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ESPEN Congress Geneva 2014LLL LIVE COURSE: ICU NUTRITION AND PROBLEM SOLVING
Substitution, supplementation and pharmaco-nutritionM. Berger (CH)
Nutritional Support in Intensive Care Unit Patients
Substitution, supplementation and pharmaco-nutrition
Module 18.3
Pr. Mette M BergerService of Adult Intensive Medicine
& Burn CentreCHUV - Lausanne
Ethical dilemmasBioethical principlesApplication of bioethical
principles to “Nutrition at the end-of-life”
The decision-making process
Specific substrates for artificial nutrition in the ICU
• Fatty acids: n-3 PUFA, MUFA …
• Amino acids: Glutamine, Arginine, Leucine, ..
• Antioxidants: Selenium, Vit. C, Vit. E, …
Classification
Glyceride = glycerol containing lipid, Triglyceride = triesters of glycerol Fatty acid = long hydrocarbon chain organic
acid, that are saturated or notPhospholipid lipids containing glycerol,
phosphate, 2 fatty acids and x (choline, ethanolamine, serine, inositol)
COOHH3C
H3C COOH
H3CCOOH
Stearic acid 18:0
Oleic acid 18:1ω-9
Linoleic acid 18:2ω-6
α-Linolenic acid 18:3ω-3H3C COOH
9
6
3
Mammals cannot insert double bonds here
Fatty acids
• Lipids should be an integral part of PN for energy and to ensure essential fatty acid provision.
• I.V. lipid emulsions (LCT, MCT or mixed emulsions) can be administered safely at a rate of 0.7 g/kg up to 1.5 g/kg over 12 to 24 h.
• Olive oil-based PN is well tolerated in critically ill patients. • Addition of EPA and DHA to lipid emulsions has
demonstrable effects on cell membranes and inflammatory processes. Fish oil-enriched lipid emulsions probably decrease length of stay in critically ill patients.
Clinical Nutrition 28 (2009) 387–400
B
B
B
B
Choosing the lipid: A key consideration in PN
Intralipid®
20%1
Lipofundin®
MCT/LCT 20%1
Structolipid®
20%1
Omegaven®
10%1ClinOleic®
20%1Lipoplus®
20%2SMOFlipid®
20%1
Oil source/
% FA
100% soy 50% coconut 50% soy
36% coconut 64% soy
100% fish 80% olive 20% soy
50% coconut40% soy10% fish
30% soy30% coconut
25% olive15% fish
SFA 15.0 59.4 46.3 21.2 14.5 58.0 40.6
MUFA 24.0 11.0 14.0 24.3 63.7 11.5 29.3
PUFA 61.1 33.8 40.0 42.3 22.0 26.8 26.4
ω-3 8.0 4.5 5.0 35.2 2.8 5.4 7.3
ω-6 53.1 29.3 35.0 7.1 19.2 21.5 19.1
ω-9 24.0 11.0 14.0 15.1 62.3 10.6 27.7
1. Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):1171-1184. 2. Driscoll DF. Nutr Clin Pract. 2006;21(4):381-386.
Industry proposes different levels of SFAs, PUFAs, and MUFAs1,2
MCT, medium-chain triglyceride; LCT, long-chain triglyceride.
Infla
mm
atio
n
Hyper
Hypo
HYPERINFLAMMATION
Excess inflammatory eicosanoids,
cytokines, ROS, adhesion molecules;
NFkB activation
IMMUNOSUPPRESSIONExcess anti-inflammatory Cytokines;Suppressed HLA expression & antigen presentation;Suppressed T cell function
INSULT
POOROUTCOME
ω-3 PUFAs
Chronic Inflammation
Classic LeukotrienesProstaglandins
Pro-inflammatory Mediators
Resolution
Resolvins [Rv] Protectins [PD] Lipoxins [LX]
Protective Lipid Mediators
Pro-Resolution Programs“New Terrain”
Resolution of Acute Inflammation
Neutrophil
Host DefenseInjury/traumaMicrobial infectionChemical stimuli
Acute Inflammation
Aspirin-triggered Lipoxins [ATL]
Effects of a fish oil emulsion on plasma phospholipid fattyacids, inflammatory markers, and clinical outcomes in septic patients.A randomized, controlled, clinical trial, N=25
282245248
331
0
50
100
150
200
250
300
350
Day 1 Day 6
MCT / LCT
MCT / LCT / FO
p = 0.047
PO2/FiO2
Barbosa et al, Critical Care 2010; 14:R5
50:50 mixture: MCT, LCT or50:40:10 mixture: MCT, LCT + FO
70%60%
0%
36%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
PO2 /FiO2 < 200 PO2 /FiO2 < 300
MCT / LCTMCT / LCT / FO
p = 0.001 p = 0.015
Proportion of patients with PO2 /FiO2 < 200 and < 300 at day 6
Barbosa et al, Critical Care 2010
Effects of a fish oil emulsion on plasma phospholipidfatty acids, inflammatory markers, and clinical outcomesin septic patients.
