The Effect of a Liberal Approach to Glucose Control in Critically Ill Patients with Type 2 Diabetes: A Multicenter, Parallel-Group, Open-Label Randomized Clinical Trial.

Rationale: Blood glucose concentrations affect outcomes in critically ill patients, but the optimal target blood glucose range in those with type 2 diabetes is unknown. Objectives: To evaluate the effects of a "liberal" approach to targeted blood glucose range during ICU admission. Methods: This mutlicenter, parallel-group, open-label randomized clinical trial included 419 adult patients with type 2 diabetes expected to be in the ICU on at least three consecutive days. In the intervention group intravenous insulin was commenced at a blood glucose >252 mg/dl and titrated to a target range of 180-252 mg/dl. In the comparator group insulin was commenced at a blood glucose >180 mg/dl and titrated to a target range of 108-180 mg/dl. The primary outcome was incident hypoglycemia (<72 mg/dl). Secondary outcomes included glucose metrics and clinical outcomes. Measurements and Main Results: By Day 28, at least one episode of hypoglycemia occurred in 10 of 210 (5%) patients assigned the intervention and 38 of 209 (18%) patients assigned the comparator (incident rate ratio, 0.21 [95% confidence interval (CI), 0.09 to 0.49]; P < 0.001). Those assigned the intervention had greater blood glucose concentrations (daily mean, minimum, maximum), less glucose variability, and less relative hypoglycemia (P < 0.001 for all comparisons). By Day 90, 62 of 210 (29.5%) in the intervention and 52 of 209 (24.9%) in the comparator group had died (absolute difference, 4.6 percentage points [95% CI, -3.9% to 13.2%]; P = 0.29). Conclusions: A liberal approach to blood glucose targets reduced incident hypoglycemia but did not improve patient-centered outcomes. Clinical trial registered with Australian New Zealand Clinical Trials Registry (ACTRN 12616001135404).

Study protocol and statistical analysis plan for the Liberal Glucose Control in Critically Ill Patients with Pre-existing Type 2 Diabetes (LUCID) trial.

BACKGROUND: Contemporary glucose management of intensive care unit (ICU) patients with type 2 diabetes is based on trial data derived predominantly from patients without type 2 diabetes. This is despite the recognition that patients with type 2 diabetes may be relatively more tolerant of hyperglycaemia and more susceptible to hypoglycaemia. It is uncertain whether glucose targets should be more liberal in patients with type 2 diabetes. OBJECTIVE: To detail the protocol, analysis and reporting plans for a randomised clinical trial - the Liberal Glucose Control in Critically Ill Patients with Pre-existing Type 2 Diabetes (LUCID) trial - which will evaluate the risks and benefits of targeting a higher blood glucose range in patients with type 2 diabetes. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: A multicentre, parallel group, open label phase 2B randomised controlled clinical trial of 450 critically ill patients with type 2 diabetes. Patients will be randomised 1:1 to liberal blood glucose (target 10.0-14.0 mmol/L) or usual care (target 6.0-10.0 mmol/L). MAIN OUTCOME MEASURES: The primary endpoint is incident hypoglycaemia (< 4.0 mmol/L) during the study intervention. Secondary endpoints include biochemical and feasibility outcomes. RESULTS AND CONCLUSION: The study protocol and statistical analysis plan described will delineate conduct and analysis of the trial, such that analytical and reporting bias are minimised. TRIAL REGISTRATION: This trial has been registered on the Australian New Zealand Clinical Trials Registry (ACTRN No. 12616001135404) and has been endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group.

Opinions and practices of blood glucose control in critically ill patients with pre-existing type 2 diabetes in Australian and New Zealand intensive care units.

BACKGROUND: Approximately 9000 patients with type-2 diabetes mellitus (T2DM) are admitted to an intensive care unit (ICU) in Australia and New Zealand annually. For these patients, recent exploratory data suggest that targeting a more liberal blood glucose range during ICU admission may be safe and potentially beneficial. However, the current approach to blood glucose management of patients with T2DM in Australia and New Zealand ICUs is not well described, and there is uncertainty about clinician equipoise for trials of liberal glycaemic control in these patients. AIM: The aim is to describe self-reported blood glucose management in patients with T2DM by intensivists working in Australian and New Zealand ICUs and to establish whether equipoise exists for a trial of liberal versus standard glycaemic control in such patients. METHOD: An online questionnaire of Australia and New Zealand intensivists conducted in July-September 2016. RESULTS: Seventy-one intensivists responded. Forty-five (63%) used a basic nomogram to titrate insulin. Sixty-six (93%) reported that insulin was commenced at blood glucose concentrations >10 mmol/L and titrated to achieve a blood glucose concentration between 6.0 and 10.0 mmol/L. A majority of respondents (75%) indicated that there was insufficient evidence to define optimal blood glucose targets in patients with T2DM, and 59 (83%) were prepared to enrol such patients in a clinical trial to evaluate a more liberal approach. CONCLUSION: A majority of respondents were uncertain about the optimal blood glucose target range for patients with T2DM and would enrol such patients in a comparative trial of conventional versus liberal blood glucose control.

Long-term mortality of critically ill patients with diabetes who survive admission to the intensive care unit.

