Margaret Herridge MD MPH Professor of Medicine Scientist, Toronto General Research Institute

1. Long-term Outcomes in Survivors of Complex Critical Illness and their Family Caregivers: Towards RECOVER Phase 1:The RECOVER Program Margaret Herridge MD MPH Professor of Medicine Scientist, Toronto General Research Institute Interdepartmental Division of Critical Care University of Toronto, Canadian Critical Care Trials Group

2. Overview • Spectrum of Disability • Continuum of Weakness • Cognitive Dysfunction and Mood Disorders • RECOVER and risk stratification to optimize rehabilitation

3. Evidence of diaphragmatic atrophy and increased proteolysis at 18 hours of mechanical ventilation De Jonghe, B. et al. JAMA 2002;288:2859-2867 Ali N et al. AJRCCM 2008; 178:261-268

4. Herridge et al. N Engl J Med 2003; 348:683-93.

5. All biopsies were abnormal (6-24 months after ICU discharge) • No patients were exposed to steroids or paralytics • Most common abnormality was type II fiber atrophy • Manifested as narrow angulated fibers; myofibers were reduced to clumps of myonuclei • Myofibrillary disarray on EM • Changes not exclusively attributable to disuse atrophy Angel et al. 2007 Can J Neurol Sci 34: 427-432

6. Five-Year Outcomes in ARDS Herridge et al. NEJM 2011; 364: 1293-304 Persistent exercise limitation and reduction in Physical QOL at 5-years after ICU discharge

7. Heterotopic Ossification Alopecia Tracheal stenosis Cosmesis- Scars from CVC, Art line, CT, drain sites Nerve and Muscle Brain Hearing Loss Bronchiectasis Pulmonary fibrosis Taste changes Weakness Mental Health & Cognition frozen joints contractures striae Ischemic digits Disability after Critical Illness Renal Impairment

9. Hopkins et al. AJRCCM 1999; 160:50 Hopkins et al. J Int Neuropsych Assoc 2003;9:584

10. Enrolment in a conservative fluid-management strategy was associated with • cognitive impairment • Lower partial pressure of oxygen was associated with cognitive and psychiatric • impairment • Hypoglycemia was associated with mood disorders Am J Respir Crit Care Med 2012; 185:1307-13

11. Pandharipande et al. NEJM 2013

12. Sepsis survivors had a reduction in verbal learning and memory • Reduction in left hippocampal volume • Increase in low frequency EEG activity consistent with brain dysfunction • No clinical difference in HRQOL, psychological dysfunction, mood disorders

13. Ischemic Changes Brain Atrophy Suchyta et al. Brain Imaging and Behavior 4:22-34, 2010

14. Risk Factors for Cognitive Dysfunction • Duration of Delirium • Blood Glucose Dysregulation • Conservative Fluid Management • Hypoxia • Hypotension • Corticosteroids • Sedatives, Analgesics Mikkelsen et al. AJRCCM 2012; 185:1307-15 Girard et al. Crit Care Med 2010;38: 1513-1520 Hopkins et al. Brain Inj 2010; Sept 21 Epub Hopkins et al. AJRCCM 1999; 160:50-56 Hopkins et al. AJRCCM 2005; 171:340-347 Rothenhausler et al. Gen Hosp Psychiatry 2001; 23: 90-96

15. Depression • Prevalence 17-43% • May decrease or stay the same over time ( Hopkins 2010; Adhikari 2011) • Risks include: alcohol dependence, female gender, younger age, cognitive dysfunction, hypoglycemia, severity of illness measures, mean ICU benzodiazepine dose • Associated with ability to return to work Davydow et al. Psychosom Med 2008; 70:512-9 Adhikari et al. Chest 2009;135: 678-687 Hopkins et al. Gen Hosp Psychiatry 2010; 32: 147-55 Dowdy et al. Crit Care Med 2009; 37: 1702-7 Dowdy et al. Crit Care Med 2008; 36:2726-33 Douglas et al. J Crit Care 2010; 25: 364 Adhikari et al. Chest 2011; 140: 1484-93

