Iatrogenic Malnutrition in the ICU: Time for a Change! Daren K. Heyland Professor of Medicine Queen’s University, Kingston General Hospital Kingston, ON Canada Add data from iatrogenic malnutrition slides

Learning Objectives Define iatrogenic malnutrition Describe the nature of the evidence related to optimal amount of calories/protein List key variables to consider in assessing nutritional risk in ICU patients List strategies to improve nutritional adequacy in the critical care setting.

A different form of malnutrition? Need picture of malnourshed child

Health Care Associated Malnutrition Nutrition deficiencies associated with physiological derangement and organ dysfunction that occurs in a health care facility Patients who will benefit the most from nutrition therapy and who will be harmed the most from by iatrogenic malnutrition (underfeeding)

Early and Adequate Nutrition is therapy that modulates the underlying disease process and impacts patient outcomes Adjunctive Supportive Care Proactive Primary Therapy

Early Feeding Supports Gastrointestinal Structure and Function Maintenance of gut barrier function Increased secretion of mucus, bile, IgA Maintenance of peristalsis and blood flow Attenuates oxidative stress and inflammation Supports GALT Improves glucose absorption Alverdy (CCM 2003;31:598) Kotzampassi Mol Nutr Food Research 2009 Nguyen CCM 2011

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

Feeding the Hypotensive Patient? Prospectively collected multi-institutional ICU database of 1,174 patients who required mechanical ventilation for more than two days and were on vasopressor agents to support blood pressure. The beneficial effect of early feeding is more evident in the sickest patients, i.e, those on multiple vasopressor agents. DiGiovine et al. AJCC 2010

Optimal Amount of Protein and Calories for Critically Ill Patients? Early EN (within 24-48 hrs of admission) is recommended! Optimal Amount of Protein and Calories for Critically Ill Patients?

 Caloric debt associated with: Increasing Calorie Debt Associated with worse Outcomes 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

for increase of 1000 cal/day, OR of infection at 28 days 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 infection at 28 days Heyland Clinical Nutrition 2010

Relationship between increased nutrition intake and physical function (as defined by SF-36 scores) following critical illness Multicenter RCT of glutamine and antioxidants (REDOXS Study) First 364 patients with SF 36 at 3 months and/or 6 months Model * Estimate (CI) P values (A) Increased energy intake PHYSICAL FUNCTIONING (PF) at 3 months 3.2 (-1.0, 7.3)   P=0.14 ROLE PHYSICAL (RP) at 3 months 4.2 (-0.0, 8.5) P=0.05 STANDARDIZED PHYSICAL COMPONENT SCALE (PCS) at 3 months 1.8 (0.3, 3.4) P=0.02 PHYSICAL FUNCTIONING (PF) at 6 months 0.8 (-3.6, 5.1) P=0.73 ROLE PHYSICAL (RP) at 6 months 2.0 (-2.5, 6.5) P=0.38 STANDARDIZED PHYSICAL COMPONENT SCALE (PCS) at 6 months 0.70 (-1.0, 2.4) P=0.41 for increase of 30 gram/day, OR of infection at 28 days Heyland Unpublished Data

Mechancially Vent’d patients >7days (average ICU LOS 28 days) Faisy BJN 2009;101:1079

More (and Earlier) is Better! If you feed them (better!) They will leave (sooner!)

Permissive Underfeeding (Starvation)? 187 critically ill patients Tertiles according to ACCP recommended levels of caloric intake Highest tertile (>66% recommended calories) vs. Lowest tertile (<33% recommended calories)  in hospital mortality  Discharge from ICU breathing spontaneously Middle tertile (33-65% recommended calories) vs. lowest tertile Discharge from ICU breathing spontaneously Krishnan et al Chest 2003

Optimal Amount of Calories for Critically Ill Patients: Depends on how you slice the cake! Objective: To examine the relationship between the amount of calories recieved and mortality using various sample restriction and statistical adjustment techniques and demonstrate the influence of the analytic approach on the results. Design: Prospective, multi-institutional audit Setting: 352 Intensive Care Units (ICUs) from 33 countries. Patients: 7,872 mechanically ventilated, critically ill patients who remained in ICU for at least 96 hours. Heyland Crit Care Med 2011

