Neither the dose of antibiotic nor the class of antibiotic is affected by a procalcitonin level. Our protocol resulted in frequent and direct adjustments in DAA infusions and www.selleckchem.com/products/FTY720.html affords a potentially novel way to shift paradigms in how we treat critically ill patients. Thus, as a proof of concept, our trial emphasizes that it is indeed possible to titrate and individualize novel therapies in critically ill patients. Furthermore, it is possible to study such interventions in a rigorous fashion. Currently, however, we would not recommend titration of DAA outside the clinical trial setting.It is worth noting that the restoration of normal protein C measurements does not necessarily account for all of the treatment effect of DAA.

In an analysis from PROWESS [3] and ENHANCE [17] patients to test which biomarkers could serve as surrogate end-points by predicting clinical benefit, restoration to normal protein C level accounted for 57% of the treatment effect [9]. Indeed, the key test of protein C as a clinically relevant biomarker with which to titrate DAA therapy will come from a future phase 3 study powered to investigate if normalization of plasma protein C levels by DAA correlates with patient benefit.Our study has some limitations. These include stratification of patients to moderate and severe deficiency at 24 hours rather than at baseline, which delayed some patients receiving higher doses, and also resulted in an imbalance of numbers between the severe deficiency alternative and standard therapy groups.

This study design was incorporated to ensure that only patients who remained at high-risk of early death despite 24 hours of standard therapy were exposed to higher doses. However, now that this study has collected additional safety information related to higher doses this would most likely not be repeated in potential future studies. During this 24-hour common treatment period, the slight imbalance in protein C deficiency noted at baseline between treatment group became statistically significant in the moderately deficient subgroups. Alternative therapy only differed from standard therapy after study Day 4, so there was no opportunity for alternative therapy to improve protein C levels until after this point in time and although the percent change was higher for alternative therapy compared to standard, absolute levels actually remained lower than standard therapy for the majority of the infusion period (Figure (Figure3).3). Given the link demonstrated in this and other studies between lower protein C levels and Cilengitide higher mortality, it is possible that these baseline differences in protein C that remained for much of the infusion period, may have contributed, at least in part, to the observed mortality differences.

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