Serum fibroblast growth factor 21 levels after out of hospital cardiac arrest are associated with neurological outcome

Pirkka T Pekkarinen,Marjaana Tiainen,Pekka Jakkula,Pekka Loisa,Ville Lievonen,Johanna Hästbacka,Laura Albrecht,Markus B Skrifvars,Matti Reinikainen,Ville Pettilä

doi:10.1038/s41598-020-80086-7

Abstract

Fibroblast growth factor (FGF) 21 is a marker associated with mitochondrial and cellular stress. Cardiac arrest causes mitochondrial stress, and we tested if FGF 21 would reflect the severity of hypoxia-reperfusion injury after cardiac arrest. We measured serum concentrations of FGF 21 in 112 patients on ICU admission and 24, 48 and 72 h after out-of-hospital cardiac arrest with shockable initial rhythm included in the COMACARE study (NCT02698917). All patients received targeted temperature management for 24 h. We defined 6-month cerebral performance category 1–2 as good and 3–5 as poor neurological outcome. We used samples from 40 non-critically ill emergency room patients as controls. We assessed group differences with the Mann Whitney U test and temporal differences with linear modeling with restricted maximum likelihood estimation. We used multivariate logistic regression to assess the independent predictive value of FGF 21 concentration for neurologic outcome. The median (inter-quartile range, IQR) FGF 21 concentration was 0.25 (0.094–0.91) ng/ml in controls, 0.79 (0.37–1.6) ng/ml in patients at ICU admission (P < 0.001 compared to controls) and peaked at 48 h [1.2 (0.46–2.5) ng/ml]. We found no association between arterial blood oxygen partial pressure and FGF 21 concentrations. We observed with linear modeling an effect of sample timepoint (F 5.6, P < 0.01), poor neurological outcome (F 6.1, P = 0.01), and their interaction (F 3.0, P = 0.03), on FGF 21 concentration. In multivariate logistic regression analysis, adjusting for relevant clinical covariates, higher average FGF 21 concentration during the first 72 h was independently associated with poor neurological outcome (odds ratio 1.60, 95% confidence interval 1.10–2.32). We conclude that post cardiac arrest patients experience cellular and mitochondrial stress, reflected as a systemic FGF 21 response. This response is higher with a more severe hypoxic injury but it is not exacerbated by hyperoxia.

Highlights

Cardiac arrest causes great morbidity, mortality and economic loss[1]
Blood samples available for analysis included 111 samples collected at ICU admission [median (IQR) delay from collapse to admission sample was 200 (160–230) min], 111 samples collected at 24 h, 109 samples collected at 48 h and 106 samples collected at 72 h
We found no association between arterial blood oxygen partial pressures ( PaO2) and the Fibroblast growth factor (FGF) 21 concentrations in patients after cardiac arrest

Summary

Introduction

Cardiac arrest causes great morbidity, mortality and economic loss[1]. Neurological injury is the most common cause of death during post-resuscitation care[2] and less than half of those successfully resuscitated survive without neurological sequelae[3]. The brain is vulnerable to the hypoxia-reperfusion injury in cardiac arrest due to its high metabolic activity and limited energy reserves[5], and extracerebral organ failure complicates. Oxidative and inflammatory stress activate the integrated mitochondrial stress response leading to FGF 21 upregulation in the liver and the pancreas, and in skeletal muscle and adipose tissue[11,12]. Due to the pivotal role of mitochondria in oxidative metabolism and oxidative stress we tested the hypothesis that FGF 21 would reflect the severity of hypoxia-reperfusion injury after cardiac arrest. Based on previous reports from animal models of brain ischaemia indicating that hyperoxic reperfusion exacerbates mitochondrial d ysfunction[16] and impairs long-term neurological r ecovery[17], we asked, if post-arrest arterial blood oxygen partial pressure (PaO2) has an impact on the FGF 21 response

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Conclusion