John P. Grant, MD, CNSP Director Nutrition Support Service Professor of Surgery

1. Nutrition Support in Critically IllLater Nutritional Needs and Metabolic Aberrations in Ventilated Patients John P. Grant, MD, CNSP Director Nutrition Support Service Professor of Surgery Duke University Medical Center Durham, NC

2. Optimal Metabolic Care of the Critically Ill Patient • Provide Optimal Metabolic Milieu • Maintain oxygenation • Adjust pH • Ensure perfusion • Control waste (dialysis - vol,lytes,prot)

3. Optimal Metabolic Care of the Critically Ill Patient • Minimize Metabolic Stress Response • Control pain • Debridement of necrotic/infected tissue • Drain abscesses • Dress or cover wounds

4. Optimal Metabolic Care of the Critically Ill Patient • Optimize milieu for cell metabolism • Minimize stress response • Provide adequate and appropriate nutritional support

5. Importance of Adequate Nutrition in the Critically Ill Patient • Nutrient balance and mortality in ICU patients • 4/15 with positive nitrogen balance died (27%) • 11/28 with 0 to -10,000 Kcal balance died (39%) • 12/14 with > -10,000 Kcal balance died (86%) Bartlett et al., Surgery 92:771, 1982

6. Caloric Balance and Outcome in ICU A = positive caloric balance B = 0 to -10,000 kcal balance C = > -10,000 kcal balance Caloric Balance vs % Mortality 86 90 80 70 60 50 39 40 27 30 20 10 0 A B C Bartlett et al., Surgery 92:771, 1982

7. Days of Survival Without Nutrition Days = { [(UBW X 2430) x K] - [(UBW - BW) x 2430]} AEE - Ei Where: UBW = usual body weight in kgBW = current body weight in kg K = 0.35 with stress; 0.4 with simple starvation AEE = actual energy expenditure (kcal/d)Ei = energy intake (kcal/d)

8. Importance of Adequate Nutritionin Respirator Dependent Patients • Arora and Rochester evaluated the effects of malnutrition on diaphragmatic muscle dimensions at necropsy and in vivo function in patients after prolonged illness (75% UBW) as compared with well nourished patients. Arora, N.S., and Rochester, D.F.: Am. Rev. Respir. Dis., 126:5-8, 1982.

9. Adequate Nutritional Support of Respirator Dependent Patients • Excessive calories, especially excess glucose calories, can result in excessive CO2 production and increased ventilatory demand in the already compromised patient. May delay weaning. • In ventilatory dependent patients, a high caloric load (2 X REE) has been shown to result in significantly higher O2 consumption and CO2 production than a moderate load (1.5 X REE) in patients otherwise receiving an identical diet. Van den Berg, B., and Stam, H.: Intensive Care Medicine, 14:206-211, 1988.

10. Adequate Nutritional Support of Respirator Dependent Patients • Formulas for estimating caloric needs: Ireton-Jones formula was designed specificallyfor patients with burns or trauma who simultaneously had pulmonary failure. The Ireton-Jones formula is: • BEE = 1925 - 10(A) + 5(W) + 281(S) 292(T) + 851(B) • where A = age in years, W = weight in kilograms,S = sex (male = 1, female = 0), and T = trauma and B = burn (present = 1, absent = 0)

11. Adequate Nutritional Support of Respirator Dependent Patients • Formulas for estimating caloric needs: Cal Long AEE (men) = (66.47 + 13.75 W + 5.0 H - 6.76 A) x (activity factor) x (injury factor) AEE (women) = (655.10 + 9.56 W + 1.85 H - 4.68 A) x (activity factor) x (injury factor)

12. Caloric Support of the ICU PatientOrgan Specific Substrate Support • Carbohydrate • Long-chain fatty acids • Medium-chain fatty acids (Structured Lipids) • Branched-chain amino acids • Glutamine

13. Organ Specific Substrate SupportGlucose • Glucose is required by the brain, renal medulla, red blood cells, and fibroblasts • Recommended daily consumption: Minimum of 200 and up to 700 grams/day (700 to 2400 kcal/day)

