We envisage that PERSEVERE will be dynamic and require periodic updating. As we include more patients into the modeling process, some of the biomarker cutoff values www.selleckchem.com/products/Vorinostat-saha.html that drive the decision tree may change. It is also possible that new biomarkers are identified that might contribute to the decision tree, or that previously tested biomarkers might be useful for refining the risk stratification. This evolution would enhance predictive performance and further increase generalizability of the decision tree. These assertions are evident in the updating process involving the combined derivation and test cohorts. Finally, we also envisage that PERSEVERE could provide the foundation for deriving an analogous stratification model for adult septic shock.

A potential weakness of PERSEVERE is that it is focused on relatively short-term outcomes and does not evaluate longer-term outcomes. Twenty-eight day all-cause mortality has been a standard primary outcome measure for multiple septic shock interventional clinical trials, but its usefulness has been questioned and there is increasing recognition that septic shock has significant negative consequences for quality of life beyond the dichotomy of the patient being alive or dead at 28 days [1,5]. The PERSEVERE protocol was not specifically designed to assess longer-term outcomes. However, the increased illness severity found in the false-positive patients, compared to the true-negative patients, indirectly suggests that PERSEVERE may have the capability of stratifying longer-term outcomes, but this assertion requires formal testing.

We maintain that 28 day mortality remains a clinically relevant outcome variable in clinical septic shock; at the very least, one must be alive beyond 28 days in order to assess longer-term outcomes.Another potential weakness of our study is that it is difficult to unambiguously assign septic shock as the primary cause of death in all non-survivors. However, all-cause mortality is a common outcome variable in septic shock clinical trials, and the distribution of co-morbidities across the survivors and non-survivors indirectly suggests that many of the deaths could be, at least partially, attributed to septic shock per se.ConclusionsWe have derived and successfully tested a biomarker-based risk model to stratify pediatric septic shock outcome.

The basis of the model is a high throughput, relatively unbiased, microarray-based approach, and the derivation and test cohorts well represent the intrinsic heterogeneity and broad spectrum of pediatric septic shock encountered in clinical practice. We propose that PERSEVERE has the potential to substantially enhance the conduct of clinical trials, inform clinical Cilengitide decision making, and serve to inform septic shock-specific quality improvement measures.Key messages? We have derived a multi-biomarker-based risk model to predict outcome in pediatric septic shock.