Pharmacokinetic–pharmacodynamic modeling of the hypotensive effect of remifentanil in infants undergoing cranioplasty

Objectives:  Although remifentanil has been used to induce hypotension during surgery in infants, no pharmacokinetic–pharmacodynamic (PKPD) model exists for its quantitative analysis. Our aim was to determine the quantitative relationship between whole blood remifentanil concentration and its hypotensive effect during surgery in infants.
Methods/materials:  We studied seven infants (age 0.3–1 year) who underwent cranioplasty surgery and received remifentanil delivered by a computer-controlled infusion pump during the maintenance of anesthesia. Arterial blood samples to determine remifentanil concentration and mean arterial blood pressure (MAP) measurements were collected. A simultaneous PKPD mixed-effects model was built in NONMEM.
Results:  A total of 77 remifentanil concentrations and 185 MAP measurements were collected. Remifentanil pharmacokinetics was described with a two-compartment model, parameter estimates were 2.99 l·min⁻¹·70 kg⁻¹ for clearance and 16.23 l·70 kg⁻¹ for steady state volume of distribution. Mean baseline MAP was 69.7 mmHg and was decreased as per clinical requirements. A sigmoidal E _max model driven by an effect compartment described the decrease in MAP, with an estimated concentration to decrease MAP by half (EC₅₀) being 17.1 ng·ml⁻¹.
Conclusions:  Remifentanil is effective in causing hypotension. The final model predicts that a steady state remifentanil concentration of 14 ng·ml⁻¹ would typically achieve a 30% decrease in MAP.