Early Enteral Nutrition 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 Adequacy of EN 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?

Medical Error 44,000 to 98,000 deaths per year in the US October 9th, 2002 Medical Error 44,000 to 98,000 deaths per year in the US total heath care costs of errors resulting in injury between $17 to $29 billion On an annual basis More people die from medical error than traffic accidents, breast cancer, or AlDs. Contribution related to misapplication or non application of artificial nutrition? Institute of Medicine 1999 Rupinder Dhaliwal, RD

In patients with high gastric residual volumes: use of motility agents 58.7% (site average range: 0-100%) use of small bowel feeding 14.7% (range: 0-100%) Cahill N Crit Care Med 2010 (in press)

Average time to start of EN was 46. 5 hours (site average range: 8 Average time to start of EN was 46.5 hours (site average range: 8.2-149.1 hours) Cahill NE CCM 2010 (in press)

Loss of Gut Epithelial Integrity Underlying Pathophysiology of Critical Illness (1) Loss of Gut Epithelial Integrity INTESTINAL EPITHELIUM SIRS Bacteria DISTAL ORGAN INJURY (Lung, Kidneys) via thoracic duct

Disuse Causes Loss of Functional and Stuctural Integrity Increased Gut Permeability Characteristics : Time dependent Correlation to disease severity Consequences: Risk of infection Risk of MOFS

Feeding Supports Gastrointestinal Structure and Function Maintenance of gut barrier function Increased secretion of mucus, bile, IgA Maintenance of peristalsis and blood flow Favorable effects on GALT/MALT 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%) P=0.007 P=0.02 P=0.0005 Artinian Chest 2006:129;960

Effect of Early Enteral Feeding on the Outcome of Critically ill Mechanically Ventilated Medical Patients Data evaluating the effect of n-3 FFAs on clinical outcomes is relatively sparse, and in this study, is confounded by the fact that they combined fish oils with antioxidants. Artinian Chest 2006:129;960 12

Early vs. Delayed EN: Effect on Infectious Complications R-make sure up to date. DONE Updated 2009 www.criticalcarenutrition.com

Early vs. Delayed EN: Effect on Mortality R- make sure up to date. DONE Updated 2009 www.criticalcarenutrition.com

What About Feeding the Hypotensive Patient? Resuscitation is the priority No sense in feeding someone dying of progressive circulatory failure However, if on stable or declining doses of vasopressors: Safety and Efficacy of Enteral Feeding??

Dog Model with IV oleic acid lung injury Purcell Am J Surg 1993;165:188

9 patients day 1 Post-op following CPB requiring inotropes and vasopressors Feed enterally; metabolic response consistent with substrates being utilized ICG clearance suggestive of increase mesenteric blood flow

Feeding the Hypotensive Patient? Retrospective analysis of a prospectively collected multi-institutional medical intensive care unit (ICU) database. A total of 1,174 patients were identified who required mechanical ventilation for more than two days and were placed on vasopressor agents to support their blood pressure. Patients divided according to whether or not they received enteral nutrition within 48 hours of mechanical ventilation onset. 707 patients (60%) who did were labeled as the “early enteral nutrition group” and the remaining 467 patients (40%) were labeled as “late enteral nutrition group”. The primary endpoints were overall ICU and hospital mortality. Data also analyzed after controlling for confounding by matching for propensity score DiGiovine et al. AJCC 2009 (in press)

Feeding the Hypotensive Patient? The beneficial effect of early feeding is more evident in the sickest patients, i.e, those on multiple vasopressor agents. DiGiovine et al. AJCC 2009 (in press)

Feeding enterally the hemodynamically unstable critically ill patient: Experience with a multicenter trial (The REDOXS study) 20 ICUs enrolling patients on vasopressors into REDOXS study 159 patients [28 day mortality- 31%] 85% started on EN (2% PN, 13% none) Time from ICU admission to start of EN: 20.2 hrs (0-204 hrs) Duration of EN 9.2 days (0.1-30 days) Overall, rec’d 68% of goal calories and protein 55% had high gastric residual volumes Of those, 78% got motility agents Daily adequacy pre and post motility agents improved (35% vs. 56%, p=0.009) Heyland ESICM Brussels 2009

Underlying Pathophysiology (2) Caloric Debt Adequacy of EN  Caloric debt associated with:  Longer ICU stay  Days on mechanical ventilation  Complications  Mortality Rubinson CCM 2004; Villet Clin Nutr 2005; Dvir Clin Nutr 2006; Petros Clin Nutr 2006

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 60% medical; 40% surgical Average APACHE II 22; BMI 27

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

What Study Patients Actually Rec’d Average Calories in all groups: 1034 kcals and 47 gm of protein Result: Average caloric deficit in Lean Pts: 7500kcal/10days Average caloric deficit in Severely Obese: 12000kcal/10days

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 0.033 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.

