FRAILTY: KEYSTONE IN THE ARCH BETWEEN INTERNAL

MEDICINE AND GERIATRICS ---MOVING BEYOND

“YOU KNOW IT WHEN YOU SEE IT”

William R. Hazzard MD

January 2008

Dr. William Hazzard is the Director of Geriatrics and Extended Care for the VA Puget Sound Health Care System. He is also Professor of Medicine at the University of Washington.

He has no significant financial interest and/or relationship with the manufacturer(s) of any product(s) or provider(s) of any of the services or products that may be addressed in this educational seminar.

The Story of Life: a Postcard from 19th Century Germany

*Courtesy of Elizabeth Barrett-Connor

Icons of Gerontology and Geriatrics

The Gerontological Holy Grail:Determination of

“Physiological Age”

“How old would you be if you didn’t know how old you

were?”

Satchel Paige

Approaches to Assessmentof Frailty in our Patient

• List his diagnoses (co-morbidities)?• List his geriatric syndromes?• Begin with his functional assessment and

work backward?• Does he meet the criteria for the diagnosis of

FRAILTY? Why/why not?• For FAILURE to Thrive? Why/why not? • Does the way he is classified make an

important difference in his management? In his outcome?

FRAILTY: The new-old syndromeA Working Definition

• “A biologic syndrome of decreased reserve and resistance to stressors, resulting from cumulative declines across multiple physiologic systems and causing vulnerability to adverse outcomes” ---

Fried et al, J. Geront, 2001, 56A, M146-M156

FRAILTY: Toward a scientific definition and diagnosis

THE CARDIOVASCULAR HEALTH STUDY

(CHS)

Fried, et al, Frailty in Older Adults: Evidence for a Phenotype

2001; J. Geront. 56A, M146-156

Cardiovascular Health Study (CHS)• Population-based, prospective, community-

based observational epidemiological study • Subjects 65 yrs: Recruited from HCFA Medicare

eligibility lists– 1989-90: n = 5201 from 4 Communities – + 1992-3 cohort enriched in African-Americans– Total n = 5317, 15% African-American

• Excluded:– Institutionalized– Mentally impaired (MMSE<19)– Active cancer treatment

CHS• Baseline Evaluations

• Self-assessed/self-reported health, diagnoses, health habits

• Minnesota Leisure Time Activities• Difficulty with daily life tasks: mobility, upper

extremity function, ADL’s , and IADL’s• Falls in the past 6 months• Depression assessment (CES-D)• CVD: history, symptoms, ECG, ankle-arm Bp ratio;

carotid US• Weight; Blood pressure;• Glucose, albumin, creatinine, fibrinogen• Fasting Lipids (LDL calculated)• Cognitive function: MMSE, digit-symbol substitution• Walking Speed (15 ft)• Maximum grip strength

CHS –follow-up

• Annual examinations:– Repeat of Baseline Evaluations– Incident disease review– Hospitalizations– Falls– Disability

• Mortality: semi-annual contacts (100% complete through 8yrs)

• Frailty assessments (per definitions - see below)

– Baseline Evaluation– 3 yr. (cohort 1)– 4 yr. (cohort 2)– 7 yr. (cohort 1)

CHS: Prospective DefinitionPhenotype of Frailty syndrome

• “Shrinking”: unintentional weight loss (>10 lb past year)

• Weakness (Grip strength: lowest 20%)• Poor endurance: exhaustion (self-report)• Slowness (walking 15 ft: slowest 20%)• Low activity (Kcal/wk: lowest 20%)

FRAILTY: 3 or more criteria metPRE-FRAILTY: 1-2 criteria met

FRAILTY IN THE CHS• Baseline frailty in 6.3%:

– Age 65-70: 3.2%– Increased progressively with age: 25.9% aged 85-

89– 2-fold higher in women than men at all ages <90– 2-fold higher in African-Americans at each age– Increased (co-variable-adjusted) 3-year risk of:

• Falls (29%)• Worsening mobility (29%)• Worsening ADL disability (98%)• 1st Hospitalization (125%)• Death (124%)

FRAILTY AND SURVIVAL IN CHS

PRE-FRAILTY

• Increased risk of conversion to Frailty at 3-4 years:

– Unadjusted: 4.51x

– Co-variate-adjusted: 2.63x

FRAILTY/ DISABILITY/ CO-MORBIDITY

• What are the differences?• What are the similarities?• What are the overlapping

domains?• What are the health care

implications?

