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Mechanically ventilated critically ill adults may require prolonged administration of opioids to facilitate ventilator support and maintain comfort. The prolonged use has been associated with withdrawal symptoms upon rapid weaning in critically ill patients, known as the opioid-associated withdrawal syndrome (OIWS). Such withdrawal symptoms are well described in the paediatric population, however there is a lack of information in the adult population. Currently there is no bedside tool to rapidly identify such patients. Recognition of withdrawal symptoms is the basis for the development of an assessment tool to identify patients with OIWS.
Objectives:
Hypotheses:
Methods:
A prospective multicentre observational study will be carried out in two university-affiliated hospital ICUs (Montreal General Hospital and Royal Victoria Hospital). All mechanically ventilated adult ICU patients receiving regular (continuous or intermittent) opioids for more than 72 hours will be prospectively screened daily for withdrawal symptoms once the opioid dose is reduced by 10% or more. From that moment, daily evaluation by a physician using the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for opioid withdrawal will be conducted. Concomitantly, signs and symptoms of withdrawal will be collected by an investigator blinded to the DSM-5 assessment. These assessments will continue daily until the patient is transferred out of ICU or a maximum of 14 days and will be repeated once more between day 1 and day 4 post-transfer out of ICU.
A serum cortisol will be drawn on the first day of dose reduction by 10% or more (baseline) and will be repeated either after 72 hours or upon patient discharge from the ICU, whichever one occurs first.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Critically ill patients | Mechanically ventilated critically ill adults receiving regular opioids for more than 72 hours will be prospectively followed for the emergence of withdrawal symptoms upon weaning of opioids. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Opioids | Drug | Once an opioid dose reduction of 10% or greater is achieved, a daily assessment will be conducted by a physician using the DSM-5 criteria for opioid withdrawal. In addition, signs and symptoms of withdrawal will be collected daily by a blinded investigator. |
| Measure | Description | Time Frame |
|---|---|---|
| Description of Signs and Symptoms of OIWS in Patients Who Scored Positive for Withdrawal Syndrome (OIWS) According to Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Criteria | Percentage of daily assessments associated with each of the following signs and symptoms experienced by patients with and without OIWS (Restlessness (Richmond Agitation-Sedation scale = 1), Agitation (RASS > 1), Anxiety, Hallucinations, Insomnia/sleep disturbance (< 4 hours of continuous sleep), Mydriasis (Pupil diameter > 2 mm) and systolic blood pressure (SBP) > 140 mmHg. These assessments were performed once daily. Note that for the group of patients experiencing IWS, the data on signs and symptoms are limited to the assessment on the day that patients experienced OIWS. The signs and symptoms presented (Restlessness; Agitation; Anxiety, Hallucinations, Insomnia/sleep disturbance; mydriasis; SBP > 140) were selected based on a > 15 % absolute difference between both groups which was judged to be clinically significant. | From first day of opioid dose reduction until transfer out of Intensive care unit (ICU) or a maximum of 14 days, including one further assessment post-ICU transfer |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Serum Cortisol Level | Cortisol level were drawn on the first day of opioid weaning and repeated 72 hours after onset of weaning | Baseline cortisol on first day of opioid dose reduction and on day 3 post-dose reduction, or on day of transfer out of ICU if patient is transferred before day 3. |
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Inclusion Criteria:
Exclusion Criteria:
Patient for whom consent cannot be obtained
Patient and/or family unable to communicate in French or English
Patient who is deaf without appropriate hearing aid
Imminent and predictable death (< 72 hours) according to medical team
Severe brain injury, defined as Glasgow Coma Scale (GCS) score of 8 or less at ICU admission
Moderate brain injury, defined as GCS between 9 and 12, with elevated intracranial pressure (ICP > 20 mmHg) which requires ICP monitoring and osmotherapy
Acute neurological condition (e.g. status epilepticus, encephalopathy, stroke). If the acute neurological condition resolves within 72 hours, the patient may be included in the study.
Substance abuse prior to ICU admission.
Readmission to the MGH or RVH ICU during the recruitment period (limit of one study entry per patient)
Spinal cord injury above the lumbar region
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Mechanically ventilated adult ICU patients receiving continuous or regular intermittent opioids for more than 72 hours.
