General Critical Care - October 2007

Citation
Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C, Martin C, Troché G, Ricard JD, Nitenberg G, Papazian L, Azoulay E, Bellissant E; CATS Study Group.
Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet. 2007 Aug;370:676-84.

Link
http://www.thelancet.com/journals/lancet/article/PIIS0140673607613440/abstract

Reviewer

A. Combes, MD, PhD
Professor of Critical Care Medicine,
Department of Critical Care Medicine, Cardiology Institute of Paris,
Groupe Hospitalier Pitié-Salpêtrière
47 bd de l'Hôpital, 75651 PARIS, France

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 efficacy 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 difference in efficacy and safety between epinephrine alone and norepinephrine plus dobutamine for the management of septic shock.

Comment:
Patients with septic shock commonly receive catecholamines to reverse sepsis-induced hypotension. Recent international guidelines recommend dopamine or norepinephrine as first line therapy and epinephrine in patients who respond poorly to dopamine or norepinephrine (Hollenberg, Crit Care Med, 2004;32:1928-48). However, epinephrine is commonly used as the first line catecholamine in sepsis by many intensivists, despite its reported deleterious effects on splanchnic blood flow and acid-base balance. Up to now, the advantage of norepinephrine plus dobutamine vs. epinephrine had not been tested in adequately powered randomized trials, with meaningful endpoints, such as all-cause mortality.

Results of the CATS study by Annane et al, comparing norepinephrine plus dobutamine vs. epinephrine in 330 patients with septic shock, were therefore eagerly awaited. These authors found no superiority of either treatment option on short- and long-term all-cause mortality, and on all other endpoints evaluated (delay in hemodynamic stabilization, resolution of organ dysfunction or adverse events).
This study has much strength. It is the largest cohort evaluated to date. Patients studied were really sick: 95% on mechanical ventilation, mean SAPS 2 of 53 (corresponding to a 53% probability of hospital death). The main outcome was meaningful, and not confined to the evaluation of physiologic or metabolic parameters.

Some limitations should nonetheless be noted. The authors designed the study expecting a 60% mortality rate in the epinephrine group but the observed mortality was only 40%. This difference could relate to the generalization of corticoids and activated protein C use during the course of the study. Additionally, they based their sample calculation on an absolute reduction in mortality of 20% in the norepinephrine plus dobutamine group, which certainly was an optimistic hypothesis. However, given the lack of signal observed in more than 300 patients, it seems unlikely that a large difference in mortality really exists.

Emergency and ICU physicians could therefore use either of these treatment protocol in patients with septic shock and a low cardiac index. However, as underlined by Dr Singer in the accompanying editorial to this paper (Lancet. 2007;370:636), “the choice of catecholamine for septic shock is equally good or equally bad…”. Better alternative to catecholamine are needed and optimum hemodynamic goals of vasopressor therapy should be better defined.

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