Adjunctive Supportive Care Proactive Primary Therapy Nutrition therapy that modulates the underlying...

Adjunctive Supportive Care

ProactivePrimaryTherapy

Nutrition therapy that modulates the underlying disease process



Nutrition therapy impacts clinical outcomes



Timeliness of administration of nutritional therapy matters!

• infection• trauma• I/R• hypoxemic/ hypotensive

= oxidative stress

Death

organ = failure

mitochondrial dysfunction

Key nutrient deficiencies(e.g. glutamine, selenium)

activation of coagulation

generation of OFR (ROS + RNOS)

endothelial dysfunction

elaboration of cytokines, NO, and other mediators

cellular = energetic failure

Microcirculatory Dysfunction

Fish Oil supplemented diets?

Copyright ©2007 The American Society for Nutrition

Mechanisms by which fatty acids can affect immune cell function

Wanten, G. J. et al. Am J Clin Nutr 2007;85:1171-1184

• 21 patients with sepsis requiring TPN

• Randomized to recieve PN with an n-3 or n-6 lipid emulsion for 5 days

• Dose: 350 ml og s 10% n-3 lipid emulsion (Omegevan)

Am J Respir Crit Care Med 2003; 167: 1321

TPN with N-3 vs n-6 FAs in severe sepsis. Monocyte membrane FA composition:

arachidonic, EPA, DHA

Mayer K, Am J Respir Crit Care med 2003; 167: 1321

N- 3 group

N- 6 group

TPN with N-3 vs n-6 FAs in severe sepsis. Ex vivo monocyte cytokine release in response to LPS

Mayer AJRCCM 2003; 167: 1321

N- 3 group

N- 6 group

• 25 Patients with SIRS or sepsis receiving PN

• Randomized to 50:50 MCT/soybean emulsion or lipid emulsion with 50% MCT, 40% soy, and 10% Fish oil x 5 days

• Dose of fish oils: – rec’d 6.4 gms/day– .09 g/kg/d

Barbosa Critical Care 2010;14:R5

Barbosa Critical Care 2010;14:R5

• Fish oil group resulted in:

• Greater attenuation of IL-1B, IL-6, and TNF

• Improved Pa02/FiO2 ration by day 6

• No difference in vent days, ICU stay

• Tendency to reduced hospital stay (22 vs 55 days, p=0.08) and fewer deaths 31% vs 40% (p=ns).

Greater treatment effect with higher dose?? treatment effect if control group not

receiving any lipids?

• Retrospective study of 194 patients with intraabdominal infection leading to sepsis

• Control group rec’d standard PN with soybean/olive oil (80%/20%).

• Treatment group had 10% FO (omegaven) infused on top of standard PN over 30-60 mins

• No effect with fish oils on CRP, organ failure or any clinical outcomes

• Dose of fish oils: rec’d 0.12 g/kg/d over 1 hr! (infusion >0.05 g/kg/hr may be harmful!)

Wohlmuth JPEN 2010

There appears to be a dose-response curve with IV FO

Pittet Intensive Care Med 2010;36:289-295

However, in this small study of healthy volunteers, no correlation with biological effect

Fish Oil optimal Dose Determination Study

The FOILED Study• Phase 2 dose finding study

• Mechanically ven’t patients with sepsis with high IL-6 level receiving EN (NO PN lipids)

• Open label use 10% Fish Oil (Omegaven) to 3 groups:

– Group 1: standard care only, no FO

– Group 2: 0.20 kg/day of IBW

– Group 3: 0.50 kg/day of IBW

• Outcomes:

– Safety- SOFA scores, complications, bleeding

– Systemic inflammation: IL-6 and IL-10

– Immunity: LPS ex-vivo stimulation of TNF and IL-6

– Clinical outcomes

What about enteral fish oils?

