Is It Time to Jump off the Intensive Insulin Therapy Bandwagon?

Abstract & Commentary

By Andrew M. Luks, MD, Pulmonary and Critical Care Medicine, University of Washington, Seattle, is Associate Editor for Critical Care Alert.

Dr. Luks reports no financial relationship to this field of study.

Synopsis: This single-center, randomized controlled trial demonstrated that intensive insulin therapy targeting blood glucose values of 80-110 mg/dL does not improve mortality, but does increase the incidence of hypoglycemia in a group of critically ill medical and surgical patients.

Source: Arabi YM, et al. Intensive versus conventional insulin therapy: A randomized controlled trial in medical and surgical critically ill patients. Crit Care Med 2008;36:3190-3197.

Although the original study by Van den Berghe et al sparked interest in the use of intensive insulin therapy in the ICU,1 subsequent studies have cast doubt on the efficacy and safety of this practice.2 Arabi and colleagues sought to further clarify these issues by comparing the use of intensive (IIT) and conventional (CIT) insulin protocols in a combined medical-surgical intensive care unit (ICU) patient population.

The authors conducted a randomized controlled trial in a combined medical-surgical-trauma ICU at a single institution. They included all ICU patients > 18 years of age with a serum glucose > 110 mg/dL within the first 24 hours of admission, and excluded all patients with Type 1 diabetes mellitus, diabetic ketoacidosis, documented hypoglycemia on the current admission, or a variety of other criteria. All included patients were started on an insulin drip (250 units Humulin® R insulin in 250 mL of 0.9% normal saline) and were then randomized to have blood glucose values maintained between either 80-110 mg/dL or 180-200 mg/dL. There was no blinding of the treatment assignment. Blood glucose values were initially monitored every hour with adjustments in the frequency of monitoring based on whether the patient had low or stable glucose values. The primary outcome variable was ICU mortality and secondary endpoints included hospital mortality, ICU and hospital length of stay, duration of mechanical ventilation, number of hypoglycemic events, the need for renal replacement therapy, and the incidence of ICU-acquired infections. These outcome variables were compared using t-tests, chi-square tests, and proportional tests and the analysis was based on the intention-to-treat principle.

A total of 523 patients were enrolled in the study, 266 in the IIT group and 257 in the CT group. The groups were well matched except the IIT group was younger and had less diabetes and lower inclusion blood glucose values. The average daily insulin dose was 71.2 ± 50.2 units in the IIT group and 31.4 ± 42.4 units in the CIT group. The average glucose level was 115 ± 18 mg/dL in the IIT group and 171 ± 34.2 mg/dL in the CIT group. There were no differences in mortality between the IIT and CIT groups (13.5% vs 17.1%; P = 0.30), but IIT was associated with a higher incidence of hypoglycemia (defined as blood glucose < 40 mg/dL), with 28.6% of the IIT patients experiencing at least one episode of hypoglycemia compared to only 3.1% in the CIT group. Patients who had hypoglycemia had higher ICU mortality than those who did not (23.8% vs 13.7%); in sub-group analysis, IIT was associated with decreased mortality in patients with BMI < 26.2 kg/m2 or APACHE II < 22 and increased ICU mortality in patients with GCS < 9. There were no differences between IIT and CIT in any of the other secondary endpoints.

Commentary

Even though it was a single-center trial involving only surgical patients, the study by van den Berghe et al provoked a sea-change in ICU practice marked by the widespread adoption of intensive insulin therapy protocols in both medical and surgical ICU patients.1 This bandwagon effect was similar to that seen after single trials showed possible benefits from recombinant activated protein C and corticosteroid therapy in patients with septic shock. The data from Arabi and colleagues, along with a growing literature on the topic, suggest it may be time to jump off the IIT bandwagon and reevaluate our current practices. Granted, the current study was a non-blinded trial at a single institution with only 21 ICU beds, but the results are in line with those of other recent trials demonstrating that intensive insulin therapy with tight glucose targets is associated with an increased incidence of hypoglycemia and/or no clear mortality benefit.2,3 Whether these protocols should be abandoned altogether is not clear from these studies, but the increased incidence of hypoglycemia, which is being increasingly documented in these and other trials, suggests that we should at a minimum move away from protocols with strict glucose targets of 80-110 mg/dL and instead accept more modest goals of glucose values in the mid-100 mg/dL range and focus on avoiding severe hyperglycemia.

References

  1. van den Berghe G, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359-1367.
  2. Brunkhorst FM, et al; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125-139.
  3. Treggiari MM, et al. Intensive insulin therapy and mortality in critically ill patients. Crit Care Med 2008;12:R29.