Study author	Duncan 2018
Brief name	Intraoperative hyperinsulinaemic normoglycaemia or standard glycaemic management
Recipient	Patients undergoing cardiac surgery
Why	Previous studies have demonstrated that hyperglycaemia is associated with mortality and morbidity in critically ill patients undergoing cardiac surgery. This study determined whether hyperinsulinaemic normoglycaemia reduces 30‐day mortality and morbidity after cardiac surgery.
What (materials)	Accu‐Check (Roche Diagnostics, Switzerland) glucose monitor Insulin therapy protocol (Cleveland clinic operating room): Appendix 1
What (procedures)	Intraoperative glycaemic management with hyperinsulinaemic normoglycaemia, a fixed high‐dose insulin and concomitant variable glucose infusion titrated to glucose concentrations of 80 mg/dL to 100 mg/dL; or standard glycaemic management, low‐dose insulin infusion targeting glucose greater than 150 mg/dL
Who provided	Research personnel (specific training not reported)
How (mode of delivery; individual or group)	Individual, face to face
Where	Operating room. Intensive care unit (upon intensive care unit admission, both groups transitioned to the same standardised postoperative insulin treatment protocol)
When and how much	I: a fixed‐dose insulin infusion of 5 mU/kg/min with a concomitant variable glucose (dextrose 20%) infusion supplemented with potassium (40 mEq/L) and phosphate (30 mmol/L) The glucose infusion was initiated at approximately 40 to 60 mL/hr – when serum glucose concentration was approximately 110 mg/dL or less, and manually titrated to target glucose concentrations of 80 to 110 mg/dL every 10 to 15 min throughout surgery. Additional boluses of insulin were given for blood glucose greater than 110 mg/dL. At sternal closure, the insulin infusion was reduced to 1 mU/kg/min and converted to a standard low‐dose insulin infusion upon intensive care unit admission. After intensive care unit arrival, the glucose infusion was decreased by 25% to 50% every 20 min when the blood glucose was greater than 110 mg/dL. When the infusion was at 20 mL/h or less and blood glucose was greater than 110 mg/dL, the infusion was discontinued. Blood glucose concentrations were followed for 45 to 60 minutes after discontinuation of the dextrose infusion to ensure that hypoglycaemia was avoided. C: a conventional low‐dose insulin infusion titrated to blood glucose concentrations measured by arterial blood gas analysis every 30 to 90 min throughout surgery. This low‐dose insulin infusion was initiated for blood glucose concentration greater than 120 mg/dL before initiation of cardiopulmonary bypass or greater than 150 mg/dL during or after cardiopulmonary bypass, at a rate based on patient weight and current glucose concentration. Subsequent adjustments were based on a sliding scale of current blood glucose concentration and the change from the previous measurement. Supplemental boluses of insulin were given with acute increases (greater than 30 mg/dL) in blood glucose. The insulin protocol for patients assigned to standard glucose management is listed in appendix 1. Upon intensive care unit admission, both groups transitioned to the same standardised postoperative insulin treatment protocol in the intensive care unit.
Tailoring	The intervention was titrated I: manually titrated to target glucose concentrations of 80 mg/dL to 110 mg/dL every 10‐15 min throughout surgery C: titrated to blood glucose concentrations every 30 to 90 min throughout surgery. Low‐dose insulin infusion was initiated for blood glucose concentrations greater than 120 mg/dL before initiation of cardiopulmonary bypass or greater than 150 mg/dL during or after cardiopulmonar bypass
Modification of intervention throughout the trial	The intervention was not modified during the course of the study
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Study author	Wallia 2017
Brief name	Glycaemic control reduces infections in post‐liver transplant patients
Recipient	Post liver transplant patients
Why	Clinical trials have shown morbidity and mortality benefits from intensive inpatient hyperglycaemia management. Very few studies have been performed that evaluate the relationship of glucose levels to outcomes in patients undergoing solid organ transplantation.
What (materials)	Insulin infusion according to the Northwestern protocol adjusted if needed. Discharge instructions for patients, which included details regarding home self‐blood glucose monitoring.
What (procedures)	Surgical ICU stay: the patients were seen daily by a member of the GMS, and the glucose levels were reviewed at least daily to assess whether insulin protocol adjustments were needed. Hospital stay: the insulin doses were adjusted daily by the GMS team to maintain the premeal glucose levels as close as possible to the respective target of 140 mg/dL and 180 mg/dL. Discharge from hospital: patient's primary care physician, in consultation with the transplantation service and the GMS, generally managed the hyperglycaemia in the first month. This subsequent posthospital care and glycaemic target were at the discretion of these healthcare providers and were not be governed by the in‐hospital protocol.
Who provided	The glucose management service team (GMS): experienced nurse practitioners and endocrinologist Experienced transplant ICU and floor nurses
How (mode of delivery; individual or group)	Individual, face to face
Where	Surgical intensive care unit (ICU)
When and how much	An intravenous insulin infusion was started according to the protocols for insulin infusion. These protocols had been modified from the earlier Northwestern protocol, such that glucose levels of 140 mg/dL and 180 mg/dL were targeted in the 2 groups rather than 110 mg/dL. The patients were seen daily by a member of the GMS, and the glucose levels were reviewed at least daily to assess whether insulin protocol adjustments were needed. Once the patients were stable and had begun to eat, rapid acting insulin was given to cover their food intake in doses of approximately 10% of the basal (glargine) insulin dose. If patients were still otherwise unstable, the insulin infusion was continued. Once patients were stable, the insulin infusion was converted to a basal bolus regimen. A member of the GMS started the basal insulin, usually at a dose that was about 50% to 60% of the basal infusion rate. In this setting, an additional rapid acting insulin analog was given to cover food intake at approximately 10% of the basal insulin dose. At conversion, subcutaneous injection of rapid acting insulin was also administered at 15% of the stable hourly insulin infusion rate given during the previous several hours (324 hours to calculate the total daily dose) to maintain adequate insulin levels as a “bridge” dose. Once patients were fully receiving the subcutaneous insulin regimen, the doses of glargine were generally reduced by about 50% daily (with flexibility from 40% to 60% according to the patient’s clinical status and BG values). The doses of premeal rapid‐acting insulin were maintained, reflecting a decrease in insulin resistance and an increase in meal size as the patient’s clinical status improved. Again, the insulin doses were adjusted daily by the GMS team to maintain the premeal glucose levels as close as possible to the respective target of 140 mg/dL and 180 mg/dL while patients were in the hospital. At discharge from the hospital, the patients received discharge instructions, which included details regarding home selfBG monitoring. If the patients were still hyperglycaemic, a medication regimen was recommended in an effort to maintain the BG goal of 140 mg/dL or 180 mg/dL.