14. As increasing amounts of glucose are infused, a maximal rate of glucose oxidation and whole body protein synthesis is obtained at 5.0 to 6.0 mg/kg/min (~630 g/d for 80 kg patient) Burke et al., Ann Surg, 190:274, 1979

15. Use of Insulin to Stimulate Glucose Utilization • Does lower blood sugar in most cases • Drives glucose mainly into muscle • No documented increase in glucose oxidation or nitrogen sparing Vary et al., JPEN 10:351, 1986

16. Use of Insulin in Glucose Utilization Anaerobic Glycolysis Pyruvate Pyruvate Dehydrogenase Insulin Krebs cycle Fat Synthesis å

17. Organ Specific Substrate SupportLong-Chain Fatty Acids • Used as a fuel by many organs in the body • Must provide essential fatty acids (Linoleic, Arachidonic, Linolenic) = 15 grams/day

18. Organ Specific Substrate SupportLong-Chain Fatty Acids • Increased fat clearance from bloodstream during stress • Yet only about 8% is oxidized immediately Goodenough et al., JPEN 8:357, 1984

19. Organ Specific Substrate SupportLong-Chain Fatty Acids • In severe stress, fat clearance is minimalCerra et al., Surgery 86:409, 1979Lundholm et al., Crit Care Med 10:740, 1982 • May depress RES (>1 kcal/kg/h)Hamaway et al., JPEN 9:559, 1985

20. Organ Specific Substrate SupportLong-Chain Fatty Acids • Substituted glucose isocalorically with fat in an experimental animal burn model • Demonstrated a linear decrease in nitrogen balance as glucose was reduced N loss = 17.44 - 1.997 log e (glucose intake Kcal/sq m/d) + 0.0752 RME (kcal/sq m/d) Long et al., Ann Surg 185:417, 1977

21. Long-Chain Fatty Acids Require carnitine for transport through the inner mitochondrial membrane for beta oxidation

22. Organ Specific Substrate SupportLong-Chain Fatty Acids • Average recommended dose = 40 - 60 grams/day (360 to 540 kcal/day)

23. Adequate Nutritional Support of Respirator Dependent Patients • Lipid Support - Intravenous lipid emulsions can be harmful There is a nonlinier relationship between triglyceride concentration and rate of lipoprotein lipase-mediated triglyceride hydrolysis. When infusion of triglyceride exceeds hydrolysis, serum triglyceride concentrations rise. If triglyceride concentrations exceed a certain level, triglyceride-rich lipoproteins can be removed via nonenzymatic pathways, particularly by the reticuloendothelial system and the lung.

24. Adequate Nutritional Support of Respirator Dependent Patients • Lipid Support - Intravenous lipid emulsions can be harmful Higher infection rate, prolonged pulmonary failure, and delayed recovery was observed in a group of trauma patients given TPN with lipid infusions compared to a second group given TPN without lipids. Battistella, F.D., et al.: J. Trauma, 43:52-58, 1997.

25. Adequate Nutritional Support of Respirator Dependent Patients • Lipid Support – • A minimum of 1 to 2 percent of total caloric intake should be in the form of essential fatty acids to meet nutritional requirements • Give a mixture of glucose and long-chain fatty acids in a ratio of 60 to 80 percent glucose to 20 to 40 percent fat

26. Organ Specific Substrate SupportStructured Lipids • Contain both long-chain (40-50%) and medium-chain (50-60%) fatty acids (MCFA) • MCFA are used as a fuel by most tissues

27. Organ Specific Substrate SupportStructured Lipids • MCFA do not require carnitine for entry into mitochondria • Provide adequate essential fatty acids

28. Organ Specific Substrate SupportStructured Lipids • Improved N2 balance in burned ratsMaiz et al., Metabolism 33:901, 1984 • Improved N2 balance in stressed patientsDennison et al., JPEN 12:15, 1988 • Less interference with the RESHamaway et al., JPEN 9:559, 1985

29. Adequate Nutritional Support of Respirator Dependent Patients • Protein Support – adjusted for positive nitrogen balance, reduced for renal and hepatic dysfunction

