1. NUTRITION and IMMUNONUTRITION in the ICU
Marcia McDougall
October 2007

2. ‘A slender and restricted diet is always dangerous in chronic and in acute diseases’
Hippocrates 400 B.C.

4. 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

5. 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

6. 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

7. ICU Nutrition in the 1970s

8. ICU Nutrition through the ages
Overfeeding
1980s

9. 1970s: TPN - separate CH, AAs and Lipids
kcals/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

10. 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

11. 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

12. 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?

13. Current practice - Scotland
SICS Nutrition Survey
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

14. % patients receiving PN/year

15. NJ feed: patient use per year

16. What is the maximum amount of time an ICU patient should go without nutrition?

17. 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

19. Guidelines

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

21. 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

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

23. 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’

24. 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

25. 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

26. 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

27. Routes
Of feeding

28. 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

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

30. 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

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

32. 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

33. 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

34. 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 % 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

35. 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

36. Refeeding Syndrome
Prisoners of war , 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

37. 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

38. 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!

39. 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+)

40. 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

41. 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

42. 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

43. 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

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

45. 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?

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

47. 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

48. 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

49. 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: , 2003

50. 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

51. 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

52. 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

53. 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

54. 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

55. 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?)

56. 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

57. 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

58. 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

59. 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

60. 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)

61. 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)

62. 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

63. 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

64. 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

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

66. 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

67. 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

68. 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

69. 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

70. Maintains Stimulates the environment defences
FEEDING
Provides energy