Natural history of frailty
The cycle concept raises the question as to whether an individual can enter at any point, or if there is an ordered pattern of development of signs and symptoms. Longitudinal studies indicate some hierarchical order despite heterogeneity in initial symptoms.[20] Different patterns may represent different causative pathways linked to specific systemic physiologic dysregulation. Elucidating the common patterns of clinical onset might lead to early identification and intervention.
Transitions across frailty stages (e.g., non-frail, pre-frail, frail) are of clinical and research interest. In a longitudinal study of community-living older adults,[21] more than half had at least one transition, and nearly a quarter had two transitions, although regression from frail to non-frail was extremely unlikely.
Immune system
Abnormal inflammation appears to have a major role in the development of frailty, and an accumulation of pro-inflammatory responses is one of the fundamental findings in frailty syndrome.[22] These responses are unlike typical acute inflammatory responses; rather, they are characterized by high levels of pro-inflammatory cytokines.[23] An expanding number of pro-inflammatory cytokines has been independently associated with the frailty syndrome, including interleukin 6,[24] C-reactive protein (CRP), and tumor necrosis factor-alpha (TNFα). Since inflammation is associated with catabolism of skeletal muscle and adiposity and shares several core features of frailty – such as malnutrition, anorexia, sarcopenia, weight loss, and cognitive changes – assigning inflammation a major causative role in frailty is very attractive. However, the elevation of pro-inflammatory cytokines as a root cause is not well understood. Additionally, there is an association between frailty and several clotting markers (factor VIII, fibrinogen, and D-dimer) as well as evidence that immune system activation may generate the clotting cascade. Lastly, white blood cell and monocyte counts are elevated in frail older adults living in the community, which provides further evidence for immune activation.[25]
Abnormal inflammation appears to have a major role in the development of frailty.
Endocrine pathways
Aging is associated with changes in the hypothalamo-pituitary axis, which have an impact on metabolism and energy through several hormones. There is a decrease in growth hormone synthesis, which results in a reduction in insulin-like growth factor-1 (IGF-1). IGF-1 is involved in anabolic activity, specifically skeletal muscle strength. There are reductions in estradiol and testosterone secretion, reduction in the activity of adrenocortical cells that produce the sex steroid precursors such as adrenal dehydroepiandrosterone sulfate (DHEA-S), and a slow rise in cortisol levels. The impact of these changes in IGF-1, sex hormones, steroid precursors, and cortisol secretion, and their association with frailty are not well understood. Although levels of IGF-1 are significantly lower in frail than non-frail older women,[26] trials of IGF-1 supplementation in older adults have not shown benefit. There is mixed evidence that lower levels of reproductive hormones are linked to frailty.[27, 28] Similarly, the link between frailty and elevated cortisol concentrations that was demonstrated in one cross-sectional study is under investigation.[29, 30]
Musculoskeletal system
Sarcopenia, the progressive and generalized age-related loss of skeletal muscle mass and either low muscle strength and/or low physical performance, is an important physiologic contributor to frailty.[31, 32] It begins between the ages of 20 and 30, accelerates after age 50, and is a major cause of disability, poor quality of life, and death. Skeletal muscle mass measurements alone do not capture functionality, and thus do not define sarcopenia. The societal and economic costs of sarcopenia are significant. Direct health-care costs due to the associated physical disability were estimated to be approximately $18.5 billion in 2000 in the United States, and is expected to rise with our aging population.[B]
With aging, there is a delicate balance between muscle formation and loss coordinated by hormonal and immune systems, the brain, nutritional factors, and physical activity.[29] Usual age-related musculoskeletal changes include declines in skeletal muscle fibers, satellite cells, and neuromuscular junctions; infiltration by fibrous and adipose tissue, and an increase in apoptosis. There is evidence for alterations in mitochondrial function and the renin-angiotensin axis affecting muscle quality. The physiologic changes in frailty, including inflammatory cytokines and lower levels of growth hormone and sex steroids, and higher levels of cortisol, accelerate the decline in muscle mass and strength. With sarcopenic obesity, fatty infiltration is associated with lower muscle quality, a hyper-inflammatory state, and an accelerated loss of lean body mass, despite a high body mass index.
Clinical applications
Clinicians encounter frail individuals in a wide variety of stages and settings. Some may be able to recover after a stressful event, and others may never regain full function. An older patient may appear vigorous yet be unable to tolerate the stress of elective surgery. An individual at home may experience an apparent minor insult, such as a mild infection or a new medication, and decline rapidly, quickly transitioning from independent to dependent, from ambulatory to immobile.
