Article Identification

Authors: Samuel I. Garcia, MD; Troy G. Seelhammer, MD; Sahar A. Saddoughi, MD, PhD; Alexander S. Finch, MD; John G. Park, MD

Journal Name: American Journal of Emergency Medicine

Year: 2024

Volume: 80

Issue: Not specified

Type of Study: Retrospective Cohort Study

DOI: 10.1016/j.ajem.2024.03.013

Quick Reference Summary

• High cumulative doses of epinephrine (>3 mg) during cardiac arrest are associated with a significantly lower rate of favorable neurologic outcomes (24%) compared to low-dose groups (55%) at hospital discharge (p = 0.025).
• After adjusting for age, higher epinephrine doses increase the likelihood of unfavorable outcomes (odds ratio 4.6, 95% CI 1.3–18.0, p = 0.017).

Core Clinical Question

Does the cumulative dose of epinephrine administered during cardiac arrest affect the neurologic outcomes of patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR)?

Background

Cardiac Arrest Overview:

• Leading cause of morbidity and mortality worldwide.
• Refractory cardiac arrest: requires >10 minutes of conventional CPR or ≥3 defibrillation attempts with poor outcomes.

Prior Data:

• ECPR usage has increased, with over 1500 cases annually worldwide.
• Epinephrine is commonly administered every 3-5 minutes during CPR without a defined maximum dose.

Current Standard of Care:

• Epinephrine is recommended to improve systemic blood pressure and coronary perfusion.
• No specific guidelines for epinephrine dosing in the context of ECPR.

Knowledge Gaps Addressed by Study:

• Impact of high cumulative doses of epinephrine on neurologic outcomes in ECPR patients.
• Potential adverse effects of excessive adrenergic stimulation during ECPR.

Study Rationale:

• Excessive epinephrine may impair cerebral microvascular flow and contribute to unfavorable neurologic outcomes.
• Limited evidence on optimal epinephrine dosing in ECPR scenarios.

Methods Summary

• Study Design: Retrospective cohort study
• Setting and Time Period: Large academic ECMO center, 2018-2022
• Population Characteristics: Adults (≥18 years) receiving ECPR after non-traumatic cardiac arrest
• Inclusion/Exclusion Criteria:
  • Included: Successfully resuscitated with ECPR
  • Excluded: Unauthorized medical record review, missing cardiac arrest information, unsuccessful ECMO initiation, ECMO indications other than ECPR, duplicate ECPR cases
• Intervention Details:
  • Epinephrine Administration: Classified into low (≤3 mg) and high (>3 mg) groups based on prior studies.
• Control/Comparison Group: Low-dose vs. high-dose epinephrine groups
• Primary and Secondary Outcomes:
  • Primary: Favorable neurologic outcome at hospital discharge (CPC 1–2)
  • Secondary: Incidence of adverse events (e.g., vasoplegia, cerebral edema)
• Statistical Analysis Approach:
  • Multivariable logistic regression adjusting for age
  • Odds ratios with 95% confidence intervals
• Sample Size Calculations: Limited by small sample size (N=51), only age included as a covariate
• Ethics and Funding Information:
  • Approved by Institutional Review Board (no. 22–011710) with a waiver of informed consent
  • Funding: None

Detailed Results

Participant Flow and Demographics:

• Total ECPR Cases: 51
• Median Age: 60 years
• Gender: 55% male
• Cardiac Arrest Location: 78% in-hospital (42% ICU)
• Initial Rhythm: PEA (51%), VF (33%), VT (10%), asystole (6%)
• Presumed Causes: Myocardial infarction (31%), massive PE (10%), cardiac tamponade (10%)

Primary Outcome Results:

• Significant improvement in favorable neurologic outcomes in low-dose group (55% vs. 24%, p = 0.025)
• Adjusted odds ratio for unfavorable outcome with high-dose: 4.6 (95% CI 1.3–18.0, p = 0.017)

Secondary Outcome Results:

• Most adverse events showed no significant difference between groups except for comfort care (p = 0.012)

Subgroup Analyses:

Not explicitly detailed

Adverse Events/Safety Data:

• High incidence of vasoplegia, cerebral edema, CNS ischemia, seizures, and acute renal failure, but similar across groups.

