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

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

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.

Study Overview

• Status: Completed
• Conditions: Infections; Septic Shock; Severe Sepsis
• Intervention / Treatment: Drug: norepinephrine and dobutamine; Drug: epinephrine plus placebo of dobutamine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 330
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Colombes, France, 92700
    • Réanimation Médicale - Hôpital Louis Mourier
  • Corbeil, France, 91100
    • Réanimation Polyvalente - Hôpital de Corbeil
  • Garches, France, 92380
    • Service de Réanimation Médicale - Hôpital Poincaré
  • Le Chesnay, France, 78157
    • Réanimation Médicale - Hôpital André Mignot
  • Limoges, France, 87000
    • Réanimation Polyvalente - Hôpital Dupuytren
  • Marseille, France, 13009
    • Réanimation Polyvalente - Hôpital Nord
  • Nancy, France, 54035
    • Réanimation Chirurgicale - Hôpital Central
  • Nancy, France, 54035
    • Service de Réanimation Médicale - Hôpital Central
  • Paris, France, 75005
    • Service d'anesthésiologie - HIA Val de Grâce
  • Paris, France, 75010
    • Réanimation Médicale - Hôpital Saint Louis
  • Paris, France, 75014
    • Réanimation Polyvalente - Hôpital Saint Joseph
  • Paris, France, 75908
    • Réanimation Médicale - Hôpital Georges Pompidou
  • Poissy, France, 78303
    • Réanimation Médicale - CHI de Poissy
  • Roubaix, France, 59100
    • Réanimation - CH Victor Provo
  • Villejuif, France, 94800
    • Réanimation Polyvalente - Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1; norepinephrine plus dobutamine	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
ACTIVE_COMPARATOR: 2; epinephrine	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
28 Day mortality	28 Day

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Versailles
• Collaborators: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Director: Djillali Annane, MD, PhD, Assistance Publique Hôpitaux de Paris - University of Versailles

Publications and helpful links

General Publications

• Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C, Martin C, Troche 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 25;370(9588):676-84. doi: 10.1016/S0140-6736(07)61344-0. Erratum In: Lancet. 2007 Sep 22;370(9592):1034.

Study record dates

Study Major Dates

• Study Start: October 1, 1999
• Primary Completion (ACTUAL): December 1, 2004
• Study Completion (ACTUAL): December 1, 2005

Study Registration Dates

• First Submitted: September 1, 2005
• First Submitted That Met QC Criteria: September 2, 2005
• First Posted (ESTIMATE): September 7, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): July 22, 2010
• Last Update Submitted That Met QC Criteria: July 21, 2010
• Last Verified: July 1, 2010

More Information

Terms related to this study

• Keywords: Septic shock; Catecholamines
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Cardiotonic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-Agonists; Sympathomimetics; Adrenergic beta-1 Receptor Agonists; Vasoconstrictor Agents; Mydriatics; Norepinephrine; Epinephrine; Dobutamine
• Other Study ID Numbers: AFSSAPS 990931; AOM97123; CIC0203/001