The Effect of Dexmedetomidine on Microcirculation in Severe Sepsis

The Effect of Dexmedetomidine on the Microcirculation in Patients With Severe Sepsis and Septic Shock

Despite early goal-directed maintenance of normal macrocirculation, the reduction of 60-day mortality of patients with severe sepsis and septic shock remained unsatisfied (56.9% to 44.3%). One of the major causes of high mortality is microcirculatory dysfunction. Delayed diagnosis and treatment of microcirculatory dysfunction may cause tissue hypoperfusion and resulted in multiple organ dysfunction and death. Dexmedetomidine is a highly selective α2-adrenoreceptor agonist which exhibits sedative and analgesic effects. Recent studies suggest that dexmedetomidine also has anti-coagulation and anti-inflammatory effects, and it can reduce the mortality of endotoxemic rats and patients with severe sepsis. The investigators will conduct two animal studies and one clinical trial to investigate the effect of dexmedetomidine on microcirculatory dysfunction and organ injury in rat with endotoxemia and patients with severe sepsis and septic shock.

Sixty patients with severe sepsis and septic shock will be enrolled and randomized to control group or dexmedetomidine group. In the control group, the patients will be treated according to the clinical practice guideline. If sedation is required, non-dexmedetomidine sedative agents will be used. In the dexmedetomidine group, the patients will be treated according to the clinical practice guideline, and they will also receive continuous infusion of dexmedetomidine (infusion rate ranged from 0.1 to 0.7 mcg/kg/h) for 24 hours as needed. The sublingual microcirculation, serum level of Endocan, NGAL(Neutrophil Gelatinase-Associated Lipocalin), and BNP(B-type natriuretic peptide) will be examined at preset time points up to 24 hours. The vital signs, hemodynamic parameters, and survival of 28-day and 90-day will be recorded and analyzed.

Study Overview

• Status: Terminated
• Conditions: Severe Sepsis
• Intervention / Treatment: Drug: Midazolam; Drug: Propofol; Drug: Dexmedetomidine

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 4

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• ICU patients who require sedation
• Patients who have diagnosis of severe sepsis / septic shock
• meet 2 or more of the 4 SIRS criteria
• with one organ dysfunction according the definition of Surviving Sepsis Campaign

Exclusion Criteria:

• less than 20 y/o
• refractory bradycardia (heart rate slower than 60 bpm despite of adequate treatment)
• 2nd and 3rd degree of AV-block
• the onset of severe sepsis/septic shock is more than 24h before enrollment
• APACHE II > 30 at enrollment
• Severe liver cirrhosis (Child B or C)
• New onset of myocardial infarction within 30 days or heart failure (NYHA 4)
• attend other trial in ICU within one month
• patient who is pregnant
• receive organ transplantation within one year
• expected survival is less than 30 days by attending physician
• receive cardiopulmonary resuscitation within 4 weeks
• patients who have signed consent of refusal of cardiopulmonary resuscitation and invasive therapy
• have allergic history to dexmedetomidine
• receive renal replacement therapy within 24 hours before enrollment
• patient with HIV infection
• non-native speaker
• other factors not eligible for enrollment concerned by attending physician

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control; Use midazolam or propofol for sedation	Drug: Midazolam; CIF Goal of sedation: Richmonad agitation-sedation scale 0 to -2; Other Names: Dormicium; Drug: Propofol; CIF Goal of sedation: Richmonad agitation-sedation scale 0 to -2; Other Names: Propofol-Lipuro
Experimental: Dexmedetomidine; Use dexmedetomidine for sedation	Drug: Dexmedetomidine; Continue infusion (CIF) 0.1 - 0.7 mcg/kg/h Goal of sedation: Richmonad agitation-sedation scale 0 to -2; Other Names: Precedex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Changes of total small vessel density and perfused small vessel density	6h

Secondary Outcome Measures

Outcome Measure	Time Frame
Changes of total small vessel density and perfused small vessel density	24h
Change of microvascular flow index	6h and 24h

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endocan level		24h
Hemodynamic variables	Use EV1000 clinical platform MAP HR Cardiac index Stroke volume index Systemic vascular resistance index	6h and 24h
NGAL level	Neutrophil Gelatinase-Associated Lipocalin	6h and 24h
BNP level	B-type natriuretic peptide)	24h

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Investigators: Study Director: Yu-Chang Yeh, MD, PhD, National Taiwan University Hospital

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (Actual): February 24, 2016
• Study Completion (Actual): February 24, 2018

Study Registration Dates

• First Submitted: April 8, 2014
• First Submitted That Met QC Criteria: April 9, 2014
• First Posted (Estimate): April 10, 2014

Study Record Updates

• Last Update Posted (Actual): March 4, 2019
• Last Update Submitted That Met QC Criteria: February 28, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; Propofol; Dexmedetomidine
• Other Study ID Numbers: 201311031MINB