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  1. Journal Club Grand Rounds Nilda Franco, MD Richard Gerkin, MD Kristin Manley, DO Cheryl W. O’Malley, MD

  2. Revamped Journal Club • Teach critical appraisal: “JAMA User’s Guides” • Review 2 important articles around a common theme • One retro “landmark” • One recent • Statistical Principle • Review how to apply these studies to current practice

  3. November 2001

  4. What we knew… • Hyperglycemia in critically ill patients was common • Hyperglycemia was associated with worse outcomes • Physiologic rationale for improvements with glycemic control. • Outpatient control benefited type 1 and type 2 DM • Diabetes and Insulin-Glucose infusion in Acute MI (DIGAMI)

  5. First DIGAMI: Insulin Therapy Improves Outcomes in Patients with MI • IV insulin in AMI X 24 hours • Then subcutaneous for 3 months • Target glucose 126-180mg/dL • 29% reduction in mortality- 1 year • 28% reduction in mortality- 3.4 year • Which component (type of insulin) was responsible for the reduction?

  6. Intensive Insulin Therapy in Critically Ill Patients • Known famously as the “Van Den Berghe” trial • Published in the New England Journal of Medicine in November 2001

  7. Hypothesis of the study: • Study was to determine whether normalization of blood glucose levels with intensive insulin therapy reduces mortality and morbidity in critically ill patients.

  8. Study design • Prospective, randomized controlled trial at one university hospital in Belgium. • Involved adults admitted to the surgical ICU between 2/2/2000 and 1/18/2001 who were mechanically ventilated. • A total of 1548 patients were enrolled • On admission to the ICU patients were randomly assigned to either intensive or conventional insulin therapy

  9. Study design continued…. • Assignments to the treatment groups were made with the use of sealed envelopes • “Permuted block randomization” and stratification according to the type of illness were used to balance the two groups

  10. . Van den Berghe G et al. N Engl J Med 2001;345:1359-1367

  11. Study design continued…. • Pts were given IV glucose 200-300gm over the first 24 hours followed by parental/enteral/combined feeding • Undiluted arterial blood was used obtain the whole blood glucose on admission and Q4hours • The dose of the insulin was adjusted by a team of nurses and a study physician that were not involved in the clinical care of the patients. • The laboratory staff, electrophysiologist, and pathologist involved in the patients care were unaware of the treatment assignments of the patients.

  12. Study design: Conventional Group • The group had a continuous infusion of insulin mixed with normal saline and administered via pump if the glucose level exceeded 215 mg/dL. • Whole blood glucose levels were maintained between 180-200 mg/dL

  13. Study design: Intensive Treatment • In the group the insulin infusion was started if the blood glucose level exceeded 110 mg/dL. • Whole blood glucose levels were maintained between 80-110 mg/dL

  14. What Data Was Collected? • Baseline demographics, information to calculate APACHE scores, and Therapeutic Intervention Scoring System scores, blood glucose levels. • Blood cultures were obtained if there was a temperature of 38.5 degrees Celsius or above. • Weekly electromyographic screening for critical illness polyneuropathy was performed if duration of ICU stay was greater than 1 week

  15. Outcome Measures of the Study • Death from any cause during ICU stay • Number of days in ICU, prolonged stay or need for readmission • Ventilatory support • Renal replacement therapy • Inotropic/pressor support • Critical-illness polyneuropathy • C-reactive protein, WBC, body temperature • Bloodstream infection • Use of antibiotics for more than 10 days • Hyperbilirubinemia

  16. Results of the Study • Intensive Insulin Group: • Almost all required insulin. • AM glucose was 103 mg/dL on average. • 39 patients affected by hypoglycemia • Conventional Treatment Group: • 39% required insulin therapy • Average AM blood glucose was 153 mg/dL. • The remainder of the group had average AM glucose of 140 mg/dL.

  17. Results… • The trial had interim analyses of the overall mortality that were investigated at 3 month intervals. During the 4th interval it was determined that the conventional treatment was inferior and the study should be terminated early.

  18. Results on Mortality • 35 patients in the intensive-treatment group died during ICU stay as compared to 63 patients in the conventional group. • Apparent Risk reduction of 42 • Greatest reduction in deaths were those due to multiple-organ failure and associated sepsis

  19. Leuven Study: Intensive Insulin Therapy in the Surgical ICU 100 96 92 88 84 80 0 100 96 92 88 84 80 0 Intensive treatment Intensive treatment Conventional treatment Survival in ICU, % In-Hospital Survival, % Conventional treatment Mortality  42%, P<.04 Mortality  34%, P<.01 0 20 40 60 80 100 120 140 160 0 50 100 150 200 250 Days After Admission Days After Admission Van den Berghe G, et al. N Engl J Med. 2001.

