OPIOID-FREE ANALGESIA IN ICU IN INTENSIVE CARE UNIT

Study Overview
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Brief Summary
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ICU patients experience moderate to severe pain. Studies and guidelines point out the benefits of multimodal analgesia on pain control, opioid spare and on lowering its adverse effects. However, no recommendation about drugs or protocol has been formulated. In our study, we studied the feasibility and the impact on Remifentanil spare of a standardized protocol using multimodal analgesia (Paracetamol, Nefopam, Tramadol, Ketamine, Remifentanil) compared to the standard-of-care strategy using Paracetamol and Remifentanil. We conducted a prospective, ''proof of concept'', randomized, double-blind, parallel group, placebo-controlled trial. We studied multimodal analgesia versus standard-of-care in ICU patients requiring sedation-analgesia for invasive mechanical ventilation.We hypothesized that Remifentanil consumption decrease by 15% with the use of a standardized multimodal analgesia strategy

Detailed Description
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ICU patients requiring sedation-analgesia for mechanical ventilation for at least 72 hours are randomized in 2 parallel groups : control arm using ''standard of care'' analgesia (Paracetamol and Remifentanil), and interventional arm using multimodal analgesia at different level according to pain accessed by BPS (Step 1 : Paracetamol, Nefopam, Tramadol, Step 2 : Ketamine, Step 3 : Remifentanil). Sedation drugs are standard of care (Propofol and Midazolam if Propofol isn't enough) to obtain prescribed sedation accessed by RASS. Double-bling is kept for 72 hours until the primary outcome is obtained. We hypothesize a 15% reduction of Remifentanil consumption in the interventional group.

Official Title
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OPIOID-FREE ANALGESIA IN INTENSIVE CARE UNIT : A PROSPECTIVE, MONOCENTRIC, RANDOMIZED, DOUBLE-BLIND, FEASIBILITY CLINICAL TRIAL

Conditions
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Intubation

Intervention / Treatment
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* Drug: OFA multimodal analgesia
* Drug: Standard multimodal analgesia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient hospitalized in ICU and requiring sedation-analgesia for mechanical ventilation. Patient undergoing mechanical ventilation for more than 2 hours and less than 24 hours. Informed consent signed by the patient or his trusted person, legal representative, family member, curator or tutor, or emergency consent procedure. Patient affiliated to the French Government Public Health Insurance. Patient over 18 years old. Exclusion Criteria: Patient already involved in a trial that might influence our primary endpoint. Patient in exclusion-period determined by another trial or study. Patient who is likely to be requiring less than 72 hours of mechanical ventilation. Patient with contraindication or allergies to at least one of the following medication : paracetamol, nefopam, tramadol, ketamine, remifentanil. Patient with hepatic insufficiency (defined as PT < 50%). Parturient or breast-feeding patient. Patient suffering from moderate to severe Acute Respiratory Distress Syndrome (ARDS), with decreased PaO2/FiO2 ratio under 150mmHg after respiratory optimization (courant volume 6mL/kg and PEEP > 5mbar). Patient requiring curare treatment. Patient requiring ICU after undergoing major surgery (laparotomy or thoracotomy).

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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control group<br>Analgesia combines paracetamol (1g every 6 to 8 hours according to age and weight recommendations) and remifentanil, adapted according to a tiered administration system depending on the Behavior Pain Scale (BPS) and the theoretical ideal weight. Remifentanil doses are adjusted so that the patient has a BPS score of 4 or less. Reassessment of analgesia will be carried out every 30 minutes until analgesic adaptation is complete, then every 2 hours as is usually done in our department. If the BPS is less than or equal to 4, the therapeutic de-escalation will be done with a reverse algorithm until the analgesic drugs are stopped. After the sedation balance phase, the patient's BPS will be assessed every 2 hours. | Drug: Standard multimodal analgesia<br>* Standard remifentanil analgesia<br>|
| Experimental: OFA Group<br>A fixed combination of nefopam and tramadol will be initiated at daily doses. An initial dose of 50mg tramadol and 20mg nefopam IV over 30 min. will be administered. Reassessment of analgesia will be performed every 30 min. for two hour and then every 2 hours. If BPS is > 4, administration of ketamine with an initial bolus of 0.15mg/kg followed by continuous administration at a dose of 0.15mg/kg/hour. If the BPS is < 4, remifentanil is introduced at the minimum effective dose, in a stepwise fashion according to the theoretical ideal weight In the event of maximum pain requiring the full range of therapies in the algorithm the total dose of tramadol will be 450mg/day and nefopam 120mg/day, in accordance with summaries of product characteristics. If the BPS < or = 4, the therapeutic de-escalation will be done with a reverse algorithm until the analgesic drugs are stopped, according to the following scheme: remifentanil, ketamine, tramadol and then nefopam. | Drug: OFA multimodal analgesia<br>* Multimodal opioid free analgesia<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily remifentanil consumption (after randomisation) | daily consumption of remifentanil between the 24th hour and the 48th hour after randomisation of patients admitted to the ICU and requiring at least 72 hours of mechanical ventilation | 48th hour after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of a non-opioid analgesia strategy on morphine savings at D7 | Cumulative dose of remifentanil | Day 28 | 
| Impact of an opioid-free analgesia strategy on sedative consumption | Number of lived days free of remifentanil | Day 28 | 
| Impact of an opioid-free analgesia strategy on sedative consumption | Daily consumption of sedative drugs from inclusion to D28 | Day 28 | 
| Impact of a non-opioid analgesia strategy on the duration of mechanical ventilation | Number of live days free of mechanical ventilation | Day 28 | 
| Impact of an opioid-free analgesia strategy on norepinephrine | Number of lived days free of norepinephrine | Day 28 | 
| Impact of a non-opioid analgesia strategy on organ failure at D28 | SOFA Score (Sepsis-related Organ Failure Assessment) | Day 28 | 
| Impact of a non-opioid analgesia strategy on fluid intake | Daily fuid intake in milliliter | Day 28 | 
| Impact of a non-opioid analgesia strategy on mental confusion | CAM ICU test | Day 28 | 
| Impact of a non-opioid analgesia strategy on the occurrence of morphine-related adverse events | Presence of one or more events of special interest or expected adverse events: constipation, bradycardia, bladder globe, nausea, vomiting, liver disturbance, serotonin syndrome | Day 28 | 
| Impact of a non-opioid analgesia strategy on the incidence of ventilator-associated pneumonia | Presence of pneumonia associated with mechanical ventilation | Day 28 | 
| Impact of a non-opioid analgesia strategy on extubation failure rates | extubation failure and cause (reintubation within 48 hours of first extubation) | 48 hours after extubation | 
| Impact of a non-opioid analgesia strategy onICU and hospital length of stay | Length of stay in the intensive care unit and in the hospital | Day 90 | 
| Impact of the non-opioid analgesia strategy on vital prognosis at D28 and D90. | Vital status at day 28 and day 90 | Day 90 | 
| Impact of a non-opioid analgesia strategy on morphine dependence at D90 | Opioid use at D90 | Day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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orotracheal intubation, mechanical ventilation, sedation analgesia