NUTRITION and IMMUNONUTRITION in the ICU Marcia McDougall October 2007
‘ A slender and restricted diet is always dangerous in chronic and in acute diseases’ Hippocrates 400 B.C.
 
Critical Illness <ul><li>Heterogeneous patients </li></ul><ul><li>Extreme physiological stress/organ failure </li></ul><ul...
Consequences   of malnutrition <ul><li>Increased morbidity and mortality </li></ul><ul><li>Prolonged hospital stay </li></...
Scale of the problem  <ul><li>McWhirter and Pennington 1994: </li></ul><ul><li>>40% of hospital patients malnourished on a...
ICU Nutrition in the 1970s
ICU Nutrition through the ages Overfeeding 1980s
<ul><li>1970s: TPN - separate CH, AAs and Lipids </li></ul><ul><li>2500-3000kcals/day: Lactic acidosis, high glucose loads...
Nutrition trials in ICU <ul><li>Small, underpowered </li></ul><ul><li>Heterogeneous and complex patients </li></ul><ul><li...
What is the evidence in ICU? <ul><li>Early enteral feeding is best  </li></ul><ul><li>Hyperglycaemia/overfeeding are bad <...
Unanswered questions <ul><li>Should we aim for full calorific delivery ASAP using EN + PN? </li></ul><ul><li>What are the ...
Current practice - Scotland <ul><li>SICS Nutrition Survey 2005-2006 </li></ul><ul><li>Wide variation in PN and NJ feeding ...
% patients receiving PN/year
NJ feed: patient use per year
What is the maximum amount of time an ICU patient should go without nutrition?
Nutrition QI Study <ul><li>Canadian Critical Care Network </li></ul><ul><li>156 units cf CCCN guidelines </li></ul><ul><li...
 
Guidelines
“ systematically developed statements to assist practitioner and patient decisions about appropriate health care for speci...
What Guidelines are available? <ul><li>Canadian Critical Care Network 2003/2007: Clinical Practice Guidelines  </li></ul><...
Organisation of Nutrition Support 3. NICE Guidelines for Nutrition Support in Adults 2006 Screen Recognise Treat Oral Ente...
Screen <ul><li>Various nutritional screening tools </li></ul><ul><li>NRS 2002, SGA, MNA </li></ul><ul><li>Malnutrition Uni...
Screening in ICU <ul><li>MUST not very helpful in guiding decisions </li></ul><ul><li>Almost all patients require artifici...
Step 3 Treat: Enteral use the most appropriate route of access and mode of delivery   has a functional and accessible gast...
Step 3 Treat: PN and has either introduce progressively and  monitor closely if patient malnourished/at risk of malnutriti...
Routes Of feeding
REDUCED ENTERAL STIMULATION <ul><li>DECREASED: </li></ul><ul><li>Peyer’s patch leukotrienes + MAdCAM-1 </li></ul><ul><li>T...
Enteral <ul><li>Preserves intestinal mucosal structure and function </li></ul><ul><li>More physiological </li></ul><ul><li...
NG problems <ul><li>Risk of microaspiration in ICU  </li></ul><ul><li>Risk of displacement  </li></ul><ul><li>High gastric...
Jejunal Feeding <ul><li>Insertion </li></ul><ul><li>Surgical jejunostomy: at laparotomy  </li></ul><ul><li>May reduce inci...
Parenteral Nutrition <ul><li>GI tract not functional  </li></ul><ul><li>GI tract cannot be accessed  </li></ul><ul><li>Ina...
Supplemental PN <ul><li>Optimize EN first if possible (??)  </li></ul><ul><li>Villet:  Clin Nutr  24, 2005:  Caloric debt ...
How much to give in ICU? <ul><li>Schofield equation/Harris Benedict  </li></ul><ul><li>e.g. for 65 year old woman: BMR = (...
How much to give? <ul><li>0.2g/Kg/day of Nitrogen (1.25g/kg/day protein) </li></ul><ul><li>30 – 35ml fluid/kg/24 hours bas...
Refeeding Syndrome <ul><li>Prisoners of war 1944-5, 1944: conscientious objectors in USA studied </li></ul><ul><li>Starvat...
Refeeding syndrome <ul><li>CH Feeding: shift to CH metabolism: insulin release </li></ul><ul><li>Stimulates PO 4 2-  and K...
Refeeding Syndrome in ICU <ul><li>Unlikely to be a clear diagnosis </li></ul><ul><li>Many deleterious effects: oedema, arr...
Risk of re-feeding syndrome <ul><li>Two  or more of the following: </li></ul><ul><li>BMI less than 18.5 kg/m 2  (<16) </li...
Managing refeeding problems <ul><li>provide Thiamine/multivitamin/trace element supplementation </li></ul><ul><li>start nu...
IMMUNONUTRITION Human Evolution <ul><li>No ambulances/hospitals </li></ul><ul><li>First 72 hours after severe illness or i...
The Immune System <ul><li>A complex and interactive biological system that coordinates the detection, destruction and elim...
Critical Illness <ul><li>Sepsis: Battle between inflammatory response and microbes/toxins </li></ul><ul><li>Trauma: SIRS t...
THE ICU GAMBLE How to tip the scales? Inflammation,  organ failure Inflammation and resolution DEATH LIFE DISABILITY
Critical Illness <ul><li>Small reductions in mortality over years </li></ul><ul><li>Increasing problems with infection </l...
Failed ICU strategies <ul><li>Anti-TNF antibodies </li></ul><ul><li>Steroids in sepsis – recent work suggests little effec...
Immuno/Pharmaconutrition <ul><li>‘ Disease-modulating’ nutrients </li></ul><ul><li>Attenuate metabolic response </li></ul>...
Glutamine <ul><li>Non-essential amino acid – ‘conditionally essential’ in sepsis/major trauma </li></ul><ul><li>Vital to g...
Potential Beneficial Effects of Glutamine GLN pool Wischmeyer PE,  Curr Opin Clin Nutr Metab Care 6: 217-222, 2003 Fuel fo...
Glutamine trials <ul><li>Modest reduction in mortality/infections in 9 studies of glutamine-supplemented PN </li></ul><ul>...
PROBIOTICS <ul><li>Live micro-organisms which when  </li></ul><ul><li>administered in adequate amounts  </li></ul><ul><li>...
Probiotics <ul><li>Critical illness causes virulence of gut bacteria; treatment worsens gut function  </li></ul><ul><li>Pr...
Probiotics <ul><li>Potential to cut VAP and C. diff </li></ul><ul><li>BUT: safety concerns </li></ul><ul><li>dosage </li><...
Arginine <ul><li>‘ Conditionally essential’ amino acid derived from glutamine and citrulline  </li></ul><ul><li>For protei...
Sepsis <ul><li>Sepsis: iNOS, dendritic cells, IL-1, IL-6 </li></ul><ul><li>TH1 cytokine profile: IL-2,TNF,interferon- ү </...
Trauma <ul><li>Trauma: IL-10, poor antigen presentation, TH2 cytokine profile: IL-4, IL-13 </li></ul><ul><li>Pathologic re...
PUFAs <ul><li>Arachidonic Acid:  </li></ul><ul><li>COX and LOX precursor: Omega-6 </li></ul><ul><li>ү -Linoleic acid (GLA)...
Dietary Lipids <ul><li>Ratios in paleolithic diet  ω -6: ω -3 1:1 </li></ul><ul><li>Current Western diet 16.7:1 </li></ul>...
Mechanisms of Action <ul><li>ω -3s  EPA/DHA are incorporated quickly into cell membrane: inhibit  ω -6 activity  </li></ul...
Borage Oil DGLA PGE 1  and fewer Inflammatory  Eicosanoids Substitution of AA By DGLA  resulting in: Fish Oil Fewer Inflam...
3 Studies: OXEPA <ul><li>Patients with ARDS fed with GLA, EPA and antioxidants had a reduction in pulmonary neutrophils  <...
Omega-3 Fatty Acids <ul><li>BUT </li></ul><ul><li>Control group had high fat diet – bad? </li></ul><ul><li>Was it the FAs ...
Anti-oxidants <ul><li>Normal state: reduction > oxidation  </li></ul><ul><li>Acute stress: injury/sepsis causes acute dysr...
Reactive Oxygen Species O - , NO - <ul><li>Positive actions: </li></ul><ul><li>Bactericidal  </li></ul><ul><li>Regulation ...
ACUTE INSULT Exacerbation of cell and tissue injury Inflammatory  mediators ROS/RNOS Healing/repair/defence
Antioxidants <ul><li>Glutathione, Vitamins A, C and E </li></ul><ul><li>Zinc, copper, manganese, iron, selenium </li></ul>...
Which Nutrient for Which Population? Canadian Clinical Practice Guidelines  JPEN 2003;27:355 Recom-mend … … … … … Omega 3 ...
Immunonutrition- the future? <ul><li>The right nutrient or combination  </li></ul><ul><li>Correct dose </li></ul><ul><li>T...
Now <ul><li>More & better trials of Immunonutrition </li></ul><ul><li>Early PN supplementation trial </li></ul><ul><li>Mea...
