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

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.

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.

Eligibility Criteria:
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.