Targeted Temperature Management on Delayed Neurocognitive Recovery in Older Patients After Major Cancer Surgery

Официальное название

Intraoperative Targeted Temperature Management on Delayed Neurocognitive Recovery in Older Patients After Major Cancer Surgery: a Multicenter Randomized Trial

Обзор

With aging population, more older patients will receive major surgery for cancer. Older patients are at increased risk of postoperative neurocognitive complications including delayed neurocognitive recovery (dNCR), which is associated with prolonged hospital stay, raised complications, and impaired quality of life. Intraoperative hypothermia occurs in 57.1%-78.6% of patients undergoing major cancer surgery, especially in the elderly. Studies show that intraoperative hypothermia suppresses immune function, interferes with anesthetic metabolism, and delays anesthesia emergence. All these may be correlated with the occurrence of early postoperative dNCR. This study aims to verify whether intraoperative targeted temperature management (target core temperature: 36.8°C) compared with conventional temperature management (core temperature: 35.5°C) can reduce the incidence of dNCR in older patients undergoing major cancer surgery.

Подробное описание

With aging population, more older patients will undergo major surgery for cancer. Due to age-related cognitive decline, cancer-related frailty, as well as impacts from surgical trauma and anesthesia, older patients are at increased risk of postoperative neurocognitive complications including delayed neurocognitive recovery (dNCR), which refers to new-onset cognitive decline within 30 days after surgery. Studies reported that the incidence of dNCR within 7 days ranges from 23.2% to 41.4% in older patients after non-cardiac surgery. Patients with dNCR tend to have prolonged hospital stay, impaired quality of life, and even increased long-term cognitive disorders, and thus imposing a heavy burden on patients, their families, and the healthcare system.

The occurrence of dNCR after surgery results from the combined effects of predisposing factors (e.g., advanced age, preoperative cognitive impairment, comorbidities, malnutrition) and precipitating factors (e.g., anesthetic management, surgical stress, residual drug effects, postoperative complications). Among modifiable precipitating factors, unintended intraoperative hypothermia (core temperature \<36 °C) is a common yet long underappreciated clinical issue. Due to prolonged operative duration, extensive body cavity exposure, and massive intraoperative fluid and blood transfusion, patients undergoing major cancer surgery have an incidence of intraoperative hypothermia between 57.1% and 78.6%.

Previous studies demonstrated that a core temperature below 35.5 °C is associated with multiple adverse events, including higher risks of intraoperative bleeding and blood transfusion and postoperative surgical site infections. The international multicenter randomized controlled PROTECT trial enrolled 5,056 patients over 45 years undergoing major non-cardiac surgery but found no significant differences in postoperative myocardial injury, surgical site infection, and blood loss between the routine management group (core temperature 35.5 °C) and the active warming group (core temperature 37 °C); these indicated that maintaining core temperature at 35.5 °C is safe with regard to these complications. However, neurocognitive function was not assessed in the PROTECT trial. Whether an intraoperative temperature of 35.5 °C is safe for the neurocognitive outcomes requires further investigation.

The pathogenesis of neurocognitive complications is complex, involving multiple pathological processes such as neuroinflammation, blood-brain barrier disruption, oxidative stress, and hippocampal neuronal injury. Perioperative hypothermia may trigger similar pathophysiological changes. Studies showed that hypothermia suppresses the immune function and promotes the release of peripheral pro-inflammatory cytokines including IL-6 and IL-1β, and thereby exacerbating central neuroinflammation, which is one of the core mechanisms underlying dNCR. Animal experiments demonstrated that hypothermia-induced cognitive dysfunction is associated with damage to hippocampal neurons and reduced expression of proteins related to synaptic plasticity. Furthermore, hypothermia impairs the metabolism of anesthetics and prolongs emergence time, which may contribute to the early manifestations of postoperative cognitive dysfunction.

There is still a lack of definitive evidence regarding whether intraoperative targeted temperature management can reduce dNCR in older patients undergoing major cancer surgery. Meanwhile, there remains debate over the hypothermia threshold and optimal target temperature range. We are currently conducting a multicenter randomized trial to verify whether intraoperative targeted temperature management (36.8 °C) reduces the incidence of delirium within 4 days in older patients after major cancer surgery. Based on patients enrolled at our institution, this study aims to verify whether intraoperative targeted temperature management (target core temperature: 36.8°C) compared with conventional temperature management (core temperature: 35.5°C) can reduce the incidence of delayed neurocognitive recovery in older patients undergoing major cancer surgery.

