Impact of Remimazolam on Prognosis After Bladder Cancer Surgery

Study Overview
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Brief Summary
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Bladder cancer is one of the most common genitourinary cancers. Transurethral resection of bladder tumor (TURBT) is the standard therapy for nonmuscle invasive bladder cancer. However, patients after TURBT are at risk for recurrence and progression. Benzodiazepines are proved to inhibit proliferation of multiple types of cancer cells in vitro. Delirium is an acute onset and transient cerebral dysfunction and is associated with worse outcomes. Previous studies indicated that benzodiazepines increase incidence of postoperative delirium. Remimazolam is a new benzodiazepine with rapid onset and ultra-short activity. The aims of this study are to explore the impact of remimazolam for general anesthesia on emergency delirium and recurrence-free survival in patients undergoing bladder cancer surgery.

Detailed Description
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Bladder cancer is one of the most common genitourinary cancers. Approximately 70-80% of bladder cancers are nonmuscle invasive, including those of Ta-T1 stage and carcinoma in situ. Transurethral resection of bladder tumor (TURBT) is the standard therapy for nonmuscle invasive bladder cancer. However, patients after TURBT are at a high risk of recurrence and progression. Recently, impacts of anesthetic agents on tumor cells have attracted more attention. Benzodiazepines are found to inhibit proliferation of lymphoma, neural tumor, lung cancer, rectal cancer and breast cancer cells in vitro. Midazolam may have anti-tumor effects through induction of apoptosis and inhibition of inflammatory reaction. However, clinical evidence regarding effects of benzodiazepines on outcomes after cancer surgery remains lacking. Remimazolam is a new benzodiazepine with rapid onset and ultra-short activity. It is rapidly metabolized by tissue esterases to inactive metabolite and can be reversed by flumazenil. Therefore, patients wake up rapidly even after prolonged infusions. It is also found to produce less respiratory and circulatory depression when compared with propofol. Delirium is an acute onset and transient cerebral dysfunction, and is associated with worse outcomes including prolonged hospitalization, worse functional recovery, cognitive decline, and increased mortality rate. Previous studies indicated that benzodiazepines increase incidence of postoperative delirium, possibly due to prolonged action. With the property of ultra-short activity, remimazolam may not increase the incidence of delirium. But evidence is lacking in this aspect. The aims of this study are to explore the impact of remimazolam on emergency delirium and recurrence-free survival in patients undergoing bladder cancer surgery.

Official Title
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Impact of Remimazolam Tosilate for General Anesthesia on Prognosis After Bladder Cancer Surgery: a Randomized Controlled Trial

Conditions
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Benzodiazepines, Bladder Cancer, Delirium, Surgery, Cancer Recurrence

Intervention / Treatment
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* Drug: Remimazolam
* Drug: Propofol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥50 years and <90 years; Preoperative diagnosis is non-muscle-invasive bladder cancer(Ta-T1); Scheduled to undergo transurethral resection of bladder tumor; Agree to participate, and provide written informed consent. Exclusion Criteria: Refuse to participate; Emergent surgery; Combined with other malignant tumors; Use of benzodiazepines for 1 week within the last month before surgery; Preoperative history of schizophrenia, epilepsy, parkinsonism or myasthenia gravis; Inability to communicate in the preoperative period due to coma, profound dementia, language barrier, or end-stage disease; Critical illness (preoperative American Society of Anesthesiologists physical status classification ≥IV), severe hepatic dysfunction (Child-Pugh class C), or severe renal dysfunction (undergoing dialysis before surgery); The purpose of surgery is to make a diagnosis or preoperative judgement is that tumor cannot be completely removed.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remimazolam group<br>Remimazolam is administered intravenously for anesthesia induction and maintenance. The dose and infusion rate is adjusted to maintain Bispectral Index (BIS) value between 40 and 60. Analgesia is maintained with remifentanil and/or sufentanil. Muscle relaxation is maintained with rocuronium and/or cisatracurium. Sevoflurane inhalation is provided when considered necessary. | Drug: Remimazolam<br>* Remimazolam is administered intravenously for anesthesia induction and maintenance. The dose and infusion rate is adjusted to maintain BIS value between 40 and 60. Analgesia is maintained with remifentanil and/or sufentanil. Muscle relaxation is maintained with rocuronium and/or cisatracurium. Sevoflurane inhalation is provided when considered necessary.<br>* Other names: Remimazolam anesthesia;|
| Active Comparator: Propofol group<br>Propofol is administered intravenously for anesthesia induction and maintenance. The dose and infusion rate is adjusted to maintain BIS value between 40 and 60. Analgesia is maintained with remifentanil and/or sufentanil. Muscle relaxation is maintained with rocuronium and/or cisatracurium. Sevoflurane inhalation is provided when considered necessary. | Drug: Propofol<br>* Propofol is administered intravenously for anesthesia induction and maintenance. The dose and infusion rate is adjusted to maintain BIS value between 40 and 60. Analgesia is maintained with remifentanil and/or sufentanil. Muscle relaxation is maintained with rocuronium and/or cisatracurium. Sevoflurane is provided when considered necessary.<br>* Other names: Propofol anesthesia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of emergence delirium (early). | Emergence delirium is assessed with the Confusion Assessment Method for the Intensive Care Unit at 10 and 30 minutes after admission to the post-anesthesia care unit after surgery. | Up to 2 hours during the stay in post-anesthesia care unit after surgery. | 
| Recurrence-free survival (long-term). | Time from surgery to recurrence/metastasis or all-cause death, whichever come first. | Up to 3 years after surgery. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of postoperative delirium (early). | Delirium is assessed twice daily with the Chinese version of the 3-minute diagnostic interview for Confusion Assessment Method-defined delirium. | During the first 3 days after surgery. | 
| Incidence of postoperative nausea and vomiting (early). | Incidence of postoperative nausea and vomiting. | Up to 24 hours after surgery. | 
| Incidence of intraoperative awareness (early). | Intraoperative awareness is assessed with modified Brice interview before discharge from the post-anesthesia care unit and on the 1st day after surgery. The interview included five questions: (1) What was the last thing you remembered happening before you went to sleep? (2) What is the first thing you remember after your operation? (3) Can you remember anything in between? (4) Can you remember if you had any dreams during your operation? (5) What was the worst thing about your operation? | Up to 1 day after surgery. | 
| Length of stay in hospital after surgery (early). | Length of stay in hospital after surgery. | Up to 30 days after surgery. | 
| Incidence of non-delirium complications (early). | Non-delirium complications are defined as newly occurred medical conditions other than delirium that are harmful for patients' recovery and required therapeutic intervention, i.e., grade 2 or higher on Clavien-Dindo classification. | Up to 30 days after surgery. | 
| All-cause 30-day mortality (early). | All-cause 30-day mortality. | Up to 30 days after surgery. | 
| Overall survival (long-term). | Time from surgery to all-cause death. | Up to 3 years after surgery. | 
| Event-free survival (long-term). | Time from surgery to serious events, cancer recurrence/metastasis, or all-cause death, whichever come first. Serious events are defined as any new onset disease that required hospitalization and/or surgical intervention. | Up to 3 years after surgery. | 
| Health related quality of life of 1-year survivors (long-term). | Health related quality of life is assessed with the World Health Organization Quality of Life-brief version (WHOQOL-BREF) which is a 24-item questionnaire that assesses the quality of life in physical, psychological, and social relationship, and environmental domains. The score ranges from 0 to 100 for each domain, with higher score indicating better function. | At the end of the 1st year after surgery. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Remimazolam, Bladder Cancer, Surgery, Emergence Delirium, Recurrence-free Survival