Authors’ Conclusions

Primary Conclusions:

• Cumulative epinephrine doses above 3 mg during cardiac arrest are associated with unfavorable neurologic outcomes after ECPR.

Authors’ Interpretation:

• High doses of epinephrine may impair cerebral microvascular flow and contribute to adverse neurologic outcomes.

Clinical Implications:

• Limiting epinephrine administration to ≤3 mg during cardiac arrest in ECPR candidates may preserve neurologic function.

Future Research Recommendations:

• Larger, randomized, multicenter studies are needed to confirm findings and explore long-term effects of epinephrine dosing in ECPR settings.

Literature Review

Comparisons to Other Studies:

• Findings align with prior research indicating adverse effects of high epinephrine doses on cerebral perfusion.
• Consistent with studies showing no improvement in favorable neurologic outcomes despite increased survival with epinephrine.

Study Positioning:

• Adds evidence suggesting a ceiling dose for epinephrine in ECPR is beneficial.

Current Guidelines:

• No existing guidelines specify epinephrine dosing limits in ECPR contexts.

Knowledge Gaps:

• Optimal epinephrine dosing in ECPR remains unclear.

Ongoing Research:

• Authors call for randomized controlled trials to establish dosing guidelines.

Critical Analysis

A. Strengths

• Methodological Strengths:
  • Use of multivariable logistic regression to adjust for confounders (age).
  • Clear definition of primary and secondary outcomes using standardized CPC scores.
• Internal Validity:
  • Strict inclusion and exclusion criteria minimize selection bias.
  • Data abstraction was validated by a senior investigator.
• External Validity:
  • Single-center study may limit generalizability but provides detailed context.

B. Limitations

• Study Design Limitations:
  • Retrospective design inherent to observational studies.
  • Potential for unmeasured confounding variables.
• Potential Biases:
  • Reliance on accurate clinical documentation.
• Generalizability Issues:
  • Conducted at a single large academic center with predominantly in-hospital cardiac arrests.
• Statistical Limitations:
  • Small sample size (N=51) limits the power and number of variables in regression models.
  • Only age was adjusted for due to collinearity with epinephrine dose.
• Missing Data Handling:
  • Exclusion of patients who did not authorize record review or had missing information may introduce bias.

C. Literature Context

• Previous Studies and Meta-Analyses:
  • Consistent Findings: Epinephrine administration beyond 3 mg may impair cerebral perfusion (Mavroudis et al., 2020; Ristagno et al., 2009).
  • Comparative Studies: Similar associations found in out-of-hospital cardiac arrest populations (Jaeger et al., 2012; Shi et al., 2021).
• Contrasting Methodological Quality:
  • Differentiates from studies with larger, multicenter cohorts by being single-center with a smaller sample size.
• Comparisons with Guidelines:
  • Highlights the absence of specific epinephrine dosing guidelines in current ECPR protocols.
• This Trial’s Contribution:
  • Adds Evidence for limiting epinephrine doses in ECPR.
  • Confirms detrimental effects of high-dose epinephrine on neurologic outcomes.

Clinical Application

Impact on Current Practice:

• Findings suggest implementing a maximum cumulative epinephrine dose of 3 mg during cardiac arrest in ECPR patients to enhance neurologic outcomes.

Applicable Patient Populations:

• Patients undergoing ECPR for refractory cardiac arrest, particularly in-hospital arrests.

Implementation Considerations:

• Monitoring and controlling epinephrine administration during resuscitation efforts.
• Training and protocols may need updates to reflect dosing limits.

Integration with Existing Evidence:

• Aligns with studies advocating for cautious epinephrine use to preserve cerebral perfusion.

How To Use This Info In Practice

Practitioners should consider limiting cumulative epinephrine doses to ≤3 mg during cardiac arrest in ECPR candidates to potentially improve neurologic outcomes.

Notes for Clarity

• Statistical Significance:
  • Primary outcomes showing significant differences are bolded.
• Confidence Intervals:
  • Included where available (e.g., odds ratio 4.6, 95% CI 1.3–18.0).
• Conflicts of Interest:
  • None declared.
• Areas of Uncertainty:
  • Effect of each individual epinephrine dose remains unclear.
• Funding Sources:
  • None reported.