Efficacy and Safety of Remifentanil for Mechanically Ventilated Patients in Intensive Care Unit

Study Overview
=================
Brief Summary
-----------------
Remifentanil has been approved by the FDA for continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting. However, National Medical Products Administration(NMPA) did not approve this indication. Therefore, the purpose of this study is to confirm the efficacy and safety of remifentanil in the analgesic therapy of critical ill patients in China.

Detailed Description
-----------------
The study was conducted in accordance with good clinical practice and with the guidelines set out in the Declaration of Helsinki. After approval from local and national ethics committees, patients from 18 centres in China were recruited. All patients were randomized, in a double-blind manner, to receive either a remifentanil-propofol regimen or a fentanyl-propofol regimen for analgesia and sedation in the ICU. The aim of the study was to achieve optimal sedation and patient comfort by maintaining an optimal Critical Care Pain Observation Tool (CPOT) score of 2, without clinically significant pain, until the start of the extubation process or for 72 hours, whichever occurred first. CPOT scoring criteria: Facial expressions(Relaxed, neutral=0; Tense=1; Grimacing=2); Body movements(Absence of movements or normal position=0; Protection=1; Restlessness/Agitation=2); Muscle tension(Relaxed=0; Tense, rigid=1; Very tense or rigid=2); Compliance with the ventilator or Vocalization(Tolerating ventilator or movement/Talking in normal tone or no sound=0; Coughing but tolerating/Sighing, moaning=1; Fighting ventilator/Crying out, sobbing=2).

Official Title
-----------------
Efficacy and Safety of Remifentanil for Mechanically Ventilated Patients in Intensive Care: Multicenter, Random, Double-blind, Parallel, Positive Control Clinical Trials

