Inna Sheyner MD, ABPLM, AGSF. University of South Florida School of Medicine JAHVA Hospital Geriatric and Extended Care Service Tampa, FL

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1 Inna Sheyner MD, ABPLM, AGSF University of South Florida School of Medicine JAHVA Hospital Geriatric and Extended Care Service Tampa, FL

2 I know when I see it, but what I see may not be the same as what everyone else sees

3 Frailty is a clinically recognizable state of increased vulnerability, resulting from agingassociated decline in reserve and function across multiple physiological systems such that the ability to cope with everyday or acute stressors is compromised.(1-3) Frailty is a common clinical geriatric syndrome, which carries an increased risk for poor health outcomes, incident disability, hospitalization, and mortality.

4 1. Frailty Phenotype (Freid s definition) (2) 2. Frailty Index (4) 3. FRAIL ( Fatigue, Resistance, Ambulation, Illness, Loss of weight) International Academy of Nutrition and Aging (5) 4. Frailty Instrument for Primary Care of the Survey of Health, Aging and Retirement in Europe (SHARE-FI) (6) 5. Groningen Frailty Indicator (7)

5 Frailty has been defined as a condition meeting 3 of the 5 phenotypic criteria: 1. Weakness: Grip strength lowest 20 % (by sex, BMI) 2. Slowness: Walking time /15 feet slowest 20% (by sex, height) 3. Low level of physical activity: Kcal/week- lowest 20%; males 383 Kcal/week, females 270 Kcal/week 4. Exhaustion, poor endurance: Exhaustion self report 5.Weight loss: >10 lb unintentionally in prior year

6 1. Weakness: grip strength by hand held dynamometer Men - BMI < 24 - < 29 kg - BMI <30 kg - BMI > 28 - <32 Women - BMI <23 - <17 kg - BMI < 18 kg - BMI >29 - <21 kg

7 Slowness: time to walk 15 feet Men Height <173 cm - > 7 seconds Height >173 cm - > 6 seconds Women Height < 159 cm - > 7 seconds Height >159 cm - > 6 seconds

8 Low level of physical activity Kcal/week based on the Minnesota Leisure Time Activity questionnaire (self report) Men < 383 Kcal/week Women < <270 Kcal/week Equivalent to spending most of the time sitting or rarely (less than 2 hours/week having a short walk) Kcal/week calculated by using MET (metabolic equivalent of task) Kcal/kg x h 1 MET quiet sitting ( range:0.9 MET sleeping 23 MET running at 22.5 km/h)

9 Exhaustion: self report on Center for Epidemiologic Studies Depression Scale : Answers often or most of the time 1. In the last week I felt that everything I did was an effort In the last week I could not get going

10 Nonfrail ( none of the above criteria) Prefrail ( 1 or 2 of the above criteria) Frail ( 3 5 of the above criteria)

11 Frailty Disability (measured by impairment in ADL) Comorbidity (2 or more chronic diseases)

12

13 Overlap: Frail with disability 5.7% (n=21) Frail with comorbidity 46.2% (n=170) Frail with disability and comorbidity 21.5% (n=79)(8)

14 All three conditions are predictive of adverse health outcomes, but - while many (not all) frail individuals are disables, not all disabled persons are frail - presence of two or more chronic conditions in itself may not make someone frail - when comorbid conditions worsen or more diseases are accumulated, this patients may develop frailty

15 In US overall prevalence in adults 65 in older ranges from 7% to 12%, it increases with age from 3.9% in the age group years to 25% in the age group older than 85 years (9) Prevalence of frailty higher in women than in men (8% v.5%) and higher in African Americans than in Caucasians (13%v. 6%) The overall prevalence in Europe is 17%, ranging from 5.8% in Switzerland to 27% in Spain (10)

16 Developed by Rockwood and his colleagues based on the comprehensive geriatric assessment by counting the number of deficits accumulated, including diseases, physical and cognitive impairments, psychosocial risk factors and common geriatric syndromes other than frailty (4) The total number of deficits that can be used in the FI is considered to be 80, with items being typically counted Compared to FP, FI is more sensitive to predict negative health outcomes (more finely graded risk scale), but does not distinguish frailty from disability and comorbidity (includes them in the deficits) FI makes it difficult(if not impossible) to further investigate frailty as a separate geriatric syndrome

17 Frailty is a multisystem dysregulation, leading to a loss of dynamic homeostasis, decreased physiological reserve, and increased vulnerability for subsequent morbidity and mortality. This is manifested by maladaptive response to stressors, leading to vicious cycle toward functional decline.

