Comparison of the efficacy of Epinephrine vs. Norepinephrine in clinical outcomes among children with Post-Cardiac arrest shock:A Hospital based, open-label, Randomized Controlled Trial

Title of the study:

Comparison of the Efficacy of Norepinephrine versus Epinephrine in Clinical Outcomes Among Children with Post-Cardiac Arrest Shock: A Hospital-Based, Open-Label, Randomized Controlled Trial.

Acronym:

NEST-POSH (Norepinephrine vs. Epinephrine in Supporting Treatment for Post-ROSC Shock in Hemodynamic Optimization)

Introduction:

The management of post-cardiac arrest shock in pediatric patients presents a significant clinical challenge, particularly given the high rates of morbidity and mortality associated with this condition. Despite advancements in resuscitation techniques, achieving return of spontaneous circulation (ROSC) is only the first step in a complex recovery process that often leads to post-cardiac arrest syndrome, characterized by hemodynamic instability and multi-organ dysfunction(1). Post-cardiac arrest shock is a prevalent complication, occurring in approximately 50-70% of patients following OHCA (2). Thus, post-cardiac arrest shock not only results from cardiac dysfunction but is also significantly complicated by the profound vasoplegia, similar to that of septic shock, thus this situation is also known as sepsis-like syndrome (3). Traditionally, epinephrine has been the go-to agent for managing cardiac arrest and post-resuscitation shock due to its potent alpha and beta-adrenergic effects (4).

Recent studies have raised concerns regarding the safety and efficacy of epinephrine compared to norepinephrine, another commonly used vasopressor (5). Norepinephrine, primarily an alpha-adrenergic agonist with some beta-1 activity, has gained attention for its potential advantages in maintaining mean arterial pressure (MAP) and improving organ perfusion, without the adverse effects associated with epinephrine, such as increased heart rate and myocardial oxygen demand (6). Previous studies have primarily focused on adult populations, leaving a gap in knowledge regarding pediatric patients. This study aims to compare the efficacy and safety of norepinephrine versus epinephrine as continuous intravenous vasopressors in children experiencing post-cardiac arrest shock (7,8).

 Problem statement

Epinephrine, traditionally used for post-cardiac arrest shock, may be associated with adverse effects, while norepinephrine has shown promise in adult populations but lacks sufficient evidence in children

Rationale

Epinephrine has been the standard vasopressor, emerging evidence suggests it may lead to adverse effects that could hinder recovery.

While, norepinephrine has demonstrated favorable hemodynamic effects in adults but has not been adequately studied in children.

Novelty

This study is expected to be the first to compare the efficacy of adrenaline versus noradrenaline for treating post-cardiac arrest shock in the pediatric population.

 Aim and Objectives:

Aim:

1.     To evaluate the efficacy and safety of norepinephrine compared to epinephrine in improving hemodynamic parameters and clinical outcomes in pediatric patients experiencing post-cardiac arrest shock.

Objectives:

Primary Objective:

1.     To compare the incidence of in-hospital mortality between the two groups receiving norepinephrine and epinephrine.

Secondary Objectives:

1.     To determine the duration of vasopressor support required for hemodynamic stabilization in each treatment group.

2.     To compare the effects of norepinephrine and epinephrine on mean arterial pressure (MAP) in children with post-cardiac arrest shock.

3.     To analyze the neurological outcomes at hospital discharge using the Cerebral Performance Category (CPC) scale.

4.     To evaluate the occurrence of arrhythmias and catecholamine resistant shock in patients treated with either vasopressor.

 Methodology:

Study design

This study will be a single-centered, open-label, randomized controlled trial in the Department of Pediatrics, AIIMS, Patna.

Inclusion criteria

All children aged between 1month to 18 years who present to the pediatric emergency in cardiac arrest (OHCA) “or” children admitted under the Department of Paediatrics who are not on any ionotropic support develops cardiac arrest due to a non-cardiac cause, “and” achieves return of spontaneous circulation (ROSC) after the resuscitation “and” exhibiting features of post-resuscitation shock.