Maintains Stimulates  the environment defences <ul><li>FEEDING </li></ul><ul><li>Provides energy </li></ul>
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Nutrition and Immunonutrition in ICU

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  • NOTES FOR PRESENTERS For the purposes of this guideline, enteral tube feeding refers to the delivery of a nutritionally complete feed (containing protein or amino acids, carbohydrate with or without fibre, fat, water, minerals and vitamins) directly into the gut via a tube. The tube is usually placed into the stomach, duodenum or jejunum via either the nose, mouth or the direct percutaneous route. Enteral tube feeding is not exclusive and can be used in combination with oral and/or parenteral nutrition. Patients receiving enteral tube feeding should be reviewed regularly to enable re-instigation of oral nutrition when appropriate. Most enteral feeding tubes are introduced at the bedside but some are placed surgically, at endoscopy or using radiological techniques, and some are inserted in the community. Enteral tube feeding should be considered for patients who are malnourished or at risk of malnourishment, who can’t be fed orally and who have a working and accessible gut. Whenever possible the patient should be aware of why this form of nutrition support is necessary, how it will be given, for how long, and the potential risks involved. There may be considerable ethical difficulties in deciding if it is in a patient’s best interests to start a tube feed.
  • NOTES FOR PRESENTERS Parenteral nutrition refers to the administration of nutrients by the intravenous route. It is usually administered via a dedicated central or peripheral placed line. Parenteral feeding should be considered in patients for whom oral or enteral feeding isn’t appropriate or they have an inaccessible or perforated gut. Parenteral nutrition is an invasive and relatively expensive form of nutrition support (equivalent to most ‘new generation’ IV antibiotics daily) and in inexperienced hands, can be associated with risks from line placement, line infections, thrombosis and metabolic disturbance. Careful consideration is therefore needed when deciding to who, when and how this form of nutrition support should be given. Whenever possible, patients should be aware of why this form of nutrition support is needed and its potential risks and benefits. The feed should be given progressively, and monitored closely. Parenteral feeding should be stopped when the patient is established on feeding from the oral or enteral route. Whichever method of feeding is chosen, the patient should be monitored, and any adjustments needed made accordingly.
  • NOTES FOR PRESENTERS Please refer to the NICE Quick Reference Guide – page 19
  • Nutrition and Immunonutrition in ICU

    1. 1. NUTRITION and IMMUNONUTRITION in the ICU Marcia McDougall October 2007
    2. 2. ‘ A slender and restricted diet is always dangerous in chronic and in acute diseases’ Hippocrates 400 B.C.
    3. 4. Critical Illness <ul><li>Heterogeneous patients </li></ul><ul><li>Extreme physiological stress/organ failure </li></ul><ul><li>Acute phase response: TNF, IL-6, IL-1 β </li></ul><ul><li>Immuno-suppression: monocytes, M Ø, NK cells, T and B lymphocytes </li></ul><ul><li>Insulin resistance: hyperglycaemia </li></ul><ul><li>Protein loss and fat gain in muscle </li></ul><ul><li>Impaired gut function </li></ul>
    4. 5. Consequences of malnutrition <ul><li>Increased morbidity and mortality </li></ul><ul><li>Prolonged hospital stay </li></ul><ul><li>Impaired tissue function and wound healing </li></ul><ul><li>Defective muscle function, reduced respiratory and cardiac function </li></ul><ul><li>Immuno-suppression, increased risk of infection </li></ul><ul><li>CIPs lose around 2%/day muscle protein </li></ul>
    5. 6. Scale of the problem <ul><li>McWhirter and Pennington 1994: </li></ul><ul><li>>40% of hospital patients malnourished on admission </li></ul><ul><li>Recent Scottish data 35% </li></ul><ul><li>Estimated cost to hospitals: £3.8bn/yr </li></ul><ul><li>Many ICU patients malnourished or at risk on ICU admission </li></ul>
    6. 7. ICU Nutrition in the 1970s
    7. 8. ICU Nutrition through the ages Overfeeding 1980s
