Elsevier

Resuscitation

Volume 148, 1 March 2020, Pages 207-214
Resuscitation

Clinical paper
Serum tau as a predictor for neurological outcome after cardiopulmonary resuscitation

https://doi.org/10.1016/j.resuscitation.2020.01.022Get rights and content

Abstract

Aim

We evaluated serum tau protein as biomarker for poor neurological outcome over an extended observation period in patients after successful cardiopulmonary resuscitation (CPR) treated with mild therapeutic hypothermia (MTH) or normothermia (NT).

Methods

This is a retrospective analysis of a prospective observational study including 132 patients after successful CPR. Serum tau was determined in 24 h intervals for up to 168 h after CPR. Patients were treated with MTH targeting a temperature of 33 °C for 24 h or NT according to current guidelines. Neurological outcome was assessed with the Cerebral Performance Categories Scale (CPC) at hospital discharge.

Results

Forty-three percent of the patients were treated with MTH. Serial serum tau levels (pg/ml) showed a peak between 72–96 h after CPR (159 (IQR 27–625). Patients with poor neurological outcome (CPC 3–5) at hospital discharge (n = 68) had significantly higher serum tau levels compared to patients with good neurological outcome at 0–24 h (164 (48–946) vs. 69 (12–224); p = 0.009), at 24–48 h (414 (124–1049) vs. 74 (0–215); p < 0.001), at 48–72 h (456 (94–1225) vs. 69 (0–215); p < 0.001) and at 72–96 h (691 (197–1173) vs. 73 (0–170); p < 0.001). At 72–96 h the AUC to predict poor neurological outcome was 0.848 (95% CI: 0.737–0.959). Serum tau levels were not significantly different between patients with MTH and NT in multivariate analysis after adjusting for clinical relevant covariates.

Conclusion

Serum tau showed highest values and the best prognostic discrimination of poor neurological outcome at 72–96 h after CPR. Prolonged elevation may indicate ongoing axonal damage in patients with hypoxic encephalopathy.

Introduction

Despite advances in the critical care management of patients after out-of-hospital and in-hospital cardiac arrest (CA) including targeted temperature management (TTM),1, 2 favourable long-term outcomes only range between 7 and 22%.3, 4, 5, 6

Neuro-prognostication remains difficult and is currently based on a multimodal approach including clinical assessment, electroencephalography, somatosensory evoked potentials (SSEP), neuroimaging and blood derived biomarkers.7, 8 Neuron–specific enolase (NSE) is still considered as the gold standard9, 10 and is used beside S-100B,11, 12, 13, 14 and others including secretoneurin (SN),15 glial fibrillary acidic protein (GFAP),12, 16 brain- derived neurotrophic factor (BDNF)12 and neurofilament light chain (NF-L).17

Recently serum tau levels showed a high accuracy in predicting poor outcome after out-of-hospital cardiac arrest (OHCA) independent if mild hypothermia (MTH) (33 °C) or normothermia (NT) (°36 °C) was applied.18 In two smaller observational studies, delayed increase of serum tau was associated with poor outcome in hypothermic patients.19, 20 Tau is a microtubule-associated axonal protein with a stabilizing function under physiological conditions. Following axonal disruption, tau can be detected in brain extracellular fluid,21 cerebrospinal fluid (CSF)22, 23, 24 and serum.25, 26, 27, 28 Whereas brain extracellular tau is only elevated for 48 h after traumatic brain injury, prolonged and sustained elevated serum levels have been reported in severe subarachnoid hemorrhage (SAH) patients21 and CA patients19, 20 with poor outcome. Because of prolonged elevated serum tau levels despite of the relatively short half-life of tau protein (115 h),29 we speculate there is ongoing axonal injury possibly triggered by inflammatory processes. The association of tau in the brain extracellular fluid with elevated IL-6 levels in SAH patients30 and the association of elevated tau fragments with systemic inflammatory markers31 support our considerations.

Therefore, we hypothesized that serum tau elevation beyond 72 h may occur in patients with poor neurological outcome after successful cardiopulmonary resuscitation (CPR) possibly indicating ongoing axonal damage.

The aim of our study was to investigate serum tau kinetics and predictive performance of serum tau over an extended observation period to better understand ongoing pathophysiological processes and improve prognostication, independent if MTH or NT is applied.

Section snippets

Study design

This is a secondary analysis of our previously published study investigating SN after successful CPR.15 This prospective observational single centre trial included 152 consecutive adult patients (age ≥ 18 years) with an in-hospital or out-of-hospital cardiac arrest with presumed cardiac cause admitted to the medical intensive care unit (ICU) of the University Hospital of Innsbruck from September 2008 to April 2013 after successful CPR. The presence of a neuroendocrine tumor, stroke,

Results

The median age was 64 (IQR 53–75) years, and 26% (34/132) were female. Ninety patients (68%) received bystander resuscitation and 17 patients (13%) encountered in-hospital CA. The initial rhythm was ventricular fibrillation in 75 patients (57%) (Table 1). In 68 patients (52%) poor neurological outcome (CPC 3–5) was recorded at hospital discharge, of whom 11 received the maximal ICU care, in 10 and 47 patients therapy was withheld or withdrawn, respectively. (ESM Fig. 1)

Patients with beneficial

Discussion

In the present study, we analysed serum tau in patients after successful CPR treated with MTH or NT over an extended observation period of 168 h. Serum tau showed significantly higher levels in patients with poor (vs. good) neurological outcome with a peak at 72–96 h. Best performance for prognostication could be also demonstrated at 72–96 h. Application of MTH seemed to have minor influence on serum tau levels.

In patients with poor neurological outcome serum tau levels peaked at 72–96 h after

Conclusions

In our study, we could show that peak levels and best prognostication of serum tau is achieved at 72–96 h after CPR in a population consisting of hypothermic and normothermic patients. Sustained elevations beyond 72 h after CPR might be a sign of ongoing neuroinflammatory processes in hypoxic ischemic injury. The influence of MTH seems to be negligible. Further studies are needed to support repeated biomarker assessment beyond 72 h after cardiac arrest.

Conflicts of interest

None.

Acknowledgement

None.

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