Tailoring	I: personalised according to patient glucose levels and insulin protocol was adjusted if needed to maintain the BG goal of 140 mg/dL C: personalised according to patient glucose levels and insulin protocol was adjusted if needed to maintain the BG goal of 180 mg/dL
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	The adherence was assessed, but the results were not reported in this paper
Study author	Wahby 2016
Brief name	Tight versus moderate glycaemic control in patients with diabetes undergoing coronary artery bypass graft surgery (CABG)
Recipient	Patients with diabetes planned for CABG surgery
Why	Perioperative glycaemic control in patients undergoing cardiac surgery was conducted in many studies but remains unclear how tight the glycaemic control should be.
What (materials)	Syringe pump, blood glucose meter
What (procedures)	Tight glycaemic control during operation to maintain blood glucose levels between 110 mg/dL and 149 mg/dL versus conventional moderate glycaemic control to achieve blood glucose level between 150 mg/dLand 180 mg/dL during operation. Perioperative tight glycaemic control was achieved by continuous insulin infusion using insulin actrapid HM Novonordisk 50 unit in 500 mL saline 0.9% by syringe pump started before anaesthesia induction and continued till patient weaned from mechanical ventilation in ICU. The blood glucose was checked hourly by blood glucose meter.
Who provided	—
How (mode of delivery; individual or group)	Individual, face to face
Where	Perioperative and ICU
When and how much	Continuos insulin infusion started before anaesthesia induction and continued till the patient is extubated in ICU
Tailoring	I: Tight glycaemic control during operation to maintain blood glucose levels between 110 mg/dL and 149 mg/dL C: conventional moderate glycaemic control to achieve blood glucose level between 150 mg/dL and 180 mg/dL
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Study author	Parekh 2016
Brief name	Effect of moderately intense perioperative glucose control on renal allograft function
Recipient	Adult patients with diabetes undergoing deceased donor renal transplant
Why	To determine whether moderately intense glucose control, with the primary goal of achieving a blood glucose level between 80 mg/dL and 160 mg/dL at the time of allograft reperfusion, would reduce the incidence of poor graft function and reduce the hyperglycaemia that occur after transplant
What (materials)	Accu‐chek Hospital Meters (Roche Diagnostics, Indianapolis, IN, USA). Insulin treatment algorithms in use at University of California San Francisco Medical Center.
What (procedures)	I: Preoperatively, recipients in the moderately intense glucose control group were started on an insulin infusion if their blood glucose was greater than 120 mg/dL. To avoid prolonged treatment, the infusion was started no earlier than 4 hours before the anticipated start of the transplant. Intraoperatively, the anaesthesia team was advised to check the blood glucose every 30 to 45 minutes with the goal of keeping it between 80 mg/dL and 160 mg/dL. The decision to target a blood glucose of less than 160 mg/dL was based on our previous work that indicated a threshold effect above that level, resulting in greater rates of DGF and markers of ischaemic injury. The use of bolus therapy or insulin infusion was left to the discretion of the anaesthesia team. C: standard preoperative management consisting of ordering an insulin sliding scale or no intervention unless blood glucose exceeded 200 mg/dL Postoperatively, intervention and control recipients were placed on an insulin infusion (existing protocol already approved by the medical centre for use on standard medical–surgical wards) that targeted blood glucose levels of 100 mg/dL to 180 mg/dL. This infusion was continued for 24 hours postoperatively. After 24 hours of the infusion, the primary transplant team was given complete control over glucose management
Who provided	Primary transplant team, anaesthesia team, nephrology team, research team
How (mode of delivery; individual or group)	Individual, face to face
Where	Pre‐operatively and during surgery
When and how much	Intervention was delivered 1 time during perioperatively period
Tailoring	Adapted by insulin scale if blood glucose was > 200 mg/dL (not personalised)
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Study author	Yuan 2015
Brief name	Intensive versus conventional glycaemic management strategies in patients with diabetes receiving enteral nutrition after gastrectomy
Recipient	Adult patients with diabetes who underwent gastrectomy
Why	Hyperglycaemia is a stress response to surgery. Early enteral nutrition after upper gastrointestinal surgical resection has been associated with a significantly shorted length of hospital stay and improved clinical outcomes. Because of the inability to assess the exact amount of glucose absorbed through the intestines, it is difficult to control blood glucose in patients receiving enteral nutrition. This study assessed whether intensive glycaemic control was well‐tolerated, safe and improved clinical outcomes in patients with diabetes receiving enteral nutrition after gastrectomy
What (materials)	Intensive group intravenous insulin algorithm and conventional group insulin algorithm
What (procedures)	Intensive glycaemic (IG) management: with continuous insulin infusion to a target blood glucose concentration 4.4 mmol/L to –6.1 mmol/L (80 mg/dL to 110 mg/dL) Conventional glycaemic (CG) management: with intermittent bolus insulin to o a target blood glucose concentration < 11.1 mmol/L (< 200 mg/dL)
Who provided	—
How (mode of delivery; individual or group)	Individual, face to face
Where	Postoperative
When and how much	I: started on intravenous infusion of 0.5 to 1 U/h insulin. Blood glucose was monitored hourly (every 2 to 4 h when stable), with the insulin infusion rate adjusted according to an algorithm. C: administered insulin subcutaneously every 4 to 6 h, based on the results of bedside glucose monitoring, with extra injections administered if necessary Postoperative management: patients were infused with 250 mL of normal saline, starting within 12 h after surgery. Patients received feedings of 20 mL/h SP or TPF (Nutricia) through a naso‐jejunal tube beginning on the first postoperative day, with the rate increasing 10 mL/h as tolerated every 12 to 24 h, to a maximum rate of 80 mL/h.8 The average caloric intake was 25 to 30 kcal/kg/day. Between the 8th and 10th days, the naso‐jejunal tube was removed except for special reasons
