1. Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2009 年 4 月 2 日 8:30-8:55 ８階 医局 Vlasselaers D, Milants I, Desmet L, Wouters PJ, Vanhorebeek I, van den Heuvel I, Mesotten D, Casaer MP, Meyfroidt G, Ingels C, Muller J, Van Cromphaut S, Schetz M, Van den Berghe G. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet. 2009 Feb 14;373(9663):547-56. The NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hébert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283-97.

2. 入院患者総死亡率 Mortality Rate During Hospitalization

3. Medical ICU での高血糖と死亡率

4. Surgical ICU でのインスリン強化療法による 死亡率減少

5. 重症入院患者へのインスリン治療：死亡 率 （無作為ランダム化研究のメタ解析） 35 publications, n=8478

7. Lancet 2009; 373: 547–56 Department of Intensive Care Medicine (Paediatric Intensive Care Unit), Catholic University Leuven, Leuven, Belgium (D Vlasselaers MD, I Milants RN, L Desmet MD, P J Wouters MSc, I Vanhorebeek PhD, I van den Heuvel MD, D Mesotten MD, M P Casaer MD, G Meyfroidt MD, C Ingels MD, J Muller MD, S Van Cromphaut MD, M Schetz MD, Prof G Van den Berghe MD)

8. Background Critically ill infants and children often develop hyperglycaemia, which is associated with adverse outcome; however, whether lowering blood glucose concentrations to age-adjusted normal fasting values improves outcome is unknown. We investigated the effect of targeting age-adjusted normoglycaemia with insulin infusion in critically ill infants and children on outcome. Funding Research Foundation (Belgium); Research Fund of the University of Leuven (Belgium) and the EU Information Society Technologies Integrated project “CLINICIP”; and Institute for Science and Technology (Belgium).

9. Methods In a prospective, randomised controlled study, we enrolled 700 critically ill patients, 317 infants (aged <1 year) and 383 children (aged ≥1 year), who were admitted to the paediatric intensive care unit (PICU) of the University Hospital of Leuven, Belgium. Patients were randomly assigned by blinded envelopes to target blood glucose concentrations of 2 ・ 8–4 ・ 4 mmol/L in infants and 3 ・ 9– 5 ・ 6 mmol/L in children with insulin infusion throughout PICU stay (intensive group [n=349]), or to insulin infusion only to prevent blood glucose from exceeding 11 ・ 9 mmol/L (conventional group [n=351]). Patients and laboratory staff were blinded to treatment allocation. Primary endpoints were duration of PICU stay and inflammation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00214916.

10. 50-80 70-90mg/dl 6585 5070 3040 Figure 1: Insulin titration guideline for intensive insulin therapy in the paediatric intensive care unit

11. Table 1: Baseline demographics

12. Figure 2: Trial profile PICU=paediatric intensive care unit. ICU=intensive care unit. DNR=do not resuscitate. *The 19 medical disorders that were considered unsuitable by the treating physician consisted of two patients dependent on home ventilation, six metabolic disorders, two patients for whom it was the personal opinion of the treating physician that it would be inappropriate to participate in a study in view of poor prognosis (although the patients formally did not have a DNR code), and nine patients who had already been treated with intensive insulin therapy elsewhere before assessment for participation.

13. Insulin infusions were prepared as 10 IU Actrapid HM (Novo Nordisk, Bagsvard, Denmark) in 50 mL NaCl 0 ・ 9% for patients weighing less than 15 kg, as 20 IU Actrapid HM in 50 mL NaCl 0 ・ 9% for those weighing 15– 30 kg, and as 50 IU Actrapid HM in 50 mL NaCl 0 ・ 9% for those weighing more than 30 kg. We used a syringe-driven infusion pump (B/Braun- Perfusor-Space, B Braun, Melsungen, Germany). We set the starting insulin dose at 0.1 IU/kg/h for a first measurement above upper normal limit and at 0.2 IU/kg/h for a first measurement above twice the upper normal limit. The insulin dose was adjusted by 0 ・ 02 IU/h to 1 IU/h increments, on the basis of measurement of blood glucose concentration in undiluted arterial blood at 1–4 h intervals with the ABL700 analyser (Radiometer Medical A/S, Copenhagen, Denmark). The ABL700 analyser reported results as corrected to plasma concentrations. For infants, insulin infusions were stopped when blood glucose fell to less than 2.8 mmol/L, and 1 mL/kg of a 50% dextrose solution was given when blood glucose fell to less than 1.7 mmol/L. For children, we stopped insulin infusions when blood glucose fell to less than 3.9 mmol/L, and 1 mL/kg of a 50% dextrose solution was given when blood glucose fell to less than 2.2 mmol/L (figure 1). Insulin Infusion Protocol

14. The middle horizontal lines within the boxes represent medians, boxes show IQR. Data are shown for the first 10 days and the last day (LD) in PICU. (A) Daily amounts of total kcal/kg per day for each age group. (B) Daily amounts of infused glucose (mg/kg per min). The two groups were comparable for the feeding strategy on all time points. (C) Daily doses of insulin (IU/kg per day). (D) Morning blood glucose concentrations for each age group. ADM=admission. Figure 3: Nutrition and blood glucose control

15. The middle horizontal lines within the boxes represent medians, boxes show IQR. Data are shown for the first 10 days and the last day (LD) in PICU. (A) Daily amounts of total kcal/kg per day for each age group. (B) Daily amounts of infused glucose (mg/kg per min). The two groups were comparable for the feeding strategy on all time points. (C) Daily doses of insulin (IU/kg per day). (D) Morning blood glucose concentrations for each age group. ADM=admission.

