Understanding Blood Glucose Control in the ICU: A Critical Review

Summary of the Study

This study was a single-center, randomized controlled trial conducted in a Medical ICU. It compared two approaches to blood glucose (BG) control. The first approach aimed for a conventional BG target of 180 to 200 mg/dL. The second approach, known as the intensive regime, aimed to normalize BG levels, targeting 80 to 110 mg/dL for patients with BG levels exceeding 110 mg/dL.

Unlike the original Leuven trial, which focused on a different patient population, this study specifically examined patients in a Medical ICU. The results indicated that the intensive approach did not reduce mortality rates. However, some secondary outcomes, such as renal failure (without the need for renal replacement therapy) and ventilator time, appeared to favor the intensive regime. Additionally, a subgroup analysis of patients who stayed more than three days in the ICU suggested a potential decrease in mortality.

Study Design and Population

PICOTT Framework

Population:

N= 1200

• Inclusion Criteria: Adult patients admitted to a medical ICU with an expected stay of at least three days.

• Exclusion Criteria: Surgical patients, medical patients able to eat, patients expected to stay less than three days, and patients with DNR (Do Not Resuscitate) orders.

  
  

Intervention:

• Treatment: Strict normalization of BG. Insulin infusion was administered when BG exceeded 110 mg/dL to maintain levels between 80 and 110 mg/dL.

  
  

Comparator:

• Control: Insulin infusion was given when BG exceeded 215 mg/dL to maintain levels between 180 and 200 mg/dL.

  
  

Outcomes:

• Primary Outcome: Death from any cause during hospitalization.

• Secondary Outcomes: Mortality in the ICU, 90-day mortality, ventilator days, ICU and hospital length of stay (LOS), new dialysis, inotropic or vasopressor support, critical illness polyneuropathy, markers of infection, transfusion requirements, and hyperbilirubinemia.

  
  

Type of Study:

Randomized controlled trial

Type of Question:

Therapy

Interpretation of the Study

The authors found statistically significant secondary outcomes, including reductions in renal failure, ventilator time, and ICU & hospital stay. However, there was no reduction in mortality in the intention-to-treat group (the primary outcome). The benefits observed in morbidity are primarily hypothesis-generating.

Interestingly, for those who remained in the ICU for more than three days, the intensive insulin regimen did reduce mortality and also showed similar reductions in morbidity as the intention-to-treat group. It raises questions about why a longer ICU stay might correlate with improved mortality. Are we paying closer attention to these patients? Is there some other co-intervention at play? A larger study was warranted, and indeed, a larger study was forthcoming in the form of the NICE-SUGAR study.

Primary Outcome: Intention-to-Treat Group

• All-cause mortality in the hospital:

- Intensive Insulin Rx: 222/595 (37.3%)

- Conventional Rx: 242/605 (40%)

- P < 0.33

Secondary Outcomes: Intention-to-Treat Group

• ICU Mortality Day 3:

- Intensive Rx: 23/595 (3.9%)

- Conventional Rx: 17/605 (2.8%)

- P = 0.31

• ICU Mortality 90 Day:

- Intensive Rx: 214/595 (35.9%)

- Conventional Rx: 228/605 (37.7%)

- P = 0.53

• New Renal Injury:

- Intensive Rx: 5.9%

- Conventional Rx: 8.9%

- P = 0.04.

- ARR: 3%, NNT: 34

• Mechanical Vent Weaning:

- Intensive Rx Hazard Ratio (HR): 1.21 (95% CI 1.02 to 1.44) P = 0.03

• ICU LOS:

- Intensive Rx HR: 1.15 (95% CI 1.01 to 1.32) P = 0.04

• Hospital LOS:

- Intensive Rx HR: 1.16; 95% CI 1.00 to 1.35 P = 0.05 (not statistically significant, HR touches one)

Primary Outcome: Extended Stay Group (>3 days)

• All-cause mortality in the hospital:

- Intensive Insulin Rx: 166/386 (43%)

- Conventional Rx: 200/381 (52.5%)

- P = 0.009

- RR: 82%, RRR: 18%,

- ARR (RD): 9.5%, NNT: 11

• All-cause mortality increased in the short intensive insulin group.

  
  

Secondary Outcomes: Extended Stay

• New Dialysis:

- Intensive Rx: 27.2%

- Conventional Rx: 28.6%

- P = 0.7

• Mechanical Vent Weaning:

- Intensive Rx HR: 1.43; 95% CI 1.16 to 1.75 P < 0.001

• ICU LOS:

- Intensive Rx HR: 1.34; 95% CI 1.12 to 1.61 P = 0.002

• Hospital LOS:

- Intensive Rx HR: 1.58; 95% CI 1.28 to 1.95 P < 0.001

Overall Risk of Bias

The study authors met most validity criteria. They randomized, blocked, and stratified by diagnosis, which was unnecessary due to the sample size and created too many strata. They could not blind the treatment groups, which could lead to different co-interventions (not detailed in the article). The lack of blinding could have unintentionally affected outcomes such as ventilator length of stay and ICU length of stay, which can be more subjective.

The intention-to-treat group was well-powered, and there was minimal loss to follow-up, adequately informing us on the chosen outcomes. However, the extended group signaling a mortality benefit did not have the same robustness.

Key Teaching Points

• Subgroup Analysis: Understanding how different patient groups respond to treatment can guide future research and clinical practice.

• Primary vs. Secondary Outcomes: Distinguishing between these outcomes is crucial for interpreting study results.

• Blinding: The importance of blinding in clinical trials to minimize bias.

• Similar Co-interventions: Recognizing the potential impact of other treatments on study outcomes.

• Hazard Ratios: Understanding how to interpret hazard ratios in clinical research.

  
  

Verdict

Somewhat settled - Might change with more data

In conclusion, this study provides valuable insights into blood glucose control in the ICU. While the intensive insulin regimen did not reduce mortality in the overall population, it showed potential benefits for patients with longer ICU stays. Further research is needed to clarify these findings and improve patient care.

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