Effects of Intraoperative Targeted Temperature Management on Incidence of Postoperative Delirium and Long-term Survival

Delirium Clinical Trial

Official title:

Effects of Intraoperative Targeted Temperature Management on Incidence of Postoperative Delirium and Long-term Survival in Older Patients Having Major Cancer Surgery: A Multicenter Randomized Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06256354
• Other study ID #: 2024-185
• Status: Not yet recruiting
• Phase: N/A
• Start date: April 2024
• Est. completion date: January 2030

Study information

• Verified date: April 2024
• Source: Peking University First Hospital
• Contact: Dong-Xin Wang, MD, PhD
• Phone: 8610 83572784
• Email: wangdongxin[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Intraoperative hypothermia is common in patients having major surgery and the compliance with intraoperative temperature monitoring and management remains poor. Studies suggest that intraoperative hypothermia is an important risk factor of postoperative delirium, which is associated with worse early and long-term outcomes. Furthermore, perioperative hypothermia increases stress responses and provokes immune suppression, which might promote cancer recurrence and metastasis. In a recent trial, targeted temperature management reduced intraoperative hypothermia and emergence delirium. There was also a trend of reduced postoperative delirium, although not statistically significant. This trial is designed to test the hypothesis that intraoperative targeted temperature management may reduce postoperative delirium and improves progression-free survival in older patients recovering from major cancer surgery.

Description:

Perioperative hypothermia results from anesthetic-impaired thermoregulatory responses combined with cool operating rooms and exposed body cavities. Core temperatures <35.5°C increases perioperative blood loss, delays post anesthetic recovery, and increases surgical wound infections. Despite guideline recommendations, compliance with intraoperative temperature monitoring and management remains poor. In a national survey published in 2017, intraoperative hypothermia (core temperature <36.0°C) occurred in 44% of patients having elective surgery with general anesthesia. According to a survey of anesthesiologists in six Asia-Pacific countries (Singapore, Malaysia, Philippines, Thailand, India, and South Korea), only 67% of respondents measured temperature intraoperatively during general anesthesia, and only 44% report intraoperative active warming and warming was ineffective in more than half of their patients. Perioperative hypothermia thus remains common. The 5,056-patient PROTECT trial showed that myocardial injury, surgical site infections, and blood loss were similar in patients randomized to intraoperative core temperatures of 35.5 or 37°C. However, there are other important complications that may be caused by intraoperative hypothermia including delirium, cancer recurrence, shivering, and thermal discomfort. Perioperative neurocognitive disorders (NCDs), especially postoperative delirium and postoperative cognitive dysfunction (POCD), are significant challenges to older patients scheduled for surgery. Delirium is a syndrome of acutely occurring and fluctuating changes in attention, level of consciousness, and cognitive function. Postoperative cognitive dysfunction refers to cognitive decline (including the ability of study, memory, action, and judgement) detected from 30 days to 12 months after surgery. In patients aged 60 years or above, the incidence of postoperative delirium is about 12-24%. The incidence of POCD is about 7-12% at 3-month follow-up and is associated with delirium, although the relationship is probably not causal. Delirium and POCD are associated with worse perioperative outcomes including prolonged hospitalization, increased complications, and high mortality, and worse long-term outcomes including shortened overall survival, as well as increased dementia and lowered life quality. Postoperative delirium and POCD are multifactorial. Predisposing factors include advanced age, lower educational level, cognitive impairment, comorbidities (e.g., cerebrovascular disease, diabetes, and kidney disease), alcohol abuse, and malnutrition. Precipitating factors include deep anesthesia, opioid use, benzodiazepines, intraoperative blood loss/blood transfusion, and severe pain. Hypothermia may also increase the risk of delirium. Hypothermia provokes both autonomic and behavioral protective responses. The first autonomic response is arterio-venous shunt constriction. Thermoregulatory vasoconstriction occurs many times a day in a typical hospital environment. It is highly effective, but does not usually disturb people and is generally considered to be of little consequence. Shivering is the other primary autonomic thermoregulatory defense against cold and has a triggering threshold about 1°C below the core temperature that triggers vasoconstriction. Unlike vasoconstriction, shivering is uncomfortable for patients. Furthermore, it is accompanied by a tripling of catecholamine concentrations, hypertension, and tachycardia. Behavioral thermoregulatory defenses are mediated by thermal comfort, and provoke voluntary defensive measures such as putting on a sweater, open windows, etc. Behavioral defenses include air conditioning and building shelters and are thus far stronger than autonomic responses. Thermal comfort matters to patients and is thus worth evaluating. Despite advances in surgery and oncology, postoperative survival decreases about 10% per year, mainly due to cancer recurrence. The development of cancer recurrence mainly depends on the balance between the invasive ability of residual cancer cells and the anti-cancer immune function. Perioperative hypothermia increases stress responses and provokes immune suppression. The investigators therefore propose to determine whether intraoperative targeted temperature management decreases the incidence of delirium, improves thermal comfort, reduces postoperative shivering, and improves long-term survival in older patients recovering from major cancer surgery. Specifically, the investigators will test the primary short-term hypothesis that perioperative normothermia (core temperature near 36.8°C) reduces delirium over the initial 4 postoperative days. Secondary short-term hypotheses are that perioperative normothermia improves thermal comfort, reduces shivering, and reduces delayed neurocognitive recovery. The primary long-term hypothesis is that perioperative normothermia improves progression-free survival.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 3992
• Est. completion date: January 2030
• Est. primary completion date: February 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years and older

Eligibility

Inclusion Criteria:

1. Age =65 years.

2. Planned potentially curative initial cancer surgery with an expected duration of 2 hours or longer under general anesthesia.

