Effects of Levosimendan on Microcirculation in Septic Shock

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

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.

Study Overview

• Status: Completed
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Levosimendan; Drug: dobutamine

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Rome, Italy, 00161
    • Departement of Anesthesiology and Intensive Care of the University of Rome "La Sapienza" Viale del Policlinico 155

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:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control	Drug: dobutamine; 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.
Experimental: levosimendan	Drug: Levosimendan; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: University of Roma La Sapienza
• Investigators: Principal Investigator: Andrea Morelli, M.D., University of Rome "La Sapienza", Department of Anesthesiology and Intensive Care

Publications and helpful links

General Publications

• Morelli A, Donati A, Ertmer C, Rehberg S, Lange M, Orecchioni A, Cecchini V, Landoni G, Pelaia P, Pietropaoli P, Van Aken H, Teboul JL, Ince C, Westphal M. Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study. Crit Care. 2010;14(6):R232. doi: 10.1186/cc9387. Epub 2010 Dec 23.

Study record dates

Study Major Dates

• Study Start: November 1, 2007
• Primary Completion (Actual): February 1, 2008
• Study Completion (Actual): April 1, 2009

Study Registration Dates

• First Submitted: December 1, 2008
• First Submitted That Met QC Criteria: December 1, 2008
• First Posted (Estimate): December 2, 2008

Study Record Updates

• Last Update Posted (Estimate): October 15, 2009
• Last Update Submitted That Met QC Criteria: October 14, 2009
• Last Verified: October 1, 2009

More Information

Terms related to this study

• Keywords: septic shock; microcirculation; sepsis; levosimendan; inhaled nitric oxide; dobutamine; inotropes
• 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; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Protective Agents; Adrenergic Agonists; Cardiotonic Agents; Phosphodiesterase Inhibitors; Adrenergic beta-Agonists; Sympathomimetics; Adrenergic beta-1 Receptor Agonists; Phosphodiesterase 3 Inhibitors; Simendan; Dobutamine
• Other Study ID Numbers: 1102