Dexmedetomidine Versus Midazolam for Facilitating Extubation

Dexmedetomidine vs. Midazolam for Facilitating Extubation in Medical and Surgical ICU Patients: A Randomized, Double-Blind Study

The purpose of this randomized, double-blind study is to evaluate the utility, safety, and cost of transitioning benzodiazepine sedation to dexmedetomidine in medical or surgical intensive care unit (ICU) patients requiring sedation when tracheal extubation is nearing. Fifty medical or surgical ICU patients requiring sedation with existing benzodiazepine therapy and qualifying for daily awakenings will be randomized in a double-blind manner to receive additional midazolam or dexmedetomidine.

Study Overview

• Status: Completed
• Conditions: Critical Illness
• Intervention / Treatment: Drug: Midazolam; Drug: Dexmedetomidine

Detailed Description

This study is unique because midazolam or dexmedetomidine will be added, in a blinded fashion, to existing sedation and analgesia in an effort to decrease or possibly discontinue these therapies.

Objectives:

The objectives of this study are to determine if transitioning conventional sedation to dexmedetomidine safely facilitates tracheal extubation after study initiation; alters the amounts of sedative and analgesic agents required after study initiation; influences the levels of sedation and analgesia; alters the adverse event profile (neurologic, hemodynamic, or gastrointestinal) during and after discontinuing sedation; and impacts the total cost of sedation during and after discontinuing sedation.

Hypothesis 1: Transitioning conventional sedation to dexmedetomidine expedites tracheal extubation to shorten ventilator time.

Specific Aim 1: Comparatively determine the time from study initiation to tracheal extubation with midazolam and dexmedetomidine when the practice of daily awakenings is used.

Hypothesis 2: Transitioning conventional sedation to dexmedetomidine reduces the doses of conventional sedatives and analgesics while maintaining equivalent levels of sedation and analgesia and not incurring adverse events.

Specific Aim 2a: Comparatively determine the hourly, daily, and cumulative doses of conventional sedatives and analgesics from study initiation to sedation discontinuation with midazolam and dexmedetomidine when the practice of daily awakenings is used.

Specific Aim 2b: Comparatively evaluate the quality of sedation and analgesia of midazolam and dexmedetomidine by determining the proportion of Riker sedation scores at 3 - 4 (desired level of sedation) and ≤ 2 or ≥ 5 (undesired levels of sedation) and the proportion of Pain Assessment Behavioral Scores (PABS) ≤ 3 (comfortable) and ≥ 4 (pain).

Specific Aim 2c: Comparatively evaluate sedation-related adverse effects (neurologic, hemodynamic, or gastrointestinal) of midazolam and dexmedetomidine when the practice of daily awakenings is used.

Hypothesis 3: Transitioning conventional sedation to dexmedetomidine increases the cost of administering sedation but minimizes the incidental costs associated with sedation to counterbalance and possibly reduce the total cost of sedation (sum of administration costs and incidental costs).

Specific Aim 3a: Comparatively determine the hourly, daily, and cumulative administration costs of midazolam and dexmedetomidine when the practice of daily awakenings is used.

Specific Aim 3b: Comparatively determine the hourly, daily, and cumulative incidental costs of conventional sedatives and dexmedetomidine; including neurologic dysfunction, antipsychotic requirements, cardiovascular dysfunction, constipation or ileus, differences in times to ventilator discontinuation, personnel time, and patient transfer from the ICU after sedation discontinuation.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80010
      • University of Colorado Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients requiring mechanical ventilation in the medical or surgical ICUs.
2. Currently receiving lorazepam or midazolam by continuous infusion for the purpose of sedation therapy.
3. Sedation in these ICUs is provided using an ICU-wide order form that preferentially uses either lorazepam or midazolam with the infusion rate titrated by the bedside nurse to the desired Riker sedation-agitation score(s). Continuous analgesia is provided with fentanyl only with the infusion rate titrated by the bedside nurse to PABS ≤ 3 .
4. Anticipated duration of continuous sedation > 12 hours with the level of sedation expected to be maintained at Riker sedation-agitation score(s) of 3 - 4.

5. Patients qualifying for daily awakenings as determined by all of the following:

   • fraction of inspired oxygen (FiO2) ≤ 70% or
   • positive end expiratory pressure (PEEP) ≤ 14 cmH2O,
   • hemodynamically stable, and
   • NOT receiving pharmacologic neuromuscular blockade.
6. Informed consent and HIPAA authorization within 24 hours of qualifying for daily awakenings.

Exclusion Criteria:

