Clinical trial NCT02120404: Pilot Phase II Study: Hemodynamic Tolerance and Anti-inflammatory Effects of Esmolol During the Treatment of Septic Shock
Official title: Pilot Phase II Study: Hemodynamic Tolerance and Anti-inflammatory Effects of Esmolol During the Treatment of Septic Shock
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Septic Shock
Keywords: septic shock, hemodynamic tolerance, esmolol
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Baxter Healthcare Corporation
First posted: 2014-04-22
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Comparison of hemodynamic parameters between 3 groups
timeFrame: 24 hours
measure: Immunomodulatory effect
timeFrame: 24 hours
Secondary outcomes:
measure: Comparison of number and severity of organ failures, between the 3 groups
timeFrame: 28 days
measure: Comparison of autonomic nervous system activity between the 3 groups
timeFrame: 24 hours
measure: Comparison of mortality in the 3 groups
timeFrame: 28 days
measure: Comparison in the 3 groups of the correlations between the biomarkers and the hemodynamic data
timeFrame: 24 hours
Other outcomes:
Locations:
city: Garches
country: France
facility: ICU, Hôpital Raymond Poincaré
state: Haute Des Seine
Study officials:
affiliation: ICU, Hôpital Raymond Poincaré, 92380 Garches, France
name: Djillali ANNANE, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: