Glucose Control Literature Summaries

THE DIGAMI TRIALS 

Malmberg K, Rydén L, Efendic S, Herlitz J, Nicol P, Waldenström A, Wedel H, Welin L. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995 Jul;26(1):57-65. PMID: 7797776.

• Swedish SC RCT
• n = 620 patients with acute myocardial infarction who had diabetes mellitus or an elevated glucose on presentation
• Intervention: insulin-glucose infusion followed by multidose subcutaneous insulin for ≥3 months
• comparison: conentional therapy
• results:
  — no reduction in mortality at 3 months but significant reduction in mortality at 1 year (18.6% vs 26.1%, RRR 29%, p = 0.027 ), which  persisted for 3 years
  — most significant decrease in mortality was in patients not previously on insulin and those with low cardiovascular risk prior to MI
• Commentary and criticisms:
  -> followed up and published in BMJ: mortality reduced from 44% to 33% with same benefits as seen for thrombolysis in acute MI

Malmberg K, et al; DIGAMI 2 Investigators. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J. 2005 Apr;26(7):650-61. PMID: 15728645.

• Swedish SC RCT
• n = 1253 with type 2 diabetes and suspected acute myocardial infarction
• DM II with MI
• Interventions and comparison: group 1: acute insulin-glucose infusion followed by insulin-based long-term glucose control; group 2: insulin-glucose infusion followed by standard glucose control; and group 3: conventional therapy according to local practice
• Outcomes: all cause mortality groups 1 versus 2 (primary), and between groups 2 and 3 (secondary); morbidity (tertiary)
• Results:
  — no reduction in mortality, CVA or re-infarction
• Commentary and criticisms:
  — By the end of follow-up, HbA1c did not differ significantly among groups 1-3 ( approximately 6.8%); all were improved from baseline
  — this study does not support one glucose control strategy over another

THE LEUVEN TRIALS 

Van Den Berghe G, et al. Intensive insulin therapy in  critically ill patients. N Engl J Med. 2001 Nov 8;345(19):1359-67. PMID: 11794168.

• aka The Leuven Surgical trial
• SC RCT in Leuven, Belgium
• n = 1548 adult surgical ICU patients receiving mechanical ventilation
• Intervention and comparison: target BSL 10-11 mM versus 4.5-6.5 mM
• Outcome: mortality (primary); multiple secondary outcomes
• Results:
  —ICU mortality was less with intensive insulin therapy (8% vs 4.6%; RR 0.42; 95% CI 22-62%; P<0.04)
  — Also less were: in-hospital mortality was less (RRR 34%), sepsis (RRR 46%), ARF (RRR 41%), RBC transfusion (RRR 50%)
• Commentary and criticisms:
  — patients with pre-existing diabetes mellitus did not benefit
  — patients received high glucose loads (on ICU day #1, both arms received 200-300 g of IV glucose) and high rates of parenteral nutrition(majority on day 2 to meet caloric targets); hence questionable external validity
  — single center, unblinded
  — not subsequently replicated, and was contra-indicated and superseded by the NICE-SUGAR study
  — study was stopped early after multiple looks at the data

Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006 Feb 2;354(5):449-61. PMID: 16452557.

• aka The Leuven Medical Trial
• SC RCT in Leuven, Belgium
• n = 1200 medical ICU patients (requiring at least 3 days in ICU)
• Intervention and comparison: target BSL >12 mM versus 4.4-6.1 mM
• Results:
  — no reduction in in-hospital mortality (primary outcome)
  — reduction in renal injury, duration of MV, LOS in ICU and hospital
• Commentary and criticisms:
  — as for the Leuven Surgical Trial (see above)

VISEP 

Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008 Jan 10;358(2):125-39. PMID: 18184958.