1. Patients < 18 years of age or > 85 years of age.
2. Patients receiving intermittent or "as needed" administration of lorazepam or midazolam.
3. Patients receiving lorazepam or midazolam for purposes other than sedation (e.g. seizure control).
4. Patients receiving epidural administration of medication(s).
5. Patients with Childs-Pugh class C liver disease.
6. Comatose patients by metabolic or neurologic affectation.
7. Patients with active myocardial ischemia or second- or third-degree heart block.
8. Moribund state with planned withdrawal of life support.
9. Patients with known or suspected severe adverse reactions to midazolam (or any other benzodiazepine) or dexmedetomidine (or clonidine).
10. Patients with alcohol abuse within six months of study eligibility.
11. Pregnant females or females suspected of being pregnant.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Midazolam; Midazolam infusion of 1 mg/hour (final infusion concentration of 0.5 mg/mL) and adjusted by 1 mg/hour by the bedside nurse as needed for the desired level of sedation (Riker sedation-agitation score of 3 - 4) as other sedatives are down titrated. Daily awakenings are used.	Drug: Midazolam; Midazolam infusion of 1 mg/hour (final infusion concentration of 0.5 mg/mL) and adjusted by 1 mg/hour by the bedside nurse as needed for the desired level of sedation (Riker sedation-agitation score of 3 - 4); Other Names: Versed
Experimental: Dexmedetomidine; Dexmedetomidine 0.15 µg/kg per hour (final infusion concentration of 0.075 µg/kg per mL) and adjusted by 0.15 µg/kg per hour by the bedside nurse as needed for the desired level of sedation (Riker sedation-agitation score of 3 - 4)as other sedatives are down titrated. Daily awakenings are used.	Drug: Dexmedetomidine; Dexmedetomidine 0.15 µg/kg per hour (final infusion concentration of 0.075 µg/kg per mL) and adjusted by 0.15 µg/kg per hour by the bedside nurse as needed for the desired level of sedation (Riker sedation-agitation score of 3 - 4); Other Names: Precedex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time From Study Drug Initiation to Tracheal Extubation	Duration of ICU stay, for up to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Doses of Conventional Sedatives and Analgesics		Duration of ICU stay, for up to 24 weeks
The Quality of Sedation (Assessed by the Riker Sedation-Agitation Score) and Analgesia (Assessed by the Pain Assessment Behavioral Score)	The Riker sedation-agitation score (range 1-7) and PABS (range 0-10) are assessed hourly by the bedside nurse. Riker scores assess restlessness and cooperation. Riker scores of 5 - 7 indicate agitation, 3 - 4 represent adequate sedation and 1 - 2 represent excessive sedation. PABS assessments include domains of restlessness, muscle tone, vocalization, consolability, and facial expressions. PABS assessments of 0 represent no pain, 1 - 3 represent mild pain, 4 - 6 represent moderate pain, and ≥ 7 represent severe pain.	Duration of ICU stay, for up to 24 weeks
Sedation-related Adverse Effects		Duration of ICU stay, up to 24 weeks
ICU Experiences by Administering ICU Stressful Experiences Questionnaire (ICU-SEQ)	The ICU-SEQ assesses patient recall of their ICU experience. The ICU-SEQ assesses both psychological (e.g. fearfulness, anxiety) and physical (e.g. pain, difficulty breathing) perceptions of ICU patients who have received mechanical ventilation. It consists of 29 potentially stressful experiences with seven items specifically addressing the endotracheal tube. The extent that patients are bothered by each item is scored on a five point scale: 0 = "not at all," 1 = "a little bit," 2 = "moderately," 3 = "quite a bit," and 4 = "extremely." The cumulative score is an integer interpreted as interval data with higher scores indicating greater stressful experiences associated with the ICU. The minimum score is 0 and the maximum score possible is 116.	Duration of hospital stay, up to 24 weeks
Duration of Study Drug Administration		Duration of ICU stay, up to 24 weeks
Manifestations of Acute Stress Disorder by Impact of Event Scale - Revised (IES-R)	The IES-R evaluates subjective distress caused by traumatic events and assesses manifestations of post-traumatic stress disorder (PTSD) or acute stress disorder. It is not diagnostic but possesses excellent reliability and validity for manifestations of PTSD. The IES-R has three subscales (eight items on intrusion, eight items on avoidance, and six items on hyperarousal). Each item is scored on a four point scale: 0 = "not at all," 1 = "a little bit," 2 = "moderately often," 3 = "quite a bit," and 4 = "extremely often." The total score of each subscale may be averaged and a cumulative score of 30 is indicative of the presence of PTSD. The maximum score for each subscale is 32 for intrusion, 32 for avoidance, and 24 for hyperarousal. The minimum cumulative score is 0 and the maximum cumulative score possible is 88.	Duration of hospital stay, up to 24 weeks
Hospital Anxiety and Depression Scale (HADS) Score	The HADS consists of 14 questions, seven for anxiety and seven for depression. Each item is scored from 0 to 3, with a cut-off cumulative score of 11 for both subscales indicative of anxiety or depression. This scoring tool has been used for 30 years, possesses excellent reliability and validity, and avoids reliance conditions that are also common somatic symptoms of illness such fatigue, insomnia, and hypersomnia. The maximum score for each subscale is 21 with a maximum possible cumulative score of 42. The minimum score for each subscale is 0. The minimum cumulative score is 0	Duration of hospital stay, up to 24 weeks

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Hospira, now a wholly owned subsidiary of Pfizer
• Investigators: Principal Investigator: Robert MacLaren, PharmD, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences

Publications and helpful links

General Publications

• MacLaren R, Preslaski CR, Mueller SW, Kiser TH, Fish DN, Lavelle JC, Malkoski SP. A randomized, double-blind pilot study of dexmedetomidine versus midazolam for intensive care unit sedation: patient recall of their experiences and short-term psychological outcomes. J Intensive Care Med. 2015 Mar;30(3):167-75. doi: 10.1177/0885066613510874. Epub 2013 Nov 12.

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: August 28, 2008
• First Submitted That Met QC Criteria: August 29, 2008
• First Posted (Estimate): September 1, 2008

Study Record Updates

• Last Update Posted (Estimate): September 28, 2016
• Last Update Submitted That Met QC Criteria: August 4, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Analgesia; Mechanical ventilation
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; 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; Dexmedetomidine
• Other Study ID Numbers: 08-0570

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Publication