Understanding time to peak effect of propofol as sole agent on bispectral index in children aged 2-12 years

Abstract

Background: The pharmacodynamics of propofol in children have previously been described with the proprietary bispectral index (BIS) as an effect-site marker, and it has been suggested that the rate of onset of propofol might be age dependent, that is, a shorter time to peak effect in younger children. However, these analyses were potentially confounded by co-administered drugs, in particular opioids and benzodiazepines. Thus, the goal of this prospective study was to characterize the influence of age and weight on the onset of hypnotic effects from propofol, reflected by the time to peak of propofol effect-site concentration in the absence of additional drugs.

Methods: A total of 46 healthy children aged 2-12 years presenting for elective surgery were included in our observational cohort study. Solely propofol was administered via a target-controlled infusion pump programmed with the Paedfusor pharmacokinetic model. The BIS and infusion pump data were recorded. The effect of an induction "bolus" was recorded having stopped the pump once a propofol plasma target concentration of 7 μg.mL^-1 was achieved. A direct-response and an indirect-response model in the context of nonlinear mixed-effects modeling was used to characterize and compare BIS data in children aged 2-6 years and older children aged 8-12 years.

Results: Time to peak of propofol effect-site concentration had a difference (p-value <.01) for age and weight, that is 84 [74, 96] (median [IQR] secs for children aged 2-6 years vs. 99 [91, 113] secs for children aged 8-12 years and 82 [71, 95] secs for weight 11-25 kg vs. 99 [91, 114] secs for weight 30-63 kg). The plasma effect-site equilibration rate constant for propofol had a heterogeneous distribution with a median of 2.36 (IQR: 2.05-2.93; range: 0.83-7.31) per minute but showed a weight-dependent effect in patients with weight below 45 kg.

Conclusions: In children, the age and weight have an influence on time to peak effect of propofol. In the absence of opioids and benzodiazepines, time to peak effect was approximately 20% longer in children aged 8-12 years as compared to younger children. Such clinically relevant age and weight effects are an important consideration in the individualized titration of propofol dosing.

Keywords: EEG; anesthesia; bispectral index; mathematical model; peak effect; pediatrics; pharmacodynamics; pharmacometrics; propofol.