The immunology of the post-cardiac arrest syndrome

Abstract

Patients successfully resuscitated from cardiac arrest often have brain injury, myocardial dysfunction, and systemic ischemia–reperfusion injury, collectively termed the post-cardiac arrest syndrome (PCAS). To improve outcomes, potential therapies must be able to be administered early in the post-arrest course and provide broad cytoprotection, as ischemia–reperfusion injury affects all organ systems. Our understanding of the immune system contributions to the PCAS has expanded, with animal models detailing biologically plausible mechanisms of secondary injury, the protective effects of available immunomodulatory drugs, and how immune dysregulation underlies infection susceptibility after arrest. In this narrative review, we discuss the dysregulated immune response in PCAS, human trials of targeted immunomodulation therapies, and future directions for immunomodulation following cardiac arrest.

Introduction

Out of hospital cardiac arrest (OHCA) affects approximately 350,000 adults in the United States every year.¹ Despite improvements in the ‘chain of survival’ of early recognition of cardiac arrest, bystander cardiopulmonary resuscitation (CPR), early defibrillation, and in hospital post-arrest care, approximately 10.5% of patients who suffer an OHCA survive to hospital discharge. Even if CPR is successful and return of spontaneous circulation (ROSC) is achieved, multi-organ dysfunction and cardiovascular instability in the first days after arrest and withdrawal of life-sustaining treatment (WSLT) due to perceived poor neurological prognosis result in high mortality.2., 3.

During cardiac arrest, forward arterial blood flow ceases and oxygen delivery to tissues falls to zero. This pathologic process leads to whole body ischemia and metabolic failure that is only partially counteracted by CPR, which generates ∼25% of pre-arrest cardiac output.⁴ In patients that achieve ROSC, blood flow is restored but reperfusion causes a surge in reactive oxygen species (ROS) and sterile inflammation.⁵ While reperfusion injury begins at the time of ROSC, tissue ischemia can persist post-ROSC due to multiple systemic and tissue level derangements including cardiogenic shock, microthrombosis, and endothelial injury.⁶

Described by Vladimir Negovsky as the “post-resuscitation disease” the concept of the post-cardiac arrest syndrome (PCAS) was formalized in 2008.6., 7. This syndrome is a constellation of physiologic disturbances observed in patients who achieve ROSC following cardiac arrest. PCAS is generally defined as post-cardiac arrest brain injury, myocardial dysfunction, systemic ischemia–reperfusion injury, and an unresolved pathologic process that precipitated the arrest.⁶

Critical care for patients following cardiac arrest remains supportive and includes addressing the underlying etiology of arrest, hemodynamic support, lung protective mechanical ventilation, avoidance of hyperoxia and hypoxia, and treatment of infection if present.⁸ Temperature control following cardiac arrest has been shown to improve outcomes in some9., 10., 11. but not all12., 13. clinical trials. Observational studies have suggested the effect of temperature control may depend on the severity of brain injury,14., 15., 16. however this notion was not supported by a recent meta-analysis.¹⁷ Numerous therapeutic agents are undergoing evaluation, yet none have demonstrated improvement in patient centered outcomes in large trials.18., 19., 20. A better understanding of PCAS and the development of therapeutic strategies to reduce organ dysfunction and secondary brain injury are of critical importance given the morbidity and mortality associated with the syndrome. Emerging evidence suggests that the immune system contributes to the pathophysiology of PCAS. In this review, we will discuss the dysregulated immune response that occurs following cardiac arrest and how it contributes to organ injury and infectious susceptibility. We will also highlight recent clinical trials of immunomodulation following cardiac arrest and emerging therapeutic avenues for manipulating the immune system following cardiac arrest.