Chest
Volume 137, Issue 3, March 2010, Pages 544-551
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Original Research
Critical Care Medicine
Toward Understanding Tight Glycemic Control in the ICU: A Systematic Review and Metaanalysis

https://doi.org/10.1378/chest.09-1737Get rights and content

Background

Following publication of the Leuven Intensive Insulin Therapy Trial in 2001, tight glycemic control became the standard of care in ICUs around the world. Recent studies suggest that this approach may be flawed. The goal of this systematic review was to determine the benefits and risks of tight glycemic control in ICU patients and to explain the differences in outcomes among reported trials.

Methods

Prospective, randomized controlled clinical trials (RCTs) that studied the impact of tight glycemic control (blood glucose 80-110 mg/dL) on mortality in ICU patients were identified through a search of MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, and a citation review of relevant primary and review articles. Data were abstracted on study design, study size, and patient characteristics, as well as on the mean (or median) and SD of the ICU blood glucose level, mean daily dose of insulin administered, average daily caloric intake, percentage of calories given intravenously (parenteral nutrition), incidence of hypoglycemia, need for dialysis, and 28-day/hospital mortality. Metaanalytic techniques were used to analyze the data; subgroup analysis and metaregression were used to explain differences in the treatment effect.

Results

We identified seven RCT studies that included 11,425 patients. Overall, tight glycemic control did not reduce the 28-day mortality (odds ratio [OR] 0.95; 95% CI, 0.87-1.05), the incidence of blood stream infections (OR 1.04; 95% CI, 0.93-1.17), or the requirement for renal replacement therapy (OR 1.01; 95% CI, 0.89-1.13). The incidence of hypoglycemia was significantly higher in patients randomized to tight glycemic control (OR 7.7; 95% CI, 6.0-9.9; P < .001). Metaregression demonstrated a significant relationship between the treatment effect (28-day mortality) and the proportion of calories provided parenterally (P = .005). This suggests that the difference in outcome between the two Leuven Intensive Insulin Therapy Trials and the subsequent trials could be related to the use of parenteral nutrition. When the two Leuven Intensive Insulin Therapy Trials were excluded from the metaanalysis, mortality was lower in the control patients (OR 0.90; 95% CI, 0.81-0.99; P = .04; I2 = 0%).

Conclusions

There is no evidence to support the use of intensive insulin therapy in general medical-surgical ICU patients who are fed according to current guidelines. Tight glycemic control is associated with a high incidence of hypoglycemia and an increased risk of death in patients not receiving parenteral nutrition.

Section snippets

Identification of Trials

Our aim was to identify all relevant RCTs that compared the mortality of ICU patients randomized to an IIT protocol aimed to achieve tight glycemic control (glucose of 80-110 mg/dL) with those randomized to a control arm that received less strict glucose control. The primary outcome measure was 28-day (or hospital) mortality. Secondary outcome measures included the need for dialysis, acquired blood stream infections, and the incidence of hypoglycemia (defined as a blood glucose of < 40 mg/dL).

Trials Included

Figure 1 shows details of study identification, inclusion, and exclusion. Our search strategy initially yielded 62 citations. Of these, six unique studies met our inclusion criteria.4, 14, 15, 27, 28, 29 One additional study (published in abstract form) was identified from a review of articles identified by the initial search strategy30; this study has subsequently been published in full.31 In all, seven studies met the inclusion criteria; these included the two Leuven Intensive Insulin Therapy

Discussion

The NICE-SUGAR study, as well as four additional RCTs, were unable to replicate the findings of the two Leuven Intensive Insulin Therapy Trials and, indeed, raised the possibility that tight glycemic control may increase organ failure and death in patients fed according to current guidelines. It seems unlikely that the difference in outcome between these trials was due to a failure to reach the target blood glucose levels, because the mean daily glucose and insulin use was similar among

Conclusions

In conclusion, we believe that the variation in intravenous glucose load may explain the conflicting outcomes between the Leuven Intensive Insulin Therapy studies and the subsequent confirmatory studies. Furthermore, our metaanalysis suggests that there are no data to support the use of IIT in patients who are fed enterally.

Acknowledgments

Author contributions: Dr Marik: was responsible for performing the metaanalysis, interpreting the data, and writing the manuscript.

Dr Preiser: was responsible for performing the metaanalysis, interpreting the data, and writing the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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