Modeling the respiratory depressant effect of opioids: application to fentanyl

The respiratory depressant effect of fentanyl is described quantitatively by using a mathematical model. The model is an extension of a previous one reproducing the human ventilatory control system on physiological bases. The model includes three compartments (lung, body tissue and brain tissue), the main mechanisms involved in respiratory regulation (peripheral and central chemoreceptors, and the central hypoxic depression), and local blood flow regulation. Fentanyl effects on respiratory system include a weakening of the peripheral and central chemoreceptor gains on ventilation, a depression of body metabolism, and a direct inhibition of respiratory activity. All parameter values in the model have been chosen in accordance with clinical data from the literature. The model, with suitable values of its parameters, is able to reproduce the main respiratory variables in a wide range of fentanyl plasma concentrations, showing that minute ventilation in spontaneously breathing subjects depends on two antagonistic actions: opiod inhibitory influences, which abate ventilation, and the consequent chemoreflex stimulation. Simulations of resumption of spontaneous breathing after artificial ventilation in anesthetized patients indicate that a safe resumption can be achieved through approaches that increase patient CO₂ tension, since they shorten the time for chemoreceptor activation to overcome fentanyl-induced inhibition of respiratory activity.