A randomized, controlled, clinical trial, N=25
Safety and efficacy of fish oil-enriched PN regimen on postoperative patients undergoing major abdominal surgery
Fish-Oil enriched PN - Infections
Chen et al, JPEN 2010
Safety and efficacy of fish oil-enriched PN regimen on postoperative patients undergoing major abdominal surgeryFish-Oil enriched PN - LICUS
Chen et al, JPEN 2010
Chen et al, JPEN 2010
Safety and efficacy of fish oil-enriched PN regimen on postoperative patients undergoing major abdominal surgeryFish-Oil enriched PN - LHOS
Role of PN in etiology and pathogenesis of liver disease
• Absence of enteral feeding– Reduction in bile flow cholestasis– Bile acid toxic to hepatocyte, inflammation mediated
by cytokines from activated macrophages– Diminished gut motility, more bacterial overgrowth
and translocation• Excess provided by PN
– Excess total calorie intake, CHO (>50 kcal/kg/day)– Excess lipid (> 1g/kg/day)– Excess Mn, phytosterol, methionine
44 postop patients with indication for PN (for 5 days)
Hepatocellular integrity after PN: comparison of a FO-lipid emulsion with an olive-soybean oil emulsion.
Piper et al, Eur J Anaesthesiol. 2009;26:1076
Fig. 2 Trends over time of markers of liver dysfunction in fish oil versus soybean oil cohorts
Prevention of PN-associated liver disease: role of ω-3 FOFallon E et al, CO in Organ Transplantation. 2010, 15:334-340.
FO
FO
Impact of Fish Oil-Based Lipid Emulsion on Serum Triglyceride, Bilirubin, and Albumin Levels in Children with PN Liver Disease
Lee et al, Pediatr Res, 2009;66:698
Individual trajectory of TG after beginning fish oil week 19
FO n=18Soy-Bean n=59
fish oil = dots, soybean oil = stars
Observed weekly geometric mean
• N=44, double-blind randomized trial.• Omegaven gr (0.2g) post-op vs control group. • Reduced ASAT, ALAT, bilirubin, lipase.• Maintained weight in FO g vs 1.1+ 2.2 kg loss in SO g.
Combination of EPA/GLA and antioxidant vitamins on mortality
2007 taken from www.criticalcare.comCanadian Clinical Practice Guidelines
Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN 2009; 33 277
Patients with ARDS and severe acute lung injury (ALI) should be placed on an enteral formulation characterized by an anti-inflammatory lipid profile (ie, omega-3 fish oils, borage oil) and antioxidants. (Grade:A)
A.S.P.E.N and SCCM “Guidelines for the Use of Parenteral and Enteral Nutrition In Adult and Pediatric Patients” * position about the EPA+GLA formula?
Enteral n-3 Areas of controversy• Choice of control formula
- 3 of 5 studies used high fat (omega-6-FA) as control: Positive results in the EPA/GLA!(Gadek 1999, Singer 2006, Pontes Arruda 2006)
- 2 studies used low fat (omega-6-FA) as control: No benefit! But enteral administration was as a bolus!(Rice 2011, Stapleton 2011)
• Good studies vs doubtful studies - 1 Study with recruitment problems:
Positive results! (INTERCEPT Pontes Arruda 2011)- 1 Good new study: No benefit! (Grau-Carmona 2011)
A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury.Stapleton et al
Stapleton et al CCM, 2011
Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with ALI
Main difference with previous studies
Enteral or parenteral feeding was at the discretion of treating cliniciansStandard feeding solutionEN started 1.8±1.2 (FO) and 1.9±1.3 days after ICU admission (p=0.65). Mean caloric intake during the study’s first week was 7362±3800 kcal (1051 kcal/d) in the fish oil group and 7495±3831 kcal (1070 kcal/d) in the placebo group (p=0.87).
