Association of deranged cerebrovascular reactivity with brain injury following cardiac arrest: a post-hoc analysis of the COMACARE trial

Johanna Laurikkala, Anders Aneman, Alexander Peng, Matti Reinikainen, Paul Pham, Pekka Jakkula, Johanna Hästbacka, Erika Wilkman, Pekka Loisa, Jussi Toppila, Thomas Birkelund, Kaj Blennow, Henrik Zetterberg, Markus B Skrifvars, Johanna Laurikkala, Anders Aneman, Alexander Peng, Matti Reinikainen, Paul Pham, Pekka Jakkula, Johanna Hästbacka, Erika Wilkman, Pekka Loisa, Jussi Toppila, Thomas Birkelund, Kaj Blennow, Henrik Zetterberg, Markus B Skrifvars

Abstract

Background: Impaired cerebrovascular reactivity (CVR) is one feature of post cardiac arrest encephalopathy. We studied the incidence and features of CVR by near infrared spectroscopy (NIRS) and associations with outcome and biomarkers of brain injury.

Methods: A post-hoc analysis of 120 comatose OHCA patients continuously monitored with NIRS and randomised to low- or high-normal oxygen, carbon dioxide and mean arterial blood pressure (MAP) targets for 48 h. The tissue oximetry index (TOx) generated by the moving correlation coefficient between cerebral tissue oxygenation measured by NIRS and MAP was used as a dynamic index of CVR with TOx > 0 indicating impaired reactivity and TOx > 0.3 used to delineate the lower and upper MAP bounds for disrupted CVR. TOx was analysed in the 0-12, 12-24, 24-48 h time-periods and integrated over 0-48 h. The primary outcome was the association between TOx and six-month functional outcome dichotomised by the cerebral performance category (CPC1-2 good vs. 3-5 poor). Secondary outcomes included associations with MAP bounds for CVR and biomarkers of brain injury.

Results: In 108 patients with sufficient data to calculate TOx, 76 patients (70%) had impaired CVR and among these, chronic hypertension was more common (58% vs. 31%, p = 0.002). Integrated TOx for 0-48 h was higher in patients with poor outcome than in patients with good outcome (0.89 95% CI [- 1.17 to 2.94] vs. - 2.71 95% CI [- 4.16 to - 1.26], p = 0.05). Patients with poor outcomes had a decreased upper MAP bound of CVR over time (p = 0.001), including the high-normal oxygen (p = 0.002), carbon dioxide (p = 0.012) and MAP (p = 0.001) groups. The MAP range of maintained CVR was narrower in all time intervals and intervention groups (p < 0.05). NfL concentrations were higher in patients with impaired CVR compared to those with intact CVR (43 IQR [15-650] vs 20 IQR [13-199] pg/ml, p = 0.042).

Conclusion: Impaired CVR over 48 h was more common in patients with chronic hypertension and associated with poor outcome. Decreased upper MAP bound and a narrower MAP range for maintained CVR were associated with poor outcome and more severe brain injury assessed with NfL. Trial registration ClinicalTrials.gov, NCT02698917 .

Keywords: Cerebrovascular reactivity; Hypoxic-ischaemic brain injury; Out-of-hospital cardiac arrest.

Conflict of interest statement

HZ has served at scientific advisory boards for Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). Markus Skrifvars reports a lecture fee and travel grant from BARD Medical (Ireland). Erika Wilkman reports an external research support agreement (Research-Devices Grant, INVOS) with Medtronic (Covidien Ag).

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Flowchart of excluded and included study patients
Fig. 2
Fig. 2
Optimal MAP (OptMAP) in three time periods: a 0–12 h, b 12–24 h and c 24–48 h, with good or poor six-month neurologic outcomes
Fig. 3
Fig. 3
a–c 48 h neuron-specific enolase (NSE) concentrations (μg/l), d–f 48 h S100B concentrations (μg/l) and g–i 48 h neurofilament (NfL) concentrations (pg/ml) against mean cerebrovascular reactivity (mean TOx) during the time intervals 0–12 h, 12–24 h and 24–48 h. Patients are classified according to good or poor neurologic outcomes. Data is presented with logharitmic X-axes

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