Critical Illness
Conditions
Keywords
Analgesia, Mechanical ventilation
Brief summary
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.
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.
Interventions
DRUGMidazolam
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)
DRUGDexmedetomidine
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)
Sponsors
Hospira, now a wholly owned subsidiary of Pfizer
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Time From Study Drug Initiation to Tracheal Extubation | Duration of ICU stay, for up to 24 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Quality of Sedation (Assessed by the Riker Sedation-Agitation Score) and Analgesia (Assessed by the Pain Assessment Behavioral Score) | Duration of ICU stay, for up to 24 weeks | 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. |
| Sedation-related Adverse Effects | Duration of ICU stay, up to 24 weeks | — |
| ICU Experiences by Administering ICU Stressful Experiences Questionnaire (ICU-SEQ) | Duration of hospital stay, up to 24 weeks | 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. |
| Cumulative Doses of Conventional Sedatives and Analgesics | Duration of ICU stay, for up to 24 weeks | — |
| Manifestations of Acute Stress Disorder by Impact of Event Scale - Revised (IES-R) | Duration of hospital stay, up to 24 weeks | 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. |
| Hospital Anxiety and Depression Scale (HADS) Score | Duration of hospital stay, up to 24 weeks | 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 Study Drug Administration | Duration of ICU stay, up to 24 weeks | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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) | 12 |
| 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) | 11 |
| Total | 23 |
Baseline characteristics
| Characteristic | Midazolam | Total | Dexmedetomidine |
|---|---|---|---|
| Acute Physiologic And Chronic Health Evaluation III Score | 70.4 units on a scale STANDARD_DEVIATION 33.5 | 72.8 units on a scale STANDARD_DEVIATION 25 | 74.1 units on a scale STANDARD_DEVIATION 18.2 |
| Age, Continuous | 57.8 years STANDARD_DEVIATION 9.3 | 58.1 years STANDARD_DEVIATION 13.5 | 58.3 years STANDARD_DEVIATION 15.3 |
| Baseline Sedative Lorazepam | 2 participants | 7 participants | 5 participants |
| Baseline Sedative Midazolam | 10 participants | 16 participants | 6 participants |
| Primary Diagnosis Other | 2 participants | 4 participants | 2 participants |
| Primary Diagnosis Respiratory failure | 5 participants | 10 participants | 5 participants |
| Primary Diagnosis Sepsis | 5 participants | 9 participants | 4 participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Male | 7 Participants | 13 Participants | 6 Participants |
| Time from qualifying to randomization | 1 days | 0.9 days | 0.7 days |
| Time in ICU before qualifying | 1.1 days | 1.1 days | 1.2 days |
| Weight | 105.2 kg STANDARD_DEVIATION 40.9 | 103 kg STANDARD_DEVIATION 38.5 | 100.8 kg STANDARD_DEVIATION 37.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 12 | 11 / 11 |
| serious Total, serious adverse events | 0 / 12 | 1 / 11 |
Outcome results
Primary
Time From Study Drug Initiation to Tracheal Extubation
Time frame: Duration of ICU stay, for up to 24 weeks
Population: The analysis only includes patients successfully extubated for at least 72 hours. Eight subjects were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Midazolam | Time From Study Drug Initiation to Tracheal Extubation | 2.9 days |
| Dexmedetomidine | Time From Study Drug Initiation to Tracheal Extubation | 3.4 days |
p-value: 0.8Wilcoxon (Mann-Whitney)
Secondary
Cumulative Doses of Conventional Sedatives and Analgesics
Time frame: Duration of ICU stay, for up to 24 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Midazolam | Cumulative Doses of Conventional Sedatives and Analgesics | All midazolam whil eon study drug | 126.9 mg |
| Midazolam | Cumulative Doses of Conventional Sedatives and Analgesics | All fentanyl while on study drug | 5.4 mg |
| Midazolam | Cumulative Doses of Conventional Sedatives and Analgesics | Open-label midazolam while on study drug | 29 mg |
| Dexmedetomidine | Cumulative Doses of Conventional Sedatives and Analgesics | Open-label midazolam while on study drug | 65.3 mg |
| Dexmedetomidine | Cumulative Doses of Conventional Sedatives and Analgesics | All midazolam whil eon study drug | 65.3 mg |
| Dexmedetomidine | Cumulative Doses of Conventional Sedatives and Analgesics | All fentanyl while on study drug | 4.1 mg |
Comparison: For open label midazolamp-value: 0.25Wilcoxon (Mann-Whitney)
Comparison: For all midazolamp-value: 0.048Wilcoxon (Mann-Whitney)
Comparison: For fentanylp-value: 0.88Wilcoxon (Mann-Whitney)
Secondary
Duration of Study Drug Administration
Time frame: Duration of ICU stay, up to 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Midazolam | Duration of Study Drug Administration | 3 days |
| Dexmedetomidine | Duration of Study Drug Administration | 3.5 days |
p-value: 0.5Wilcoxon (Mann-Whitney)
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
Time frame: Duration of hospital stay, up to 24 weeks
Population: Only subjects capable of performing the HADS were provided the assessment. Seven subjects were excluded.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Midazolam | Hospital Anxiety and Depression Scale (HADS) Score | Anxiety | 3 units on a scale | Standard Deviation 3.1 |
| Midazolam | Hospital Anxiety and Depression Scale (HADS) Score | Depression | 6 units on a scale | Standard Deviation 6.7 |
| Dexmedetomidine | Hospital Anxiety and Depression Scale (HADS) Score | Anxiety | 6 units on a scale | Standard Deviation 7.6 |
| Dexmedetomidine | Hospital Anxiety and Depression Scale (HADS) Score | Depression | 4 units on a scale | Standard Deviation 5.3 |
Comparison: For anxietyp-value: >0.1t-test, 2 sided
Comparison: For depressionp-value: >0.1t-test, 2 sided
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.
