Clinical trials have produced inconclusive results regarding the optimal glucose range for a patient with sepsis in the intensive care unit (ICU) receiving insulin treatment.

To investigate the optimal glucose range in patients with sepsis in the ICU independent of confounding covariates.

Targeted trial emulation of glucose ranges using causal inference targeted maximum likelihood estimation and longitudinal mixed-effects models combined with survival models.

Single-centre, academic referral hospital in Boston, Massachusetts, USA.

Adults fulfilling sepsis 3 criteria with at least three glucose readings and insulin treatment from the Medical Information Mart for Intensive Care (MIMIC)-IV database (2008–2019).

Five predefined glucose distributions with means at 100, 130, 160 (baseline), 190 and 220 mg/dL mimicking current guidelines’ recommendations (140–180 mg/dL).

The primary outcome was in-hospital mortality. Modified counterfactual treatment-policy risks across distinct time-weighted glucose ranges were estimated.

Of 73 181 eligible patients, 8002 patients with a median age of 66 years (41% women, 67% white ethnicity, 57% diabetes) were included. There was a U-shaped curve between glucose range and mortality in patients without diabetes, but overall, this association was not significant (mean glucose at 100 mg/dL with 21% mortality and mean glucose at 220 mg/dL with 26% mortality, p-for-trend 0.26). Mortality was lowest at 17%, with mean glucose between 130 and 160 mg/dL. Hypoglycaemic events (

Our data suggest a U-shaped association of glucose and mortality with an optimal average glucose between 160 and 190 mg/dL. These results confirm current guideline recommendations. Together with recent results from randomised controlled trials, intensivists should aim for a liberal glucose range in most patients.