Morelli et al: Esmolol in Septic Shock (2013)

“In patients with septic shock, targeting a heart rate of 80 to 94 beats/min with esmolol was associated with a reduction in heart rate to the target range without adverse effects and with a reduction in mortality.”

  • Andrea Morelli, M.D., et al.

1. Publication Details

  • Trial Title: Effect of Tachycardia Control With Esmolol on Survival in Septic Shock: A Prospective, Randomized, Controlled Trial
  • Citation: Morelli A, Ertmer C, Westphal M, et al. Effect of tachycardia control with esmolol on survival in septic shock: a prospective, randomized, controlled trial. JAMA. 2013;310(16):1683-1691. DOI: 10.1001/jama.2013.278477
  • Published: October 23, 2013, in The Journal of the American Medical Association (JAMA)
  • Author: Andrea Morelli, M.D.
  • Funding: Unrestricted grant from the University of Rome La Sapienza.

2. Keywords

  • Sepsis, Septic Shock, Esmolol, Beta-Blockers, Tachycardia, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with septic shock who remain tachycardic (heart rate ≥ 95/min) after 24 hours of resuscitation (Population), does an infusion of esmolol to control heart rate (Intervention) compared to standard care (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Persistent tachycardia in septic shock is associated with a poor prognosis. It was thought to be a maladaptive response that increased myocardial oxygen demand and could lead to cardiac dysfunction. While beta-blockers could control heart rate, their use was controversial due to fears of worsening shock by reducing cardiac output.
  • Knowledge Gap: Following smaller safety studies (e.g., Besson et al. 1995), it was still unknown if intentionally lowering the heart rate with a beta-blocker in septic shock was safe and, more importantly, if it could improve survival.
  • Proposed Hypothesis: The authors hypothesized that controlling tachycardia with the short-acting beta-blocker esmolol would be superior to standard care in reducing 28-day mortality in patients with septic shock.

5. Study Design and Methods

  • Design: A single-center, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: A single university hospital ICU in Rome, Italy.
  • Trial Period: Enrollment ran from November 2010 to July 2012.
  • Population:
    • Inclusion Criteria: Adult patients with septic shock requiring high-dose norepinephrine (>0.4 µg/kg/min) who had a persistent heart rate of 95/min or higher after at least 24 hours of initial resuscitation.
    • Exclusion Criteria: Included pre-existing severe heart failure, significant valvular disease, and recent use of beta-blockers.
  • Intervention: Patients received a continuous intravenous infusion of esmolol, titrated to maintain a target heart rate between 80 and 94 beats/min.
  • Control: Patients received standard care without esmolol.
  • Management Common to Both Groups: All patients were managed with a standardized resuscitation protocol, including hemodynamic monitoring with a pulmonary artery catheter.
  • Power and Sample Size: The authors calculated that a sample size of 154 patients would be required to have 80% power to detect a 20% absolute risk reduction in 28-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 28 days.
    • Secondary Outcomes: Included hemodynamic parameters, vasopressor requirements, and organ function scores.

6. Key Results

  • Enrollment and Baseline: 154 patients were randomized (77 to esmolol and 77 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: 28-day mortality was dramatically lower in the esmolol group: 38 of 77 patients (49.4%) died, compared with 62 of 77 patients (80.5%) in the control group (p<0.001).
  • Secondary Outcomes: Patients in the esmolol group had a significant reduction in their heart rate as intended. Despite the lower heart rate, their stroke volume increased, and their vasopressor requirements were lower over time.
  • Adverse Events: The study monitored for adverse hemodynamic effects. Esmolol was generally well-tolerated, with no significant increase in hypotension or other major adverse events.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test and a log-rank test for survival analysis.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of <0.001 for the primary outcome is extremely low, indicating that the observed difference in mortality is highly statistically significant and very unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 80.5% – 49.4% = 31.1%.
      • Clinical Meaning: For every 100 patients treated with esmolol according to this protocol, about 31 additional deaths were prevented.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.311 = 3.2, which is rounded down to 3.
      • Clinical Meaning: You would only need to treat 3 patients with esmolol to prevent one additional death.
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: The randomized, controlled design provided a high level of evidence for a novel therapeutic strategy. The use of advanced hemodynamic monitoring provided important physiological insights.
  • Patient-Centered Outcomes: The primary outcome of 28-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The single-center design is a major limitation, as the results may not be applicable to other centers with different patient populations or practices. The study population was a highly selected group of hyperdynamic, tachycardic patients, and the results cannot be generalized to all patients with septic shock.
  • Other: The mortality rate in the control group (80.5%) was extremely high, which may have exaggerated the benefit of the intervention. The very large treatment effect (NNT of 3) is rare in critical care trials and raises questions about its replicability.

10. Conclusion of the Authors

  • The authors concluded that in patients with septic shock, titrating esmolol to a heart rate of 80-94 beats/min reduced 28-day mortality without causing adverse events.

11. To Summarize

  • Impact on Current Practice: This was a highly influential but also very controversial trial. It provided the first strong evidence that beta-blockade could be beneficial in septic shock, completely challenging the long-standing dogma that it was harmful. However, due to its significant limitations, it did not lead to the widespread adoption of this practice but rather generated a new and important hypothesis.
  • Specific Recommendations:
    • Patient Selection: The findings are only applicable to the highly selected group of patients studied: those with septic shock who remain hyperdynamic (high cardiac index) and tachycardic (>94 bpm) after initial fluid resuscitation.
    • Actionable Intervention: In this specific patient group, the results suggest that esmolol may be considered to control heart rate.
  • What This Trial Does NOT Mean: This trial does NOT mean that all patients with septic shock should receive a beta-blocker. Administering esmolol to patients who are not hyperdynamic could be extremely dangerous.
  • Implementation Caveats: The use of esmolol in septic shock requires advanced hemodynamic monitoring (like a pulmonary artery catheter) to ensure the patient has a high cardiac index before starting the drug, and to monitor for safety. This is not a therapy to be used without expert oversight.

12. Context and Related Studies

  • Building on Previous Evidence: The Morelli et al. trial (2013) was a direct follow-up to smaller, earlier studies (e.g., Besson et al. 1995) that had suggested the safety but not the efficacy of beta-blockers in sepsis.
  • Influence on Subsequent Research: The dramatic but controversial findings of this trial have spurred a great deal of further research into the role of beta-blockade in sepsis, though no subsequent large, multicenter trial has yet replicated this massive mortality benefit.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether the remarkable findings of this single-center trial are replicable in a large, multicenter setting.
  • Future Directions: A large, multicenter randomized controlled trial is needed to definitively confirm or refute the benefit of esmolol in this highly selected patient population.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant and innovative, challenging a long-standing clinical dogma.
  • Methods: The randomized controlled design was a strength. However, the single-center, open-label design and the extremely high mortality in the control group are major methodological limitations that raise significant concerns about the internal and external validity of the findings.
  • Results: The study reported a very large and statistically significant mortality benefit (NNT of 3). An effect size this large from a small, single-center trial must be interpreted with extreme caution, as such results are often not replicated in larger, multicenter studies.
  • Conclusions and Applicability: The authors’ conclusion is a fair reflection of their data, but the applicability of the findings is very narrow and fraught with risk. This trial is a classic example of a “fragile” but profoundly important, hypothesis-generating study. It has not changed the standard of care, but it has opened up a major new avenue of clinical research.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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