Tailoring	Adapted by blood glucose/insulin algorithm
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Study author	Umpierrez 2015
Brief name	GLUCO‐CABG trial. Intensive versus conservative glucose control in patients undergoing CABG
Recipient	Patients undergoing primary, elective and emergency CABG
Why	The optimal level of glycaemic control needed to improve outcomes in patients undergoing cardiac surgery remains controversial
What (materials)	Glucommander computer‐guided continuous insulin infusion device/algorithm
What (procedures)	I: continuous insulin infusion (CII) adjusted to maintain a glucose target between 100 mg/dL and 140 mg/dL during ICU admission C: continuous insulin infusion (CII) adjusted to maintain a glucose target between 140 mg/dL and 180 mg/dL during ICU admission After discontinuation of CII, intervention and control participants were transitioned to a single treatment protocol aimed to maintain a glucose target of 140 mg/dL before meals during the hospital stay and during the 90 days after discharge
Who provided	—
How (mode of delivery; individual or group)	Individual, face to face
Where	Post surgical holding area and ICU of 3 academic medical centres, including Emory University Hospital, Emory Midtown Hospital, and Grady Memorial Hospital in Atlanta, GA
When and how much	Postoperative and during ICU stay until patient could eat
Tailoring	Adjusted to maintain a glucose target between 100 mg/dL and 140 mg/dL. No tailoring was performed.
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Study author	Abdelmalak 2013
Brief name	Potential anti‐inflammatory interventions to reduce perioperative mortality of patients undergoing major non‐cardiac surgery
Recipient	Patients undergoing mayor non‐cardiac surgery
Why	The inflammatory response to surgery may be an important part of the pathophysiology of adverse outcomes after surgery. Dexamethasone, tight glycaemic control and light anaesthesia may attenuate these inflammatory responses.
What (materials)	DeLiT trial intravenous insulin infusion algorithm
What (procedures)	Glucose control began shortly after induction of anaesthesia using pre‐designed protocols and continued through the first 2 hours of post‐anaesthesia care unit stay I: blood glucose concentrations were targeted to 80 mg/dL to 110 mg/dL C: blood glucose concentrations were targeted to 180 mg/dL to 200 mg/dL Patients followed the routine of the ICU/hospital ward where they were admitted: hospital ward (70 mg/dL to 150 mg/dL) or critical care unit (80 mg/dL to 120 mg/dL)
Who provided	Clinicians
How (mode of delivery; individual or group)	Individual, face to face
Where	Operating room
When and how much	The intervention was delivered once during the period between induction of anaesthesia and the first 2 postoperative hours Glucose was subsequently managed per routine for the hospital ward (target of 3.9 mmol/L to 8.3 mmol/L 21 (70 mg/dL to 150 mg dL 21)) or critical care unit (target of 4.4 mmol/L 6.7 mmol/L 21 (80 mg/dL to 120 mg dL 21)) to which they were admitted
Tailoring	—
Modification of intervention throughout the trial	The intervention was not modified during the course of the study
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Study author	Hermayer 2012
Brief name	Evaluate the effect of glycaemic control on renal transplantation outcomes: intensive versus standard control
Recipient	Renal transplant candidates who were 18 year of age or greater and who had a DM diagnosis (type 1 and type 2), a fasting blood glucose (BG) over 100 mg/dL per admission screening labs, and a random BG over 120 mg/dL per admission screening labs
Why	Outcomes from intensive glycaemic control post renal transplant have not been studied
What (materials)	Finger stick BG method using the Precision QID monitor; insulin treatment protocol
What (procedures)	I: BG level checked in the Operating Room (OR) via indwelling venous cannula or finger‐stick BG just before starting the iv insulin infusion. The iv insulin infusion solution was prepared as a mixture of 250 U regular insulin (Novolin Regular) with 250 mg 0.9% NaCl rendering 1 U insulin/mL saline. The formula was (current BG 60 mg/dL) 0.03 rate of insulin infusion per hour. BG levels were maintained according to study protocol (70 mg/dL to 110 mg/dL). BG levels were checked every 1 to 2 h per study protocol to maintain glycaemic control at 70 mg/dL to 110 mg/dL and were followed by the DMS team. The at least 72‐h time period started at the beginning of surgery and continued until 0700 h on postoperative day 3. Experimental participants in the intensive group had all BG levels checked by the fingerstick BG method using the Precision QID monitor. BG management followed the iv insulin infusion calculator study protocol (70 mg/dL to 110 mg/dL). After diet consumption, BG levels followed the iv insulin infusion calculator study protocol for the remainder of the at least 72 h. The doses of insulin were adjusted daily according to protocol. After the 72‐h period concluded, the intensive group was transitioned to long‐acting and rapid‐acting sc insulin for glycaemic control (70 mg/dL to 140 mg/dL). C: BG levels checked every hour while in the OR via indwelling venous cannula or finger‐stick BG and was treated with rapid‐acting sc insulin as needed to aim for target BG levels (70 mg/dL to 180 mg/dL). Control participants had BG levels checked every 4 h while in the postoperative acute care unit (PACU), treated with long‐acting and rapid‐acting sc insulin to aim for target BG levels (70 mg/dL to 180 mg/dL), and were followed by the DMS team. After control participants were transferred to the transplant unit, BG levels were checked every 4 h and treated with long‐acting (neutral protamine hagedorn insulin or glargine insulin) and rapid‐acting (aspart) sc insulin to maintain glycaemic control at 70 mg/dL to 180 mg/dL and were followed by the DMS team. After diet consumption, BG levels were checked before meals, at bedtime and at 0300 h. The doses of insulin were adjusted daily according to protocol. It was DMS protocol to maintain glycaemic control at 70 mg/dL to 180 mg/dL for the remainder of the at least 72 h. Control participants were placed on a regimen of a minimum of one to two insulin sc injections per protocol at discharge to maintain glycaemic control at 90 mg/dL to 180 mg/dL.
