Clinical paperAssociation of post-resuscitation inflammatory response with favorable neurologic outcomes in adults with in-hospital cardiac arrest
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.
Section snippets
Study population
We conducted a prospective study in a single academic tertiary medical center using a convenience sample of IHCA patients enrolled between March 2014 and May 2019. Inclusion criteria were all adult patients (age > 18 years) with IHCA (defined as cessation of heart beat and respirations) requiring a resuscitation attempt lasting >5 min. This time point was selected given that patients with IHCA undergoing conventional CPR for less than 5 min have a greater than 70% survival with favorable
Patient characteristics
Of the 105 adults studied, 36 (34.3%) survived to hospital discharge and 69 (65.7%) did not. Twenty-seven adults (25.7%) survived 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) (Table 1). No difference in age or Charlson Comorbidity Index was noted. Rates of targeted
Discussion
Two major findings are noteworthy in this contemporary observational study of 105 adults with IHCA receiving ACLS-guided resuscitative and post-resuscitative care. First, early levels of IL-6, IL-8, IL-10, and TNF-R1 were significantly lower in patients who survived with favorable neurologic outcome compared with those who did not. Second, lower levels of early IL-10 were noted to be independently associated with higher rates of survival with favorable neurologic outcome. To our knowledge, this
Conclusions
In this contemporary observational study of adults with IHCA receiving ACLS-guided resuscitative and post-resuscitative care, higher early levels of certain inflammatory cytokines are associated with worse outcomes in adults with IHCA. Further larger scale studies examining the association of these inflammatory cytokines with prognosis are warranted. Early identification of resuscitated victims at greatest risk for worse clinical outcomes may facilitate the use of early hospital-based
Author contributions
Conception or design of the work: JKP, SP; Acquisition of data: JKP, NS, RS, AQ, LT; Statistical analysis: WH; PBP; Data interpretation: JKP, WH, PBP; SP; Drafting the work or revising it critically for important intellectual content: JKP, SP; Final approval of the version to be published: JKP, SP; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: JKP, SP.
Financial support
Feldstein Medical Foundation Grant; Stony Brook University Targeted Research Opportunity Grant; Stony Brook Department of Medicine Pilot Project Grant.
Conflict of interest
None declared.
CRediT authorship contribution statement
Jignesh K. Patel: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. Niraj Sinha: Data curation. Wei Hou: Formal analysis. Rian Shah: Data curation. Asem Qadeer: Data curation. Linh Tran: Data curation. Puja B. Parikh: Formal analysis. Sam Parnia: Conceptualization, Investigation, Methodology, Supervision, Validation,
Acknowledgements
Cytokine level measurements were performed by the Genomics Core Facility at Stony Brook University Medical Center.
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