Association between 12 day average caloric adequacy and 60 day hospital mortality (Comparing patients rec’d >2/3 to those who rec’d <1/3) A. In ICU for at least 96 hours. Days after permanent progression to exclusive oral feeding are included as zero calories* B. In ICU for at least 96 hours. Days after permanent progression to exclusive oral feeding are excluded from average adequacy calculation.* C. In ICU for at least 4 days before permanent progression to exclusive oral feeding. Days after permanent progression to exclusive oral feeding are excluded from average adequacy calculation.* D. In ICU at least 12 days prior to permanent progression to exclusive oral feeding* Remove the 1/3-2/3 data *Adjusted for evaluable days and covariates,covariates include region (Canada, Australia and New Zealand, USA, Europe and South Africa, Latin America, Asia), admission category (medical, surgical), APACHE II score, age, gender and BMI.

Association Between 12-day Caloric Adequacy and 60-Day Hospital Mortality Optimal amount= 80-85% Heyland CCM 2011

More (and Earlier) is Better! If you feed them (better!) They will leave (sooner!)

JAMA 1994;271:56

Trophic vs. Full enteral feeding in critically ill patients with acute respiratory failure Single center study of 200 mechanically ventilated patients Trophic feeds: 10 ml/hr x 5 days Rice CCM 2011;39:967

What other outcomes might be important? Trophic vs. Full enteral feeding in critically ill patients with acute respiratory failure What other outcomes might be important? Rice CCM 2011;39:967

Trophic vs. Full enteral feeding in critically ill patients with acute respiratory failure “survivors who received initial full-energy enteral nutrition were more likely to be discharged home with or without help as compared to a rehabilitation facility (68.3% for the full-energy group vs. 51.3% for the trophic group; p = .04).” Rice CCM 2011;39:967

Rice et al. JAMA 2012;307

Still no measure of physical function! Rice et al. JAMA 2012;307

Enrolled 12% of patients screened Rice et al. JAMA 2012;307

No effect in young, healthy, overweight patients who have short stays! Trophic vs. Full enteral feeding in critically ill patients with acute respiratory failure Average age 52 Few comorbidities Average BMI 29-30 All fed within 24 hrs (benefits of early EN) Average duration of study intervention 5 days No effect in young, healthy, overweight patients who have short stays!

What about the physically recovery of underfed patients? Trophic vs. Full enteral feeding in critically ill patients with acute respiratory failure Randomized Good follow up ITT No blinding Internally valid How representative are these patients to ALL the patients in your ICU? May miss an important negative effect in ‘high risk’ patients What about the physically recovery of underfed patients? No benefit, potential harm, minimal cost advantage= Do not use routinely!

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

How do we figure out who will benefit the most from Nutrition Therapy? Need picture of malnourshed child

Health Care Associated Malnutrition Do Nutrition Screening tools help us discriminate those ICU patients that will benefit the most from artificial nutrition? Patients who will benefit the most from nutrition therapy and who will be harmed the most from by iatrogenic malnutrition (underfeeding)

All ICU patients treated the same

Albumin: a marker of malnutrition? Low levels very prevalent in critically ill patients Negative acute-phase reactant such that synthesis, breakdown, and leakage out of the vascular compartment with edema are influenced by cytokine-mediated inflammatory responses Proxy for severity of underlying disease (inflammation) not malnutrition Pre-albumin shorter half life but same limitation

Subjective Global Assessment?

When training provided in advance, can produce reliable estimates of malnutrition Note rates of missing data

mostly medical patients; not all ICU rate of missing data? no difference between well-nourished and malnourished patients with regard to the serum protein values on admission, LOS, and mortality rate.

“We must develop and validate diagnostic criteria for appropriate assignment of the described malnutrition syndromes to individual patients.”

A Conceptual Model for Nutrition Risk Assessment in the Critically Ill Chronic Recent weight loss BMI? Acute Reduced po intake pre ICU hospital stay Starvation Nutrition Status micronutrient levels - immune markers - muscle mass Inflammation Acute IL-6 CRP PCT Chronic Comorbid illness

Multi institutional data base of 598 patients The Development of the NUTrition Risk in the Critically ill Score (NUTRIC Score). When adjusting for age, APACHE II, and SOFA, what effect of nutritional risk factors on clinical outcomes? Multi institutional data base of 598 patients Historical po intake and weight loss only available in 171 patients Outcome: 28 day vent-free days and mortality Heyland Critical Care 2011, 15:R28

