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| Name | Class |
|---|---|
| Hospira, now a wholly owned subsidiary of Pfizer | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Midazolam | Active Comparator | 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. |
|
| Dexmedetomidine | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Midazolam | Drug | 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Time From Study Drug Initiation to Tracheal Extubation | Duration of ICU stay, for up to 24 weeks |
| 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. |
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Inclusion Criteria:
Patients requiring mechanical ventilation in the medical or surgical ICUs.
Currently receiving lorazepam or midazolam by continuous infusion for the purpose of sedation therapy.
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 .
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.
Patients qualifying for daily awakenings as determined by all of the following:
Informed consent and HIPAA authorization within 24 hours of qualifying for daily awakenings.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Robert MacLaren, PharmD | University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Colorado Hospital | Aurora | Colorado | 80010 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24227448 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. 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) |
| FG001 | 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. 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) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. 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) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Time From Study Drug Initiation to Tracheal Extubation | The analysis only includes patients successfully extubated for at least 72 hours. Eight subjects were excluded. | Posted | Median | Inter-Quartile Range | days | Duration of ICU stay, for up to 24 weeks |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. 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) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute Neurologic Encephalopathy | Nervous system disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypotension | Cardiac disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Robert MacLaren | University of Colorado | 303 724-2622 | rob.maclaren@ucdenver.edu |
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| ID | Term |
|---|---|
| D016638 | Critical Illness |
| D000377 | Agnosia |
| ID | Term |
|---|---|
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010468 | Perceptual Disorders |
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| ID | Term |
|---|---|
| D008874 | Midazolam |
| D020927 | Dexmedetomidine |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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|
| Dexmedetomidine | Drug | 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) |
|
|
| 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 |
| BG001 | 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. 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) |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Weight | Mean | Standard Deviation | kg |
|
| Acute Physiologic And Chronic Health Evaluation III Score | APACHE III measures the severity of disease for adult patients admitted to intensive care units. The point score is calculated as a summation from scores assigned to a patient's age, primary comorbidity, preexisting comorbidities, location prior to ICU admission, Glasgow Coma Scale, and 20 routine physiological measurements. APACHE III scores range from 0 to 299. This provides an initial risk classification of severely ill hospitalized patients in defined groups with higher scores indicating greater disease severity and correlated to higher mortality risk. | Mean | Standard Deviation | units on a scale |
|
| Primary Diagnosis | Number | participants |
|
| Time in ICU before qualifying | Median | Inter-Quartile Range | days |
|
| Time from qualifying to randomization | Median | Inter-Quartile Range | days |
|
| Baseline Sedative | Number | participants |
|
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. 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) |
|
|
|
| Secondary | Cumulative Doses of Conventional Sedatives and Analgesics | Posted | Median | Inter-Quartile Range | mg | Duration of ICU stay, for up to 24 weeks |
|
|
|
|
| Secondary | 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. | Posted | Number | percentage of assessments while on study | Duration of ICU stay, for up to 24 weeks |
|
|
|
|
| Secondary | Sedation-related Adverse Effects | Posted | Number | participants | Duration of ICU stay, up to 24 weeks |
|
|
|
|
| Secondary | 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. | Only subjects capable of performing the ICU-SEQ were provided the assessment. Seven subjects were excluded. | Posted | Median | Full Range | units on a scale | Duration of hospital stay, up to 24 weeks |
|
|
|
|
| Secondary | Duration of Study Drug Administration | Posted | Median | Inter-Quartile Range | days | Duration of ICU stay, up to 24 weeks |
|
|
|
|
| Secondary | 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. | Only subjects capable of performing the IES-R were provided the assessment. Seven subjects were excluded. | Posted | Mean | Standard Deviation | units on a scale | Duration of hospital stay, up to 24 weeks |
|
|
|
|
| Secondary | 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 | Only subjects capable of performing the HADS were provided the assessment. Seven subjects were excluded. | Posted | Mean | Standard Deviation | units on a scale | Duration of hospital stay, up to 24 weeks |
|
|
|
|
| 0 |
| 12 |
| 12 |
| 12 |
| EG001 | 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. 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) | 1 | 11 | 11 | 11 |
| Bradycardia | Cardiac disorders | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | Systematic Assessment |
|
| Delirium, new onset | Nervous system disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D006571 | Heterocyclic Compounds |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| All fentanyl while on study drug |
|
| 0.048 |
| No |
| Superiority or Other |
| For fentanyl | Wilcoxon (Mann-Whitney) | 0.88 | No | Superiority or Other |
| Riker score 5-7 while on study drug |
|
| Pain score > 3 while on study drug |
|
| 0.17 |
| No |
| Superiority or Other |
| Tachycardia |
|
| Delirium, new onset |
|
| >0.1 |
| No |
| Superiority or Other |
| For tachycardia | Fisher Exact | >0.1 | No | Superiority or Other |
| For delirium, new onset | Fisher Exact | 0.07 | No | Superiority or Other |
| >0.1 |
| No |
| Superiority or Other |