Who provided	Transplant unit registered nurses and assigned certified diabetes educators of the Diabetes Management Service (DMS)
How (mode of delivery; individual or group)O	Individual, face to face
Where	Operating room, postoperative acute care unit, discharge
When and how much
Tailoring	Adapted by insulin treatment protocol
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	All study participants received routine nursing care and patient education specific to self‐care management (insulin therapy and BG monitoring) by the transplant unit Registered Nurses and assigned Certified Diabetes Educators
Extent of intervention fidelity	—
Study author	Desai 2012
Brief name	Strict versus liberal target range for perioperative glucose in patients undergoing CABG
Recipient	Patients after first‐time isolated CABG
Why	Strict glycaemic control increased the incidence of hypoglycaemic events, but did not result in any significant improvement in clinical outcomes that was achieved with the more moderate control
What (materials)	Glucommander (Gluco Tec, Greenville, SC). Glucose Accu‐Chek Advantage with the AccuData GTS/ GTS manufactured by Roche (Basel, Switzerland).
What (procedures)	Maintenance of BG levels according to their randomised arm was started in the ICU using the programmed Glucommander to adjust the BG level to patients’ assigned range. Hourly BG monitoring was performed with blood obtained from a patient’s arterial line and analysed by point‐of‐care testing through Glucose Accu‐Chek Advantage with the AccuData GTS/ GTS. BG levels less than 40 mg/dL or greater than 500 mg/dL we sent to the laboratory for further analysis; however, treatment was initiated for low BG if indicated. Patients were maintained on the electronic‐based protocol of intravenous insulin for a minimum of 72 hours perioperatively. I: BG maintained at less than 180 mg/dL (121 mg/dL to 180 mg/dL) C: BG maintained in the range of 90 to less than 120 mg/dL
Who provided	The bedside nurses, the anaesthesiologist, nursing staff
How (mode of delivery; individual or group)	Individual, face to face
Where	Postoperative ICU
When and how much	Maintenance of BG levels according to their randomised arm was started in the ICU. Patients were maintained on the electronic‐based protocol of intravenous insulin for a minimum of 72 hours perioperatively.
Tailoring	Adapted
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Study author	Lazar 2011
Brief name	Effects of aggressive versus moderate glycaemic control on clinical outcomes in patients with diabetes undergoing CABG
Recipient	Patients with diabetes mellitus undergoing CABG
Why	There is general consensus that tighter glycaemic control improves outcomes in patients with diabetes undergoing CABG, but the optimal target for serum glucose levels is unknown. Recent trials in both ICU and non‐ICU patients have raised concerns that more aggressive glycaemic control may actually result in increased mortality from cardiovascular disease and increases episodes of hypoglycaemia.
What (materials)	Algorithm for moderate and aggressive glycaemic control
What (procedures)	After induction of general anaesthesia, a continuous insulin infusion with 100 units of regular insulin in 100 mL of 0.9% normal saline was initiated at 3 mL/hour and titrated to maintain the targeted glucose level on the basis of the algorithm. The study protocol continued during the periods of cardiopulmonary bypass and cardioplegic arrest, after the discontinuation of bypass, and for 18 hours in the ICU. After the 18‐hour ICU period, patients were transitioned off the insulin drip using either short‐ or long‐acting insulin agents and ultimately back to their preoperative diabetic regimens maintaining a fasting glucose level of less than 120 mg/dL and 4 PM glucose levels of less than 180 mg/dL I: maintaining serum glucose 90 mg/dL to 120 mg/dL using continuous intravenous insulin solutions C: maintaining serum glucose 120 mg/dL to 180 mg/dL using continuous intravenous insulin solutions
Who provided	Clinicians
How (mode of delivery; individual or group)	Individual, face to face
Where	Operating room and ICU
When and how much	After induction of general anaesthesia, a continuous insulin infusion with 100 units of regular insulin in 100 mL of 0.9% normal saline was initiated at 3 mL/hour and titrated. After the 18‐hour ICU period, patients were transitioned off the insulin drip using either short‐ or long‐acting insulin agents and ultimately back to their preoperative diabetic regimens maintaining a fasting glucose level of less than 120 mg/dL and 4 PM glucose levels less than 180 mg/dL
Tailoring	Titrated: in both moderate and aggressive groups, a continuous insulin infusion of 100 units of regular insulin in 100 mL of 0.9% normal saline was initiated at 3 mL/hour and titrated to the target range using the earlier algorithms
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Study author	Cao 2010
Brief name	Intensive versus conventional insulin therapy in patients with type 2 diabetes undergoing D2 gastrectomy for gastric cancer
Recipient	Adult patients with type 2 diabetes who were to undergo open elective gastrectomy for gastric cancer
Why	The impact of intensive glucose control on short‐term mortality and morbidity in patients with type 2 diabetes undergoing D2 gastrectomy for gastric cancer is unclear. There has been controversy over Portland safety, increased workload and benefits.
What (materials)	Bedside glucometer (OneTouch Ultra 2, LifeScan) infusion pump (Smiths Medical Instrument Co., Zhejiang, China) Portland protocol for continuous insulin infusion
What (procedures)	I: insulin infusion was started if the blood glucose levels exceeded 6.1 mmol/l and was adjusted to maintain the blood glucose target between 4.4 mmol/L and 6.1 mmol/L. The infusions were continued postoperatively until oral intake or enteral nutrition was established, after which the usual treatment for DM was resumed. C: insulin infusion was started if the blood glucose level exceeded 12.0 mmol/L and was adjusted to maintain the blood glucose target between 10.0 mmol/L and 11.0 mmol/L. The infusions were continued postoperatively until oral intake or enteral nutrition was established, after which the usual treatment for DM was resumed.
