Nutrition Therapy in the ICU: The Clock is Ticking!

Daren K. Heyland Professor of Medicine Queen’s University, Kingston General Hospital Kingston, 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

Adequacy of EN 1 7 14 21 Prolonged ICU stay, discharged weak and debilitated. Dies on day 43 in hospital from massive PE

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 Adjunctive Supportive Care Proactive Primary Therapy

Conclusions (3)

Timeliness of administration of nutrition therapy matters! Adjunctive Supportive Care Proactive Primary Therapy

Conclusions (4)

Quantity of nutrition therapy matters! Adjunctive Supportive Care Proactive Primary Therapy

Insult

• infection • trauma • I/R • hypoxemic/ hypotensive Role of GIT Pathophysiology of Critical Illness (1) Activation of PMN’s endothelial dysfunction activation of coagulation elaboration of cytokines, NO, and other mediators Microcirculatory Dysfunction generation of OFR (ROS + RNOS) mitochondrial

=

oxidative stress dysfunction Key nutrient deficiencies (e.g. glutamine, selenium) cellular = energetic failure organ = failure

Death

Arginine-supplemented diets?

L-Ornithine

Metabolic Effects of Arginine

Urea enteral / parenteral supply L-Arginine L-Citrulline Polyamine Synthesis

• • •

Putrescine Spermidine Spermine Hormone release

• • • • • •

GH IGF Insulin Glucagon Prolactin catecholamines Nitrogenous compounds

• • •

Nitric oxide Nitrite Nitrate

Suchner Brit J Nutrition 2001

Underlying Pathophysiology

Role of Nitric Oxide Mitaka Shock 2003;19: 305

Optimal NO-Balance cNOS

Microcirculation



- Immune augmentation

 Arginine / NO availability cNOS + iNOS

- Hemodynamic instability - Immune Suppression - Cytotoxicity - Organe dysfunction

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

Is it plausible that Arginine supplemented diets may do harm?

Arginine administration associated with: Plasma arginine NO products And worse shock, worse organ injury Increased mortality!

No effect of NAC Kalil Crit Care Med 2006;34:2719

Is it plausible that Arginine supplemented diets may do harm?

  3 RCTs 3 different products  All describing excess mortality in patients with infection 1) Bower Crit Care Med 1995;23:436 2) Dent, Crit Care Med 2003;30:A17 3) Bertolini Intesive Care Med 2003;29:834

16 14 12 10 8 6 4 2 0 mortality Arginine Control

Fish Oil supplemented diets?

Mechanisms by which fatty acids can affect immune cell function

Cytokines IL-8 TNF α PGE 1 mRNA NFκB Binding

Cytokines IL-8 TNF α PGE 1 mRNA NFκB Binding

T.T. Pluess 1 , D. Hayoz 2 , M.M. Berger 1 , L. Tappy 3 , J.P. Revelly 1 , B. Michaeli 1 , Y.A. Carpentier 4 and R.L.

Chioléro 1

• 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 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 Gadek Crit Care Med 1999;27:1409

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

25

• 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

20 15 10 5 0 Vent Days ICU Days ICU Deaths Oxepa control

P=0.03

P=0.02

P=0.17

Gadek Crit Care Med 1999;27:1409

Overall Effect on Mortality

www.criticalcarenutrition.com

Glutamine supplementation?

Potential Beneficial Effects of Glutamine Enhanced insulin sensitivity Decreased Free Radical availability (Anti-inflammatory action) Enhanced Heat Shock Protein Inflammatory Cytokine Attenuation NF- B ?

Glutamine Therapy Glutathione Synthesis Fuel for Enterocytes Maintenance of Intestinal Mucosal Barrier Reduced Translocation Enteric Bacteria or Endotoxins Critical Illness Nuclotide Synthesis Preservation of TCA Function Anti-catabolic effect Fuel for Lymphocytes Maintenance of Lymphocyte Function Reduction of Infectious complications Preserved Cellular Energetics ATP content Preservation of Muscle mass

Effect of Glutamine: A Systematic Review of the Literature

Infectious Complications

www.criticalcarenutrition.com

Effect of Glutamine: A Systematic Review of the Literature

Mortality

www.criticalcarenutrition.com

Pharmaconutrients Impact Outcomes!