(Product enhanced with fish oils +borage oils

+ antioxidants)

Borage Oil

GLA

DGLA

PGE1 and eicosanoidsthat are lessinflammatory

Replacing AA with DGLA results in

Fish Oil

EPA

Eicosanoidsthat are lessinflammatory

(TXA3, PGE3, LTB5)

Replacing AA with EPA results in

CyclooxygenaseLipoxygenase

Arachidonic Acid

Decreased proinflammatory

eicosanoids(LTB4, TXA2, PGE2)

EPA + GLA Modulate InflammationEPA + GLA Modulate Inflammation

Effect of Enteral Fish Oils/Borage Oils and antioxidants in Critically Ill with ALI

• RCT of 146 critically ill patients with ALI and BAL+ for WBCs

• Double-blinded; ITT

• Experimental: Oxepa®

• Control: high fat diet

• Groups well matched at baseline

Gadek Crit Care Med 1999;27:1409

After 3-4 days

• Reduction in AA and increase in EPA in lung and alveolar macrophage

• Decrease in neutrophils recovered in BAL fluid

• Improved oxygenation

Effect of Enteral Fish Oils/Borage Oils and antioxidants in Critically Ill with ALI

• RCT of 146 critically ill patients with ALI and BAL+ for WBCs

• Double-blinded; ITT

• Experimental: Oxepa®

• Control: high fat diet

• Groups well matched at baseline

0

5

10

15

20

25

VentDays

ICUDays

ICUDeaths

Oxepa

control

Gadek Crit Care Med 1999;27:1409

P=0.03 P=0.17P=0.02

Overall Effect on Mortality

www.criticalcarenutrition.com

Diets Supplemented with fish oils, borage oils, and

antioxidants

• Recommendation:Based on 1 level 1 studies and 4 level 2 studies, we recommend the use of enteral formula with fish oils, borage oils, and antioxidants in patients with ALI/ARDS.

Canadian Clinical Practice Guidelines JPEN 2003;27:355-373

Updated 2009; www.criticalcarenutrition.com

Multicenter, Randomized, Double-blinded trial (14 Clinical Sites – Brazil)

200 Patients in the early stages of sepsis (no organ failures; within 36 hrs from onset of sepsis)

Fish oil/borage oil/antioxidant vs standard polymeric

Primary Outcome: Evolution to more severe forms of sepsis (severe sepsis or septic shock)

Secondary Outcome: 28 day all-cause mortality, organ failure development, hyper/hypoglycemic events, insulin use, hospital stay, ICU stay

Investigating Nutritional Therapy with EPA, GLA and Antioxidants Role in SEPsis

Treatment (INTERSEPT)

Pontes-Arruda Crit Care 2011;15:R144

Pontes-Arruda Crit Care 2011;15:R144

Mostly due to reduced Cardio-

resp failures

Variable Study (n=53)

Control (n=53)

P Value

Use of mechanical ventilation, n (%)

Invasive 10 (18.9%) 18 (34%) .03984

Non-invasive 5 (9.4%) 6 (11.3%) NS

Number of days using mechanical ventilation*

7 (4-12) 15 (9-21) .0033

Number of ICU days* 7 (4-12) 13 (9-18) <.0001

Number of hospital days* 9 (6-14) 19 (13-24) <.0001

SECONDARY OUTCOMES

No Difference in survival between the groups?

Timing of FeedingTiming of Feeding

SSUUPPPPLLEEMMEENNTT

““Early Early Full”Full”

Fast ramp upFast ramp up

““Early Early Trophic”Trophic”

(10 ml/hr)(10 ml/hr)N-3 +N-3 +AntioxidantsAntioxidants

(Module delivered (Module delivered as bolus bid)as bolus bid)

