OBJECTIVES: Extracorporeal membrane oxygenation provides short-term cardiopulmonary life support, but is associated with peripheral innate inflammation, disruptions in cerebral autoregulation, and acquired brain injury. We tested the hypothesis that extracorporeal membrane oxygenation also induces CNS-directed adaptive immune responses which may exacerbate extracorporeal membrane oxygenation-associated brain injury.
DESIGN: A single center prospective observational study.
SETTING: Pediatric and cardiac ICUs at a single tertiary care, academic center.
PATIENTS: Twenty pediatric extracorporeal membrane oxygenation patients (0-14 yr; 13 females, 7 males) and five nonextracorporeal membrane oxygenation Pediatric Logistic Organ Dysfunction score matched patients.
MEASUREMENTS AND MAIN RESULTS: Venous blood samples were collected from the extracorporeal membrane oxygenation circuit at day 1 (10-23 hr), day 3, and day 7 of extracorporeal membrane oxygenation. Flow cytometry quantified circulating innate and adaptive immune cells, and CNS-directed autoreactivity was detected using an in vitro recall response assay. Disruption of cerebral autoregulation was determined using continuous bedside near-infrared spectroscopy and acquired brain injury confirmed by MRI. Extracorporeal membrane oxygenation patients with acquired brain injury (n = 9) presented with a 10-fold increase in interleukin-8 over extracorporeal membrane oxygenation patients without brain injury (p < 0.01). Furthermore, brain injury within extracorporeal membrane oxygenation patients potentiated an inflammatory phenotype in adaptive immune cells and selective autoreactivity to brain peptides in circulating B cell and cytotoxic T cell populations. Correlation analysis revealed a significant relationship between adaptive immune responses of extracorporeal membrane oxygenation patients with acquired brain injury and loss of cerebral autoregulation.
CONCLUSIONS: We show that pediatric extracorporeal membrane oxygenation patients with acquired brain injury exhibit an induction of pro-inflammatory cell signaling, a robust activation of adaptive immune cells, and CNS-targeting adaptive immune responses. As these patients experience developmental delays for years after extracorporeal membrane oxygenation, it is critical to identify and characterize adaptive immune cell mechanisms that target the developing CNS.
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Drs. Tian and Raman were supported, in part by, American Heart Association (AHA) Beginning-Grant-in Aid (15BGIA25860045). Drs. Pandiyan and Raman were funded by Extracorporeal Life Support Organization research grant and UT Southwestern Center for Translational Medicine award. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001105. Dr. Stowe was supported from the AHA (14SDG 18410020), National Institutes of Health/National Institute of Neurological Disorders and Stroke (NS088555), Dr. Ortega (14POST20480373) and Ms. Selvaraj (17PRE33660147) from the AHA.
Drs. Ortega’s, Pandiyan’s, Windsor’s, and Stowe’s institutions received funding from Extracorporeal Life Support Organization and National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award number UL1TR001105. Drs. Ortega, Pandiyan, Windsor, Torres, Raman, and Stowe received support for article research from the NIH. Dr. Tian’s institution received funding from the American Heart Association, and he disclosed work for hire.
Ortega, Sterling B.; Pandiyan, Poornima; Windsor, Jana; Torres, Vanessa O.; Selvaraj, Uma M.; Lee, Amy; Morriss, Michael; Tian, Fenghua; Raman, Lakshmi; and Stowe, Ann M., "A Pilot Study Identifying Brain-Targeting Adaptive Immunity in Pediatric Extracorporeal Membrane Oxygenation Patients with Acquired Brain Injury" (2019). Neurology Faculty Publications. 62.