2. Overview Importance of preserving muscle mass/function Optimal nutrition positively influences subsequent physical function Role of early rehabilition/mobilization Need both optimal nutrition and optimal mobilization to optimize outcome!

3. Clinical Scenario  79 yo male admitted to hospital with AMI  Progressive respiratory failure  Aspirates ARDS  Low volume ventilation, high PEEP, NO  Course complicated by line sepsis resulting in need for pressors and renal failure @ 3 weeks, family asks “how much longer do we prolong this?” “not just about survival; what will he be like?” Moving Beyond Survival!

6. 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 3 rd 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. Moisey Critical Care 2013

7. Skeletal Muscle Adipose Tissue

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

9. BMI Characteristics All PatientsSarcopenic Patients (n=106) Non-sarcopenic Patients (n=43) BMI (kg/m 2 )25.8 (22.7, 28.2)24.4 (21.7, 27.3)27.6 (25.5, 30.4) Underweight, %792 Normal Weight, %374419 Overweight, %423851 Obese, %15928 Not all sarcopenics underweight!!

10. Low muscle mass associated with mortality Proportion of Deceased Patients P-value Sarcopenic patients32% 0.018 Non-sarcopenic patients14%

11. Muscle mass is associated with ventilator-free and ICU-free days All PatientsSarcopenic Patients Non- Sarcopenic Patients P-value Ventilator-free days 25 (0,28)19 (0,28)27 (18,28)0.004 ICU-free days19 (0,25)16 (0,24)23 (14,27)0.002

12. Determinants to Lean Body Mass

14. Protein balance improved with optimal caloric feeding Berg Crit Care 2013;17:R158 Whole body protein synthesisWhole body protein degradation Phenylalanine oxidationWhole body protein balance

15. Nutritional Adequacy and Health-related Quality of Life 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.

16. Estimates of association between nutritional adequacy and SF-36 scores * Adjusted for age, APACHE II score, baseline SOFA, Functional Comorbidity Index, admission category, primary ICU diagnosis, body mass index, and region

17. Subgroup analysis by admission category

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

19. 63 critically ill patients Muscle loss determined by serial US of rectus femoris (CSA) on days 1, 3, 5, 7 and 10 Histopathologic analysis also performed Protein signal pathways analyzed JAMA Published online Oct 9, 2013

21. “In a multivariable linear analysis, change in rectus femoris CSA was positively associated with the degree of organ failure, CRP level and amount of protein delivered” JAMA Published online Oct 9, 2013

22. “…increasing protein delivery was associated with increased muscle wasting.” JAMA Published online Oct 9, 2013 Clinical Implications

23. Guilty by Association Patients who stay longer in the ICU has worse outcomes Patients who stay longer in the ICU will have more muscle loss Patients in the ICU will have greater opportunity to tolerate more protein/calories Error to assume that protein causes muscle loss or adverse outcomes

24. 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

25. 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* *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.

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

27. 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

28. Early Nutrition in the ICU: Less is more! Post-hoc analysis of EPANIC Casaer Am J Respir Crit Care Med 2013;187:247–255 Treatment effect persisted in all subgroups

29. 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

30. Early vs. Late Parenteral Nutrition in Critically ill Adults How do you explain the early signal, present by day 3

31. 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 –2 other recent large scales trials (Swiss and Australian) confirm safety of early PN Cesaer NEJM 2011

32. Rice et al. JAMA 2012;307 No comment on protein intake Factorialized with OMEGA where half patients received extra 20 grams/day

33. Rice et al. JAMA 2012;307

34. Needham BMJ 2013

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

36. 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!

37. 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

38. 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?

39. More (and Earlier) is Better! Particularly in ‘High-risk’ patients If you feed them (better!) They will leave (sooner!)

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

41. 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. 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 www.criticalcarenutrition.com for more information on the PEP uP collaborativewww.criticalcarenutrition.com

42. Yes YES At 72 hrs >80% of Goal Calories? No NO No problem Anticipated Long Stay? Yes No Maximize EN with motility agents and small bowel feeding No YES Tolerating EN at 96 hrs? Yes NO Start PEP UP within 24-48 hrs High Risk? Carry on! Supplemental PN?No problem

43. Lancet 2009;273:

44. Critical Illness InflammationNutrition Muscle Atrophy & Muscular Weakness Duration of mechanical ventilation ICU/hospital LOS Functional status QOL Mobility Nutrition Therapy ? ? ? Early Rehabilitation

45. In Conclusion Immobility and Inflammation erode lean muscle mass leading to weakness and impaired HRQOL Lean body mass key determinant to outcome Optimizing nutritional intake can attenuate erosion of lean mass and is associated with improved function Combination of activity and optimal nutrition will result in greatest preservation of lean muscle mass Need to do something to reduce iatrogenic underfeeding in your ICU! –Audit your practice first (next international nutrition survey later 2014/early 2015)! –PEP uP protocol in all –TOP UP?

46. Questions?