1. Unit 2 : Macronutrient utilisation František Duška Dept. Of Anaesthesia and CCM Charles University, 3rd Faculty of Medicine, Prague, CZ

2. Maintenance or restoration of mitochondrial function and cellular energetics is another therapeutic target, in addition to optimisation of cardiac output, systemic oxygen delivery, and regional blood flow, that might improve outcome for critically ill patients. Ilse Vanhorebeek, Lancet 2005

3. 1.Methods in metabolic research 2.Carbohydrate metabolism 3.Lipid metabolism 4.Protein metabolism 5.Metabolic dearrangments of critical illness in summary

5. Metabolism of ICU patient: Methods available at the bedside Plasma levels of circulating substrates, hormones ▫easily available ▫say nothing about turnover Indirect calorimetry ▫allows to calculate EE and oxidation rates of particular substrates ▫severe limitations: steady state, FiO2, circuit leaks

6. Metabolism of ICU patient: Experimental methods Clamp techniques ▫e.g. euglycaemic clamp = gold standard in the measurement of insulin sensitivity Microdialysis Tracer methods – stable isotopes ▫EGP, HGO ▫leucine kinetics: net protein synthesis/brakdown ▫net lipogenesis (13C acetate – VLDL enrichment)

7. Phases of critical illness Ebb phase – hypometabolism, up to 24 hrs ▫  CO,  EE Flow phase – hypermetabolism, 2nd-10th day ▫hyperglycaemia, insulin resistance, hyperproteokatabolism Protracted critical illness, more than 10 days ▫„wasting syndrome“, generalized pituitary suppression Cuthbertson, 1942; van den Berghe, 1998

8. Substrate oxidation in critically ill patients after 3 day starvation Resting metabolic rate 1824 kcal/ day Glycemia 7.3 mmol/L Endogenous glucose production360 g/ day (1360 kcal/day) Net glucose oxidation 28% (512 kcal/ day) Net fat oxidation46% (840 kcal /day) Net protein oxidation26% (470 kcal/ day Net protein balance-117 g/ day

10. Prevalence of hyperglycemia in critically ill patients at intensive care unit admission Control groupIntensive TT Patients783765 History of diabetes (%)103 (13)101 (13) Admission glycemia < 6.1 mmol/l24 %27% > 6.1 mmol/l76 %73% > 11.1 mmol/l13%11 % Van den Berghe G et al, N Engl J Med 2001; 345 1359

11. (Duška et al., Metabolism, 2007)

12. Insulin-dependent and insulin-independent organs & tissues Insulin-independent-organs Brain Red blood cells Kidney medulla Inflammatory & granulation tissues, wounds Macrophages Insulin resistancepreferential glucose supply to insulin-independent tissues Insulin-dependent organs Skeletal muscle (Glut-4) Myocardium (Glut-4) Fat tissue (Glut-4)

13. Effects of intravenous glucose on endogenous glucose production in healthy subjects EGP (mg.kg.min) * * P < 0.05 * * * Glucose delivery Mg.kg -1.min -1 Wolfe RR et al, Metabolism 1979; 28: 210

14. Glucose endogenous production is not suppressed by glucose infusion in critically ill patients VariableHealthyICU 1. Fasting Glycemia 4.87.1* Insulin54115* 2. IV glucose Glycemia5.7#9.7*# Insulin89#515*# * P < 0.05 vs healthy # p < 0.05 vs fasting Mmol.kg -1.min -1 Tappy L, Am J Physiol 1995; 268:E630

15. Effects of enteral carbohydrate on glucose flow (Ra) and endogenous production (EGP) in critically ill patients  mol.kg.min # # # Schwarz JM et al, Am. J. Clin. Nutr 2000; 72: 940

16. Glucose oxidation is maintained in burned patients Wolfe RR et al, Metabolism 1979; 28: 1031 Normal values Mg / kg per min Postabsorptive + glucose infusion

17. Energy metabolism in critically ill cardiac and septic patients: RMR & substrate oxidation 6postoperative cardiac surgery patients with acute heart failure (inotropes) 6 patients with severe sepsis CardiacSepsisp Resting MR (kcal/d)13901610NS Glucose net oxidation (  mol/kg/min) 4.31.75 < 0.05 Lipid net oxidation (mg/kg/min) 0.60 1.26 < 0.05 Martinez A et al, Clin Physiol Funct Imaging 2002; 23: 286

18. Carbohydrate metabolism: conclusions Hyperglycaemia even in patients without diabetes High glucose turnover ▫insulin resistance, uncoupling of glucose disposal from insulin regulation ▫increased gluconeogenesis, unsuppressible with exogenous glucose

20. Fat metabolism: effect of a carbohydrate-rich meal in healthy subjects Frayn KN, Metabolism; 42: 504

21. Relationship between free fatty acid (NEFA) plasma concentration and turnover Issekutz, Metabolism 1967; 16: 1001

22. Metabolic changes in 5 patients with severe sepsis and 5 healthy subjects Chambrier C, Clinical Science 2000; 99: 321

24. Effects of enteral CHO on fractional hepatic DN lipogenesis in healthy ill & critically ill subjects # P < 0.05 # # # # # + bedrest Healthy Isocaloric nutrition 53% CHO 13 C acetate Minehira K et al, 2001, Clin Nutr 2002; 21: 345 Fractionnal DNL (% VLDL-palmitate) Schwarz JM et al, Am. J. Clin. Nutr 2000; 72: 940 Critically ill

25. Lipid metablism: conclusion NEFA mobilization and oxidation is higher than normal, but probably lower than required De novo lipogenesis rate is high, energy consuming. It depends rather upon glucose intake than upon plasma insulin level.

27. Cumulative N balance in mechanically ventilated patients receiving full enteral feeding Grams Days

28. Body composition in septic ICU patients receiving full nutritional support 8 ICU septic patients TPN : 31 kcal nonprotein energy + 2.3 g N /kg FFM Body composition: neutron activation analysis Streat SJ, J. Trauma 1987;27:262

29. Body composition (proteins) in patients with abdominal sepsis receiving full enteral support * P < 0.05 * * * Protein (kg) * * Plank, LD et al, Ann. Surg. 1998; 228: 146 total body protein visceral protein skeletal muscle protein

30. Protein metabolism in trauma patients with or without brain injury Petersen SR et al, J. Trauma 1993; 34: 653 G protein /kg per day

31. Glucose vs lipid for isocaloric TPN Carbohydrate (CHO) and lipid net oxidation mg / kg per min *#*# 75%glucose, 10% fat, 15% amino acids *#*# * p <0.05 vs basal # p<0.05 vs fat 70% fat, 15%glucose, 15% amino acids Tappy L et al, CCM 1998; 26:860

32. Protein breakdown & net balance are improved by hypercaloric glucose supply in burns 14 severely burned children (> 40% BSA) Hypercaloric EN: 1500 kcal/m 2 + 1500/m 2 TBSA/day High CHO diet (82% CHO, 3% fat, 15% protein) versus high- fat diet (42% CHO, 44% fat, 14% protein), Reverse crossover design Hart DW et al, CCM 2001; 29: 1318

33. Conclusions: protein metabolism The negative nitrogen balance of critical illness is due to increased net protein breakdown, whilst protein synthesis is relatively maintained The resistance of the proteocatabolism to the provision of energy substrates defines „stress starvation“ (in contrast to simple starvation)

36. Thanks for attention!