“Intensive versus conventional glucose control in critically ill patients.” – the NICE-SUGAR investigators, The New England Journal of Medicine, March 26th, 2009
“Intensive insulin therapy in critically ill patients.” – Greet van de Berghe et al., The New England Journal of Medicine, November 8, 2001
“Intensive insulin therapy in the medical ICU.” – Greet van de Berghe et al., The New England Journal of Medicine, February 2, 2006
Control of blood glucose in the Intensive Care Unit (ICU) and the hospital has implications in many disease processes, including cardiovascular, renal, and infectious problems. Elevated or abnormally low blood glucose values can compound with the primary problem and complicate a patient’s hospital stay. Over the course of the 2000s, three large studies attempted to establish and validate a strategy to control blood sugar in the ICU.
The first two trials (van de Berge 2001 and van de Berghe 2006) were conducted at a single center with patient numbers in the 1400-1500 range. The 2001 study followed patients in the Surgical ICU, and the 2006 study in the Medical ICU. These investigators proposed an intensive glucose control regimen where an insulin infusion was initiated at levels higher than 110 mg/dL (the upper limit of normal blood sugars) and titrated to blood levels in the 80-110 mg/dL normoglycemic range. This was compared with a conventionally treated group where insulin drips were started once blood sugar exceeded 215 mg/dL, and titrated to a range of 180-215 mg/dL.
The NICE-SUGAR study was a multi-centered study that included medical and surgical ICUs, with a total patient population of 6104. The intensive therapy was repeated similar to the studies above. The conventional arm of patients received an insulin drip once blood glucose levels exceeded 180 mg/dL. Insulin drip was discontinued when glucose levels fell below 144 mg/dL. The target glucose level was < 180 mg/dL. Importantly, inclusion criteria for this trial selected patients that expected to remain in the ICU > 3 days.
Van de Berghe 2001 found that the intensive therapy resulted in reduced in-hospital mortality and ICU mortality, especially in patients staying longer that 5 days. The intensive therapy group also had fewer morbidity rates including lower rates of sepsis. Hypoglycemia did occur more frequently in the intensive therapy group.
Van de Berghe 2006 also found ICU and in-hospital death was lower in the intensive treatment arm in patients who stayed in the ICU for longer than 3 days. There was no significance in mortality between the two arms in terms of in-hospital or ICU mortality for all ICU patients. Hypoglycemia occurred more frequently in the intensive therapy arm. There was an improvement in morbidities – requirements of mechanical ventilation, ICU stay and hospital stay in the intensive arm, but no significant fewer episodes of sepsis.
The NICE-SUGAR study found an increased all-cause mortality at 90 days after admission to the ICU in the intensive treatment arm when compared to conventional treatment. The majority of the deaths in both arms of the study were in-hospital or in the ICU. There was no significant difference in morbidities, including sepsis, except for an increased number of hypoglycemic episodes in the intensive glucose management group.
Why We Do What We Do
After the 2001 van de Berghe paper, intensive glucose management became the standard of practice in the ICU. However, after the striking results of the NICE-SUGAR study, the recommended practice is now a liberal approach to glucose management with a goal of blood sugars < 180 mg/dL and treatment only above this level. Large sample size and diversity in multiple trial centers provide this study with validity in a broad range of ICU and hospital applications.
Statistical significance of the data is also important – the 2006 medical ICU van de Berghe study failed to find a difference between in-hospital and ICU mortality between the two arms of the study for all patients, so the contemporary standard of practice (intensive management) was considered to be safe and valid. However, NICE-SUGAR’s results were statistically significant in showing that intensive therapy actually led to increased mortality. Clinical practice changed quickly as a result of this significant data.
After the results of the NICE-SUGAR study, there was extensive discussion into why intensive glucose control increased mortality, in stark contrast to the previous two landmark studies by van de Berghe. The authors of NICE-SUGAR did not expand on a cause for the increased mortality, but referred to lower blood sugars, increased insulin administration and increased episodes of hypoglycemia as being possible explanations. When under stress, as critical patients are, the body naturally produces a hyperglycemic state with increased corticosteroid responses, and dampening this response with artificial insulin administration may work against the complex defense mechanisms of the stressed-state body. The results of NICE-SUGAR interestingly correlate with another landmark trial on outpatient diabetes, the ACCORD trial, which also found that intensive glucose management increased mortality. However, more research was requested by both the ACCORD and NICE-SUGAR studies to explain their results.
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