Pharmacokinetic-pharmacodynamic modeling of the hypotensive effect of remifentanil in infants undergoing cranioplasty.
OBJECTIVE
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
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 x min(-1) x 70 kg(-1) for clearance and 16.23 l x 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 (EC(50)) being 17.1 ng x 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.
Standing
Joseph F
JF
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Hammer
Gregory B
GB
Sam
Wai Johnn
WJ
Drover
David R
DR
D000465:Algorithms; D000771:Anesthesia, Intravenous; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003399:Craniotomy; D003625:Data Collection; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007023:Hypotension, Controlled; D007223:Infant; D007231:Infant, Newborn; D007260:Infusion Pumps; D016014:Linear Models; D015233:Models, Statistical; D008991:Monitoring, Physiologic; D018579:Patient Selection; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077208:Remifentanil
D018686:Anesthetics, Intravenous; D010880:Piperidines; D000077208:Remifentanil