Septic shock continues to be a worldwide public health problem in both adults and children. Septic shock is a heterogeneous syndrome, not a discrete disease entity. Baseline mortality risk is widely variable, making it a major confounder for the conduct of interventional clinical trials. Current trial designs include patients with low baseline mortality risk who are unlikely to benefit from novel interventions beyond standard care, as well as patients having an extremely high baseline mortality risk who may be beyond salvage even with novel interventions. This can dilute the effect size for an experimental intervention that has benefit for patients between these extremes who have a significant, but modifiable mortality risk. Thus, an important and unmet clinical gap in the field is the lack of a robust stratification tool specific for septic shock. This proposal seeks to directly address this gap. We have derived and validated the Pediatric Sepsis Biomarker Risk Model (PERSEVERE). The biomarkers included in PERSEVERE were selected objectively based on extensive, discovery-oriented transcriptomic studies. Of note, the biomarkers are proteins measured in the blood compartment and are measured at the time of meeting clinical criteria for septic shock. We recently derived and validated the risk stratification model for adults using the same approach in 881 subjects from three different countries. The Adult Septic Shock Information and Stratification Technology (ASSIST) outperform both APACHE II and III. Consistent with our preliminary data, we propose that one application of ASSIST is to better inform the selection of patients for interventional clinical trials. In this competitive revision, we will test this concep by conducting a post hoc, risk-stratified analysis of the Protocolized Care for Early Septic Shock (ProCESS) Trial. The ProCESS Trial randomly allocated 1,341 adults with septic shock into one of three early resuscitation strategies: protocol-based early goal-directed therapy (EGDT); protocol-based standard therapy that did not require placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. An important component of the ProCESS trial was the banking of biological samples at multiple time points, coupled with extensive clinical annotations. Accordingly, the ProCESS trial has generated one the most extensive, contemporary clinical and biological repositories of adult septic shock available. In collaboration with the ProCESS Investigators, we will test the hypothesis that the potential benefits of protocolized care in patients with septic shock, relative to usual care, are dependent on baseline mortality risk as estimated by ASSIST. This focused, competitive revision represents a first step toward bridging two innovative, NIH-funded, sepsis research programs to address major gaps in the field. This highly focused effort will provide the foundation for more extensive collaborations in the near future. The major deliverable of this Aim is a direct test of the concept that baseline mortality risk-based selection is an effective means of conducting interventional clinical trials for septic shock.

Public Health Relevance

The deliverable of this proposal will be directly testing the hypothesis that reliable outcome risk stratification will enhance the conduct of clinical trials in sepsis. Public health will be positively impacted by the design of a novel approach to better inform enrollment procedures for sepsis-related clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM108025-02S1
Application #
8970115
Study Section
Special Emphasis Panel (ZRG1-SBIB-V (82))
Program Officer
Dunsmore, Sarah
Project Start
2014-05-01
Project End
2018-02-28
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
2
Fiscal Year
2015
Total Cost
$300,695
Indirect Cost
$89,730
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Wong, Hector R (2018) Embracing Enrichment and Unknown Unknowns. Crit Care Med 46:156-158
Wong, Hector R; Cvijanovich, Natalie Z; Anas, Nick et al. (2018) Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response. Crit Care Med 46:e242-e249
Yehya, Nadir; Wong, Hector R (2018) Adaptation of a Biomarker-Based Sepsis Mortality Risk Stratification Tool for Pediatric Acute Respiratory Distress Syndrome. Crit Care Med 46:e9-e16
Flores, Saul; Cooper, David S; Opoka, Amy M et al. (2018) Characterization of the Glucocorticoid Receptor in Children Undergoing Cardiac Surgery. Pediatr Crit Care Med 19:705-712
Stenson, Erin K; Cvijanovich, Natalie Z; Anas, Nick et al. (2018) Hyperchloremia Is Associated With Complicated Course and Mortality in Pediatric Patients With Septic Shock. Pediatr Crit Care Med 19:155-160
Wong, Hector R; Sweeney, Timothy E; Hart, Kimberly W et al. (2017) Pediatric Sepsis Endotypes Among Adults With Sepsis. Crit Care Med 45:e1289-e1291
Alder, Matthew N; Opoka, Amy M; Lahni, Patrick et al. (2017) Olfactomedin-4 Is a Candidate Marker for a Pathogenic Neutrophil Subset in Septic Shock. Crit Care Med 45:e426-e432
Wong, Hector R; Cvijanovich, Natalie Z; Anas, Nick et al. (2017) Improved Risk Stratification in Pediatric Septic Shock Using Both Protein and mRNA Biomarkers. PERSEVERE-XP. Am J Respir Crit Care Med 196:494-501
Flores, Saul; FitzGerald, Michael R; Iliopoulos, Ilias et al. (2017) An International Survey of Corticosteroid Use for the Management of Low Cardiac Output Syndrome. Pediatr Crit Care Med 18:630-637
Typpo, Katri V; Wong, Hector R; Finley, Stacey D et al. (2017) Monitoring Severity of Multiple Organ Dysfunction Syndrome: New Technologies. Pediatr Crit Care Med 18:S24-S31

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