The pharmacokinetics of a high intravenous dose of paracetamol after caesarean delivery: the effect of gestational age.

CONTEXT: Pregnancy affects intravenous paracetamol pharmacokinetics, but there are no studies on covariates of intravenous paracetamol pharmacokinetics around delivery. OBJECTIVES: To document the impact of gestational age at delivery on pharmacokinetics of a high intravenous dose of paracetamol. DESIGN: Pharmacokinetic study in women shortly after caesarean delivery. This study is an alternative analysis of a previously published study, using the same cohort but with added participants. SETTING: Single, tertiary perinatal care centre. PATIENTS: Of 36 patients recruited, pharmacokinetics analysis was performed in 34. Shortly following caesarean delivery, women received a loading dose (2 g) of intravenous paracetamol and four (at 1, 2, 4 and 6 h) plasma samples were collected. Of these 36 women, 28 had already been reported, but without further discrimination between preterm and term delivery, or any other covariate. Individual pharmacokinetic profiles were calculated assuming a linear one-compartment model with instantaneous input, first-order output. Covariates of between individual variability (preterm vs. term, maternal disease vs. healthy, twin vs. singleton pregnancy) of individual pharmacokinetics within this cohort were explored (Mann-Whitney U-test). MAIN OUTCOME MEASURES: Individual paracetamol pharmacokinetics. RESULTS: Mean (SD) paracetamol clearance was 22.4 l h(-1) (9.3) or - when corrected for body surface area - 11.5 l h(-1) m(-2) (4.0). No significant effects of twin pregnancy (n = 8) or maternal co-morbidity (n = 3) were observed, but mean clearance after preterm delivery (n = 12, <37 weeks gestational age) was significantly higher [13.8 (5.7) vs. 10.2 l h(-1) m(-2) (1.9), P = 0.028] compared with term delivery (n = 22). Similarly, there was a difference in mean distribution volume [0.83 (0.25) vs. 0.69 l kg(-1) (0.1), P = 0.037], resulting in the absence of differences in median elimination half-life [112 (28) vs. 119 min (19)]. CONCLUSION: Women who underwent a preterm caesarean delivery had a higher paracetamol clearance compared with term delivery. These pharmacokinetic differences illustrate the relevance of performing pharmacokinetic studies at delivery. We encourage clinicians to perform similar studies for other drugs administered in this group. TRIAL REGISTRATION: EudraCT 2010-020164-37.

Does intravenous paracetamol administration affect body temperature in neonates?

INTRODUCTION: Intravenous paracetamol (acetaminophen) has recently been registered for treatment of pain in neonates but the pharmacodynamics, including effects on body temperature, have not been reported. METHODS: A pooled analysis on body temperature recordings in neonates exposed to intravenous paracetamol was performed. Body temperature was recorded by skin probe and registered before and every 2 h following initiation of single or repeated intravenous paracetamol administration (up to 48 h). Repeated measures ANOVA and paired analysis were used to quantify differences following paracetamol exposure. RESULTS: The pooled analysis was based on 99 neonates (median weight 2.7 (range 0.5-5.4) kg, median postmenstrual age 37 (range 27-50) weeks). Based on observations in 93 normothermic (<37.8°C) neonates and six neonates with fever, it was documented that paracetamol administration does not affect body temperature in normothermic patients. In neonates with fever, the median decrease (-0.8°C) is most prominent in the first 2 h (p<0.01) following paracetamol administration with subsequent further normalisation. CONCLUSIONS: Administration of intravenous paracetamol does not result in hypothermia in normothermic neonates. In those with fever, maximal temperature reduction is achieved within 2 h following paracetamol administration.