Therapy Norepinephrine plus dobutamine versus epinephrine alone
This review may be edited
Summary
Posted By:	jon field
E-Mail:	Jonathan_Field@health.qld.gov.au
Posted Date:	04/09/07
Title:	Norepinephrine plus dobutamine versus epinephrine alone
Authors:	Djillali Annane, Philippe Vignon, Alain Renault, Pierre-Edouard Bollaert, Claire Charpentier, Claude Martin, Gilles Troché, Jean-Damien Ricard,
Reference:	Lancet. 2007 Aug 25;370(9588):676-84
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Abstract:	Background International guidelines for management of septic shock recommend that dopamine or norepinephrine are preferable to epinephrine. However, no large comparative trial has yet been done. We aimed to compare the effi cacy and safety of norepinephrine plus dobutamine (whenever needed) with those of epinephrine alone in septic shock. Methods This prospective, multicentre, randomised, double-blind study was done in 330 patients with septic shock admitted to one of 19 participating intensive care units in France. Participants were assigned to receive epinephrine (n=161) or norepinephrine plus dobutamine (n=169), which were titrated to maintain mean blood pressure at 70 mm Hg or more. The primary outcome was 28-day all-cause mortality. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148278. Findings There were no patients lost to follow-up; one patient withdrew consent after 3 days. At day 28, there were 64 (40%) deaths in the epinephrine group and 58 (34%) deaths in the norepinephrine plus dobutamine group (p=0·31; relative risk 0·86, 95% CI 0·65–1·14). There was no significant difference between the two groups in mortality rates at discharge from intensive care (75 [47%] deaths vs 75 [44%] deaths, p=0·69), at hospital discharge (84 [52%] vs 82 [49%], p=0·51), and by day 90 (84 [52%] vs 85 [50%], p=0·73), time to haemodynamic success (log-rank p=0·67), time to vasopressor withdrawal (log-rank p=0·09), and time course of SOFA score. Rates of serious adverse events were also similar. Interpretation There is no evidence for a diff erence in effi cacy and safety between epinephrine alone and norepinephrine plus dobutamine for the management of septic shock.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	Yes. Eligible patients were randomly assigned, in a 1:1 ratio, to receive either epinephrine alone or norepinephrine plus dobutamine (whenever needed) according to a computer-generated random list. Randomisation was done centrally by an independent statistician to ensure appropriate concealment, and was stratifi ed by centre, and equilibrated by blocks of six.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	Yes. No patients lost to follow-up; It is worth noting that the authors report outcomes on a patient who 'withdrew consent on day 3'. Technically if a patient withdraws consent, their outcomes should not be used. I assume this patient simply withdrew consent for therapy but gave explicit permission for the use of their data. I would have referred to this patient as 'withdrawal of therapy' or 'withdrawal of consent for therapy'. - Gord
2b. Were patients analyzed in the groups to which they were randomized?
	Yes, the authors conducted an intention to treat analysis
3. Were patients, health workers, and study personnel blind to treatment?
	Yes. Patients randomly assigned to the epinephrine group were given epinephrine plus a placebo in place of dobutamine. Study treatments were provided by the pharmacist at each site as identical syringes for norepinephrine and epinephrine(labelled in blue) and for dobutamine and its placebo (labelled in white).
4. Were the groups similar at the start of the trial?
	The two treatment groups were well balanced at baseline except that the median age was slightly higher in the epinephrine group than in the norepinephrine plus dobutamine group.
5. Aside from the experimental intervention, were the groups treated equally?
	Yes. Other sepsis therapies are listed in table 1
What are the Results?
1. How large was the treatment effect?
	There was no statistical difference in the primary outcome measure : day 28 mortality RR 0·86, p=0·31.
2. How precise was the estimate of the treatment effect?
	95% CI 0·65–1·14;
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	Yes. These are typical ICU pts
2. Were all clinically important outcomes considered?
	Yes. Mortality.
3. Are the likely treatment benefits worth the potential harms and costs?
	No difference demonstated. Be cautious applying these results to clinical decision making. Although this trial was conducted at 95% power, it can only rule out an absolute mortality difference of greater than 20% between groups. A difference as low as 5% may still be clinically meaningful. Gord
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