Association of post-resuscitation inflammatory response with favorable neurologic outcomes in adults with in-hospital cardiac arrest

Abstract

Background

Early prediction of mortality in adults after in-hospital cardiac arrest (IHCA) remains vital to optimizing treatment strategies. Inflammatory cytokines specific to early prognostication in this population have not been well studied. We evaluated whether novel inflammatory cytokines obtained from adults with IHCA helped predict favorable neurologic outcome.

Methods

The study population included adults with IHCA who underwent ACLS-guided resuscitation between March 2014 and May 2019 at an academic tertiary medical center. Peripheral blood samples were obtained within 6, 24, 48, 72, and 96 h of IHCA and analysis of 15 cytokines were performed. The primary outcome of interest was presence of favorable neurologic outcome at hospital discharge, defined as a Glasgow Outcome Score of 4 or 5.

Results

Of the 105 adults with IHCA studied, 27 (25.7%) were noted to have survival with a favorable neurologic outcome while 78 (74.3%) did not. Patients who survived with favorable neurologic outcome were more often men (88.9% vs 61.5%, p = 0.008) and had higher rates of ventricular tachyarrhythmias as their initial rhythm (34.6% vs 11.7%, p = 0.018). Levels of interleukin (IL)-6, IL-8, IL-10, and Tumor Necrosis Factor (TNF)-R1 within 6 or 24 h were significantly lower in patients with favorable neurologic outcome compared with those who had unfavorable neurologic outcome. In multivariable analysis, IL-10 levels within 6 h was the only independent predictor of favorable neurologic outcomes [odds ratio (OR) 0.895, 95% confidence interval 0.805−0.996, p = 0.041].

Conclusion

In this contemporary observational study of adults with IHCA receiving ACLS-guided resuscitative and post-resuscitative care, inflammatory cytokines specific to early prognostication in adults with IHCA exist. Further larger scale studies examining the association of these inflammatory cytokines with prognosis are warranted.

Introduction

Cardiac arrest (CA) remains a major public health concern in the United States and globally.¹ In spite of increasing use of advanced resuscitative and post-resuscitative therapies,² survival continues to remain low with only approximately 10% of individuals with out-of-hospital cardiac arrest (OHCA) and 20% of patients with in-hospital cardiac arrest (IHCA) surviving to hospital discharge.3, 4, 5, 6 Anoxic brain injury remains a major health burden with only 3–7% surviving and recovering to their pre-CA functional state.7, 8, 9, 10 Mortality and anoxic brain injury are the consequence of the post-cardiac arrest syndrome (PCAS), a complex set of pathophysiological processes consisting of brain injury, myocardial depression, and systemic ischemia-reperfusion injury as well as ongoing injury caused by the precipitating etiology of the arrest.¹¹ The American Heart Association (AHA), the European Resuscitation Council (ERC) and the International Liaison Committee on Resuscitation (ILCOR) have all increased focus on the management of patients with PCAS.11, 12, 13 Among other initiatives this includes the AHA’s addition of a fifth link to the “Chain of Survival” emphasizing the importance of post-cardiac arrest care.¹¹

Activation of major inflammatory pathways in the post-CA period has been associated with adverse outcomes following OHCA.14, 15, 16 During ischemia, accumulated oxygen debt leads to endothelial activation and causes a systemic inflammatory response syndrome, as evidenced by major elevations in inflammatory cytokines and soluble receptors within a few hours of OHCA.14, 17 Increased levels of several cytokines, including interleukin (IL)-6, IL-8, IL-1Ra, IL-10, and tumor necrosis factor-alpha (TNF-a), have been reported in non-survivors compared to survivors in the first 24 h after OHCA.14, 17 Given these cytokines correlate closely with lactate, a marker for tissue hypoxia in the post cardiac arrest period,14, 17 an association between the magnitude of ischemia during CA and that of secondary reperfusion injury and inflammatory responses after OHCA is strongly suggested.11, 18, 19, 20 More recently, the release of inflammatory markers, especially IL-6, early in the post-CA period after OHCA was independently associated with higher rates of in-hospital mortality, and to a lesser degree, poor functional status.¹⁵ Although studies have examined the association between post-CA inflammation and mortality among OHCA patients, little is known regarding post-CA inflammatory responses among IHCA patients. Compared to OHCA, IHCA typically represents a population of patients with greater heterogeneity of underlying disorders leading to CA but minimal delays to the initiation of cardiopulmonary resuscitation (CPR). Hence, the depth of ischemia is expected to be less in IHCA patients, possibly affecting its post-cardiac arrest inflammatory response. Accordingly, the goal of the current investigation was to test the hypothesis that early inflammatory markers are independently associated with in-hospital mortality and poor neurological outcome in patients resuscitated from IHCA.