Enteral Omega-3 Fatty Acid, γ-Linolenic Acid, and Antioxidant Supplementation in Acute Lung Injury
Rice et al, JAMA 2011, 306: 1574• OMEGA study, a randomized,
double-blind, placebo-controlled, multicenter trial: 272 adults within 48 hours of developing ALI requiring mechanical ventilation
• 2-daily enteral supplement of n-3 PUFAs, γ-linolenic acid, and AOXs compared with an isocaloric control
• The study was stopped early for futility after 143 and 129 patients were enrolled
n-3 fatty acid-enriched PN regimens in elective surgical and ICU patients: a meta-analysis
Pradelli et al, CritCare, 2012; 16:R184Σ 23 studies (n = 1502 patients: n = 762 admitted to the ICU) No significant ≠ in mortality rate between patients on n-3 PUFA-enriched PN vs. standard PN (RR= 0.89; 0.59, 1.33) low underlying mortality risk? But ….. Infections, LOS, inflammation, lung gas exchange, liver function, antioxidant status, plasma FA, ( impairment of kidney function?)
Infections
LOS
n-3 fatty acid-enriched PN regimens in elective surgical and ICU patients: a meta-analysis
Pradelli et al, CritCare, 2012; 16:R184
INS = International Nutrition Survey
The Effects of different IV Fat Emulsions onClinical Outcomes in Critically Ill Patients
Edmunds et al CCM, 2014: 42:1168
Cumulative hazard curve of the likelihood of patients being discharged from ICU alive for comparison of lipid free versus each IV fat emulsion category (p < 0.001).
The Effects of different IV Fat Emulsions onClinical Outcomes in Critically Ill PatientsEdmunds et al CCM, 2014: 42:1168
Adult patients who were admitted to the ICU for more than72 hours, were mechanically ventilated within 48 hours, receivedexclusive PN for > 5 days, anddid not change IV fat emulsion type during the data collection period
• n-3 PUFA supplementation in TPN shown to:- be safe and well tolerated- rapidly increase n-3 fatty acids in cellmembranes
● Exert anti-inflammatory and immunomodulatoryeffects
● complication rate (surgical patients)● length ICU and hospital stay (surgical patients)• As part of enteral nutrition n-3 PUFA provide the
benefits of a balanced diet
Conclusion – n-3 PUFA
Glutamine in the ICU• Glutamine is the most abundant amino-acid in
the body• Muscle represents the major body protein
pool• Semi-essential amino-acid during stress• Primary fuel for all rapid proliferating cells
(enterocytes, lymphocytes, etc.)• Helps to maintain gut integrity• Reduces muscle degradation• Not contained in industrial PN solutions
(stability issue) while present in EN (tiny amounts)
Critical illness is associated with low plasma levels in most patients
0100200300400500600
Glutamine (mcmol/l)
Critical illnessBone marrow TX
Brown et al 1998Mc Burney et al 1994
Schloerb et al 1999Schloerb et al 1993Ziegler et al 1992
SepsisTrauma Burns
Griffiths et al 1997Houdjik er al 1998Jensen et al 1996Jones et al 1999Schelting et al 1991
Newsholme et al 1987Powell-tuck et al 1999Rennie et al 1985Roth et al 1990Tremel et al 1994
Acute pancreatitis
Roth et al 1986
Chemotherapy Decker-Baumann et al 1989
Surgical patients Hammarquvist et al 1989Jrang et al 1999Morillon et al 1996
O’Riordin et al 1994Stehle et al 1989
ESPEN Guidelines on Enteral Nutrition: Intensive care
Kreymann G et al, Clin Nutr 2006
ESPEN Guidelines on Parenteral Nutrition: Intensive care
Singer P et al Clin Nutr 2009
A randomized trial of i.v. GLN supplementation in trauma ICU patients
Pérez-Barcena et al, ICM 2014: 40:539
PRCT: GLN not given as a component of nutrition but as an extra infusion (0.35 g of L-glutamine/kg BW/day) in 142 ICU trauma patients. Primary outcome = n new infections first 14 daysNo difference in infection rates for the global population• EN Placebo 46 (65.7) GLN 41 (58.6) 0.491 • PN 7 (10.0) 7 (10.0) 0.531 • Both EN-PN: 18 (24.3) 23 (31.4) 0.351
Patients with low glutamine levels at day 6 had more infections (58.8 vs. 80.9 %; p = 0.032), longer LICU (9 vs. 20 days; p<0.01) and LOS (24 vs. 41 days; p = 0.01)
Parenteral glutamine supplementation in critical illness: a systematic review
Wischmeyer et al, CritCare, 2014; 18:R76MORTALITY
Parenteral glutamine supplementation in criticalillness: a systematic review
Wischmeyer et al, CritCare, 2014; 18:R76
HOSPITAL MORTALITY reported in 13 studies
