Queen’s University, Kingston General Hospital Iatrogenic Underfeeding is Harmful to ‘High-Risk’ Critically ill Patients! Daren K. Heyland Professor of Medicine Queen’s University, Kingston General Hospital Kingston, ON Canada Add data from iatrogenic malnutrition slides

Learning Objectives Review the evidentiary basis for the amount of macronutrients provided to critically ill patients List approaches for risk assessment in the ICU setting List strategies to improve nutritional adequacy in the critical care setting

www.criticacarenutrition.com

Summary of Highlights Downgrade Upgrade EN vs PN (to ‘recommend’) IV and EN glutamine (to ‘strongly recommend not be used’) Selenium (recommended not to be used) Upgrade Early PN ‘should be considered’ in high-risk pts with relative contraindication to EN.

Most Controversial CPGs?

R PERMIT Trial Design Primary Outcome Protein dose the same 40-60% prescribed calories for 14 days Primary Outcome 894 ICU Patients Fed enterally Protein dose the same R 90-day mortality 70-100% prescribed for 14 days

Results of PERMIT Trial

SHOULD WE PERMIT SYSTEMATIC UNDERFEEDING IN ALL ICU PATIENTS? How do we Integrate the results of the PERMIT study in our clinical practice guidelines.

To answer these question, we need to consider…. Who were these patients studied in the PERMIT study? What was the intervention? Were all clinically important outcomes considered?

Patients Enrolled in PERMIT Trial

Initial Tropic vs. Full EN in Patients with Acute Lung Injury The EDEN randomized trial Enrolled 12% of patients screened Rice TW, et al. JAMA. 2012;307(8):795-803.

No effect in young, healthy, overweight patients who have short stays! Trophic vs. Full EN in Critically Ill Patients with Acute Respiratory Failure Average age 52 Few comorbidities Average BMI* 29-30 All fed within 24 hours (benefits of early EN) Average duration of study intervention 5 days No effect in young, healthy, overweight patients who have short stays! * BMI: body mass index Alberda C, et al. Intensive Care Med. 2009;35(10):1728-37.

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

Not all ICU Patient 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 79 women BMI 35 PMHx COPD, poor functional status, frail Admitted to hospital 1 week ago with CAP Now presents in respiratory failure requiring intubation and ICU admission

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

50% 25% 75% 100%

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

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

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.

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

In a second data set of 1200 ICU patients Minus IL-6 levels Further validation of the “modified NUTRIC” nutritional risk assessment tool In a second data set of 1200 ICU patients Minus IL-6 levels Rahman Clinical Nutrition 2015

Validation of NUTRIC Score in Large International Database >2800 patients from >200 ICUs Odds Ratio (95% CI) for 60 day mortality^ for every 10% increase in nutrition intake Protein Calories ^Faster time-to-discharge alive with more protein and calories ONLY in the high NUTRIC group Compher (in submission)