Who provided	Well‐trained surgeons, diabetologists and SICU nurses who had extensive experience in blood glucose control
How (mode of delivery; individual or group)	Individual, face to face
Where	Surgical intensive care unit (SICU) until oral intake or enteral nutrition was established
When and how much	Fifty IU of regular insulin in 50 mL of normal saline was administered using an infusion pump. The infusions were continued postoperatively until oral intake or enteral nutrition was established, after which the usual treatment for DM was resumed.
Tailoring	Adapted per protocol. In IG treatment, the insulin infusion was started if the blood glucose levels exceeded 6.1 mmol/l and was adjusted to maintain the blood glucose target between 4.4 mmol/L and 6.1 mmol/L. In CG treatment, the insulin infusion was started if the blood glucose level exceeded 12.0 mmol/L and was adjusted to maintain the blood glucose target between 10.0 and 11.0 mmol/L.
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Study author	Glucontrol 2009
Brief name	Glucontrol study: tight glucose control by intensive therapy in adult intensive care units
Recipient	Adult patients (older than 18 years) admitted to the participating ICUs
Why	An optimal target for glucose control in ICU patients remains unclear
What (materials)	Specific glucometer (Accu‐Chek Inform, Roche Diagnostics, Mannheim, Germany) Insulin infusion algorithm in electronic supplementary material on the publication
What (procedures)	Regular human insulin (Actrapid, Novo‐Nordisk, DK, 1 IU/mL NaCl 0.9%) was administered by continuous intravenous infusion (algorithm in electronic supplemental material) via the pumps available at each site. There was no standardised policy for ICU discharge, nutrition, or for the weaning of mechanical ventilation. After discharge from the ICU or when the patient was on full oral feeding, intravenous insulin was shifted to subcutaneous administration, according to the standard local practice. There was no restriction for any other treatment including nutritional support (enteral or parenteral) or intravenous glucose. The vital outcome of the patients was recorded until discharge from the hospital or until the 28th day after ICU admission if the patient was discharged before this day. In case of readmission for a second ICU stay, only the outcome data of the last stay was used. BG was measured in arterial or central venous samples when indwelling catheter were in place, or in samples drawn from the fingertip. The centres were asked to use a blood gas analyser, or a specific glucometer (Accu‐Chek Inform, Roche Diagnostics, Mannheim, Germany) to measure the glucose concentration and to check BG hourly until the achievement of the target and at least every 4 h thereafter. Built‐in checks of quality parameters were left under the responsibility of the local laboratories. At least one BG value per day was measured by the hospital central laboratory on a morning sample (‘‘morning value’’) and recorded. The other BG values measured by a blood gas analyser or by a glucose reader on plasma samples were recorded and used uncorrected for the adaptation of the insulin infusion rate. I: maintaining blood glucose target at 4.4 mmol/L to 6.1 mmol/L C: maintaining blood glucose target at 7.8 mmol/L to 10.0 mmol/L
Who provided	—
How (mode of delivery; individual or group)	Individual, face to face
Where	Twenty‐one medico‐surgical ICUs (working group on metabolism and nutrition of the European Society of Intensive Care Medicine)
When and how much	Regular human insulin (Actrapid, Novo‐Nordisk, DK, 1 IU/mL NaCl 0.9%) was administered by continuous intravenous infusion (algorithm in electronic supplemental material) via the pumps available at each site. After discharge from the ICU or when the patient was on full oral feeding, intravenous insulin was shifted to subcutaneous administration, according to the standard local practice.
Tailoring	Adapted by insulin treatment protocol
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Study author	NICE SUGAR 2009
Brief name	Intensive (i.e. tight) control target of 81 mg/dL to 108 mg/dL or conventional control target of 180 mg/dL or less in critically ill patients
Recipient	Patients expected to require treatment in the ICU on 3 or more consecutive days
Why	Hyperglycaemia is common in acutely ill patients, including those treated in intensive care units (ICUs). The occurrence of hyperglycaemia, in particular severe hyperglycaemia, is associated with increased morbidity and mortality in a variety of groups of patients. The optimal target range for blood glucose in critically ill patients remains unclear
What (materials)	Arterial catheters and blood gas analysers or laboratory analysers. Acute Physiology and Chronic Health Evaluation II (APACHE II) score (range from 0 to 71, with higher scores indicating more severe illness). Sequential Organ Failure Assessment (SOFA, for which scores can range from 0 to 4 for each organ system, with higher scores indicating more severe dysfunction) Insulin infusion algorithms accessed through a secure website (https://studies.thegeorgeinstitute.org/nice/)
What (procedures)	I: control target of 81 mg/dLto 108 mg/dL C: control target of 180 mg/dL or less Blood glucose levels were managed as part of the normal duties of the clinical staff at the participating centre guided by treatment algorithms accessed through a secure website. The trial intervention was discontinued once the patient was eating or was discharged from the ICU but was resumed if the patient was readmitted to the ICU within 90 days. It was discontinued permanently at the time of death or 90 days after randomisation, whichever occurred first.
Who provided	Clinical staff at each participating centre
How (mode of delivery; individual or group)	Individual, face to face
Where	ICUs of 42 hospitals (38 academic tertiary care hospitals and 4 community hospitals)
When and how much	Control of blood glucose was achieved with the use of an intravenous infusion of insulin in saline guided by treatment algorithms accessed through a secure website.
Tailoring	Titrated when needed to maintain blood glucose concentrations
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Study author	Subramaniam 2009
Brief name	Continuos perioperative insulin infusion decreases major cardiovascular events in patients undergoing vascular surgery
Recipient	Patients who were undergoing peripheral vascular bypass surgery, abdominal aortic surgery or major lower extremity amputation (above or below the knee)
Why	Evidence suggests that hyperglycaemia is an independent predictor of increased cardiovascular risk. Aggressive glycaemic control in the intensive care decreases mortality. The benefit of glycaemic control in noncardiac surgery is unknown.
