Low Dose Morphine to Relieve Dyspnea in Acute Respiratory Failure (OPIDYS)

Study Overview
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Brief Summary
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This study evaluates a pharmacological intervention to relieve dyspnea in intensive care unit patients. Indeed, opioids can be particularly beneficial since 1) dyspnea and pain share many similarities, 2) the benefit of opioids on dyspnea has been clearly demonstrated in other populations. However, to date, data regarding the impact of morphine on dyspnea in intensive care unit patients admitted for acute respiratory failure are scarce. There may be a reluctance of physicians to prescribe opioids that is not scientifically justified. The study will focus on patient reported outcome (PRO) criteria. The ultimate goal of this pilot study is to design the protocol of a future pragmatic trial.

Detailed Description
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Randomized, double-blind, placebo-controlled, parallel-group, single-center phase 2 pilot study.The experimental group will receive an intravenous titration of morphine followed by a subcutaneous administration of morphine hydrochloride for 24 hours according to a predefined protocol. The control group will receive placebo NaCl 0.9% administered according to the same protocol as the experimental arm Patients will be randomized 1:1 between low-dose titrated morphine (experimental group) and placebo (control group). The other treatments will be similar in both groups, according to the protocol and the recommendations. Severe dyspnea will be assessed for regularly Patients will be followed for 48 hours: 24-hour treatment duration, evaluation of primary endpoint for first 24 hours, collection of adverse events for 48 hours.

Official Title
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Relieving Dyspnea With Low Dose of Morphine in Patients Admitted to the Intensive Care Unit for an Acute Respiratory Failure: a Double-blind Randomized Controlled Pilot Study

Conditions
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Acute Respiratory Failure

Intervention / Treatment
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* Drug: Chlorhydrate de morphine
* Drug: NaCl 0,9%,


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients ≤ 75 years Admitted in intensive care for an acute respiratory failure defined as a respiratory rate> 24 / min or signs of respiratory distress such as labored breathing or paradoxical inspiration, or SpO2 <90% in ambient air Spontaneous ventilation, either under standard oxygen, high flow oxygen or non invasive ventilation Dyspnea ≥ 40 on an dyspnea-VAS from zero (no dyspnea) to 100 (worst possible dyspnea) Richmond agitation and sedation scale (RASS) between 0 and 2. No confusion, as defined by the CAM-ICU Signed informed consent Exclusion Criteria: Intubated patient Intubation planned upon admission Hearing or visual impairment Insufficient command of French Previous psychiatric or cognitive disorders known Moribund patient Known hypersensitivity to opioids Severe renal insufficiency (creatinine clearance <30 ml / min) Severe hepatocellular insufficiency (factor V <50%) Any formal contra-indication of opiates Opioid use within the 24 hours before inclusion Pregnancy or breastfeeding Minor and protected adult Exclusion period due to inclusion in another clinical trial Previous inclusion in this study No affiliation to social security

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, placebo-controlled, parallel-group,single center, phase 2 pilot study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chlorhydrate de morphine<br>initial dose of 2 mg, followed by 1 mg every 3 minutes until a VAS-dyspnea <40 then relay subcut | Drug: Chlorhydrate de morphine<br>* The experimental group will receive an intravenous titration of morphine followed by a subcutaneous administration of morphine hydrochloride for 24 hours according to a predefined protocol<br>|
| Placebo Comparator: NaCl 0,9%<br>initial dose of 2 mg, followed by 1 mg every 3 minutes until a VAS-dyspnea <40 then relay subcut | Drug: NaCl 0,9%,<br>* The control group will receive placebo NaCl 0.9% administered according to the same protocol as the experimental arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average dyspnea over 24 hours | Dyspnea will be assessed by VAS-dyspnea (ranging from zero, no dyspnea to 100, worst possible dyspnea) patient reported outcome criteria (PRO). | systematically evaluated every 4 hours over 24 hours and whenever necessary | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intensity of dyspnea | patient reported outcome measure (PRO) ; min=0;max=100(worse) | every 4 hours over 24 hours | 
| Incidence of severe dyspnea (dyspnea ≥40) | patient reported outcome measure (PRO) ; min=0;max=100(worse) | within 24 hours | 
| Anxiety | Patient reported outcome measure (PRO) ; min=0;max=100(worse) | every 4 hours as well as over the first 24 hours | 
| Incidence of moderate to severe anxiety | Incidence of moderate to severe anxiety (PRO) ; min=0;max=100(worse) | every 4 hours over 24 hours | 
| Intubation rate | Intubation rate | within the first 48 hours | 
| Vigilance level (Glasgow Coma Scale : impaired alertness defined by Glasgow Coma Scale ≤ 12) | Vigilance level ; GCS : min=3(worse) ;max=15 | every 4 hours as well as the first 48 hours | 
| Incidence of coma | Incidence of coma | within the first 48 hours | 
| Incidence of delirium | Incidence of delirium | within the first every 4 hours as well as over the first 48 hours | 
| Respiratory rate | Respiratory rate | every 4 hours as well as over the first 24 hours | 
| Proportion of patients requiring the transition from one oxygenation technique to another | Proportion of patients requiring the transition from one oxygenation technique to another | At the end of the study (12 months) | 
| Intensity of pain | Patient reported outcome measure (PRO) ; min=0;max=100(worse) | every 4 hours | 
| Duration of night sleep the first night | Duration of night sleep the first night (number of hours) | at the end of the first night | 
| Quality of sleep the first night | Patient reported outcome measure (PRO); min=0;max=100(worse) | at the end of the first night | 
| Severity of dry eye | Patient reported outcome criteria (PRO); min=0;max=100(worse) | in the first 24 hours | 
| Severity of dry nose | Patient reported outcome criteria (PRO); min=0;max=100(worse) | in the first 24 hours | 
| Severity of feeling of gastric distension | Patient reported outcome criteria (PRO); min=0;max=100(worse) | in the first 24 hours | 
| Constipation | Constipation (PRO); min=0;max=100(worse) | in the first 48 hours | 
| Nausea | Patient reported outcome criteria (PRO) ;min=0;max=100(worse) | in the first 48 hours | 
| Nurses' adherence to the protocol | Nurses' adherence to the protocol (questionnaire) | in the first 24 hours | 
| Nurses' satisfaction with the protocol | Nurses' satisfaction with the protocol (questionnaire) | in the first 24 hours | 
| Number of non invasive ventilation sessions | Number of non invasive ventilation sessions | in the first 24 hours | 
| Total duration of non invasive ventilation | Total duration of non invasive ventilation (number of hours) | in the first 24 hours | 
| Tolerance of non invasive ventilation | Tolerance of non invasive ventilation (PRO) ;min=0;max=100(worse) | in the first 24 hours | 
| Duration of HFNCO (high-flow nasal canula oxygenation) | Duration of HFNCO (number of hours) | in the first 24 hours | 
| Tolerance of HFNCO(high-flow nasal canula oxygenation) | Tolerance of HFNCO : number of adverses events | in the first 24 hours | 
| Duration of standard oxygen | Duration of standard oxygen (number of hours) | in the first 24 hours | 
| Tolerance of standard oxygen | Tolerance of standard oxygen : number of adverses events | in the first 24 hours | 
| Any adverse or serious event occurring | Any adverse or serious event occurring | within the first 48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute respiratory failure, Dyspnea, Opioids, Comfort, Intensive care unit