18 Multisystem processes: - chronic inflammation and immune activation - changes in musculoskeletal system - changes in endocrine system

19 Molecular markers: Elevated levels of: - IL-6 (proinflammatory cytokine) are directly associated with frailty (11) - C-reactive protein and TNF-a - Neopterin (molecular marker for immune activation mediated by macrophages) can be seen independently from IL-6, suggesting that immune activation can potentially be a preceding process

20 Cellular components: Increased total WBC count Increased number of CD8 T- lymphocytes

21 Clear relationship between frailty and chronic inflammation is well documented, but

22 Chronic inflammation in return contributes to frailty through its detrimental effects on other physiologic organ systems, such as musculoskeletal and endocrine systems, anemia, clinical and subclinical cardiovascular diseases and nutritional dysregulation. (12) Elevated levels of inflammatory mediators have inverse association with Hgb concentration, insulinlike growth factor (IFG-1) levels, and levels of albumin, micronutrients and vitamins. (13)

23 Chronic inflammation plays a key role in the pathogenesis of frailty directly or indirectly! But why anti-inflammatory agents ( NSAIDs, stains) have no association with reduction in frailty????

24 Musculoskeletal system - Sarcopenia is likely one of the key pathophysiologic contributor to frailty (14) - Sarcopenia is defined as the loss of muscle mass and strength, which can occur rapidly after the age of 50 years. Its causes include age-related changes in a-motor neurons, type I muscle fibers, muscular atrophy, poor nutrition, declined growth hormone production, sex-steroid levels and physical activity. - Chronic inflammation is also an important contributor to sarcopenia - Comorbidity will further exacerbate sarcopenia

25 Sex steroids and IGF-1 are essential to skeletal muscle metabolic dysregulation - age-related rapid decrease of estrogen in postmenopausal women and gradual decrease of testosterone in older men lead to decline in muscle mass and muscle strength - low levels of dehydroepiandrosterone (DHEA) and IGH-1 (signaling target of GH) are associated with frailty (15)

26 - Elevated level of cortisol (evening level and total 24-hour mean level) has been observed in frail elderly women living in the community - Vitamin D insufficiency is associated with frailty, particularly in older men

27 In summary, recent research suggest the potential role for - dysregulation of the GH IGF-1 somatotropic axis - dysregulation of the hpothalamic-pituitaryadrenal axis

28

29 Frailty assessment is a useful tool for preoperative evaluation in elderly patients wo undergo surgery. Both the FP and FI have been shown to be predictive for increased postoperative complications (18) Frailty syndrome constitutes a critical issue in geriatric oncology. Frailty assessment can help with risk stratification of older patients with cancer (19) Frailty is also useful for risk assessment in older patients with cardiovascular conditions, as it predicts increased morbidity and mortality in patients with cardiovascular disease, including CHF (20)

30 The challenge is to develop a standardized frailty definition and easy screening tool, that can be implemented in clinical practice.

31 Available screening tools: - Frailty Phenotype (2) - Frailty Index (4) - FRAIL screening tool (18) - Frailty Instrument for Primary Care of the Survey of Health, Aging and Retirement in Europe (SHARE-FI) (6) - Groningen Frailty Indicator (7)

32 1. Weakness: Grip strength measured by Jamar handheld dynamometer lowest 20 % (by sex, BMI) 2. Slowness: Walking time /15 feet slowest 20% (by sex, height) > 7 s for men 173 cm or less, woman 159 cm or less, others > 6 sec 3. Low level of physical activity: Kcal/week- lowest 20%; males 383 Kcal/week, females 270 Kcal/week basically inactive most of the time 4. Exhaustion, poor endurance: Exhaustion self report 5.Weight loss: >10 lb unintentionally in prior year or > 5% of body weight

33 Fatigue: are you fatigued? Resistance: Do you have difficulty walking one flight of steps? Aerobic: Are you unable to walk at least one block? Illness: Do you have > 5 illnesses? Loss of weight: Have you lost >5% of your weight in the last 6 month?

34 1. To prevent, delay, reverse or reduce the severity of frailty 2. To prevent or reduce adverse health outcomes in those whose frailty is not reversible

35 Once a frail, older adult is identified, potentially overlapping conditions, such as major depression, CHF, cancer) should be identified and treated first. After Frailty Syndrome is confirmed, intervention should be initiated.

36 Exercise intervention, geriatricfocused IDC management program Nursing-home eligible patients should be managed by in-patient IDC team or referred to a PACE program In the frailest patient palliative care should be implemented as soon as possible

37 To date, exercise is the interventional modality, that has most consistently shown benefit in treating frailty and its key components. (21) Nutritional intervention is another nonpharmacological modality, but RTCs of nutritional interventions remain scarce. Study done by Tieland and his colleagues assessed effect of 24 weeks of dietary protein supplementation in 65 frail patients found improvement in muscle strength and physical performance (22)

38 Tieland and colleagues explored the role of protein supplementation to augment the skeletal muscle response to resistance-type exercise training in older frail individuals. They evaluated 62 frail older subjects (mean age 78 years, FP criteria used), who participated in 2xweekx 24 weeks resistance training + 15 g x 2/day of protein supplementation v. placebo. Lean body mass increased in protein group, but not placebo group, muscle strength and physical performance improved significantly in both groups, with no added effect of dietary protein supplementation. (23)

39 Effect on frailty not adequately evaluated: - Testosterone improves muscle strength, but has significant systemic side effects - Estrogen-replacement therapy in post-menopausal women also has an unfavorable safety profile - GH supplementation has not been adequately evaluated - Anti-inflammatory agents has not been formally evaluated in clinical trials in treating frailty syndrome and also have significant adverse effects - Vitamin D and ACE-inhibitors have favorable safety profile, their clinical utility has yet to be investigated

40 The twenty first century of geriatric medicine lies ahead, and preventing and treating frailty and its dramatic consequences is crucial.

