Esmolol in septic shock

Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial.

Morelli A1 et al

JAMA. 2013 Oct 23;310(16):1683-91. doi: 10.1001/jama.2013.278477.

STUDY APPRAISER: Dr David Smith

Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/24108526

 

Background

Sepsis is:

  • Low resistance, high cardiac output circulation with tachycardia and arterial hypotension which may be poorly or entirely unresponsive to exogenous vasopressors”
  • Excessive sympathetic output
  • High plasma catecholamine levels
  • Myocardial depression
  • Vascular Hypo-activity
  • Automonic Dysfunction

Excessive adrenergic stress has multiple adverse effects – Stress Cardiomyopathy, Tachyarrhythmias, ↑ Cardiac Oxygen Consumption, Insulin resistance.

Study hypothesized that IV β-Blocker titration to achieve target HR control in septic shock is an effective approach to enhance myocardial function and improve overall outcome

Study design

  • Single-centre, open-label randomized phase 2 trial
  • Italian University Hospital between 2010 and 2012, 18 bedded critical care

Methods

  • All patients given 24 hours of haemodynamic optimization aimed at establishing adequate circulating volume (CVP > 8) + MAP > 65
  • Patients suitable for inclusion if still requriing Norad + HR > 95
  • Esmolol infusion commenced at 25mg/hr
  • Increase rate at 20 minute intervals in increments of 50mg/hr in order to obtain the target HR within 12 hours
  • Upper dose limit of 2000mg / hr
  • IVI given to maintain CVP > 8
  • Norad given to maintain MAP> 65
  • Packed RBC transfused if Hb < 7

 

Population

  • Patients admitted between 2010 and 2012 with septic shock, defined as those requiring Noradrenaline to maintain a MAP 65mmHg despite PAOP > 12mmHg and CVP greater than 8 mmHg with fluid resuscitation.
  • Excluded were patients <18 years old, pre-admission Beta-blocker use, pronounced cardiac dysfunction, pregnancy and significant valvular disease

Intervention

  • 77 patients were randomly assigned to receive an esmolol infusion to control heart rate in predefined levels

Controls

  • Further 77 patients were used as controls

Outcome

  • Primary outcome was reduction in heart rate below 95/min and maintain heart rate between 80/min and 94/min in the treatment arm over 96-hours.
  • Secondary outcomes included Noradrenaline use, cardiac and respiratory indices, safety indicators (organ dysfunction and rescue therapies) and 28 day mortality

Results

  • Median Esmolol dose 100mg/hr
  • Target HR 80-85 VS 11-115bpm
  • MAP in both groups maintained at 72-75mmHg + marked reduction of Norad dose in Esmolol group at 24 & 96 hours
  • Fluid requirements ↓ in Esmolol group
  • Renal function better maintained in Esmolol group
  • No discernible difference to % of patients requiring renal replacement therapy (~40% in both groups)
  • Markers of myocardial injury lower in Esmolol group
  • 28 day mortality 49.4% in the intervention group vs. 80.5% in the control arm. Adjusted hazard ratio of 0.39, 95% CI 0.26-0.59 p<0.001

Conclusions

  • Study authors concluded that they were able to achieve heart rate control without adverse events in septic patients. They felt the reduction in mortality observed warrented further, larger studies.

Discussion

  • Treatment of tachycardia in septic shock is controversial – main early mechanism of maintaining CO
  • Alteration to this ↑ HR may compromise O2 delivery and organ perfusion
  • ↓HR = ↑diastolic filling = ↑SV
  • Preservation of cardiac performance
  • Benefits in ultra short-acting nature & half life of Esmolol (Titration + management of SEs)

Study Limitations

  • Difficulty in defining target HR
  • Non-blinded study
  • Relatively small numbers (77 each group)
  • ? Non-cardiac benefits of Esmolol ( ↑ renin production)
  • ? Similar benefits in less sick patients

Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/24108526

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