Exclusion Criteria:

1. Preoperative fever (tympanic temperature =38?).

2. Known or suspected preoperative infection.

3. Previous history of schizophrenia, epilepsy, Parkinson disease, myasthenia gravis, or delirium.

4. Unable to communicate due to severe dementia, language barrier, or coma.

5. Critically ill (Left ventricular ejection fraction <30%, Child-Pugh grades C, requirement of renal replacement therapy, American Society of Anesthesiologists physical status>IV, or expected survival <24 hours).

6. Scheduled surgery for breast cancer, intracranial tumors, or rare cancers.

7. Planned to undergo therapeutic hypothermia.

8. Body mass index >30 kg/m2.

9. Have participated in this study previously.

10. Any other conditions that are considered unsuitable for study participation.

Related Conditions & MeSH terms

• Delirium
• Emergence Delirium
• Hypothermia
• Long-term Survivors

Intervention

Other:
• Routine thermal management
Patients assigned to routine thermal management will not be pre-warmed and ambient intraoperative temperature will be maintained near 20°C per routine. Only transfused blood will be warmed. An upper- or lower-body forced-air cover will be positioned over an appropriate non-operative site but will not initially be activated. Should core temperature decrease to 35.5°C, the warmer will be activated as necessary to prevent core temperature from decreasing further. The target nasopharyngeal temperature is 35.5°C.
• Target temperature management
Pre-warming is performed with a full-body forced-air cover and 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. Patients will be warmed during surgery using two forced-air covers or combining forced-air covers with electric heating blanket when clinically practical. All intravenous fluids will be warmed to body temperature. There is no need to control ambient temperature since ambient temperature has little effect on core temperature in patients warmed with forced air. The target nasopharyngeal temperature is 36.8?.

Locations

Country	Name	City	State
China	Dongzhimen Hospital Beijing University of Chinese Medicine	Beijing	Beijing
China	Guang'anmen Hospital China Academy of Chinese Medical Sciences	Beijing	Beijing
China	Peking Union Medical College Hospital	Beijing	Beijing
China	Xiyuan Hospital of CACMS(China Academy of Chinese Medical Sciences	Beijing	Beijing
China	Sichuan Provincial People's Hospital	Chendu	Sichuan
China	The First Affiliated Hospital of Chengdu Medical College	Chendu	Sichuan
China	Chengdu Seventh People's Hospital	Chengdu	Sichuan
China	Sichuan Cancer Hospital	Chengdu	Sichuan
China	The Pepple's Hospital of Chizhou	Chizhou	Anhui
China	The First Affiliated Hospital of Chongqing Medical University	Chongqing	Chongqing
China	Jiangyin People's Hospital	Jiangyin	Jiangsu
China	The First Affiliated Hospital Of Shandong First Medical University	Jinan	Shandong
China	The Pepple's Hospital of Liaocheng	Liaocheng	Shandong
China	Jiangsu Province Hospital	Nanjing	Jiangsu
China	Peking University Shenzhen Hospital	Shenzhen	Guangdong
China	The Fourth Hospital of Hebei Medical University (Hebei Tumor Hospital)	Shijia Zhuang	Hebei
China	The People's Hospital of Wuxi	Wuxi	Jiangsu
China	Xijing Hospital, Fourth Military Medical University	Xi'an	Shanxi
China	Henan Provincial People's Hospital	Zhengzhou	Henan
China	The First Affiliated Hospital Of Zhengzhou University	Zhengzhou	Henan

Sponsors (2)

Lead Sponsor	Collaborator
Peking University First Hospital	Peking University

Country where clinical trial is conducted

China, 

References & Publications (53)