    8. 9. <ul><li>1970s: TPN - separate CH, AAs and Lipids </li></ul><ul><li>2500-3000kcals/day: Lactic acidosis, high glucose loads, fatty livers, high insulin reqt </li></ul><ul><li>Single lumen C/Lines, no pumps </li></ul><ul><li>Urinary urea measured, N calculated </li></ul><ul><li>1980s: Scientific studies of metabolism: recognition of overfeeding </li></ul><ul><li>1990s: nitrogen limitation: 0.2g/kg/24hr, start of immunonutrition trials </li></ul><ul><li>2000s: glucose control, specific nutrients </li></ul>
    9. 10. Nutrition trials in ICU <ul><li>Small, underpowered </li></ul><ul><li>Heterogeneous and complex patients </li></ul><ul><li>Mixed nutritional status </li></ul><ul><li>Different feeding regimens </li></ul><ul><li>Underfeeding – failure to deliver nutrients </li></ul><ul><li>Overfeeding – adverse metabolic effects </li></ul><ul><li>Hyperglycaemia </li></ul><ul><li>Scientific basis essential </li></ul>
    10. 11. What is the evidence in ICU? <ul><li>Early enteral feeding is best </li></ul><ul><li>Hyperglycaemia/overfeeding are bad </li></ul><ul><li>PN meta-analyses controversial </li></ul><ul><li>Nutritional deficit a/w worse outcome </li></ul><ul><li>EN a/w aspiration and VAP, PN infection </li></ul><ul><li>EN and PN can be used to achieve goals </li></ul><ul><li>Protocols improve delivery of feed </li></ul><ul><li>Some nutrients show promising results </li></ul>
    11. 12. Unanswered questions <ul><li>Should we aim for full calorific delivery ASAP using EN + PN? </li></ul><ul><li>What are the best lipids to use in PN? </li></ul><ul><li>What is the role of small bowel feeding? </li></ul><ul><li>Are probiotics helpful? </li></ul><ul><li>Which patients will benefit from immuno-nutrition? </li></ul><ul><li>The future: targeted Nutrition Therapy? </li></ul>
    12. 13. Current practice - Scotland <ul><li>SICS Nutrition Survey 2005-2006 </li></ul><ul><li>Wide variation in PN and NJ feeding use </li></ul><ul><li>Wide variation in opinions about nutrition </li></ul><ul><li>Lack of education about nutrition </li></ul><ul><li>Lack of interest from clinicians </li></ul><ul><li>Nutrition teams in 11/24 hospitals (QIS) </li></ul><ul><li>Discussion between dietitians and doctors limited </li></ul>
    13. 14. % patients receiving PN/year
    14. 15. NJ feed: patient use per year
    15. 16. What is the maximum amount of time an ICU patient should go without nutrition?
    16. 17. Nutrition QI Study <ul><li>Canadian Critical Care Network </li></ul><ul><li>156 units cf CCCN guidelines </li></ul><ul><li>8 Scotland, 22 UK </li></ul><ul><li>Adequacy of EN </li></ul><ul><li>Use of PN </li></ul><ul><li>Use of Immunonutrition </li></ul><ul><li>Protocols/Glycaemic control/Bed elevation </li></ul>
    17. 19. Guidelines
    18. 20. “ systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances” U.S. Institute of Medicine “ EBM - the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients” Sackett DL et al. BMJ 1996
    19. 21. What Guidelines are available? <ul><li>Canadian Critical Care Network 2003/2007: Clinical Practice Guidelines </li></ul><ul><li>ICS: Practical Management of Parenteral Nutrition in Critically Ill Patients 2005 </li></ul><ul><li>ESPEN: Enteral Nutrition 2006 </li></ul><ul><li>NICE: Nutrition Support in Adults 2006 </li></ul>
    20. 22. Organisation of Nutrition Support 3. NICE Guidelines for Nutrition Support in Adults 2006 Screen Recognise Treat Oral Enteral Parenteral Monitor & Review
    21. 23. Screen <ul><li>Various nutritional screening tools </li></ul><ul><li>NRS 2002, SGA, MNA </li></ul><ul><li>Malnutrition Universal Screening Tool from the Malnutrition Advisory Group of BAPEN </li></ul><ul><li>Low risk: routine clinical care, </li></ul><ul><li>Medium risk: observe </li></ul><ul><li>High risk: treat- ‘refer to dietitian/local protocols’ </li></ul>
    22. 24. Screening in ICU <ul><li>MUST not very helpful in guiding decisions </li></ul><ul><li>Almost all patients require artificial nutrition- cannot ‘observe’ </li></ul><ul><li>What about refeeding syndrome? </li></ul><ul><li>Needs adaptation using NICE Guidelines </li></ul><ul><li>Adapted MUST for ICU: Uses BMI/weight loss/food intake + refeeding risk assessment; linked to feeding flowchart </li></ul>
