Relationship between markers of inflammation and hemodynamic stress and death in patients with out-of-hospital cardiac arrest.

Biomarkers that reflect hemodynamic stress, inflammation, extracellular matrix remodeling, angiogenesis, and endothelial dysfunction may improve risk stratification and add valuable pathobiological insight in patients with out-of-hospital cardiac arrest (OHCA). In total, 120 patients with OHCA who survived at least 48 h after return of spontaneous circulation were consecutively included in the present analysis. Concentrations of 30 biomarkers were measured simultaneously using a multi-panel biomarker assay. Cox regression models were adjusted for age, sex, estimated glomerular filtration rate, lactate concentration, bystander resuscitation, initial cardiac rhythm, and type of targeted temperature management. Overall, 57 patients (47.5%) had a favorable neurological outcome (Cerebral Performance Category ≤ 2) at 30 days, while palliative care was initiated in 49 patients (40.8%), and 52 patients (43.3%) died. After correction for multiple testing with Bonferroni-Holm, 8 biomarkers (including Angiopoietin-2, Procalcitonin, Resistin, IL-4Rα, MMP-8, TNFα, Renin, and IL-1α) were significantly associated with all-cause death. After multivariable adjustment, only angiopoietin-2 (Adjusted (Adj) hazard ratio (HR) per 1-unit increase in standardized biomarker concentrations 1.52 (95% CI 1.16-1.99)) and renin (Adj HR 1.32 (95% CI 1.06-1.65) remained independently associated with an increased risk of death. The discriminatory performance indicated good performance for angiopoietin-2 (area under the curve (AUC): 0.75 (95% CI 0.66-0.75) and was significantly higher (P = 0.011) as compared with renin (AUC: 0.60, 95% CI 0.50-0.60). In conclusion, angiopoietin-2 was significantly associated with all-cause mortality in patients with OHCA who survived the first 48 h and may prove to be useful for risk stratification of these patients.

Presepsin As a Biomarker for Evaluating Prognosis and Early Innate Immune Response of Out-of-Hospital Cardiac Arrest Patients After Return of Spontaneous Circulation.

OBJECTIVES: After return of spontaneous circulation, patients who experienced out-of-hospital cardiac arrest present an impaired innate immune response that resembles sepsis. Presepsin, a new biomarker for sepsis, has not been studied in out-of-hospital cardiac arrest patients. This study explored the role of presepsin in evaluating the prognosis and early innate immune alteration of out-of-hospital cardiac arrest patients after return of spontaneous circulation by observing presepsin levels, CD14, and human leukocyte antigen-DR expression on monocytes. DESIGN: Retrospective analysis. SETTING: The emergency department of an urban university tertiary hospital. PARTICIPANTS: One hundred sixty-five out-of-hospital cardiac arrest patients with return of spontaneous circulation more than 12 hours, and 100 healthy individuals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma presepsin and procalcitonin levels were tested after resuscitation (day 0) and on days 1 and 3 after return of spontaneous circulation. Presepsin levels were higher in out-of-hospital cardiac arrest patients than in healthy individuals. In the first 3 days, presepsin and procalcitonin levels were persistently lower in 28-day survivors and patients with favorable neurologic outcome patients than in 28-day nonsurvivors and patients with unfavorable neurologic outcome. On days 0, 1, and 3, different cut-off values of presepsin showed prognostic value for 28-day mortality and favorable neurologic outcomes similar to procalcitonin. CD14 and human leukocyte antigen-DR expression on monocytes were analyzed by flow cytometry. Compared with controls, CD14 expression in out-of-hospital cardiac arrest patients increased on day 1 and began to decrease on day 3, whereas human leukocyte antigen-DR+ monocyte percentages decreased on days 1 and 3. Presepsin and procalcitonin had a low positive correlation with CD14 expression and a strong negative correlation with human leukocyte antigen-DR+ monocyte percentages on day 1. CONCLUSIONS: Plasma presepsin concentrations are independent prognostic factors for out-of-hospital cardiac arrest patients after return of spontaneous circulation and are correlated with abnormal CD14 and human leukocyte antigen-DR expression on monocytes. Monitoring presepsin levels may be helpful for evaluating the prognosis and impaired innate immune response in the early period after return of spontaneous circulation.

Systemic Inflammatory Response and Potential Prognostic Implications After Out-of-Hospital Cardiac Arrest: A Substudy of the Target Temperature Management Trial.

