Transcript Immunonutrition

Veronica Ueckermann
2013/02/25
Baseline Nutrition –
“Metabolic Resuscitation”
 Addressing nutritional needs in the critically ill early and
adequately improves outcome
 Mortality
 Reduction ICU days and Ventilator days
 Improved wound healing
 Reduction in infection rates
 Malnutrition impairs immune function
 Adequate protein and energy provision essential
What is immunonutrition?
 Immunonutrition involves the administration of
nutrients via enteral or parenteral routes in
supranormal amounts, to achieve a pharmacological
effect on one or more components of the patient’s
response to surgery, trauma or infection.
 Role players:
 Antioxidants, vitamins, trace elements
 Macronutrients: arginine, glutamine
 Fish oils
Rationale for immunonutrition
 SIRS response:
 Innate + adaptive immunity
 Pro-inflammatory mediators
 Overwhelming or prolonged
= mitochondrial damage
oxidant/antioxidant imbalance
multi-organ dysfunction
Rationale for immunonutrition
CARS
 Transient down-regulation adaptive immunity
 Prevent downstream damage organs
 Leukocyte apoptosis and deactivation
 Limit inflammatory response and organ damage
but may increase susceptibility to infection.
NFκB
 Oxidant molecules up-regulate cytokines,
inflammatory mediators, adhesion molecules and
enzymes through the activation of nuclear
transcription factors such as NF kappa B and activator
protein-1.
 NFκB activation is a redox sensitive step, which means
that oxidant molecules promote inflammation and
antioxidants have opposite effect.
 Increased NFκB activation in sepsis is associated with
mortality rates  target for immunomodulation by
antioxidants and omega 3 fatty acids.
Efficacy of immunonutrition
 Montejo et al reviewed 26 studies on immunonutrition in critically ill:
 ↓ incidence abdominal sepsis OR 0.26
 ↓ incidence nosocomial pneumonia OR 0.54 and bacteremia OR
0.45
 ↓ time on mechanical ventilation, ICU stay, hospital stay
No reduction in mortality rates as a whole BUT severity of
illness influences efficacy of immunonutrition.
Severely or mildly ill patients least likely to benefit.
Clin nutr. 2009;22:221-223
Antioxidant vitamins and trace
elements
 Antioxidant defense system includes enzymes
(superoxide dismutase, glutathione peroxidase), trace
elements (Se, Zn), vitamins (vit C, E, beta-carotene)
and sulfhydral group donors (glutathione)
 Critical illness is associated with deficits in
antioxidants due to
 Redistribution from blood to tissues
 Increased losses
 Decreased nutritional intake
Antioxidant vitamins and trace
elements
 Antioxidants catalyze breakdown of ROS
 Low antioxidant levels are linked with immune
dysfunction, higher infection rates and increased
morbidity and mortality during critical illness.
Antioxidant vitamins and trace
elements
 Heyland et al: meta-analysis of clinical studies of trace
elements and vitamin supplementation in critically ill mixed results in literature
 Concluded trace elements and anti-oxidant vitamins,
particularly high-dose parenteral selenium are safe and
may be associated with a reduction in mortality.
 However, optimal combination and doses of
micronutrients remain to be determined.
Selenium
 Manzanares et al – high dose selenium administration
(2000mcg bolus then 1600mcg/day) in critically ill
patients decreased SOFA scores and VAP rates
 Valenta et al – 150 patients with SIRS or sepsis and
evidence of organ dysfunction. 1000mcg on day one,
500mcg for 14 days. No significant difference placebo.
 German multicenter trial Angstwurm et al found
reduced mortality in patients with severe sepsis and
septic shock in patients who received 1000mcg
selenium daily for 14 days.
Zinc
 Important role in immune function, glucose control,
wound healing, superoxide dismutase and glutathione
activity, and thiol pool stabilization.
 Cander et al – serum zinc levels inversely proportional
to SOFA scores and organ failure.
 Besecker et al – as zinc levels decreased, cytokine
levels (IL6 and IL-8 especially) increased
 No studies have demonstrated significant difference in
mortality or length of stay
Vitamin C
 In critically ill patients, normal plasma vit C levels can
be restored with 3g/day IV vitamin C.
 Benefit demonstrated in burns patients
 Tanaka et al – significantly lower resuscitation
requirements, weight gain and wound edema in patients
with thermal injury, who received ascorbic acid
 Trend towards decrease in respiratory failure in those
treated with vit C
Recommendations
Glutamine
 Glutamine is most abundant free amino acid in the body.
 Muscle stores of glutamine rapidly depleted in catabolic
stress states.
