Adjuvant Continuous Infusion of Nefopam Versus Standard of Care in Mechanically Ventilated Critically Ill Patients: Randomized Double-blind Controlled Study

Study Overview
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Brief Summary
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The aim of this prospective, randomized, active control, double blinded study is to assess the effect and safety of continuous infusion nefopam in mechanically ventilated ICU patients compared to standard of care. It is being hypothesized that continuous infusion nefopam will reduce opioid use with acceptable safety profile compared to standard of care.

Detailed Description
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Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. Critically ill patients experience pain at rest and during standard caring procedures. Arterial catheter insertion, chest tube removal, wound drain removal, wound care, and turning are associated with the greatest increased pain intensity. Pain have short and long-term sequelae on critically ill patients. Short-term sequelae include impaired tissue oxygenation, impaired wound healing, and impaired immune functions. Long-term sequelae include chronic pain, Post-traumatic stress disorder (PTSD) symptoms, and a lower health-related quality of life. The gold standard for pain assessment is patient's self-report of pain. For critically ill able to self-report pain the 0-10 numeric rating scale in a visual format (NRS-V) is the best to use. Unfortunately, a lot of critically ill patients are unable to communicate and self-report pain. So, using behavioral pain scales are suitable in this type of patients, Critical care pain observation tool (CPOT) demonstrates validity and reliability for monitoring pain in critical ill adult patient who are unable to self-report pain and in whom behaviors are observable. The 2018 Pain, Agitation/sedation, Delirium, Immobility, and Sleep disruption (PADIS) guideline panel suggests using an assessment-driven, protocol-based, stepwise approach for pain and sedation management in critically ill adults and state as a good practice statement critically ill adults should be regularly assessed for delirium using a valid tool. Opioids are a cornerstone in the management of pain in critically ill patient, but have a lot of negative consequences including constipation, urinary retention, bronchospasm, over-sedation, respiratory depression, hypotension, nausea, truncal rigidity, delirium, and immunosuppression. Also, they contribute to vasodilatation and hypotension which lead to increased resuscitation fluids volume in critically ill patient. Multi-modal analgesia also known as balanced analgesia approach via using non-opioids adjuvant or in replacement of opioids to target different pain pathways leads to optimizing analgesia and reducing opioids consumption. In France, the second most prescribed non-opioids in mechanically ventilated intensive care unit (ICU) patient is nefopam. Nefopam is a non-opioid, non-steroidal centrally acting analgesic, although the exact mechanism of action poorly understood, analgesic activity is thought to be via inhibiting dopamine, norepinephrine, serotonin reuptake. Nefopam was non-inferior to fentanyl for pain control in patients undergoing elective cardiac surgery without increase in adverse effects. Nefopam has a fentanyl sparing effect up to 50% in patients underwent laparoscopic total hysterectomy. The 2018 PADIS guideline panel made a conditional recommendation for using nefopam (if feasible) either as an adjunct or replacement for an opioid to reduce opioid use and their safety concerns for pain management in critically ill adults. Therefore, the aim of this prospective, randomized, active control, double blinded study is to assess the effect and safety of continuous infusion nefopam in mechanically ventilated ICU patients compared to standard of care. It is being hypothesized that continuous infusion nefopam will reduce opioid use with acceptable safety profile compared to standard of care.

Official Title
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Adjuvant Continuous Infusion of Nefopam Versus Standard of Care in Mechanically Ventilated Critically Ill Patients: Randomized Double-blind Controlled Study

Conditions
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Analgesia, Critical Illness, Mechanical Ventilation, Sedation

