Increased Citrullinated Histone H3 Levels in the Early Post-Resuscitative Period Are Associated with Poor Neurologic Function in Cardiac Arrest Survivors—A Prospective Observational Study

Abstract

The exact contribution of neutrophils to post-resuscitative brain damage is unknown. We aimed to investigate whether neutrophil extracellular trap (NET) formation in the early phase after return of spontaneous circulation (ROSC) may be associated with poor 30 day neurologic function in cardiac arrest survivors. This study prospectively included adult (≥18 years) out-of-hospital cardiac arrest (OHCA) survivors with cardiac origin, who were subjected to targeted temperature management. Plasma levels of specific (citrullinated histone H3, H3Cit) and putative (cell-free DNA (cfDNA) and nucleosomes) biomarkers of NET formation were assessed at 0 and 12 h after admission. The primary outcome was neurologic function on day 30 after admission, which was assessed using the five-point cerebral performance category (CPC) score, classifying patients into good (CPC 1–2) or poor (CPC 3–5) neurologic function. The main variable of interest was the effect of H3Cit level quintiles at 12 h on 30 day neurologic function, assessed by logistic regression. The first quintile was used as a baseline reference. Results are given as crude odds ratio (OR) with 95% confidence interval (95% CI). Sixty-two patients (79% male, median age: 57 years) were enrolled. The odds of poor neurologic function increased linearly, with 0 h levels of cfNDA (crude OR 1.8, 95% CI: 1.2–2.7, p = 0.007) and nucleosomes (crude OR 1.7, 95% CI: 1.0–2.2, p = 0.049), as well as with 12 h levels of cfDNA (crude OR 1.6, 95% CI: 1.1–2.4, p = 0.024), nucleosomes (crude OR 1.7, 95% CI: 1.1–2.5, p = 0.020), and H3Cit (crude OR 1.6, 95% CI: 1.1–2.3, p = 0.029). Patients in the fourth (7.9, 95% CI: 1.1–56, p = 0.039) and fifth (9.0, 95% CI: 1.3–63, p = 0.027) H3Cit quintile had significantly higher odds of poor 30 day neurologic function compared to patients in the first quintile. Increased plasma levels of H3Cit, 12 h after admission, are associated with poor 30 day neurologic function in adult OHCA survivors, which may suggest a contribution of NET formation to post-resuscitative brain damage and therefore provide a therapeutic target in the future.

Surrogate Markers of Neutrophil Extracellular Trap Formation are Associated with Ischemic Outcomes and Platelet Activation after Peripheral Angioplasty and Stenting

“…This may point towards different mechanisms for developing ischemic outcomes in cancer and atherosclerosis, respectively [26]. Finally, a recent publication by Mauracher et al demonstrated the predictive value of increased H3Cit for poor 30-day neurologic function in cardiac arrest survivors [39].…”

“…A limitation of the implementation of H3Cit measurements in clinical routine is the lack of standardization. However, we used an ELISA for the measurement of H3Cit that has been applied in several other clinical studies [22,24,26,39]. A limitation of our study is its relatively small sample size for both patients and healthy controls.…”

Low PCSK-9 levels Are Associated with Favorable Neurologic Function after Resuscitation from out of Hospital Cardiac Arrest

“…These intervals were established by immediate, structured interviews with the dispatch center, involved emergency physicians, paramedics, or bystander who performed the emergency call. All patients have undergone targeted temperature management with target temperatures between 32 and 34 • C for 24 h. Rewarming was performed at a rate of 0.25-0.5 • C. Resuscitation related parameters were analyzed and reported according to the Utstein recommendations [23,24]. Patient demographics, co-medication, and concomitant diseases were obtained by chart review.…”

“…All patients have undergone targeted temperature management with target temperatures between 32 and 34 °C for 24 h. Rewarming was performed at a rate of 0.25–0.5 °C. Resuscitation related parameters were analyzed and reported according to the Utstein recommendations [ 23 , 24 ]. Patient demographics, co-medication, and concomitant diseases were obtained by chart review.…”

Cell-Free Double-Stranded DNA to DNase Ratio Predicts Outcome after Primary Survived Cardiac Arrest

“…Therefore, several accumulating factors might determine patient outcome in CA represented by the balance of dsDNA and DNase: (1) extensive tissue damage, (2) inflammatory signaling, or (3) a reduced capacity to organize and contain the damage response. In this study, we sought to examine the dsDNA/DNase ratio as a predictor of outcome, subsuming a potentially unbalanced degree of cell death and immunological responses in a cohort comparable to previous studies, yet also including a later time point (96 h after CA) to account for a possibly even longer lasting inflammatory reaction [ 12 , 13 ]. Furthermore, we tried to contribute to a better understanding of the ongoing processes in PCAS by investigating novel inflammatory biomarkers (IL-8, MCP-1) on top.…”