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?

Design

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

Setting

• 19 ICUs in France
• 12.10.1999. – 31.12.2004.

Population

• 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%)

Intervention

• Adrenaline + placebo

Control

• 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)

Outcome

• 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

Strengths

• 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

Weaknesses

• 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

Editorial, Commentaries or Blogs

• Catecholamine treatment for shock – equally good or bad? Lancet 2007
• Choice of vasopressor in septic shock: does it matter? Crit Care 2007
• Epinephrine: Is it really the black sheep of vasoactive agents? Crit Care 2010

Metadata

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