Dexmedetomidine for Sepsis in ICU Randomized Evaluation Trial (DESIRE)

Effect of Dexmedetomidine on Mortality, Duration of Mechanical Ventilation and Multi-organ Function in Sepsis Patients Under Lighter Sedation by Randomized Control Trial

Background:

Dexmedetomidine, a highly selective arfa2-adrenergic agonist, is known to be a unique sedative agent which causes less acute tolerance, drug addiction and withdrawal compared with gamma-aminobutyrate (GABA) agonists. Dexmedetomidine was approved for short-term ICU sedation in 2004 in Japan, and it has been used particularly for surgical ICU patients. In August 2010 dexmedetomidine was approved in Japan for sedation lasting more than 24 hours.

Recent evidence demonstrated that dexmedetomidine has organ protective effects including neuroprotection, cardioprotection, renal protection, gastrointestinal tract action, and anti-inflammatory action. Dexmedetomidine was shown to significantly decrease the infarct size in isolated rat hearts. Additionally, dexmedetomidine exhibited a preconditioning effect against ischemic injury in hippocampal slices, and this result was considered an apoptosis suppression effect of dexmedetomidine. Aydin C et al reported that dexmedetomidine enhanced the spontaneous contractions of the ileum in peritonitis rats compared with propofol and midazolam. Taniguchi and colleagues demonstrated that dexmedetomidine reduced high mortality rates and the plasma cytokine concentrations, interleukin-6 and tumor necrosis factor alpha in endotoxemic rats.

A meta-analysis has shown that perioperative alfa2-adrenergic agonists, including dexmedetomidine infusion, decreased cardiovascular events on patients undergoing cardiac surgery. Dexmedetomidine treated patients undergoing thoracotomy indicated increase in urine output, reduction in serum creatinine, and the suppression of diuretics in a randomized placebo-controlled double-blind study. Septic patients receiving dexmedetomidine had improved 28-day mortality rates compared with septic patients receiving lorazepam in a sub-group analysis of MENDS randomized controlled trial.

These positive effects of dexmedetomidine on the cardiovascular system, neurons, kidneys, gastrointestinal tract action, and an anti-inflammatory action, are expected to improve mortality in septic patients. However, large clinical research studies have not been conducted yet. We designed and conducted the DESIRE trial (DExmedetomidine for Sepsis in ICU Randomized Evaluation trial) to test a hypothesis that dexmedetomidine may improve clinical outcome and has these organ protective effects on septic patients.

Objective:

To determine whether dexmedetomidine improves clinical outcome and has organ protective effects on septic patients.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Drug: Dexmedetomidine

• Study Type: Interventional
• Enrollment (Actual): 203
• Phase: Phase 4

Contacts and Locations

Study Locations

• Japan
  • Miyagi
    • Sendai, Miyagi, Japan, 9808574
      • Tohoku University

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:

• adult
• transferred to ICU
• anticipation of a need for mechanical ventilation at least 24 hours

Exclusion Criteria:

• sever chronic liver disease (Child B or C)
• acute myocardial infarction, heart disease (NYHA 4)
• Drug dependence, alcoholism
• Psychological illness, severe cognitive dysfunction
• patients who have allergy for dexmedetomidine
• attending physician's decision

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dexmedetomidine; administer dexmedetomidine (0.1-0.7ug/kg/h) from the beginning of ICU treatment	Drug: Dexmedetomidine; intervention to administer dexmedetomidine or not
Active Comparator: non-Dexmedetomidine; administer sedatives except Dexmedetomidine	Drug: Dexmedetomidine; intervention to administer dexmedetomidine or not

