Design and Organization of the Dexamethasone, Light Anesthesia and Tight Glucose Control (DeLiT) Trial: a factorial trial evaluating the effects of corticosteroids, glucose control, and depth-of-anesthesia on perioperative inflammation and morbidity from major non-cardiac surgery

major perioperative morbidity in patients having major non-cardiac surgery is reduced by: 1) low-dose dexamethasone; 2) intensive intra-operative glucose control; and 3) lighter anesthesia.

each intervention reduces circulating concentrations of the inflammatory marker CRP; CRP concentration correlates with post-operative complications; anesthetic sensitivity predicts major and minor complications, including delirium. Other secondary hypotheses are that each intervention reduces minor surgical complications, reduces 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.

Patients scheduled for elective major non-cardiac surgeries at Cleveland Clinic will be evaluated during their preoperative anesthesia clinic visits:

Patients will be randomly assigned to each of the following interventions:

Randomization will be generated by a web-based system that will be accessed before anticipated induction of anesthesia, and will be stratified by history of diabetes.

Patients may be premedicated with intravenous midazolam. Prophylactic antibiotics will be given per surgical routine. General anesthesia will be induced with fentanyl and propofol. Tracheal intubation will be facilitated by succinylcholine or a non-depolarizing muscle relaxant. Additional non-depolarizing muscle relaxants will be given as necessary. Anesthesia will be maintained with sevoflurane in O₂ and air combined with a fentanyl infusion; anesthetic drugs will be managed based on the randomized strategy; that is a BIS near 35 or 55. The lungs will be mechanically ventilated to maintain end-tidal PCO₂ near 35 mmHg. Normothermia will be maintained with forced-air warming[37]. Blood pressure will be controlled to within a range of +20% to -30% of the preoperative baseline value. Heart rate will be controlled within a range of 40-90 beats/minute.

Red blood cell transfusions are immunosuppressive[38]. Red cell transfusions will thus be controlled by protocol. Target minimum hematocrits (HCT) will be determined based on the patient's cardiovascular status. The HCT will be maintained at 25-28% in patients without substantial cardiac disease, but maintained at 30% in those with significant cardiac disease, defined as previous myocardial infarction, angina, congestive heart failure, or cardiomyopathy.

We will record demographic data, ASA physical status, medical history, drug usage, preoperative hemoglobin and hematocrit, BUN and creatinine, electrolytes, and pre-operative electrocardiogram. A BIS sensor will be applied to the forehead before induction and connected to a BIS monitor. Anesthetic data will include: the volatile anesthetic dose in MAC-hours, as well as total doses of propofol and other sedative hypnotics. Distal esophageal temperature will be recorded. Blood loss will be estimated; urine output and fluid administration including allogenic blood will be recorded. Blood pressure and heart rate will be recorded. Automated intra-operative ST segment values will be recorded every 15 minutes. BIS values will be recorded electronically at one-minute intervals. Perioperative use of antibiotics and intraoperative vasoactive drugs will be recorded.

We will record the admission glucose concentration and at least hourly glucose concentrations during surgery and during the first two postoperative hours; the results of any additional glucose determinations throughout the hospital stay (obtained for clinical purposes) will also be recorded. We will use previously described methodologies to determine efficacy and safety of the insulin infusion protocols, including proportion of time spent within target range and number of hypoglycemic episodes (< 40 mg.dL^-1)[39]. We will also measure time-weighted average (TWA) glucose and time taken to achieve desired level of glucose control. We will compare our results to other published findings in similar trials; the closest to our trial is that of Gandhi et al who investigated almost the same targets in their randomized trial in cardiac surgery patients[32]. The time to PACU discharge will be recorded, along with days in the ICU if applicable, duration of postoperative mechanical ventilation in hours, total post-operative opioid use, and the duration of hospitalization in days. Blood for high-sensitivity CRP, creatinine phospho-kinase and cardiac troponin T measurements will be sampled at the time of induction, at post-operative day 1 and 2. A 12-lead electrocardiogram will be performed immediately post-operatively and the subsequent morning.

