Nutrition Therapy in the ICU: The Clock is Ticking! Daren K. Heyland Professor of Medicine Queen’s University, Kingston General Hospital Kingston, ON Canada

Nutrition Therapy in the ICU:The Clock is Ticking!

Daren K. HeylandProfessor of Medicine

Queen’s University, Kingston General HospitalKingston, ON Canada

Case Scenario

• Mr KT• 76 per’d diverticulum• Septic shock, ARDS, MODS• Day 1- high NG drainage, distended abdomen• Day 3- trickle feeds• Feeds on and off again for whole first week• No PN, no small bowel feeds, no specialized

nutrients

Case Scenario

Prolonged ICU stay, discharged weak and debilitated. Dies on day 43 in hospital from

massive PE

1 147 21

Adequacy of EN

To what extent did nutrition therapy (or lack thereof) play a role in this

patient’s demise?

Conclusions (1)Nutrition is therapy that modulates the

underlying disease process

Adjunctive Supportive Care

Proactive Primary Therapy

Conclusions (2)Nutrition therapy impacts clinical outcomes



Conclusions (3)Timeliness of administration of nutrition

therapy matters!



Conclusions (4)Quantity of nutrition therapy matters!



Insult

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

Activation ofPMN’s

= oxidative stress

Death

organ = failure

Pathophysiology of Critical Illness (1)

mitochondrial dysfunction

Role ofGIT

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

Arginine-supplemented diets?

Metabolic Effects of Arginine

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

Suchner Brit J Nutrition 2001

Mitaka Shock 2003;19: 305

Underlying PathophysiologyRole of Nitric Oxide

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

Is it plausible that Arginine-supplemented diets may do

harm?

Randomized, double blind, placebo-controlled

Beagles Parenteral L-arginine (+

NAC) vs placebo Canine model of E. coli

peritonitis

Kalil Crit Care Med 2006;34:2719


harm?Arginine administration

associated with:Plasma arginine

NO products

And worse shock,

worse organ injury

Increased mortality!

Kalil Crit Care Med 2006;34:2719

No effect of NAC


harm?

3 RCTs 3 different products All describing excess

mortality in patients with infection

0

2

4

6

8

10

12

14

16

mortality

Arginine Control

1) Bower Crit Care Med 1995;23:436

2) Dent, Crit Care Med 2003;30:A17

3) Bertolini Intesive Care Med 2003;29:834

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

NFκB Binding

CytokinesCytokinesIL-8IL-8

TNF-αTNF-αPGEPGE11

mRNA

CytokinesCytokinesIL-8IL-8

TNF-αTNF-αPGEPGE11

mRNA

NFκB Binding

T.T. Pluess1, D. Hayoz2, M.M. Berger1, L. Tappy3, J.P. Revelly1, B. Michaeli1, Y.A. Carpentier4 and R.L. Chioléro1

• 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

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

• 47 Patients with severe acute pancreatitis

• Randomized, double blind study of PN

• N-3 lipid emulsion (omegaven 10%) vs. Soybean emulsion with TPNx 5days

• Dose of fish oils: 0.15-0.20 g/kg/d

• Patients comparable at baseline

• Control group mortality 10%; no deaths in FO group

Wang JPEN 2008;32:236

Effect of Fish Oils on Inflammatory Cytokines in Pancreatitis

• Put figure 2 and 3

Wang JPEN 2008;32:236

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

Oxepacontrol

Gadek Crit Care Med 1999;27:1409

P=0.03 P=0.17P=0.02

Overall Effect on Mortality

www.criticalcarenutrition.com

Glutamine supplementation?

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

Inflammatory Cytokine Inflammatory Cytokine AttenuationAttenuation

NF-BNF-B??

Preserved CellularEnergetics- ATP content

GLNGLNPoolPool

Critical IllnessCritical Illness

Enhanced insulin sensitivity

Effect of Glutamine:A Systematic Review of the Literature


Infectious Complications

Effect of Glutamine:A Systematic Review of the Literature


Mortality

Pharmaconutrients Impact Outcomes!


1 10 1000.1.01

Glutamine

Antioxidants

Fish/Borage OilsPlus AOX

Effect on Mortality

Arginine

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)

Mitochondrial Dysfunction is a Time-Dependent Phenonmenon

Hypoxia Accelerates Nitric Oxide Inhibition of Complex 1 Activity

Nitration of Complex 1 in Macrophages activated with LPS and IFN

21% O2 1% O2

Frost Am J Physio Regul Interg Comp Physio 2005;288:394

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

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

Smallest Randomized Trial of Selenium in Sepsis

Single center RCT double-blinded ITT analysis

40 patients with severe sepsis Mean APACHE II 18

Primary endpoint: need for RRT standard nutrition plus 474 ug x 3 days,

316 ug x 3 days; 31.6 ug thereafter vs 31.6 ug/day in control

Mishra Clinical Nutrition 2007;26:41-50

Smallest Randomized Trial of Selenium in Sepsis

• Increased selenium levels

• Increased GSH-Px activity

• No difference in

• RRT (5 vs 7 patients)

• mortality (44% vs 50%)

• Other clinical outcomes

Mishra Clinical Nutrition 2007;26:41-50

*p=<0.006

* *

Effect on SOFA scores

•

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

Largest Randomized Trial of Antioxidants

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

Effect of Combined Antioxidant

Strategies in the Critically IllEffect on Mortality


Biological Plausibility!

