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 disposition kinetics and hemodynamic response to sepsis, as well as vital support therapy, in critically ill patients with sepsis.

DESIGN

Cross-sectional study of critically ill patients with sepsis undergoing physiologic and aminoglycoside pharmacokinetic monitoring.

SETTING

Ten-bed general intensive care unit in a tertiary care center.

PATIENTS

Thirty consecutive critically ill patients who had Gram-negative sepsis treated with amikacin and who were undergoing hemodynamic monitoring.

INTERVENTIONS

Clinical, hemodynamic, oxygenation, and amikacin pharmacokinetic data were obtained simultaneously in each patient during aminoglycoside therapy.

MEASUREMENTS AND MAIN RESULTS

Aminoglycoside pharmacokinetic values were estimated from serum amikacin concentration-time data using a nonlinear least squares regression computer program, assuming a one-compartment infusion pharmacokinetic model. Individual pharmacokinetic values were subjected to statistical analysis to explain their variability. Selection of the subset of variables to be used in the final model was performed by combining principal component analysis and multiple stepwise linear regression. The mean prediction error and the root mean square error, as expressions of bias and precision, were estimated. Mean volume of distribution was 0.47 L/kg, with a coefficient of variation of 35%. Mean serum amikacin clearance was 60.2 mL/min, with a coefficient of variation of 34%. Seventy-six percent of the variability in volume of distribution was explained by three covariates: body weight (p < .0001); oxygen extraction (p < .001); and serum albumin (p < .001). For serum amikacin clearance, 70% of the variability 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 hemodynamic response and vital support measures have a significant influence on the disposition kinetics of amikacin in severely ill patients with sepsis. Consideration of hemodynamic response and vital support measures, in addition to other previously described covariates, can be of great value in the design of initial dosing regimens.