NUTRIC score - Effectiveness of a nutritional risk assessment tool in critically ill patients of Portuguese ICU MON PP-180 Rosa Mendes1*, Sara Policarpo2, Philip Fortuna1, Marta Alves3, Daniel Virella3, Daren K. Heyland4 1 - Medical Urgency Unit (General Intensive Care Unit), S. José Hospital, Central Lisbon Hospital Center, Lisbon, Portugal, 2 - Dietetics and Nutrition Department, Santa Maria University Hospital, North Lisbon Hospital Center, Lisbon, Portugal 3 - Research Unit, Central Lisbon Hospital Center, Lisbon, Portugal, 4 - Clinical Evaluation Research Unit, Kingston General Hospital, Kingston, Ontario, Canada Conclusions High nutritional risk is present in half of the patients in Portuguese ICU. NUTRIC score strongly associates with main clinical outcomes; it presented high positive predictive value and low negative predictive value to predict 28-day mortality as well. Introduction & Aim Assessing nutritional risk in critically ill patients may indicate which patients will benefit from a more aggressive nutritional therapy. Our aim was to assess the effectiveness of the NUTrition Risk in the Critically Ill (NUTRIC) score without interleucine-6 (IL-6), in Portuguese intensive care units (ICU) and to characterize the nutritional risk of our critically ill patients. Results 1143 admissions were considered. The median (P25-P75) age at admission was 64 (51-75) years. Males predominated (n=744, 64.7%). 397 (34.5%) patients presented two or more co-morbidities. Patients at high nutritional risk were 48.5% (n=558). The median (P25-P75) of the days off MV was 6 (2-12) days and of LOS was 9 (5-15) days. 21.7% (n=245/1128) of patients were deceased at day-28. High NUTRIC score was associated with LOS (p<0.001), days off MV (p<0.001) and 28-day mortality (p<0.001). The AUC of the NUTRIC score for predicting 28-day mortality was 0.718 (95%CI 0.69-0.75); NUTRIC score ≥5 predicted 73.5% of deceased and 41.4% of survivors. Variables in NUTRIC score NUTRIC scoring system Original development sample (n=598) Effectiveness study sample (n=1143) p Range Points Age <50 50-75 ≥75 1 2 130 (21.7) 345 (57.7) 123 (20.6) 255 (22.3) 574 (50.2) 314 (27.5) 0.003 APACHE II <15 15 - <20 20 - <28 ≥28 3 111 (18.6) 135 (22.6) 226 (37.8) 126 (21.1) 292 (25.6) 257 (22.5) 374 (32.7) 219 (19.2) 0.007 SOFA <6 6 - <10 ≥10 220 (36.8) 247 (41.3) 131 (21.9) 376 (32.9) 436 (38.1) 331 (29.0) Co-morbidities 0-1 ≥2 160 (26.8) 438 (73.2) 750 (65.6) 393 (34.4) <0.001 Days from hospital to ICU admission <1 ≥1 375 (62.7) 223 (37.3) 466 (40.9) 678 (59.4) Score Range 0-10 (3-6) 0-9 (3-6) Score mean 4.7 (2.2) 4.4 (2.1) 0.086 AUC 0.783 0.718 0.232 Gen R2 0.169 0.103 Gen Max-rescaled R2 0.256 0.158 Methods Prospective, observational, non-randomized study conducted over 6 months in 2014, in 15 Portuguese ICU´s. Patients ≥18 years of age, mechanically ventilated (MV), with length of ICU stay (LOS) ≥72hours were included. Brain dead patients or those previously admitted in another ICU were excluded. NUTRIC score, without IL-6 levels, was calculated at admission. The score ranges from zero to nine; those above five were considered high nutritional risk. Main outcome measures were LOS, days off MV and 28-day mortality. NUTRIC Score Portugal Group: CHLC-UUM: Mendes R., Fortuna P., Francisco A.R. MD, Graça A. MD, Guerreiro G. RD; CHLC-UCIP1: Simas A. MD, Miranda I. MD, Cruz M.V. MD, Shumanska Z. MD; CHLN-UIR: Policarpo S; CHLN-UCIR: Martins T RD; CHSJ-UCPU: Gomes J.P. MD; CHSJ-UCPG: Aguiar L MD; IPO-Porto: Cabral S RN; CHEDV-UCIP: Rodrigues P.R. MD; CHVR/PR-UCIP: Santos A. MD, Gonçalves L. MD; CHUC-UCI: Martins P. MD, PhD; CHTV-UCIP: Melo E. MD; ULSBA-UCIP: Carvalho A. MD, Barahona I. MD; HLA-UCI: Vilas M.J. MD; CHA-Med1/EUCI: Sousa A. MD; HDES-UCI: Henriques M. MD, Carvalho R. RN

Who might benefit the most from nutrition therapy? At Baseline Assessment High NUTRIC Score Clinical BMI Projected long length of stay Nutritional history variables Sarcopenia Medical vs. Surgical Others?

It is plausible that nutrition high risk patients (not well represented in these study) could still benefit from optimal nutritional delivery.

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 Nutritional Adequacy and 60-Day Hospital Mortality Optimal amount= 80-85% Heyland CCM 2011

Optimal Nutrition (>80%) is associated with Optimal Outcomes! (For High Risk Patients) If you feed them (better!) They will leave (sooner!)

