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Although respiratory depression is the most well-known and dangerous side effect of opioids, no pharmacokinetic-pharmacodynamic model exists for its quantitative analysis. The development of such a model was the aim of this study.After institutional approval and informed consent were obtained, 14 men (American Society of Anesthesiologists physical status I or II; median age, 42 yr [range, 20–71 yr]; median weight, 82.5 kg [range, 68–108 kg]) were studied before they underwent major urologic surgery. An intravenous infusion of alfentanil (2.3 [micro sign]g [middle dot] kg-1 [middle dot] min-1) was started while the patients were breathing oxygen-enriched air (fraction of inspired oxygen [FIO(2)] = 0.5) over a tightly fitting continuous positive airway pressure mask. The infusion was discontinued when a cumulative dose of 70 [micro sign]g/kg had been administered, the end-expiratory partial pressure of carbon dioxide (PECO(2)) exceeded 65 mmHg, or apneic periods lasting more than 60 s occurred. During and after the infusion, frequent arterial blood samples were drawn and analyzed for the concentration of alfentanil and the arterial carbon dioxide pressure (PaCO(2)). A mamillary two-compartment model was fitted to the pharmacokinetic data. The PaCO(2) data were described by an indirect response model. The model accounted for the respiratory stimulation resulting from increasing PaCO(2). The model parameters were estimated using NONMEM. Simulations were performed to define the respiratory response at steady state to different alfentanil concentrations.The indirect response model adequately described the time course of the PaCO(2). The following pharmacodynamic parameters were estimated (population means and interindividual variability): EC50, 60.3 [micro sign]g/l (32%); the elimination rate constant of carbon dioxide (Kel), 0.088 min-1 (44%); and the gain in the carbon dioxide response, 4 (28%) (fixed according to literature values). Simulations revealed the pronounced role of PaCO(2) in maintaining alveolar ventilation in the presence of opioid.The model described the data for the entire opioid-PaCO(2) response surface examined. Indirect response models appear to be a promising tool for the quantitative evaluation of drug-induced respiratory depression.