ControlControlStandard ENStandard EN

(480 cal/ 20 g pro)(480 cal/ 20 g pro)

n = 250 n = 250

n = 250 n = 250

EDEN-OMEGA: EDEN-OMEGA: Factorial Trial DesignFactorial Trial Design

NIH NHLBI

OMEGA: 60-Day MortalityOMEGA: 60-Day Mortality

P=0.05

26.6% 16.3%

0

5

10

15

20

25

30

OMEGAObserved

OMEGAAdjusted

ControlObserved

ControlAdjusted

FACTTConservative

%

17.9%16.3%24.6%26.6%

0

5

10

15

20

25

30

OMEGAObserved

OMEGAAdjusted

ControlObserved

ControlAdjusted

FACTTConservative

%

P=0.14

25.5%17.9%16.3%24.6%26.6%

0

5

10

15

20

25

30

OMEGAObserved

OMEGAAdjusted

ControlObserved

ControlAdjusted

FACTTConservative

%

P=0.14

JAMA on line Oct 2011

OMEGA: Plasma OMEGA: Plasma Eicosapentaenoic Acid (EPA) Eicosapentaenoic Acid (EPA)

Levels (%)Levels (%)

0

5

10

0 3 or 4 6 or 7Day

Pla

sma

Fatt

y A

cids

(%

) OmegaControlGadek-EPA/GLAGadek-Control

Problems with OMEGA• Hard to attribute excess mortality to FO when the EPA levels

were half of what Gadek achieved, what would the biological mechanism for harm be?

• Multpile tests of significance and baseline imbalances in patients disadvantaging FO group.

• More likely, problem with delivery and utilization in the context of bolus fed patients who were semi starved (fat used for fuel!)

• Improved outcomes in control group may be due to 20 grams extra/day of protein

• Because of different study design, difficult to combine with other studies of continuous administration in moderately well fed patients

Bottom Line:Continue with FO/AOX continuously

administered in optimally fed ICU patients

Cook, Heyland JAMA Oct 2011

Glutamine supplementation?

Glutamine levels drop:- following extreme physical exercice- after major surgery- during critical illness

Low glutamine levels are associated with:- immune dysfunction- higer mortality in critically ill patients

Novak F, Heyland DK, A Avenell et al., Crit Care Med 2002 Oudemans-van Straaten HM, Bosman RJ, Treskes Met al., Intensive Car Med 2001

Glutamine: A conditionally essential amino acid

=> Low plasma glutamine at ICU admission is related to mortality.

The “Oudemans-van Straaten-Study”

“high”

“low”

Potential Beneficial Effects of Glutamine

Fuel forFuel forEnterocytesEnterocytes

Fuel forFuel forLymphocytesLymphocytes

Nuclotide Nuclotide SynthesisSynthesis

Maintenance ofMaintenance ofIntestinalIntestinalMucosal BarrierMucosal Barrier

Maintenance ofMaintenance ofLymphocyteLymphocyteFunctionFunction

Preservation Preservation of TCA Functionof TCA Function

Decreased FreeRadical availability (Anti-inflammatory action)

GlutathioneGlutathioneSynthesisSynthesis

GLNGLNpoolpool

GlutamineTherapy

Enhanced HeatEnhanced Heat Shock ProteinShock Protein

Anti-cataboliceffect

Preservation of Muscle mass

Reduced Reduced TranslocationTranslocationEnteric BacteriaEnteric Bacteriaor Endotoxinsor Endotoxins

Reduction ofReduction ofInfectious Infectious complicationscomplications

Increased AutophagyIncreased Autophagy

Preserved CellularEnergetics- ATP content

GLNGLNPoolPool

Critical IllnessCritical Illness

Enhanced insulin sensitivity

Effect of Glutamine:A Systematic Review of the Literature

Infectious Complications

Updated Jan 2009, see www.criticalcarenutrition.com


Hospital Length of Stay




Mortality

1 10 1000.1.01

High Dose

Low Dose

Effect on Mortality

Novak CCM 2002;30:2022

Results of Phase I Dosing Study

• High dose appears safe • High dose associated with

– no worsening of SOFA Scores

– greater resolution of oxidative stress

– greater preservation of glutathione

– Improved mitochondrial function

Heyland JPEN Mar 2007

Parenterally Enterally

Glutamine/day 0.35 gms/kg 30 gms

Antioxidantsper day

500 mcg Selenium

Vit C 1500 mgVit E 500 mg

B carotene 10 mgZinc 20 mgSe 300 ug

RCT 368 heterogeneous critically ill patients

Double-blind Enteral nutrition supplemented

glutamine: 20 grams/L Control: Glycine 20g/L Well matched groups Glutamine group rec’d average

