Signs and Symptoms of Opioid-associated Iatrogenic Withdrawal in Critically Ill Adults

Study Overview
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Brief Summary
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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.

Detailed Description
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Objectives: To identify specific signs and symptoms of OIWS in mechanically ventilated adult intensive care unit (ICU) patients receiving at least 72 hours of regular opioids at the Montreal General Hospital (MGH) and the Royal Victoria Hospital (RVH) from February to October 2018. To determine if a change in serum cortisol is associated with the presence of OIWS. Hypotheses: Considering our first objective is purely descriptive, no hypothesis can be stated. OIWS is associated with an increase in serum cortisol. 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.

Official Title
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Signs and Symptoms of Opioid-associated Iatrogenic Withdrawal in Critically Ill Adults

Conditions
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Substance Withdrawal Syndrome

Intervention / Treatment
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* Drug: Opioids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients requiring mechanical ventilation and receiving continuous or regular intermittent opioids for at least 72 hours. Weaning of at least 10% from previous stable opioid dose. A weaning episode is defined as a ≥ 10% decrease in the total stable opioid dose received over 4 hours for opioid infusions and over 12 hours for intermittent opioid administration. 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. Chronic alcohol use defined as alcohol consumption of more than 2 drinks/day and/or more than 14 drinks/week for men and 9 drinks/week for women. Chronic use of illicit drugs and amphetamines (except amphetamines taken for therapeutic purposes) defined as a consumption of at least 3 times per week. Chronic use of opioids (e.g. transdermal fentanyl, methadone, hydromorphone, etc.) defined as a consumption of at least 3 times per week. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Critically ill patients<br>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. | Drug: Opioids<br>* 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.<br>* Other names: Narcotics;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Opioid, Withdrawal, Critically ill adults, Cortisol