30. Organ Specific Substrate SupportBranched-Chain Amino Acids • Alanine • Leucine • Isoleucine

31. Organ Specific Substrate SupportBranched-Chain Amino Acids • Main energy source for skeletal muscle during stress and sepsis • Not metabolized by the liver: safe to give during liver failure • Give 30 - 40 grams/day: 100 -160 kcal/day (45% BCAA Solution)

32. Protein BCAA can enhance nitrogen balance during periods of maximal stress Cerra et al., Crit Care Med, 11:775, 1983

33. Organ Specific Substrate SupportGlutamine • Necessary precursor for protein and nucleotide synthesis • Regulates acid-base balance through production of urinary ammonia • Major transporter of nitrogen (along with alanine)

34. Enterocytes Lymphocytes Fibroblasts Bone Marrow Pancreas Lung Tumor Cells Renal Tubular Cells Vascular Epithelial Cells Importance of Glutamine in Cell Nutrition

35. Glutamine Metabolism • Metabolized similarly whether it enters enterocyte across the brush border from intestinal lumen or across the basolateral cell membrane from the arterial blood • Oxidation via Krebs cycle yields 30 mole ATP per mole glutamine (glucose = 36)

36. Glutamine Metabolism • Gut normally extracts 20 to 30% of glutamine from blood • During stress, muscle releases amino acids with glutamine and alanine making up 60% of total • Muscle glutamine concentration decreases by up to 50% with prolonged stress

37. Glutamine Metabolism • Uptake of glutamine by the gut is greatly increased in stress, exceeding muscle release • Serum glutamine concentrations fall leading to a relative deficiency state • Provide 6 - 50 grams/day (24 - 200 kcal)

38. Appropriate Nutritional Support of Respirator Dependent Patients • Enteral vs Parenteral Support

39. Postburn Hypermetabolism and Early Enteral Feeding • 30% BSA burn in guinea pigs • Enteral feeding via g-tube at 2 or 72 hours following burn • Mucosal weight and thickness were similar RME % Initial 160 175 Kcal - 72 h 150 140 200 Kcal - 72 h 130 120 175 Kcal - 2 h 110 100 0 2 4 6 8 10 12 Postburn day Alexander, Ann Surg 200:297, 1984

42. Denham, Gastroenterology, 113:1741, 1997

43. Suppression of Cytokines • Antagonizing IL-1 and/or TNF activity or blocking receptors – antibody and receptor antagonists • Dramatic improvement in severity and mortality of experimental acute pancreatitis • Norman, Ann Surg, 221;625, 1995 • Tanaka, Crit Care Med, 23:901, 1995

44. Suppression of Cytokines • Preventing IL-1 and/or TNF production • Generic macrophage pacification • IL-10 regulation of IL-1 and TNF • Inhibiting post-transcriptional modification of pro-IL-1 • Norman, J. Interfer Cytokine Res, 17:113, 1997 • VanLaethem, Gastroenterology, 108:1917, 1995

45. Suppression of Cytokines • Gene therapy to inhibit systemic hyperinflammatory response of pancreatitis • Denham, J Gastrointest Surg, 2:95, 1998 • Norman, Gastroenterology, 112:A467, 1997

46. GALT System • Gut-associated lymphoid tissue • Intraepithelial lymphocytes • Lamina propria lymphoid tissue • Peyer’s patches • Mesenteric lymph nodes

47. GALT System • Intraepithelial lymphocytes • First to recognize foreign antigens • Lamina propria lymphoid tissue • Source of IgA • Peyer’s patches • Process antigens from intestinal lumen

48. GALT System • Responsible for reacting to harmful foreign antigens (e.g. bacterial or viral pathogens) • Must not react to non-threatening antigens to avoid chronic inflammatory condition

49. GALT System • Intravenous feeding with bowel rest and starvation result in significant suppression of the mass and function of GALT, with reduction in IgA secretion and increased gut permeability. • Oral and enteral feedings preserve GALT mass and function Li, J Trauma, 39:44, 1995

50. GALT System • Bowel rest (or an elemental diet) reduces intraluminal nutrients that bacteria need • Induces an adaptive response of bacteria to increase their adherence to the intestinal wall as a source of nutrients. • Bacterial adherence causes cellular injury, or even bacterial penetration (translocation), with an adverse host response.