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

Sponsor

Southeast University, China (Other)

Overall Status

Recruiting

CT.gov ID

NCT05641909

Collaborator

(none)

138

Enrollment

Locations

Arms

Anticipated Duration (Months)

7.7

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Analgesia	Drug: Remifentanil Drug: Fentanyl	Phase 3

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

138 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 1, 2021

Anticipated Primary Completion Date :

Dec 30, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Remifentanil 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 Remifentanil Other Names: Remifentanil Hydrochloride for Injection
Active Comparator: Fentanyl 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 Dosage forms and strengths: 50 mcg/mL Fentanyl base/10 mL ampules. Manufacturer: Yichang Humanwell Pharmaceutical Co.,Ltd Other Names: Fentanyl Citrate Injection

Arm

Intervention/Treatment

Experimental: Remifentanil

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

Remifentanil

Other Names:

Remifentanil Hydrochloride for Injection

Active Comparator: Fentanyl

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

Dosage forms and strengths: 50 mcg/mL Fentanyl base/10 mL ampules. Manufacturer: Yichang Humanwell Pharmaceutical Co.,Ltd

Other Names:

Fentanyl Citrate Injection

Outcome Measures

Primary Outcome Measures

analgesia success rate(the proportion of subjects with successful analgesia to the number of subjects in each group) [From study drug administration to actual extubation , up to 72 hours]
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).

Secondary Outcome Measures

During the study drug administration period, the subjects are in the proportion of optimal time(CPOT score≤2) [From study drug administration to actual extubation , up to 72 hours]
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).
The number of times the remedial sedative drug propofol was used [From study drug administration to actual extubation , up to 72 hours]
Use the total times of propofol
The proportion of subjects using the salvage sedative drug propofol [From study drug administration to actual extubation , up to 72 hours]
The proportion of subjects who using the salvage sedative drug propofol to the total subjects.
The dosage of the remedial sedative drug propofol [From study drug administration to actual extubation , up to 72 hours]
Use the total dose of propofol
Wearing time from mechanical ventilation [From study drug administration to wearing from mechanical ventilation, up to 72 hours]
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.
Extubation time [From the start of the extubation process until actual extubation , up to 72 hours]
The start of the extubation process until actual extubation
The success rate of wearing mechanical ventilator [From study drug administration to actual extubation , up to 72 hours]
The proportion of subjects who successfully wearing from mechanical ventilator to the total subjects.
Duration of study drug use in ICU [Through study completion, an average of 1 month]
The time from the start of the study drug administration to the time discharge ICU.
The proportion of subjects discharging the ICU [Through study completion, an average of 1 month]
The proportion of subjects who discharge ICU to the total subjects.
ICU mortality [Through study completion, an average of 1 month]
The proportion of subjects who died during ICU admission to the total subjects.
Hospital mortality [Through study completion, an average of 1 month]
The proportion of subjects who died during hospital admission to the total subjects.
Length of ICU stay [Through study completion, an average of 1 month]
The number of days the subject stayed in the ICU.
Length of hospital stay [Through study completion, an average of 1 month]
The number of days the subject stayed in the hospital.
The incidence of study drug-related Lower blood pressure [From study drug administration to actual extubation , up to 72 hours]
Lower blood pressure: mean arterial pressure (MAP) drops more than 25% from the baseline level or requires additional vasopressors.
The incidence of study drug-related slow heart rate [From study drug administration to actual extubation , up to 72 hours]
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.
The incidence of study drug-related respiratory depression [From study drug administration to actual extubation , up to 72 hours]
Respiratory depression: respiratory rate less than 10 bpm or oxygen saturation by pulse oximetry less than 90%
Analysis of the cost-effectiveness between remifentanil and fentanyl [From study drug administration to actual extubation , up to 72 hours]
Analyze the best analgesic plan based on the results of the best analgesic effect

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Anhui Provincial People's Hospital	Hefei	Anhui	China	230000
2	Beijing Tiantan Hospital, Capital Medical University	Beijing	Beijing	China	100000
3	The First Affiliated Hospital of Chongqing Medical University	Chongqing	Chongqing	China	404100
4	Qingyuan People's Hospital	Qingyuan	Guangdong	China	511500
5	Affiliated Hospital of Guizhou Medical University	Guiyang	Guizhou	China	550000
6	Affiliated Hospital of Zunyi Medical University	Zunyi	Guizhou	China	563000
7	The Fourth Hospital of Hebei Medical University	Shijiazhuang	Hebei	China	050000
8	First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan	China	450000
9	Henan Provincial People's Hospital	Zhengzhou	Henan	China	450000
10	Enshi Tujia and Miao Autonomous Prefecture Central Hospital	Enshi	Hubei	China	445000
11	Zhongnan Hospital of Wuhan University	Wuhan	Hubei	China	430000
12	The Third Xiangya Hospital of Central South University	Changsha	Hunan	China	410000
13	Xiangya Hospital of Central South University	Changsha	Hunan	China	410000
14	Northern Jiangsu People's Hospital	Yangzhou	Jiangsu	China	225000
15	The First Affiliated Hospital of Xi'an Jiaotong University	Xi'an	Shanxi	China	710000
16	Tianjin First Central Hospital	Tianjin	Tianjin	China	30000
17	Zhejiang Provincial People's Hospital	Hangzhou	Zhejiang	China	310000
18	Nanjing Zhong-Da Hospital, Southeast University	Nanjing		China	210009