or statistically significant differences in the pain scores between 60 mg/kg or 90 mg/kg doses until the intake of rescue analgesics. There was a reduction in factor VII activity with 90 mg/kg dose compared to 60 mg/kg dose. It may be concluded that the 90 mg/kg dose, though safe, does not offer any advantages over 60 mg/kg dose of paracetamol in young fit adults undergoing third molar surgery. PMID 18020073
Acetaminophen Analgesia In Children: Placebo Effect And Pain Resolution After Tonsillectomy.
Betty J. Anderson, Gerald A. Woollard and Nick H G Holford European journal of clinical pharmacology , 2001
Pharmacodynamic models of acetaminophen analgesia in children have not explored the efficacy of single oral doses greater than 40 mg/kg. Children aged 9.0 +/- 3.0 years (+/- SD) and weight 37.9+/- 16.6 kg undergoing outpatient tonsillectomy were randomised to receive acetaminophen elixir 40 mg/kg (n = 12). high dose acetaminophen elixir 100 mg/kg (n =20) or placebo (n=30) 0.5 -1 h preoperatively. No other analgesics were given. Individual acetaminophen serum concentrations and pain scores [visual analogue scale (VAS) 0-10] were measured over a 4-8 h postoperative period. These data were pooled with data from a previous study investigating acetaminophen pharmacodynamics (n = 120) and analysed using a non-linear mixed effect model. Placebo effects and drug effects were modelled using effect-site concentration models. A one-compartment model with first-order input, lag time and first-order elimination was used to describe the population pharmacokinetics of acetaminophen. Pharmacokinetic parameter estimates were similar to those previously described. Pharmacodynamic population parameter estimates [population variability coefficient of variation (CV)] for a maximum analgesic effect (Emax) model, in which the greatest possible pain relief (VAS 0-10) equates to an Emax of 10, were Emax 5.17 (64%) and 50% effective concentration 9.98 mg/l (107%). The equilibration half-life (t(eq)) of the analgesic effect compartment was 53 min (217%). A placebo drug model for the effects of placebo response had a t(eq) of 1.96 h (40%), an elimination half-life of 2.06 h (50%) and a potency of 1.54 pain relief units (24%). High dose acetaminophen (100 mg/kg) was no more effective than 40 mg/kg and was associated with increased nausea and vomiting. A target effect compartment concentration of 10 mg/l is expected to produce a pain reduction of 2.6 units. The placebo model accounted for a maximum pain reduction of 5.6 units at 3 h. The combination of placebo effect and preoperative acetaminophen 40 mg/kg results in pain scores below 4 units for 5 h postoperatively.
Anesthesiology. 2001 Mar;94(3):385-9.
Initial and subsequent dosing of rectal acetaminophen in children: a 24-hour pharmacokinetic study of new dose recommendations.
Birmingham PK1, Tobin MJ, Fisher DM, Henthorn TK, Hall SC, Coté CJ.
BACKGROUND:
Recent studies have determined that an initial rectal acetaminophen dose of approximately 40 mg/kg is needed in children to achieve target antipyretic serum concentrations. The timing and amount of subsequent doses after a 40-mg/kg dose has not been clarified for this route of administration. Based on the authors' previous pharmacokinetic data, they examined whether a 40-mg/kg loading dose followed by 20-mg/kg doses at 6-h intervals maintain serum concentrations within the target range of 10-20 microg/ml, without evidence of accumulation.
METHODS:
Children (n = 16) received rectal acetaminophen (40 mg/kg) and up to three additional doses of 20 mg/kg at 6-h intervals. Venous blood samples were taken every 30 min for 4 h, then every 60 min for 4 h, and every 4 h for 16 h. The authors assessed whether their published pharmacokinetic parameters predicted the acetaminophen concentrations in the present study. They also assessed their dosing regimen by determining the fraction of time each individual maintained the target concentration.
RESULTS:
All patients received the initial loading dose; 10 of 16 patients received three subsequent doses. Serum concentrations with the initial dose were in the target range 38 +/- 25% of the time. With subsequent dosing, the target range was maintained 60 +/- 29% of the time. The highest serum concentration with initial or subsequent dosing was 38.6 microg/ml. Pharmacokinetic parameters from the earlier study predicted the serum concentrations observed for both initial and subsequent doses.
CONCLUSIONS:
A rectal acetaminophen loading dose of 40 mg/kg followed by 20-mg/kg doses every 6 h results in serum concentrations centered at the target range of 10-20 microg/ml. There was large interindividual variability in pharmacokinetic characteristics. There was no evidence of accumulation during the 24-h sampling period. PMID 11374595
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