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 Heterogeneous patients Extreme physiological stress/organ failure Acute phase response: TNF, IL-6, IL-1β Immuno-suppression: monocytes, MØ, NK cells, T and B lymphocytes Insulin resistance: hyperglycaemia Protein loss and fat gain in muscle Impaired gut function

Consequences of malnutrition Increased morbidity and mortality Prolonged hospital stay Impaired tissue function and wound healing Defective muscle function, reduced respiratory and cardiac function Immuno-suppression, increased risk of infection CIPs lose around 2%/day muscle protein

Scale of the problem McWhirter and Pennington 1994: >40% of hospital patients malnourished on admission Recent Scottish data 35% Estimated cost to hospitals: £3.8bn/yr Many ICU patients malnourished or at risk on ICU admission

ICU Nutrition in the 1970s

ICU Nutrition through the ages Overfeeding 1980s

1970s: TPN - separate CH, AAs and Lipids 2500-3000kcals/day: Lactic acidosis, high glucose loads, fatty livers, high insulin reqt Single lumen C/Lines, no pumps Urinary urea measured, N calculated 1980s: Scientific studies of metabolism: recognition of overfeeding 1990s: nitrogen limitation: 0.2g/kg/24hr, start of immunonutrition trials 2000s: glucose control, specific nutrients

Nutrition trials in ICU Small, underpowered Heterogeneous and complex patients Mixed nutritional status Different feeding regimens Underfeeding – failure to deliver nutrients Overfeeding – adverse metabolic effects Hyperglycaemia Scientific basis essential

What is the evidence in ICU? Early enteral feeding is best Hyperglycaemia/overfeeding are bad PN meta-analyses controversial Nutritional deficit a/w worse outcome EN a/w aspiration and VAP, PN infection EN and PN can be used to achieve goals Protocols improve delivery of feed Some nutrients show promising results

Unanswered questions Should we aim for full calorific delivery ASAP using EN + PN? What are the best lipids to use in PN? What is the role of small bowel feeding? Are probiotics helpful? Which patients will benefit from immuno-nutrition? The future: targeted Nutrition Therapy?

Current practice - Scotland SICS Nutrition Survey 2005-2006 Wide variation in PN and NJ feeding use Wide variation in opinions about nutrition Lack of education about nutrition Lack of interest from clinicians Nutrition teams in 11/24 hospitals (QIS) Discussion between dietitians and doctors limited

% 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 Canadian Critical Care Network 156 units cf CCCN guidelines 8 Scotland, 22 UK Adequacy of EN Use of PN Use of Immunonutrition Protocols/Glycaemic control/Bed elevation

Guidelines

“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

What Guidelines are available? Canadian Critical Care Network 2003/2007: Clinical Practice Guidelines ICS: Practical Management of Parenteral Nutrition in Critically Ill Patients 2005 ESPEN: Enteral Nutrition 2006 NICE: Nutrition Support in Adults 2006

Organisation of Nutrition Support 3. NICE Guidelines for Nutrition Support in Adults 2006

Screen Various nutritional screening tools NRS 2002, SGA, MNA Malnutrition Universal Screening Tool from the Malnutrition Advisory Group of BAPEN Low risk: routine clinical care, Medium risk: observe High risk: treat- ‘refer to dietitian/local protocols’

Screening in ICU MUST not very helpful in guiding decisions Almost all patients require artificial nutrition- cannot ‘observe’ What about refeeding syndrome? Needs adaptation using NICE Guidelines Adapted MUST for ICU: Uses BMI/weight loss/food intake + refeeding risk assessment; linked to feeding flowchart

Step 3 Treat: Enteral if patient malnourished/at risk of malnutrition despite the use of oral interventions and has a functional and accessible gastrointestinal tract 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. use the most appropriate route of access and mode of delivery 3. NICE Guidelines for Nutrition Support in Adults 2006

Step 3 Treat: PN if patient malnourished/at risk of malnutrition a non-functional, inaccessible or perforated gastrointestinal tract and has either inadequate or unsafe oral or enteral nutritional intake introduce progressively and monitor closely 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. use the most appropriate route of access and mode of delivery 3. NICE Guidelines for Nutrition Support in Adults 2006

