Effects of Post-Operative Sedation for Endovascular Thrombectomy — POSET  

Acute Ischemic Stroke Clinical Trial

Official title: Effects of Post-operative Sedation on Clinical Outcomes in Patients Receiving Endovascular Thrombectomy for Acute Ischemic Stroke

Status Recruiting

Clinical Trial Summary

Studies from our lab indicated that long-term sedation is protective in mice with midbrain infarct. To assess whether post-operative sedation has protective effects on clinical outcomes in patients with ischemic stroke undergoing endovascular thrombectomy (ET), a multi-center, randomized clinical trial will be carried out (POSET study). In POSET study, patients receiving ET for acute ischemic stroke under general anesthesia will be randomly assigned to the control group (Con group) and the post-operative sedation group (POS group). Patients in the Con group will be recovered and extubated immediately after the surgery, whereas those in the POS group will be sedated with propofol and dexmedetomidine for another 6hrs before extubation. The primary endpoint is the score on the modified Rankin Scale assessed at 90±7 days after randomization. The hypothesis is that patients in the POS group will have improved clinical outcome in 3 months after surgery.

Clinical Trial Description

Theoretically, general anesthesia (GA) has profound brain protection potential, because it can induce a sedative status in patients, reduce brain tissue metabolism and oxygen consumption, inhibit neuro-excitotoxicity, and decrease the core body temperature to a certain degree. All these features indicate GA may possess neuro-protective properties and should be beneficial to ischemic brain, i.e., patients with acute ischemic stroke (AIS).

However, in the clinics, application of GA is limited in intra-operative period, which corresponds to only part of the ischemic period, in AIS patients undergoing endovascular thrombectomy (ET) surgery. Several recent well-designed RCT studies demonstrated that patients who underwent the surgery under GA achieved a more favorable functional outcomes at 3 months compared with those having the surgery without GA and the better outcome was mainly a direct effect of GA per se. Meanwhile, it is worth noting that, although recent studies tend to favor certain potential benefits of GA for patients undergoing ET surgery, the protective effects of GA uncovered by these trials seem consistently weak. Why? We speculate that this is mainly due to the short exposure time to GA. Around 2 hour-implementation of GA during the surgery is not long enough to exert obvious protection in such big brain damage. Ideally, GA would provide maximum protection effect if the AIS patients could receive sedation once they are diagnosed, i.e., before, during and after the ET surgery, which seems practically impossible. More feasibly, we propose that a prolonged exposure to GA in AIS patients undergoing ET, which includes both ischemic and reperfusion periods, would result in considerable improvements in these patients.

Therefore, considering the safety and feasibility of modern anesthetic technique, we intend to conduct a multi-center, prospective, randomized, controlled clinical trial to investigate whether prolonged Post-Operative Sedation would benefit AIS patients undergoing Endovascular Thrombectomy on their clinical outcomes (POSET). Patients who achieve successful reperfusion after ET surgery under GA will be randomly assigned to control group or post-operative sedation group, in which, the control group will recover from GA immediately after the surgery, whereas those assigned to the post-operative sedation group will receive mechanical ventilation under sedation for another 6 hrs before extubation. The primary outcome is the score on the mRS at around 90 days after randomization. The current study may provide new therapeutic strategy, which is both practical and safe for neuroprotection in AIS patients.

Sample size is calculated according to the results of previous studies and our previous experience. We assume distribution of mRS scores at 90 days after surgery in the control group is: 0: 4.6%; 1: 12%; 2: 10.7%; 3: 20%; 4: 19.3%; 5: 8.7%; 6: 24.7%. For the intervention group, based on our previous experience, we assume that the common odds ratio (cOR) value is 1.4, which corresponds to a difference of 7 percent points between the patients in the intervention group who have a mRS score in the range of 0~2 and those in the control group. After 5000 times of simulation using Monte Carlo, a sample size of 1152 subjects can provide a power of 90%.

Interim analysis will be carried out when 25%, 50% and 75% of patients have been enrolled, respectively. The termination rule for efficiency is defined by using the Pocock analog boundaries. Three interim analysis will increase the sample size by 1.027, therefore making the sample size 1152×1.027=1184. Taking into account a 8% dropout rate, a final sample size of 1286 is needed, 643 per arm.

Since the sample size calculation is based on results from a previous study and our retrospective data, to account for uncertainty associated with center variance, this trial uses an adaptive design. The sample size will be recalculated based on the accumulating data when 50% of patients have been enrolled.

An independent DSMB which includes a neurologist, an anesthesiologist and an independent methodologist/statistician monitors the trial. The DSMB plans to hold two interim analysis meetings when 1/3 and 2/3 cases have finished the 90±7 days follow-up, and the analysis will assess the occurrence of adverse events by center and by procedure.

For statistical analysis, baseline data are presented according to treatment allocation in an appropriate way, i.e., categorical variables and continuous variables are indicated by quantity (percentage) and mean ± standard deviation or median (interquartile range), respectively. The primary outcome parameter, mRS score at 90±7 days after the operation, is an ordinal categorical variable of 6 categories. Ordinal logistic regression will be used to estimate the unadjusted cOR and its 95% confidence interval. The cOR and its 95% confidence interval after adjusting with age, preoperative mRS score and other variables will be estimated as well. The analysis of primary outcomes will be performed according to the intention-to-treat (ITT) principle. And they will also be analyzed for a sensitivity analysis according to per-protocol (PP) principle. Linear regression or logistic regression will be used to analyze the secondary outcomes, with the same adjustments as the primary outcome. The safety data will be presented as number or proportion, and the RR (Risk Ratio) and the 95% confidence interval will be calculated and compared between the groups. Analysis of the secondary outcomes and safety data will be performed according to the ITT principle only. All the statistical analysis will be performed using SAS (v9.2) or R (v4.0.2) software. ;

Related Conditions & MeSH terms

• Acute Ischemic Stroke
• Endovascular Thrombectomy
• Ischemic Stroke

• NCT number: NCT04517383
• Study type: Interventional
• Source: RenJi Hospital
• Contact: Weifeng Yu, Ph.D.
• Phone: 86-21-68383702
• Email: ywf808@yeah.net
• Status: Recruiting
• Phase: N/A
• Start date: November 24, 2021
• Completion date: February 28, 2025