OBJECTIVE: Long-term outcomes of critically ill patients with diabetes are unknown. Our objectives were to evaluate the effect of diabetes on both long-term survival rates and the average number of years of life lost for patients admitted to an intensive care unit who survived to hospital discharge. DESIGN AND PARTICIPANTS: A data linkage study evaluating all adult patients in South Australia between 2004 and 2011 who survived hospitalisation that required admission to a public hospital ICU. MAIN OUTCOME MEASURES: All patients were evaluated using hospital coding for diabetes, which was crossreferenced with registration with the Australian National Diabetes Services Scheme for a diagnosis of diabetes. This dataset was then linked to the Australian National Death Index. Longitudinal survival was assessed using Cox proportional hazards regression. Life-years lost were calculated using age- and sex-specific life-tables from the Australian Bureau of Statistics. RESULTS: 5450 patients with diabetes and 17 023 patients without diabetes were included. Crude mortality rates were 105.5 per 1000 person-years (95% CI, 101.6-109.6 per 1000 person-years) for patients with diabetes, and 67.6 per 1000 person-years (95% CI, 65.9-69.3 per 1000 personyears) for patients without diabetes. Patients with diabetes were older and had higher illness severity scores on admission to the ICU, were more likely to die after hospital discharge (unadjusted hazard ratio [HR], 1.52 [95% CI, 1.45-1.59]; adjusted HR, 1.16 [95% CI, 1.10-1.21]; P < 0.0001) and suffered a greater number of average lifeyears lost. CONCLUSIONS: Our study indicates that crude mortality for ICU survivors with pre-existing diabetes is considerable after hospital discharge, and the risk of mortality is greater than for survivors without diabetes.

Stress Induced Hyperglycemia and the Subsequent Risk of Type 2 Diabetes in Survivors of Critical Illness.

OBJECTIVE: Stress induced hyperglycemia occurs in critically ill patients who have normal glucose tolerance following resolution of their acute illness. The objective was to evaluate the association between stress induced hyperglycemia and incident diabetes in survivors of critical illness. DESIGN: Retrospective cohort study. SETTING: All adult patients surviving admission to a public hospital intensive care unit (ICU) in South Australia between 2004 and 2011. PATIENTS: Stress induced hyperglycemia was defined as a blood glucose ≥ 11.1 mmol/L (200 mg/dL) within 24 hours of ICU admission. Prevalent diabetes was identified through ICD-10 coding or prior registration with the Australian National Diabetes Service Scheme (NDSS). Incident diabetes was identified as NDSS registration beyond 30 days after hospital discharge until July 2015. The predicted risk of developing diabetes was described as sub-hazard ratios using competing risk regression. Survival was assessed using Cox proportional hazards regression. MAIN RESULTS: Stress induced hyperglycemia was identified in 2,883 (17%) of 17,074 patients without diabetes. The incidence of type 2 diabetes following critical illness was 4.8% (821 of 17,074). The risk of diabetes in patients with stress induced hyperglycemia was approximately double that of those without (HR 1.91 (95% CI 1.62, 2.26), p<0.001) and was sustained regardless of age or severity of illness. CONCLUSIONS: Stress induced hyperglycemia identifies patients at subsequent risk of incident diabetes.

Metformin-associated lactic acidosis (MALA): clinical profile and outcomes in patients admitted to the intensive care unit.

BACKGROUND: Metformin, a widely used hypoglycaemic agent in type 2 diabetes mellitus, is uncommonly associated with lactic acidosis, a serious condition with high mortality. OBJECTIVE: To evaluate the incidence of metforminassociated lactic acidosis (MALA) in an Australian intensive care unit, and the clinical profile and outcomes of patients admitted to the ICU with this diagnosis. DESIGN, SETTING AND PARTICIPANTS: We analysed data on patients admitted to a 14-bed tertiary care adult ICU over a 5-year period (January 2003 to December 2007). We did manual searches of ICU discharge summaries, reviewing case notes and cross-referencing with the ICU electronic database to identify and characterise patients with an ICU discharge diagnosis of MALA. MALA was defined as a syndrome of elevated blood lactate level with acidaemia in patients taking metformin (after other causes of lactic acidosis had been excluded). RESULTS: There were 17 patients in our study cohort, with a mean age of 65 (SD, 9.9) years. MALA was diagnosed in 6 per 1000 ICU admissions. All patients with MALA presented with gastrointestinal symptoms of nausea, vomiting and/or diarrhoea, and 11 had clinical signs of dehydration. Patients had evidence of severe acidosis (mean pH 6.92 [SD, 0.26]; anion gap, 34 [SD, 10]); high lactate levels (mean 9.6 [SD, 4.1] mmol/L); and acute renal dysfunction (mean creatinine level 585 [SD, 305] µmol/L). The mean APACHE (Acute Physiology and Chronic Health Evaluation) III score was 106.4 (SD, 42.9). The mean invasive mechanical ventilation time (for 13 patients who required ventilation) was 23.4 (SD, 32.3) hours, and mean ICU length of stay was 62.8 (SD, 53.5) hours. Thirteen patients required dialysis and vasopressor support and two had a negative laparotomy; 5/17 patients (29%) died. APACHE III score, arterial pH on admission and male sex were associated with an increased risk of death in hospital (P < 0.05). CONCLUSION: MALA is a not uncommon cause of ICU admission. Gastrointestinal symptoms predominate in MALA, and the condition is associated with significant morbidity and mortality.