FRAILTY VS. COMORBIDITIES: Definitions 2005

• “Comorbidity: the aggregation of clinically manifest diseases present in an individual”

• “Frailty: the aggregate of subclinical losses of reserve across multiple physiologic systems”

Fried, et al, Untangling the concepts of disability, frailty, and

comorbidity …, J. Geront.2004, 59:255-263

Co-morbidity: Clinically Manifest Disease

• Present in 77% of CHS participants defined as having 2 or more of:– MI– Angina– CHF– Claudication– Arthritis– Cancer– Diabetes– Hypertension– COPD

FRAILTY/ CO-MORBIDITIES/DISABILITY

CVD Co-Morbidity and Frailty • Of the comorbidities frailty correlated most

closely with CVD, both reported and subclinical

• Most closely associated with CHF (OR 7.5)– Subclinically with

• >75% carotid stenosis (adjusted OR 3.4)• A/A index <0.8 (OR 3.17)• Major ECG abnormalities (OR 1.58)• ECG LVH (OR 1.16)• Brain infarct-like lesions on MRI (OR 1.71) Newman et al, J. Geront. 2001;56A: M158-M166

Frailty, Co-morbidities, and Disability in the CHS

• Overlapping but far from congruent: but the overlap between frailty and disability was stronger as the number of functional impairments increased

• Similarly, the overlap between frailty and co-morbidities correlated with the number of co-morbidities

• In general, multiple co-variate analysis attributed ca. half of frailty to associated baseline co-morbidities

THE PATHOGENESIS OF FRAILTY: A theoretical construct with a

gathering base in evidence

Fried and Walston, Frailty and Failure to Thrive, in Hazzard et al. (eds.), Principles of

Geriatric Medicine and Gerontology, 5th edition, 2003

Fried and Walston, Frailty and Failure to Thrive, in Principles of Geriatric Medicine and Gerontology, 2003

FRAILTY:THE CATALOGUE

What Does Aging Have to do with Frailty?

Aging & Aerobic Capacity Performance Declines with Age even in the Fittest

WHEN AGE-RELATED DECLINE BECOMES FRAILTY --- THE THRESHOLD CONSTRUCT

DECLINE + TRIGGER EVENTS + IMPAIRED RECOVERY

The 2 Main Pathways to Frailty: Diseases and Basal Dysregulation

General dysregulation

• immune

• metabolic

• neural

Disease-specific declines

FRAILTY

FRAILTY: “PRIMARY” VS. “SECONDARY”

FRAILTY: The pathogenic triad

FRAILTY: THE BIG PICTURE 2007

Can The Downward Spiral of Frailty Be Prevented?

TARGET THE TRIGGERS (one geriatrician’s favorite

mnemonic)• INFECTIONS

• INFARCTIONS

• INFRACTIONS

The Research AgendaPotential Interventions to Halt or Reverse the Catabolic Cascade

•Exercise • Pharmacological agents?

•Anabolic hormones?•Estrogens?•Androgens?

•GH/IGF?•Orexigens?

•Anti-inflammatory agents?•Other disease-modifying agents?

•Combinations of the above?

A Consensus Hypothesis: Inflammation is a Central Culprit

and a Final Common PathwayInflammation is at the center as well as on all of the arms of the complex

web of the frailty syndrome --- it often begins well before any clinical

evidence of disease and both permits and perpetuates the

process, frequently proceeding in fits and starts, in an ultimately

terminal downhill spiral

Inflammation: What are the Markers? Which are Mediators?