Routes Of feeding

REDUCED ENTERAL STIMULATION DECREASED: Peyer’s patch leukotrienes + MAdCAM-1 T & B cells in Peyer’s patches, Lamina propria & epithelium Reduced secretory IgA and altered cytokines Mucosal atrophy Altered flora Decreased gastric acid Bacterial translocation

Enteral Preserves intestinal mucosal structure and function More physiological Relatively non-invasive Reduced risk of infectious complications cf PN (?) Relatively cheap

NG problems Risk of microaspiration in ICU Risk of displacement High gastric aspirates with opioids, sepsis, electrolyte imbalances Reaching goals uncommon PEG/gastrostomy feeding for long-term >4 weeks

Jejunal Feeding Insertion Surgical jejunostomy: at laparotomy May reduce incidence of aspiration Sometimes increases dose of EN given over NG Indications

Parenteral Nutrition GI tract not functional GI tract cannot be accessed Inadequate enteral nutrition <80% 3 days Do not delay nutrition in malnourished Keep 10ml/hr EN if possible

Supplemental PN Optimize EN first if possible (??) Villet: Clin Nutr 24, 2005: Caloric debt a/w increased LOS, vent days and complications Need trial to compare early supplemental PN and early EN with early EN only North America/Europe split over use of PN Unanswered questions

How much to give in ICU? Schofield equation/Harris Benedict e.g. for 65 year old woman: BMR = (9.2x weight in kg) + 687, = requirement in Kcal/24hr Add Activity and Stress factors e.g. 10% for bedbound + 20-60% for sepsis/burns For 65kg woman ventilated woman with sepsis: 1670 Kcal = approx 25 Kcal/kg/24hr No dietitian? Rough guide: 25 Kcal/kg/day total energy. Increase to 30 as patient improves

How much to give? 0.2g/Kg/day of Nitrogen (1.25g/kg/day protein) 30 – 35ml fluid/kg/24 hours baseline Add 2-2.5ml/kg/day of fluid for each degree of temperature Account for excess fluid losses Adequate electrolytes, micronutrients, vitamins Avoid overfeeding Obesity: feed to BMR, add stress factor only if severe i.e. burns/trauma

Refeeding Syndrome Prisoners of war 1944-5, 1944: conscientious objectors in USA studied Starvation: early use of glycogen stores for AAs - gluconeogenesis; 72 hrs: FFA oxidation; use of FFAs and ketones for energy source, low insulin Atrophy of organs, reduced lean body mass

Refeeding syndrome CH Feeding: shift to CH metabolism: insulin release Stimulates PO42- and K+ shift into cells. PO42- drops lower (ATP, 2-3DPG). Mg2+ loss in urine 2o low PO42-(Na+K+ATPase) May get Lactic acidosis 2o conversion of pyruvate to lactate Na+ and H2O shift out of cells – oedema; ECF expansion 2o reduced excretion of Na+ and H2O; Hyperinsulinaemia is antinatriuretic Protein synthesis increases cellr demand for PO42- and K+ Thiamine deficiency occurs (co-factor in CH metabolism): encephalopathy

Refeeding Syndrome in ICU Unlikely to be a clear diagnosis Many deleterious effects: oedema, arrhythmias, pulmonary oedema, cardiac decompensation, respiratory weakness, fits, hypotension, leukocyte dysfunction, diarrhoea, coma, rhabdomyolysis, sudden death Screen: nutritional history and electrolytes Remember in HDU patients/malnourished ward patients Poor awareness among doctors!

Risk of re-feeding syndrome Two or more of the following: BMI less than 18.5 kg/m2 (<16) unintentional weight loss greater than 10% within the last 3-6 months (>15%) little or no nutritional intake for more than 5 days (>10) Hx alcohol abuse or drugs including insulin, chemotherapy, antacids or diuretics (Critically low levels of PO42-, K+ and Mg2+)

Managing refeeding problems provide Thiamine/multivitamin/trace element supplementation start nutrition support at 5-10 kcal/kg/day increase levels slowly restore circulatory volume monitor fluid balance and clinical status replace PO42-, K+ and Mg2+ Reduce feeding rate if problems arise NOTES FOR PRESENTERS Please refer to the NICE Quick Reference Guide – page 19 NICE Guidelines for Nutrition Support in Adults 2006

