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, …

LIPIDS

SOYn-6 pufa

OLIVE n-9 mufa

FISH ….n-3 pufa

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.

Ubiquitous effect of n-3 FA

N-3 PUFA and immunity

Buckley CD et al, Immunity, http://dx.doi.org/10.1016/j.immuni.2014.02.009

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).

Rice et al, JAMA 2011

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

5 x more protein in the control group !!!Underfeeding in both groupsBolus feeding

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

High protein Immune enhancing vs. high protein EN & Nosocomial Infections in the ICU

van Zanten ARH et al, JAMA 2014;312:514• Result: no significant ≠ in

incidence of new infections between groups:

• IMHP - 53%(95%CI, 44%-61%) vs

• HP 52% (95%CI, 44%-61%)(P = .96)

MetaPlus