Septic shock is a common cause of morbidity and mortality in children, and acute kidney injury (AKI), a common complication of sepsis, can worsen outcomes. One of the reasons for this worsening in prognosis may be related to the accumulation of fluid occurring in many critically ill children (Alobaidi et al. Crit Care Med. 2020;48:1034-1041; Abulebda et al. Crit Care Med. 2014;42:397-403). However, it is difficult at times to identify which patients will develop AKI and/or fluid overload and whether these patients might have improved outcomes with renal protective measures. Stanski et al (Am J Respir Crit Care Med. 2020;201:848-855) sought to determine whether the Pediatric Sepsis Biomarker Risk Model (PERSEVERE II), a validated biomarker risk stratification tool to estimate baseline mortality risk in pediatric septic shock, could be used on admission to estimate the risk of developing severe AKI on day 3 of pediatric septic shock.
This study is a secondary analysis of a prospective observational cohort study of children admitted with septic shock to 14 pediatric intensive care units (PICUs) in the United States (Wong et al. Sci Transl Med. 2019;11: eaax9000).Biomarkers and platelet counts were drawn from these patients within the first 24 hours after severe septic shock diagnosis per the PERSEVERE II protocol. The studied biomarkers included C-C chemokine ligand 3, granzyme B, heat shock protein A1B (HSPA1B), interleukin-8 (IL-8), and matrix metallopeptidase 8. The primary outcome focused on the association between PERSEVERE II mortality probability and the development of severe AKI (as defined by the Kidney Disease: Improving Global Outcomes score) on day 3. Secondary outcomes aimed to determine the association of PERSEVERE II and the use of renal replacement therapy (RRT) and of renal recovery in patients with early AKI.
Stanski et al examined a study cohort of 379 patients, of whom 65 (17%) developed severe AKI on day 3. Compared to those without severe AKI on day 3, those who developed AKI had higher Pediatric Risk of Mortality (PRISM) III scores, higher 28-day mortality, and greater PICU lengths of stay. After adjusting for PRISM III score and age, the PERSEVERE II mortality probability was found to be independently associated with the development of AKI on day 3. Additionally, those patients with higher PERSEVERE mortality probabilities had an increased need for RRT and decreased renal recovery.
Despite these associations, Stanski et al determined that the ability of PERSEVERE II to predict day-3 AKI was not robust enough for clinical utility, as the data reflected a sensitivity of 62% and a specificity of 69%. So they developed a new classification and regression tree for estimating the risk of developing day-3 AKI that incorporated the PERSEVERE II mortality probability, the severity of AKI on day 1, and a specific subset of biomarkers (specifically IL-8, HSPA1B, and granzyme B). Using this new model, they demonstrated a sensitivity of 92%, specificity of 89%, positive predictive value of 64%, and negative predictive value of 98%.
While the assays used to determine these biomarkers are not currently available on a large scale, this study is an important first step in the development of new strategies in the management of children with septic shock. Early recognition of the development of AKI could be used to initiate proactive therapies, including early RRT to prevent fluid overload or renal protective measures. Furthermore, early recognition of AKI could be useful in identifying cohorts for further sepsis trials.
Author of this installment of Concise Critical Appraisal:
Daniel E. Sloniewsky, MD, FCCM, is an associate professor in the Division of Pediatric Critical Care Medicine in the Department of Pediatrics at Stony Brook Long Island Children’s Hospital. Dr. Sloniewsky is an editor of Concise Critical Appraisal.