What are the nutritional risk factors associated with clinical outcomes? (validation of our candidate variables) Non-survivors by day 28 (n=138) Survivors by day 28 (n=460) p values Age 71.7 [60.8 to 77.2] 61.7 [49.7 to 71.5] <.001 Baseline APACHE II score 26.0 [21.0 to 31.0] 20.0 [15.0 to 25.0] Baseline SOFA 9.0 [6.0 to 11.0] 6.0 [4.0 to 8.5] # of days in hospital prior to ICU admission 0.9 [0.1 to 4.5] 0.3 [0.0 to 2.2] Baseline Body Mass Index 26.0 [22.6 to 29.9] 26.8 [23.4 to 31.5] 0.13 Body Mass Index 0.66 <20 6 ( 4.3%) 25 ( 5.4%) ≥20 122 ( 88.4%) 414 ( 90.0%) # of co-morbidities at baseline 3.0 [2.0 to 4.0] 3.0 [1.0 to 4.0] <0.001 Co-morbidity Patients with 0-1 co-morbidity 20 (14.5%) 140 (30.5%) Patients with 2 or more co-morbidities 118 (85.5%) 319 (69.5%) C-reactive protein¶ 135.0 [73.0 to 214.0] 108.0 [59.0 to 192.0] 0.07 Procalcitionin¶ 4.1 [1.2 to 21.3] 1.0 [0.3 to 5.1] Interleukin-6¶ 158.4 [39.2 to 1034.4] 72.0 [30.2 to 189.9] 171 patients had data of recent oral intake and weight loss (n=32) (n=139) % Oral intake (food) in the week prior to enrolment 4.0[ 1.0 to 70.0] 50.0[ 1.0 to 100.0] 0.10 % of weight loss in the last 3 month 0.0[ 0.0 to 2.5] 0.0[ 0.0 to 0.0] 0.06

Spearman correlation with VFD within 28 days Number of observations What are the nutritional risk factors associated with clinical outcomes? (validation of our candidate variables) Variable Spearman correlation with VFD within 28 days p values Number of observations Age -0.1891 <.0001 598 Baseline APACHE II score -0.3914 Baseline SOFA -0.3857 594 % Oral intake (food) in the week prior to enrollment 0.1676 0.0234 183 number of days in hospital prior to ICU admission -0.1387 0.0007 % of weight loss in the last 3 month -0.1828 0.0130 184 Baseline BMI 0.0581 0.1671 567 # of co-morbidities at baseline -0.0832 0.0420 Baseline CRP -0.1539 0.0002 589 Baseline Procalcitionin -0.3189 582 Baseline IL-6 -0.2908 581

The Development of the NUTrition Risk in the Critically ill Score (NUTRIC Score). % oral intake in the week prior was dichotomized into patients who reported less than 100% versus everyone else Weight loss was dichotomized as patients who reported any weight loss versus everyone else. BMI was dichotomized as <20 versus other Comorbidities was left as integer values range 0-5 The remaining candidate variables were categorized into five equal sized groups (quintiles).

The Development of the NUTrition Risk in the Critically ill Score (NUTRIC Score). For example, exact quintiles and logistic parameters for age Exact Quintile Parameter Points 19.3-48.8 referent 48.9-59.7 0.780 1 59.7-67.4 0.949 67.5-75.3 1.272 75.4-89.4 1.907 2

The Development of the NUTrition Risk in the Critically ill Score (NUTRIC Score). Variable Range Points Age <50 50-<75 1 >=75 2 APACHE II <15 15-<20 20-28 >=28 3 SOFA <6 6-<10 >=10 # Comorbidities 0-1 2+ Days from hospital to ICU admit 0-<1 1+ IL6 0-<400 400+ AUC 0.783 Gen R-Squared 0.169 Gen Max-rescaled R-Squared  0.256 BMI, CRP, PCT, weight loss, and oral intake were excluded because they were not significantly associated with mortality or their inclusion did not improve the fit of the final model.

The Validation of the NUTrition Risk in the Critically ill Score (NUTRIC Score).

The Validation of the NUTrition Risk in the Critically ill Score (NUTRIC Score).

