Dopexamine and Norepinephrine Compared With Epinephrine Alone in Septic Shock

Condition(s) targeted: Septic Shock

Intervention: Dopexamine and norepinephrine (Drug); Epinephrine (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: Rennes University Hospital

Official(s) and/or principal investigator(s):
Yannick Mallédant, MD, Study Director, Affiliation: Rennes University Hospital
Eric Bellissant, MD, PhD, Study Chair, Affiliation: Rennes University Hospital
Philippe Seguin, MD, Principal Investigator, Affiliation: Rennes University Hospital

In septic shock, when volume resuscitation fails to restore mean arterial pressure, catecholamines such as dopamine, dobutamine, epinephrine, or norepinephrine are used, either alone or in combination. Although they allow hemodynamic success to be obtained, they can leave some regional blood flows impaired, especially the hepatosplanchnic perfusion, which contributes to multiple organ failure.

Dopexamine is a structural and synthetic analog of dopamine that exerts systemic and gut vasodilation and stimulates cardiac contraction. In experimental models, dopexamine has been shown to exert anti-inflammatory properties and to protect the hepatic ultra structure. The combination of dopexamine and norepinephrine could therefore constitute an interesting alternative in treating septic shock patients. This study will test the efficacy (on gastric mucosal blood flow, hepatic damage and oxidative stress) and safety of the combination of dopexamine and norepinephrine (compared to those of epinephrine alone) in the treatment of patients with septic shock.

Official title: Prospective, Randomized Study on Two Parallel Groups Comparing Dopexamine and Norepinephrine in Combination to Epinephrine Alone on Systemic and Pulmonary Hemodynamics, Gastric Mucosal Perfusion, and Oxidative Stress in Septic Shock

Study design: Treatment, Randomized, Single Blind, Active Control, Parallel Assignment, Efficacy Study

Primary outcome: Gastric mucosal blood flow assessed using a laser-Doppler flowmeter

Secondary outcome:

Systemic and pulmonary hemodynamics: systolic, diastolic and mean arterial, right atrial, systolic, diastolic and mean pulmonary arterial, and pulmonary capillary wedge pressures

heart rate, stroke volume, cardiac output

systemic and pulmonary vascular resistances

arterial and venous blood gases and arterial lactate

alanine and aspartate amino transferases

bilirubin

α-glutathione S-transferase

nitric oxide and reactive oxygen species productions

Detailed description: Objective: To compare the combination of dopexamine and norepinephrine with epinephrine alone on gastric mucosal blood flow (GMBF), hepatic damage and oxidative stress in septic shock.

Setting: Surgical intensive care unit in a university hospital.

Design: Prospective, randomized, controlled study on 2 parallel groups.

Patients: Adults fulfilling usual criteria for septic shock.

Interventions: Systemic hemodynamics, GMBF (laser-Doppler), plasma α-glutathione S-transferase, aspartate aminotransferase, alanine aminotransferase and malondialdehyde were assessed just before catecholamine infusion (T0), as soon as mean arterial pressure (MAP) reached 70-80 mmHg (T1), and 2 (T2) and 6 (T3) hours after T1. Drugs were titrated from 0. 2 µg/kg/min with 0. 2 µg/kg/min increments every 3 min for epinephrine and norepinephrine, and from 0. 5 µg/kg/min with 0. 5 µg/kg/min increments every 3 min for dopexamine.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Adults over 18 years

- Informed consent

- Septic shock with:

- evidence of infection;

- at least 3 of the following criteria: temperature > 38°C or < 36. 5°C; respiratory

rate > 20 breaths per minute 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: plasma lactate > 2 mmol/L or unexplained

metabolic acidosis (pH < 7. 3); hypoxemia defined by PaO2 < 70 mmHg at room air or a PaO2/FiO2 ratio < 280 mmHg (or < 200 mmHg if pneumonia was the source of sepsis) or need for mechanical ventilation; urine output < 30 mL/h for at least 2 hours despite a fluid challenge of at least 500mL; a platelet count < 100,000/mm3, a decrease of 50% from previous value, or unexplained coagulopathy (prothrombin time < 60% and elevated fibrin degradation products > 10 μg/mL);

- systolic blood pressure < 90 mmHg despite an optimal volume loading defined by a

pulmonary capillary wedge pressure > 12 mmHg.

Exclusion Criteria:

- Pregnant women

- Patients with a history of esophageal or gastric disease

- Patients with a history of esophageal or gastric surgery

Rennes University Hospital, Rennes 35033, France

Related publications:

Schmidt W, Hacker A, Gebhard MM, Martin E, Schmidt H. Dopexamine attenuates endotoxin-induced microcirculatory changes in rat mesentery: role of beta2 adrenoceptors. Crit Care Med. 1998 Oct;26(10):1639-45.

Tighe D, Moss R, Heywood G, al-Saady N, Webb A, Bennett D. Goal-directed therapy with dopexamine, dobutamine, and volume expansion: effects of systemic oxygen transport on hepatic ultrastructure in porcine sepsis. Crit Care Med. 1995 Dec;23(12):1997-2007.

Starting date: March 2002
Ending date: June 2004
Last updated: December 30, 2005