Mechanical Ventilation, Sedation
Conditions
Keywords
Sedation, Mechanical Ventilation, ICU, Ciprofol, Propofol
Brief summary
Background: Sedation is a cornerstone of management for mechanically ventilated patients in the intensive care unit (ICU). Achieving early target sedation while maintaining hemodynamic stability remains a major clinical challenge. Ciprofol, a novel intravenous sedative agent structurally derived from propofol, has shown promising efficacy and a potentially improved hemodynamic profile in preclinical and phase II/III studies. However, high-quality evidence from large, multicenter randomized trials in real-world ICU settings is lacking. Objective: To evaluate the efficacy and safety of ciprofol versus propofol for sedation in mechanically ventilated ICU patients, as assessed by the incidence of early successful sedation without hypotension. Methods: This is a multicenter, randomized, double-blind, parallel-group, active-controlled, noninferiority clinical trial conducted across 31 centers in China. A total of 366 patients will be randomized in a 1:1 ratio to receive either ciprofol or propofol. Eligible patients are adults (aged 18-80 years) admitted to the ICU receiving mechanical ventilation, with an expected sedation duration of 6-24 hours and a target Richmond Agitation-Sedation Scale (RASS) of +1 to -2. Key exclusion criteria include known allergy to ciprofol, BMI \<18 or \>30 kg/m², prior sedation for \>3 days, severe cardiovascular, hepatic or renal dysfunction, Glasgow Coma Scale ≤12, expected survival ≤24 hours, pregnancy or lactation, and participation in other drug trials. Patients will receive a loading dose (ciprofol 0.1 mg/kg or propofol 0.5 mg/kg) over 4 minutes, followed by a maintenance infusion titrated to achieve the target RASS. Remifentanil will be used for analgesia throughout. The primary composite outcome is successful sedation without hypotension within 30 minutes of study drug administration, defined as: (1) RASS within the target range of +1 to -2; (2) no use of rescue sedation; and (3) no occurrence of hypotension. Hypotension is defined as systolic blood pressure \<90 mmHg, diastolic blood pressure \<60 mmHg, mean arterial pressure \<70 mmHg, or a \>30% drop from baseline. Secondary outcomes include sedation success without hypotension at 1 hour, sedation without circulatory depression (hypotension or bradycardia) at 1 hour, drug utilization, duration of mechanical ventilation, extubation time, awakening time, delirium incidence (CAM-ICU), ICU length of stay, 28-day mortality, and safety profiles. Based on an assumed 92% incidence in the ciprofol group versus 82% in the propofol group, with a two-sided alpha of 0.05 and 80% power, and allowing for a 5% dropout rate, the required sample size is 183 patients per group, totaling 366 patients. Analysis will be performed on the intention-to-treat population using logistic regression for the primary outcome, with results expressed as risk difference and relative risk with 95% confidence intervals. Ethics and Dissemination: The study protocol has been approved by the ethics committee of the coordinating center and will be submitted to all participating sites. The trial is registered with ClinicalTrials.gov (NCT06538883). Results will be disseminated through peer-reviewed publications and academic presentations. Keywords: Ciprofol, Propofol, Intensive care unit, Mechanical ventilation, Sedation, Hypotension, Randomized controlled trial
Interventions
DRUGCiprofol
During the drug administration period, ciprofol were IV infused at loading doses of 0.1 mg/kg, respectively, over 4 minutes ± 30 seconds depending on the physical condition of each patient. Ciprofol were then immediately administered at an initial maintenance dose of 0.3 mg/kg/hr, with a target sedation depth of RASS +1 to -2, based on the Pain, Agitation/sedation, Delirium, Immobility (rehabilitation/mobilization), and Sleep (disruption) guideline.
During the drug administration period, propofol were IV infused at loading doses of 0.5 mg/kg, respectively, over 4 minutes ± 30 seconds depending on the physical condition of each patient. Propofol were then immediately administered at an initial maintenance dose of 1.5 mg/kg/hr, with a target sedation depth of RASS +1 to -2, based on the Pain, Agitation/sedation, Delirium, Immobility (rehabilitation/mobilization), and Sleep (disruption) guideline.