Effect on Mortality Glutamine Antioxidants Fish/Borage Oils Plus AOX Arginine .01

0.1

1 10 100 www.criticalcarenutrition.com

Prolonged inflammation Underlying Pathophysiology of Critical Illness (2) Genetic down • preserved ATP •Recovery of mt DNA •Regeneration of mito regulation proteins Tissue hypoxia Survivors cytokine effect

NO

↓ mitochondrial activity •↓mt DNA •↓ ATP, ADP, NADPH •↓ Resp chain activity •Ultra structural changes Metabolic Shutdown Endocrine effects Death

Mitochondrial Dysfunction is a Time Dependent Phenonmenon Hypoxia Accelerates Nitric Oxide Inhibition of Complex 1 Activity 21% O2 1% O2 Nitration of Complex 1 in Macrophages activated with LPS and IFN Frost Am J Physio Regul Interg Comp Physio 2005;288:394

Mitochondrial Damage Cell mitochondria

Respiratory chain nDNA mtDNA

ROS RNS nucleus LPS exposure leads to GSH depletion and oxidation of mtDNA within 6-24 hours Potentially Irreversible by 48 hours Levy Shock 2004;21:110 Suliman CV research 2004;279

mtDna/nDNA Ratio by Day 28 Survival 2.0

P=0.04

1.5

1.0

0.5

0.0

0 5 10 Day 15 20 25

Alive Individuals Expired Individuals Alive Reg line Expired Reg Line 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 Effect on SOFA scores • Increased selenium levels • Increased GSH-Px activity • No difference in • RRT (5 vs 7 patients) • • mortality (44% vs 50%) Other clinical outcomes * *p=<0.006

* • Mishra Clinical Nutrition 2007;26:41-50

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

major trauma and subarachnoid hemorrhage patients.

250

    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

200 150 100 50 Cardiac Trauma SAH 0 0 1 2 3 4 5

CRP levels daily in the Control groups Significant reduction with AOX in Cardiac and Trauma but not SAH Berger Crit Care 2008

Randomized, Prospective Trial of Antioxidant Supplementation in Critically Ill Surgical Patients    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 Nathens Ann Surg 2002;236:814

  

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

100 90 80 70 60 50 40 30 20 10 0 Selenium Placebo 28 day Mortality

Greater treatment effect observed in those patients with: p=0.11

•supra normal levels vs normal levels of selenium •Higher APACHE III •More than 3 organ failures Crit Care Med 2007;135:1

Effect of Combined Antioxidant Strategies in the Critically Ill Effect on Mortality www.criticalcarenutrition.com

Biological Plausibility!

Mitochondrial dysfunction Inflammation/oxidative stress Organ dysfunction Antioxidants Antioxidants Antioxidants

Underlying Pathophysiology of Critical Illness (3) Loss of Gut Epithelial Integrity

Bacteria INTESTINAL EPITHELIUM DISTAL ORGAN INJURY (Lung, Kidneys) SIRS via thoracic duct

Disuse Causes Loss of Functional and Structural Integrity Increased 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%)

15 10 5 0 35 30 25 20 VAP

P=0.007

ICU Mort

P=0.02

Hosp Mort

P=0.0005

Early Late

Artinian Chest 2006:129;960

Early vs. Delayed EN: Effect on Infectious Complications www.criticalcarenutrition.com

Early vs. Delayed EN: Effect on Mortality www.criticalcarenutrition.com

Underlying Pathophysiology (4) Adequacy of EN Energy Received From Enteral Feed Prescribed Energy 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 Caloric Debt 7

Day

11 (18) 14 13 (15) 15 (15) 21 (12) 19 (6)     Caloric debt associated with:   Longer ICU stay (p=0001) Days on mechanical ventilation (p=0.0002)   Complications (p=0.0003) 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 Overall <20 20-<25 25-<30 30-<35 35-<40 >=40 Odds Ratio 0.76

95% Confidence Limits 0.61

0.95

P-value 0.014

0.52

0.62

1.05

1.04

0.29

0.44

0.75

0.64

0.95

0.88

1.49

1.68

0.033

0.007

0.768

0.889

0.36

0.63

0.16

0.32

0.80

1.24

0.012

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

BMI <20 20-<25 25-<30 30-<35 35-<40 >=40 0 500 1000 Total Calories Received 1500 2000

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

Mo r t a l i t y 0 . 6 7 7 0 . 4 8 6 0 . 2 9 4 0 . 1 0 3 2 0 0 0 1 3 3 3 A v e r a g e Da i l y Ca l o r i e s 6 6 7 0 1 5 6 0 3 0 4 5 B MI ( k g | m2 )

ICU patients are not all created equal…should we expect the impact of nutrition therapy to be the same across all patients?

Aggressive Gastric Feeding may be a BAD THING!

 Incidence of Intolerance= 46%  Statistically associated with worse clinical outcomes!

  Risk factors for Intolerance   Sedation Catecholamines High residuals before and during EN

43 24 Pneumonia 23 15 ICU LOS (days) Intolerance none 41 25 %Mortality

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 www.criticalcarenutrition.com

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

Nutrition Therapy for Critically ill Patients of the Future Pare n t e r a l Pharmaconutrition

? parenteral nutrition 1. enteral nutrition

Enteral Pharmaconutrition

ICU length of stay

Assement of nutritional risk Measurement of biomarker to determine which pharmaconutrient 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 Pharmaconutrients Early 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…

www.criticalcarenutrition.com

Questions?