    23. 25. Step 3 Treat: Enteral use the most appropriate route of access and mode of delivery has a functional and accessible gastrointestinal tract if patient malnourished/at risk of malnutrition despite the use of oral interventions and 3. NICE Guidelines for Nutrition Support in Adults 2006
    24. 26. Step 3 Treat: PN and has either introduce progressively and monitor closely if patient malnourished/at risk of malnutrition a non-functional, inaccessible or perforated gastrointestinal tract inadequate or unsafe oral or enteral nutritional intake use the most appropriate route of access and mode of delivery 3. NICE Guidelines for Nutrition Support in Adults 2006
    25. 27. Routes Of feeding
    26. 28. REDUCED ENTERAL STIMULATION <ul><li>DECREASED: </li></ul><ul><li>Peyer’s patch leukotrienes + MAdCAM-1 </li></ul><ul><li>T & B cells in Peyer’s patches, Lamina propria & epithelium </li></ul><ul><li>Reduced secretory IgA and altered cytokines </li></ul><ul><li>Mucosal atrophy </li></ul><ul><li>Altered flora </li></ul><ul><li>Decreased gastric acid </li></ul><ul><li>Bacterial translocation </li></ul>
    27. 29. Enteral <ul><li>Preserves intestinal mucosal structure and function </li></ul><ul><li>More physiological </li></ul><ul><li>Relatively non-invasive </li></ul><ul><li>Reduced risk of infectious complications cf PN (?) </li></ul><ul><li>Relatively cheap </li></ul>
    28. 30. NG problems <ul><li>Risk of microaspiration in ICU </li></ul><ul><li>Risk of displacement </li></ul><ul><li>High gastric aspirates with opioids, sepsis, electrolyte imbalances </li></ul><ul><li>Reaching goals uncommon </li></ul><ul><li>PEG/gastrostomy feeding for long-term >4 weeks </li></ul>
    29. 31. Jejunal Feeding <ul><li>Insertion </li></ul><ul><li>Surgical jejunostomy: at laparotomy </li></ul><ul><li>May reduce incidence of aspiration </li></ul><ul><li>Sometimes increases dose of EN given over NG </li></ul><ul><li>Indications </li></ul>
    30. 32. Parenteral Nutrition <ul><li>GI tract not functional </li></ul><ul><li>GI tract cannot be accessed </li></ul><ul><li>Inadequate enteral nutrition <80% 3 days </li></ul><ul><li>Do not delay nutrition in malnourished </li></ul><ul><li>Keep 10ml/hr EN if possible </li></ul>
    31. 33. Supplemental PN <ul><li>Optimize EN first if possible (??) </li></ul><ul><li>Villet: Clin Nutr 24, 2005: Caloric debt a/w increased LOS, vent days and complications </li></ul><ul><li>Need trial to compare early supplemental PN and early EN with early EN only </li></ul><ul><li>North America/Europe split over use of PN </li></ul><ul><li>Unanswered questions </li></ul>
    32. 34. How much to give in ICU? <ul><li>Schofield equation/Harris Benedict </li></ul><ul><li>e.g. for 65 year old woman: BMR = (9.2x weight in kg) + 687, = requirement in Kcal/24hr </li></ul><ul><li>Add Activity and Stress factors e.g. 10% for bedbound + 20-60% for sepsis/burns </li></ul><ul><li>For 65kg woman ventilated woman with sepsis: 1670 Kcal = approx 25 Kcal/kg/24hr </li></ul><ul><li>No dietitian? Rough guide: 25 Kcal/kg/day total energy. Increase to 30 as patient improves </li></ul>
    33. 35. How much to give? <ul><li>0.2g/Kg/day of Nitrogen (1.25g/kg/day protein) </li></ul><ul><li>30 – 35ml fluid/kg/24 hours baseline </li></ul><ul><li>Add 2-2.5ml/kg/day of fluid for each degree of temperature </li></ul><ul><li>Account for excess fluid losses </li></ul><ul><li>Adequate electrolytes, micronutrients, vitamins </li></ul><ul><li>Avoid overfeeding </li></ul><ul><li>Obesity: feed to BMR, add stress factor only if severe i.e. burns/trauma </li></ul>
    34. 36. Refeeding Syndrome <ul><li>Prisoners of war 1944-5, 1944: conscientious objectors in USA studied </li></ul><ul><li>Starvation: early use of glycogen stores for AAs - gluconeogenesis; 72 hrs: FFA oxidation; use of FFAs and ketones for energy source, low insulin </li></ul><ul><li>Atrophy of organs, reduced lean body mass </li></ul>
    35. 37. Refeeding syndrome <ul><li>CH Feeding: shift to CH metabolism: insulin release </li></ul><ul><li>Stimulates PO 4 2- and K + shift into cells. PO 4 2- drops lower (ATP, 2-3DPG). Mg 2+ loss in urine 2 o low PO 4 2- (Na+K + ATPase) </li></ul><ul><li>May get Lactic acidosis 2 o conversion of pyruvate to lactate </li></ul><ul><li>Na + and H 2 O shift out of cells – oedema; ECF expansion 2 o reduced excretion of Na + and H 2 O; </li></ul><ul><li>Hyperinsulinaemia is antinatriuretic </li></ul><ul><li>Protein synthesis increases cellr demand for PO 4 2- and K + </li></ul><ul><li>Thiamine deficiency occurs (co-factor in CH metabolism): encephalopathy </li></ul>