Sponsors
Zhongda Hospital
The First Affiliated Hospital of Air Force Medicial University
First Affiliated Hospital, Sun Yat-Sen University
Zhongnan University Xiangya Second Hospital
Renmin Hospital of Wuhan University
First Affiliated Hospital of Suzhou Medical College
The First Affiliated Hospital of Nanchang University
China-Japan Union Hospital, Jilin University
Zhongnan Hospital
The First Affiliated Hospital of China University of Science and Technology (Anhui Provincial)
First Affiliated Hospital Xi'an Jiaotong University
First Affiliated Hospital of Kunming Medical University
Sichuan Academy of Medical Sciences
Anhui provincial chest hospital
The Guangxi Zhuang Autonomous Region People's Hospital
Second Affiliated Hospital of Suzhou University
The Ninth People's Hospital of Suzhou
Fifth Affiliated Hospital of Xinjiang Medical University
Xuzhou Medical University Hospital
First People's Hospital of Hangzhou
Hebei Medical University Fourth Hospital
Huai'an First People's Hospital
Jinan City People's Hospital
The First People's Hospital of Lianyungang
Jiangsu Subei People's Hospital
Suqian First Hospital
Taian City Central Hospital
Xuzhou Central Hospital
The first People's Hospital of Yancheng City
The First People's Hospital of Zunyi
Jiangxi Provincial People's Hopital
Henan Provincial People's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
(patients who met all the following criteria): 1. Adults are sequentially admitted to ICU undergoing mechanical ventilation; Patients are expected to need 6-24 hours of sedation for the target RASS ranged from +1 to -2 after randomization; 2. Aged ≥ 18 and ≤ 80 years old, with no gender requirement; 3. The patients or their family members fully understood the objectives and significance of this study and voluntarily participated and signed informed consent forms.
Exclusion criteria
(patients who met 1 of the following criteria were excluded): 1\. Patients known to be allergic or contraindicated to ciprofol. 2. BMI\<18 kg/m2 or \>30 kg/m2. 3. Patients who had received sedation for more than 3 days in an ICU or in a general ward prior to being transferred to the ICU before signing an informed consent form. 4\. Patients have the following medical history or evidence of any of the following conditions at screening, which may increase the sedation/anesthesia risk: 1. Cardiovascular system: New York Heart Association (NYHA) Class III and IV heart failure, Adams-stokes syndrome; patients who required vasopressor (equivalent norepinephrine ≥ 1μg/kg/min) to maintain a normal blood pressure. 2. Patients with hepatic and renal failure (liver function: refer to Child-Pugh grade C; renal function: eGFR ≤ 30 mL/(min·1.73 m2) \[eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) equation: eGFR = 175 × serum creatinine (SCr) - 1.234 × age - 0.179 × 0.79 (females)\]; patients undergoing dialysis. 3. Patients with grand mal epilepsy and convulsion; a Glasgow coma scale (GCS) ≤ 12 points. 5\. Patients with an expected survival of ≤ 24 h. 6. Pregnant or lactating females. 7. Patients participated in other drug clinical trials before screening. 8. Other conditions that patients were judged by the investigator to be unsuitable for inclusion in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The primary outcome is the rate of successful sedation without hypotension | within the first 30 minutes of administering the study drug | The primary outcome is the rate of successful sedation without hypotension, which have to meet the following three criteria simultaneously: 1) Sedation within the RASS target (+1 to -2); 2) No rescue therapy is used; 3) No hypotension occurs, within the first 30 minutes of administering the study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| the rate of within sedation target (RASS: +1 to -2) without hypotension in the first 1hour of administering the study drug; | within the first 1hour of administering the study drug | — |
| the rate of within sedation target (RASS: +1 to -2) without circulatory inhibition (defined as either hypotension or bradycardia) in the first 1hour of administering the study drug; | within the first 1hour of administering the study drug | — |
| Usage of study drugs | within the first 24hours of administering the study drug | the total additional dose will be recorded; |
| Duration of mechanical ventilation | from randomization until the date of first extubation or date of death from any cause, whichever came first, assessed up to 28 days | Duration of mechanical ventilation: defined as the time from randomization to extubation in 28 days |
| Extubation time | from stopping the study drug to extubation, or death from any cause, or 28 days | defined as time from stopping the study drug to extubation, or death from any cause; not applicable for patients who withdraw early or do not plan to extubate after stopping the drug, in 28 days; |
| Awakening time | from stopping the study drug until the time of awakening from sedation (RASS ≥ 0) or death from any cause, whichever came first, assessed up to 24h after stopping the drug. | defined as the time from stopping the study drug to awakening from sedation (RASS ≥ 0) in 24h after stopping the drug. If RASS is ≥ 0 at the time of stopping the drug, the awakening time is recorded as 0; If RASS is less than 0 in 24h after stopping the drug, the awakening time is recorded as 24h; |
| Incidence of delirium | from administation of study drug until the time of awakening from sedation (RASS ≥ 0) or death from any cause, whichever came first, assessed up to 28 days | Incidence of delirium, which is assessed using the CAM-ICU; |
| Length of ICU stay | the time from randomization to discharge from the ICU or death from any cause, whichever came first, assessed up to 28 days | defined as the time from randomization to discharge from the ICU; |
| The 28-day mortality | from randomization to 28 days | all caused mortality within 28 days. |
| Incidence of hypotension | from randomization to 48 hours after the end of study drug administration | Hypotension was defined as SBP \< 90 mmHg, or DBP \< 60 mmHg, or MAP \< 70 mmHg, or a drop of more than 30% from baseline, or as determined by the investigator; and the use of vasopressor medications will be recorded; |
| Incidence of bradycardia | from randomization to 48 hours after the end of study drug administration | HR \< 40 bpm or a drop of more than 30% from baseline; the use of medications for bradycardia intervention |
Countries
China
Outcome results
None listed