What (materials)	Continuous insulin infusion protocol and standard intermittent sliding‐scale insulin bolus, both available in the publication (appendix 1 and 2)
What (procedures)	I: using a continuous insulin infusion (CII) protocol. The target blood glucose concentration was 100 mg/dL to 150 mg/dL. If blood glucose levels exceeded 150 mg/dL, a continuous insulin infusion was initiated. Adjustments to the insulin infusion were determined by both the current blood glucose concentrations and insulin infusion rates and as specified in the protocol. Most of the target population resumed oral intake at 48 hours, and they were started on their original antidiabetic regimen. C: using a standard intermittent sliding‐scale insulin bolus (IIB) protocol.
Who provided	Changes in the insulin infusion rate were made by the anaesthesiologist in the operating room (intraoperative) and by the registered nurse in the postanesthetic care unit and vascular intensive care unit (postoperative)
How (mode of delivery; individual or group)	Individual, face to face
Where	In the operating room and in the postanesthetic care unit/vascular intensive care unit
When and how much	I: Start insulin infusion when blood glucose concentration is greater than 150 mg/dL. All patients with diabetes received half of their baseline long‐acting insulin regimen. No oral hypoglycaemic drugs were given throughout the study period. All patients had hourly blood glucose checks. Drug: regular insulin only. Route: by intravenous route only. C: received half of their long‐acting insulin on the morning of surgery. Oral hypoglycaemic drugs were withheld. The long‐acting insulin was reinitiated during the transition period at 48 h. Regular insulin was used intravenously in the operating rooms at the discretion of the treating anaesthesiologist, as is the standard of care, and in the postoperative period was initiated for blood glucose greater than 150 mg/dL. All patients received 4‐hourly blood glucose checks.
Tailoring	Adapted per protocol. Continuous insulin infusion group: start insulin infusion when blood glucose concentration is greater than 150 mg/dL. All patients with diabetes received half of their baseline long‐acting insulin regime. No oral hypoglycaemic drugs were given during the study period. All patients had hourly blood glucose checks. Intermittent insulin bolus group: all patients with diabetes received half of their long‐acting insulin on the morning of surgery. Oral hypoglycaemic drugs were withheld. The long‐acting insulin was reinitiated during the transition period at 48 hours. Regular insulin was used intravenously in the operating rooms at the discretion of the treating anaesthesiologist, as is the standard care, and in the postoperative period was initiated for blood glucose greater than 150 mg/dL. All patients received 4‐hourly blood glucose checks
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
Extent of intervention fidelity	—
Study author	Chan 2009
Brief name	Intensive perioperative glucose control does not improve outcomes of patients submitted to open‐heart surgery
Recipient	Adults from both genders who were older than 21 years of age and who were undergoing open‐heart cardiac surgery with cardiopulmonary bypass
Why	Data provided by recently completed trials reveal that we should regard tight glucose control during cardiac surgery as experimental and confine its use to clinical trials.
What (materials)	Glucose meter (Accu Check Advantage, Roche, Manheim, Germany). Glucose analyzer (ABL700, Radiometer Medical A/S, Copenhagen, Denmark). Infusion device (B. Braun, Melsungen, Germany). Insulin dose adjusted according to Leuven modified algorithm.
What (procedures)	At the beginning of the study, all patients were kept in intraoperative rooms and were started on intravenous glucose (8 g to 12 g/h), which was maintained for the first 24 hours after arrival in the ICU. After 24 hours, patients started a standardised feeding schedule, intended to deliver 20 to 30 nonprotein calories/kg‐1/24 h‐1 with a balanced composition (0.13 g to 0.26 g nitrogen/kg‐1/24 hrs‐1 and 20% to 40% of nonprotein calories as lipids) of enteral feeding. All of the patients were able to receive enteral feeding after surgery. Parenteral nutrition was not prescribed for any patients in the study. I: target glucose level between 80 mg/dL to 130 mg/dL C: target glucose level between 160 mg/dL to 200 mg/dL Adjustment of the insulin dose was based on the measurements of whole blood glucose in undiluted arterial blood every one to four hours, using a glucose analyser (ABL700, Radiometer Medical A/S, Copenhagen, Denmark). The dose was adjusted by the intensive care nurses according to a titration algorithm. These insulin doses were approved by a study physician not involved in the clinical care of the patients. Insulin was given exclusively by continuous intravenous infusion through a central venous catheter using an infusion device (B. Braun, Melsungen, Germany). The standard concentration was 100 IU of Actrapid HM (Novo Nordisk, Copenhagen, Denmark) in 100 mL of 0.9% NaCl. Prepared solutions, which were stable for up to 12 hours when kept at < 25 °C, were not to be used beyond that time. During the intraoperative period and during the first 24 hours after admission to the ICU, measurement of blood glucose was advised every 1 to 2 hours until the targeted level of blood glucose was achieved. Thereafter, blood glucose was measured every 4 hours, unless dramatic decreases or increases in the blood glucose level occurred. In these cases, hourly control was performed after each dose adjustment. Adequate administration of the prescribed nutrients was emphasised. Intravenous glucose‐containing solutions were administered by an infusion pump to avoid fluctuation of blood glucose levels and frequent adjustment of the insulin dose. At the time of planned interruptions of feeding, the insulin dose was proportionately reduced to avoid hypoglycaemia. Hence, in a patient receiving total enteral nutrition, insulin was virtually stopped during the twice daily, 2‐hour interruptions of tube feeding. In some patients, however, including those with diabetes and those requiring insulin before ICU admission, a low maintenance dose was needed during that time. At the time of patient transportation to an investigation or to the operating room for surgery, all intravenous and enteral administration of feeding was halted, and insulin infusion was temporarily discontinued. The blood glucose level was measured to ensure that it was adequate before transport. Whenever a patient was extubated and allowed to initiate a limited intake of oral foods, the intravenous or tube feeding was usually reduced to allow the patient’s appetite to return. The insulin dose was proportionately reduced and often temporarily discontinued.