The inaccurate identification of a patient as frail may limit appropriate interventions, resulting in denial of elective surgery, or may, alternatively, expose an unrecognized frail patient to unrealistic and invasive interventions that are not aligned with the patient’s and/or family’s goals, preferences, or values. Especially in the early stages, frailty is often overlooked. Thus a systematic approach to frailty assessment is recommended.
Recognition of frailty is important to guide clinical care and decision making.
Clinical settings
Frailty is recognized as an important syndrome to guide clinical care and decision making. Screening is recommended by the American College of Surgeons, as frailty independently predicts postoperative complications, length of stay, and need for transition to a skilled or assisted living facility in older adults undergoing surgery.[33] A comprehensive frailty score has been shown to be more predictive for adverse postoperative outcomes in older surgical patients than traditional assessment tools.[C] For geriatric trauma patients, the Frailty Index has been shown to be an independent predictor of in-hospital complications and adverse discharge disposition, and superior to age for clinical risk stratification.[D]
Frailty risk assessment is important in caring for older patients with cardiovascular conditions; it predicts increased morbidity and mortality.[19] It can help in risk stratification for older adults with cancer. Frail patients may fail to launch an adequate immune response to the influenza and pneumococcal vaccines.[34, 35] As more conditions are studied, the expectation is that frailty will emerge as a core measure for risk assessment.
Common related signs and symptoms
Weakness is a frequent complaint among older adults and a common symptom of frailty. It is strongly associated with impaired function and disability as well as increased risk for future mobility disability. Studies into the relationships among weakness, muscle mass, muscle quality, muscle strength, and function have demonstrated that although low muscle mass is associated with weakness, low muscle mass alone is poorly or not associated with impaired function and disability. Dynopenia refers to muscle weakness, emphasizing the difference between low muscle mass and impaired performance. A recent national consensus project proposed screening based on mobility performance (e.g., gait speed), strength testing (e.g., grip strength), and adjusted body composition assessment to guide research to identify individuals who will benefit from interventions.[36] Most frail people suffer from sarcopenia.
Other syndromes, such as cachexia, are associated with prominent muscle wasting and may be confused with sarcopenia. Cachexia is a severe wasting condition accompanying disease states such as cancer or end-stage renal disease, and is characterized by loss of muscle with or without loss of fat mass. It is frequently associated with inflammation and anorexia and breakdown of muscles. It is distinct from starvation, malabsorption, and age-related loss of muscle mass. Most sarcopenic individuals are not cachectic.
Malnutrition occurs in approximately 5% of older community dwellers, 35% of hospitalized older adults, and ~50% of patients in rehabilitation settings. It implies a mechanism of protein-energy status imbalance, does not imply wasting, and should be applied to conditions that clearly respond to feeding. The nutritional needs of older adults are determined by multiple factors – including specific acute or chronic medical problems; their activity level, energy expenditures, and caloric needs; and their ability to access, prepare, and digest food – and criteria have been established to diagnose malnutrition.[37, 38] Additionally, the six-question Mini-Nutritional Assessment – Short Form (MNA-SF) is easy to administer, validated with high sensitivity and specificity, and predictive of poor outcomes.
Older individuals are at greater risk for undernutrition and involuntary weight loss than younger adults. Older adults are less able to adapt to periods of low food intake that may occur due to illness or other medical, psychological, or socioeconomic conditions. Clinically important weight loss is the loss of 4%–5% of total body weight over 6–12 months, though recommendations vary depending upon the amount of weight lost and the period of time involved. The recommended clinical approach to weight loss is beyond the scope of this review.
Interventions
Goals for interventions include reduced prevalence and severity of frailty, and improved clinical outcomes aligned with patient and family goals of care. Currently there are no available curative treatments for frailty.
Physical activity: aerobic and resistance exercise
Exercise is currently the most effective intervention to improve function and quality of life among frail elders. The many demonstrated benefits of exercise in older adults include increased muscle strength, decreased falls, enhanced gait and mobility, reduced inflammation, enhanced cognition, and improved well-being. Several studies have demonstrated that even the frailest adults can benefit from physical activity that includes resistance training and aerobic activity.[39–41] Obese frail elders also benefit from a weight loss and exercise. A randomized clinical trial comparing the independent and combined effects of weight loss and exercise demonstrated that a combination program resulted in the greatest improvement in physical function.[A]
Exercise is currently the most effective intervention to improve function and quality of life among frail elders.
