ICU Glucose Control

Stress hyperglycaemia was long considered an adaptive response in critical illness — a 'fight or flight' epiphenomenon best left untreated. In 2001, Greet Van den Berghe's Leuven I trial transformed this paradigm by demonstrating that intensive insulin therapy (targeting blood glucose 80-110 mg/dL) reduced ICU mortality by 34% compared to conventional treatment (glucose <215 mg/dL) in surgical ICU patients. With 1,548 patients and a striking mortality reduction from 8.0% to 4.6%, the trial made immediate global impact. Intensive insulin therapy was rapidly adopted worldwide, and tight glycaemic control became a quality metric in many ICUs. The effect appeared largely mediated through reductions in sepsis, renal failure, and polyneuropathy.

The Leuven II trial (2006) attempted to replicate these findings in medical ICU patients but failed to show a mortality benefit in the intention-to-treat population, though it demonstrated reductions in morbidity including earlier weaning from mechanical ventilation and shorter ICU stay. The trial also highlighted the risk of severe hypoglycaemia (18.7% in the intensive group), raising safety concerns. Multiple subsequent single-centre and multicentre studies produced conflicting results, creating genuine clinical equipoise about the risk-benefit balance of tight glucose control.

The NICE-SUGAR trial (2009) definitively resolved the debate. This landmark study of 6,104 patients across 42 hospitals in Australia, New Zealand, and Canada compared intensive glucose control (81-108 mg/dL) to conventional control (<180 mg/dL) and found that tight control significantly increased 90-day mortality (27.5% vs 24.9%, OR 1.14). Severe hypoglycaemia was six times more common with intensive therapy (6.8% vs 0.5%), and the excess deaths were predominantly cardiovascular. NICE-SUGAR was the definitive corrective: it demonstrated that the harms of tight glucose control — principally hypoglycaemia — outweighed any benefits in a general ICU population. The trial swung the pendulum from 'tighter is better' to moderate glucose targets, fundamentally changing practice worldwide.

Post-NICE-SUGAR, all major guidelines abandoned tight glucose targets. The Surviving Sepsis Campaign 2021 recommends initiating insulin when two consecutive glucose levels exceed 180 mg/dL, targeting an upper limit of 180 mg/dL (10 mmol/L) rather than the 80-110 mg/dL range previously advocated. The guidelines explicitly recommend against tight glycaemic control (80-110 mg/dL) due to the demonstrated harm from hypoglycaemia. ADA and AACE guidelines for hospitalised patients similarly recommend a target range of 140-180 mg/dL for most ICU patients, with avoidance of both hyperglycaemia above 180 mg/dL and hypoglycaemia below 70 mg/dL.

Current practice targets blood glucose below 180 mg/dL in most ICU patients, with a pragmatic range of 140-180 mg/dL. The emphasis has shifted from the glucose target itself to avoiding both extremes — hyperglycaemia above 180 mg/dL and hypoglycaemia below 70 mg/dL — as well as minimising glycaemic variability, which observational data increasingly identify as an independent predictor of mortality. Continuous glucose monitoring (CGM) technology is being evaluated in the ICU setting, with the potential to reduce hypoglycaemia through real-time alerts and trend information. Closed-loop insulin delivery systems — combining CGM with algorithmic insulin dosing — represent the frontier of ICU glucose management. The TGC-Fast and CONTROLING trials are investigating whether technology-enabled tight control can deliver the theoretical benefits without the hypoglycaemic harms that undermined the Leuven approach.