Physiologic implications of mechanical ventilation on pharmacokinetics

Numerous factors present in the critically ill patient decrease drug clearance. The contribution of one factor, mechanical ventilation, to this decrease is largely unknown and unquantified. This article attempts to review the physiologic effects of mechanical ventilation and to propose theoretical changes in the pharmacokinetics of concomitantly administered drugs. Mechanical ventilation with or without positive end-expiratory pressure is a well-documented cause of decreases in cardiac output, hepatic and renal blood flow, glomerular filtration rate, and urine flow. The mean airway pressure delivered, the pathophysiologic state of the patient, and coexisting therapeutic interventions affect the degree of hemodynamic alteration. Theoretically, these hemodynamic changes can decrease the clearance of several drugs frequently administered to critically ill patients. Decreased hepatic blood flow decreases the clearance of nonrestrictively cleared drugs. The pharmacokinetics of drugs predominantly renally cleared, by either glomerular filtration or tubular secretion, are affected by a decrease in renal blood flow or glomerular filtration rate. Also, the clearance of agents for which tubular reabsorption is important may decrease because the reduction in urine flow resulting from mechanical ventilation allows increased time for drug reabsorption. Interventions that minimize the decrease in cardiac output and organ blood flow and, theoretically, the risk of the adverse drug reactions from decreased drug clearance include expansion of intravascular volume, administering positive inotropic agents, and decreasing mean airway pressure. Monitoring serum concentration of critical and toxic agents suspected to have altered clearance in patients receiving mechanical ventilation is recommended. We hope that our article will stimulate future research in this area to give clinicians guidelines for drug dosing in patients receiving mechanical ventilation.