Interaction between NUTRIC Score and nutritional adequacy (n=211)* The Validation of the NUTrition Risk in the Critically ill Score (NUTRIC Score). Interaction between NUTRIC Score and nutritional adequacy (n=211)* P value for the interaction=0.01 Heyland Critical Care 2011, 15:R28

Who might benefit the most from nutrition therapy? High NUTRIC Score? Clinical BMI Projected long length of stay Others?

Do we have a problem?

Preliminary Results of INS 2011 Overall Performance: Kcals 84% 56% 15% N=211

Failure Rate % patients who failed to meet minimal quality targets (80% overall energy adequacy)

Strategies to Maximize the Benefits and Minimize the Risks of EN weak evidence feeding protocols motility agents elevation of HOB small bowel feeds stronger evidence Canadian CPGs www.criticalcarenutrition.com

Use of Nurse-directed Feeding Protocols Start feeds at 25 ml/hr < 250 ml advance rate by 25 ml reassess q 4h > 250 ml hold feeds add motility agent reassess q 4h Check Residuals q4h “Should be considered as a strategy to optimize delivery of enteral nutrition in critically ill adult patients.” 2009 Canadian CPGs www.criticalcarenutrition.com

Get a copy of the one nestle uses for their tool kit

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

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

The same thinking that got you into this mess won’t get you out of it! Can we do better? The same thinking that got you into this mess won’t get you out of it!

Reasons for Inadequate Intake Slow starts and slow ramp ups Interruptions Mostly related to procedures Not related to GI dysfunction Can be overcome by better feeding protocols Impaired motility Medications Metabolic, electrolyte abnormalities Underlying disease Prophylactic use of motility agents

Protocol to Manage Interruptions to EN due to non-GI Reasons Add slide on interrruptions to EN re procedures. Can be downloaded from www.criticalcarenutrition.com

Daren K. Heyland Enhanced Protein-Energy Provision via the Enteral Route in Critically Ill Patients: The PEP uP Protocol Daren K. Heyland Professor of Medicine Queen’s University, Kingston General Hospital Kingston, ON Canada

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! 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. Start with a semi elemental solution, progress to polymeric Tolerate higher GRV threshold (250 ml or more) Motility agents and protein supplements are started immediately Nurse reports daily on nutritional adequacy. A Major Paradigm Shift in How we Feed Enterally

The PEP uP Protocol Stable patients should be able to tolerate goal rate We use a concentrated solution to maximize calories per ml Begin 24 hour volume-based feeds. After initial tube placement confirmed, start Pepatmen 1.5. Total volume to receive in 24 hours is 17ml x weight (kg)= <write in 24 target volume>. Determine initial rate as per Volume Based Feeding Schedule. Monitor gastric residual volumes as per Adult Gastric Flow Chart and Volume Based Feeding Schedule. OR Begin Peptamen 1.5 at 10 mL/h after initial tube placement confirmed. Hold if gastric residual volume >500 ml and ask Doctor to reassess. Reassess ability to transition to 24 hour volume-based feeds next day. {Intended for patient who is hemodynamically unstable (on high dose or escalating doses of vasopressors, or inadequately resuscitated) or not suitable for high volume enteral feeding (ruptured AAA, upper intestinal anastomosis, or impending intubation)} NPO. Please write in reason: __________________ ______. (only if contraindication to EN present: bowel perforation, bowel obstruction, proximal high output fistula. Recent operation and high NG output not a contraindication to EN.) Reassess ability to transition to 24 hour volume-based feeds next day. If unstable or unsuitable, just use trophic feeds Note indications for trophic feeds Drs need to justify why there are keeping patients NPO We want to minimize the use of NPO but if selected, need to reassess next day Note, there are only a few absolute contraindications to EN

It’s not just about calories... Inadequate protein intake Loss of lean muscle mass Immune dysfunction Weak Prolonged mechanical ventilation So in order to minimize this, we order: Protein supplement Beneprotein® 14 grams mixed in 120 mls sterile water administered bid via NG

Other Strategies to Maximize the Benefits and Minimize the Risks of EN Motility agents started at initiation of EN rather that waiting till problems with High GRV develop. Maxeran 10 mg IV q 6h (halved in renal failure) If still develops high gastric residuals, add Erythromycin 200 mg q 12h. Can be used together for up to 7 days but should be discontinued when not needed any more Reassess need for motility agents daily

The Efficacy of Enhanced Protein-Energy Provision via the Enteral Route in Critically Ill Patients: The PEP uP Protocol! Adequacy of Calories from EN (Before Group vs. After Group on Full Volume Feeds) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Total P-value 0.08 0.0003 0.10 0.19 0.48 0.18 0.11 <0.0001 Heyland Crit Care 2010

% calories received/prescribed Change of nutritional intake from baseline to follow-up of all the study sites (all patients) % calories received/prescribed Xuran, I need these redone without distinguishing commuinty from academic. Just one summary slope per figure.