Conditions
-----------------
Analgesia

Intervention / Treatment
-----------------
* Drug: Remifentanil
* Drug: Fentanyl


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Intubated in the past 24 hours with invasive mechanical ventilation Expected to continue mechanical ventilation for more than 48 hours Informed consent/assent was obtained from all patients or their representatives Exclusion Criteria: Patients with a history of allergy to opioids, benzodiazepines, propofol, or alcohol/drug abuse were excluded from the study Patients who are known or suspected to be allergic to the study drug Patients whose expected survival time is less than 48h Patients receiving deep sedation (RASS≥-4) Patients using neuromuscular blocking agent Patients who cannot be assessed by RASS Patients with myasthenia gravis patients with bronchial asthma patients with abdominal compartment syndrome Patients who need surgery or tracheotomy during the study drug treatment period Women during pregnancy and lactation Patients who have used short-acting non-steroidal anti-inflammatory drugs within 6 hours Patients who have used long-acting non-steroidal anti-inflammatory drugs within 12 hours Patients with a history of chronic pain for more than 3 months or who are receiving regular analgesia for more than 3 months Patients who have used monoamine oxidase inhibitors within two weeks Patients who participate in any clinical trials as subjects within 1 month Patients with a history of drug abuse, drug abuse, alcohol abuse* and long-term use of psychotropic drugs within 2 years Alcoholism: Drinking more than 14 times/week (1 time=150ml wine or 360ml beer or 45ml spirits)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remifentanil<br>Remifentanil analgesia combined with propofol sedation. Treatment was started in patients with an CPOT score of 2 or greater after completion of baseline assessments. All patients received an initial infusion of blinded opioid (placebo bolus dose(6ml) + 6ug/kg per hour infusion at 6 ml/hour). Optimal analgesia (CPOT score ≤2) was then targeted by titrating the infusion in 1.5 ml/hour increments (placebo bolus dose + 1.5ug/kg per hour rate increase). Only when the opioid infusion rate had reached the 'propofol trigger dose' (12ml/h; 12ug/ kg per hour) was propofol to be administered as an initial bolus dose of up to 0.5 mg/kg and an infusion of 0.5mg/kg per hour, and titrated in 25% increments (0.25mg/kg bolus dose + 0.125mg/kg per hour rate increase to treat agitation. | Drug: Remifentanil<br>* Remifentanil<br>* Other names: Remifentanil Hydrochloride for Injection;|
| Active Comparator: Fentanyl<br>Fentanyl analgesia combined with propofol sedation. Treatment was started in patients with an CPOT score of 2 or greater after completion of baseline assessments. All patients received an initial infusion of blinded opioid (1ug/kg bolus(6ml) + 1ug/kg per hour infusion at 6ml/hour). Optimal analgesia (CPOT score ≤2) was then targeted by titrating the infusion in 1.5 ml/hour increments (1ug/kg bolus dose + 0.25ug/kg per hour rate increase). Only when the opioid infusion rate had reached the 'propofol trigger dose' (12ml/h; 2ug/kg per hour) was propofol to be administered as an initial bolus dose of up to 0.5 mg/kg and an infusion of 0.5mg/kg per hour, and titrated in 25% increments (0.25mg/kg bolus dose + 0.125mg/kg per hour rate increase to treat agitation. | Drug: Fentanyl<br>* Dosage forms and strengths: 50 mcg/mL Fentanyl base/10 mL ampules. Manufacturer: Yichang Humanwell Pharmaceutical Co.,Ltd<br>* Other names: Fentanyl Citrate Injection;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| analgesia success rate(the proportion of subjects with successful analgesia to the number of subjects in each group) | Analgesia success is defined as: 1. No salvage analgesics were used during the administration of the study drug; 2 During the administration of the study drug, the time for the analgesia score of subjects to reach the standard (CPOT score ≤ 2) was greater than 70%. CPOT scoring criteria: Facial expressions(Relaxed, neutral=0; Tense=1; Grimacing=2); Body movements(Absence of movements or normal position=0; Protection=1; Restlessness/ Agitation=2); Muscle tension(Relaxed=0; Tense, rigid=1; Very tense or rigid=2); Compliance with the ventilator or Vocalization(Tolerating ventilator or movement/Talking in normal tone or no sound=0; Coughing but tolerating/Sighing, moaning=1; Fighting ventilator/Crying out, sobbing=2). | From study drug administration to actual extubation , up to 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| During the study drug administration period, the subjects are in the proportion of optimal time(CPOT score≤2) | CPOT scoring criteria: Facial expressions(Relaxed, neutral=0; Tense=1; Grimacing=2); Body movements(Absence of movements or normal position=0; Protection=1; Restlessness/Agitation=2); Muscle tension(Relaxed=0; Tense, rigid=1; Very tense or rigid=2); Compliance with the ventilator or Vocalization(Tolerating ventilator or movement/Talking in normal tone or no sound=0; Coughing but tolerating/Sighing, moaning=1; Fighting ventilator/Crying out, sobbing=2). | From study drug administration to actual extubation , up to 72 hours | 
| The number of times the remedial sedative drug propofol was used | Use the total times of propofol | From study drug administration to actual extubation , up to 72 hours | 
| The proportion of subjects using the salvage sedative drug propofol | The proportion of subjects who using the salvage sedative drug propofol to the total subjects. | From study drug administration to actual extubation , up to 72 hours | 
| The dosage of the remedial sedative drug propofol | Use the total dose of propofol | From study drug administration to actual extubation , up to 72 hours | 
| Wearing time from mechanical ventilation | Wearing time criteria: The primary disease is improved, and there is no new disease; no use of vasopressors or continuous application of sedative drugs; cough reflex during sputum suction; PEEP≤5cmH2O; PaO2/FiO2≥200mmHg; Minute ventilation less than 15L/min; 2-minute spontaneous breathing test and passed. | From study drug administration to wearing from mechanical ventilation, up to 72 hours | 
| Extubation time | The start of the extubation process until actual extubation | From the start of the extubation process until actual extubation , up to 72 hours | 
| The success rate of wearing mechanical ventilator | The proportion of subjects who successfully wearing from mechanical ventilator to the total subjects. | From study drug administration to actual extubation , up to 72 hours | 
| Duration of study drug use in ICU | The time from the start of the study drug administration to the time discharge ICU. | Through study completion, an average of 1 month | 
| The proportion of subjects discharging the ICU | The proportion of subjects who discharge ICU to the total subjects. | Through study completion, an average of 1 month | 
| ICU mortality | The proportion of subjects who died during ICU admission to the total subjects. | Through study completion, an average of 1 month | 
| Hospital mortality | The proportion of subjects who died during hospital admission to the total subjects. | Through study completion, an average of 1 month | 
| Length of ICU stay | The number of days the subject stayed in the ICU. | Through study completion, an average of 1 month | 
| Length of hospital stay | The number of days the subject stayed in the hospital. | Through study completion, an average of 1 month | 
| The incidence of study drug-related Lower blood pressure | Lower blood pressure: mean arterial pressure (MAP) drops more than 25% from the baseline level or requires additional vasopressors. | From study drug administration to actual extubation , up to 72 hours | 
| The incidence of study drug-related slow heart rate | Slow heart rate: heart rate less than 40bpm for less than 1 minute or heart rate less than 60 bpm for more than 1 minute. | From study drug administration to actual extubation , up to 72 hours | 
| The incidence of study drug-related respiratory depression | Respiratory depression: respiratory rate less than 10 bpm or oxygen saturation by pulse oximetry less than 90% | From study drug administration to actual extubation , up to 72 hours | 
| Analysis of the cost-effectiveness between remifentanil and fentanyl | Analyze the best analgesic plan based on the results of the best analgesic effect | From study drug administration to actual extubation , up to 72 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
analgesia, analgesia based sedation, critical care, fentanyl, propofol, remifentanil, sedation