This reinforces the mechanistic connection between the alternate treatment regimen and protein C levels. Since MEK162 606143-89-9 the patients with severe protein C deficiency could potentially have the greatest increases in protein C activity given their very low starting points, one logically would predict that the relative impact of a variable dose and duration would be more extensive and thus one cannot assume that the effect of higher doses in the moderately protein C deficient group would be similar. Third, and similarly, among moderately deficient individuals protein C levels did not diverge until subjects actually could be treated differentially. Fourth, and reflecting the effect of absolute changes in protein C levels, fewer patients treated under the alternative therapy strategy had final protein C levels that either fell or failed to increase.

As noted above, the option for an extended infusion appeared to have a more modest impact than that noted with a higher dose coupled with the option for an extended duration. In part this reflects a numerical fact that there was essentially more potential for an increase in protein C values for those starting with very low protein C levels. However and perhaps more importantly, around half of subjects in the moderate deficiency group randomized to the option of an extended duration actually only required a 96 hr infusion at 24 ��g/kg/hr. This observation suggests that the dose administered in PROWESS [3] and currently approved for clinical use by regulatory authorities is likely correct for most patients.

In contrast to PROWESS [3], we observed that many subjects had only moderately suppressed protein C levels after 24 hours of standard therapy. In PROWESS [3], approximately 40% of subjects had severe protein C deficiency [11] while in our study only approximately 20% had a similar deficiency. This may in part be due to the relatively smaller sample size of the current study. However, it may reflect that physicians are either identifying subjects earlier in the course of their sepsis or, perhaps, treating patients more aggressively at presentation [16]. In other respects, our population appears similar to others reported in trials either assessing novel therapies for severe sepsis or describing the epidemiology of this syndrome. For example, the vast majority of subjects we enrolled required both vasopressors and mechanical ventilation and the lung was the most common site for infection.

With respect to safety, the overall rates of serious bleeding events mirror those seen in previous DAA studies (PROWESS [3], ENHANCE [17]). However, in the moderately protein C deficiency group, there were higher rates of serious bleeding in patients receiving alternative therapy, which is difficult to explain as the majority of these events Brefeldin_A occur during the first four days when patients are receiving the same treatment.