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InternalMed_Harrison. even close family members, cannot accurately predict what the patient would have wanted. Therefore, substituted judgment becomes more of a guessing game than a way of fulfilling the patient’s wishes. Finally, the best-interests criterion holds that proxies should evaluate treatments by balancing their benefits and risks and select those treatments in which the benefits maximally outweigh the burdens of treatment. Clinicians have a clear and crucial role in this by carefully and dispassionately explaining the known benefits and burdens of specific treatments. Yet even when that information is as clear as possible, different individuals can have very different views of what is in the patient’s best interests, and families may have disagreements or even overt conflicts. This criterion has been criticized because there is no single way to determine the balance between benefits and burdens; it depends on a patient’s personal values. For instance, for some people, being alive even if


InternalMed_Harrison

InternalMed_Harrison. has been criticized because there is no single way to determine the balance between benefits and burdens; it depends on a patient’s personal values. For instance, for some people, being alive even if mentally incapacitated is a benefit, whereas for others, it may be the worst possible existence. As a matter of practice, physicians rely on family members to make decisions that they feel are best and object only if those decisions seem to demand treatments that the physicians consider not beneficial.


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InternalMed_Harrison. practIces Withholding and withdrawing acutely life-sustaining medical interventions from terminally ill patients are now standard practice. More than 90% of American patients die without cardiopulmonary resuscitation (CPR), and just as many forgo other potentially life-sustaining interventions. For instance, in ICUs in the period 1987–1988, CPR was performed 49% of the time, but it was performed only 10% of the time in 1992–1993. On average, 3.8 interventions, such as vasopressors and transfusions, were stopped for each dying ICU patient. However, up to 19% of decedents in hospitals received interventions such as extubation, ventilation, and surgery in the 48 h preceding death. However, practices vary widely among hospitals and ICUs, suggesting an important element of physician preferences rather than objective data.


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InternalMed_Harrison. Mechanical ventilation may be the most challenging intervention to withdraw. The two approaches are terminal extubation, which is the removal of the endotracheal tube, and terminal weaning, which is the gradual reduction of the or ventilator rate. One-third of ICU physicians prefer to use the terminal weaning technique, and 13% extubate; the majority of physicians use both techniques. The American Thoracic Society’s 2008 clinical policy guidelines note that there is no single correct process of ventilator withdrawal and that physicians use and should be proficient in both methods but that the chosen approach should carefully balance benefits and burdens as well as patient and caregiver preferences. Physicians’ assessment of patients’ likelihood of survival, their prediction of possible cognitive damage, and patients’ preferences about the use of life support are primary factors in determining the likelihood of withdrawal of mechanical ventilation. Some recommend terminal weaning


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InternalMed_Harrison. cognitive damage, and patients’ preferences about the use of life support are primary factors in determining the likelihood of withdrawal of mechanical ventilation. Some recommend terminal weaning because patients do not develop upper airway obstruction and the distress caused by secretions or stridor; however, terminal weaning can prolong the dying process and not allow a patient’s family to be with him or her unencumbered by an endotracheal tube. To ensure comfort for conscious or semiconscious patients before withdrawal of the ventilator, neuromuscular blocking agents should be terminated and sedatives and analgesics administered. Removing the neuromuscular blocking agents permits patients to show discomfort, facilitating the titration of sedatives and analgesics; it also permits interactions between patients and their families. A common practice is to inject a bolus of midazolam (2–4 mg) or lorazepam (2–4 mg) before withdrawal, followed by 5–10 mg of morphine and continuous


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InternalMed_Harrison. interactions between patients and their families. A common practice is to inject a bolus of midazolam (2–4 mg) or lorazepam (2–4 mg) before withdrawal, followed by 5–10 mg of morphine and continuous infusion of morphine (50% of the bolus dose per hour) during weaning. In patients who have significant upper airway secretions, IV scopolamine at a rate of 100 μg/h can be administered. Additional boluses of morphine or increases in the infusion rate should be administered for respiratory distress or signs of pain. Higher doses will be needed for patients already receiving sedatives and opioids. Families need to be reassured about treatments for common symptoms after withdrawal of ventilatory support, such as dyspnea and agitation, and warned about the uncertainty of length of survival after withdrawal of ventilatory support: up to 10% of patients unexpectedly survive for 1 day or more after mechanical ventilation is stopped.


