Impact of Remimazolam on Prognosis After Bladder Cancer Surgery

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Remimazolam
  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.
• Препарат Propofol
  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.

Первичные конечные точки

• Incidence of emergence delirium (early). [Срок оценки: Up to 2 hours during the stay in post-anesthesia care unit after surgery.]
• Recurrence-free survival (long-term). [Срок оценки: Up to 3 years after surgery.]

Вторичные конечные точки (9)

• Incidence of postoperative delirium (early). [Срок оценки: During the first 3 days after surgery.]
• Incidence of postoperative nausea and vomiting (early). [Срок оценки: Up to 24 hours after surgery.]
• Incidence of intraoperative awareness (early). [Срок оценки: Up to 1 day after surgery.]
• Length of stay in hospital after surgery (early). [Срок оценки: Up to 30 days after surgery.]
• Incidence of non-delirium complications (early). [Срок оценки: Up to 30 days after surgery.]
• All-cause 30-day mortality (early). [Срок оценки: Up to 30 days after surgery.]
• Overall survival (long-term). [Срок оценки: Up to 3 years after surgery.]
• Event-free survival (long-term). [Срок оценки: Up to 3 years after surgery.]
• Health related quality of life of 1-year survivors (long-term). [Срок оценки: At the end of the 1st year after surgery.]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Профилактика

Центры проведения

Китай · 6 центров

• Beijing Tsinghua Chang Gung Hospital — Пекин
• The Sixth Medical Center of PLA General Hospital — Пекин
• Peking University First Hospital — Beijin
• Guizhou Provincial People's Hospital — Guiyang
• Jiangsu Provincial People's Hospital — Нанкин
• Shanghai 10th People's Hospital — Шанхай

Публикации

• Chen W, Zheng R, Zhang S, Zeng H, Xia C, Zuo T, Yang Z, Zou X, He J. Cancer incidence and mortality in China, 2013. Cancer Lett. 2017 Aug 10;401:63-71. doi: 10.1016/j.canlet.2017.04.024. Epub 2017 May 3. PMID 28476483
• Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, Hernandez V, Kaasinen E, Palou J, Roupret M, van Rhijn BWG, Shariat SF, Soukup V, Sylvester RJ, Zigeuner R. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 2017 Mar;71(3):447-461. doi: 10.1016/j.eururo.2016.05.041. Epub 2016 Jun 17. PMID 27324428
• Soukup V, Capoun O, Cohen D, Hernandez V, Babjuk M, Burger M, Comperat E, Gontero P, Lam T, MacLennan S, Mostafid AH, Palou J, van Rhijn BWG, Roupret M, Shariat SF, Sylvester R, Yuan Y, Zigeuner R. Prognostic Performance and Reproducibility of the 1973 and 2004/2016 World Health Organization Grading Classification Systems in Non-muscle-invasive Bladder Cancer: A European Association of Urology Non PMID 28457661
• Allard P, Bernard P, Fradet Y, Tetu B. The early clinical course of primary Ta and T1 bladder cancer: a proposed prognostic index. Br J Urol. 1998 May;81(5):692-8. doi: 10.1046/j.1464-410x.1998.00628.x. PMID 9634043
• Holmgren L, O'Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 1995 Feb;1(2):149-53. doi: 10.1038/nm0295-149. PMID 7585012
• Hofer SO, Molema G, Hermens RA, Wanebo HJ, Reichner JS, Hoekstra HJ. The effect of surgical wounding on tumour development. Eur J Surg Oncol. 1999 Jun;25(3):231-43. doi: 10.1053/ejso.1998.0634. PMID 10336800
• Eggermont AM, Steller EP, Marquet RL, Jeekel J, Sugarbaker PH. Local regional promotion of tumor growth after abdominal surgery is dominant over immunotherapy with interleukin-2 and lymphokine activated killer cells. Cancer Detect Prev. 1988;12(1-6):421-9. PMID 3263198
• Stevens MF, Werdehausen R, Gaza N, Hermanns H, Kremer D, Bauer I, Kury P, Hollmann MW, Braun S. Midazolam activates the intrinsic pathway of apoptosis independent of benzodiazepine and death receptor signaling. Reg Anesth Pain Med. 2011 Jul-Aug;36(4):343-9. doi: 10.1097/AAP.0b013e318217a6c7. PMID 21701267

Идентификаторы

NCT: NCT04532606 · 2020-212

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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