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

Summary of Highlights Downgrade –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?

Patients who are at low nutrition risk do not require specialized nutrition therapy over the first week of hospitalization in the ICU Either trophic or full nutrition by EN is appropriate for patients with acute respiratory distress syndrome (ARDS) / acute lung injury (ALI) and those expected to have a duration of mechanical ventilation ≥72 hours

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

Results of PERMIT Trial

HOW DO WE INTEGRATE THE RESULTS OF THE PERMIT STUDY IN OUR CLINICAL PRACTICE GUIDELINES. SHOULD WE PERMIT SYSTEMATIC UNDERFEEDING IN ALL ICU PATIENTS?

To answer these question, we need to consider…. 1.Who were these patients studied in the PERMIT study? 2.What was the intervention? 3.Were all clinically important outcomes considered?

Patients Enrolled in PERMIT Trial

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

25% 50% 75% 100%

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

How do we figure out who will benefit the most from Nutrition Therapy?

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

The Development of the NUTrition Risk in the Critically ill Score (NUTRIC Score). VariableRangePoints Age< <751 >=752 APACHE II< < >=283 SOFA<60 6-<101 >=102 # Comorbidities Days from hospital to ICU admit0-< IL60-< AUC0.783 Gen R-Squared0.169 Gen Max-rescaled R-Squared 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).

Interaction between NUTRIC Score and nutritional adequacy (n=211) * P value for the interaction=0.01 Heyland Critical Care 2011, 15:R28

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 Protein Calories Compher (in submission) ^Faster time-to-discharge alive with more protein and calories ONLY in the high NUTRIC group

Who might benefit the most from nutrition therapy? 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 Heyland CCM 2011 Optimal amount= 80-85%

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

To answer these question, we need to consider…. 1.Who were these patients studied in the PERMIT study? 2.What was the intervention? 3.Were all clinically important outcomes considered?

RCTs of Early vs. Delayed EN Infection RR 0.76 (0.69, 0.98) Mortality RR 0.68 (0.46, 1.01)

↑Dominance of anti-inflammatory Th2 over pro-inflammatory Th1 responses Modulate adhesion molecules to ↓ transendothelial migration of macrophages and neutrophils Maintain gut integrity ↓Gut permeability Support commensal bacteria Stimulate oral tolerance ↑Butyrate production Promote insulin sensitivity, ↓hyperglycemia (AGEs) Reduce gut/lung axis of inflammation Maintain MALT tissue ↑Production of Secretory IgA at epithelial surfaces Provide micro & macronutrients, antioxidants Maintain lean body mass ↓Muscle and tissue glycosylation ↑ Mitochondrial function ↑ Protein synthesis to meet metabolic demand Attenuate oxidative stress ↓ Systemic Inflammatory Response Syndrome (SIRS) ↑ Muscle function, mobility, return to baseline function ↑ Absorptive capacity Influence anti-inflammatory receptors in GI tract ↓ Virulence of pathogenic organisms ↑ Motility, contractility Nutritional and Non-nutritional benefits of Early Enteral Nutrition McClave CCM 2015

Pragmatic RCT in 33 ICUs in England 2400 patients expected to require nutrition support for at least 2 days after unplanned admission Early EN vs Early PN According to local products and policies Powered to detect a 6.4% ARR in 30 day mortality NEJM Oct

High mortality rates: 35% at 30 days No difference in 30 day or 90 day mortality or infection nor 14 other secondary outcomes Protein Delivered: EN 0.7 gm/kg; PN 1.0 gm/kg Suboptimal method of determining infection

Updated Meta-analysis of EN vs PN Effect on Infection Unpublished data RR 0.64 (95%CI 0.48, 0.87)

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

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

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

Impact of Protein Intake on 60-day Mortality Data from 2828 patients from 2013 International Nutrition Survey Patients in ICU ≥ 4 d Variable60-Day Mortality, Odds Ratio (95% CI) Adjusted¹Adjusted² 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 (in press)

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

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…. 1.Who were these patients studied in the PERMIT study? 2.What was the intervention? 3.Were all clinically important outcomes considered?