    36. 38. Refeeding Syndrome in ICU <ul><li>Unlikely to be a clear diagnosis </li></ul><ul><li>Many deleterious effects: oedema, arrhythmias, pulmonary oedema, cardiac decompensation, respiratory weakness, fits, hypotension, leukocyte dysfunction, diarrhoea, coma, rhabdomyolysis, sudden death </li></ul><ul><li>Screen: nutritional history and electrolytes </li></ul><ul><li>Remember in HDU patients/malnourished ward patients </li></ul><ul><li>Poor awareness among doctors! </li></ul>
    37. 39. Risk of re-feeding syndrome <ul><li>Two or more of the following: </li></ul><ul><li>BMI less than 18.5 kg/m 2 (<16) </li></ul><ul><li>unintentional weight loss greater than 10% within the last 3-6 months (>15%) </li></ul><ul><li>little or no nutritional intake for more than 5 days (>10) </li></ul><ul><li>Hx alcohol abuse or drugs including insulin, chemotherapy, antacids or diuretics </li></ul><ul><li>(Critically low levels of PO 4 2- , K + and Mg 2+) </li></ul>
    38. 40. Managing refeeding problems <ul><li>provide Thiamine/multivitamin/trace element supplementation </li></ul><ul><li>start nutrition support at 5-10 kcal/kg/day </li></ul><ul><li>increase levels slowly </li></ul><ul><li>restore circulatory volume </li></ul><ul><li>monitor fluid balance and clinical status </li></ul><ul><li>replace PO 4 2- , K + and Mg 2+ </li></ul><ul><li>Reduce feeding rate if problems arise </li></ul>NICE Guidelines for Nutrition Support in Adults 2006
    39. 41. IMMUNONUTRITION Human Evolution <ul><li>No ambulances/hospitals </li></ul><ul><li>First 72 hours after severe illness or injury crucial </li></ul><ul><li>Little hope of survival past this; not desirable </li></ul><ul><li>Significant stores of stress substrates not necessary e.g. glutamine </li></ul>
    40. 42. The Immune System <ul><li>A complex and interactive biological system that coordinates the detection, destruction and elimination of any foreign material or organism entering the body. </li></ul><ul><li>Oxidants: cytokines, NFkB, genes, inflam n </li></ul><ul><li>Nutrients: glutamine, FFAs, protein </li></ul><ul><li>Glutathione: oxidant defence </li></ul><ul><li>Anti-inflammatory molecules: attenuation </li></ul>
    41. 43. Critical Illness <ul><li>Sepsis: Battle between inflammatory response and microbes/toxins </li></ul><ul><li>Trauma: SIRS to non-infectious insult </li></ul><ul><li>Minor insult: inflammatory response wins </li></ul><ul><li>Major insult: with support (antibiotics, fluids) body may be able to fight insult but in severe insult inflammatory response continues and causes organ damage, f/b immune paresis and 2 ° infection; death </li></ul>
    42. 44. THE ICU GAMBLE How to tip the scales? Inflammation, organ failure Inflammation and resolution DEATH LIFE DISABILITY
    43. 45. Critical Illness <ul><li>Small reductions in mortality over years </li></ul><ul><li>Increasing problems with infection </li></ul><ul><li>Advances in treatment have limited effects </li></ul><ul><li>Pathophysiology complex </li></ul><ul><li>The future: replacement of the body’s own ‘stress substrates’ </li></ul><ul><li>Could immunonutrition be the most important area in critical care development? </li></ul>
    44. 46. Failed ICU strategies <ul><li>Anti-TNF antibodies </li></ul><ul><li>Steroids in sepsis – recent work suggests little effect </li></ul><ul><li>NO synthetase inhibitor: increased mortality </li></ul><ul><li>??? Activated protein C - controversial </li></ul>
    45. 47. Immuno/Pharmaconutrition <ul><li>‘ Disease-modulating’ nutrients </li></ul><ul><li>Attenuate metabolic response </li></ul><ul><li>Prevent oxidant stress </li></ul><ul><li>Favourably modulate immune response </li></ul><ul><li>Probiotics to alter gut environment </li></ul><ul><li>Glycaemic control: keep blood glucose <8mmol/l: reduces infections and organ failures </li></ul>
    46. 48. Glutamine <ul><li>Non-essential amino acid – ‘conditionally essential’ in sepsis/major trauma </li></ul><ul><li>Vital to gut, immune cells, and kidney </li></ul><ul><li>Serves as metabolic fuel; precursor to DNA synthesis </li></ul><ul><li>BUT Levels drop after injury, exercise and stress. Very low in critical illness first 72 hours </li></ul><ul><li>Glutamine deficiency at onset of critical illness/sepsis correlated with increased mortality </li></ul>
