🧭 REBEL Rundown
🗝️ Key Points
📊 Meta-Analysis: Synthesized data from 6 studies involving 3,458 patients (1 RCT and 5 observational studies) to compare norepinephrine (NE) versus epinephrine (EPI) for the management of post-resuscitative shock.
⚖️ Survival/Neuro Comparison: No statistically significant difference between the epinephrine (EPI) vs norepinephrine (NE) regarding survival to hospital discharge or favorable functional neurological outcomes
🔄 Recurrent Arrest: Norepinephrine in post cardiac arrest patients was associated with lower odds of recurrent cardiac arrest.
🚑 Pre-Hospital: The benefit of norepinephrine was most pronounced in patients with Out-of-Hospital Cardiac Arrest (OHCA)
💡 Clinical Choice: While survival rates remain similar, norepinephrine reduces the resource-heavy burden of re-arrest (a “second code”). This profile makes it a reasonable first-line vasopressor for stabilizing post-ROSC patients
📝 Introduction
Cardiac arrest is a major cause of morbidity and mortality with 50 – 70% of survivors experiencing post-resuscitative shock, which can lead to multi-organ failure and even death.3,6 While epinephrine may be the traditional medication of choice given it provides both inotropic and vasopressor support, it also increases myocardial oxygen demand, and at lower doses can cause hypotension via activation of beta-2 receptors.5 Current literature has suggested that norepinephrine, with its more potent alpha receptor activation, may be as effective as epinephrine in managing post-resuscitative shock and may have improvement in outcomes such as mortality, re-arrest rates, and neurologic outcomes.1 The authors of this study sought to evaluate if there was any difference in rate of recurrent cardiac arrest in post-ROSC patients started on norepinephrine versus epinephrine drips.
🧾 Paper
Williams et al. Norepinephrine versus epinephrine after cardiac arrest: A systematic review and meta-analysis. Am J Emerg Med. 2025 Sep;95:107-114. Epub 2025 May 22. PMID: 40440817
🔙PREVIOUSLY COVERED ON REBEL EM:
⚙️ What They Did
📈 Results
Patient Demographics & Group Breakdown:
- Total Population: 3,458 patients across 6 studies.
- Age & Sex: Mean age 64 years (±3); 63% Male.
- Group Allocation:
- Norepinephrine Group: 1,833 patients (53%).
- Epinephrine Group: 1,625 patients (47%).
• Arrest Location: The majority of patients were Out-of-Hospital Cardiac Arrest (OHCA), with only two smaller studies (Weiss, Pansiritanachot) including In-Hospital Cardiac Arrest (IHCA)
💥 Critical Results
- Recurrent Cardiac Arrest: Occurred in 703 patients (20%) out of the total 3,458 patients included across all 6 studies.
- Survival to Discharge: Occurred in 494 patients (14%) out of 3,418 patients across 5 studies (The RCT by Pansiritanachot et al. did not report this outcome).
- Unfavorable Neurological Outcome: Occurred in 222 patients (15%) out of 1,525 patients across 4 studies (outcomes were not reported by the RCT or the large pre-hospital study by Smida et al.)
- Heterogeneity & Study Size: The primary outcome showed high initial heterogeneity (I2= 89%). However, moderator analysis revealed that this variation was driven by smaller studies; in studies with >250 patients, the heterogeneity dropped to 3%
💪🏽 Strengths
- High-Yield clinical question: The study addresses a ubiquitous, high-stakes decision in Emergency Medicine. With post-resuscitation shock occurring in 50–70% of ROSC patients, determining the optimal vasopressor has immediate clinical and operational implications for reducing the resource burden of re-arrests in the ED6
- Quality of studies: Five of the six studies included in the meta analysis were retrospective observational studies and received 7 (80%) and 8 (20%) on the Newcastle-Ottawa Scale (NOS,) representing lower risk for bias in these studies
- Low risk of bias: One of the six studies was a randomized controlled trial which showed some concerns for bias based on the Risk of Bias (RoB2,) but only comprised 40 of the total patients included in the meta analysis
- Large sample size: 3458 patients included in the meta analysis
- Population specificity: The strict exclusion of traumatic cardiac arrest ensures the findings apply specifically to medical causes of arrest. This avoids confounding the data with hemorrhagic shock physiology, where volume resuscitation and surgical control—not vasopressor selection—are the priorities.
