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))

Not Applicable

Terminated

Conditions: Inflammation
Perioperative Morbidity

Interventions: Drug: Dexamethasone Sodium Sulfate
Drug: Insulin
Drug: anesthesia management
Other: Anesthesia management -Placebo
Other: Insulin - Placebo
Other: Dexamethasone - placebo

Registration Number: NCT00995501

Lead Sponsor: d sessler

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 381

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Intensive Glucose Control, placebo, Light anesthesia	Dexamethasone Sodium Sulfate	* 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
Intensive Glucose Control, Dexamethasone, light anesthesia	Dexamethasone Sodium Sulfate	* 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
Intensive Glucose Control, Dexamethasone, light anesthesia	anesthesia management	* 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
Intensive Glucose Control, Dexamethasone, Deep anesthesia	Insulin	* 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
Intensive Glucose Control, Dexamethasone, Deep anesthesia	Anesthesia management -Placebo	* 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
Intensive Glucose Control, placebo, Light anesthesia	anesthesia management	* 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
Intensive Glucose Control, placebo, Light anesthesia	Insulin - Placebo	* 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
Conventional Glucose Control, Dexamethasone, Light anesthesia	anesthesia management	* 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
Conventional Glucose Control, Dexamethasone, Light anesthesia	Dexamethasone - placebo	* 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
Intensive Glucose Control, Dexamethasone, Deep anesthesia	Dexamethasone Sodium Sulfate	* 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
Intensive Glucose Control, Placebo, Deep anesthesia	Dexamethasone Sodium Sulfate	* 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
Intensive Glucose Control, Placebo, Deep anesthesia	Insulin - Placebo	* 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
Intensive Glucose Control, Placebo, Deep anesthesia	Anesthesia management -Placebo	* 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
Conventional Glucose Control, Dexamethasone, Deep anesthesia	Insulin	* 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
Conventional Glucose Control, Dexamethasone, Deep anesthesia	Dexamethasone - placebo	* 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
Conventional Glucose Control, Dexamethasone, Deep anesthesia	Anesthesia management -Placebo	* 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
Conventional Glucose Control, Placebo, Light anesthesia	anesthesia management	* 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
Conventional Glucose Control, Placebo, Light anesthesia	Dexamethasone - placebo	* 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
Conventional Glucose Control, Placebo, Light anesthesia	Insulin - Placebo	* 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
Conventional Glucose Control, Placebo, Deep anesthesia	Dexamethasone - placebo	* 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
Conventional Glucose Control, Placebo, Deep anesthesia	Insulin - Placebo	* 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
Conventional Glucose Control, Placebo, Deep anesthesia	Anesthesia management -Placebo	* 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
Intensive Glucose Control, Dexamethasone, light anesthesia	Insulin	* 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
Conventional Glucose Control, Dexamethasone, Light anesthesia	Insulin	* 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

Primary Outcome Measures

Name	Time	Method
Major Perioperative Morbidity	30 day after surgery	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.

Secondary Outcome Measures