41 Define the most simple and accurate criteria to select older, community-dwelling, pre-frail elders Implement long-term, accurately powered randomized controlled interventions Choose adequate tools to accurately evaluate the most relevant and important concerns of the patients, and not only scientific measurements Use modern technology to facilitate the entire research procedure Evaluate carefully the best way of increasing the cost-effectiveness of such interventions

42 1. Freid LP, Hadley EC, Walston JD, et al. From bedside to bench:research agenda for frailty. Sci Aging Knoweledge Environ.2005; 2005(31):24 2. Freid LP, Tangen C, Walston J, et al. Frailty in older adults: evidence for a phenotype. J GerontolA Biol Sci Med Sci.2001; 56A: M1-M11 3. Bortz WM. The physics of Frailty.J Am Geriatr Soc. 1993;41: Jones DM, Song X, Rockwood K. Operationalizing a frailty index from a standardized comprehensive geriatric assessment. J Am Geriatr Soc. 2004; 52: Abellan van KG, Rolland Y, Bergman H et al. Task Force on frailty assessment of older people in clinical practice. J Nutr Health Aging.2008; 12: Romero-Ortuno R, Walsh CD, Lawlor BA, Kenny RA. A frailty instrument for primary care: findings from the Survey of Health, Aging and Retirement in Europe (SHARE). BMC Geriatr.2010; 10:57

43 7. Peters LL, Boter H, Buskens E, Slaets JP. Measurement properties of the Groningen Frailty Indicator in home-dwelling and institutionalized elderly people. J Am Med Dir Assoc. 2012; 13: Freid LP, Borhani NO. Enright P, et al. The cardiovascular Health Study: design and rationale. Ann Epidemiol : Bandeen-Roche K, Xue QL, FerucciL, et al. Phenotype of frailty: characterization in the women s health and aging studies. J Gerontol A Biol Sci Med Sci.2006; 61: Santos-Eggiman B, Cuenoud P, Spagnoli J. Prevalence of frailty in middle-aged and older community-dwelling Europeans living in 10 countries. J Gerontol A Biol Sci Med Sci. 2009; 64: Leng S, Chaves P, Koenig K, Walston J. Serum interleukin -6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J Am Geriatr Soc 2002; 50: Dreid LP, Xue QL, Cappola AR, et al. Nonlinear multisystem physiological dysregulation associated with frailty in older women: implication for etiology and treatment. J Gerontol A Biol Sci Med Sci. 2009; 64:

44 13. HubbardRE, O Mahony MS, Savva GM, Calver BL,et al. Inflammation and frailty measures in older people. J Cell Mol Med. 2009; 13: Liu LK, Lee J, Liu CL, et al. Age-related skeletal muscle mass loss and physical performance in Taiwan: implications to diagnostic strategy of sarcopenia in Asia. Geriatr Gerontol Int. 2013; 13: Puts MT, Visser M, Twisk JW, et al. Endocrine and inflammatory markers as predictors of frailty. Clin Endocrinol (Oxf) 2005; 63: Shardell M, Hicks GE, Miller RR, et al. Association of low vitamin D level with the frailty syndrome in men and women. J Gerontol A Biol Sci Med Sci.2009; 64: Rolfson DB, Majumdar SR, Tsuyuki RT, et al. Validity and reliability of the Edmonton Frail Scale. Age Ageing 2006; 35: Makary MA, Segev DL, Pronovost PJ, et al. Frailty as a predictor of surgical outcomes in older patients. J Am Coll Surg.2010; 210:

45 19. Hamaker ME, Jonker JM, de Rooij SE, Vos AG, Smorenburg CH, van Munster BC. Frailty screening methods for predicting outcome of a comprehensive geriatric assessment in elderly patients with cancer: a systematic review. Lancet Oncol.2012; 13:c437-c AfilaloJ, Karunananthan S, Eisenberg MJ, et al. Role of frailty in patients with cardiovascular disease. Am J Cardiol. 2009; 103: Theou O. Stathokostas L, Roland KP, et al. The effectiveness of exercise interventions for management of frailty: a systematic review. J Aging re. 2011; 2011: Tieland M, Borgonjen-Van den Berg KJ, van Loon LJ, et al.dietary protein intake in community-dwelling, frail, and institutionalized elderly people: scope for improvement. Eur J Nutr 2012; 51: Tieland M, Dirks ML, van der Zwaluw et al. Protein supplemention increased muscle mass gain during prolonged resistance-type exercise training in frail elderly people: a randomized, double-blind, placebo controlled trial. J Am med Dir Association 2012;13:

* I know when I see it, but what I see may not be the same as what everyone else sees

* I know when I see it, but what I see may not be the same as what everyone else sees Inna Sheyner MD, ABPLM, AGSF University of South Florida School of Medicine JAHVA Hospital Geriatric and Extended Care Service Tampa, FL I know when I see it, but what I see may not be the same as what

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