Journal Club

1. Journal Club 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. Epub 2009 Jan 26. Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, McManus K, Champagne CM, Bishop LM, Laranjo N, Leboff MS, Rood JC, de Jonge L, Greenway FL, Loria CM, Obarzanek E, Williamson DA. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med. 2009 Feb 26;360(9):859-73. 亀田メディカルセンター　糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田　昌文 Matsuda, Masafumi 2009年3月19日　8:20-8:50 B棟８階　カンファレンス室

2. 入院患者総死亡率

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） 35publications, n=8478

6. 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) Lancet 2009; 373: 547–56

7. 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).

8. 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.

9. Figure 1: Insulin titration guideline for intensive insulin therapy in the paediatric intensive care unit 50-8070-90mg/dl 65 85 50 70 30 40

10. Table 1: Baseline demographics

11. 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.

12. Figure 3: Nutrition and blood glucose control 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.

13. Figure 3: Nutrition and blood glucose control 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.

14. Table 2: Morbidity outcomes

19. Figure 4: Effect on infllammation and mortality

20. Figure 4: Effect on infllammation and mortality (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.

21. Table 3: Mortality in the two treatment groups

22. 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<0・0001; children: 5・3 [1・1] mmol/L vs 8・2 [3・3] mmol/L, p<0・0001). Hypoglycaemia (defined as blood glucose ≤2・2 mmol/L) occurred in 87 (25%) patients in the intensive group (p<0・0001) versus fi ve (1%) patients in the conventional group; hypoglycaemia defined as blood glucose less than 1・7 mmol/L arose in 17 (5%) patients versus three (1%) (p=0・001). Duration of PICU stay was shortest in the intensively treated group (5・51 days [95% CI 4・65–6・37] vs 6・15 days [5・25–7・05], p=0・017). The inflammatory response was attenuated at day 5, as indicated by lower C-reactive protein in the intensive group compared with baseline (–9・75 mg/L [95% CI –19・93 to 0・43] vs 8・97 mg/L [–0・9 to 18・84], p=0・007). The number of patients with extended (>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).

23. 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.

25. Original ArticleComparison of Weight-Loss Diets with Different Compositions of Fat, Protein, and Carbohydrates Frank M. Sacks, M.D., George A. Bray, M.D., Vincent J. Carey, Ph.D., Steven R. Smith, M.D., Donna H. Ryan, M.D., Stephen D. Anton, Ph.D., Katherine McManus, M.S., R.D., Catherine M. Champagne, Ph.D., Louise M. Bishop, M.S., R.D., Nancy Laranjo, B.A., Meryl S. Leboff, M.D., Jennifer C. Rood, Ph.D., Lilian de Jonge, Ph.D., Frank L. Greenway, M.D., Catherine M. Loria, Ph.D., Eva Obarzanek, Ph.D., and Donald A. Williamson, Ph.D. N Engl J Med Volume 360(9):859-873 February 26, 2009

26. From the Department of Nutrition, Harvard School of Public Health (F.M.S., L.M.B.); the Channing Laboratory (F.M.S., V.J.C., N.L.) and the Endocrine Division (M.S.L.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School; and the Department of Nutrition, Brigham and Women’s Hospital (K.M.) — all in Boston; Pennington Biomedical Research Center of the Louisiana State University System, Baton Rouge (G.A.B., S.R.S., D.H.R., S.D.A., C.M.C., J.C.R., L.J., F.L.G., D.A.W.); and the National Heart, Lung, and Blood Institute, Bethesda, MD (C.M.L., E.O.).

27. This randomized trial compared the effect of reduced-calorie diets with various compositions of fat, protein, and carbohydrates on weight loss over a 2-year period

28. Baseline Characteristics of the Study Participants

29. Baseline Characteristics of the Study Participants

30. Mean Change in Body Weight and Waist Circumference from Baseline to 2 Years According to Dietary Macronutrient Content

31. Mean Changes in Body Weight and Waist Circumference at Various Time Points

32. Risk Factors, Nutrient Intake, and Biomarkers of Adherence, According to Diet, at 6 Months and 2 Years

33. Factorial-Design Estimates of Effect of Diet Type on Mean Changes from Baseline in Risk Factors, Nutrient Intake, and Biomarkers of Adherence

34. Change in Body Weight from Baseline to 2 Years According to Attendance at Counseling Sessions for Weight Loss, among the 645 Participants Who Completed the Study

35. Weight Loss at 2 Years According to Adherence to Dietary Fat and Protein Goals Sacks FM et al. N Engl J Med 2009;360:859-873

36. Study Overview • This randomized trial compared the effect of reduced-calorie diets with various compositions of fat, protein, and carbohydrates on weight loss over a 2-year period • Compliance with the diets was not high • No significant differences in weight loss were observed among the various diets • Reduced-calorie diets appear to have similar effects on weight loss regardless of their particular compositions N Engl J Med 2009;360:859-73.

37. Conclusion • Reduced-calorie diets result in clinically meaningful weight loss regardless of which macronutrients they emphasize N Engl J Med 2009;360:859-73.