The Effect of Desflurane Versus Sevoflurane Versus Propofol on Postoperative Delirium

Study Overview
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Brief Summary
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Patients over the age of 65 years are at increased risk for developing delirium after noncardiac surgeries, resulting in increased morbidity and mortality. The prevention of postoperative delirium has been classified as a public health priority. However, so far data regarding possible intraoperative interventions to reduce the incidence of postoperative delirium is very scarce. Due to the more rapid wash-in and wash-out times of desflurane as compared to sevoflurane or propofol it seems reasonable that desflurane might be beneficial for the prevention of postoperative delirium. Therefore, we evaluate the effect of maintenance of anesthesia using desflurane, sevoflurane or propofol on postoperative delirium in elderly patients undergoing moderate- to high-risk major noncardiac surgery.

Detailed Description
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Background: Postoperative delirium occurs in approximately 25% of patients over the age of 60 years undergoing major noncardiac surgery and is significantly associated with an increase in postoperative neurocognitive decline, morbidity, and mortality. The prevention of postoperative delirium has been classified as a public health priority. However, so far data regarding possible intraoperative interventions to reduce the incidence of postoperative delirium is very scarce. Previous small studies compared the effect of administration of sevoflurane versus propofol for maintenance of anesthesia on postoperative delirium and found beneficial effects of volatile anesthesia for the prevention of postoperative delirium. Furthermore, in small studies the administration of desflurane led to significantly shorter recovery periods after noncardiac surgery as compared to sevoflurane. Due to the more rapid wash-in and wash-out times of desflurane as compared to sevoflurane or propofol it seems reasonable that desflurane might be beneficial for the prevention of postoperative delirium. Therefore, we evaluate the effect of maintenance of anesthesia using desflurane, sevoflurane or propofol on postoperative delirium in elderly patients undergoing moderate- to high-risk major noncardiac surgery. Methods: We will include 1332 patients ≥ 65 years of age undergoing moderate- to high-risk major noncardiac surgery lasting at least two hours in this prospective observer-blinded randomized controlled clinical trial. After induction of anesthesia patients will be randomly assigned to receive desflurane, sevoflurane or propofol for maintenance of anesthesia. Our primary outcome will be the incidence of postoperative delirium in the first five postoperative days. Postoperative delirium will be diagnosed using the 3D-CAM or 3D-CAM-ICU in the morning and evening of the first five postoperative days as appropriate assessed by blinded study personnel. Two-interim analyses after 1/3 and 2/3 of recruitment are pre-planned. Statistics: The primary outcome, the incidence of postoperative delirium in the first five postoperative days, will be compared between the groups using a Chi-Square-test as well as a logistic regression model for the incidence of postoperative delirium will be performed accounting for randomized group, age and other possible confounding factors. Level of originality: Data regarding possible intraoperative interventions for the prevention of postoperative delirium are scarce. In detail, the effects of commonly used anesthetics on the incidence of postoperative delirium and neurocognitive dysfunction have only been studied in retrospective analyses or small prospective studies, which showed inconsistent results. Nevertheless, delirium is a major event after surgery and is associated with postoperative complications, worse neurocognitive recovery and increased mortality, especially in elderly patients. Thus, the results of this trial will help to choose the right anesthetic according to individual patients' requirements to reduce the risk for postoperative delirium in future.

Official Title
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The Effect of Desflurane Versus Sevoflurane Versus Propofol on Postoperative Delirium in Elderly Patients Undergoing Moderate- to High-risk Major Noncardiac Surgery - a Prospective, Observer-blinded, Randomized, Clinical Trial

Conditions
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Postoperative Delirium, Major Noncardiac Surgery, Postoperative Cognitive Dysfunction

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent ≥65 years of age Scheduled for elective major noncardiac surgery with estimated time of surgery ≥ 2 hours Exclusion Criteria: Patients undergoing emergency surgery BMI > 45 kg/m^2 History of diagnosed dementia Language, vision, or hearing impairments that may compromise cognitive assessments History of malignant hyperthermia History of structural muscle disease History of organ transplantation (kidney, liver, lung, heart) Patients undergoing hyperthermic intraperitoneal chemotherapy ICU patients undergoing surgery

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Desflurane Group<br>After induction of anesthesia, maintenance of anesthesia will be performed using goal-directed administration of desflurane with an intraoperative goal of bispectral index (BIS) 50±10. | Drug: Desflurane<br>* After induction of anesthesia, maintenance of anesthesia will be performed using goal-directed administration of desflurane with an intraoperative goal of bispectral index (BIS) 50±10.<br>|
| Active Comparator: Sevoflurane Group<br>After induction of anesthesia, maintenance of anesthesia will be performed using goal-directed administration of sevoflurane with an intraoperative goal of bispectral index (BIS) 50±10. | Drug: Sevoflurane<br>* After induction of anesthesia, maintenance of anesthesia will be performed using goal-directed administration of sevoflurane with an intraoperative goal of bispectral index (BIS) 50±10.<br>|
| Active Comparator: Propofol Group<br>After induction of anesthesia, maintenance of anesthesia will be performed using goal-directed administration of propofol with an intraoperative goal of bispectral index (BIS) 50±10. | Drug: Propofol<br>* After induction of anesthesia, maintenance of anesthesia will be performed using goal-directed administration of propofol with an intraoperative goal of bispectral index (BIS) 50±10.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of postoperative delirium | Delirium will be assessed via 3D-cognitive assessment method (3D-CAM) test as early in the morning as practical and in the early evening for the initial five postoperative days while the patients remain hospitalized according to current recommendations. In patients in the intensive care unit (ICU), we will perform the 3D-CAM-ICU. Any positive CAM test will be considered evidence of delirium, which will be analyzed dichotomously. | First five postoperative days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Digit Symbol-Substitution-Test for the incidence of postoperative cognitive dysfunction (POCD) | POCD will be assessed using the Digit-Symbol-Substitution-Test (DSST). The occurrence of POCD will be defined when a patient has a Z score on two or all tests or the combined Z score is below -1.96 standard deviation (SD). | First five postoperative days | 
| Trail Making Test (TMT) for the incidence of postoperative cognitive dysfunction (POCD) | POCD will be assessed using the Trail Making Test (TMT). The occurrence of POCD will be defined when a patient has a Z score on two or all tests or the combined Z score is below -1.96 standard deviation (SD). | First five postoperative days | 
| Postoperative need of supplemental oxygen | We will record postoperative need for administration of supplemental oxygen to maintain a SpO2 of 93% during PACU or ICU stay. | During PACU/ICU stay after surgery (max. of first 24 hours after surgery) | 
| Length of stay in ICU | Length of stay in ICU after surgery. | First 30 days after surgery | 
| Incidence of Postoperative nausea and vomiting in the early postoperative period | Episode of nausea and/or vomiting within the first two hours after surgery | First two hours after surgery | 
| Incidence of Postoperative nausea and vomiting in the late postoperative period | Episode of nausea and/or vomiting from two hours after surgery until the fifth postoperative day. | First five postoperative days | 
| Intraoperative hypotension | Intraoperative duration of mean arterial pressure <65mmHg and overall amount of intraoperatively administered catecholamines (including phenylephrine, norepinephrine, epinephrine, etilefrine, ephedrine). | During surgery | 
| Death within 5 days after surgery | Mortality in the first five postoperative days. | First five postoperative days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Propofol, Sevoflurane, Desflurane