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.

Inflammatory response after out‐of‐hospital cardiac arrest—Impact on outcome and organ failure development

“…31 The prognostic value of PCT after OHCA has been recently evaluated in a metaanalysis. 32 We found 14 individual studies on PCT, 3,[11][12][13]15,20,21,25,[33][34][35][36][37][38][39][40] including a total of 2608 patients. Nine studies reported an AUC value for the association between PCT concentration and poor outcome.…”

“…11 Pekkarinen et al found no independent prognostic value of PCT when day two neurofilament light (NFL) was included in the multivariable model but a significant fixed effect for PCT was found for poor six-month neurological outcome. 39 Seven studies assessed PCT's prognostic value for neurological outcome or mortality after OHCA without adjusting for confounding variables. In a multicenter study of 932 patients, PCT on days one to three was significantly higher in patients with poor six-month neurological outcomes.…”

“…41 Thirteen individual studies with a total of 3005 patients evaluated CRP as a prognostic marker, 12,13,16,20,21,25,27,33,[42][43][44][45][46][47] and four studies with 792 patients assessed high-sensitivity CRP (hsCRP). 19,39,48,49 While conventional CRP assays have a detection limit of 3 to 8 mg/L, hsCRP assays can detect CRP levels as low as 0.3 mg/L. 50 Seven studies reported AUC values for poor outcome ranging from 0.52 to 0.76 (Table 1).…”

“…reported significant fixed effect of hsCRP for neurological outcome, but this was not independent when combined with day two NFL in a multivariable model. 39 Regarding organ failure, Bro-Jeppesen et al and Ristagno et al…”

“…65 One study reported no association with six-month neurological outcome. 39 HMGB1 is a nuclear protein of human cells released into circulation from damaged tissue or activated monocytes and macrophages. 66 HMGB1 was assessed in two unadjusted studies with limited sample sizes.…”