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| Name | Affiliation | Role |
|---|---|---|
| Marie-Soleil Delisle, MSc | McGill University Health Centre/Research Institute of the McGill University Health Centre | Principal Investigator |
| Marc M Perreault, PharmD | McGill University Health Centre/Research Institute of the McGill University Health Centre | Principal Investigator |
| Marc-Alexandre Duceppe, MSc | McGill University Health Centre/Research Institute of the McGill University Health Centre | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| McGill University Health Centre | Montreal | Quebec | H4A3J1 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28793780 | Background | Chiu AW, Contreras S, Mehta S, Korman J, Perreault MM, Williamson DR, Burry LD. Iatrogenic Opioid Withdrawal in Critically Ill Patients: A Review of Assessment Tools and Management. Ann Pharmacother. 2017 Dec;51(12):1099-1111. doi: 10.1177/1060028017724538. Epub 2017 Aug 9. | |
| 28866754 | Background | Wang PP, Huang E, Feng X, Bray CA, Perreault MM, Rico P, Bellemare P, Murgoi P, Gelinas C, Lecavalier A, Jayaraman D, Frenette AJ, Williamson D. Opioid-associated iatrogenic withdrawal in critically ill adult patients: a multicenter prospective observational study. Ann Intensive Care. 2017 Sep 2;7(1):88. doi: 10.1186/s13613-017-0310-5. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Iatrogenic Withdrawal Syndrome (IWS) Positive | Group of patients displaying signs and symptoms of IWS |
| FG001 | Iatrogenic Withdrawal Syndrome (IWS) Negative | Group of patients not displaying signs and symptoms of IWS |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
1128 patients screened; 59 eligible as per entry criteria; 29 enrolled and included in the analysis
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| ID | Title | Description |
|---|---|---|
| BG000 | Opioid Iatrogenic WIthdrawal Syndrome (OIWS) Positive Patients | Mechanically ventilated critically ill adults receiving regular opioids for more than 72 hours whose at least one daily DSM-5 assessment for OIWS was positive following the reduction in opioid dose (opioid dose reduction of 10% or greater). |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| 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 | Description of Signs and Symptoms of OIWS in Patients Who Scored Positive for Withdrawal Syndrome (OIWS) According to Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Criteria | Percentage of daily assessments associated with each of the following signs and symptoms experienced by patients with and without OIWS (Restlessness (Richmond Agitation-Sedation scale = 1), Agitation (RASS > 1), Anxiety, Hallucinations, Insomnia/sleep disturbance (< 4 hours of continuous sleep), Mydriasis (Pupil diameter > 2 mm) and systolic blood pressure (SBP) > 140 mmHg. These assessments were performed once daily. Note that for the group of patients experiencing IWS, the data on signs and symptoms are limited to the assessment on the day that patients experienced OIWS. The signs and symptoms presented (Restlessness; Agitation; Anxiety, Hallucinations, Insomnia/sleep disturbance; mydriasis; SBP > 140) were selected based on a > 15 % absolute difference between both groups which was judged to be clinically significant. | Posted | Number | percentage of assessments | From first day of opioid dose reduction until transfer out of Intensive care unit (ICU) or a maximum of 14 days, including one further assessment post-ICU transfer |
Symptom assessments were collected daily until transfer out of ICU, death or 14 days after start of patient remained in ICU; If patient was transferred, one additional data was collected up to 96 hours post-transfer out of ICU
Observational study of IWS - Non interventional
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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 | Critically Ill Patients | Mechanically ventilated critically ill adults receiving regular opioids for more than 72 hours will be prospectively followed for the emergence of withdrawal symptoms upon weaning of opioids. Opioids: Once an opioid dose reduction of 10% or greater is achieved, a daily assessment will be conducted by a physician using the DSM-5 criteria for opioid withdrawal. In addition, signs and symptoms of withdrawal will be collected daily by a blinded investigator. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Marc Perreault | MUHC-RIMUHC | 514-343-6111 | 3788 | marc.perreault@umontreal.ca |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 4, 2018 | Aug 31, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D013375 | Substance Withdrawal Syndrome |
| ID | Term |
|---|---|
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D000701 | Analgesics, Opioid |
| D000700 | Analgesics |
| D009294 | Narcotics |
| ID | Term |
|---|---|
| D002492 | Central Nervous System Depressants |
| D045505 | Physiological Effects of Drugs |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
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|
| 9559604 | Background | Cammarano WB, Pittet JF, Weitz S, Schlobohm RM, Marks JD. Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients. Crit Care Med. 1998 Apr;26(4):676-84. doi: 10.1097/00003246-199804000-00015. |
| Opioid Iatrogenic Withdrawal Syndrome (OIWS) Negative Patients |
Mechanically ventilated critically ill adults receiving regular opioids for more than 72 hours whose daily DSM-5 assessments for OIWS remained negative for the duration of follow up following the reduction in opioid dose (opioid dose reduction of 10% or greater). |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Serum Creatinine at ICU admission (umol/L) | Median | Inter-Quartile Range | umol/L |
|
| Reason for ICU admission (ICD-10) | Count of Participants | Participants |
|
| Length of ICU stay | Median | Inter-Quartile Range | Days |
|
| Duration of mechanical ventilation | Median | Inter-Quartile Range | Days |
|
| Co-morbidities | Number | participants |
|
| As needed use of opioids prior to ICU admission | Count of Participants | Participants |
|
| Use of benzodiazepines prior to ICU admission | Count of Participants | Participants |
|
| ID |
|---|
| Title |
|---|
| Description |
|---|
| OG000 | IWS Positive | Group of patients with OIWS positive as per DSM-V criteria |
| OG001 | IWS Negative | Group of patients without OIWS as per DSM-V criteria |
|
|
|
| Secondary | Change in Serum Cortisol Level | Cortisol level were drawn on the first day of opioid weaning and repeated 72 hours after onset of weaning | Only 9 patients had two sets of blood samples drawn for cortisol levels measurement | Posted | Median | Inter-Quartile Range | nmol/L | Baseline cortisol on first day of opioid dose reduction and on day 3 post-dose reduction, or on day of transfer out of ICU if patient is transferred before day 3. |
|
|
|
| 0 |
| 29 |
| 0 |
| 29 |
| 0 |
| 29 |
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| D018689 | Sensory System Agents |
| D018373 | Peripheral Nervous System Agents |
| D002491 | Central Nervous System Agents |
| D045506 | Therapeutic Uses |