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InternalMed_Harrison. Beginning in the late 1980s, some commentators argued that physicians could terminate futile treatments demanded by the families of terminally ill patients. Although no objective definition or standard of futility exists, several categories have been proposed. Physiologic futility means that an intervention will have no physiologic effect. Some have defined qualitative futility as applying to procedures that “fail to end a patient’s total dependence on intensive medical care.” Quantitative futility occurs “when physicians conclude (through personal experience, experiences shared with colleagues, or consideration of reported empiric data) that in the last 100 cases, a medical treatment has been useless.” The term conceals subjective value judgments about when a treatment is “not beneficial.” Deciding whether a treatment that obtains an additional 6 weeks of life or a 1% survival advantage confers benefit depends on patients’ preferences and goals. Furthermore, physicians’ predictions


InternalMed_Harrison

InternalMed_Harrison. Deciding whether a treatment that obtains an additional 6 weeks of life or a 1% survival advantage confers benefit depends on patients’ preferences and goals. Furthermore, physicians’ predictions of when treatments were futile deviated markedly from the quantitative definition. When residents thought CPR was quantitatively futile, more than one in five patients had a >10% chance of survival to hospital discharge. Most studies that purport to guide determinations of futility are based on insufficient data to provide statistical confidence for clinical decision making. Quantitative futility rarely applies in ICU settings. Many commentators reject using futility as a criterion for withdrawing care, preferring instead to consider futility situations as ones that represent conflict that calls for careful negotiation between families and health care providers.


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InternalMed_Harrison. In the wake of a lack of consensus over quantitative measures of futility, many hospitals adopted process-based approaches to resolve disputes over futility and enhance communication with patients and surrogates, including focusing on interests and alternatives rather than opposing positions and generating a wide range of options. Some hospitals have enacted “unilateral do not resuscitate (DNR)” policies to allow clinicians to provide a DNR order in cases in which consensus cannot be reached with families and medical opinion is that resuscitation would be futile if attempted. This type of a policy is not a replacement for careful and patient communication and negotiation but recognizes that agreement cannot always be reached. Over the last 15 years, many states, such as Texas, Virginia, Maryland, and California, have enacted so-called medical futility laws that provide physicians a “safe harbor” from liability if they refuse a patient or family’s request for life-sustaining


InternalMed_Harrison

InternalMed_Harrison. Maryland, and California, have enacted so-called medical futility laws that provide physicians a “safe harbor” from liability if they refuse a patient or family’s request for life-sustaining interventions. For instance, in Texas when a disagreement about terminating interventions between the medical team and the family has not been resolved by an ethics consultation, the hospital is supposed to try to facilitate transfer of the patient to an institution willing to provide treatment. If this fails after 10 days, the hospital and physician may unilaterally withdraw treatments determined to be futile. The family may appeal to a state court. Early data suggest that the law increases futility consultations for the ethics committee and that although most families concur with withdrawal, about 10–15% of families refuse to withdraw treatment. Approximately 12 cases have gone to court in Texas in the 7 years since the adoption of the law. As of 2007, there had been 974 ethics committee


InternalMed_Harrison

InternalMed_Harrison. about 10–15% of families refuse to withdraw treatment. Approximately 12 cases have gone to court in Texas in the 7 years since the adoption of the law. As of 2007, there had been 974 ethics committee consultations on medical futility cases and 65 in which committees ruled against families and gave notice that treatment would be terminated. Treatment was withdrawn for 27 of those patients, and the remainder were transferred to other facilities or died while awaiting transfer.


