Impact of Anesthesia Maintenance Methods on Incidence of Postoperative Delirium

Study Overview
=================
Brief Summary
-----------------
Surgery is one of the major treatment methods for patients with malignant tumor. And, alone with ageing process, more and more elderly patients undergo surgery for malignant tumor. Evidence emerges that choice of anesthetics, i.e., either inhalational or intravenous anesthetics, may influence the outcome of elderly patients undergoing cancer surgery. Delirium is a commonly occurred early postoperative cognitive complication in the elderly, and its occurrence is associated with the worsening outcomes. Choice anesthetics may influence the occurrence of postoperative delirium. However, evidence in this aspect is conflicting.

Detailed Description
-----------------
It is estimated that 234.2 million major surgical procedures are undertaken every year worldwide. Surgery is one of the major treatment methods for patients with malignant tumor. And, alone with ageing process, more and more elderly patients undergo surgery for malignant tumor. Evidence emerges that choice of anesthetics, i.e., either inhalational or intravenous anesthetics, may influence the outcome of elderly patients undergoing cancer surgery. Delirium is a commonly occurred cognitive complication in elderly patients after surgery. The occurrence of delirium is associated with the worsening outcomes, including increased morbidity and mortality, prolonged hospital stay, elevated medical care cost, and declined cognitive function. High age, major surgery, and critical illness are major risk factors of postoperative delirium (POD). However, the relationship between use of general anesthetics and occurrence of delirium cannot be excluded. There are studies that compared the effects of two kinds of anesthetics on the cognitive outcomes after surgery. In the study of Nishikawa et al., 50 elderly (≥ 65 years) patients undergoing long-duration laparoscope-assisted surgery randomly received sevoflurane or propofol anesthesia. The results showed that, although the incidence of POD was not significantly different between the two groups, the delirium rating scale (DRS) score was significantly lower in the sevoflurane group than in the propofol group at postoperative days 2-3 (P = 0.007 and 0.002, respectively). In the study of Schoen et al., 128 patients undergoing on-pump cardiac surgery were randomized into two groups. The results showed that early postoperative cognitive function was significantly better in sevoflurane group than in the propofol group, especially in those who experienced cerebral desaturation during surgery. On the other hand, some studies reported contrary results. In a large sample size study of 2000 patients undergoing general anesthesia, patients carrying ApoE4 epsilon 4 allele were more likely to develop early postoperative cognitive decline after inhalational anesthesia (odd ratio 3.31, 95% confidence interval 1.25-6.39, P < 0.05), but not after intravenous anesthesia (odd ratio 0.93, 95% confidence interval 0.37-2.39, P > 0.05). In a randomized control trail of 44 patients undergoing carotid endarterectomy, the mini-mental state examination (MMSE) score was significantly higher, whereas blood S100B concentration was significantly lower in the propofol group than in the sevoflurane group at 24 hours after surgery. In the study of Tang et al., 200 elderly (≥ 60 years) patients with mild cognitive impairment who planned to undergo radical rectal resection randomly received either sevoflurane or propofol anesthesia. The results showed that, although there was no difference in the incidence of cognitive dysfunction at 7 days after surgery, the negative cognitive effects was more severe after sevoflurane anesthesia than after propofol anesthesia (P = 0.01). It seems that more evidence suggests the harmful cognitive effects of inhalational anesthetics. However, care must be taken when explaining these results: (1) target patients population were different; (2) sample size were small in the majority of studies; (3) the diagnostic criteria of cognitive complications were different, make it hard to do meta-analysis; (4) the clinical significance the of early postoperative cognitive complication remains to be elucidated.

Official Title
-----------------
Impact of Inhalational Versus Intravenous Anesthesia Maintenance Methods on Incidence of Postoperative Delirium in Elderly Patients After Cancer Surgery: An Open-label, Randomized Controlled Trial

Conditions
-----------------
Delirium, Postoperative Complications, Postoperative Cognitive Dysfunction

Intervention / Treatment
-----------------
* Drug: Sevoflurane
* Drug: Propofol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria Participants will be included if they meet all the following criteria: Age ≥ 65 years and < 90 years; Primary malignant tumor; Do not receive radiation therapy or chemotherapy before surgery; Scheduled to undergo surgery for the treatment of tumors, with an expected duration of 2 hours or more, under general anesthesia; Agree to participate, and give signed written informed consent. Exclusion criteria Patients will be excluded if they meet any of the following criteria: Preoperative history of schizophrenia, epilepsy, parkinsonism or myasthenia gravis; Inability to communicate in the preoperative period (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); Neurosurgery; Other reasons that are considered unsuitable for participation by the responsible surgeons or investigators (reasons must be recorded in the case report form).

