Bryan DeHaven

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.

Real-time continuous estimation of gas exchange by dual oximetry

We designed a ventilation-perfusion index (VQI) to estimate venous admixture (Qsp/Qt) in a real-time fashion by simultaneous pulse and pulmonary artery oximetry in 17 patients with acute respiratory failure. Changes in Qsp/Qt were produced by altering the level of continuous positive airway pressure. VQI correlated well with Qsp/Qt (r=0.78). This contrasts with the poor correlation found between Qsp/Qt and the commonly used oxygen tension based indices such as PaO2/FIO2 (r=-0.51), PaO2/PAO2 (r=-0.47), and PAO2-PaO2 (r=0.23). The use of dual oximetry to derive a VQI appears to be a reliable and accurate method for real-time assessment of pulmonary gas exchange in patients with acute respiratory failure.

Estimation of oxygen utilization by dual oximetry.

Total body oxygen utilization coefficient was estimated using continuous pulse and pulmonary artery oximetry (dual oximetry) in 17 patients with respiratory failure. Change in arterial and mixed venous oxygen saturations was induced by altering airway pressure. Continuous measurement of mixed venous oxygen saturation provided an accurate and linear estimate of oxygen utilization coefficient (r = -0.92), the true values being overestimated by 0.05 +/- 0.06 (mean +/- SD). Addition of pulse oximetry improved the correlation (r = 0.93) and decreased the difference between absolute values (0.02 +/- 0.06). Oxygen utilization coefficient can be estimated reliably in an online fashion using pulmonary artery oximetry. However, the use of dual oximetry will further improve the estimate.

A model to decrease hepatic blood flow and cardiac output with pressure breathing

This randomized, controlled, crossover study evaluated the effect of continuous positive airway pressure (CPAP) breathing on hepatic blood flow (HBF) and cardiac output in 10 healthy male subjects. A CPAP mask was placed on the face and the subject breathed at either CPAP 12.5 cm H2O or ambient airway pressure. The estimated HBF was calculated as the ratio of indocyanine green plasma clearance to one minus the hematocrit. Cardiac output was measured with Doppler ultrasound. CPAP caused HBF to decrease in 8 of 10 subjects (14.1% ± 15.3%, mean ± SD, p = 0.033) and cardiac index (CI) to decrease in all subjects (14.1% ± 5.7%, p = 0.0001). Stroke volume and respiratory rate were significantly decreased; heart rate was unchanged. These results indicate that CPAP at 12.5 cm H2O causes a small, but significant decrease in both HBF and CI.

TITRATION OF CONTINUOUS POSITIVE AIRWAY PRESSURE BY REAL-TIME DUAL OXIMETRY

The clinical utility of combined pulse and pulmonary artery oximetry (dual oximetry) in titrating continuous positive airway pressure (CPAP) therapy was tested in 17 patients with acute respiratory failure. The level of CPAP was altered in 2.5 cmH2O increments and decrements, while conventional measurements of cardiopulmonary function and continuous dual oximetry were performed. Then, optimum CPAP levels were selected using both techniques independently. The difference in optimum CPAP determined by the two methods was 0 cmH2O in ten of 17 patients, less than or equal to 2.5 cmH2O in 14 of 17 patients, and 5.0 to 7.5 cmH2O in the remaining three patients. When a difference existed, CPAP level determined with dual oximetry was consistently lower than the level selected by conventional means. The results indicate that the estimates of venous admixture and oxygen utilization coefficient obtained using dual oximetry provide sufficient information for rapid and accurate titration of CPAP in the majority of patients with acute respiratory failure.