- Procedural rigor: The study followed strict PRISMA 2020 guidelines and was pre-registered with the PROSPERO database. This minimizes retrospective data dredging and ensures that the methodology was transparent and defined prior to analysis.
- Moderator analysis: The authors went beyond the primary outcome by analyzing specific subgroups to identify the source of heterogeneity. They successfully identified that the benefit of norepinephrine was strongest in Out-of-Hospital Cardiac Arrest (OHCA) populations (OR 0.32), whereas mixed populations showed no statistical difference
- Publication bias testing: The authors performed formal statistical testing (Egger’s and Begg’s tests) and funnel plot analysis, which indicated a low likelihood of publication bias. This suggests the findings represent the true landscape of available data rather than just selectively published positive studies.
⚠️ Limitations
- Study type: Majority of the studies included were observational studies which are particularly prone to selection and reporting biases
- Demographic representation: Patient population was 63% male. While this limits the quantity of data specific to female physiology, it is largely consistent with the historical epidemiology of cardiac arrest in the US3
- Generalizability: Two studies were conducted outside of the United States; the study by Bougouin et al. was conducted in France, while the study by Pansiritanachot et al. was done in Thailand, which may limit generalizability of the data given the differences in patient populations between France, Thailand, and the United States
- Poorly defined & Incomplete Neuro Outcomes: Only one patient-centered outcome was reported in some of the studies (unfavorable neurologic outcome). The definition of “unfavorable outcome” was broadly used to include any discharge to a healthcare facility, lacking nuance.
- High heterogeneity: The primary outcome had an I2 of 89%, indicating significant variation between studies regarding practice environments and protocols, which limits the certainty of the findings.
- Missing dosing data: The analysis could not account for the actual dosages used (e.g., initial, median, or cumulative doses), as most included studies failed to report them. This is a significant confounder, as it is impossible to determine if the higher re-arrest rates in the epinephrine group were caused by the drug itself or by high-dose beta-adrenergic toxicity
- Missing prognostic variables: The analysis was unable to control for critical variables that determine survival, including bystander CPR, CPR duration, and initial lactate/pH. Additionally there is no data on other interventions that may affect long term neurologic outcome/survival such as cardiac cath.
🗣️ Discussion
- The study found a statistically significant reduction in recurrent cardiac arrest (OR 0.47) when norepinephrine was used compared to epinephrine. This is not a trivial finding; re-arrest is associated with increased mortality and poor neurological outcomes.
- This benefit was most pronounced in the Out-of-Hospital Cardiac Arrest (OHCA) population (OR 0.32), suggesting that early stabilization with an agent that minimizes dysrhythmia risk is clinically impactful. That said, preventing rearrest doesn’t trend towards increased survival, as there are no mortality benefits between NE and EPI.
- We must interpret these results with caution. Since 5 of the 6 studies were observational, we cannot rule out indication bias: clinicians likely reached for epinephrine in patients who were already more hemodynamically unstable or had longer downtimes.
- Notably, the only included RCT (Pansiritanachot et al.)—though small (n=40)—showed a non-significant trend favoring epinephrine for preventing re-arrest. The fact that randomization flipped the signal suggests the observational data favoring norepinephrine may be confounded by baseline severity.
- The analysis failed to control for key prognostic markers such as downtime (CPR duration), initial metabolic derangement (pH/lactate), or—crucially—dosing. Without knowing if the epinephrine group received larger, toxic doses while the norepinephrine group received conservative titration, we cannot rule out that the adverse outcomes were driven by the severity of the patient rather than the choice of the drug. Leading to a risk of selection bias.
- The study found no significant difference in favorable neurological outcomes (OR 1.72; p=0.09), but the data quality for this outcome was poor. Additionally standardized prognostic tools like the Cerebral Performance Category (CPC) or Modified Rankin Scale (mRS) were not used. Instead, they imputed “discharge to a facility” as an unfavorable outcome. This lacks granularity, treating a patient requiring short-term rehab the same as one requiring a tracheostomy and PEG.
