Jeremy Herrmann
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania
Disclosure information not submitted.
Ericka Fink, MD, FCCM
Childrens Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania
Disclosure information not submitted.
Anthony Fabio, MPH, PhD
Associate Professor of Epidemiology
University of Pittsburgh, United States
Disclosure information not submitted.
Alicia Au, MD
Assistant Professor, Critical Care Medicine. Associate Medical Director, PICU
Children's Hospital of Pittsburgh of UPMC, United States
Disclosure information not submitted.
Rachel Berger, MD
Professor of Pediatrics and Clinical and Translational Science
Childrens Hospital of Pittsburgh of UPMC, United States
Disclosure information not submitted.
Keri Janesko-Feldman, B.S.
Lab Manager
University of Pittsburgh, United States
Disclosure information not submitted.
Robert Clark, MD, FCCM
Professor of Critical Care Medicine and Pediatrics
Childrens Hospital of Pittsburgh of UPMC, United States
Disclosure information not submitted.
.jpg "Patrick Kochanek, MD, MCCM photo")
Patrick Kochanek, MD, MCCM
Director, Safar Center for Resuscitation Research
UPMC Presbyterian
Pittsburgh, Pennsylvania
Disclosure information not submitted.
Travis Jackson, PhD
Associate Professor of Molecular Pharmacology and Physiology
University of South Florida, United States
Disclosure information not submitted.
Title: Divergent effects of therapeutic hypothermia on cold stress hormones after pediatric cardiac arrest
Introduction/Hypothesis: Cold-stressors stimulate production of cold stress hormones (CSHs) which promote thermogenesis and may be neuroprotective. Levels of CSHs after cold exposure have been assessed in healthy humans; it is unclear if cooling critically ill patients increases circulating CSHs. Fibroblast Growth Factor-21 (FGF21) and Growth Differentiation Factor-15 (GDF-15) are putative neuroprotective CSHs upregulated by cold exposure and other stimuli. FGF21 binds to the β-klotho co-receptor, activating downstream FGF receptors; GDF-15 binds to GDNF-family receptor α-like (GFRAL). β-klotho levels are abundant in infant brain, decrease with age (low-to-absent in adults) while GFRAL is absent across ages. This suggests that therapeutic hypothermia (TH) preferentially activates FGF21-mediated neuroprotection in infants/children vs adults. FGF21 also upregulates GDF-15. Both proteins associate with poor outcome in adult cardiac arrest (CA), which may reflect insult severity not neurotoxicity. This study examined whether FGF21 and GDF-15 are increased in the pediatric CA population and are augmented by TH.
Methods: We report a secondary analysis of serum samples collected in clinical trials and measured FGF21 and GDF-15 levels (ELISA) in pediatric patients post-CA. We compared post-CA levels to healthy controls and children admitted to the PICU for non-neurologic causes. We also compared levels at < 24h, 24h, 48h, and 72h in CA cohorts treated with normothermia (NT) vs TH (33°C for 72h) to test the hypothesis that CSHs are increased by TH, and to explore associations between hospital mortality and < 24h levels.
Results: We analyzed 144 samples from 68 patients (27 CA [14 TH, 13 NT], 9 PICU and 32 healthy controls). Initial FGF21 and GDF-15 were higher post-CA (392pg/mL, 7,089pg/mL, respectively) vs healthy controls (40pg/mL, 396pg/mL) (P < 0.001, P< 0.001 vs all groups). Mortality was associated with higher initial GDF-15 post-CA (19,450pg/mL vs 5,337pg/mL, P< 0.05), but not FGF21 (757pg/mL vs 248pg/mL, NS). At 72h, the change in FGF21 vs baseline was higher in TH (231pg/mL) vs NT (–20pg/mL) (P < 0.05), with no difference in GDF-15 (-2,816pg/mL vs -1,867pg/mL, NS).
Conclusion: Both CSHs increased after pediatric CA but only FGF21 responded to TH, warranting further study of its role in neuroprotection.