Comparative effectiveness of balanced fluids versus normal saline to reduce acute and chronic kidney disease in children with sepsis

点击翻译按钮获取中文摘要

PROJECT SUMMARY Acute kidney injury (AKI) is a risk factor for adverse outcomes in critically ill children, including prolonged hospitalization, disability, and death. AKI is particularly significant for children with sepsis, a medical emergency due to life-threatening organ dysfunction from infection that affects over 72,000 children in the US and four million children worldwide each year. Children with sepsis-induced AKI and acute kidney disease (AKD, persistent kidney dysfunction of <90 days duration) may also be at risk for chronic kidney disease (CKD). Specific risk factors for AKI and CKD among children with sepsis remain poorly defined and, importantly, gaps remain in identifying the best therapies to prevent sepsis-induced AKI, AKD, and CKD. Crystalloid fluid, the cornerstone of resuscitation for septic shock, has key biological effects on kidney function. Emerging data in adults suggest that resuscitation with 0.9% “normal” saline (NS) is more likely to induceAKI and AKD compared to resuscitation with balanced fluids (BF). Few data on the impact of fluid resuscitation on kidney function in children exist. In this study, we will perform an ancillary study to the PRagMatic Pediatric Trial of Balanced vs. nOrmaL saline flUid in Sepsis (PRoMPT BOLUS) randomized clinical trial. That trial is randomizing children in emergency departments with suspected septic shock to fluid resuscitation with either NS or BF. The trial will determine the comparative effectiveness of different crystalloids on 30-day kidney function and death in children with suspected septic shock. However, data on outcomes such as AKI or CKD will not be collected in direct follow-up of trial participants. A remaining knowledge gap after trial completion will therefore be whether BF resuscitation in pediatric sepsis protects against AKI and translates to a decrease in CKD. To assess these important kidney outcomes, we will use the Pediatric Center of Excellence in Nephrology (PCEN) Learning Health System Core to link clinical trial data to electronic health record data available in PEDSnet (pedsnet.org) to augment trial outcome analyses. The primary objectives of this study are to: 1) assess whether resuscitation with BF instead of NS will decrease AKI and translate to a decrease in CKD in trial participants, and 2) measure the real-world impact of crystalloid fluid choice on sepsis-induced AKI and CKD in the larger PEDSnet source population. To achieve these objectives, we will utilize electronic health record data in PEDSnet to measure AKI and CKD in 2,450 children enrolled in the PRoMPT BOLUS study at 7 trial sites. To demonstrate generalizability of trial results using a real-world comparison, we will determine the impact of crystalloid fluid exposure on AKI and CKD in a broader cohort of over 16,600 children in PEDSnet presenting to an ED for treatment of septic shock using a quasi-experimental observational study design. We will also determine other risk factors for progression from AKI to AKD to CKD in children with sepsis. This proposal aligns with the PCEN goal to facilitate extensive collaborative research around the causes, diagnosis, and treatment of kidney diseases in children with increased efficiency and NIDDK’s mission to evaluate treatments to prevent the development of kidney disease.