Effects of propofol on vasopressor use in patients with sepsis and severe sepsis: A pilot study.

PURPOSE: Propofol is one of the most commonly used sedatives in the intensive care unit (ICU) despite its undesirable hypotensive effects. The purpose of this study was to determine the effects of continuous intravenous (CIV) propofol on vasopressor requirements in mechanically ventilated patients with sepsis. MATERIALS AND METHODS: A multicenter, retrospective, propensity-matched pilot study was conducted comparing patients with sepsis or severe sepsis who received CIV propofol for sedation to those who did not. The primary outcome was incidence of vasopressor support. Secondary outcomes included change in mean arterial pressure, mortality, and length of stay. RESULTS: A total of 279 patients (149 CIV propofol, 130 non-CIV propofol) were evaluated, with 174 patients matched 1:1 based on propensity score. There was no difference in vasopressor support requirements (49.4% vs 54%; P= .65) or in those experiencing a greater than 20% decrease in mean arterial pressure from baseline (58.6% vs 63.2%; P= .53) in the CIV propofol and non-CIV propofol groups. Furthermore, there were no differences in any secondary outcomes including hospital mortality (32.2% vs 33.3%; P= .87). CONCLUSIONS: Continuous intravenous propofol for sedation did not increase vasopressor requirements in this septic population. Furthermore, CIV propofol was not associated with significant differences in the use of multiple vasopressors, change in mean arterial pressure, length of stay, or mortality.

Mathematical formulation of additivity for antimicrobial agents.

The ability to describe and quantify pharmacodynamic interaction objectively is of paramount importance in the study of combination chemotherapy. Current methods based on Loewe additivity and Bliss independence are associated with implicit assumptions of the interacting system. We reviewed the hyperplane theorem that used a generalized equation for defining the isobols (surfaces of equal effect) for 2 noninteracting drugs. We showed that under certain conditions, the original equation might lead to nonintuitive results, which were inconsistent with the definition of additivity. To circumvent these limitations, an alternative model for defining additivity based on effect summation is proposed. This alternative definition for isobols deviates from the Loewe additivity, the null interaction criterion used as the foundation for Berenbaum's isobol equation. However, its results are simple, easily interpreted, and may be more applicable to a wide variety of clinical and experimental circumstances.

Novel approach to characterization of combined pharmacodynamic effects of antimicrobial agents.

There is considerable need for new modeling approaches in the study of combined antimicrobial effects. Current methods based on the Loewe additivity and Bliss independence models are associated with implicit assumptions about the interacting system. To circumvent these limitations, we propose an alternative approach to the quantification of pharmacodynamic drug interaction (PDI). Pilot time-kill studies were performed with 10(8) CFU of Pseudomonas aeruginosa/ml at baseline with meropenem or tobramycin alone. The studies were repeated with 25 concentration combinations of meropenem (0 to 64 mg/liter) and tobramycin (0 to 32 mg/liter) in a five-by-five array. The data were modeled with a three-dimensional response surface using effect summation as the basis of null interaction. The interaction index (Ii) is defined as the ratio of the volumes under the planes (VUP) of the observed and expected surfaces: VUP(observed)/VUP(expected). Synergy and antagonism are defined as Ii values of <1 and >1, respectively. In all combinations, an enhanced killing effect was seen compared to that of either drug at the same concentration. The most significant synergism was observed between 1 and 5 mg/liter of meropenem and between 1 and 4 mg/liter of tobramycin; seven out of nine combinations had a >2-log drop compared to the more potent agent. The Ii was found to be 0.76 (95% confidence interval, 0.65 to 0.91) for the concentration ranges of the agents. The results corroborate previous data indicating that meropenem is synergistic with an aminoglycoside when used in combination against P. aeruginosa. Our parametric approach to quantifying PDI appears robust and warrants further investigations.