19 g/day of glutamine

Hall Intensive Care Med 2003;29:1710

Inadequate Dose and Wrong Patient Population?

0

5

10

15

20

Mortality

Glutamine

Control

No differences noted

CCM 2002;30:2032

No difference in outcome for patients who stayed <9 days

but significant survival advantage for those who

stayed >9 days

The longer you stay, the greater duration of exposure, the greater the benefit

Canadian Critical Care Nutrition Clinical Practice

Guidelines• “If using parental nutrition, we strongly

recommend supplementing with parenteral glutamine.”

• “Enteral Glutamine should be considered for Burns and Trauma Patients.”

• “There are insufficient data to support the routine use of enteral glutamine in other critically ill patients.”

• Benefit of Parenteral Glutamine in Patients on EN?

JPEN 2003;27:355 see www.criticalcarenutrition.com for current version

http://www.criticalcarenutrition.com/

Admitted to ICU

? PN

Glu Se Glu + Se None

Andrews BMJ 2011:342

• 10 centres in Scotland • 502 Patients expected to be in ICU for at least

48h and required PN meet at least half their requirements

• Randomized 2.6 days after admission to ICU• Trial PN isocaloric and isonitrogenous, given for

up to 7 days unless died or stopped PN» Glutamine 20g/d» Selenium 500μg/d» Both» Neither

• Main Outcomes:– New infections – Mortality (ICU/HDU and at 6 months)

• Prespecifed analysis of people having ≥ 5• Median duration of study PN was 4-5 days

The SIGNET Trial - DesignThe SIGNET Trial - Design

The SIGNET Trial – RESULTSThe SIGNET Trial – RESULTS

Effect of GlutamineEffect of Glutamine

No significant differences

Confirmed infections within 14 daysMortality


The SIGNET Trial – RESULTSThe SIGNET Trial – RESULTS

Effect of SeleniumEffect of Selenium


Confirmed infections within 14 days

P=0.12 P=0.02

Mortality

• Right patient population?– Only about half getting PN at time of

randomization

• Timing of intervention?– Started too late (2.6 days plus time

to get PN running)

• Inadequate exposure to intervention?– Too small of dose– Too short of duration (4-5 days)

The SIGNET Trial – The SIGNET Trial – QuestionsQuestions!!

• Multicenter trial in Spain• 127 patients with APACHE II score >12 and

requiring PN for 5–9 days• Standard PN vs. Supplemented with 0.5

g/kg/d of Ala-Gln dipeptide• Enrolled patients rec’d only 5-6 days of PN

Grau CCM 2011; 39

P=0.10 P=0.03

Grau CCM 2011; 39

Scandinavian Glutamine Trial: a Pragmatic Clinical Multi-Centre RCT of ICU patients

• 413 Patients given nutrition by EN and/or PN route • Within 72 hrs of ICU admission• supplemented as IV L-Ala-Glutamine, 0.283 g/kg/day administered

separate from PN (Placebo was saline in identical bottles.)• Primary endpoint SOFA; infections not recorded• All included patients were considered as intention-to-treat (ITT) patients.• Patients given supplementation for > 3 days (68%) were considered as

predetermined per protocol (PP) patients.