• aka VISEP study
• MC RCT with two-by-two factorial trial
• n = 537 patients with severe sepsis
• Interventions and comparators: intensive insulin therapy (IIT) to maintain euglycemia or conventional insulin therapy (CIT) AND either 10% pentastarch  (HES 200/0.5) or modified Ringer’s lactate for fluid resuscitation
• Outcomes: mortality at 28 days and the mean score for organ failure were ‘coprimary’ end points
• Results:
  — no significant difference between the IIT and CIT groups in the rate of death or the mean score for organ failure
  — IIT group had lower mean blood glucose levels than CIT group (6.2 vs 8.4 mM, P<0.001) and higher rates of severe hypoglycaemia (i.e. <2.2 mM; 17.0% vs. 4.1%, P<0.001) and serious adverse events (10.9% vs. 5.2%, P=0.01)
  — higher rates of acute renal failure and renal-replacement therapy with HES compared to Ringer’s lactate
• Commentary and criticisms:
  —  trial was stopped early for safety reasons (under-powered)

NICE-SUGAR

NICE-SUGAR Study Investigators, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283-97. PMID: 19318384.

• MC RCT in Australia, New Zealand and  Canada
• n = 6,104 patients in 42 medical and surgical ICUs
• Intervention: intensive glucose control with a target BSL 4.5 – 6 mmol/L
• Comparison: standard care
• Outcomes:
  — Primary: mortality at 90 days
• Results:
  — intensive control increased mortality at 90 days (27.5% vs 24.9%)
  -> more deaths from cardiovascular causes
  -> more severe hypoglycaemias (<2.2 mM) (6.8% vs 0.5%; OR 14, 95% CI 9.0-25.9; P<0.001)
  -> tight glucose control does not benefit unselected ICU patients, may be harmful
  —  no difference between medical or surgical ICU patients
  — no differences in LOS, duration of ventilator therapy, or need for renal replacement therapy
• Commentary and criticisms:
  — intention-to-treat analysis was used
  — contradicted and superseded the intensive glucose control approach of the Leuven trials
  — widely adopted e.g. Surviving Sepsis Campaign Guidelines 2012
  — continuous glucose monitoring was not used
  — Patients received enteral nutrition exclusively, whereas supplemental parenteral nutrition was used in the Leuven studies
  — used subjective length of stay criteria
  — blinding was not possible

NICE-SUGAR Study Investigators, et al. Hypoglycemia and risk of death in critically ill patients. N Engl J Med. 2012 Sep 20;367(12):1108-18. PMID: 22992074.

• Post-hoc analysis of the NICE-SUGAR trial
• Patients with severe hypoglycaemia (BSL ≤ 2.2) 2x likely to die cf those without hypoglycemic episodes
• Patients with intensive control 10 x more likely to have severe  hypoglycemic episodes
• Patients with moderate hypoglycemic episodes 5% absolute greater risk of death than those with no hypoglycaemic episodes
• Dose-response relationship exists between hypoglycaemia and mortality
• Hypoglycaemia associated with longer ICU LOS
• Commentary: remember that correlation does not imply causation!

GLUCOSE CONTROL IN PAEDIATRIC ICU

Macrae D, et al; CHiP Investigators. A randomized trial of hyperglycemic control in pediatric intensive care. N Engl J Med. 2014 Jan 9;370(2):107-18. PMID: 24401049.

• MC RCT involving 13 ICUs in England
• n= 1369 patients ≤16 years of age admitted to pediatric ICU and  expected to require mechanical ventilation and vasoactive drugs for at least 12 hours
• Intervention: tight glycemic control, with a target blood glucose range of 72 to 126 mg per deciliter (4.0 to 7.0 mmol per liter)
• Comparison: conventional glycemic control, with a target level <12.0 mM
• Outcomes:
  — Primary: number of days alive and free from mechanical ventilation at 30 days
  — Secondary: prespecified subgroup analysis of children who had undergone cardiac surgery (60%); costs of hospital and community health services
• Results:
  — no difference in primary outcome (difference of 0.36 days, 95% CI = -0.42 to 1.14)
  — incidence of severe hypoglycemia (<2.0 mM) was higher with tight glucose control (7.3% vs. 1.5%, P<0.001)
  — hypoglycemia was significantly assocated with mortality in the cardiac surgery group, but not the non-cardiac surgery group
  — the mean 12-month costs were lower in the tight-glycemic-control group than in the conventional-glycemic-control group
• Criticisms and commentary:
  — continuous glucose monitoring was not used

References and Links

LITFL

• CCC — Glucose Control in ICU
• CCC — Stress Induced Hyperglycaemia