Markers of neutrophil mediated inflammation associate with disturbed continuous electroencephalogram after out of hospital cardiac arrest

Abstract

Background: Achieving an acceptable neurological outcome in cardiac arrest survivors remains challenging. Ischemia-reperfusion injury induces inflammation, which may cause secondary neurological damage. We studied the association of ICU admission levels of inflammatory biomarkers with disturbed 48-hour continuous electroencephalogram (cEEG), and the association of the daily levels of these markers up to 72 h with poor 6-month neurological outcome.

Methods: This is an observational, post hoc sub-study of the COMACARE trial. We measured serum concentrations of procalcitonin (PCT), high-sensitivity C-reactive protein (hsCRP), osteopontin (OPN), myeloperoxidase (MPO), resistin, and proprotein convertase subtilisin/kexin type 9 (PCSK9) in 112 unconscious, mechanically ventilated ICU-treated adult OHCA survivors with initial shockable rhythm. We used grading of 48-hour cEEG monitoring as a measure for the severity of the early neurological disturbance. We defined 6-month cerebral performance category (CPC) 1-2 as good and CPC 3-5 as poor long-term neurological outcome. We compared the prognostic value of biomarkers for 6-month neurological outcome to neurofilament light (NFL) measured at 48 h.

Results: Higher OPN (p = .03), MPO (p < .01), and resistin (p = .01) concentrations at ICU admission were associated with poor grade 48-hour cEEG. Higher levels of ICU admission OPN (OR 3.18; 95% CI 1.25-8.11 per ln[ng/ml]) and MPO (OR 2.34; 95% CI 1.30-4.21) were independently associated with poor 48-hour cEEG in a multivariable logistic regression model. Poor 6-month neurological outcome was more common in the poor cEEG group (63% vs. 19% p < .001, respectively). We found a significant fixed effect of poor 6-month neurological outcome on concentrations of PCT (F = 7.7, p < .01), hsCRP (F = 4.0, p < .05), and OPN (F = 5.6, p < .05) measured daily from ICU admission to 72 h. However, the biomarkers did not have independent predictive value for poor 6-month outcome in a multivariable logistic regression model with 48-hour NFL.

Conclusion: Elevated ICU admission levels of OPN and MPO predicted disturbances in cEEG during the subsequent 48 h after cardiac arrest. Thus, they may provide early information about the risk of secondary neurological damage. However, the studied inflammatory markers had little value for long-term prognostication compared to 48-hour NFL.

Keywords: cardiac arrest; continuous electroencephalogram; hypoxia; inflammation; ischemia; neutrophilic granulocyte; postcardiac arrest syndrome; prognostication; reperfusion injury; seizures.

FIGURE 1

ICU admission biomarker concentrations in relation to poor grade continuous EEG (cEEG) recording of the first 48 h after OHCA. cEEG recording was graded as suggested by Crepeau et al.; we defined grade 1 as good cEEG result (open circles, N = 71), and grade 2 (N = 7) and grade 3 (N = 31) as poor cEEG result (closed circles). Mean values (circles) with SD (error bars) calculated from the ln transformed data are presented. Note the logarithmic scale. *Statistically significant at the p < .05 level. **Statistically significant at the p < .01 level. EEG, electroencephalogram; hsCRP, high‐sensitivity C‐reactive protein; MPO, myeloperoxidase; OPN, Osteopontin; PCT, Procalcitonin; PCSK9, Proprotein convertase subtilisin/kexin type 9

FIGURE 2

Biomarker concentrations in 6‐month neurological outcome groups. Violin plots with median (thick line) and IQR (thin lines) are presented. Note the logarithmic scale. ICU adm., ICU admission; Good neurological outcome, 6‐month Cerebral Performance Categories (CPC) 1–2; Poor outcome, 6‐month CPC 3–5. *Statistically significant at the p < .05 level. **Statistically significant at the p < .01 level. hsCRP, high‐sensitivity C‐reactive protein; MPO, myeloperoxidase; OPN, Osteopontin; PCT, Procalcitonin; PCSK9, Proprotein convertase subtilisin/kexin type 9