No effect on SOFA

ICU 28d 6m

0

10

20

30

40

mo

rtal

ity, %

ITT GLN (n=205)

PP GLN (n=145)

ITT CON (n=208)

PP CON (n=139)

P < 0.05

NS

NS

jw -10

Scandinavian Glutamine Trial (prel results)

Updated Meta-AnalysisEffect on Mortality

According to control group mortality highest to lowest

April 2011

Updated Meta-AnalysisEffect on Infection

April 2011

Updated Meta-AnalysisEffect on Hospital LOS

April 2011

Antioxidant supplementation?

Death

MetabolicShutdown

Survivors

•↓mt DNA•↓ ATP, ADP, NADPH•↓ Resp chain activity•Ultra structural changes

↓ mitochondrial activityProlonged

inflammationNO

Endocrineeffects

cytokine effect

Genetic down regulation

Tissue hypoxia

• preserved ATP•Recovery of mt DNA•Regeneration of mito proteins

Underlying Pathophysiology of Critical Illness (2)

mtDna/nDNA Ratio by Day 28 Survival

0 5 10 15 20 250.0

0.5

1.0

1.5

2.0

Alive IndividualsExpired IndividualsAlive Reg lineExpired Reg Line

P=0.04

Day

mtD

na

/nD

NA

Ra

tio

Heyland JPEN 2007;31:109

Effect of Antioxidants on Mitochondrial Function

Heyland JPEN 2007;31:109

mitochondria

Cell

Respiratorychain

nucleus

nDNA mtDNA

Mitochondrial Damage

ROS

RNS

LPS exposure leads to GSH depletion and oxidation of mtDNA within 6-24 hours

Levy Shock 2004;21:110 Suliman CV research 2004;279

Potentially Irreversible by 48 hours

N-Acetylcysteine Treatment to Prevent the Progression of Multisystem Organ Failure:

A prospective, randomized, placebo-controlled study

• 100 patients admitted to ICU with MODS

• Randomized to NAC (150 mg/kg bolus followed by 12 mg/hr) vs placebo

• No difference in clinical outcomes

• Median time to treatment 24 hrs

P=0.05

% mortality

What do the clinical studies show?

Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma and subarachnoid

hemorrhage patients.

0

50

100

150

200

250

0 1 2 3 4 5

CardiacTraumaSAH

CRP levels daily in the Control groups

Significant reduction with AOX in Cardiac and Trauma but not SAH

Berger Crit Care 2008

RCT 200 patients IV supplements for 5 days

after admission (Se 270 mcg, Zn 30 mg, Vit C 1.1 g, Vit B1 100 mg) with a double loading dose on days 1 and 2 (AOX group), or placebo.

No affect on clinical outcomes

Randomized, Prospective Trial of AntioxidantSupplementation in Critically Ill Surgical

Patients

Nathens Ann Surg 2002;236:814

Surgical ICU patients, mostly trauma

770 randomized; 595 analysed

alpha-tocopherol 1,000 IU (20 mL) q8h per naso- or orogastric tube and 1,000 mg ascorbic acid IV q8h or placebo

Tendency to less pulmonary morbidity and shorter duration of vent days

Treatment Stratgy For Sepsis?

Multicenter RCT in Germany double-blinded non-ITT analysis

249 patients with severe sepsis

standard nutrition plus 1000 ug bolus followed by 1000 ug/day or placebo x14 days

0102030405060708090

100

28 day Mortality

SeleniumPlacebo

Greater treatment effect observed in those

patients with: •supra normal levels vs normal levels of selenium

•Higher APACHE III

•More than 3 organ failures Crit Care Med 2007;135:1

p=0.11

• Phase II study building on previous dosing work• 35 Patients with SIRS and APACHE II >15• Randomized within 24 hrs of admission • Received either placebo or IV Se as a bolus-loading dose of

2,000 ug followed by continuous infusion of 1,600 ug/ day for 10 days.

