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For critically ill patients, strictly controlling glucose to a normal level without early parenteral nutrition neither helped nor harmed outcomes, the randomized TGC-Fast trial showed.

Duration of stay in the intensive care unit (ICU) was similar (HR 1.00, P=0.94) whether insulin was initiated only for blood glucose above 215 mg/dL (liberal control) or was given to maintain levels in the 80-110 mg/dL range, guided by a computer algorithm to avoid causing severe hypoglycemia, reported Greet Van den Berghe, MD, PhD, of University Hospitals of KU Leuven in Belgium, and colleagues.

Tight glucose control didn't impact 90-day mortality either, compared with liberal glucose control (10.5% vs 10.1%, P=0.51), they noted in the .

"The results of this new trial help to settle and contextualize the long-­term controversy about the safety and efficacy of intensive glucose control in the ICU," wrote Guillermo E. Umpierrez, MD, of Emory University in Atlanta, in an .

Prior randomized controlled trials have come to conflicting conclusions about the best glucose control strategy in the ICU. Three single-center trials had shown better outcomes with tight control to the healthy, age-adjusted fasting range, whereas subsequent multicenter trials didn't confirm that benefit and the largest () actually showed greater mortality risk, attributed to substantially increased severe hypoglycemia.

One key explanation for the difference among trials appears to have been how patients were fed after admission.

"In the earlier studies, patients received medical nutrition with intravenous glucose, parenteral nutrition, enteral feeding, or combined feeding within 24 hours after ICU admission, an uncommon practice that has not been followed in other trials," Umpierrez noted.

In TGC-Fast, both groups received parenteral nutrition no sooner than 1 week after admission to avoid hyperglycemia.

"These findings suggest that the use of early parenteral nutrition in previous studies was an important iatrogenic factor that increased hyperglycemia into a potentially toxic range," Van den Berghe and colleagues wrote. The TGC-Fast data "add evidence to the recommendation to omit early parenteral nutrition for adult patients in the ICU because this omission reduces the need for blood-glucose control."

The American Diabetes Association recommends starting insulin for most critically ill patients with persistent blood glucose levels over 180 mg/dL, with a target of 140-180 mg/dL. More stringent goals are deemed potentially appropriate if achievable without clinically significant hypoglycemia.

Umpierrez concluded that clinicians should continue to avoid the extremes of hyperglycemia, "which have acute ad­verse effects with respect to inflammation and oxidative stress, neutrophil function, renal function, and hemodynamics."

The trial included 9,230 consecutive adults admitted across 11 ICUs at two university hospitals and one district hospital in Belgium from September 2018 through August 2022 with a temporary pause during the first COVID-19 wave in 2020. Patients admitted to closed COVID-19 units were not eligible for the trial after the trial resumed.

Even so, the primary outcome -- length of time that ICU care was needed (time to discharge alive from the ICU or until readiness for discharge) -- "may have been confounded by fluctuating discharge policies owing to a shortage of ICU beds, a major problem during the COVID-19 pandemic," the researchers noted.

Participants were randomized to the two glucose control arms, with the trial intervention stopped after the patient started to eat, no longer had a central venous catheter, or was discharged from the ICU.

Among the prespecified secondary endpoints, incidence of new infections, the duration of respiratory and hemodynamic support, time to discharge alive from the hospital, and mortality in the ICU and hospital were similar between groups. Tight glucose control led to less severe acute kidney injury (7.2% vs 8.6%, relative risk [RR] 0.84, 95% CI 0.73-0.97) and cholestatic liver dysfunction (28.3% vs 32.9% with plasma γ-glutamyl transferase levels ≥90 U/L, RR 0.86, 95% CI 0.81-0.92, and 11.5% vs 13.0% with plasma alkaline phosphatase levels ≥195 U/L, RR 0.88, 95% CI 0.78-0.99).

"Also, the clinical relevance of the lower incidence of kidney and liver dysfunction with tight glucose control and of the possible treatment heterogeneity in patients with a neurologic or neurosurgical admission diagnosis remains uncertain," the researchers wrote.

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