We will use the Confusion Assessment Method (CAM) as it is the most commonly used tool in the study of delirium. It is easily performed, has a sensitivity of 94% to 100% and a specificity of 90% to 95%[40]. Christensen's fatigue VAS [41] is one of the most widely used measures of postoperative fatigue. The test will be administered pre-operatively and on post-operative days 1 and 3. An increase of three or more units on the 10- point scale will be considered a clinically significant increase.

Our primary outcome is the occurrence of at least one major complication (Table 1) in a patient within the same hospitalization and 30-day mortality. Our composite is a minor modification of the composite outcome used by Brandstrup et al.[42] and Nisanevich et al.[43]. The use of a composite adverse outcome indicator rather than independently evaluating specific complications likely reduces the chance of Type 2 error. More importantly, using any single outcome may not capture the entire effect of any of our interventions or the complex disease processes. All analyses will be intention-to-treat.

The first stage of the study will be a traditional (i.e., non-adaptive) group sequential design[44, 45], where interim analyses for both efficacy and futility will be conducted after 25%, 50% and 75% of the patients have been enrolled, and at the end of planned enrollment, as needed. Interventions with either a large or very small treatment effect will likely cross boundaries for efficacy or futility, respectively, at one of the interim analyses, and be stopped early. By the final analysis (including a possible adaptive stage, as explained below), all of the interventions will have either crossed an efficacy or futility boundary.

We estimate that 25% of patients receiving no intervention (i.e., the control) will have at least one major complication. We further hypothesize that all interventions will not have the same effect and will power the study for a relative reduction of 40% or more for at least one intervention, and 20% and 10% versus respective controls for the other two. Our design will thus require a maximum of 970 total patients for the original group sequential portion of the study to have 90% power at the 0.05 significance level to detect a 40% reduction on the primary outcome for the most promising intervention.

The dose of steroids we have chosen may prove sub-optimal. Large-dose steroids have been shown to improve perioperative outcomes in patients undergoing cardiac or colorectal surgery[11, 14]. However, concerns were raised about the possibility of theoretical side effects of such a large dose. Subsequent work by Kilger and associates suggests that much smaller doses are also effective,[15] and are -- presumably -- considerably safer. The anti-inflammatory potency of the dose we have chosen is comparable to that used by Kilger, although, we used dexamethasone rather than hydrocortisone[49]. It is also in line with the study by Bisgaard et al. that resulted in significantly lower CRP levels and improved recovery parameters. There was no increase in wound infection or other adverse outcomes[16]. Steroid administration will start 1-2 hours before surgery because the effects of steroids are believed to be mediated by protein synthesis which usually takes an hour or two[50].

Patients will be randomized to either a tight glucose control group with a goal of 80-110 mg·dl^-1 or to a conventional care group with a goal of 180-200 mg·dl^-1. The lower range is that used by Van den Berghe et al, [28] and was shown to be beneficial in critical care patients. There were few complications associated with tight control in such a low range. The higher range essentially corresponds to current routine clinical practice. For example, a recent retrospective study showed that the rates of insulin treatment among academic anesthesiologists for glucose values < 140 mg·dl^-1, 140-200 mg·dl^-1, or > 200 mg·dl^-1 were 0.1%, 1.4%, and 11.9%, confirming that many anesthesiologists do not treat intraoperative glucose values less than 200 mg·dl^-1[51].

Clinicians and study coordinators will be blinded to dexamethasone treatment. But due to the nature of the interventions, clinicians will not be blinded to the randomization regarding level of glucose control and depth of anesthesia in any given patient. The data collectors for postoperative events will be blinded to all three interventions.

The DeLiT Trial is a multi-factorial randomized single-center trial of dexamethasone vs placebo, intraoperative tight vs. conventional glucose control, and light vs deep anesthesia in patients undergoing major non-cardiac surgery. The primary outcome is a composite of major post-operative morbidity including myocardial infarction, stroke, sepsis, and 30-day mortality. C-Reactive protein, a measure of the inflammatory response, will be evaluated as a secondary outcome. One-year all-cause mortality as well as post-operative delirium will be additional secondary outcomes. We will enroll up to 970 patients which will provide 90% power to detect a 40% reduction for the primary outcome, including three equally spaced interim analyses for efficacy and futility.