Inflammation/oxidative stress

Mitochondrial dysfunction

Organ dysfunction

Antioxidants

Antioxidants

Antioxidants

Loss of Gut Epithelial Integrity

INTESTINAL EPITHELIUM

SIRS

Bacteria

DISTAL ORGAN DISTAL ORGAN INJURY INJURY (Lung, Kidneys)(Lung, Kidneys)

via thoracic duct

Underlying Pathophysiology of Critical Illness (3)

Disuse Causes Loss of Functional and Structural IntegrityIncreased Gut Permeability

Characteristics : Time dependent Correlation to disease severity

Consequences: Risk of infection Risk of MOFS

Enteral Feeding Supports Gastrointestinal Structure and Function

• Maintenance of gut barrier function• Increased secretion of mucus, bile, IgA

• Maintenance of peristalsis and blood flow•Attenuates the stress response

Alverdy (CCM 2003;31:598)

Effect of Early Enteral Feeding on the Outcome of Critically ill

Mechanically Ventilated Medical Patients

• Retrospective analysis of multiinstitutional database

• 4049 patients requiring mech vent > 2 days

• Categorized as “Early EN” if rec’d feeds within 48 hours of admission (n=2537, 63%)

0

5

10

15

20

25

30

35

VAP ICUMort

HospMort

EarlyLate

Artinian Chest 2006:129;960

P=0.007 P=0.0005P=0.02

Early vs. Delayed EN: Effect on Infectious

Complications


Early vs. Delayed EN: Effect on Mortality


0100020003000400050006000700080009000

10000

1 (28) 3 (27) 5 (25) 7 (23) 9 (22) 11 (18)

13 (15)

15 (15)

17 (12)

19 (6)

En

erg

y (k

J)

Day

Energy Received From Enteral Feed

Prescribed Energy

Underlying Pathophysiology (4)

Caloric debt associated with: Longer ICU stay (p=0001)

Days on mechanical ventilation (p=0.0002) Complications (p=0.0003)

1 147 21

Adequacy of EN

Caloric Debt

Villet et al Clin Nutr 2005

2007 International Nutrition Practice Survey

• Point prevalence survey of nutrition practices in ICU’s around the world conducted Jan. 27, 2007

• Enrolled 2772 patients from 158 ICU’s over 5 continents

• Included ventilated adult patients who remained in ICU >72 hours

Hypothesis

• There is a relationship between amount of energy and protein received and clinical outcomes (mortality and # of days on ventilator)

• The relationship is influenced by nutritional risk

• BMI is used to define chronic nutritional risk

Relationship Between Increased Calories and 60 day Mortality

BMI Group Odds Ratio

95% Confidence

Limits

P-value

Overall 0.76 0.61 0.95 0.014

<20 0.52 0.29 0.95 0.033

20-<25 0.62 0.44 0.88 0.007

25-<30 1.05 0.75 1.49 0.768

30-<35 1.04 0.64 1.68 0.889

35-<40 0.36 0.16 0.80 0.012

>=40 0.63 0.32 1.24 0.180

Legend: Odds of 60-day Mortality per 1000 kcals received per day adjusting for nutrition days, BMI, age, admission category, admission diagnosis and APACHE II score.

The Relationship between 60-Day Mortality, Average Daily Total Calories Received and BMI

0 500 1000 1500 2000

02

04

06

08

01

00

Total Calories Received

Mo

rta

lity

(%

)

BMI

<2020-<2525-<3030-<3535-<40>=40

15

30

45

60

BMI ( kg| m2)

0

667

1333

2000

Aver age Dai l y Cal or i es

Mor t al i t y

0. 103

0. 294

0. 486

0. 677

The Relationship between 60-Day Mortality, Average Daily Total Calories Received and BMI

ICU patients are not all created equal…should we expect the impact of nutrition

therapy to be the same across all patients?

Incidence of Intolerance= 46%

Statistically associated with worse clinical

outcomes! Risk factors for

Intolerance Sedation

Catecholamines High residuals before and

during EN

43

23

41

24

15

25

Pneumonia ICU LOS(days)

%Mortality

Intolerance none

Aggressive Gastric Feeding may be a BAD

THING!

Strategies to Maximize the Benefits and Minimize the Risks

of EN

• concentrated feeding formulas

• feeding protocols

• motility agents

• elevation of HOB

• small bowel feeds

weak evidence

stronger evidence

Canadian CPGs www.criticalcarenutrition.com

What if you can’t provide adequate nutrition enterally?

… to TPN or not to TPN,

that is the question!

Prospective Studies of Supplemental PN

Effect on Mortality


What if you can’t provide adequate nutrition enterally?

… to TPN or not to TPN,

that is the question!

Maximize EN delivery prior to initiating PN

Summary

• Nutrients/Nutritional strategies– Modulate underlying pathphysiological processes– Improve clinical outcomes– Disease processes and treatment effects are time

dependent– Quantity of nutrition therapy associated with

outcomes, particularly in low and high BMI patients

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

Case Scenario

• Mr KT• 76 per’d diverticulum• Septic shock, ARDS, MODS• Day 1- high NG drainage, distended abdomen• Day 3- trickle feeds• Feeds on and off again for whole first week• No PN, no small bowel feeds, no specialized

nutrients

Case Scenario

• Treatment effect function of timeliness– Early goal resuscitation– Appropriate antibiotics– Use of Activated Protein C– Hydrocortisone

Early PharmaconutrientsEarly EN

How long do we allow the status quo remain?

How many more Mr. KTs have to die before we do something to

improve practice?

Remember, the clock is ticking…


Questions?

Documents

Nutrition Therapy in the ICU: The Clock is Ticking! Daren K. Heyland Professor of Medicine Queen’s University, Kingston General Hospital Kingston, ON Canada