Effects of Levosimendan on Microcirculation in Septic Shock

Study Overview
=================
Brief Summary
-----------------
The present study was conducted as a prospective, randomized, controlled study to: investigate the effects of a combination of levosimendan and inhaled nitric oxide on systemic hemodynamics and microcirculation in patients with catecholamine-dependent septic shock; test the hypothesis that levosimendan plus inhaled nitric oxide may be effective in restoring microvascular function in septic shock.

Detailed Description
-----------------
40 septic shock patients requiring norepinephrine to maintain mean arterial pressure between 65 and 75 mmHg despite adequate volume resuscitation will be enrolled in the study. After an initial hemodynamic resuscitation aimed at achieve a mean arterial pressure between 65 and 75 mmHg and a mixed venous oxygen saturation (SvO2) ≥ 65%, patients will be randomly allocated to be treated with either a) intravenous administration of levosimendan 0.2 µg∙kg-1∙min-1 for 24 hrs, b)intravenous administration of dobutamine 5 µg∙kg-1∙min-1 for 36 hrs(control; each n = 20). At the end of the first 24 hrs of the study period, both groups will receive inhaled nitric oxide at the concentration of 35 ppm for further 12 hrs. In all patients norepinephrine was titrated to maintain mean arterial pressure between 65 and 75 mmHg. Data from right heart catheterization and sublingual microvascular network will be obtained just before randomization (baseline) and then after 24 and 36 hours. The sublingual microvascular network will be studied using the sidestream dark field (SDF) imaging. The device will be applied on the lateral side of the tongue, in an area approximately 2-4 cm from the tip of the tongue. Sequences of 10 secs from eight adjacent areas will be recorded on disk using a personal computer. These sequences will be later analyzed by an investigator blinded to the patient's diagnosis and therapy.

Official Title
-----------------
Levosimendan and Inhaled Nitric Oxide for Resuscitating the Microcirculation in Septic Shock. A Randomized Controlled Trial

Conditions
-----------------
Septic Shock

Intervention / Treatment
-----------------
* Drug: Levosimendan
* Drug: dobutamine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Clinical diagnosis of Septic shock Vasopressor support to maintain mean arterial pressure (MAP) between 65 and 75 mmHg despite adequate volume resuscitation (pulmonary artery occlusion pressure = 13-18 mmHg and central venous pressure = 8-12 mmHg) Exclusion Criteria: Pregnancy Age < 18 years Ventricular outflow tract obstruction Mitral valve systolic anterior motion

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: levosimendan<br> | Drug: Levosimendan<br>* Intravenous administration of Levosimendan 0,2 µg•kg-1•min-1 for 24 hrs followed by the addition of 35 ppm of inhaled nitric oxide<br>|
| Active Comparator: Control<br> | Drug: dobutamine<br>* Intravenous administration of dobutamine 5 µg•kg-1•min-1 for 36 hrs. At the end of the first 24 hrs drug infusion, inhaled nitric oxide at the concentration of 35 ppm will be added for further 12 hrs.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic hemodynamic and Microcirculatory flow index of small and medium vessels (MFI) |  | over a period of 36 hrs from the time of randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acid-base homeostasis |  | over a period of 36 hrs from the time of randomization | 
| Oxygen transport variables |  | over a period of 36 hrs from the time of randomization | 
| Functional capillary density (mm/mm2) (FCD) |  | over a period of 36 hrs from the time of randomization | 
| De Backer score |  | over a period of 36 hrs from the time of randomization | 
| Perfused Vessel Density (PVD) (mm/mm2) |  | over a period of 36 hrs from the time of randomization | 
| Proportion of Perfused vessels (%) (PPV) |  | over a period of 36 hrs from the time of randomization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
sepsis, septic shock, microcirculation, levosimendan, dobutamine, inotropes, inhaled nitric oxide