Norepinephrine Plus Dobutamine Versus Epinephrine Alone for the Management of Septic Shock (CATS)

• -28-day survival distribution [ Time Frame: Day 28 ] [ Designated as safety issue: Yes ]
• -Survival rate at days 14, 28, 90, 6 months and 1 year. [ Time Frame: one year ] [ Designated as safety issue: Yes ]
• -Rate of patients with secondary care limitation [ Time Frame: one year ] [ Designated as safety issue: No ]
• -Organ failure between randomization and day 28. [ Time Frame: Day 28 ] [ Designated as safety issue: Yes ]
• -Serious adverse events between randomization and exit of intensive care unit. [ Time Frame: one year ] [ Designated as safety issue: Yes ]
• -Onset of a reversible clinical event between randomization and exit of intensive care unit (bronchospasm, cutaneous rash, tachycardia) [ Time Frame: one year ] [ Designated as safety issue: Yes ]
• -Time on vasopressors [ Time Frame: Day 90 ] [ Designated as safety issue: No ]
• -Time in intensive care unit [ Time Frame: one year ] [ Designated as safety issue: Yes ]
• -Time in hospital [ Time Frame: one year ] [ Designated as safety issue: Yes ]
• -Costs [ Time Frame: Day 90 ] [ Designated as safety issue: No ]

• -28-day survival distribution
• -Survival rate at days 14, 28, 90, 6 months and 1 year.
• -Rate of patients with secondary care limitation
• -Rate of hemodynamic success
• -Organ failure between randomization and day 28.
• -Serious adverse events between randomization and exit of intensive care unit.
• -Onset of a reversible clinical event between randomization and exit of intensive care unit (bronchospasm, cutaneous rash, tachycardia)
• -Time on vasopressors
• -Time in intensive care unit
• -Time in hospital
• -Costs

Catecholamines infusion is a major component of septic shock management. International guidelines recommend that norepinephrine should be preferred to epinephrine, though phase III trials are lacking. The present study aimed at comparing the efficacy and safety of norepinephrine plus dobutamine to that of epinephrine in adults with septic shock.

The french Conference on Consensus on catecholamines use in septic shock has underlined the importance of carrying out a clinical trial to clarify the use of epinephrine, norepinephrine and dobutamine in the management of multiple organ failure associated with severe sepsis. The main objective of the study was therefore to compare the effects of the combination of dobutamine and norepinephrine to those of epinephrine alone in patients with septic shock. In this purpose, patients were randomly assigned to receive either epinephrine or norepinephrine plus dobutamine and drugs were titrated to maintain blood pressure over 70 mmHg. Main outcome was 28-day mortality.

• Septic Shock
• Severe Sepsis
• Infections

• Drug: norepinephrine and dobutamine
  continuous infusion of norepinephrine titrated to maintain a mean arterial pressure at 70mmHg or more and dobutamine could be added as a continuous infusion when cardiac index was of less than 2.5 liters per squared meter of body surface
• Drug: epinephrine plus placebo of dobutamine
  epinephrine was titrated to maintain a mean arterial pressure at 70mmHg or more and placebo of dobutamine was titrated in case of a cardiac index lower than 2.5 liters per squared meters of body surface

• Experimental: 1
  norepinephrine plus dobutamine
  Intervention: Drug: norepinephrine and dobutamine
• Active Comparator: 2
  epinephrine
  Intervention: Drug: epinephrine plus placebo of dobutamine

Inclusion Criteria:

• Adults over 18 years
• Informed consent

Presenting from less than 7 days :

• One or more infectious site
• At least 2 of the following criteria: temperature > 38°C or < 36.5°C, respiratory rate > 20 breaths per min or PaCO2 < 32 mmHg or mechanical ventilation, heart rate > 90 beats/min, white blood cell count > 12,000/mm3 or < 4,000/mm3
• At least 2 of the following criteria: PaO2/FiO2 ratio <280 mmHg (if mechanical ventilation, urinary output of less than 0.5 mL/kg of body weight or < 30 mL/h at least 1 hour, plasma lactate > 2 mmol/L, platelet count < 100,000 /mm3

And presenting from at least 24 hours:

• Systolic blood pressure < 90 mmHg or mean blood pressure < 70 mmHg (for at least 30 min);
• 1000 mL fluid replacement or pulmonary capillary wedge pressure > 12 mmHg
• Dopamine infusion at 15 µg/kg/min for at least 1 hour, or epinephrine or norepinephrine in first intention

Exclusion Criteria:

• Pregnant woman
• Obstructive cardiomyopathy
• Acute coronary disease
• Non infectious shock
• Care limitation
• White blood cell count < 500 /mm3