RELATIONSHIP BETWEEN HEMODYNAMIC AND VITAL SUPPORT MEASURES AND PHARMACOKINETIC VARIABILITY OF AMIKACIN IN CRITICALLY ILL PATIENTS WITH SEPSIS

Objective: To examine the relationship between aminoglycoside disposit ion kinetics and hemodynamic response to sepsis, as well as vital supp ort therapy, in critically ill patients with sepsis. Design: Cross sec tional study of critically ill patients with sepsis undergoing physiol ogic and aminoglycoside pharmacokinetic monitoring. Setting: Ten bed g eneral intensive care unit in a tertiary care center. Patients: Thirty consecutive critically ill patients who had Gramnegative sepsis treat ed with amikacin and who were undergoing hemodynamic monitoring. Inter ventions: Clinical, hemodynamic, oxygenation, and amikacin pharmacokin etic data were obtained simultaneously in each patient during aminogly coside therapy. Measurements and Main Results: Aminoglycoside pharmaco kinetic values were estimated from serum amikacin concentration time data using a nonlinear least squares regression computer program, assu ming a one-compartment infusion pharmacokinetic model. Individual phar macokinetic values were subjected to statistical analysis to explain t heir variability. Selection of the subset of variables to be used in t he final model was performed by combining principal component analysis and multiple stepwise linear regression. The mean prediction error an d the root mean square error, as expressions of bias and precision, we re estimated. Mean volume of distribution was 0.47 L/kg, with a coeffi cient of variation of 35%. Mean serum amikacin clearance was 60.2 mL/m in, with a coefficient of variation of 34%. Seventy-six percent of the variability in volume of distribution was explained by three covariat es: body weight (p < .0001); oxygen extraction (p < .001); and serum a lbumin (p < .001). For serum amikacin clearance, 70% of the variabilit y was explained by three covariates: creatinine clearance (p < .001); positive end-expiratory pressure (p < .01); and use of catecholamines as vital support therapy (p < .05). Conclusions: Factors related to he modynamic response and vital support measures have a significant influ ence on the disposition kinetics of amikacin in severely ill patients with sepsis. Consideration of hemodynamic response and vital support m easures, in addition to other previously described covariates, can be of great value in the design of initial dosing regimens.