Elsevier

Resuscitation

Volume 172, March 2022, Pages 173-180
Resuscitation

Clinical paper
Serum levels of the cold stress hormones FGF21 and GDF-15 after cardiac arrest in infants and children enrolled in single center therapeutic hypothermia clinical trials

https://doi.org/10.1016/j.resuscitation.2021.11.016Get rights and content

Abstract

Objective

Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor-15 (GDF-15) are putative neuroprotective cold stress hormones (CSHs) provoked by cold exposure that may be age-dependent. We sought to characterize serum FGF21 and GDF-15 levels in pediatric cardiac arrest (CA) patients and their association with use of therapeutic hypothermia (TH).

Methods

Secondary analysis of serum samples from clinical trials. We measured FGF21 and GDF-15 levels in pediatric patients post-CA and compared levels to both pediatric intensive care (PICU) and healthy controls. Post-CA, we compared normothermia (NT) vs TH (33 °C for 72 h) treated cohorts at < 24 h, 24 h, 48 h, 72 h, and examined the change in CSHs over 72 h. We also assessed association between hospital mortality and initial levels.

Results

We assessed 144 samples from 68 patients (27 CA [14 TH, 13 NT], 9 PICU and 32 healthy controls). Median initial FGF21 levels were higher post-CA vs. healthy controls (392 vs. 40 pg/mL, respectively, P < 0.001). Median GDF-15 levels were higher post-CA vs. healthy controls (7,089 vs. 396 pg/mL, respectively, P < 0.001). In the CA group, the median change in FGF21 from PICU day 1–3 (after 72 h of temperature control), was higher in TH vs. NT (231 vs. –20 pg/mL, respectively, P < 0.05), with no difference in GDF-15 over time. Serum GDF-15 levels were higher in CA patients that died vs. survived (19,450 vs. 5,337 pg/mL, respectively, P < 0.05), whereas serum FGF21 levels were not associated with mortality.

Conclusion

Serum levels of FGF21 and GDF-15 increased after pediatric CA, and FGF21 appears to be augmented by TH.

Introduction

Therapeutic hypothermia (TH) to 33 °C for 72 h is standard of care for term newborns with hypoxic-ischaemic encephalopathy (HIE).1 The neuroprotective benefit of TH in children and adults after cardiac arrest (CA) is less clear; thus, targeted temperature management (TTM) is recommended encompassing a wider range of temperatures including strict fever prevention.2, 3 Evidence suggests that neuroprotective cooling is more effective during early neurodevelopment, but factors that explain this observation remain to be defined.

Cold stress hormones (CSHs)—hormones upregulated by cold exposure–may mediate some aspects of neuroprotection during TH.4 To our knowledge, no study has examined the effect of TTM protocols in the intensive care unit (ICU) on serums levels of CSHs. Moreover, brown adipose tissue (BAT) plays a major role in CSH secretion. Germane to the observation that TH is more protective in early neurodevelopment, BAT content is abundant during infancy and is inversely correlated with age in adults.5, 6 Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor 15 (GDF-15) are two CSHs that show promise as putative neuroprotectants and are increased in adults after CA.4, 7, 8, 9, 10 We recently reported that the receptors for these ligands in the human brain are developmentally regulated (highest in newborns), supporting the concept that CSHs may mediate differences in the neuroprotective efficacy of TH in the very young vs. older cohorts with HIE.11, 12. Specifically, the FGF21 co-receptor (β-Klotho) was expressed in hippocampus and cortex and highly age dependent, with robust expression in infants vs. children or adults.11 The GDF-15 receptor (GFRAL) was minimal in these regions in the infant (<12-month) brain, but not seen in older children or adults.12 We now investigate serum levels of FGF21 and GDF-15 in a cohort of pediatric post-CA patients at our institution, managed for 72 h with either normothermia or 33 °C TH.

Section snippets

Methods

Design and Setting: This was a secondary analysis of prospectively collected serum samples from patients (n = 27) enrolled in clinical trials of pediatric CA at a single institution. We also included: (a) pediatric ICU (PICU) controls (n = 9) who were critically ill children admitted to the PICU for non-neurologic, non-CA aetiology with prospectively collected serum samples, and (b) healthy controls (n = 32) who were healthy children recruited at the outpatient phlebotomy lab at our

Results

The final analysis encompassed 56 samples from 14 CA patients receiving TH (32.0–34.0 °C for 72 h) and 47 samples from 13 CA patients in normothermia study arms, 9 samples from 9 PICU controls, and 32 samples from 32 healthy controls. The median age of CA patients was 7.8 yrs (IQR: 1.1–12.7) and did not differ vs. PICU controls (3.6 yrs; IQR: 2.5–10.6) or healthy controls (3.3 yrs; IQR: 1.0–7.1) (P = 0.49). The CA cohort was 44% male and did not differ vs. PICU controls (67%) or healthy

Discussion

To our knowledge this is the first characterization of FGF21 and GDF-15 levels in a pediatric CA population. Initial levels of FGF21 and GDF-15 significantly increased in serum from CA patients vs. healthy controls. Supporting our primary aim, TH was associated with augmented FGF21 levels over 72 h cooling vs. normothermia, but not for GDF-15. FGF21 levels were not associated with either mortality or 6-mo outcome, while higher initial GDF-15 levels were associated with increased rates of

Declaration of Competing Interest

Travis C. Jackson and Patrick M. Kochanek are co-inventors on a pending patent on the use of FGF21 therapy in temperature managed patients and titled “Method to Improve Neurologic Outcomes in Temperature Managed Patients.” (USPTO Application No. 15/573,006).

Acknowledgement

Supported by the Lloyd Reback Family Gift (JRH), T32HD040686 (JRH), R01NS105721 (TCJ), R01NS096714 (ELF), 5K23NS104133 (AKA), and UL1TR001857 (Pitt CTSI). Data were presented in part at Wolf Creek XVI. We thank Dave Maloney for assistance with the IRB process, and the patients and their families who agreed to participate in these studies.

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