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* Note: There are 53 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of emergence delirium	Patients are firstly be evaluated with the Richmond Agitation-Sedation Scale (RASS; scores range from -5 [unarousable] to +4 [combative] and 0 indicates alert and calm). Patients will then be evaluated with the Confusion Assessment Method for the Intensive Care Unit. For patients who are extubated in the operation room, evaluation is conducted at 5 and 30 minutes after arriving post-anesthesia care unit (PACU)/intensive care unit (ICU). For patients who are admitted to PACU/ICU with endotracheal intubation, evaluation is conducted at 5 and 30 minutes after extubation.	Up to 30 minutes after arriving PACU/ICU or after extubation.
Other	Length of stay in post-anesthesia care unit (PACU)	Length of stay in post-anesthesia care unit (PACU)	Up to 24 hours after surgery.
Other	Change of blood hemoglobin in the first postoperative day	Blood hemoglobin in the first postoperative day minus preoperative value.	Up to 24 hours after surgery.
Other	Quality of recovery in the first postoperative day	Quality of recovery is assessed with the Quality of Recovery-15 questionaire in the first postoperative day.	Up to 24 hours after surgery.
Other	Proportion of patients requiring blood transfusion	Proportion of patients who required blood transfusion during the first 4 days after surgery.	Up to 4 days after surgery.
Other	Length of stay in hospital after surgery	Length of stay in hospital after surgery.	Up to 30 days after surgery.
Other	Incidence of surgical site infections with 30 days after surgery	The surgical site infection includes superficial, deep, and organ-space surgical site infections. The definitions were modified from "Guideline for prevention of surgical site infection, 1999" (https://stacks.cdc.gov/view/cdc/7160).	Up to 30 days after surgery.
Other	Incidence of non-delirium major complications within 30 days after surgery.	Non-delirium major complications are defined as new-onset medical events other than delirium that are deemed harmful and require therapeutic intervention, that is grade II or higher on the Clavien-Dindo classification.	Up to 30 days after surgery
Other	All-cause 30-day mortality	All-cause 30-day mortality	Up to 30 days after surgery.
Other	Overall survival after surgery	Time interval from index surgery to all-cause death.	Up to 2 years after surgery of the last enrolled patient.
Other	Cancer-specific survival after surgery	Time interval from index surgery to cancer-specific death, with deaths from other causes being censored at the time of death. Cancer-specific death is defined as death fully attributable to the cancer for which the index surgery is performed and usually involves cancer recurrence/metastasis/progression after exclusion of other causes such as stroke and myocardial infarction.	Up to 2 years after surgery of the last enrolled patient.
Other	Event-free survival after surgery	Time interval from index surgery to cancer recurrence/metastasis/progression, new-onset cancer, new-onset serious illness (requiring hospitalization), or all-cause death, whichever comes first.	Up to 2 years after surgery of the last enrolled patient.
Primary	Incidence of delirium within 4 days after surgery	Occurrence of delirium during the first four postoperative days is assessed with the 3D-Confusion Assessment Method or Confusion Assessment Method for the Intensive Care Unit (for intubated patients) twice daily (8-10 am and 6-8 pm). Immediately before assessing delirium, sedation or agitation is assessed with the Richmond Agitation-Sedation Scale (RASS; scores range from -5 [unarousable] to +4 [combative] and 0 indicates alert and calm). Deeply sedated or unarousable patients (RASS -4 or -5) is recorded as comatose and not assessed for delirium.	During the first four days after surgery.
Primary	Progression-free survival after surgery	Time interval from index surgery to cancer recurrence/metastasis/progression or all-cause death, whichever comes first.	Up to 2 years after surgery of the last enrolled patient.
Secondary	Postoperative thermal comfort	Postoperative thermal comfort is evaluated with the Numerical Rating Scale (NRS; an 11-point scale where 0=intense cold, 5=thermal comfort, and 10=intense warm). For patients who are extubated in the operation room, evaluation is conducted at 5 and 30 minutes after arriving post-anesthesia care unit (PACU)/intensive care unit (ICU). For patients who are admitted to PACU/ICU with endotracheal intubation, evaluation is conducted at 5 and 30 minutes after extubation.	Up to 30 minutes after arriving PACU/ICU or after extubation.
Secondary	Postoperative shivering intensity	Postoperative shivering intensity is evaluated with a four-point scale (0=no shivering, 1=intermittent, mild shivering, 2=moderate shivering, and 3=persistent, intense shivering). For patients who are extubated in the operation room, evaluation is conducted at 5 and 30 minutes after arriving post-anesthesia care unit (PACU)/intensive care unit (ICU). For patients who are admitted to PACU/ICU with endotracheal intubation, evaluation is conducted at 5 and 30 minutes after extubation.	Up to 30 minutes after arriving PACU/ICU or after extubation.
Secondary	Incidence of delayed neurocognitive recovery	Cognitive function will be assessed with the Telephone Montreal Cognitive Assessment (T-MoCA; scores range from 0 to 22, with higher score indicating better function) before surgery and at 30 days after surgery. A T-MoCA score reduction of 1 standard deviation (SD) or more from baseline will be considered the occurrence of delayed neurocognitive recovery.	At 30 days after surgery.
Secondary	Incidence of postoperative neurocognitive disorders	Cognitive function will be assessed with the Telephone Montreal Cognitive Assessment (T-MoCA; scores range from 0 to 22, with higher score indicating better function) before surgery and at 6 months and 12 months after surgery. A T-MoCA score reduction of 1 standard deviation (SD) or more from baseline will be considered as the occurrence of postoperative neurocognitive disorders.	At 6 months and 12 months after surgery.