Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial

Annane et al. Lancet 2007; 676-84.

Clinical Question

  • In patients with septic shock, is mortality affected by the use of adrenaline (epinephrine) alone in comparison to noradrenaline ± dobutamine?


  • Randomised, controlled trial
  • Randomised centrally to achieve allocation concealment
  • Block randomisation, stratified by centre
  • Triple blinded
  • Intention to treat analysis


  • 19 ICUs in France
  • 12.10.1999. – 31.12.2004.


  • Inclusion Criteria:
    • evidence of infection for <7 days and 2 SIRS critieria
    • at least 2 of the following: PaO2/FiO2 <280mmHg (if ventilated), urine output <0.5ml/kg for >1hr, lactate >2mmol/l, platelet <100
    • and all 3 of the following for <24hrs
      • systolic BP <90 or MAP <70
      • administration of fluid bolus of ≥ 1000ml+ or capillary wedge pressure 12-18mmHg
      • need for >15μg/kg/min dopamine or any dose or adrenaline/noradrenaline
  • Major Exclusion Criteria: Pregnancy, obstructive cardiomyopathy, acute MI/PE
  • 330 randomised out of 1591 who were assessed for eligibility
  • The source of sepsis was lung primary in around 50% of patients (abdominal in 25%)


  • Adrenaline + placebo


  • Noradrenaline + dobutamine (whenever needed)
  • In both intervention group and control group the use of adrenaline/noradrenaline and dobutamine/placebo was set by a pre-determined protocol shown below
    • Is MAP inadequate? If yes -> are they underfilled? If yes -> give fluids
    • Is MAP inadequate? If yes -> are they underfilled? If No -> check cardiac output (by whatever means) -> if ok then increase vasopressors; if not increase dobutamine (or placebo in the control group)


  • Primary outcome: All cause 28 day mortality – no significant difference
    • 40% in adrenaline group vs. 34% in noradrenaline + dobutamine group, (RR 0.86, 95% C.I. 0.65-1.14, P=0.31)
  • Secondary outcomes:
    • No significant difference in rate of severe arrhythmias, myocardial events, length of stay and time to pressor withdrawal
    • Lactate significantly increased in adrenaline group at day 1 only (P=0.003); pH significantly lower in adrenaline group from day 1-4

Authors’ Conclusions

  • Physicians could use either adrenaline alone or noradrenaline ± dobutamine in patients with septic shock


  • Triple blinded
  • Pre-determine protocol for use pressors/dobutamine
  • Intention to treat analysis with minimal loss to follow up
  • Considered specific concomitant therapy including, APC, steroids, adequacy of initial antibiotics and renal replacement therapy. These were well matched although no statistical data was conducted
  • No conflict of interest declared. Supported by the French Ministry of Health


  • Number of patients excluded – 98 due to physician refusal and 409 due to ‘other reasons’
  • Based on results found, the study had a power of 85% to detect an absolute reduction of 15% mortality, from a baseline mortality of 40%. A benefit as great as this is probably unrealistic and there could still be large differences that this trial was not powered to detect
  • No mention of time to antibiotic therapy although standard treatment and adequate initial antibiotic cover similar

The Bottom Line

  • There was no significant difference found between the use of adrenaline vs. noradrenaline ± dobutamine in patients with septic shock. However, the study was under-powered and with a trend towards harm in the adrenaline group, highlights the need to conduct larger studies before considering adrenaline as the first agent for the management of septic shock. I will continue to reach for noradrenaline for patients with septic shock. The study does provide some reassurance that adrenaline infusion is a reasonable alternative in the early phase of shock or in resource limited settings.


Full text pdf / abstract / doi: 10.1016/S0140-6736(07)61344-0

Editorial, Commentaries or Blogs


Summary author: @DavidSlessor
Summary date: 30th April 2014
Peer-review editor: @stevemathieu75

Leave a Reply

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.