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

Initial Tropic vs. Full EN in Patients with Acute Lung Injury The EDEN randomized trial

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

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 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.

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

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

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

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 Motility agents and protein supplements are started immediately, rather than started when there is a problem. Tolerate higher GRV threshold (300 ml or more) The Efficacy of Enhanced Protein-Energy Provision via the Enteral Route in Critically Ill Patients: The PEP uP Protocol! A Major Paradigm Shift in How we Feed Enterally Heyland Crit Care 2010; see for more information on the PEP uP collaborativewww.criticalcarenutrition.com

Volume-based Feeding Schedule How much left to give/how much time left in day

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 Motility agents and protein supplements are started immediately, rather than started when there is a problem. Tolerate higher GRV threshold (300 ml or more) The Efficacy of Enhanced Protein-Energy Provision via the Enteral Route in Critically Ill Patients: The PEP uP Protocol! A Major Paradigm Shift in How we Feed Enterally Heyland Crit Care 2010; see for more information on the PEP uP collaborativewww.criticalcarenutrition.com

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

Bedside Written MaterialsDescription EN initiation ordersPhysician standardized order sheet for starting EN. Gastric feeding flow chart Flow diagram illustrating the procedure for management of gastric residual volumes. Volume-based feeding schedule Table for determining goal rates of EN based on the 24 hour goal volume. Daily monitoring checklistExcel spreadsheet used to monitor the progress of EN. Materials to Increase Knowledge and Awareness Study information sheets Information about the study rationale and guidelines for implementation of the PEP uP protocol. Three versions of the sheets were developed targeted at nurses, physicians, and patients’ family, respectively. PowerPoint presentations Information about the study rationale and how to implement the PEP uP protocol. A long (30-40 minute) and short (10-15 minute) version were available. Self-learning module Information about the PEP uP protocol and case example to work through independently. PostersA variety of posters were available to hang in the ICU during the study. Frequently Asked Questions (FAQ) documentDocument addresses common questions about the PEP uP Protocol. Electronic reminder messages Animated reminder messages about key elements of the PEP uP protocol to be displayed on a monitor in the ICU. Monthly newslettersMonthly circular with updates about the study. Tools to Operationalize the PEP uP Protocol McCall Nutrition Clinical Practice 2014 see for more information on the PEP uP collaborativewww.criticalcarenutrition.com

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

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 Cesaer NEJM 2011 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

Early Nutrition in the ICU: Less is more! Post-hoc analysis of EPANIC Casaer Am J Respir Crit Care Med 2013;187:247–255 Protein is the bad guy!! Indication bias: 1) patients with longer projected stay would have been fed more aggressively; hence more protein/calories is associated with longer lengths of stay. (remember this is an unblinded study). 2) 90% of these patients are elective surgery. there would have been little effort to feed them and they would have categorically different outcomes than the longer stay patients in which their were efforts to feed

Early vs. Late Parenteral Nutrition in Critically ill Adults 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 –Clear separation of groups after 2-3 days –Early group only rec’d PN on day 3 for 1-2 days on average –Late group –only ¼ rec’d any PN Cesaer NEJM 2011

Lancet Dec 2012 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

End of day 3: >80% of goal? Carry on! High risk?* YesNo Consider supplemental PN Good job! Continue monitoring nutritional adequacy! Maximize EN with motility agents small bowel feeding protein supplements End of day 4: Tolerating EN>80%? YESNO YESNO Good job! Continue monitoring nutritional adequacy! EN * Nutric Score > 5 or * ICU LOS > 96 hrs Start PEP uP Protocol in all patients within hrs of admission Heyland, Right here, Right now!

Dates for 2017 International Nutrition Survey to be announced soon

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?