Time frame: Duration of hospital stay, up to 24 weeks
Population: Only subjects capable of performing the ICU-SEQ were provided the assessment. Seven subjects were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Midazolam | ICU Experiences by Administering ICU Stressful Experiences Questionnaire (ICU-SEQ) | 8.5 units on a scale |
| Dexmedetomidine | ICU Experiences by Administering ICU Stressful Experiences Questionnaire (ICU-SEQ) | 18.5 units on a scale |
Comparison: Median number of experiences rememberedp-value: 0.015Wilcoxon (Mann-Whitney)
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.
Time frame: Duration of hospital stay, up to 24 weeks
Population: Only subjects capable of performing the IES-R were provided the assessment. Seven subjects were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam | Manifestations of Acute Stress Disorder by Impact of Event Scale - Revised (IES-R) | 13 units on a scale | Standard Deviation 12 |
| Dexmedetomidine | Manifestations of Acute Stress Disorder by Impact of Event Scale - Revised (IES-R) | 36 units on a scale | Standard Deviation 12 |
p-value: 0.029t-test, 2 sided
Secondary
Sedation-related Adverse Effects
Time frame: Duration of ICU stay, up to 24 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midazolam | Sedation-related Adverse Effects | Hypotension | 6 participants |
| Midazolam | Sedation-related Adverse Effects | Bradycardia | 7 participants |
| Midazolam | Sedation-related Adverse Effects | Tachycardia | 5 participants |
| Midazolam | Sedation-related Adverse Effects | Delirium, new onset | 5 participants |
| Dexmedetomidine | Sedation-related Adverse Effects | Delirium, new onset | 1 participants |
| Dexmedetomidine | Sedation-related Adverse Effects | Hypotension | 10 participants |
| Dexmedetomidine | Sedation-related Adverse Effects | Tachycardia | 7 participants |
| Dexmedetomidine | Sedation-related Adverse Effects | Bradycardia | 7 participants |
Comparison: For hypotensionp-value: >0.1Chi-squared, Corrected
Comparison: For bradycardiap-value: >0.1Chi-squared, Corrected
Comparison: For tachycardiap-value: >0.1Fisher Exact
Comparison: For delirium, new onsetp-value: 0.07Fisher Exact
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.
Time frame: Duration of ICU stay, for up to 24 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Midazolam | The Quality of Sedation (Assessed by the Riker Sedation-Agitation Score) and Analgesia (Assessed by the Pain Assessment Behavioral Score) | Riker score 5-7 while on study drug | 6.6 percentage of assessments while on study |
| Midazolam | The Quality of Sedation (Assessed by the Riker Sedation-Agitation Score) and Analgesia (Assessed by the Pain Assessment Behavioral Score) | Riker score 3-4 while on study drug | 84.1 percentage of assessments while on study |
| Midazolam | The Quality of Sedation (Assessed by the Riker Sedation-Agitation Score) and Analgesia (Assessed by the Pain Assessment Behavioral Score) | Pain score > 3 while on study drug | 13.3 percentage of assessments while on study |
| Midazolam | The Quality of Sedation (Assessed by the Riker Sedation-Agitation Score) and Analgesia (Assessed by the Pain Assessment Behavioral Score) | Riker score 1-2 while on study drug | 5.4 percentage of assessments while on study |
| Dexmedetomidine | The Quality of Sedation (Assessed by the Riker Sedation-Agitation Score) and Analgesia (Assessed by the Pain Assessment Behavioral Score) | Pain score > 3 while on study drug | 21.4 percentage of assessments while on study |
| Dexmedetomidine | The Quality of Sedation (Assessed by the Riker Sedation-Agitation Score) and Analgesia (Assessed by the Pain Assessment Behavioral Score) | Riker score 1-2 while on study drug | 4.1 percentage of assessments while on study |
| Dexmedetomidine | The Quality of Sedation (Assessed by the Riker Sedation-Agitation Score) and Analgesia (Assessed by the Pain Assessment Behavioral Score) | Riker score 3-4 while on study drug | 71.2 percentage of assessments while on study |
| Dexmedetomidine | The Quality of Sedation (Assessed by the Riker Sedation-Agitation Score) and Analgesia (Assessed by the Pain Assessment Behavioral Score) | Riker score 5-7 while on study drug | 27.1 percentage of assessments while on study |
Comparison: For Riker scoresp-value: 0.75Chi-squared, Corrected
Comparison: For pain scoresp-value: 0.17Chi-squared