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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Prospective, Multicenter, Randomized, Double-Blind Study Comparing Safety and Efficacy of Norepinephrine Plus Dobutamine Versus Epinephrine Alone in Septic Shock.

Conditions
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Septic Shock, Severe Sepsis, Infections

Intervention / Treatment
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* Drug: norepinephrine and dobutamine
* Drug: epinephrine plus placebo of dobutamine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>norepinephrine plus dobutamine | Drug: norepinephrine and dobutamine<br>* 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<br>|
| Active Comparator: 2<br>epinephrine | Drug: epinephrine plus placebo of dobutamine<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28 Day mortality |  | 28 Day | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Catecholamines, Septic shock