The Effects of Corticosteroids, Glucose Control, and Depth-of-Anesthesia on Perioperative Inflammation and Morbidity From Major Non-cardiac Surgery (Dexamethasone, Light Anesthesia and Tight Glucose Control (DeLiT Trial))

Study Overview
=================
Brief Summary
-----------------
Evidence thus suggests that steroid administration, tight glucose control, and avoidance of deep anesthesia may decrease perioperative morbidity by reducing the inflammatory response to surgery. Using a three-way factorial approach, the investigators thus propose to test the primary hypotheses that major perioperative morbidity is reduced by: 1) low-dose dexamethasone; 2) intensive perioperative glucose control; and 3) lighter anesthesia. Secondary hypotheses include that each intervention reduces circulating concentrations of the inflammatory marker CRP, and that there is a correlation between C-reactive protein (CRP) and post-operative complications. Anesthetic sensitivity predicts major and minor complications, and delirium Other secondary hypotheses are that each intervention, reduces minor surgical complications, reduces postoperative nausea and vomiting (PONV), reduces postoperative delirium, speeds hospital discharge, improves quality of life (SF-12v2 Health Survey, Christensen's VAS fatigue score), and reduces all-cause one-year mortality.

Detailed Description
-----------------
The perioperative period is characterized by an intense inflammatory response marked by elevated concentrations of inflammatory markers like C-Reactive Protein (CRP). This response has been linked to increased perioperative morbidity and mortality. Available evidence suggests that blunting the inflammatory response to surgical trauma might improve perioperative outcomes. The putative benefits from blunting the surgical stress response are likely to be greatest in high-risk patients such as those having major non-cardiac surgery. We will study three interventions potentially modulating perioperative inflammation, corticosteroids, tight glucose control and light anesthesia and their effects on major morbidity and mortality resulting from major non-cardiac surgery. Steroids are the most powerful routinely available anti-inflammatory drugs. They decrease perioperative concentrations of inflammatory markers and improve outcomes after cardiac and abdominal surgery. Poorly controlled blood glucose worsens the inflammatory response to surgery. Hyperglycemia impairs wound healing, increases infection risk, increases overall hospital mortality, increases the risk of perioperative renal failure, and augments transfusion requirements. Treatment of hyperglycemia has been shown to improve outcomes and decrease mortality in cardiac patients. Also in critically ill patients, it decreased inflammatory markers, overall hospital mortality by 34%, blood stream infections by 46%, and acute renal failure by 41%. Cumulative deep hypnotic time is associated with increased one-year all-cause mortality, possibly through aggravation of the inflammatory response to surgery. In contrast, avoidance of deep anesthesia appears to reduce postoperative CRP levels, the risk of nausea and vomiting, as well as postoperative hemodynamic, respiratory and infectious complications. Evidence thus suggests that steroid administration, tight glucose control, and avoidance of deep anesthesia may decrease perioperative morbidity by reducing the inflammatory response to surgery. Using a three-way factorial approach, we thus propose to test the primary hypotheses that major perioperative morbidity is reduced by: 1) low-dose dexamethasone; 2) intensive perioperative glucose control; and, 3) lighter anesthesia. Secondary hypotheses include that each intervention reduces circulating concentrations of the inflammatory marker CRP, and that there is a correlation between CRP and post-operative complications. Anesthetic sensitivity predicts major and minor complications, and delirium Other secondary hypotheses are that each intervention, reduces minor surgical complications, reduces postoperative nausea and vomiting (PONV), reduces postoperative delirium, speeds hospital discharge, improves quality of life (SF-12v2 Health Survey, Christensen's VAS fatigue score), and reduces all-cause one-year mortality.

Official Title
-----------------
The Effects of Corticosteroids, Glucose Control, and Depth-of-Anesthesia on Perioperative Inflammation and Morbidity From Major Non-cardiac Surgery (Dexamethasone, Light Anesthesia and Tight Glucose Control (DeLiT Trial))

Conditions
-----------------
Inflammation, Perioperative Morbidity

Intervention / Treatment
-----------------
* Drug: Dexamethasone Sodium Sulfate
* Drug: Insulin
* Drug: anesthesia management
* Other: Dexamethasone - placebo
* Other: Insulin - Placebo
* Other: Anesthesia management -Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥40 years old. Major non-cardiac surgical procedures scheduled to take ≥ two hours done under general anesthesia. Written informed consent Exclusion Criteria: Recent intravenous or oral steroid therapy (within 30 days); inhaled steroids are permitted Any contraindications to the proposed interventions ASA Physical Status > 4 Non English speaking patients Procedures done under regional anesthesia

