Pilot Phase II Study: Hemodynamic Tolerance and Anti-inflammatory Effects of Esmolol During the Treatment of Septic Shock

NCT ID: NCT02120404

Last Updated: 2023-08-31

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-30
• Study Completion Date: 2023-10-31

Brief Summary

The purpose of this study is :

• to evaluate the hemodynamic tolerance of esmolol titrated to obtain a lowering of heart rate of 10% or 20%.

Detailed Description

During septic shock, the consequences of treatment by a β1-blocker on inflammation and cardiovascular variability are unknown. The use of esmolol should have positive effects on inflammation and hemodynamic tolerance. These effects are probably dose-dependent.

The study will enroll adult patients hospitalized in ICU, for severe septic shock requiring treatment by a vasopressor.

A total of 45 patients will be included. Among these 45 patients, 15 patients will be randomized in the control group. 30 patients will be randomized to Esmolol with the objective to decrease heart rate by 10% (Group G10, n=15) or 20% (Group G20, n=15). Esmolol will be administered for 24 hours.

This multicenter study will be performed in 3 investigation sites.

The following parameters will be evaluated at different moments during the 28 days follow up of each patient, mainly:

• Origin of sepsis, SOFA score.
• Hemodynamic parameters will be continuously recorded for the 24 hours of experimental period.
• Cardiovascular variability (arterial pressure and heart rate) will be recorded for 24 hours.
• 3 echocardiograms at H0, H12 and H24 will be performed.
• Biological parameters will be sampled at H0, H6, H12 and H24: They include standard biological parameters (Urea, Creatinin, Bilirubin,……) and specific parameters (catecholamines, vasopressin, insulin, cortisol, proinflammatory cytokines and anti-inflammatory cytokines. Dosages will be performed only at H0, H12 and H24 in order to study:

• The expression of adrenergic receptors and their genetic polymorphisms on circulating immune cells.
• The Th1/Th2 balance in immune cells.

Each patient will be followed-up for 28 days.

The variation of MAP and of cardiac output induced by esmolol should not exceed 15% of baseline values. If the variation is more important esmolol administration will be stopped and the hemodynamical tolerance will be defined as poor.

Conditions

Septic Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Control group (GC)

Control group: no esmolol administration

Group Type: NO_INTERVENTION

No interventions assigned to this group

Group 10 (G10)

Esmolol titrated in order to reduce heart rate by 10% as compared to baseline heart rate

Group Type: EXPERIMENTAL

Esmolol administration

Intervention Type: DRUG

Esmolol will be administered during 24 hours, beginning with a titration period to determine the minimal dose allowing to achieve the randomized heart rate reduction of 10% or 20%, as defined by randomization.

Titration will be performed in sequences of increasing doses, beginning with 5 μg/kg/min as initial dose, and increasing by 5 μg/kg/min each 30 minutes until the target heart rate reduction is obtained. The maximum dose is 200 μg/kg/min.

The titrated dose will be maintained for a total duration of 24 hours.

Group 20 (G20)

Esmolol titrated in order to reduce heart rate by 20% as compared to baseline heart rate

Group Type: EXPERIMENTAL

Esmolol administration

Intervention Type: DRUG

Esmolol will be administered during 24 hours, beginning with a titration period to determine the minimal dose allowing to achieve the randomized heart rate reduction of 10% or 20%, as defined by randomization.

Titration will be performed in sequences of increasing doses, beginning with 5 μg/kg/min as initial dose, and increasing by 5 μg/kg/min each 30 minutes until the target heart rate reduction is obtained. The maximum dose is 200 μg/kg/min.

The titrated dose will be maintained for a total duration of 24 hours.

Interventions

Esmolol administration

Esmolol will be administered during 24 hours, beginning with a titration period to determine the minimal dose allowing to achieve the randomized heart rate reduction of 10% or 20%, as defined by randomization.

Titration will be performed in sequences of increasing doses, beginning with 5 μg/kg/min as initial dose, and increasing by 5 μg/kg/min each 30 minutes until the target heart rate reduction is obtained. The maximum dose is 200 μg/kg/min.

The titrated dose will be maintained for a total duration of 24 hours.

Intervention Type: DRUG

Other Intervention Names

BREVIBLOC 10 mg/ml

Eligibility Criteria

Inclusion Criteria

• Patient aged ≥ 18 years;
• Patient with septic shock;
• Patient with arterial catheter, central venous catheter with PVC and PiCCO;
• Consent signed by patient. In the absence of a consent signed by patient himself, a consent by a family member will be sought. As soon as possible, the patient will be informed and asked to sign a consent for continuing of study;
• Hemodynamic stability of patient during 1 hour without change in norepinephrine dosage;
• Treatment with noradrenaline for less than 48 hours.

Exclusion Criteria

• Need of noradrenaline > 3 mg/h;
• Treatment with dobutamine;
• Personal history of severe asthma;
• Personal history of severe chronic obstructive pulmonary disease;
• Personal history of pulmonary hypertension;
• Personal history of second degree or third degree atrioventricular block without pacemaker;
• Personal history of sinoatrial block without pacemaker;
• Chronic heart failure with ejection fraction < 40%;
• Severe atrioventricular nodal bradycardia (heart rate < 70 bpm);
• Mean arterial pressure < 65 mm Hg;
• Hypersensitivity to esmolol;
• Prinzmetal angina;
• Pheochromocytoma without treatment;
• Pregnancy woman;
• Breastfeeding woman;
• Peripheral arterial disease;
• Patient with pacemaker;
• Chronic treatment with a beta blocker;
• Concomitant treatment with bepridil, diltiazem, verapamil, amiodarone, propafenone, Class Ia antiarrythmics (hydroquinidine, disopyramide) or baclofen;
• Patient < 18 years;
• Patient under the care of a guardian;
• Therapeutic futility;
• Lack of medical insurance.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Baxter Healthcare Corporation

INDUSTRY

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Djillali ANNANE, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

ICU, Hôpital Raymond Poincaré, 92380 Garches, France

Locations

ICU, Hôpital Raymond Poincaré

Garches, Haute Des Seine, France

Countries

France

Other Identifiers

2013-005174-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

P120912

Identifier Type: -

Identifier Source: org_study_id