Parenteral glutamine supplementation in critical illness: a systematic review
Wischmeyer et al, CritCare, 2014; 18:R76INFECTIONS
REDOXSHeyland et al, NEJM 2013
n 300 301 307 310First organ dysfunction to initiation of parenteral supplements (hours)†
22.3 [16.5 to 26.5]
21.0 [14.8 to 25.0]
21.1 [16.0 to 25.5]
21.5 [16.3 to 26.0]
First organ dysfunction to initiation of EN (hours)†
22.0 [12.5 to 36.8]
21.0 [11.1 to 35.0]
20.4 [12.0 to 34.8]
20.0 [11.8 to 36.2]
Patient Characteristics PLACEBO GLN AOX AOX+GLNn 300 301 307 310
Inclusion criteria A PaO2/FiO2 ratio ≤300 282 (94.0%) 285 (94.7%) 287 (93.5%) 285 (91.9%)
Clinical evidence of hypo-perfusion 277 (92.3%) 278 (92.4%) 286 (93.2%) 293 (94.5%)Renal dysfunction 104 (34.7%) 117 (38.9%) 99 (32.2%) 122 (39.4%)
Platelet count of ≤50 x 109/L 16 (5.3%) 21 (7.0%) 12 (3.9%) 18 (5.8%)Hours in ICU prior to randomization† 17.9 17.7 18.4 18.0
PRCT: April 2005 and December 2011 in 40 international ICUsRandomized within 18 hours of admission2x2Factorial design n=1218
Glutamine – que passa?REDOXS: highest dose ever 0.78 g/kg/d very early (<24hrs) during shock phase, no deficit
Death rate
AOX
Yes NoGLN Yes 31% 31%
No 27.6% 24.5%
P=0.06
n = 611
n = 607
424 187
459 148
chi2P = 0.0153 or more organ failures
GNL
NoGln
By courtesy Prof Jan Wernerman
Specificities of REDOXS• Very sick patients: > 2 organ failures, 35 %
ARF• Total Dose 0.78 g/kg > recommendations• Very early delivery of a full GLN dose
WITHOUT feeding: mean nutrition US 40% of target
• Mortality Predicrs: >2 organ failures, ARF, <30% of energy delivery, steroids, vasopressors
Role of Glutamine Supplementation in Critical Illness Given the Results of the REDOXS StudyHeyland & Dhaliwal, JPEN 2013: in press
Nutrition in ICUAntioxidants
1. Oxidative stress is increased in criticallyill patients and contributes to organdamage / malignant inflammation.
2. As the increase in oxidative stress isassociated with depletion of the stores ofanti-oxidants, the administration of antioxidants can be beneficial
3. Adding anti-oxidant compounds to nutrition support is physiological.
Plasma redox status relates to severity in critically ill patients
Alonso de Vega J et al, CCM 28:1812, 2000APACHE III scores and plasma redox status (r2 = 0.56; p < .001) as defined by the ratio total antioxidant capacity (mM) /lipoperoxides (uM)
APACHE III scores and plasma myeloperoxidase concentrations (r2 = 058; p < .001)
73 patients at admission to a mixed ICU: 8 deaths
Oxidative stress and metallothionein expression -liver of rats with severe thermal injury
Ding et al Burns, 28:215, 2002
Effects of severe thermal injury on the zinc concentrations both in the serum and in the liver. mean±sem, n=5. *P<0.001, **P<0.01 and # P<0.05 vs. the corresponding normal control
Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients
Forceville X et al, CCM 26:1536, 1998
Admission plasma [Se] related to severity of sepsis
Replacementof lossesObjective =
restore a biological function
Major burnsMajor traumaCVVHIntestinal lossesIsolated deficit
Trace element (Cu,Se,Zn) substitution in Burns –Reduction of nosocomial pneumoniaBerger et al, 2006, Crit Care 10:R153
Log Rank p=0.0014Wilcoxon p=0.0019
Aggregation of 2 consecutiveRandomizedTrials IV- Cu 3 mg- Se 300 mcg- Zn 30 mg
65% reductionof pneumonia
risk
n = 41Burns 46% BSA
AOX trial - 200 critically ill: trauma-cardiac-SAHSe, Zn, Vit E, Vit C, Vit B1
Berger et al Crit Care 2008 12:R101
– 11 days
Impact of high-dose antioxidants on outcomes in acutely injured patients
Collier and all, JPEN 2008Retrospective study, before / afterTTT: vitamin C 1g, E 1000 ui, selenium 200 mcgResults: 4,294 patients (AO+, N = 2,272; AO-, N = 2022). Hospital (4 vs 3 days, P < .001) and ICU stay (3 vs 2 days, P =
.001) median length of stays were significantly shorter in the AO+ group. Mortality significantly lower in the AO+ group (6.1% vs 8.5%, P = .001), translating into a 28% RR reduction for mortality with AOX
After adjusting for age, gender, and probability of survival, AO exposure was associated with even lower mortality (OR 0.32, 95% CI 0.22-0.46). Patients with an expected survival <50% benefited most
high-dose AOX protocol a 28% RR in mortality and a significant in both hospital and ICU length of stay.