 Glutamine is important for:
 Rapidly dividing immune cells (energy substrate for



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lymphocytes and neutrophils)
Nucleotide synthesis stimulated
Gut barrier function (fuel for enterocytes)
Inducing production heat shock proteins
Synthesis of endogenous anti-oxidant glutathione
(suboptimal in HIV, hep C, DM II, MI, cirrhosis)
Glutamine
 Supplementation protects against effects of oxidising stress
 Patients in ICU have low p-glutathione levels at time of
admission  related to illness severity and mortality rates
 Novak et al meta-analysis glutamine supplementation in
serious illness:
 Elective surgery patients – reduced infectious complications,
decreased length hospital stay
 Critically ill patients – reduced complications and mortality
rates in high doses parenteral glutamine(>0.2g/kg/day)
 Grimble et al:
 Glutamine supplementation reduced infection and
inflammation, decreased length of stay in surgical patients,
no effect mortality
Glutamine
 Fuentes et al:
 Glutamine supplementation reduced mortality in
patients with peritonitis
 Enteral glutamine decreased mucositis in patients
receiving chemotherapy
 Wernerman et al:
 Multicenter, RCT
 IV glutamine dipeptide reduced mortality
Glutamine administration
 To overcome low stability of glutamine in aqueous
environment, it is coupled with another amino acid
(glucine or alanine) to form a dipeptide.
 Dosages
 Oral glutamine at 0.3mg/kg/d showed beneficial effects
on intestinal integrity.
 glutamine enriched formula (30.5g/100g protein)
resulted in decreased infection in critically ill patients.
 Parenteral 0.4g/kg/day decreased leukocyte and NK cell
count (suppressing inflammation)
Arginine
 Arginine is essential in CERTAIN TYPES of critical
illness.
 Beneficial effects:
 Secretagogue for release of anabolic hormones (GH,
IGF)
 Supporting immune (especially T-cell) function
 Detoxification of ammonia
 Improving wound healing via metabolism of polyamines
to proline
 BUT excessive production linked to mortality in septic
shock (3 studies)
Risk vs Benefit Arginine
Arginine plus fish oil
 2008 meta-analysis immunonutrition in critically ill
patients showed that the addition of arginine to fish oil
appeared to counteract the benefits of fish oil on outcome
of ICU and trauma patients with sepsis/SIRS.
 Mechanism unknown, but following postulated:
 Cytokines induce type 2 isoform NO synthase.
 Once induced, NO production is dependent largely on
availability of arginine.
 Therefore, supplemental arginine in severe sepsis promotes
large quantities NO, subsequently metabolised to
peroxynitrite  damages mitochondria, increases gut barrier
permeability, promotes organ dysfunction.
Arginine . . .
Post-operative and trauma are typically
arginine deficient states, and these patients
consistently benefit from arginine
supplementation. However, critically ill
medical patients exhibit little if any benefit and
a strong possibility of increased mortality exists
when arginine is supplemented during severe
sepsis and MODS.
Fish oils
 Cold water fish are rich in eicosapentaenoic acid (EPA)
and docosahexonoic acids (DHA)
 Humans have limited capacity to synthesis DHA and
EPA during basal conditions from alpha-linolenic acid
(ALA), through desaturase enzymes.
 During acute illness these desaturases are markedly
downregulated so that EPA and DHA synthesis from
ALA is negligible.
 Thus supplementation of omega 3 fatty acids in
critically ill patients requires administration of fishoil-based lipids.
Fish Oils – omega 3 fatty acids
 Mechanism anti-inflammatory action of omega 3 fatty acids:
 Displaces AA from phospholipid core of the inflammatory cell
(macrophage, neutrophil) membrane, reducing synthesis of proinflammatory eicosanoids
 Reduction in synthesis of pro-inflammatory eicosanoids by
competing with AA for metabolism by the enzymes COX and
lipoxygenase
 Reducing leukocyte and platelet adhesive interaction with
endothelium
 Inhibition inflammatory gene expression
 Reduction of oxidative injury by stimulating glutathione production
 Enhancing synthesis of anti-inflammatory resolvins
 Lung-protective effect mediated by reducing release of gut-derived
inflammatory mediators into mesenteric lymphatics and thoracic
duct.
Gama linolenic acid
 GLA is an omega-6 polyunsaturated fatty acid
 Synergistic effect with EPA and DHA in reducing lung
inflammation.
 GLA is metabolized to one-series prostaglandins that
promote pulmonary vasodilatation  counteracts
excessive vasoconstriction that occurs in ARDS
Evidence for fish oil
 ARDS or ALI effects demonstrated in 3 major RCT
 ↓ duration ventilation
 ↓ ICU and hospital stay
 ↓ new organ failure
 2 studies also showed mortality reduction
 Meta-analysis of 3 trials (n=441)
NNT to save an additional life at 28 days 5
Enteral omega 3 in ARDS
 Reduced
 Mortality
 Rate of new organ failure
 Length of ICU stay
 Length of ventilation
 Faster improvement PaO2/FiO2
 Early administration of fish-oil based formula to
ventilated patients exceptionally safe
 BAL reduced inflammatory markers
 Benefit lost if combined with arginine in medical ICU
Sepsis and omega 3 lipids
 In animal models, fish oil has shown beneficial effects
 May increase bacterial killing
 Improves survival
 Maintains blood flow to intestine
Surgical patients omega 3
 Enteral and partenteral omega 3
 Prevention infections
 Reduced length of hospital stay
 Pre-op use in cardiac surgery patients - reduction AF
post-op, reduction length of hospital stay
 Good safety profile
When to use what???