    47. 49. Potential Beneficial Effects of Glutamine GLN pool Wischmeyer PE, Curr Opin Clin Nutr Metab Care 6: 217-222, 2003 Fuel for Enterocytes Fuel for Lymphocytes Nuclotide Synthesis Maintenance of Intestinal Mucosal Barrier Maintenance of Lymphocyte Function Preservation of TCA Function Decreased Free Radical availability (Anti-inflammatory action) Glutathione Synthesis Glutamine Therapy Enhanced Heat Shock Protein Anti-catabolic effect Preservation of Muscle mass Reduced Translocation Enteric Bacteria or Endotoxins Reduction of Infectious complications Inflammatory Cytokine Attenuation NF-kB ? Preserved Cellular Energetics- ATP content GLN Pool Critical Illness Enhanced insulin sensitivity
    48. 50. Glutamine trials <ul><li>Modest reduction in mortality/infections in 9 studies of glutamine-supplemented PN </li></ul><ul><li>Improvement in morbidity and mortality in 2 studies of enteral glutamine in burns and trauma patients </li></ul><ul><li>CCCN recommend enteral glutamine for burns and trauma and IV glutamine to be given with parenteral nutrition </li></ul><ul><li>SIGNET and REDOXs awaited </li></ul>
    49. 51. PROBIOTICS <ul><li>Live micro-organisms which when </li></ul><ul><li>administered in adequate amounts </li></ul><ul><li>confer a health benefit on the host </li></ul><ul><li>Bioecological control: Supply viable beneficial bacteria, or a substrate which enhances specific beneficial bacteria, instead of trying to eliminate the pathogen </li></ul>
    50. 52. Probiotics <ul><li>Critical illness causes virulence of gut bacteria; treatment worsens gut function </li></ul><ul><li>Probiotics inhibit growth of pathogenic enteric bacteria </li></ul><ul><li>block epithelial invasion by pathogens </li></ul><ul><li>eliminate pathogenic toxins </li></ul><ul><li>improve mucosal barrier function </li></ul><ul><li>enhance T-cell and macrophage function </li></ul><ul><li>reduce production of TNF and NFkB </li></ul>
    51. 53. Probiotics <ul><li>Potential to cut VAP and C. diff </li></ul><ul><li>BUT: safety concerns </li></ul><ul><li>dosage </li></ul><ul><li>which bacteria to use </li></ul><ul><li>viability in the gut </li></ul><ul><li>storage issues </li></ul><ul><li>unforeseen effects </li></ul><ul><li>More research required </li></ul>
    52. 54. Arginine <ul><li>‘ Conditionally essential’ amino acid derived from glutamine and citrulline </li></ul><ul><li>For protein synthesis, cell division, NO, urea cycle, creatine phosphate (ATP) </li></ul><ul><li>Stimulates hormone release </li></ul><ul><li>Deficiency: Immune suppression, ↓TH2 cell function, free radical formation </li></ul><ul><li>Abnormal microperfusion </li></ul><ul><li>Abnormal wound healing </li></ul>
    53. 55. Sepsis <ul><li>Sepsis: iNOS, dendritic cells, IL-1, IL-6 </li></ul><ul><li>TH1 cytokine profile: IL-2,TNF,interferon- ү </li></ul><ul><li>Arginine deficiency not severe in sepsis </li></ul><ul><li>Little drop in plasma arginine levels </li></ul><ul><li>CCCN: not recommended (harm?) </li></ul>
    54. 56. Trauma <ul><li>Trauma: IL-10, poor antigen presentation, TH2 cytokine profile: IL-4, IL-13 </li></ul><ul><li>Pathologic release of arginase from myeloid suppressor cells, hepatocytes, RBCs </li></ul><ul><li>Significant drop in arginine levels in trauma </li></ul><ul><li>CCCN: not recommended – future role? </li></ul><ul><li>Pre-operative patients, cancer, sickle cell, haemolytic anaemia, PIH </li></ul>
    55. 57. PUFAs <ul><li>Arachidonic Acid: </li></ul><ul><li>COX and LOX precursor: Omega-6 </li></ul><ul><li>ү -Linoleic acid (GLA) – borage oil </li></ul><ul><li>Fish oils: Eicosapentanoic acid (EPA) and Docosahexanoic acid (DHA): Omega-3 FAs </li></ul>
    56. 58. Dietary Lipids <ul><li>Ratios in paleolithic diet ω -6: ω -3 1:1 </li></ul><ul><li>Current Western diet 16.7:1 </li></ul><ul><li>Current UK PN Soybean oil base 7:1 (LCT) </li></ul><ul><li>New PN (‘SMOF’) 2.5:1 (LCT/MCT) </li></ul><ul><li>Membrane composition depends on diet </li></ul><ul><li>AA arises from GLA </li></ul><ul><li>AA, DHA and EPA are present in inflammatory cell membrane phospholipids </li></ul><ul><li>Hydrolysis of FAs by phospholipase to mediators </li></ul>