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mortality	mortality of patients on 28 days or on a day of discharge if patients are discharged earlier than 28 days	on 28 days
duration of mechanical ventilation	duration of mechanical ventilation in the ICU involving non-invasive ventilation	up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
length of stay in the ICU		up to 28 days
length of stay in the hospital		up to 28 days
Evaluation of restlessness and delirium	evaluation of Richmond agitation-sedation scale (RASS) and Confusion Assessment Method for ICU patients (CAM-ICU)	up to 28 days in the ICU
Evaluation of cognitive function	evaluation of Mini mental state examination (MMSE) on the 28 days or on a day of discharge if patients are discharged earlier than 28 days	on 28 days or on the day of discharge
Occurrence of arrythmia or myocardial ischemia		up to 28 days in the ICU
Renal function	blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR), daily urinary output, need of renal replacement therapy	up to 28 days in the ICU
infection control	Duration of antimicrobial agents use within 28 days or a day of discharge if patients are discharged earlier than 28 days	within 28 days until discharge
inflammation marker	Laboratory marker of inflammation (CRP, PCT) on 1,3,7,14 days	for 14days
organ failure control	Sequential Organ Failure Assessment (SOFA) score during in the ICU	up to 28 days in the ICU
coagulopathy control	Disseminated Intravascular Coagulation (DIC) score by the Japanese Association for Acute Medicine during in the ICU	for 14 days
nutrition control	daily energy intake by enteral nutrition	up to 28 days in the ICU
sedation control	dose of sedative drugs and analgesic drugs during in the ICU	up to 28 days in the ICU

Collaborators and Investigators

• Sponsor: Wakayama Medical University
• Collaborators: Osaka City University; Tohoku University; Hyogo College of Medicine; Osaka City General Hospital; National Hospital Organization Kyoto Medical Center; Saga University; Yamaguchi Grand Medical Center; Sapporo Medical University; Hirosaki University; Kyoto Medical Center
• Investigators: Study Chair: Yu Kawazoe, Tohoku University; Study Director: Hitoshi Yamamura, doctor, Hirosaki University; Study Director: Takeshi Morimoto, doctor, Hyogo Medical University

Publications and helpful links

General Publications

• Ohta Y, Miyamoto K, Kawazoe Y, Yamamura H, Morimoto T. Effect of dexmedetomidine on inflammation in patients with sepsis requiring mechanical ventilation: a sub-analysis of a multicenter randomized clinical trial. Crit Care. 2020 Aug 10;24(1):493. doi: 10.1186/s13054-020-03207-8.
• Nakashima T, Miyamoto K, Shima N, Kato S, Kawazoe Y, Ohta Y, Morimoto T, Yamamura H; DESIRE Trial Investigators. Dexmedetomidine improved renal function in patients with severe sepsis: an exploratory analysis of a randomized controlled trial. J Intensive Care. 2020 Jan 2;8:1. doi: 10.1186/s40560-019-0415-z. eCollection 2020.
• Yamamura H, Kawazoe Y, Miyamoto K, Yamamoto T, Ohta Y, Morimoto T. Effect of norepinephrine dosage on mortality in patients with septic shock. J Intensive Care. 2018 Feb 26;6:12. doi: 10.1186/s40560-018-0280-1. eCollection 2018.
• Kawazoe Y, Miyamoto K, Morimoto T, Yamamoto T, Fuke A, Hashimoto A, Koami H, Beppu S, Katayama Y, Itoh M, Ohta Y, Yamamura H; Dexmedetomidine for Sepsis in Intensive Care Unit Randomized Evaluation (DESIRE) Trial Investigators. Effect of Dexmedetomidine on Mortality and Ventilator-Free Days in Patients Requiring Mechanical Ventilation With Sepsis: A Randomized Clinical Trial. JAMA. 2017 Apr 4;317(13):1321-1328. doi: 10.1001/jama.2017.2088.
• Rudiger A, Singer M. Decatecholaminisation during sepsis. Crit Care. 2016 Oct 4;20(1):309. doi: 10.1186/s13054-016-1488-x. No abstract available.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: December 26, 2012
• First Submitted That Met QC Criteria: January 2, 2013
• First Posted (Estimate): January 4, 2013

Study Record Updates

• Last Update Posted (Actual): February 28, 2017
• Last Update Submitted That Met QC Criteria: February 25, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: sepsis; mortality; Dexmedetomidine; organ failure; duration of mechanical ventilation
• 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; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Dexmedetomidine
• Other Study ID Numbers: DESIRE; UMIN000009665 (Other Identifier: UMIN-CTR)