Relationship Between Increased Energy and Ventilator-Free days BMI Group Adjusted Estimate 95% CI P-value LCL UCL Overall 3.5 1.2 5.9 0.003 <20 2.8 -2.9 8.5 0.337 20-<25 4.7 1.5 7.8 0.004 25-<30 0.1 -3.0 3.2 0.958 30-<35 -1.5 -5.8 2.9 0.508 35-<40 8.7 2.0 15.3 0.011 >=40 6.4 -0.1 12.8 0.053 Legend: # of VFD per 1000 kcals received per day adjusting for nutrition days, BMI, age, admission category, admission diagnosis and APACHE II score.

Effect of increasing amounts of EN on infectious complications Multicenter observational database 597 patients prospectively followed for development of ICU-acquired infection 2 independent adjudicators Examined the relationship between nutritional adequacy and infection Heyland (in submission)

for increase of 1000 cal/day, OR of ICU-acquired infection Effect of Increasing Amounts of Calories from EN on Infectious Complications Multicenter observational study of 207 patients >72 hrs in ICU followed prospectively for development of infection for increase of 1000 cal/day, OR of ICU-acquired infection Heyland (in submission)

for increase of 30 gram/day, OR of ICU-acquired infection Effect of Increasing Amounts of Protein from EN on Infectious Complications Multicenter observational study of 207 patients >72 hrs in ICU followed prospectively for development of infection for increase of 30 gram/day, OR of ICU-acquired infection Heyland (in submission)

RCT Level of Evidence that More EN= Improved Outcomes RCTs of aggressive feeding protocols Results in better protein-energy intake Associated with reduced complications and improved survival Taylor et al Crit Care Med 1999; Martin CMAJ 2004 Meta-analysis of Early vs Delayed EN Reduced infections: RR 0.76 (.59,0.98),p=0.04 Reduced Mortality: RR 0.68 (0.46, 1.01) p=0.06 www.criticalcarenutrition.com

More is Better! Our Field of Dream If you feed them (better!) They will leave (sooner!)

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! Observational study of 153 medical/surgical ICU patients receiving EN in stomach Intolerance= residual volume>500ml, vomiting, or residual volume 150-500x2. Patients followed for development of VAP (diagnosed invasively) Mentec CCM 2001;29:1955

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

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

Updated 2009, see www.criticalcarenutrition.com Rupinder to update “Use of a feeding protocol that incorporates motility agents and small bowel feeding tubes should be considered” Updated 2009, see www.criticalcarenutrition.com

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Sites recorded the presence or absence of a feeding protocol The Impact of Enteral Feeding Protocols on Enteral Nutrition Delivery: Results of a multicenter observational study International, prospective, observational, cohort studies conducted in 2007 and 2008 from 269 Intensive Care Units (ICUs) in 28 countries Included 5497 mechanically ventilated adult patients > 3 days in ICU Sites recorded the presence or absence of a feeding protocol Sites provided nutritional data on enrolled patients from ICU admission to ICU discharge for a max of 12 days. Heyland JPEN 2010 ( in press)

15.2% using the recommended threshold volume of 250 ml The Impact of Enteral Feeding Protocols on Enteral Nutrition Delivery: Results of a multicenter observational study Characteristics Total n=269 Feeding Protocol Yes 208 (78%) Gastric Residual Volume Tolerated in Protocol Mean (range) 217 ml (50, 500) Elements included in Protocol Motility agents 68.5% Small bowel feeding 55.2% HOB Elevation 71.2 % 15.2% using the recommended threshold volume of 250 ml Heyland JPEN 2010 ( in press)

The Impact of Enteral Feeding Protocols on Enteral Nutrition Delivery: Results of a multicenter observational study P<0.05 Time to start EN from ICU admission 41.2 in protocolized sites vs 57.1 hours in those without a protocol Patients rec’ing motility agents 61.3% in protocolized sites vs 49.0% in those without P<0.05 Heyland JPEN 2010 ( in press)

Initial Efficacy and Tolerability of Early Enteral Nutrition with Immediate or Gradual Introduction in Intubated Patients This study randomized 100 mechanically ventilated patients (not in shock) to Immediate goal rate vs gradual ramp up (our usual standard). The immediate goal group rec’d more calories with no increase in complications Desachy ICM 2008;34:1054

A Major Paradigm Shift in How we Feed Enterally The Efficacy of Enhanced Protein-Energy Provision via the Enteral Route in Critically Ill Patients: The PEP uP Protocol! Not all critically ill patients are the same; we have different feeding options based on hemodynamic stability and suitability for high volume intragastric feeds. In select patients, we start the EN immediately at goal rate, not at 25 ml/hr. We target a 24 hour volume of EN rather than an hourly rate and provide the nurse with the latitude to increase the hourly rate to make up the 24 hour volume. Tolerate higher GRV threshold (250 ml or more) Motility agents and protein supplements are started immediately, rather than started when there is a problem. A Major Paradigm Shift in How we Feed Enterally

The Efficacy of Enhanced Protein-Energy Provision via the Enteral Route in Critically Ill Patients: The PEP uP Protocol! Heyland (in submission)

The Efficacy of Enhanced Protein-Energy Provision via the Enteral Route in Critically Ill Patients: The PEP uP Protocol! Heyland (in submission)

Conclusions Early EN associated with improvement in clinically important outcomes Audits suggest lots of opportunities for improvement Second generation feeding protocols may address unmet need to help with nutritional adequacy

Questions?