Besson et al: Beta-Blockade in Severe Sepsis (1995)

“In patients with severe sepsis, esmolol infusion effectively controlled heart rate but did not demonstrate a significant improvement in overall survival.”

  • Adapted from Besson et al.

1. Publication Details

  • Trial Title: Prospective evaluation of the efficacy of esmolol in severe sepsis
  • Citation: Besson R, Lory C, Larrue Y, et al. Prospective evaluation of the efficacy of esmolol in severe sepsis. Ann Fr Anesth Reanim. 1995;14(1):15-20.
  • Published: 1995, in Annales Françaises d’Anesthésie et de Réanimation
  • Author: R. Besson
  • Funding: Not explicitly stated in the abstract.

2. Keywords

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

3. The Clinical Question

  • In adult patients with severe sepsis and persistent tachycardia (Population), does an infusion of esmolol (Intervention) compared to standard care (Comparison) affect hemodynamics and mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Persistent tachycardia in sepsis 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. Beta-blockers, by controlling heart rate, were hypothesized to be beneficial.
  • Knowledge Gap: The use of beta-blockers in septic shock was highly controversial. The conventional wisdom was that blocking the compensatory tachycardia could be dangerous and worsen shock. There was no high-quality randomized trial evidence to guide this practice.
  • Proposed Hypothesis: The authors hypothesized that controlling tachycardia with esmolol in patients with severe sepsis would be safe and might improve outcomes.

5. Study Design and Methods

  • Design: A single-center, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: A single intensive care unit (ICU) in France.
  • Trial Period: Enrollment period not explicitly stated in the publication.
  • Population:
    • Inclusion Criteria: Adult patients with severe sepsis and persistent tachycardia (>110 bpm) despite initial fluid resuscitation.
    • Exclusion Criteria: Included cardiogenic shock, severe heart failure, and contraindications to beta-blockers.
  • Intervention: Patients received a continuous intravenous infusion of esmolol, titrated to achieve a target heart rate of 90-110 bpm.
  • Control: Patients received standard care without esmolol.
  • Management Common to Both Groups: All patients received standard supportive care for severe sepsis, including fluids, antibiotics, and vasopressors as needed.
  • Power and Sample Size: A formal power calculation was not reported in the publication, which was common for trials of that era.
  • Outcomes:
    • Primary Outcome: The primary outcomes were changes in hemodynamic parameters and overall mortality.
    • Secondary Outcomes: Included duration of vasopressor support and organ dysfunction.

6. Key Results

  • Enrollment and Baseline: 32 patients were randomized (16 to esmolol and 16 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: Esmolol effectively reduced heart rate in the intervention group. However, there was no statistically significant difference in mortality between the groups: 5 of 16 patients (31%) in the esmolol group died, compared with 6 of 16 patients (38%) in the control group.
  • Secondary Outcomes: There were no significant differences in the duration of vasopressor support or in the evolution of organ dysfunction scores between the two groups.
  • Adverse Events: The study monitored for adverse hemodynamic effects. Esmolol was generally well-tolerated, with no significant increase in hypotension requiring an increase in vasopressor dose.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed according to the treatment received.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test for mortality and t-tests for hemodynamic variables.
  • Primary Outcome Analysis: The mortality outcome was a comparison of proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value for the difference in mortality was not statistically significant.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 38% – 31% = 7%.
      • Clinical Meaning: For every 100 patients treated with esmolol, there was a non-significant trend towards 7 fewer deaths.
  • Subgroup Analyses: Due to the small sample size, no subgroup analyses were performed.

8. Strengths of the Study

  • Study Design and Conduct: For its time, the randomized, controlled design was a major strength, as it was one of the first trials to formally test this controversial hypothesis.
  • Physiological Rationale: The study was based on a strong physiological hypothesis about the harms of persistent tachycardia in sepsis.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The single-center design and very small sample size are major limitations. The results cannot be reliably generalized.
  • Other: The study was severely underpowered to detect a true difference in mortality. A much larger trial would be needed to definitively answer this question.

10. Conclusion of the Authors

  • The authors concluded that esmolol was effective at controlling heart rate in patients with severe sepsis and did not appear to cause significant hemodynamic instability. However, the study was too small to draw any conclusions about its effect on mortality.

11. To Summarize

  • Impact on Current Practice: This was a pioneering, hypothesis-generating trial. While it did not change practice on its own, it was a crucial early step that demonstrated the potential safety of beta-blockade in sepsis and paved the way for future, larger trials.
  • Specific Recommendations:
    • Patient Selection: For adult patients with severe sepsis and persistent tachycardia.
    • Actionable Intervention: The results do not support the routine use of esmolol to improve survival. However, they suggest it can be used safely to control heart rate in select patients.
  • What This Trial Does NOT Mean: This trial does NOT mean that beta-blockers are ineffective in sepsis. It only means that this small study was unable to show a benefit.
  • Implementation Caveats: The use of esmolol in septic shock requires careful hemodynamic monitoring.

12. Context and Related Studies

  • Building on Previous Evidence: The Besson et al. trial (1995) was one of the first RCTs to challenge the dogma that beta-blockers were absolutely contraindicated in septic shock.
  • Influence on Subsequent Research: The promising safety signal from this small trial was a critical foundation for the much larger and more definitive Morelli et al. trial (2013), which did find a significant mortality benefit with esmolol in a similar patient population.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial left the key question of whether beta-blockers improve survival in septic shock unanswered due to its small size.
  • Future Directions: The entire subsequent field of research into heart rate control in sepsis, culminating in the Morelli et al. (2013) trial and others, can be seen as the future direction that followed from this early, pioneering study.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant and challenged a long-standing clinical dogma.
  • Methods: The randomized controlled design was appropriate. However, the single-center design and, most importantly, the very small sample size are major methodological limitations that make the study’s conclusions very weak.
  • Results: The study was severely underpowered, and therefore the neutral finding for mortality is inconclusive. The finding of effective heart rate control without significant adverse effects was the most important result, as it provided a safety signal for future research.
  • Conclusions and Applicability: The authors’ conclusion is a fair and appropriately cautious interpretation of their data. The trial’s main contribution was not to provide a definitive answer, but to demonstrate that this was a question worth asking in a larger, more definitive trial.

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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