Leuven II trial- Intensive Insulin Therapy in the Medical ICU significantly reduced morbidity but not mortality.

Find the original article here:

https://www.nejm.org/doi/full/10.1056/NEJMoa052521

Summary:

This was a single center, randomized controlled trial in a Medical ICU that compared a conventional approach to blood glucose (BG) control with a goal of 180 to 200 mg/dL to a strict normalization goal (intensive regime) treating BG > 110 mg/dL to target 80 to 110 mg/dL.

Unlike the original Leuven trial, this studied a Medical ICU population, and the intensive approach was shown not show to reduce mortality.

Less informing were hypothesis generating secondary outcomes of renal failure (but not need for renal replacement therapy) and ventilator time, which seemed to favor intensive regimes. Additionally, a subgroup analysis of patients staying more than 3 days in the ICU also pointed to a potential decrease in mortality.

PICOTT:

POPULATION:  

N= 1200 

Inclusion: Adult patients admitted to a medical ICU and expected to require 3 days. 

Exclusion: Surgical patients and medical patients able to eat, patients with <3 days expected stay and patients with DNR.  

INTERVENTION: 

Treatment: Strict normalization of BG. Rx insulin infusion when BG >110 mg/dL to maintain BG 80 to 110 mg/dL  

COMPARATOR:  

Control: Rx insulin infusion when BG >215 mg/dL to maintain BG 180 to 200 mg/dL 

OUTCOMES:  

• Primary: death from any cause during hospitalization. 

• Secondary: Mortality in the ICU, 90-day mortality, ventilator days, ICU & Hospital LOS, new dialysis, inotropic or vasopressor support, Critical illness polyneuropathy, markers of infection, transfusion requirement and hyperbilirubinemia. 

TYPE OF STUDY: 

Randomized controlled trial 

TYPE OF QUESTION: 

Therapy 

Interpretation of the Study: 

The authors found statistically significant secondary outcomes such as reductions in renal failure, ventilator time, ICU & hospital stay even though there was no mortality reduction in the intention to treat group (primary outcome). The benefits of reduced morbidity are only hypothesis generating. Beyond the selected intention to treat group, those who remained in the ICU more than three days; the extended group, intensive insulin Rx did reduce mortality and enjoyed the same reductions in morbidity as the intention to treat group. Subgroup analyses are also hypothesis generating and should be interpreted as such. Why would a longer ICU stay improve mortality? Are we paying more attention to these patients? Is there any other co-intervention? A larger study was needed, and 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%) v Conventional Rx 242/605 (40%); P <0.33 

  
  

Secondary Outcomes: Intention to treat Group 

• ICU Mortality Day 3: Intensive Rx 23/595 (3.9%) vs Conventional Rx 17/605 (2.8%); P= 0.31.  

• ICU Mortality 90 Day: Intensive Rx 214/595 (35.9%) vs Conventional Rx 228/605 (37.7%); P= 0.53. 

• New Renal Injury:  Intensive Rx 5.9% vs 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 (No statistically significant, HR touches one)

Primary outcome: Extended Stay group (>3 days)

• All-cause mortality in the hospital: Intensive Insulin Rx 166/386 (43%) vs 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

  
  

Secondary Outcomes: Extended Stay 

• New Dialysis: Intensive Rx 27.2% vs 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: Low

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 were not able to blind the treatment groups, which could lead to different co-interventions (not detailed in the article). The lack of blinding could have involuntarily affected outcomes such as the ventilator length of stay and ICU length of stay which could be more subjective.

The intention to treat group was well powered and there was minimal loss to follow adequately inform us on the chosen outcomes, while the extended group signaling mortality benefit did not.

Teaching points:

Subgroup Analysis.

Primary vs Secondary outcomes.

Blinding.

Similar Co-interventions.

Hazard Ratios.

Verdict:

Somewhat settled - Might change with more data