IMMUNONUTRITION Human Evolution No ambulances/hospitals First 72 hours after severe illness or injury crucial Little hope of survival past this; not desirable Significant stores of stress substrates not necessary e.g. glutamine

The Immune System A complex and interactive biological system that coordinates the detection, destruction and elimination of any foreign material or organism entering the body. Oxidants: cytokines, NFkB, genes, inflamn Nutrients: glutamine, FFAs, protein Glutathione: oxidant defence Anti-inflammatory molecules: attenuation

Critical Illness Sepsis: Battle between inflammatory response and microbes/toxins Trauma: SIRS to non-infectious insult Minor insult: inflammatory response wins 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

THE ICU GAMBLE How to tip the scales? LIFE DISABILITY Inflammation and resolution Inflammation, organ failure DEATH

Critical Illness Small reductions in mortality over years Increasing problems with infection Advances in treatment have limited effects Pathophysiology complex The future: replacement of the body’s own ‘stress substrates’ Could immunonutrition be the most important area in critical care development?

Failed ICU strategies Anti-TNF antibodies Steroids in sepsis – recent work suggests little effect NO synthetase inhibitor: increased mortality ??? Activated protein C - controversial

Immuno/Pharmaconutrition ‘Disease-modulating’ nutrients Attenuate metabolic response Prevent oxidant stress Favourably modulate immune response Probiotics to alter gut environment Glycaemic control: keep blood glucose <8mmol/l: reduces infections and organ failures

Glutamine Non-essential amino acid – ‘conditionally essential’ in sepsis/major trauma Vital to gut, immune cells, and kidney Serves as metabolic fuel; precursor to DNA synthesis BUT Levels drop after injury, exercise and stress. Very low in critical illness first 72 hours Glutamine deficiency at onset of critical illness/sepsis correlated with increased mortality

Potential Beneficial Effects of Glutamine Enhanced Heat Shock Protein Enhanced insulin sensitivity Decreased Free Radical availability (Anti-inflammatory action) Inflammatory Cytokine Attenuation NF-kB ? Glutamine Therapy Glutathione Synthesis Reduced Translocation Enteric Bacteria or Endotoxins Reduction of Infectious complications Maintenance of Intestinal Mucosal Barrier Lymphocyte Function Fuel for Enterocytes Lymphocytes Nuclotide Synthesis Critical Illness GLN pool GLN Pool Preservation of TCA Function Anti-catabolic effect Preservation of Muscle mass Preserved Cellular Energetics- ATP content Wischmeyer PE, Curr Opin Clin Nutr Metab Care 6: 217-222, 2003

Glutamine trials Modest reduction in mortality/infections in 9 studies of glutamine-supplemented PN Improvement in morbidity and mortality in 2 studies of enteral glutamine in burns and trauma patients CCCN recommend enteral glutamine for burns and trauma and IV glutamine to be given with parenteral nutrition SIGNET and REDOXs awaited

PROBIOTICS Live micro-organisms which when administered in adequate amounts confer a health benefit on the host Bioecological control: Supply viable beneficial bacteria, or a substrate which enhances specific beneficial bacteria, instead of trying to eliminate the pathogen

Probiotics Critical illness causes virulence of gut bacteria; treatment worsens gut function Probiotics inhibit growth of pathogenic enteric bacteria block epithelial invasion by pathogens eliminate pathogenic toxins improve mucosal barrier function enhance T-cell and macrophage function reduce production of TNF and NFkB

Probiotics Potential to cut VAP and C. diff BUT: safety concerns dosage which bacteria to use viability in the gut storage issues unforeseen effects More research required

Arginine ‘Conditionally essential’ amino acid derived from glutamine and citrulline For protein synthesis, cell division, NO, urea cycle, creatine phosphate (ATP) Stimulates hormone release Deficiency: Immune suppression, ↓TH2 cell function, free radical formation Abnormal microperfusion Abnormal wound healing

Sepsis Sepsis: iNOS, dendritic cells, IL-1, IL-6 TH1 cytokine profile: IL-2,TNF,interferon-ү Arginine deficiency not severe in sepsis Little drop in plasma arginine levels CCCN: not recommended (harm?)