Who provided	Intensivists and ICU nurses
How (mode of delivery; individual or group)	Individual, face to face
Where	Intraoperative room, surgery, ICU
When and how much	One time during surgery and ICU
Tailoring	Titrated. Dose adjustments were always proportionate to the observed change in blood glucose. When blood glucose decreased by > 50%, the dose of insulin was reduced to half, and the blood glucose level was checked within the next hour. When blood glucose was 60 mg/dL to 80 mg/dL, insulin was reduced depending on the previous blood glucose level, and the blood glucose level was checked again within the next hour. When blood glucose was 40 mg/dL to 60 mg/dL, insulin infusion was stopped, an adequate baseline glucose intake was ensured, and the blood glucose level was checked within the next hour. When the blood glucose was < 40 mg/dL, insulin infusion was stopped, an adequate baseline glucose intake was ensured, glucose was administered via 10 g intravenous boluses, and the blood glucose level was checked within the next hour. When blood glucose started to decrease within the normal range in a stable patient, recovery of insulin sensitivity was assumed, and the insulin dose was reduced by 20%. Additional blood glucose controls were advised whenever changes in body temperature or infection occurred
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
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Study author	De La Rosa 2008
Brief name	Effect of intensive insulin therapy compared with standard therapy in patients hospitalised in a mixed ICU
Recipient	Patients aged 15 years or older admitted to the ICU at the Hospital Pablo Tobón Uribe with an expected ICU stay of at least 2 days
Why	It remains unclear if intensive insulin therapy is equally efficacious in both medical and surgical patients
What (materials)	Continuous infusion pump. A point‐of‐care glucometer (MediSense Optium, Abbot Laboratories MediSense Products Bedford, MA, USA). Insulin therapy protocol in additional files 1 and 2 of the publications
What (procedures)	The standard concentration of insulin was 100 units in 100 mL of 0.9% saline solution. I: insulin infusion was started when blood glucose levels exceeded 110 mg/dL, and was adjusted to maintain a glucose level of between 80 mg/dL and 110 mg/dL (4.4 mmol/L to 6.1 mmol/L). Blood glucose levels were measured in undiluted arterial blood. Undiluted samples were obtained by removing at least 4 times the flush‐volume in the line between the sampling point and the arterial puncture site before the actual sample was taken or, when an arterial catheter was not available, in capillary blood with the use of a point‐of‐care glucometer. Glucose levels were determined with a glucometer at admission to ICU. They were repeated every 1, 2 and 4 hours if the patient had insulin infusion, and every 4 and 6 hours if no insulin was required according to the algorithm. C: insulin infusion was started when glucose levels exceeded 215 mg/dL and was adjusted to maintain blood glucose levels between 180 mg/dL and 200 mg/dL (10.0 mmol/L to 11.1 mmol/L)
Who provided	ICU nurse
How (mode of delivery; individual or group)	Individual, face to face
Where	ICU
When and how much	Glucose levels were determined with a glucometer at admission to ICU. They were repeated every 1, 2 and 4 hours if the patient had insulin infusion, and every 4 and 6 hours if no insulin was required according to the algorithm
Tailoring	Titration of insulin. A protocol (original paper) managed by the ICU nurses, was used for the adjustment of the insulin dose. Protocols were consistently followed throughout the patient's whole ICU stay.
Modification of intervention throughout the trial	—
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Study author	Gandhi 2007
Brief name	Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery
Recipient	Adults with and without diabetes who were undergoing on‐pump cardiac surgery
Why	Intensive insulin therapy used to maintain normoglycaemia during intensive care after cardiac surgery improves perioperative outcomes. Its effect during cardiac surgery is unknown.
What (materials)	Double P Modular System (Roche Diagnostics, Indianapolis, Indiana). Accu‐Check Inform blood glucose monitoring system (glucometer) (Roche Diagnostics).
What (procedures)	I: continuous intravenous insulin infusion, 250 units of NovoLin R (Novo Nordisk, Princeton, New Jersey) in 250 mL of 0.45% sodium chloride, when their blood glucose levels exceeded 5.6 mmol/L (> 100 mg/dL). We adjusted the infusions to maintain blood glucose levels between 4.4 (80 mg/dL) and 5.6 mmol/L (100 mg/dL). We adjusted the dose according to a standardised algorithm used by anaesthesiologist. C: did not receive insulin during surgery unless their glucose levels exceeded 11.1 mmol/L (≥ 200 mg/dL). If glucose concentration was between 11.1 (200 mg/dL) and 13.9 mmol/L (250 mg/dL), patients received an intravenous bolus of 4 units insulin every hour until the glucose concentration was less than 11.1 mmol/L (< 200 mg/dL). If the intraoperative glucose concentration was greater than 13.9 mmol/L (> 250 mg/dL), patients received an intravenous infusion of insulin that was continued until the glucose level was less than 8.3 mmol/L (< 150 mg/dL) Postoperative period: intravenous insulin infusion was started in patients in the conventional treatment group on their arrival in the ICU. Thereafter, both study groups were treated identically, with the intravenous insulin infusion rates adjusted by a nursing staff that was not involved with the study according to a standard protocol. During the first 24 hours after surgery, patients were given only clear liquids by mouth; we did not administer subcutaneous insulin or oral diabetic medications during this time.
Who provided	Anaesthesiologist in the operating room and nursing staff in the ICU
How (mode of delivery; individual or group)	Individual, face to face
Where	Operating room
When and how much	I: the infusions were adjusted to maintain blood glucose levels between 4.4 mmol/L (80 mg/dL) and 5.6 mmol/L (100 mg/dL). Dose was adjusted according to a standardised algorithm used by anaesthesiologist. C: patients did not receive insulin during surgery unless their glucose levels exceeded 11.1 mmol/L (> 200 mg/dL). If glucose concentration was between 11.1 (200 mg/dL) and 13.9 mmol/L (250 mg/dL), patients received an intravenous bolus of 4 units insulin every hour until the glucose concentration was less than 11.1 mmol/L (< 200 mg/dL). If the intraoperative glucose concentration was greater than 13.9 mmol/L (> 250 mg/dL), patients received an intravenous infusion of insulin that was continued until the glucose level was less than 8.3 mmol/L (< 150 mg/dL).