Ages Eligible for Study
-----------------
Minimum Age: 65 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sevoflurane group<br>Sevoflurane will be administered by inhalation for anesthesia maintenance. The concentration of inhaled sevoflurane will be adjusted to maintain the bispectral index (BIS) value between 40 and 60. Analgesia will be supplemented with remifentanil (administered by continuous infusion), sufentanil (administered by intermittent injection/continuous infusion), or fentanyl (administered by intermittent injection). Towards the end of surgery, sevoflurane inhalational concentration will be decreased and fentanyl/sufentanil will be administered when necessary. Sevoflurane inhalation will be stopped at the end of surgery. | Drug: Sevoflurane<br>* Sevoflurane will be administered by inhalation for anesthesia maintenance. The concentration of inhaled sevoflurane will be adjusted to maintain the bispectral index (BIS) value between 40 and 60. Analgesia will be supplemented with remifentanil (administered by continuous infusion), sufentanil (administered by intermittent injection/continuous infusion), or fentanyl (administered by intermittent injection). Towards the end of surgery, sevoflurane inhalational concentration will be decreased and fentanyl/sufentanil will be administered when necessary. Sevoflurane inhalation will be stopped at the end of surgery.<br>* Other names: Sevoflurane for inhalation;|
| Experimental: Propofol group<br>Propofol will be administered by intravenous infusion for anesthesia maintenance. The infusion rate of propofol will be adjusted to maintain the BIS value between 40 and 60. Analgesia will be supplemented with remifentanil (administered by continuous infusion), sufentanil (administered by intermittent injection/continuous infusion), or fentanyl (administered by intermittent injection). Towards the end of surgery, propofol infusion rate will be decreased and fentanyl/sufentanil will be administered when necessary. Propofol infusion will be stopped at the end of surgery. | Drug: Propofol<br>* Propofol will be administered by intravenous infusion for anesthesia maintenance. The infusion rate of propofol will be adjusted to maintain the BIS value between 40 and 60. Analgesia will be supplemented with remifentanil (administered by continuous infusion), sufentanil (administered by intermittent injection/continuous infusion), or fentanyl (administered by intermittent injection). Towards the end of surgery, propofol infusion rate will be decreased and fentanyl/sufentanil will be administered when necessary. Propofol infusion will be stopped at the end of surgery.<br>* Other names: Propofol for injection;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of delirium within 7 days after surgery. | Delirium is assessed twice daily (8-10 AM and 6-8 PM) with the Confusion Assessment Method for patients without endotracheal intubation or the Confusion Assessment Method for the Intensive Care Unit for patients with endotracheal intubation. | Up to 7 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of intensive care unit (ICU) admission after surgery. | Percentage of intensive care unit (ICU) admission after surgery. | Within 24 hours after surgery. | 
| Percentage of ICU admission with endotracheal intubation after surgery. | Percentage of ICU admission with endotracheal intubation after surgery. | Within 24 hours after surgery. | 
| Length of stay in ICU after surgery. | Length of stay in ICU after surgery (in patients admitted to the ICU after surgery). | Up to 30 days after surgery. | 
| Length of stay in hospital after surgery. | Length of stay in hospital after surgery. | Up to 30 days after surgery. | 
| Incidence of non-delirium complications within 30 days. | Non-delirium complications are defined as newly occurred events other than delirium that are harmful to patients' recovery and required therapeutic intervention, i.e., grade 2 or higher on the Clavien-Dindo classification. | Up to 30 days after surgery. | 
| Cognitive function at 30 days after surgery. | Cognitive function assessed with Telephone Interview for Cognitive Status-Modified (TICS-m). | On the 30th day after surgery. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sevoflurane, Propofol, Aged, Neoplasm, Surgical Procedure, Operative, Delirium, Postoperative Complications, Postoperative Cognitive Dysfunction