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)

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 For every 1000 kcal/day received: Model * Estimate (CI) P values At 3 months PHYSICAL FUNCTIONING 3.2 (-1.0, 7.3)   P=0.14 ROLE PHYSICAL 4.2 (-0.0, 8.5) P=0.05 STANDARDIZED PHYSICAL COMPONENT SCALE 1.8 (0.3, 3.4) P=0.02 At 6 months 0.8 (-3.6, 5.1) P=0.73 2.0 (-2.5, 6.5) P=0.38 0.70 (-1.0, 2.4) P=0.41 for increase of 30 gram/day, OR of infection at 28 days Unpublished data from Multicenter RCT of glutamine and antioxidants (REDOXS Study); n=364

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

113 select ICU patients with sepsis or burns On average, receiving 1900 kcal/day and 84 grams of protein No significant relationship with energy intake but…… Clinical Nutrition 2012

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

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!)

Rice et al. JAMA 2012;307

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!

Nutritional Management of ICU Patients: Are these both the same? Low Risk 34 year former football player, BMI 35 otherwise healthy involved in motor vehicle accident Mild head injury and fractured R leg requiring ORIF High Risk 72 women BMI 35 PMHx COPD, poor functional status Admitted to hospital 1 week ago with CAP Now presents in respiratory failure requiring intubation and ICU admission

ICU-acquired Weakness (ICUAW) Muscle weakness develops in 25%-60% of patients who have been mechanically ventilated for > 1 week1 Prolongs:1-4 mechanical ventilation weaning from the ventilator ICU stay ICUAW main clinical manifestation of critical illness neuromyopathy (CINM)5 de Jonghe B, et al. Crit Care Med. 2004;30:1117-1121. Garnacho-Montero J, et al. Crit Care Med. 2005;33:349-354. van den Berghe G, et al. Crit Care Med. 2003;31:359-366. Hermans G, et al. Am J Respir Crit Care Med. 2007;175:480-489. de Jonghe B, et al. Crit Care Med. 2009;37(suppl.):S309-S315.

Determinants to Lean Body Mass

Muscle Matters! Skeletal muscle mass predicts ventilator-free days, ICU-free days, and mortality in elderly ICU patients Patients > 65 years with an admission abdominal computed tomography scan and requiring intensive care unit stay at a Level I trauma center in 2009-2010 were reviewed. Muscle cross-sectional area at the 3rd lumbar vertebra was calculated and sarcopenia identified using sex-specific cut-points. Muscle cross-sectional area was then related to clinical parameters including ventilator-free days, ICU-free days, and mortality. Kozar (in submission)

Body Composition Lab CT Imaging Analysis Skeletal Muscle Adipose Tissue To date we have used weight/BMI as a descriptor of patient body composition and we have looked at change in weight as a marker of change in nutritional status or to evaluate success/failure of nutritional intervention However, with weight, we cannot discern specific body composition profile or changes in profile; Use of already existing CT scans can provide this information… -L3 bony landmark – literature; longitudinal

Physical Characteristics of Patients N=149 patients Median age: 79 years old 57% males ISS: 19 Prevalence of sarcopenia: 71%

Sarcopenic Patients (n=106) Non-sarcopenic Patients (n=43) BMI Characteristics All Patients Sarcopenic Patients (n=106) Non-sarcopenic Patients (n=43) BMI (kg/m2) 25.8 (22.7, 28.2) 24.4 (21.7, 27.3) 27.6 (25.5, 30.4) Underweight, % 7 9 2 Normal Weight, % 37 44 19 Overweight, % 42 38 51 Obese, % 15 28

Low muscle mass associated with mortality Proportion of Deceased Patients P-value Sarcopenic patients 32% 0.018 Non-sarcopenic patients 14%

Muscle mass is associated with ventilator-free and ICU-free days All Patients Sarcopenic Patients Non-Sarcopenic Patients P-value Ventilator-free days 25 (0,28) 19 (0,28) 27 (18,28) 0.004 ICU-free days 19 (0,25) 16 (0,24) 23 (14,27) 0.002

After day 5, when awake, performed muscle testing Prospective multicenter observational trial of 136 patients requiring min 5 days of mechanical ventilation After day 5, when awake, performed muscle testing Am J Respir CCM 2008;178:261-268

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.

Mostly surgical patients; 100% data available for SGA

“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

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

P=0.008 P=0.04 P=0.04 Multicenter prospective study of nutrition practice in abdominal surgery All patients had nutrition screening, not all patients had peri op nutrition support Benefit of nutrition support seen in NRS>5 compared to controls, no benefit seen in low risk patients (NRS<5). Patients with NRS >5

Who might benefit the most from nutrition therapy in the ICU? 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

Nutritional Adequacy of High Risk Patients compared to Low Risk Patients

Failure Rate % high risk patients who failed to meet minimal quality targets (80% overall energy adequacy) 91.2 87.0 78.1 79.9 75.6 75.1 69.8 Unpublished observations. Results of 2011 International Nutrition Survey (INS).

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

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!

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 (300 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 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 (intervention group only) % calories received/prescribed

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

Lancet Dec 2012

Lancet Dec 2012

Lancet Dec 2012

Adult patients were eligible for enrollment within 24 hours of ICU admission if they were expected to remain in the ICU on the calendar day after enrollment, were considered ineligible for enteral nutrition by the attending clinician due to a short-term relative contraindication and were not expected to PN or oral nutrition Doig, ANZICS, JAMA May 2013

Who were these patients? Overall, standard care group remained unfed for 2.8 days after randomization 40% of standard care group never rec’d any artificial nutrition; remained in ICU 3.5 days

Intervention not intense enough? 40% of both groups got EN (delayed) 40% of standard care group got PN for an average of 3.0 days Average PN use in early PN group was 6.0 days

Main inference: No harm by early PN (in contrast to EPaNIC) Doig, ANZICS, JAMA May 2013

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

Start PEP UP within 24-48 hrs At 72 hrs >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 Yes NO Tolerating EN at 96 hrs? No Supplemental PN? No problem

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

Muscle Outcome Assessments in TOP UP Measures of muscle mass and function mitochondrial complex I activity US of femoral quad (baseline and follow up CTs when available) Hand grip strength 6 min walk test SF 36 (RP and PCS)

Reliability of US measure of Quad Muscle Layer Thickness 46 pairs of within operator measurements with an ICC of .98 73 pairs of operator 1 to operator 2 measurements with an ICC of .94. There was a small but statistically significant difference between the operator 1 and 2 results Mean (operator 1-2) (95% CI) = -0.061 cm (-0.100 to -0.022), p= 0.0028. 

Lancet 2009;273:

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! (JOIN International Critical Care Nutrition Survey in 2013) PEP uP protocol in all Selective use of small bowel feeds then sPN in high risk patients

Questions?