Ages Eligible for Study
-----------------
Minimum Age: 40 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: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intensive Glucose Control, Dexamethasone, light anesthesia<br>Intensive Glucose Control The target range for blood glucose will be 80-110 mg/dl Dexamethasone Dexamethasone administered at 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning. Light anesthesia target BIS of 55 | Drug: Dexamethasone Sodium Sulfate<br>* 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning<br>Drug: Insulin<br>* Insulin to maintain blood glucose 80-110 mg/dl.<br>Drug: anesthesia management<br>* Light anesthesia to maintain BIS about 55<br>|
| Active Comparator: Intensive Glucose Control, Dexamethasone, Deep anesthesia<br>Intensive Glucose Control The target range for blood glucose will be 80-110 mg/dl Dexamethasone Dexamethasone administered at 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning. Deep anesthesia target BIS of 35 | Drug: Dexamethasone Sodium Sulfate<br>* 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning<br>Drug: Insulin<br>* Insulin to maintain blood glucose 80-110 mg/dl.<br>Other: Anesthesia management -Placebo<br>* Deep anesthesia to maintain BIS about 35<br>|
| Active Comparator: Intensive Glucose Control, placebo, Light anesthesia<br>Intensive Glucose Control The target range for blood glucose will be 80-110 mg/dl Placebo Placebo administered at 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning. Light anesthesia target BIS of 55 | Drug: Dexamethasone Sodium Sulfate<br>* 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning<br>Drug: anesthesia management<br>* Light anesthesia to maintain BIS about 55<br>Other: Insulin - Placebo<br>* Insulin to maintain blood glucose 180-200 mg/dl.<br>|
| Active Comparator: Conventional Glucose Control, Dexamethasone, Light anesthesia<br>Conventional Glucose Control The target range for blood glucose will be 180-200 mg/dl Dexamethasone Dexamethasone administered at 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning. Light anesthesia target BIS of 55 | Drug: Insulin<br>* Insulin to maintain blood glucose 80-110 mg/dl.<br>Drug: anesthesia management<br>* Light anesthesia to maintain BIS about 55<br>Other: Dexamethasone - placebo<br>* 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning<br>|
| Active Comparator: Intensive Glucose Control, Placebo, Deep anesthesia<br>Intensive Glucose Control The target range for blood glucose will be 80-110 mg/dl Placebo Placebo administered at 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning. Deep anesthesia target BIS of 35 | Drug: Dexamethasone Sodium Sulfate<br>* 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning<br>Other: Insulin - Placebo<br>* Insulin to maintain blood glucose 180-200 mg/dl.<br>Other: Anesthesia management -Placebo<br>* Deep anesthesia to maintain BIS about 35<br>|
| Active Comparator: Conventional Glucose Control, Dexamethasone, Deep anesthesia<br>Conventional Glucose Control The target range for blood glucose will be 180-200 mg/dl Dexamethasone Dexamethasone administered at 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning. Deep anesthesia target BIS of 35 | Drug: Insulin<br>* Insulin to maintain blood glucose 80-110 mg/dl.<br>Other: Dexamethasone - placebo<br>* 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning<br>Other: Anesthesia management -Placebo<br>* Deep anesthesia to maintain BIS about 35<br>|
| Active Comparator: Conventional Glucose Control, Placebo, Light anesthesia<br>Conventional Glucose Control The target range for blood glucose will be 180-200 mg/dl Placebo Placebo administered at 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning. Light anesthesia target BIS of 55 | Drug: anesthesia management<br>* Light anesthesia to maintain BIS about 55<br>Other: Dexamethasone - placebo<br>* 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning<br>Other: Insulin - Placebo<br>* Insulin to maintain blood glucose 180-200 mg/dl.<br>|
| Placebo Comparator: Conventional Glucose Control, Placebo, Deep anesthesia<br>Conventional Glucose Control The target range for blood glucose will be 180-200 mg/dl Placebo Placebo administered at 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning. Deep anesthesia target BIS of 35 | Other: Dexamethasone - placebo<br>* 8 mg given 1-2 hours before surgery (incision time), 4 mg on the first postoperative morning, and 2 mg on the second postoperative morning<br>Other: Insulin - Placebo<br>* Insulin to maintain blood glucose 180-200 mg/dl.<br>Other: Anesthesia management -Placebo<br>* Deep anesthesia to maintain BIS about 35<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Perioperative Morbidity | Our primary outcome was a collapsed composite endpoint (any versus none) defined as the occurrence of at least one of sixteen major complications before hospital discharge, including sepsis, severe surgical site infection, myocardial infarction, heart failure, stroke, unstable ventricular arrhythmias, pulmonary embolism, pneumonia, respiratory failure, dialysis dependent renal failure, large pleural or peritoneal effusions, major bleeding, major wound and surgical site healing complications, vascular graft thrombosis, and 30-day mortality. | 30 day after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1 Year Mortality | All-cause mortality | 1 year after surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
a, steroid administration, tight glucose control, light anesthesiReducing inflammatory response to surgical stress