To answer these question, we need to consider…. Who were these patients studied in the PERMIT study? What was the intervention? Were all clinically important outcomes considered?

R PERMIT Trial Design Primary Outcome Protein dose the same 40-60% prescribed calories for 14 days Primary Outcome 894 ICU Patients Fed enterally Protein dose the same R 90-day mortality 70-100% prescribed for 14 days

0.7 g/kg/day in both groups How well did they do? 0.7 g/kg/day in both groups 68% 46% vs. 71%

Impact of Protein Intake on 60-day Mortality Data from 2828 patients from 2013 International Nutrition Survey   Patients in ICU ≥ 4 d Variable 60-Day Mortality, Odds Ratio (95% CI) Adjusted¹ Adjusted² Protein Intake (Delivery > 80% of prescribed vs. < 80%) 0.61 (0.47, 0.818) 0.66 (0.50, 0.88) Energy Intake (Delivery > 80% vs. < 80% of Prescribed) 0.71 (0.56, 0.89) 0.88 (0.70, 1.11) ¹ Adjusted for BMI, Gender, Admission Type, Age, Evaluable Days, APACHE II Score, SOFA Score ² Adjusted for all in model 1 plus for calories and protein Nicolo JPEN 2015

Rate of Mortality Relative to Adequacy of Protein and Energy Intake Delivered Heyland JPEN 2015

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…… 1.45 gm/kg/d 1.06 gm/kg/d 0.79 gm/kg/d Clinical Nutrition 2012

It is an open question whether higher amounts of protein will translate into improved clinical outcomes for such heterogeneous critically ill patients.

To answer these question, we need to consider…. Who were these patients studied in the PERMIT study? What was the intervention? Were all clinically important outcomes considered?

Initial Tropic vs. Full EN in Patients with Acute Lung Injury The EDEN randomized trial Rice TW, et al. JAMA. 2012;307(8):795-803.

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

Nutritional Adequacy and Long-term Outcomes in Critically Ill Patients Requiring Prolonged Mechanical Ventilation Sub study of the REDOXS study 302 patients survived to 6-months follow-up and were mechanically ventilated for more than eight days in the intensive care unit were included. Nutritional adequacy was obtained from the average proportion of prescribed calories received during the first eight days of mechanical ventilation in the ICU. HRQoL was prospectively assessed using Short-Form 36 Health Survey (SF-36) questionnaire at three-months and six-months post ICU admission.  Wei CCM 2015

Estimates of association between nutritional adequacy and SF-36 scores *Every 25% increase in nutritional adequacy; adjusted for age, APACHE II score, baseline SOFA, Functional Comorbidity Index, admission category, primary ICU diagnosis, body mass index, and region

So if we follow the results from the PERMIT study and continue to permit underfeeding, it is possible that we are harming some ICU patients, particularly those with long ICU stays.

On our website www. criticalcarenutrition On our website www.criticalcarenutrition.com and published in JPEN 2015

Earlier and Optimal Nutrition (>80%) is Better! (For High Risk Patients) If you feed them (better!) They will leave (sooner!)

Failure Rate The Prevalence of Iatrogenic Underfeeding in the Nutritionally ‘At-Risk’ Critically Ill Patient % high risk patients who failed to meet minimal quality targets (80% overall energy adequacy) Of all at-risk patients, 14% were ever prescribed volume-based feeds 15% ever received sPN Heyland Clinical Nutrition 2015 Failure Rate

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, rather than started when there is a problem. A Major Paradigm Shift in How we Feed Enterally Heyland Crit Care 2010; see www.criticalcarenutrition.com for more information on the PEP uP collaborative

Results of 2013 International Nutrition Survey Results of the Canadian PEP uP Collaborative Results of 2013 International Nutrition Survey Heyland JPEN 2014

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

In Conclusion 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, LOS, and/or NUTRIC Score is one way to quantify that risk Need to do something to reduce iatrogenic underfeeding in your ICU! PEP uP protocol in all Selective use of small bowel feeds then sPN in high risk patients Monitor performance

Questions?