💭Additional Expert Thoughts
The shift toward using norepinephrine (NE) for post-ROSC shock is moving from expert opinion to evidence-based practice. I frequently encounter OHCA patients arriving via EMS with NE infusions, a practice supported by this meta-analysis, which found the strongest support for preventing re-arrest specifically in the OHCA population (OR 0.32).
In my own practice, I prioritize early NE initiation. While this study confirms that NE alone does not statistically improve survival to discharge—likely because survival is multifactorial and extends beyond a single vasopressor—it validates the clinical stability I observe. The data shows NE cuts the odds of re-arrest by roughly half (OR 0.47). Avoiding the hemodynamic collapse and resource burden of a ‘second code’ is a meaningful patient-centered and operational victory.
Furthermore, these findings highlight the potential harm of ‘epinephrine burden’ (beta-adrenergic toxicity). If stabilizing a patient with NE post-arrest offers such a clear benefit, it suggests there is room to investigate earlier initiation—perhaps even intra-arrest—to reduce the cumulative dose of epinephrine and its arrhythmogenic side effects
📘 Author's Conclusion
“Post ROSC hypotension is a major cause of morbidity and mortality, highlighting the need for vasopressors and inotropes in patients with post-resuscitative shock. In our meta-analysis, we found no association between the use of NE post-ROSC and odds of survival to hospital discharge or functional neurological outcome when compared to EPI. However, the use of NE was associated with lower odds of recurrent cardiac arrest when compared to EPI, suggesting a potential benefit of preventing further hemodynamic decline. Future research should include randomized clinical trials that evaluate additional patient factors, resuscitation variables, and long-term prognostic data to determine which vasopressor is best for patient outcomes post-ROSC.”
💬 Our Conclusion
This meta-analysis validates the physiological danger of “epinephrine burden,” quantifying it as a significantly higher rate of recurrent arrest in the epinephrine group. While the data is limited by observational bias and a lack of mortality benefit, there is a clinical and operational advantage: norepinephrine leads to a reduction in rearrest rate. Avoiding the “second code” is a meaningful patient-centered outcome. Until high-quality RCTs can control for dosing, severity and timing of initiation, norepinephrine represents a safe, and clinically sound first-line agent for post-ROSC hypotension.
🚨 Clinical Bottom Line
Norepinephrine significantly reduces the risk of recurrent cardiac arrest and the massive resource burden associated with managing a second resuscitation. While it does not improve overall survival rates compared to epinephrine, its clinical advantage in preventing hemodynamic collapse makes it the preferred first-line vasopressor for post-ROSC hypotension
📚 References
- Williams et al.
Norepinephrine versus epinephrine after cardiac arrest: A systematic review and meta-analysis.
Am J Emerg Med. 2025 Sep;95:107-114. Epub 2025 May 22.
PMID: 40440817 - Johnson NJ, Rea TD.
Defining, divining, and defeating recurrent cardiac arrest.
Resuscitation. 2024
PMID: 38479651 - Martin SS, et al.
Heart disease and stroke statistics: a report of US and global data from the American Heart Association.
Circulation. 2024;149:e347–913
PMID: 38264914 - Jung YH, et al.
Rearrest during hospitalization in adult comatose out-of-hospital cardiac arrest patients… Resuscitation. 2022.
PMID: 34871759 - Jaeger D, et al.
A narrative review of drug therapy in adult and pediatric cardiac arrest.
Rev Cardiovasc Med. 2023.
PMID: 39077526 - Jozwiak M, et al.
Post-resuscitation shock: recent advances in pathophysiology and treatment.
Ann Intensive Care. 2020;10:170
PMID: 33315152 - Pansiritanachot W, et al.
Early post-resuscitation outcomes in patients receiving norepinephrine versus epinephrine for post-resuscitation shock in a non-trauma emergency department: a parallel-group, open-label, feasibility randomized controlled trial.
Resusc Plus. 2024
PMID: 38313404
Post Peer Reviewed By: Mark Ramzy, DO (X: @MRamzyDO), and Frank Lodeserto, MD
👤 Guest Authors
Dorian Alexander, MD