16. Table 2: Morbidity outcomes

21. Figure 4: Effect on infllammation and mortality

22. (A) Mean changes from day 1 concentrations of C-reactive protein (CRP) in the conventional and intensive insulin groups for the first 5 days in PICU. Error bars indicate SE. p value was obtained by repeated measures ANOVA for overall significance of the difference in time course of CRP (time*treatment interaction). The p value for the change in CRP on day 5, calculated by Mann-Whitney U test, was 0 ・ 007. (B) Kaplan-Meier analysis depicting cumulative incidence of PICU death(%) for time (days) in PICU in the conventional and intensive insulin groups. The p value was obtained by log-rank testing.

23. Table 3: Mortality in the two treatment groups

24. Findings Mean blood glucose concentrations were lower in the intensive group than in the conventional group (infants: 4 ・ 8 [SD 1 ・ 2] mmol/L vs 6 ・ 4 [1 ・ 2] mmol/L, p median) stay in PICU was 132 (38%) in the intensive group versus 165 (47%) in the conventional group (p=0 ・ 013). Nine (3%) patients died in the intensively treated group versus 20 (6%) in the conventional group (p=0 ・ 038).

25. Interpretation Targeting of blood glucose concentrations to age- adjusted normal fasting concentrations improved short-term outcome of patients in PICU. The effect on long-term survival, morbidity, and neurocognitive development needs to be investigated.

27. The NICE-SUGAR study is a collaboration of the Australian and New Zealand Intensive Care Society Clinical Trials Group, the George Institute for International Health (University of Sydney), the Canadian Critical Care Trials Group, and the Vancouver Coastal Health Research Institute (University of British Columbia). The NICE-SUGAR study writing committee (Simon Finfer, F.R.C.P., F.J.F.I.C.M., Dean R. Chittock, F.R.C.P.C., Steve Yu- Shuo Su, Ph.D., Deborah Blair, R.N., Denise Foster, R.N., Vinay Dhingra, F.R.C.P.C., Rinaldo Bellomo, F.J.F.I.C.M., Deborah Cook, M.D., Peter Dodek, M.D., William R. Henderson, F.R.C.P.C., Paul C. Hebert, M.D., Stephane Heritier, Ph.D., Daren K. Heyland, M.D., Colin McArthur, F.J.F.I.C.M., Ellen McDonald, R.N., Imogen Mitchell, F.R.C.P., F.J.F.I.C.M., John A. Myburgh, Ph.D., F.J.F.I.C.M., Robyn Norton, Ph.D., M.P.H., Julie Potter, R.N., M.H.Sc.(Ed.), Bruce G. Robinson, F.R.A.C.P., and Juan J. Ronco, F.R.C.P.C.) assumes full responsibility for the overall content and integrity of the article. Address reprint requests to Dr. Finfer at the George Institute for International Health, P.O. Box M201, Missenden Rd., Sydney NSW 2050, Australia, or at sfinfer@george.org.au.

28. In this study, adults who were expected to require treatment in the intensive care unit on 3 or more consecutive days were randomly assigned to undergo intensive blood glucose control (target range, 81 to 108 mg per deciliter [4.5 to 6.0 mmol per liter]) or conventional blood glucose control (180 mg per deciliter [10.0 mmol per liter])

29. Assessment, Randomization, and Follow-up of the Study Patient The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

30. Baseline Characteristics of the Study Patients The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

31. Blood Glucose Management and Levels, Calorie Administration, and Corticosteroid Treatment, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

32. Data on Blood Glucose Level, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

33. Outcomes and Adverse Events The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

34. Probability of Survival and Odds Ratios for Death, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

35. Study Overview In this study, adults who were expected to require treatment in the intensive care unit on 3 or more consecutive days were randomly assigned to undergo intensive blood glucose control (target range, 81 to 108 mg per deciliter [4.5 to 6.0 mmol per liter]) or conventional blood glucose control (180 mg per deciliter [10.0 mmol per liter]) The primary end point was death from any cause within 90 days after randomization Intensive glucose control increased mortality among the patients The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

36. Conclusion In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

37. Message It would be a disservice to our critically ill patients to infer from the NICE- SUGAR data that neglectful glycemic control involving haphazard therapeutic approaches (e.g., use of insulin “sliding scales”) — all too common a decade ago — is again acceptable practice in our ICUs. Glucose Control in the ICU — How Tight Is Too Tight? Silvio E. Inzucchi, M.D., and Mark D. Siegel, M.D. N Engl J Med 2009;360:1346-1348.

39. Insulin Infusion Protocol The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297 https://studies.thegeorgeinstitute.org/nice/