  20. Risk Factors for Increased Mortality • APACHE II score of 9 or higher during the first 24 hours • Older in age • Admission involving non-cardiac surgery • Outside hospital referral • In the conventional insulin group without a prior history of diabetes or hyperglycemia

  21. Intensive Insulin Therapy in Critically Ill Surgical Patients: Morbidity and Mortality Benefits Mortality Sepsis Dialysis Blood Transfusion Polyneuropathy N = 1,548 34% 41% 44% 46% Reduction(%) 50% van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367.

  22. Van den Berghe Morbidity Data 30 Glucose 180-200 Glucose 80-110 25 20 % of Patients 15 10 5 0 >14d on Ventilator >14d in ICU Peak Cr. >2.5 ICU Sepsis Hyperbilirubinemia Antibiotics >10d Polyneuropathy

  23. Are the Results of the Study Valid? • Was the Assignment of the Patients to Treatment Randomized? • The assignment to the two groups was randomized using “permuted blocks.”

  24. Were All Patients Who Entered the Trial Properly Accounted for and Attributed at Its Conclusion? • Patients were accounted for but the trial was stopped early secondary to results showing a better outcome with mortality in the intensive insulin group.

  25. Were Patients, Their Clinicians, and Study Personnel “Blind” to Treatment? • Mostly-The clinicians involved could not be completely blinded because the blood sugar monitoring basically revealed the patient group. To minimize the bias the physician and ICU nurses involved in the insulin adjustment were blinded to important outcome measures and did not take part in clinical decisions. • Lab personnel, EMG physician, pathologist were all blinded to the treatment groups of the patients.

  26. Were the Groups Similar at the Start of the Trial? • Yes. Secondary to the randomization with permuted blocks-the groups had no significant difference between them at the beginning of the trial.

  27. Aside From the Experimental Intervention, Were the Groups Treated Equally? • The only differences in the treatments between the two groups were the insulin therapy and the antibiotics for the patients. The patients in the intensive insulin group required a shorter duration and less frequency of use of the antibiotics since there was an overall lower significant outcome of sepsis.

  28. What Were the Results? • How Large was the Treatment Effect? • Is significant with the risk reduction of death being 42% (ARR = 8.0%-4.6% = 3.4%) • Number needed to treat: • 1/ARR = 1/0.034 = 29.4

  29. How Precise Was the Estimate of Treatment Effect? • Precision is the relative width of the confidence interval • For mortality, the risk reduction was 42% (95% CI 22%-62%). This is slightly wide.

  30. Were all Clinically Important Outcomes Considered? • Yes • Mortality • Morbidity (Table 4) • Hypoglycemia

  31. Are the Likely Treatment Benefits Worth the Potential Harms and Costs? • According to this study results the treatment benefits do outweigh the harm and costs • 39 patients in the intensive insulin control group did have hypoglycemic episodes • The study using whole arterial blood with the measurement of the glucose likely was protective of hypoglycemic events as usually whole blood glucose is measured 15% lower than plasma glucose • The study also gave the patients 24 hours of IV glucose at the start of the study which probably helped lower the adverse outcome of severe hypoglycemia and death

  32. Can the Results be Applied to My Patient Care? -Single European center -Largely surgical patients

  33. Examples of clinical trials and other studies demonstrating better outcomes with improved glycemic control. *No diabetes †Diabetes

  34. Even more conditions have better outcomes with better glycemic control: • Chemotherapy outcomes (remission, survival, and infection rates) Weiser et al. Cancer 2004 Mar 15;100(6):1179-85 • Reduced rates of kidney transplant rejection Mathew et al, Transplantation 2001 Oct 15;72(7):1321-4 • Better outcomes in a mixed med / surgical “real world” ICU settingKrinsley JS. Mayo Clin Proc. 2004;79:992–1000. • Better outcomes in community acquired pneumonia The weight of evidence supports a goal of good glycemic control for all inpatients!

  35. American Association of Clinical EndocrinologistsInpatient Consensus Conference - 2003 • Conference Conclusions: • Improved glycemic control during hospitalization results in improved clinical outcomes • Diabetes management during hospitalization needs to become a much greater priority • Upper Limit Inpatient Glycemic Targets: • ICU: 110 mg/dl (6.1 mmol/L) • [Non-critical care • Pre-prandial: 110 mg/dl (6.1 mM) • Maximum: 180 mg/dL (10 mM) AACE Position Statement on Inpatient Diabetes and Metabolic Control Endocrine Practice 10 (1): 77-82, 2004

  36. Targets established in Dec 2003 • AACE Position Statement on Inpatient Diabetes and Metabolic Control • Endocrine Practice 10 (1): 77-82, 2004 • Garber AJ et al.; American College of Endocrinology Task Force on Inpatient Diabetes Metabolic Control. Endocr Pract. 2004;10:77-82. American Diabetes Association. Diabetes Care. 2005;28:S4-S36.