• IL-1beta, TNFalpha (“cachectin”), other pro-inflammatory cytokines and mediators

• IL-6 as final common mediator/marker (?) of the above (and modulated by hormones, such as testosterone and estrogen)

• Soluble cytokine receptors • Hepatic acute phase markers

– CRP -----SAA– Fibrinogen ---- Others

Frailty Vs. Failure to Thrive

• “Frailty and failure to thrive represent a continuum of a clinical syndrome, with failure to thrive being the most extreme manifestation associated with a low rate of recovery and that presages death” ---

Fried and Walston, Principles of Geriatric Medicine and Gerontology,2003

When Does Frailty Become Failure to Thrive?• “When the elderly patient … is no longer responsive

to medical and non-medical interventions” ……….• Hallmark: unexplained severe, progressive weight

loss (esp. >15%)• Multiple “geriatric” syndromes: dementia,

depression, delirium, drug reactions, major chronic diseases

• Anorexia, pain, malnutrition, falls, limited ability to undertake rehabilitation and follow medical recommendations

• Hypoalbuminemia/hypocholesterolemia/low creatinine (markers of sarcopenia and low protein stores)

HOW DOES THE PHYSICIAN IDENTIFY WHEN THE BRIDGE

BETWEEN FRAILTY AND FAILURE TO THRIVE HAS

BEEN IRREVERSIBLY CROSSED????

THE BRIDGE BETWEEN FRAILTY & FAILURE TO THRIVE (& PALLIATIVE CARE?)

• Recognition of the patient who has failure to thrive and is no longer responsive to curative/restorative care (hardest to accept in patients without cancer)

• Collaboration with other specialists and especially the patient and supporters in assuring an optimal continuum in the transition to comfort care

• Palliative care as a core competency in medicine:e.g., – Pain management– Nutrition management– Psychological and spiritual care– Advance directives– Family/caregiver support– Bereavement care

ARE “STATINS”* THE PANACEA FOR FRAILTY?

*HMG CoA reductase inhibitors?

(When will we put them in the water?)

Metabolic Path to the Pleiotropic Effects of Statins

Statins and Inflammation• Statins reduce CHD in patients at all LDL levels

(and, per British Heart Protection Study, by equivalent [%] extent)

• Statins may exert special CHD reduction in patients with activated immune systems (and elevated hsCRP levels - per Ridker)

• Statins may have anti-inflammatory effects via general effect on isoprenoids (“pleiotropism”)

• Hence statins may reduce FRAILTY via anti-inflammatory action

A Case of Frailty• 84 year-old male veteran recently moved to your area; brought by

his daughter with whom he lives• CC: weight loss of 15 lb over 6 months; lack of physical activity

and vitality • Other complaints: housebound, little interaction with family,

withdrawn, sleepless, falls, incontinent, immobile, needs help with meals, little interest in food or self care

• PH: CVA 1 year ago; 80 pack-years; remote alcoholism; CHF; Type 2 diabetes X 18 years

• Other problems:hypertension, atrial fibrillation, osteoarthritis, GERD, depression

• Meds: glyburide, thiazide, beta blocker, ACE inhibitor, omeprazole, ASA, naproxen, OTC multivitamins, melatonin, donazepil, trazodone

• Disabilities: dressing, bathing, continence, mobility, several IADLs

Examination findingsBp 145/72. Pain 7/10. Poorly nourished.Weak handshake; seems exhausted by the walk down the hall; little emotion or eye contact; bursts into tears inappropriately; dysarthic speech

Stooped, bitemporal and general muscular wasting;

Enlarged, smooth prostate

Diminished anal tone

Soft, atrophic testes

Cataracts

Homonymous hemianopsia

Cardiomegaly; irregularly irregular rhythm;

Distant breath sounds;

Bilateral knee OA

Gait slow and awkward

Affect: 12/15 on GDS

Cognition: 18/30 on MMSE

Absent pedal pulses; diminished sensation

Laboratory Values

• Hct 33; hgb 10.2• Albumin 3.2• Glucose (random) 160;

HgbA1c 7.2• Folate/B 12 normal• TSH 2.8• Creatinine: 2.2; BUN 35• CRP 5.5 • Fasting lipids:

Cholesterol 142; HDL 32; LDL 58; TG 260

• Microalbuminuria

• CXR: cardiomegaly; central congestion and cephalization

• EKG: AF;LVH, non-specific T wave changes

HAVE YOU SEEN THIS PATIENT IN YOUR CLINIC?

ON YOUR HOSPITAL SERVICE? ON YOUR TRANSITIONAL CARE

SERVICE? ON YOUR HOME CARE SERVICE?

ON YOUR LONG TERM CARE SERVICE?

ON THE PALLIATIVE CARE SERVICE?

IN HOSPICE?