% protein received/prescribed Change of nutritional intake from baseline to follow-up of all the study sites (all patients) % protein received/prescribed Xuran, Re do as previous

Small Bowel vs. Gastric Feeding: A meta-analysis Other Strategies to Maximize the Benefits and Minimize the Risks of EN Small Bowel vs. Gastric Feeding: A meta-analysis Effect on VAP Updated 2011,www.criticalcarenutrition.com

Does Postpyloric Feeding Reduce Risk of GER and Aspiration? Tube Position # of patients % positive for GER % positive for Aspiration Stomach 21 32 5.8 D1 8 27 4.1 D2 3 11 1.8 D4 1 5 Total 33 75 11.7 P=0.004 P=0.09 Heyland CCM 2001;29:1495-1501

FRICTIONAL ENTERAL FEEDING TUBE (TIGER TUBETM) Flaps to allow peristalsis to pull tube passively forward Sucessful jejunal placement >95%

CORTRAK® A new paradigm in feeding tube placement Aid to placement of feeding tubes into the stomach or small bowel The tip of the stylet is a transmitter. Signal is picked up by an external receiver unit. Signal is fed to an attached Monitor unit. Provides user with a real-time, graphic display that represents the path of the feeding tube.

A Change to Nursing Report Please report this % on rounds as part of the GI systems report Adequacy of Nutrition Support = 24 hour volume of EN received Volume prescribed to meet caloric requirements in 24 hours

When performance is measured, performance improves. When performance is measured and reported back, the rate of improvement accelerates. Thomas Monson

Health Care Associated Malnutrition What if you can’t provide adequate nutrition enterally? … to add PN or not to add PN, that is the question!

Early vs. Late Parenteral Nutrition in Critically ill Adults 4620 critically ill patients Randomized to early PN Rec’d 20% glucose 20 ml/hr then PN on day 3 OR late PN D5W IV then PN on day 8 All patients standard EN plus ‘tight’ glycemic control Results: Late PN associated with 6.3% likelihood of early discharge alive from ICU and hospital Shorter ICU length of stay (3 vs 4 days) Fewer infections (22.8 vs 26.2 %) No mortality difference Cesaer NEJM 2011

Early vs. Late Parenteral Nutrition in Critically ill Adults ? Applicability of data No one give so much IV glucose in first few days No one practice tight glycemic control Right patient population? Majority (90%) surgical patients (mostly cardiac-60%) Short stay in ICU (3-4 days) Low mortality (8% ICU, 11% hospital) >70% normal to slightly overweight Not an indictment of PN Early group only rec’d PN for 1-2 days on average Late group –only ¼ rec’d any PN Cesaer NEJM 2011

What if you can’t provide adequate nutrition enterally? … to TPN or not to TPN, that is the question! Case by case decision Maximize EN delivery prior to initiating PN Use early in high risk cases

R The TOP UP Trial Primary Outcome 60-day mortality PN for 7 days Stratified by: Site BMI Med vs Surg ICU patients R BMI <25 60-day mortality BMI >35 Fed enterally Control

In Conclusion Health Care Associate Malnutrition is rampant Not all ICU patients are the same in terms of ‘risk’ Iatrogenic underfeeding is harmful in some ICU patients or some will benefit more from aggressive feeding (avoiding protein/calorie debt) BMI and/or NUTRIC Score is one way to quantify that risk Need to do something to reduce iatrogenic malnutrition in your ICU! Audit your practice first! PEP uP protocol in all Selective use of small bowel feeds then sPN in high risk patients

Not tolerating EN at 96 hrs? Start PEP UP Day 3 >80% of Goal Calories YES No NO Yes Anticipated Long Stay? High Risk? Yes Carry on! No Maximize EN with motility agents and small bowel feeding No problem YES Not tolerating EN at 96 hrs? No NO Yes Supplemental PN?

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Questions?