Intervention / Treatment
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* Drug: Nefopam
* Drug: Standard of care in the ICU for assessment and management of pain, sedation, and delirium.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients >18 years on mechanical ventilation and expected to need ventilatory support for the next 24 hours. Candidate for sedation and analgesia protocol Exclusion Criteria: Pregnant and/or lactating woman. Has been intubated for duration longer than 12 hours in an intensive care unit. Proven or suspected acute primary brain lesion such as traumatic brain injury, intracranial haemorrhage, stroke, or hypoxic brain injury. Proven or suspected spinal cord injury or other pathology that may result in permanent or prolonged weakness. Admission as a consequence of a suspected or proven drug overdose Mean arterial pressure (MAP) < 50 mmHg despite adequate resuscitation and vasopressor therapy at time of randomization. Death is deemed to be imminent or inevitable during this admission and either the attending physician, patient or substitute decision maker is not committed to active treatment. Patients with severe hepatic impairment (Child-Pugh class C) or end stage renal disease (ESRD) (creatinine clearance < 30 ml/min or on chronic hemodialysis) due to altered pharmacokinetics [20]. Need for deep sedation such as administration of neuromuscular blockers. Convulsions or previous history of convulsions. Risk of urinary retention linked to uretroprostatic disorders. Risk of acute angle glaucoma. Known intolerance of or hypersensitivity to study medications or constituents.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nefopam group<br>Adjunct continuous infusion of nefopam plus standard of care in ICU for assessment and management of pain, sedation, and delirium. Nefopam will be administered as an initial dose of 20 mg IV dose infused over 15 minutes then, as continuous infusion of 5 mg/hr for 24 hours. | Drug: Nefopam<br>* Nefopam will be administered as an initial dose of 20 mg IV dose infused over 15 minutes then, as continuous infusion of 5 mg/hr for 24 hours.<br>* Other names: Acupan;Drug: Standard of care in the ICU for assessment and management of pain, sedation, and delirium.<br>* In our protocol we use analgiosedation approach (an opioid is used before a sedative to reach the sedation goal), targeting light sedation using richmond agitation sedation scale (RASS) score -1 to 0, and assess delirium using confusion assessment method for the ICU (CAM-ICU).<br>* Other names: Standard of care;|
| Placebo Comparator: Control group<br>Standard of care in the ICU for assessment and management of pain, sedation, and delirium. | Drug: Standard of care in the ICU for assessment and management of pain, sedation, and delirium.<br>* In our protocol we use analgiosedation approach (an opioid is used before a sedative to reach the sedation goal), targeting light sedation using richmond agitation sedation scale (RASS) score -1 to 0, and assess delirium using confusion assessment method for the ICU (CAM-ICU).<br>* Other names: Standard of care;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative dose of fentanyl | To compare the cumulative dose of fentanyl | First 24 hour after randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Richmond Agitation and Sedation Score (RASS) | To compare number of patients are in RASS score goal. RASS score minumum -5 (unarousable), maximun +4 (Combative). Goal RASS score from -1 (drowsy) to 0 (alert and calm). | First 24 hours after randomization. | 
| pain score | To compare number of patients are in Pain score goal. If patient able to communicate we use the 0-10 numeric rating scale in a visual format (NRS-V), 0 indicate no pain and 10 indicate the worst pain imaginable. For patient unable to communicate we use Critical care pain observation tool (CPOT) score, a score ≥3 indicate significant pain. | First 24 hours after randomization. | 
| Duration of mechanical ventilation (MV) | To assess whether nefopam can help to shorten the of being mechanically ventilated. | The number of calendar days from intubation date to extubation date, until ICU discharge, death, or 28 days post-randomization, whichever comes first. | 
| vasopressor requirements | To compare vasopressors requirement | First 24 hours after randomization. | 
| Hemodynamics | changes in Mean Arterial Pressure (MAP) mmHg | First 24 hours after randomization. | 
| Hemodynamics | changes in Heart Rate (HR) beats/minute. | First 24 hours after randomization. | 
| ICU length of stay (LOS) | To compare ICU LOS | From randomization to ICU discharge date | 
| Tracheostomy | Tracheostomy rate | 28 days post-randomization | 
| Unplanned extubation (self-extubation) | Unplanned extubation date rate | 28 days post-randomization | 
| Re-intubation | Re-intubation rate | 28 days post-randomization | 
| Incidence of delirium | Rate of positive confusion assessment method for the ICU (CAM-ICU) score | 24 hour after randomization | 
| Use of antipsychotics | Rate of using antipsychotics for confirmed ICU-acquired delirium | 24 hour after randomization | 
| Use of physical restraint | Use of physical restraint | 24 hour after randomization | 
| Mortality rate at the time of hospital discharge or 28 days after randomization, whichever comes first. | Mortality rate at the time of hospital discharge or 28 days after randomization, whichever comes first. | 28 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nefopam, Ketamine, Standard of care, Sedation, Critically ill, Mechanical ventilation, Propofol, Fentanyl, Midazolam, Delirium, Vasopressors.