16. Persecutory Delusions/PTSD Griffiths and Jones BMJ 1999; 319:427-9.

17. Post Traumatic Stress Disorder • Prevalence 21-35% • Risk factors include benzodiazepine exposure, delusional memory, female sex, younger age, physical restraint in the ICU, low serum cortisol, not receiving corticosteroids, Vent days, ICU LOS • Endogenous personality traits: pessimism Jones et al. Critical Care 2010; 14(5): R168 Myhren et al. Crit Care 2010 ;14: R14 Davydow Crit Care 2010; 14: 125 Kapfhammer et al. Am J Psychiatry 2004; 161: 45-52 Jones, Griffiths et al. Crit Care Med 2001; 29: 573-80 Stoll et al. Int Care Med 1999; 25: 697-704 Schelling et al. Crit Care Med 1998; 26: 651-9

18. Caregiver Burden CCM 2008; 36: 1722-1728 PTSD symptoms consistent with a moderate to major risk of PTSD were found in 33% of family members. Azoulay et al. AJRCCM 2005; 17: 987-994 Jones et al. Int Care Med 2004; 30: 456-460 Caregiver depression risk was 34%, 31% and 23% at 2, 6, 12 months Lifestyle disruption and employment reduction were common. Compromised HRQOL similar to caregivers of stroke/dementia Depressive symptomatology associated with depression in ARDS survivors . Van Pelt et al. AJRCCM 2007; 175: 167-173 Cameron et al. Crit Care Med 2006;34:26-33

19. Higher re-experiencing scores on PTSD measures were associated with • higher arousal ratings of negative pictures and reduced amygdala, thalamus • and globuspallidus volumes. • Chronic re-experiencing of traumatic events may result in structural changes • associated with autonomic arousal and acquisition of conditioned fear

22. Caregiving as a Risk Factor for Mortality:  The Caregiver Health Effects Study JAMA. 1999;282(23):2215-2219

23. UHN/TRI Lead Canadian Multi-Centre Interprofessional Program of Outcomes and Rehabilitation in Survivors and Family Caregivers after Critical Illness- Program initiated in 2007 • Co-Principal Investigators- Margaret Herridge MD MPH and Jill Cameron PhD

24. The RECOVER Research Program consists of Four Phases: • Phase II: RECOVER development and pilot testing • Phase III: RECOVER randomized controlled trial • Phase IV: RECOVER KT and Health Policy Change • Phase I: Towards RECOVER

26. Patient Outcomes (Quantitative) FIM Total Score 6MWT (% of predicted) Total Functional Independence Measure scores at 7-days, 3, 6, and 12-months post ICU discharge Distance walked in 6 minutes (percent of predicted values) at 7-days, 3, 6, and 12-months post ICU discharge 26

27. Patient Outcomes (Quantitative) SF-36 Physical Component Score MRC Total Score SF-36v2 Physical Component Scores at 3-months, 6-months and 12-months post ICU discharge Total MRC scores at 3-months, 6-months and 12-months post ICU discharge 27

28. Caregiver Outcomes (Quantitative) Care-giving Impact Scale Centre for Epidemiological Studies Depression Scale Centre for Epidemiological Studies Depression (CESD) at 7 day, 3-months, 6-months and 12-months post ICU discharge Care-giving impact scale at 7 day, 3-months, 6-months and 12-months post ICU discharge ≥16 considered at risk for symptoms of depression 28

37. Etiologically Neutral Clinical Phenotypes • Different clinical phenotypes for outcome and possibly muscle and nerve correlates for this • Spectrum determined by age, burden of comorbid disease, ICU LOS • Younger group- more intensive rehab, assist with return to work, children • Middle-aged group with comorbidities- Some rehab, OT, planning for ‘new normal’ • Older patients- goals of care, disposition, complex medical management, OT/social work to optimize supports

38. Challenges and Opportunities • There is a spectrum of disability across clinical phenotypes both in terms of muscle injury/atrophy/dysfunction/ other morbidities and also repair and clinical recovery • We need to understand the basic science correlates of muscle, brain and nerve injury • Different risk groups will require very different interventions and these need to be constructed and tested • The family caregiver needs support and is a key risk modifier of outcome