Early fluid and norepinephrine resuscitation in septic acute kidney injury diminishes pro-inflammatory cytokine levels and kidney hypoperfusion in newborn pigs

Abstract

Background and Objective: Sepsis is the most frequent risk factor for acute kidney injury (AKI) in critically ill infants. Whereas sepsis-induced AKI has been studied in several animal models, alterations in renal microcirculation are unclear. The objective of this study was to use the translational swine model to evaluate the changes in renal hemodynamics during the early phase of sepsis in the first week of life. We also examined the impact of early fluid and norepinephrine (NE) resuscitation on renal hemodynamics in newborn septic AKI. Methodology: Newborn pigs (3-7 days old) were randomly allocated to three groups; 1) Sham, 2) Sepsis (cecal ligation and puncture; CLP) without subsequent resuscitation, and 3) CLP-induced sepsis with fluid and vasopressor NE resuscitation. All animals underwent standard anesthesia induction, mechanical ventilation, and intravenous fluid. Cardiac output (COP) and GFR were measured non-invasively using electrical velocimetry and a transdermal system. The pigs were instrumented to measure the mean arterial pressure (MAP), total renal blood flow (tRBF), cortical perfusion (coPf), and medullary perfusion (mePf). Also, a fiber-optic probe was placed in the medulla to measure medullary tissue oxygen tension (tPO2). Baseline values were recorded for the above indices in all groups. In resuscitated animals, fluid bolus and NE infusion were started at the 4-h to maintain MAP within 15 mmHg from baseline. The pigs were euthanized after twelve hours. Results: Compared to baseline values, MAP and COP decreased by more than two-thirds in non-resuscitated sepsis, with a proportional increase in RVR and reduction in tRBF, coPf, mePf, and tPO2 in contrast to sham. CLP also decreased GFR and increased serum creatinine, BUN, and NGAL. A few tubular coagulative necroses were observed in the septic pigs. Changes in all these parameters, except tPO2, were ameliorated in resuscitated pigs. Resuscitation also attenuated sepsis-induced increase in the levels of serum C-reactive protein, inflammatory cytokines (IL-6, IL-8, IL-12, and IL-18), liver enzymes (aspartate aminotransferase and alanine aminotransferase), and renal NLRP3 inflammasome. Conclusions: Early implementation of resuscitation to maintain MAP, COP, and kidney perfusion lessens the degree of inflammation, AKI, and liver injury in newborn pigs. The discrepancy between medullary perfusion and oxygenation indicates that optimizing perfusion and blood flow does not always correlate with improved medullary oxygen delivery in newborns, especially in cases of increased metabolic demand, as in sepsis. Sepsis is a dynamic illness with phases of hypodynamic and hyperdynamic renal perfusion; therefore, management strategies would differ based on hemodynamic status. NIH R01DK120595 and R01DK127625 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.