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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

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nutrition and immunonutrition in the icu


Marcia McDougall

October 2007

a slender and restricted diet is always dangerous in chronic and in acute diseases

‘A slender and restricted diet is always dangerous in chronic and in acute diseases’

Hippocrates 400 B.C.

critical illness
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
Consequencesof 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
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
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
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
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
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
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
nutrition qi study
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

“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
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
Organisation of Nutrition Support

3. NICE Guidelines for Nutrition Support in Adults 2006

  • 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
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
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

use the most appropriate route of access and mode of delivery

3. NICE Guidelines for Nutrition Support in Adults 2006

step 3 treat pn
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

use the most appropriate route of access and mode of delivery

3. NICE Guidelines for Nutrition Support in Adults 2006



Of feeding

reduced enteral stimulation


  • 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
  • Preserves intestinal mucosal structure and function
  • More physiological
  • Relatively non-invasive
  • Reduced risk of infectious complications cf PN (?)
  • Relatively cheap
ng problems
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
Jejunal Feeding
  • Insertion
  • Surgical jejunostomy: at laparotomy
  • May reduce incidence of aspiration
  • Sometimes increases dose of EN given over NG
  • Indications
parenteral nutrition
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
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
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
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
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 syndrome37
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 lowPO42-(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
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
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
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+
  • Reducefeeding rate if problems arise

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
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 illness43
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

THE ICU GAMBLEHow to tip the scales?




and resolution


organ failure


critical illness45
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
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
  • 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






Decreased Free

Radical availability

(Anti-inflammatory action)



Inflammatory Cytokine








Enteric Bacteria

or Endotoxins

Maintenance of


Mucosal Barrier

Fuel for


Critical Illness




of TCA Function

Reduction of

Infectious complications

Maintenance of



Fuel for







ATP content

Preservation of

Muscle mass



Wischmeyer PE, Curr Opin Clin Nutr Metab

Care 6: 217-222, 2003

glutamine trials
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

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

  • 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
  • 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
  • ‘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: 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: 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
  • 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
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
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
3 studies oxepa
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
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



reactive oxygen species o no
Positive actions:


Regulation of vascular tone

Cell signalling

But mostly detrimental:

Cell injury (ischaemia /reperfusion)

DNA, Lipids, Proteins

Organ dysfunction

Lungs, Heart, Kidney

Liver, Blood, Brain

Reactive Oxygen Species O-, NO-



acute insult





Exacerbation of cell and tissue injury


  • 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?

Canadian Clinical Practice Guidelines JPEN 2003;27:355

immunonutrition the future
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
  • 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