The Health, Aging, and Body Composition observational study demonstrated that participation in self-selected exercise could both prevent the onset of frailty and delay the progression of frailty.[42] A randomized clinical trial of a home-based physical activity program for frail elders reduced the progression of functional decline among those with moderate frailty, but not those with severe frailty.[43] A systematic review demonstrated that long-term multicomponent exercise interventions performed several times per week for 30–45 minutes may be helpful for the management of frail elders.[40] There is growing evidence that frail adults in a wide variety of settings can improve their functional performance, activity of living performance, and quality of life by regular exercise training, but more high-quality trials are still needed.
Nutritional intervention
Despite the belief that the core components of frailty, including weight loss and weakness, would be amenable to nutritional interventions, evidence supporting the efficacy of this approach is scarce. According to a Cochrane review, nutritional supplementation with extra protein and energy produced a small but consistent weight gain in older people, and a small reduction in mortality for undernourished elders, but yielded no improvement in function.[44] Although there is some indication that high protein supplements produce clinical benefits to counteract the catabolic effects of disease and recovery from illness, strong evidence for its use in frail elders has not been demonstrated.[45] For frail elders, facilitating access to food, optimizing food preparation, and encouraging socialization at meals can be helpful in improving nutritional status. Appetite stimulants and micronutrient supplements are not currently recommended.
Hormonal intervention
Various hormonal therapies have been proposed, but the benefits and risks are currently unknown. Testosterone improves muscle mass by increasing protein synthesis and muscle strength, and although there may be a role for low dose testosterone in combination with nutritional supplementation in frail older men who are hypogonadal, testosterone therapy brings significant systemic side effects and is not recommended.[46]
Vitamin D prescription for elderly people who are deficient might reduce the number of falls. Vitamin D supplements along with calcium can improve muscle strength and balance.[47] Despite the evidence that low vitamin D levels are strongly associated with frailty,[48] the benefits of vitamin D to treat frailty in nondeficient elders have not been demonstrated.[2] Further studies are indicated.
Growth hormone therapy results in an increase in muscle mass in normal elderly, but there is no increase in strength unless exercise is also added to the intervention. Since there is no demonstrated clinical benefit, and the short- and long-term safety is not known, supplementation is not recommended.[49]
Other pharmacological approaches
Polypharmacy contributes to frailty, and avoidance of inappropriate medications is highly recommended. Several guidelines are helpful in reducing unnecessary or potentially harmful medications in this vulnerable group.[50] Other areas of investigation include angiotensin-converting enzyme inhibitors because of their impact on the structure and function of skeletal muscle.[51] The use of systemic anti-inflammatory agents, although not formally evaluated in frail elders, carries significant adverse effects.[4]
Comprehensive geriatric evaluation and specialized clinical programs
Comprehensive geriatric evaluation by a skilled interprofessional team is commonly considered to be the gold standard for developing and implementing a plan of care that is consistent with the patient’s goals, values, and preferences. A targeted approach to prevent the range of biological, socioeconomic, and environmental stressors to improve clinical outcomes is appealing. However, the evidence for improved outcomes, especially among frail elders, is still emerging.
Interprofessional clinical programs targeted to the frail elderly have been shown to improve clinical outcomes in a variety of settings.
Clinical programs targeted to the frail elderly have been shown to improve clinical outcomes in a variety of settings.[29] Frail patients cared for in specialized inpatient units are more likely to return to their homes, are less likely to suffer functional or cognitive decline, and have lower mortality rates than usual ward care.[52] A recent small study examined the impact of frailty on rehabilitation outcomes in a geriatric evaluation and management unit, and although all patients experienced functional improvement, the frailest patients experienced greater improvement than those who were less frail.[53] The results of community-based care demonstrate mixed results, indicating the complexity of the task and the need for more research.[52]
Conclusion
Frailty is an important geriatric syndrome associated with high morbidity and mortality. The prevention, early diagnosis, and management across the spectrum of frailty represent crucial areas in the clinical care of older adults. Early risk assessment, implementation of exercise programs, and access to geriatric interprofessional assessment and management represent the most effective ways to improve health outcomes. However, more research is needed. An understanding of the underlying mechanisms of frailty at the level of molecules, cells, and tissues may open the door to pharmacologic prevention and treatment strategies.[23] Objective, easily administered assessment tools, including biomarkers and biosensors, are sorely needed. High-value team-based models of care linked with community resources are required for this rapidly growing, vulnerable population.
References
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