    57. 59. Mechanisms of Action <ul><li>ω -3s EPA/DHA are incorporated quickly into cell membrane: inhibit ω -6 activity </li></ul><ul><li>Promote synthesis of low activity PGs and LTs </li></ul><ul><li>Decrease expression of adhesion molecules </li></ul><ul><li>Inhibits monocyte prod n of pro-inflamm cytokines </li></ul><ul><li>Decreases NFkB, increases lymphocyte apoptosis </li></ul><ul><li>Decreases pro-inflammatory gene expression </li></ul><ul><li>Lipoxins, resolvins and protectins </li></ul>
    58. 60. Borage Oil DGLA PGE 1 and fewer Inflammatory Eicosanoids Substitution of AA By DGLA resulting in: Fish Oil Fewer Inflammatory Eicosanoids (TXA 3 , PGE 3 , LTB 5 ) Substitution of AA By EPA Resulting in: Arachidonic Acid Cyclooxygenase Lipoxygenase Pro-Inflammatory Eicosanoids (LTB 4 , TXA 2 , PGE 2 ) Decrease in X Mechanisms of Action GLA EPA
    59. 61. 3 Studies: OXEPA <ul><li>Patients with ARDS fed with GLA, EPA and antioxidants had a reduction in pulmonary neutrophils </li></ul><ul><li>Improvement in oxygenation </li></ul><ul><li>Decrease in ventilator days </li></ul><ul><li>Decrease in ICU and hospital days </li></ul><ul><li>Gadek, Singer, Pontes-Arruda (sepsis) </li></ul>
    60. 62. Omega-3 Fatty Acids <ul><li>BUT </li></ul><ul><li>Control group had high fat diet – bad? </li></ul><ul><li>Was it the FAs or the antioxidants or both? </li></ul><ul><li>CCCN – consider in ARDS i.e. OXEPA mix </li></ul><ul><li>Other researchers: not enough evidence </li></ul><ul><li>Science makes sense; works in IHD, PVD </li></ul>
    61. 63. Anti-oxidants <ul><li>Normal state: reduction > oxidation </li></ul><ul><li>Acute stress: injury/sepsis causes acute dysregulation: ROS/RNOS formed </li></ul><ul><li>Mitochondria are both sources and targets </li></ul><ul><li>Observational studies: anti-oxidant capacity inversely correlated with disease severity due to depletion during oxidative stress </li></ul>REDUCTION OXIDATION
    62. 64. Reactive Oxygen Species O - , NO - <ul><li>Positive actions: </li></ul><ul><li>Bactericidal </li></ul><ul><li>Regulation of vascular tone </li></ul><ul><li>Cell signalling </li></ul><ul><li>But mostly detrimental: </li></ul><ul><li>Cell injury (ischaemia /reperfusion) </li></ul><ul><li>DNA, Lipids, Proteins </li></ul><ul><li>Organ dysfunction </li></ul><ul><li>Lungs, Heart, Kidney </li></ul><ul><li>Liver, Blood, Brain </li></ul>OXIDATION REDUCTION
    63. 65. ACUTE INSULT Exacerbation of cell and tissue injury Inflammatory mediators ROS/RNOS Healing/repair/defence
    64. 66. Antioxidants <ul><li>Glutathione, Vitamins A, C and E </li></ul><ul><li>Zinc, copper, manganese, iron, selenium </li></ul><ul><li>Already added to feeds </li></ul><ul><li>Should we give extra CCCN – ‘consider’ </li></ul><ul><li>Results of SIGNET and REDOXs awaited </li></ul><ul><li>Oxidative stress in critically ill patients contributes to organ damage / malignant inflammation </li></ul>
    65. 67. Which Nutrient for Which Population? Canadian Clinical Practice Guidelines JPEN 2003;27:355 Recom-mend … … … … … Omega 3 FFA … … … … Consider … Anti-oxidants … EN Possibly Beneficial: Consider EN Possibly Beneficial: Consider … PN Beneficial Recom-mend Possible Benefit Glutamine No benefit No benefit (Possible benefit) Harm(?) No benefit Benefit Arginine Acute Lung Injury Burns Trauma Septic General Elective Surgery Critically Ill
    66. 68. Immunonutrition- the future? <ul><li>The right nutrient or combination </li></ul><ul><li>Correct dose </li></ul><ul><li>The appropriate timing </li></ul><ul><li>The right patient and circumstance </li></ul><ul><li>The appropriate assessment of efficacy </li></ul><ul><li>Balance between harm and benefit of the immune response </li></ul><ul><li>?? Nutrient-gene interactions </li></ul>
    67. 69. Now <ul><li>More & better trials of Immunonutrition </li></ul><ul><li>Early PN supplementation trial </li></ul><ul><li>Meanwhile: the basics- screening, reaching goals, protocols, refeeding </li></ul><ul><li>HDU feeding </li></ul><ul><li>Profile of Nutrition: Education, dialogue </li></ul><ul><li>Funding </li></ul>
    68. 70. Maintains Stimulates the environment defences <ul><li>FEEDING </li></ul><ul><li>Provides energy </li></ul>

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