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. 2022 Mar:172:173-180.
doi: 10.1016/j.resuscitation.2021.11.016. Epub 2021 Nov 22.

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

Jeremy R Herrmann  1 , Ericka L Fink  2 , Anthony Fabio  3 , Alicia K Au  2 , Rachel P Berger  4 , Keri Janesko-Feldman  1 , Robert S B Clark  2 , Patrick M Kochanek  5 , Travis C Jackson  6
Affiliations

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

Jeremy R Herrmann et al. Resuscitation. 2022 Mar.

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.

Keywords: Cold stress; Neuroprotection; Pediatric cardiac arrest; Therapeutic hypothermia.

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Conflict of interest statement

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).

Figures

Figure 1:
Figure 1:
Temperatures of the two cardiac arrest cohorts at the time of blood sampling.
Figure 2:
Figure 2:
Box plot comparing initial FGF21 and GDF-15 levels in the cardiac arrest group to PICU and healthy controls (Figure 2a and 2b, respectively). FGF21 and GDF-15 plotted on a log scale. Levels initially compared using a Kruskal-Wallis test between all groups (P=0.0001 for FGF21 and GDF-15). Individual group differences were then compared using a Wilcoxon Rank sum test (CA: n=32, PICU control: n=9, healthy controls: n=32 for FGF21, n=31 for GDF-15)
Figure 3:
Figure 3:
Box plot comparing initial FGF21 and GDF-15 levels post-arrest between hospital survivors and non-survivors (Figure 3a and 3b, respectively). FGF21 and GDF-15 plotted on a log scale. Groups compared using a Wilcoxon Rank sum test (survivors: n=21, non-survivors: n=6).
Figure 4:
Figure 4:
FGF21 and GDF-15 levels at each measured timepoint (a and b, respectively). FGF21 and GDF-15 plotted on a log scale.
Figure 5:
Figure 5:
Box plot examining the change in FGF21 and GDF-15 levels over the first 72h after cardiac arrest between the normothermia and therapeutic hypothermia (33°C for 72h) cohorts. Comparisons made using a Wilcoxon Rank sum test (hypothermia: n=14 for FGF21, n=13 for GDF-15, normothermia: n=9 both groups).
See this image and copyright information in PMC

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