  37. History of Inpatient Glucose Control: 2006 • ACE, AACE & ADA plus numerous co-sponsoring organizations – “Call to Action Consensus Conference” • Addressing systemic implementation barriers • Inpatient hyperglycemia – a quality-of-care measure ACE/ADA Task Force on Inpatient Diabetes. Endocr Pract. 2006;12:458-468.

  38. Joint CommissionInpatient Diabetes Certification http://www.jointcommission.org/certificationprograms/inpatient+diabetes; accessed May 20, 2010. Specific staff education requirements Written blood glucose monitoring protocols Plans for treatment of hypoglycemia and hyperglycemia Data collection of incidences of hypoglycemia Diabetes self-care education Identified program champion or team

  39. Intensive Insulin Therapy in the Medical ICU Greet Van den Berghe, M.D., Ph.D., and the Leuven Group N Engl J Med, Volume 354;5:449-461, February 2, 2006 • RCT of insulin infusion to goal of 80-110 mg/dL vs usual therapy (180-200 mg/dL). • 1,200 patients randomized • A priori outcome of interest: patients in MICU for > 3 days • Only 17% were diabetic

  40. Conclusions: MICU study • Intention to treat: Intensive insulin therapy significantly reduced overall morbidity but not mortality. • Morbidity Reduced (newly acquired kidney injury, ICU days, hospital days and days on the vent.) • Predefined population analysis (ICU > 3 d): • In-house mortality reduced (ARR 9.5%-NNT10) • ICU mortality reduced (ARR 7.2%-NNT 14) p=.05 • BUT, More deaths (18.8 vs 26.8%) in patients in ICU < 3 days • -Once adjusted for patients with care limited or withdrawn in the first 72 hours it was (37.8% vs 33.5%-p=.1) • “More studies needed”

  41. Glucontrol Study (abstract info) • Mixed population of ICU patients (medical, scheduled and trauma surgery) • N = ~3500, multicenter, Europe • Target glucose: • 80 – 110 mg/dl vs. 140 – 180 mg/dl • Endpoint: in-hospital and 28 day mortality • Start: October 2004

  42. VISEP Brunkhorst et al, N Engl J Med 358:125-39, 2008

  43. VISEP Trial Study Aim: 600 subjects with sepsis randomized to conventional or intensive insulin therapy Methods: • Conventional Therapy: CII started at BG > 200 mg/dl and adjusted to maintain a BG 180 - 200 mg/dl. • Intensive Therapy group: CII started at BG > 110 mg/dl and adjusted to maintain BG 80 -110 mg/dl (Leuven’s protocol) Primary Outcomes: • Mortality (28 days) and morbidity (sequential organ failure dysfunction, SOFA) • Safety end-point: hypoglycemia (BG<40 mg/dl)

  44. IIT (n = 247) CIT (n = 290) P - 28 days - 90 days 24.7% 39.7% 26% 35.4% 0.74 0.31 < 0.0001 Patients with hypoglycemia < 40, % 17.0 % 4.1 % SOFA Score 7.7 7.3-8.3 7.8 7.3-8.3 0.16 VISEP Trial Mortality rate, % Data from 488 patients: IIT [goal: 80 – 110 mg/dL]: mean BG 112 mg/dl CIT [goal: 180 – 200 mg/dL]: mean BG 151 mg/dl Brunkhorst et al, N Engl J Med 358:125-39, 2008

  45. Infusion Protocols – Variable Hypoglycemia Rates

  46. Wiener, R. S. et al. JAMA 2008;300:933-944.

  47. Association of Tight Glucose Control vs Usual Care With Outcomes Among Critically Ill Adults Wiener, R. S. et al. JAMA 2008;300:933-944.

  48. Meta-Analysis results Percent of patients with >1 BG Less than 40 13.7% of patients VS 2.5% NNH=8.9

  49. Bringing it home: What’s been happening at Good Sam? • IV order set • Early 2004- multidisciplinary group • May 2004- subcut order set • Oct 2005- larger scale data collection • 2006- revisions in protocol and data analysis • June 2007- new tube feed order set • Dec 2007- IV order set standardized and data collection • Jan 2008-System-wide initiative targeting glycemic control (70-140 mg/dL) in the ICU