Exclusion criteria

1.   Pre-existing cardiac disease

2.     Parents not willing to provide consent for this study.

 Sample size calculation

The multicentric observational study conducted by Bougouin et al. (2022) compared the effects of epinephrine and norepinephrine in patients experiencing post-resuscitation shock following cardiac arrest. The findings revealed that the use of epinephrine was associated with significantly higher all-cause hospital mortality during the hospital stay, with rates of 83% for epinephrine compared to 61% for norepinephrine (P < 0.001) (7). To achieve these results, the sample size was calculated to be approximately 45 patients in each group (Total of 90 participants). This calculation was based on an 90% power, a 5% alpha error, a 10% inferiority margin, and an anticipated 10% attrition rate.

Study Procedure:

I.         Ethical Clearances: Ethical clearances will be obtained from the institution.

 II.         Patient Selection and Informed Consent:

All children aged between 1month to 18 years who present to the pediatric emergency in cardiac arrest (OHCA) “or” children admitted under the Department of Paediatrics who are not on any ionotropic support develops cardiac arrest due to a non-cardiac cause, “and” achieves return of spontaneous circulation (ROSC) after the resuscitation “and” exhibiting features of post-resuscitation shock. Informed consent will be obtained from one of the parents prior to participation.

 III.         Enrolment and randomization:

After excluding ineligible cases based on the exclusion criteria, eligible participants will be enrolled in the study. Enrolled participants will be randomly assigned to either the adrenaline infusion group or the noradrenaline infusion group using a pre-generated randomization sequence. Allocation will be concealed using opaque sealed envelopes. The randomization sequence will be maintained by the head of the department, who is not involved in the study.

 IV.         Interventions:

After sample selection and randomization based on the assigned group, patients will be initiated on either adrenaline infusion or noradrenaline infusion according to the study protocol, starting with an initial dose of 0.1 mcg/kg/min, which may be increased up to a maximum of 0.3 mcg/kg/min. If shock persists despite following the study protocol, the treating team may decide to use additional inotropes as per the treatment protocol, based on the type of shock and the clinical profile of the patient.

 V.         Blinding & Matching:

This study will be an open-label trial involving the use of adrenaline and noradrenaline. Both drugs have comparable dose ranges, starting at 0.1 mcg/kg/min and reaching a maximum of 0.3 mcg/kg/min, which allows for effective matching between the treatment groups.

 VI.         Data collection:

The demographic profile and baseline characteristics will be noted.

Whether the child achieved resolution or not will be noted.

Whether there is a need for additional inotropic support will be noted.

The time required for the resolution of shock after starting the inotropes will be noted.

The overall outcome in terms of mortality will be noted.

Neurological outcomes at hospital discharge using the Cerebral Performance Category (CPC) scale will be noted.

Any adverse events in terms of arrhythmias will be noted.

 VII.         Data analysis:

Data will be analyzed to compare overall mortality, time required for the resolution of shock, neurological outcomes at hospital discharge, and incidence of adverse events.

  References:

1.     Lazzarin T, Tonon CR, Martins D, et al. Post-Cardiac Arrest: Mechanisms, Management, and Future Perspectives. J Clin Med. 2022;12(1):259.

2.     Jozwiak M, Bougouin W, Geri G, Grimaldi D, Cariou A. Post-resuscitation shock: recent advances in pathophysiology and treatment. Ann Intensive Care. 2020;10(1):170.

3.     Adrie C, Laurent I, Monchi M, Cariou A, Dhainaou JF, Spaulding C. Postresuscitation disease after cardiac arrest: a sepsis-like syndrome?. Curr Opin Crit Care. 2004;10(3):208-212.

4.     Nolan JP, Neumar RW, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation. 2008;79(3):350-379.

5.     Andersen, L. W., Grossestreuer, A. V., & Donnino, M. W. (2019). Resuscitation duration and survival in septic shock: When should we change to vasopressin? Journal of Critical Care, 49, 202-207.

6.     Levy, B., Perez, P., Perny, J., Thivilier, C., & Gerard, A. (2011). Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study. Critical Care Medicine, 39(3), 450-455.

7.     Bougouin W, Slimani K, Renaudier M, et al. Epinephrine versus norepinephrine in cardiac arrest patients with post-resuscitation shock. Intensive Care Med. 2022;48(3):300-310.

8.     Lawson CK, Faine BA, Rech MA, et al. Norepinephrine versus epinephrine for hemodynamic support in post-cardiac arrest shock: A systematic review. Am J Emerg Med. 2024;77:158-163.