Inexpensive intervention to reduce mortality/morbidity in trauma patientS.
High-dose antioxidant administration is associated with a reduction in post-injury complications in
critically ill trauma patientsGiladi AM et al Int. J. Care Injured 42 (2011) 78–82
Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis
Manzanares et al. Critical Care 2012, 16:R66
Effects of AOX on mortality n=20 studiesAOX
Current recommendationsSource ASPEN SCCM
May 09Canadian GL
Jan 09ESPEN
06 (EN) 09 (PN)
A combination of AOX vitamins and trace minerals (specifically including selenium) should be provided to all critically ill patients receiving specializednutrition therapy. (Grade: B)
Based on 3 level 1 and 13 level 2 studies, the use of supplemental combined vitamins and trace elements should be considered in critically ill patients. There are insufficient data to make a recommendation regarding IV/PN selenium supplementation, alone or in combination with other antioxidants, in ICU patients.
Burns : Trace elements(Cu, Se, Zn) should be supplemented in a higher than standard dose (A).Any prescription of PN includes 1 daily dose of multivitamins and 1 daily dose of trace elements (C).
Adjuvant selenium supplementation in the form of sodium selenite in postoperative critically ill patients
with severe sepsisSakr et al, Critical Care 2014, 18:R68
retrospective study, all adult patients admitted to a 50-bed surgical ICU with severesepsis (January 2004 April 2010) analysis: whether or not received adjuvant Se supplementation (given at the discretion of the attending physician). Se was administered in the form of Na selenite pentahydrate (Na2SeO3.5H2O): 100 μg of Se ≅ 333 μg of sodium selenite. A bolus of Na selenite corresponding to 1000 μg of Se was injected IV through a central venous line over 30 minutes followed by infusion of 1000 μg/day over 24 hours for 14 days ICU discharge or death.Adjuvant Se in 413 (39.7%) of the 1047 severe sepsis patients.Se supplementation was not independently associated with favorable outcome(OR = 1.19, 95% CI: 0.86 to 1.65, P = 0.288)
46 vs 39.1%
JenaGermany
REDOXS: A randomized trial of high dose Glutamine and Antioxidants in critically ill patients with MOF
Heyland et al, NEJM 2013Antioxidant vs. no- AOX
Kaplan-Meier 6 Month Survival curves
n=1218No effect
Replace or supplement?2 distinct aims
normal
Losses +++InsufficientIntakes
Deficit
Replace
+ +++
SupplementToxicity ?
Dose response curveB
iolo
gicc
al a
ctiv
ity
A+B+C deficieny, D suboptimal, E optimal, G toxicity, H lethal
Adjusted hazard ratios for all-cause mortality by serum selenium concentration in adult participants of the US 3rd National Health & Nutrition Examination Survey followed up for up to 18 years until the end of 2006.Shaded area: 95% CIs. Reference value (hazard ratio 1) set at the 10th percentile of the serum selenium distribution (105,8 μg/L) (Bleys et al 2008)
Selenium and human healthRayman M, Lancet 2012
13 887 adult participants Study participants were recruited from 1988 to 1994
Conclusions• n-3 PUFA: Strong positive evidence in surgical
and ICU patients • Glutamine: Strong nutritional evidence for
parenteral in ICU patients, • Limited evidence for enteral Glutamine except
Burns, Trauma• Antioxidant micronutrients : differentiate
repletion from supplementation !! • more PRCTs are required for general ICU
patients – strong evidence in burns and trauma patients
High protein Immune enhancing vs. high protein EN & Nosocomial Infections in the ICU
van Zanten ARH et al, JAMA 2014;312:514• 301 adult patients, expected to be ventilated for >72hrs
and to require EN for >72 hrs were randomized to the IMHP (n = 152) or HP (n = 149). EN initiated within 48 hrs of ICU admission for ICU stay
• IMPH glutamine,omega-3 fatty acid, and antioxidant enriched tube feed
MetaPlus