Guidelines:
Canadian Clinical Practice Guidelines
(CCPG)
European Society of Parenteral and
Enteral Nutrition (ESPEN)
Society of Critical Care Medicine and
American society of Enteral and
Parenteral nutrition (SCCM/ASPEN)
Guidelines
Enteral or Parenteral?
 Many investigators and opinion-leaders feel that the route
of nutrient administration makes a difference in critically
ill patients.
 Delivery directly to intestinal lumen makes biological
sense
 Usually the opinion is that enteral nutrition is superior to
parenteral nutrition. This is probably true for infectious
complications in patients randomized to enteral or
parenteral nutrition, but no studies or meta-analyses
demonstrate a mortality difference. In fact the metaanalysis that demonstrates a difference, does so in favor of
parenteral nutrition.
 Enterocyte function enhanced by enteral glutamine.
Timing of immunonutrition
 Data available in surgery patients
 Pre-operative immunonutirition had most beneficial
effects
 Greatest benefit in malnourished patients
 Reduction post-op mortality
 Reduction in non-infective post-op complications and
wound infections
 Reduced hospital stay
 Evidence favours early use in sepsis and MOD
Heterogeneous population group
 Great inter-individual variation in response to
immunonutrition.
 Many genes have single base changes in their promoter
regions (single nucleotide polymorphisms) which
influence amount of gene product formed when
activated.
 SNP in genes for cytokines and inflammatory
molecules.
 The clinical outcome of virtually all of the diseases and
conditions to which immunonutrition is applies is
influenced by SNP.
One size does not fit all
 Variation in degrees of acute phase response, protein
loss, gut function and immune system alterations.
 15-70% of hospitalised patients are undernourished or
malnourished on admission, further complicating the
provision of optimal nutrition therapy.
 A “one nutrition therapy regimen will fit all” approach
is simplistic and unable to provide optimal therapeutic
support.
Answers in the pipeline
 REducing Deaths due to OXidative Stress (The
REDOXS Study): Rationale and study design for a
randomized trial of glutamine and antioxidant
supplementation in critically-ill patients.
 ICU patients with severe organ dysfunction
randomized to one of 4 treatments:
 Glutamine (dipeptiven 0.35g/kg/d)
 Antioxidant therapy (Se, Zn, vit C, vit E, beta-carotene)
 Glutamine and antioxidant therapy
 Placebo
REDOXS Study
 Primary outcome 28d mortality
 Secondary outcomes
 ICU stay duration
 Infection
 Multiple organ dysfunction
 Duration mechanical ventilation
 Length hospital stay
 Quality of life at 3 and 6 months
What about South Africa?
South Africa
 High incidnence of malnutrition, HIV and
tuberculosis.
 Malnutrition itself is associated with higher care costs
due to increased complication rates.
 In our resource-limited setting it is imperative to first
provide basic nutrition support to avoid impaired
immune response, delayed wound healing and
increased infections associated with insufficient
protein and energy provision.
SA
 In South African setting, the final verdict regarding
implementation of immunonutrition is influenced by
cost.
 Costs, however, may be offset by savings due to
decreased ICU stay and antibiotic use
 US: Arginine-containing formula in surgery patients.
Extra cost $45 000, savings due to decrease infections $1
442 000.
 Italy: Glutamine supplementation in critically ill
reduced mortality and hospital stay. Treatment cost
offset by savings on ICU and antibiotic costs.
IV glutamine can decrease
LICU by 2-3 days.
7 days IV glutamine R5 171.67
vs 3 days ICU R20 066.62
References
 Barry et al. Immunonutrition and critical illness: An
update. Nutrition 46(2010):701-707
 Grimble. Immunonutrition. Current Opinion in
Gastroenterology 2005, 21:216-222.
 Singer et al. Enteral omega-3 in acute respiratory
distress syndrome. Curr Opinion in Clinical nutrition
and metabolic care 2009; 12:123-128
 Prins et al. Immunonutrition: a South African
perspective. S Afr J Clin Nutr 2012;25(3)
References
 Reddell et al. Antioxidants and micronutrient
supplementation in trauma patients. Curr Opin Clin
Nutr Metab Care 2013, 15:181-187
 Weijs et al. Optimising energy and protein balance in
the ICU. Curr Opin Clin Nutr Metab Care 2013, 16.
 Metchteld et al. Specific amino acids in the critically ill
patient – exogenous glutamine/arginine: A common
denomenator? Crit Care Med 2007, 35:568-576.
 Martin et al.Omega 3 fatty acids in critical illness.
Nutrition reviews 68(9):531-541
References
 Mayer et al. Fish oil in critical illness. Curr opin Clin Nutr
Metab Care 11:121-127.
 Hyeyoung. Glutamine as an immunonutrient. Yonsei Med
J 2011; 52(6)892-897
 Heyland et al. Zinc Supplementation in Critically ill
patients: A key pharmaconutrient? Jnl Parenteral and
Enteral Nutr. 2008 32:509.
 Heyland et al. REDOXS Study: A Rationale and study
design for a randomized trial of glutamine and antioxidant
supplementation in critically-ill patients. Proceedings of
the Nutrition Society (2006), 65:250-263