Critical Care, Critical Care Alert, Cardiology, Sepsis

Critical Care Alerts: Effect of Ultra-Short-Acting Beta-blockers on Mortality in Patients with Persistent Tachycardia Despite Initial Fluid Resuscitation: A Systematic Review and Meta-Analysis

Critical Care Alert

ARTICLE
Hasegawa D, Sato R, Prasitlumkum N, et al. Effect of Ultra-Short-Acting Beta-blockers on Mortality in Patients with Persistent Tachycardia Despite Initial Fluid Resuscitation: A Systematic Review and Meta-Analysis. Chest. 2021; Jan 9:S0012-3692(21)00035-0. Epub ahead of print. PMID: 33434497.

OBJECTIVE
Authors aimed to determine if ultra-short-acting beta-blockers, such as esmolol and landiolol, reduced 28-day mortality in septic patients with persistent tachycardia despite initial adequate resuscitation.

BACKGROUND
Cardiac dysfunction secondary to tachycardia, including atrial fibrillation (AFib), has been linked to increased mortality rates in patients with septic shock or sepsis.1 Increased myocardial oxygen demand, poor coronary perfusion, and limited diastolic filling time mediated by tachycardia are among key contributors to sepsis-induced cardiomyopathy.1 Once thought to be a relative contraindication in sepsis treatment due to cardiac suppression, ultra-short-acting beta-blockers such as esmolol and landiolol have been proposed to decrease mortality in septic patients. Ultra-short-acting beta-blockers with high selectivity for beta-1 receptors may attenuate cardiac dysfunction associated with excess beta-adrenergic stimulation from both endogenous and exogenous sources of catecholamines common in cases of sepsis.

While prior investigations into the use of esmolol and landiolol in sepsis have focused on heart rate reduction, here the authors set out to determine if esmolol and landiolol reduced patient mortality.

DESIGN
Systematic review and meta-analysis of seven randomized control trials

Study Selection and Inclusion Criteria

  • Must be a randomized control trial
  • Patient aged ≥18 years with sepsis based on Sepsis-1, Sepsis-2, and Sepsis-3 definitions.
  • Patient must receive intravenous esmolol or landilol
  • Control group: placebo or no intervention

OUTCOMES
Primary

  • 28-day mortality in patients with septic shock with persistent tachycardia given intravenous esmolol or landiolol.

Secondary

  • Lactic acid levels at baseline, 24, 48, and 72 hours after enrollment
  • Heart rate; Mean arterial pressure (MAP); Norepinephrine dose; Cardiac index; Stroke volume index (SVI); and white blood cell (WBC) count 24 hours after enrollment.

KEY RESULTS
Primary Outcomes

6 out of the 7 randomized control trials, sampling 572 patients reported 28-day mortality.

  • Significant reduction in 28-day mortality in patients with septic shock or sepsis with persistent tachycardia when treated with esmolol or landiolol (RR 0.68; 95% CI, 0.54-0.85; P < .001). Absolute risk reduction (ARR) 18.2%; Number needed to treat (NNT) to prevent one death 5.5.

Secondary Outcomes

  • No significant difference between treatment and control groups in baseline, 24 or 48 hour lactic acid levels
    • Significant reduction at 72 hours
  • Significant reduction in HR 24 hours after enrollment in esmolol/landiolol group compared to control (SMD, -1.99: 95% CI, -2.99 to -0.99)
  • Significant increase in SVI 24 hours after enrollment in esmolol/landiol group compared to control (SMD, 0.26: 95% CI, 0.03–0.49)
  • Significant reduction in WBC count in esmolol/landiolol group compared to control (SMD, -0.19; 95% CI, -0.37 to -0.01)
  • No significant reduction in MAP 24 hours after enrollment in esmolol/landiolol group compared to control
  • No significant difference in norepinephrine dose 24 hours after enrollment between esmolol/landiolol group and control
  • No significant difference in cardiac index 24 hours after enrollment between esmolol/landiol group and control

STRENGTHS

  • Meta-analysis, limited heterogeneity among studies (I2 = 31%).
  • Detailed discussion of the physiology of why selective beta-1 adrenergic antagonists could be beneficial in tachycardic septic patients
  • Discusses the dichotomy between a role of beta-blockade in compensatory and non-compensatory tachycardia

LIMITATIONS

  • With all meta-analysis and systematic reviews, the results can only be as strong as the studies which comprise the final data.
  • 6 of the 7 trials examined were single center.
  • Relatively small sample size (n=613).
  • 4 of 7 trials took place in Asia with an assumed Asian ethnicity population, potentially limiting generalizability.
  • Studies excluded patients with cardiac dysfunction and compensatory tachycardia further limiting generalizability.
  • Variable duration of beta-blocker administration, baseline norepinephrine dose, and severity of illness based on APACHE-II score among trials.

EM TAKE-AWAYS

This systematic review and meta-analysis demonstrated a significant reduction in 28-day mortality in septic patients with persistent tachycardia despite adequate resuscitation who were treated with esmolol or landiolol. Given the negative inotropic, chronotropic, and vasodilatory effects of beta-blockers, their use in treating sepsis may give emergency physicians pause and seem counterintuitive to the hemodynamic needs of the patient. However, beta-blockade in certain patients may allow for increased cardiac efficiency by slowing the heart rate down, subsequently increasing stroke volume and end-organ perfusion without increases in vasopressor support. This meta-analysis demonstrates plausible safe use in treating septic patients with non-compensatory tachycardia with ultra-short-acting beta-blockers, warranting institutions to consider implementing titration parameters in their sepsis protocols. Consideration of use of ultra-short acting beta-blockers comes after standard initial resuscitation. The efficacy and safety of such medications remains unclear in patients with cardiac dysfunction, those who received inadequate fluid resuscitation, and in patients without tachycardia.


References

  1. Cruz MC, Reis L. beta-blockers in septic shock: are we there yet?. Betabloqueadores no choque séptico: já chegamos lá?. Rev Bras Ter Intensiva. 2017;29(1):1-3. doi:10.5935/0103-507X.20170001.

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