Trauma Trauma: IL-10, poor antigen presentation, TH2 cytokine profile: IL-4, IL-13 Pathologic release of arginase from myeloid suppressor cells, hepatocytes, RBCs Significant drop in arginine levels in trauma CCCN: not recommended – future role? Pre-operative patients, cancer, sickle cell, haemolytic anaemia, PIH

PUFAs Arachidonic Acid: COX and LOX precursor: Omega-6 ү-Linoleic acid (GLA) – borage oil Fish oils: Eicosapentanoic acid (EPA) and Docosahexanoic acid (DHA): Omega-3 FAs

Dietary Lipids Ratios in paleolithic diet ω-6:ω-3 1:1 Current Western diet 16.7:1 Current UK PN Soybean oil base 7:1 (LCT) New PN (‘SMOF’) 2.5:1 (LCT/MCT) Membrane composition depends on diet AA arises from GLA AA, DHA and EPA are present in inflammatory cell membrane phospholipids Hydrolysis of FAs by phospholipase to mediators

Mechanisms of Action ω-3s EPA/DHA are incorporated quickly into cell membrane: inhibit ω-6 activity Promote synthesis of low activity PGs and LTs Decrease expression of adhesion molecules Inhibits monocyte prodn of pro-inflamm cytokines Decreases NFkB, increases lymphocyte apoptosis Decreases pro-inflammatory gene expression Lipoxins, resolvins and protectins

Cyclooxygenase Lipoxygenase Mechanisms of Action GLA EPA Arachidonic Acid Borage Oil Fish Oil X Cyclooxygenase Lipoxygenase DGLA Substitution of AA By EPA Resulting in: Substitution of AA By DGLA resulting in: Decrease in Pro-Inflammatory Eicosanoids (LTB4, TXA2, PGE2) PGE1 and fewer Inflammatory Eicosanoids Fewer Inflammatory Eicosanoids (TXA3, PGE3, LTB5)

3 Studies: OXEPA Patients with ARDS fed with GLA, EPA and antioxidants had a reduction in pulmonary neutrophils Improvement in oxygenation Decrease in ventilator days Decrease in ICU and hospital days Gadek, Singer, Pontes-Arruda (sepsis)

Omega-3 Fatty Acids BUT Control group had high fat diet – bad? Was it the FAs or the antioxidants or both? CCCN – consider in ARDS i.e. OXEPA mix Other researchers: not enough evidence Science makes sense; works in IHD, PVD

Anti-oxidants Normal state: reduction > oxidation Acute stress: injury/sepsis causes acute dysregulation: ROS/RNOS formed Mitochondria are both sources and targets Observational studies: anti-oxidant capacity inversely correlated with disease severity due to depletion during oxidative stress OXIDATION REDUCTION

Reactive Oxygen Species O-, NO- Positive actions: Bactericidal Regulation of vascular tone Cell signalling But mostly detrimental: Cell injury (ischaemia /reperfusion) DNA, Lipids, Proteins Organ dysfunction Lungs, Heart, Kidney Liver, Blood, Brain REDUCTION OXIDATION

Exacerbation of cell and tissue injury ACUTE INSULT Inflammatory mediators ROS/RNOS Exacerbation of cell and tissue injury Healing/repair/defence

Antioxidants Glutathione, Vitamins A, C and E Zinc, copper, manganese, iron, selenium Already added to feeds Should we give extra CCCN – ‘consider’ Results of SIGNET and REDOXs awaited Oxidative stress in critically ill patients contributes to organ damage / malignant inflammation

Which Nutrient for Which Population? Elective Surgery Critically Ill General Septic Trauma Burns Acute Lung Injury Arginine Benefit No benefit Harm(?) (Possible benefit) Glutamine Possible Benefit PN Beneficial Recom-mend … EN Possibly Beneficial: Consider Omega 3 FFA Anti-oxidants Canadian Clinical Practice Guidelines JPEN 2003;27:355

Immunonutrition- the future? The right nutrient or combination Correct dose The appropriate timing The right patient and circumstance The appropriate assessment of efficacy Balance between harm and benefit of the immune response ?? Nutrient-gene interactions

Now More & better trials of Immunonutrition Early PN supplementation trial Meanwhile: the basics- screening, reaching goals, protocols, refeeding HDU feeding Profile of Nutrition: Education, dialogue Funding

Maintains Stimulates the environment defences FEEDING Provides energy