Tailoring	We adjusted the dose according to a standardised algorithm used by anaesthesiologist
Modification of intervention throughout the trial	—
Strategies to improve or maintain intervention fidelity	—
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Study author	Li 2006
Brief name	Glucometer‐guided insulin (GGI) versus continuous insulin infusion (CII) in postoperative patients with diabetes
Recipient	People with diabetes who were undergoing CABG for the 1st time
Why	Postulating that continuous insulin infusion would provide better control of postoperative blood glucose levels
What (materials)	Insulin infusion protocol modified from the Portland protocol
What (procedures)	I: continuous insulin infusion (CII) group. The CII protocol (Appendix published in the original paper) used in this group was modified from the Portland protocol. Insulin was initiated and the dosage titrated according to the results of glucose testing to maintain the blood glucose between the desired target levels. C: glucometer‐guided insulin (GGI) group received subcutaneous insulin injections (Humulin® R, Eli Lilly and Company; Indianapolis, Ind) every 2 hours in an attempt to maintain blood glucose levels between 150 and 200 mg/dL. The dose of insulin was adjusted on the basis of each patient’s response to the previous insulin injection. When 2 consecutive measurements showed that the target glucose level was attained, the frequency of GGI injections was decreased to once every 4 hours. When the patients began eating, the frequency of injections was changed to 4 times per day (before every meal and at bedtime). Given continuing stability in glucose‐level readings, the patient’s usual preoperative glucose‐control regimen was resumed 5 days after the operation.
Who provided	—
How (mode of delivery; individual or group)	Individual, face to face
Where	ICU
When and how much
Tailoring	Insulin was titrated according to the results of glucose testing to maintain the blood glucose between the desired target levels
Modification of intervention throughout the trial	—
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Study author	Lazar 2004
Brief name	Tight glycaemic control (serum glucose 125 mg/dL to 200 mg/dL) with glucose‐insulin‐potassium (GIK) versus standard therapy (serum glucose > 250 mg/dL) in people with diabetes undergoing CABG
Recipient	Patients with diabetes mellitus undergoing primary or preoperative CABG performed on cardiopulmonary bypass
Why	There is now evidence to suggest that achieving tighter glycaemic control in people with diabetes during acute coronary syndromes improves survival
What (materials)	—
What (procedures)	I: patients received an infusion through a central line consisting of 500 mL D5W with 80 U of regular insulin and 40 mEq of KCl infused at 30 mL/h, prepared by a research pharmacist. The GIK was started just before anaesthetic induction and continued until cardiopulmonary bypass was instituted. It was then discontinued and restarted after the aorta was unclamped and continued for 12 hours after arrival in the Intensive Care Unit (ICU). Blood glucose and K were monitored every hour. C: Patients in the No‐GIK group received D5W infused at 30 mL/h. Blood glucose and K were also monitored every hour, and the scale shown in original paper (Table 3) was used to administer subcutaneous insulin. After the 18‐hour study period, patients resumed their preoperative diabetic regimens (oral agents or insulin) titrated to keep blood glucose 200 mg/dL
Who provided	—
How (mode of delivery; individual or group)	Individual, face to face. Follow‐up was obtained by directly by telephone.
Where	Operating room and ICU
When and how much	The intervention was started just before anaesthetic induction and continued until cardiopulmonary bypass was instituted. It was discontinued and restarted after the aorta was unclamped and continued for 12 hours after arrival in the ICU.
Tailoring	Adjustments in the rate of GIK infusion via protocol
Modification of intervention throughout the trial	—
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Study author	Rassias 1999
Brief name	Standard insulin therapy (SIT group) versus aggressive insulin therapy (AIT group) in coronary artery bypass surgery of people with diabetes
Recipient	Patients with diabetes scheduled to undergo elective cardiac surgery with cardiopulmonary bypass
Why	To examine the effect of aggressive insulin therapy on polymorphonuclear neutrophils I (PMN) function in patients with diabetes undergoing cardiac surgery
What (materials)	Glucose levels were checked using an automated device (AccuDataTMGTS; Boehringer Mannheim Corporation, Indianapolis, IN) Insulin infusion according to modified from Zerr et al. PMNs were isolated over PolymorphprepTM per the manufacturer's directors. Suspension concentrations were determined using a model JT Coulter Counter (Beckman Coulter, Inc., Fullerton, CA). Insulin administration according to a schedule detailed on the publication
What (procedures)	I: glucose levels were checked 1 hour before surgery and then repeated intraoperatively. Patients were started on an insulin infusion according to the protocols modified from Zerr et al. Further insulin was titrated according to the protocol. Postoperative insulin therapy was not controlled by the study protocol and consisted of an IV infusion of insulin as directed by the protocol of Zerr et al C: glucose levels were checked 1 hour before surgery and then repeated intraoperatively. IV regular insulin was administered according to the schedule published in the original paper. For high glucose levels (> 450 mg %), an infusion of insulin was started after an IV bolus of 13 U. The infusion was started at 4 U/h and titrated hourly.
Who provided	—
How (mode of delivery; individual or group)	Individual, face to face
Where	Operating room of Dartmouth‐Hitchcock Medical Cener
When and how much	Patients who were taking insulin were given one half of their usual subcutaneous NPH insulin dosage the morning of surgery and started on an infusion of 5% dextrose with 0.45% sodium chloride solution at 50 mL/h. Oral hypoglycemics were not given the morning of surgery in both groups.
Tailoring	Insulin was titrated according to the protocol
Modification of intervention throughout the trial	—
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