•Confirms observation of SIGNET trial and Berger study in burns•Mechanism related to:• increase neutrophil and macrophage function?• reversible inhibition of NF-kB binding to DNA• induction of apoptosis and cytotoxicity in activated pro-inflammatory cells• a direct virucidal or bactericidal effect

No serous adverse events noted

• Randomized, open-label, single-centre clinical trial

• 150 patients with SIRS/sepsis and a SOFA score of >5.

• Patients in the Se group received 1,000 ug on day followed by 500 ug/day on days 2–14.

• Administered daily over 30 mins.

• Patients in both groups received a standard Se dose (75 ug/day).

Greater treatment effect in sicker patients!

P=0.10

o 16 RCTso Single nutrients (selenium) and combination

strategies (selenium, copper, zinc, Vit A, C, & E, and NAC)

o Administered various routes (IV/parenteral, enteral and oral)

o Patients:o Critically ill surgical, trauma, head injuredo SIRS, Pancreatitis, Pancreatic necrosiso Burnso Medical o Sepsis, Septic Shock

Supplementation with Antioxidants in the Critically Ill: A meta-analysis

Heyland Int Care Med 2005:31;327;updated 2011

Effect of Combined Antioxidant

Strategies in the Critically IllEffect on Mortality

Updated April 2011

Effect of Combined Antioxidant

Strategies in the Critically IllEffect on Infection

Updated April 2011

Biological Plausibility!

Inflammation/oxidative stress

Mitochondrial + Microvascular dysfunction

Organ dysfunction

Antioxidants

Antioxidants

Antioxidants

Supplemental Antioxidant Nutrients

• Recommendation:Based on 3 level 1 studies and 13 level 2 studies, the use of supplemental vitamins and trace elements should be considered.



Pharmaconutrients Impact Outcomes!


1 10 1000.1.01

Glutamine

Antioxidants

Fish/Borage OilsPlus AOX

Effect on Mortality

enteral / parenteralsupply

L-Arginine L-CitrullineL-Ornithine

Polyamine Synthesis • Putrescine• Spermidine• Spermine

Hormone release

• GH• IGF• Insulin• Glucagon• Prolactin• catecholamines

Urea

Nitrogenous compounds

• Nitric oxide• Nitrite• Nitrate

Figert… Ochoa Surg Forum 1998

Arginine Metabolism after Trauma in Mice

cNOS

cNOS + iNOS

Eff

ect o

f A

rgin

i ne

ind u

ced

NO

for

mat

ion

Har

mfu

lB

enef

itia

l

Arginine / NO availability

Optimal NO-Balance

- Hemodynamic instability- Immune Suppression- Cytotoxicity- Organe dysfunction

- Microcirculation - Immune augmentation

Suchner Brit J Nutrition 2001

Overall Effect on Mortality (2009)



Overall Effect on Infection (2009)



Diets Supplemented with arginine

and select other nutrients

• Recommendation:Based on 4 level 1 studies and 18 level 2 studies, we recommend that diets supplemented with arginine and other select nutrients not be

used for critically ill pts.



=

Critically Ill patient not the same as Elective Surgery

patient!

Heyland JAMA 2001;286:944

Elective Surgical Patient

• cellular immune dysfunction – T-cell

• decrease cytokine activation – IL-2, IFN

Elective Surgical Patient

arginase

arginine

expression of zeta chain

Taheri Clin Cancer Res 2001 ;7:958

Summary

• Nutrients/Nutritional strategies– Modulate underlying pathphysiological processes– Improve clinical outcomes, particularly in sickest

patients– Disease processes and treatment effects are time

dependent

ICU length of stay

Nutrition Therapy for Critically ill Patients of the Future

Pare n t e r a l Pharmaconutrition

Enteral Pharmaconutrition

Assement of nutritional risk

Measurement of biomarker to determine which pharmaconutrient

1. enteral nutrition

? parenteral nutrition

Set of tools to monitor response to nutrition/nutrient therapy

Questions?

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