OBJECTIVES: Whole-body ischemia during out-of-hospital cardiac arrest triggers immediate activation of inflammatory systems leading to a sepsis-like syndrome. The aim was to investigate the association between level of systemic inflammation and mortality in survivors after out-of-hospital cardiac arrest treated with targeted temperature management. DESIGN: Post hoc analysis. SETTING: Single-center study of a prospective multicenter randomized study. PATIENTS: One hundred sixty-nine patients (99%) with available blood samples out of 171 patients included in the Target Temperature Management trial, randomly assigning patients to targeted temperature management at 33°C or 36°C. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: At baseline and 24, 48, and 72 hours after out-of-hospital cardiac arrest, blood samples were obtained and screened for a battery of inflammatory markers. Level of interleukin-1ß, interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-9, interleukin-10, interleukin-12, interleukin-13, tumor necrosis factor-α, interferon-γ, C-reactive protein, and procalcitonin were measured. Mortality at 30 days was evaluated by Cox analysis, and the predictive capability of inflammatory markers was evaluated by area under the curve. Level of all inflammatory markers changed significantly within 72 hours after out-of-hospital cardiac arrest (all p values<0.001), but only procalcitonin levels showed overall differences between nonsurvivors and survivors (p=0.0002). At baseline, interleukin-6 was independently associated with mortality, whereas both interleukin-6 levels (hazard ratio=1.23 [1.01-1.49]; p=0.04) and procalcitonin levels (hazard ratio=1.20 [1.03-1.39]; p=0.02) 24 hours after out-of-hospital cardiac arrest were associated with 30-day mortality with no interactions between targeted temperature management group and levels of interleukin-6 (p=0.25) or procalcitonin (p=0.85). None of the other inflammatory markers were independently associated with mortality. Area under the curve for procalcitonin and interleukin-6, 24 hours after out-of-hospital cardiac arrest, were 0.74 and 0.63, respectively. CONCLUSIONS: Level of inflammation, assessed by interleukin-6 and procalcitonin, was independently associated with increased mortality with the highest discriminative value obtained 24 hours after out-of-hospital cardiac arrest. Interventions aiming at decreasing level of inflammation as a way to improve outcome may be investigated in future studies.

Rewarming after hypothermia after cardiac arrest shifts the inflammatory balance.

OBJECTIVES: The aim of this study was to simultaneously analyze the key components of the cerebral and systemic inflammatory response over time in cardiac arrest patients during mild therapeutic hypothermia and rewarming. DESIGN AND SETTING: Clinical observational study in a tertiary care university hospital. PATIENTS: Ten comatose patients after out-of-hospital cardiac arrest. INTERVENTIONS: All patients were cooled to 32-34°C for 24 hrs. After 24 hrs patients were passively rewarmed to normothermia. MEASUREMENTS AND MAIN RESULTS: On admission and at 3, 6, 12, 24, and 48 hrs blood samples were taken from the arterial and jugular bulb catheter. Proinflammatory and anti-inflammatory cytokines and chemokines (interleukin-1ra, interleukin-1ß, interleukin-6, interleukin-8, interleukin-10, interleukin-18, monocyte chemotactic protein-1, high-mobility group box-1 and tumor necrosis factor-α), complement activation products (C4d, Bb, C3a, and terminal complement complex), and the adhesion molecule soluble intercellular adhesion molecule were measured. Mean temperatures at the start of the study and at 12 and 24 hrs were 33.7 ± 0.9°C, 32.7 ± 0.92°C, and 34.5 ± 1.5°C, respectively. Passive rewarming resulted in a temperature of 37.8 ± 0.5°C at 48 hrs. The proinflammatory cytokine interleukin-6 increased from 12 to 24 hrs and returned to baseline levels after 48 hrs. In contrast, the chemokines interleukin-8 and monocyte chemotactic protein-1 stayed relatively high from the start and during the hypothermia period, decreasing to baseline levels after 48 hrs. The anti-inflammatory cytokines interleukin-10 and interleukin-1ra did not significantly change during mild therapeutic hypothermia and rewarming, although low values of interleukin-10 were observed after rewarming. A significant increase after rewarming was demonstrated on high-mobility group box-1 concentrations in the jugular bulb, whereas soluble intercellular adhesion molecule increased significantly during hypothermia and remained at this level after rewarming. Complement activation was increased on admission and decreased after induction of hypothermia, followed by a secondary increase during rewarming. No significant differences between any of the biomarkers were found between samples from the arterial and jugular bulb catheter. CONCLUSIONS: Complement activation occurs during rewarming from mild therapeutic hypothermia after cardiac arrest. Interleukin-6 increased already from 12 to 24 hrs, concomitantly with a significant increase in the temperature seen during this period of mild therapeutic hypothermia. The optimal rate of rewarming is unknown. Additional clinical studies are needed to determine the optimal rewarming rate and strategy.