Вмешательства

• Другое Target temperature management
  Pre-warming will be performed with a full-body forced-air cover and/or an electrically heated blanket for about 30 minutes before induction of anesthesia. The warmer will initially be set to "high" which corresponds to about 43°C. It will be subsequently adjusted to make patients feel warm, but not uncomfortably so. All intravenous fluids and blood products administered intraoperatively will be pre-warmed, and fluid/blood warming devices will be used as clinically indicated. Two forced-air warmi
• Другое Routine thermal management
  Pre-warming will not be performed before induction of anesthesia and ambient intraoperative temperature will be maintained near 20°C per routine. Only blood products will be pre-warmed before transfusion. One forced-air warming blanket will be placed over the patient's upper or lower body, but warming will only be initiated when the core temperature drops below 35.5°C to prevent further temperature reduction. The target core temperature is set at 35.5°C.

Первичные конечные точки

• Incidence of delayed neurocognitive recovery (dNCR) [Срок оценки: At 5 days after surgery or before hospital discharge, whichever came first]

Вторичные конечные точки (2)

• Incidence of postoperative delirium [Срок оценки: Up to 4 days after surgery]
• Incidence of postoperative neurocognitive disorder [Срок оценки: At 30 days after surgery]

Критерии участия

Критерии включения

• Age ≥ 65 years.
• Planned potentially curative initial cancer surgery with an expected duration of 2 hours or longer under general anesthesia.

Критерии исключения

• Preoperative fever (tympanic temperature ≥ 38℃).
• Known or suspected preoperative infection.
• Previous schizophrenia, epilepsy, Parkinson's disease, myasthenia gravis, or preexisting delirium.
• Inability to communicate due to coma, severe dementia, or hearing or speech impairment.
• Critically ill patients, defined as NYHA functional class > III or LVEF < 30%, Child-Pugh class C, preoperative dialysis dependence, ASA physical status > IV, or expected survival < 24 hours.
• Surgery for breast cancer, intracranial tumors, or rare cancers.
• Planned to undergo therapeutic hypothermia.
• Body mass index > 30 kg/m² (to facilitate temperature management).
• Previous enrollment in this study.
• Other conditions deemed unsuitable for study participation.

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

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Профилактика

Центры проведения

Китай · 2 центра

• Peking University First Hospital — Пекин
• Peking University Shenzhen Hospital — Шэньчжэнь

Публикации

• Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivariate Behav Res. 2011 May;46(3):399-424. doi: 10.1080/00273171.2011.568786. Epub 2011 Jun 8. PMID 21818162
• Sessler DI. Perioperative thermoregulation and heat balance. Lancet. 2016 Jun 25;387(10038):2655-2664. doi: 10.1016/S0140-6736(15)00981-2. Epub 2016 Jan 8. PMID 26775126
• Sessler DI. Perianesthetic thermoregulation and heat balance in humans. FASEB J. 1993 May;7(8):638-44. doi: 10.1096/fasebj.7.8.8500688. PMID 8500688
• Katayama H, Kurokawa Y, Nakamura K, Ito H, Kanemitsu Y, Masuda N, Tsubosa Y, Satoh T, Yokomizo A, Fukuda H, Sasako M. Extended Clavien-Dindo classification of surgical complications: Japan Clinical Oncology Group postoperative complications criteria. Surg Today. 2016 Jun;46(6):668-85. doi: 10.1007/s00595-015-1236-x. Epub 2015 Aug 20. PMID 26289837
• Horn EP, Sessler DI, Standl T, Schroeder F, Bartz HJ, Beyer JC, Schulte am Esch J. Non-thermoregulatory shivering in patients recovering from isoflurane or desflurane anesthesia. Anesthesiology. 1998 Oct;89(4):878-86. doi: 10.1097/00000542-199810000-00012. PMID 9778005
• Kurz A, Sessler DI, Narzt E, Bekar A, Lenhardt R, Huemer G, Lackner F. Postoperative hemodynamic and thermoregulatory consequences of intraoperative core hypothermia. J Clin Anesth. 1995 Aug;7(5):359-66. doi: 10.1016/0952-8180(95)00028-g. PMID 7576669
• Shinall MC Jr, Arya S, Youk A, Varley P, Shah R, Massarweh NN, Shireman PK, Johanning JM, Brown AJ, Christie NA, Crist L, Curtin CM, Drolet BC, Dhupar R, Griffin J, Ibinson JW, Johnson JT, Kinney S, LaGrange C, Langerman A, Loyd GE, Mady LJ, Mott MP, Patri M, Siebler JC, Stimson CJ, Thorell WE, Vincent SA, Hall DE. Association of Preoperative Patient Frailty and Operative Stress With Postoperative PMID 31721994
• Rajek A, Greif R, Sessler DI, Baumgardner J, Laciny S, Bastanmehr H. Core cooling by central venous infusion of ice-cold (4 degrees C and 20 degrees C) fluid: isolation of core and peripheral thermal compartments. Anesthesiology. 2000 Sep;93(3):629-37. doi: 10.1097/00000542-200009000-00010. PMID 10969294

Идентификаторы

NCT: NCT07655687 · 2026R0324

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