Intensive insulin helped those with long ICU stays

Current data support careful maintenance of normoglycemia in most ICU patients, from admission onwards.

Issue: April 2006

Intensive insulin therapy administered from admission onwards in patients in the medical intensive care unit reduced morbidity among all patients and mortality among those who remained in the ICU for at least a third day.

“Hyperglycemia and insulin resistance are common in severe illness and are associated with adverse outcomes,” investigators wrote in the New England Journal of Medicine. Greet Van den Berghe, MD, PhD, and colleagues conducted a randomized, controlled study of intensive insulin therapy for patients in the medical ICU, targeting those requiring intensive care for at least a third day. Van den Berghe is a professor of medicine at the Catholic Unversity of Leuven in Belgium.

A previous study found that patients in the surgical ICU had a pronounced mortality benefit from intensive insulin therapy if treatment lasted into the the third day and beyond.

“Several potential mechanisms may explain these benefits – prevention of immune dysfunction, reduction of systemic inflammation, and protection of the endothelium and of mitochondrial ultrastructure and function,” the researchers wrote.

Study cohort

Between March 2002 and May 2005, 1,200 adult patients admitted to the medical ICU were enrolled in the study. Patients were excluded if they had do-not-resuscitate orders upon admission or if they were able to receive oral nutrition; investigators wrote that the latter group of patients generally do not require three or more days of intensive care.

Patients were randomized to either intensive insulin treatment (n=595) or conventional insulin treatment (n=605). Conventional therapy consisted of continuous insulin infusion starting when the blood glucose level exceeded 215 mg/dL.

The dose was then adjusted to maintain a glucose level between 180 mg/dL and 200 mg/dL, and the infusion was tapered and stopped when the glucose level dropped below 180 mg/dL. Intensive therapy began with insulin infusion when glucose levels exceeded 110 mg/dL; normoglycemia (80 mg/dL to 110 mg/dL) was maintained.

There were no significant differences in baseline characteristics between the two groups, including medications other than insulin.

Morbidity was reduced in the intensive treatment group, with a reduction in newly acquired kidney injury (8.9% in the conventional group vs. 5.9% in the intensive group, P=.04), earlier weaning from mechanical ventilation (HR 1.21, 95% CI, 1.02-1.44) and earlier discharge from the ICU (HR 1.15, 95% CI, 1.01-1.32).

There were no significant effects on bacteremia, prolonged requirement of antibiotics, hyperbilirubinemia or hyperinflammation. More patients had hypoglycemia in the intensive treatment group, but there were no detectable adverse effects as the hypoglycemia was always detected and treated promptly.

Benefit after three days

Among all patients, there were nodifferences in mortality between the two treatment groups (26.8% in the conventional group vs. 24.2% in the intensive group, P=.31). However, a decrease in mortality was seen among the 767 patients who stayed in the ICU for at least three days (38.1% vs. 31.3%, P=.05). Investigators wrote that “death from all causes in the ICU appeared to be reduced.” In-hospital deaths among patients with longer stays were also reduced (52.5% vs. 43%, P=.009).

“Looking back at the data from our previous surgical study, it was clear that three days or more of intensive insulin therapy, started upon ICU admission, are needed to reduce hospital mortality,” Van den Berghe told Endocrine Today. “It’s like giving antibiotics; if you do not continue them long enough, they don’t work either. Three days of blood glucose control in ICU appears the minimum you need.”

In an accompanying editorial in the New England Journal of Medicine, Atul Malhotra, MD, expressed concern about possible risks of the shorter duration of intensive insulin therapy.

“Notably, among patients whose stays in the ICU were shorter … there was an apparent increase in mortality among those receiving intensive insulin therapy (56 deaths), as compared with those in the conventional-treatment group (42 deaths),” he wrote. “Unfortunately, there is no easy way to predict the duration of a patient’s stay in the ICU; therefore, it remains unclear which patients should receive intensive insulin therapy as they enter the ICU.”

More data needed?

Malhotra, who is an assistant professor of medicine at Brigham and Women’s Hospital in Boston, suggested that a more conventional approach should be used until conclusive data on the risks and benefits of intensive therapy are obtained.

“A reasonable approach would be to provide adequate exogenous insulin to achieve target glucose values of less than 150 mg/dL, at least during the first three days in the ICU. If critical illness persists beyond three days despite the provision of other proven therapies and resuscitation, a goal of normoglycemia (80 to 110 mg/dL) could then be considered, to maximize the potential benefits.”

Van den Berghe, however, said that the current study’s results offer enough clear evidence to warrant intensive insulin therapy in most patients in the medical ICU upon admission. “Sustained blood glucose control in patients with diabetes or critical illness prevents cellular damage inflicted by hyperglycemia and this benefit outweighs the risk of hypoglycemia,” she told Endocrine Today.

“Current data support careful maintenance of normoglycemia in most ICU patients, from admission onwards.” Because this study was designed to start treatment upon admission, she said, there is currently no evidence to support waiting until the third day to begin intensive therapy.

Van den Berghe also said that a larger study may have had the power to demonstrate mortality benefit even in a patient population that also included those whose medical ICU stays were shorter. Furthermore, the morbidity benefit among all patients should not be ignored.

“I’m sure that patients and insurance companies will not consider the reduced mechanical ventilation time, shorter ICU and hospital stays as negligible,” she said. “We’re currently investigating [potential risks of intensive insulin therapy], but thus far we feel quite confident that the risks of hyperglycemia are much more important than those of hypoglycemia.” – by Dave Levitan

For more information:

Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449-461.

Malhotra A. Intensive insulin in intensive care. N Engl J Med. 2006;354:516-518.