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Epinephrine vs Norepinephrine and Dobutamine for the management of septic shock

 Citation/s: Norepinephrine plus dobutamine versus epinephrine alone for the management of septic shock: a randomised trial. Lancet 2007; 370: 676 – 84

Lead author's name and email: D Annane, Raymond Poincaré Hospital (AP-HP), University of Versailles Saint Quentin, PRES UniverSud, Paris, France. Djillali.annane@rpc.aphp.fr

Three-part Clinical Question:

Patients: Intensive care patients with septic shock.

Intervention: Epinephrine alone versus norepinephrine ± dobutamine.

Outcomes: Primary – mortality, secondary – safety

Search Terms: Septic shock, therapy, humans, RCT 

The Study: Double-blinded, randomised controlled trial without intention-to-treat.

The Study Patients: Patients aged over 18 admitted to one of nineteen intensive care units in France between 12/10/1999 and 31/12/2004.

Inclusion criteria:  presence for < 7 days of : 1) evidence of infection 2) at least 2 out of 4 criteria for systemic inflammatory response syndrome  3) At least two signs of tissue hypoperfusion or organ dysfunction. Three additional criteria: 1) SBP < 90 mmHg or MAP < 70 mmHg 2) administration of fluid bolus 3) Need for > 15 µg per kilogram of bodyweight per minute of dobutamine or any dose of epinephrine or norepinephrine.  

Exclusion criteria:  pregnancy; evidence of obstructive cardiomyopathy, acute myocardial ischaemia or pulmonary embolus; advanced stage cancer, haematological malignancy or AIDS (with a decision to withhold or withdraw aggressive therapies); persistent (longer than one week) neutrophil count of < 0.5 x 10⁹ ; inclusion in another trial.  

1591 assessed for eligibility, 1261 excluded.  330 randomised: 161 epinephrine, 169norepinephrine. (8 did not receive either drug due to consent withdrawal, early death or problem in drug supply). All patients MAP was targeted using a treatment algorithm which included assessment and optimisation of both volume status and cardiac output.

Epinephrine group (N = 161; 161 analysed): Patients commenced on starting dose epinephrine 0.2 µg/kg per min ± placebo and titrated to algorithm to maintain MAP >70 mmHg. 

Dobutamine & norepinephrine group (N = 169; 169 analysed): Patients commenced on norepinephrine 0.2µg/kg per min ± dobutamine 5 µg/kg per min starting dose and titrated to algorithm to maintain MAP >70 mmHg.

The Evidence:

There was also no difference with regard to: length of stay, number of days not on ICU until day 28, number of days not on intensive care until day 90, number of pressor free days until day 28 or 90, time to haemodynamic success, time to vasopressor withdrawal, mean cost per patient. 

With the epinephrine group arterial blood pH was significantly lower over the first four days. Arterial lactate levels were also significantly increased in this group on day 1 (p=0.0003).

EBM Comments: 

1. Do the methods allow accurate testing of the hypothesis? Yes. There was a sizable difference between the expected mortality (60%) in the epinephrine group used for the power calculation and actual (40%) mortality. However this is unlikely to bias the results. It is of some concern that 409 patients assessed for eligibility were excluded for “other reasons”. The study took 5 years to recruit only 330 patients in 19 units suggesting either an abnormally low incidence of septic shock or a low recruitment rate. During this prolonged study duration other elements of patient management may have changes. Apart from these concerns it was a well conducted study.
2. Do the statistical tests correctly test the results to allow differentiation of statistically significant results? Yes. Statistical analysis by intention-to-treat. Chi-squared test used to compare the effects of treatment on frequency of fatal events.
3. Are the conclusions valid in light of the results?  Yes
4. Did any results get omitted and why? No
5. Did they suggest further areas of research? Yes. 1) Clarification of optimum haemodynamic goals of vasopressor therapy in septic shock 2) Comparing efficacy and safety of epinephrine or norepinephrine with those of dobutamine.
6. Did they make any recommendations based on the results and were they appropriate?  Yes. We can use either epinephrine or norepinephrine ± dobutamine in patients with septic shock.
7. Is the study relevant to my clinical practice? Yes.  Intensive care units in the UK routinely use the study vasopressors; this article tries to challenge aspects of our practice.
8. What level of evidence does the study represent? 1⁺
9. What grade of recommendation can I make on this result alone?  B
10. What grade of recommendation can I make when this study is considered along with other available evidence? B
11. Should I change my practice because of these results? No. This study demonstrated that there is no difference in outcome between the two treatment regimens if they are part of a management package that assesses volume status and cardiac index. If one does not routinely measure these variables one cannot apply these results to their own patients.  A different question to ask, but one more relevant to most patients in intensive care, would be: Is there a difference in outcome between “blind” use of norepinephrine or epinephrine for hypotensive patients in intensive care. We are sure many clinicians have seen patients failing on norepinephrine, with an “adequate” blood pressure due to hypovolaemia, high after load and a resultant low cardiac output state.
12. Should I audit my current practice because of these results?  Yes

Appraised by: Dr Katrina Bramley (ST2) & Dr Chris Cairns (Consultant), Intensive Care Unit, Stirling Royal Infirmary. September 2007.
Email: Chris.cairns@fvah.scot.nhs.uk
Kill or Update By: September 2012.

Reviewed & edited by Martyn Hawkins & Bruce Taylor

©SICS EBMG 2009

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