Tight Glucose Control in the ICU—Risks May Outweigh Benefits

SAN FRANCISCO—The results of two separate studies discussed at the American Thoracic Society’s 103rd International Conference showed that tight glucose control in the ICU may significantly increase the incidence of adverse events, compared with standard glucose control.

Liberal and intensive insulin therapy regimens were analyzed in the Glucontrol trial, where hypoglycemia rates were about four times higher in ICU patients in the intensive therapy arm than in the liberal therapy arm, with no significant benefits. Jean-Charles Preiser, MD, PhD, and researchers stopped this trial early due to safety and protocol concerns.

“There are a number of reasons against maintaining tight glucose control in critically ill patients,” remarked Konrad Reinhart, MD, who presented the results of the Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial. Dr. Reinhart and colleagues, too, stopped their study early when a comparatively much higher rate of hypoglycemia was observed in patients with severe sepsis and sepsis shock treated under a strict glucose control protocol.

In a second component of the VISEP trial, researchers compared volume resuscitation with the use of hydroxyethyl starch (HES) therapy and with use of Ringer’s lactated solution. Use of the starch solution was linked to renal failure and increased mortality, particularly in patients who received higher-than-recommended dosages.

THE EFFECTS OF TWO GLUCOSE REGIMENS IN THE GLUCONTROL TRIAL

A 2001 study led by Greet Van den Berghe, MD, brought attention to glucose control in critical care when intensive insulin therapy (maintenance of blood glucose levels between 80 and 110 mg/dL) was found to reduce both morbidity and mortality in surgical ICU patients. In a 2006 study led by the same author, intensive insulin therapy reduced morbidity but not mortality in the medical ICU.

The publication of these studies was like “a dream that came true,” Dr. Preiser recalled. “We had a new therapeutic modality, which was easily accessible, cheap, reduced complication rate, reduced mortality, decreased length of stay … with some risks and constraints,” he noted. “At the time, it seemed that the benefits outweighed the risks.”

However, Dr. Van den Berghe’s findings have since been criticized as being limited to single-center ICUs and as such cannot be extrapolated to other conditions. Controversies remain regarding the optimal target for blood glucose levels, the issue of hypoglycemia as a life-threatening event, and the category of patients who could benefit from tight glucose control, Dr. Preiser said. To address these concerns, the Glucontrol study was conducted in seven European countries to determine the effects of intensive and liberal insulin regimens, with blood glucose targets of 80 to 110 mg/dL and 140 to 180 mg/dL, respectively. Investigators enrolled a broad range of subjects ages 18 and older who had been admitted to 21 participating ICUs.

The initial plan was to enroll 3,500 patients to determine if a 4% decrease in absolute ICU mortality could be detected, but the study was halted after randomization of 1,101 patients because of protocol issues and a fourfold-higher rate of hypoglycemia in the intensive group than in the liberal group (8.6% vs 2.4%). Although there was a trend toward higher mortality in the intensive arm, there was no statistically significant difference between ICU, hospital, or 28-day mortality rates.

These findings made the dream of tight glucose control a “less convenient truth,” Dr. Preiser said. “Based on the data that we have collected, a glucose control target between 80 and 110 mg/dL is too hazardous. An intermediate-range target between 140 and 180 mg/dL would be more ideal.”

INSULIN THERAPY IN SEVERE SEPSIS

The purpose of the VISEP trial was to determine if the benefit of strict glucose control, as seen in Dr. Van den Berghe’s initial study, applies to patients with severe sepsis and septic shock. Using the same targets and protocol as Dr. Van den Berghe, investigators randomized patients to conventional insulin therapy (goal, 180 to 200 mg/dL) or intensive insulin therapy (goal, 80 to 110 mg/dL).

The trial was stopped early, after enrollment of 480 patients, due to the increased incidence of hypoglycemia in the intensive arm (17.6%) versus the conventional therapy arm (4.5%). The reporting of hypoglycemia as a life-threatening incident was also significantly higher in the treatment arm than in the control arm (5.3% vs 2.1%, respectively). There were no significant differences in the 28- or 90-day mortality rates between the two arms. A trend toward longer ICU stay by approximately two days was seen in patients in the intensive arm. Multivariate analyses showed intensive insulin therapy and the patients’ age to be risk factors for hypoglycemia.

“I believe hypoglycemia is adaptive. It’s a marker, not a mediator of disease,” commented Dr. Reinhart. “The sicker your patient is, the more careful you have to be with tight glucose control.”

FLUID VOLUME RESUSCITATION

In a separate analysis of the VISEP study, Dr. Reinhart and colleagues examined two options of fluid resuscitation—10% HES (10% Hemohes) and Ringer’s lactated solution (Sterofundin)—in patients with severe sepsis and sepsis shock.

There was no significant difference in total sepsis-related organ failure assessment (SOFA) scores; however, coagulation and renal SOFA scores were significantly higher in the patients who received HES. The need for renal replacement therapy was much higher in the HES group than in patients who received Ringer’s lactate (35% vs 18.6%, respectively). In addition, the HES group spent a total of 650 days on renal replacement therapy, compared with only 321 days in those who received the crystalloid, Dr. Reinhart noted.

In some cases, researchers administered more than the highest recommended dose of HES, which is 22 mL/kg. In patients who received high doses for at least one day, the mortality rate increased by about 20%. “The higher the cumulative doses of HES, the higher the mortality rate,” Dr. Reinhart noted. “Thus, there is a clear association between the amount of HES that is administered and mortality.”           

—Jessica Jannicelli

Reference
Devos P, Preiser JC. Current controversies around tight glucose control in critically ill patients. Curr Opin Clin Nutr Metab Care. 2007;10(2):206-209.
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449-461.
Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345(19):1359-1367.

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