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InternalMed_Harrison. Euthanasia and physician-assisted suicide are defined in Table 10-8. Terminating life-sustaining care and providing opioid medications to manage symptoms have long been considered ethical by the medical profession and legal by courts and should not be confused with euthanasia or physician-assisted suicide.


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InternalMed_Harrison. legal aspects Euthanasia is legal in the Netherlands, Belgium, and Luxembourg. It was legalized in the Northern Territory of Australia in 1995, but that legislation was repealed in 1997. Euthanasia is not legal in any state in the United States. With certain conditions, in Switzerland, a layperson can legally assist suicide. In the United States, physician-assisted suicide is legal in four states: Oregon, Vermont, and Washington State by legislation and Montana by court ruling. In jurisdictions where physician-assisted suicide is legal, physicians wishing to prescribe the necessary medication must fulfill multiple criteria and complete processes that include a waiting period. In other countries and all other states in the United States, physician-assisted suicide and euthanasia are illegal explicitly or by common law.


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InternalMed_Harrison. practIces Fewer than 10–20% of terminally ill patients actually consider euthanasia and/or physician-assisted suicide for themselves. In the Netherlands and Oregon, >70% of patients using these interventions are dying of cancer; in Oregon, in 2013, just 1.2% of physician-assisted suicide cases involved patients with HIV/AIDS and 7.2% involved patients with amyotrophic lateral sclerosis. In the Netherlands, the share of deaths attributable to euthanasia or physician-assisted suicide declined from around 2.8% of all deaths in 2001 to around 1.8% in 2005. In 2013, the last year with complete data, around 71 patients in Oregon (just 0.2% of all deaths) died by physician-assisted suicide, although this may be an underestimate. In Washington State, between March 2009 (when the law allowing physician-assisted suicide went into force) and December 2009, 36 individuals died from prescribed lethal doses.


InternalMed_Harrison

InternalMed_Harrison. Pain is not a primary motivator for patients’ requests for or interest in euthanasia and/or physician-assisted suicide. Fewer than 25% of all patients in Oregon cite inadequate pain control as the reason for desiring physician-assisted suicide. Depression, hopelessness, and, more profoundly, concerns about loss of dignity or autonomy or being a burden on family members appear to be primary factors motivating a desire for euthanasia or physician-assisted suicide. Over 75% cite loss of autonomy or dignity and inability to engage in enjoyable activities as the reason for wanting physician-assisted suicide. About 40% cite being a burden on family. A study from the Netherlands showed that depressed terminally ill cancer patients were four times more likely


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InternalMed_Harrison. Voluntary active Intentionally administering medica-Netherlands, euthanasia tions or other interventions to cause Belgium the patient’s death with the patient’s informed consent euthanasia tions or other interventions to cause the patient’s death when the patient was competent to consent but did not—e.g., the patient may not have been asked Passive euthanasia Withholding or withdrawing life-Everywhere sustaining medical treatments from a patient to let him or her die (terminating life-sustaining treatments)


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InternalMed_Harrison. Passive euthanasia Withholding or withdrawing life-Everywhere sustaining medical treatments from a patient to let him or her die (terminating life-sustaining treatments) Physician-assisted A physician provides medications or Oregon, suicide other interventions to a patient with Netherlands, the understanding that the patient Belgium, can use them to commit suicide Switzerland to request euthanasia and confirmed that uncontrolled pain was not associated with greater interest in euthanasia. Interestingly, despite the importance of emotional distress in motivating requests for euthanasia and physician-assisted suicide, few patients receive psychiatric care. For instance, in Oregon, only 5.9% of patients have been referred for psychiatric evaluation.


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InternalMed_Harrison. Euthanasia and physician-assisted suicide are no guarantee of a painless, quick death. Data from the Netherlands indicate that in as many as 20% of cases technical and other problems arose, including patients waking from coma, not becoming comatose, regurgitating medications, and experiencing a prolonged time to death. Data from Oregon indicate that between 1997 and 2013, 22 patients (~5%) regurgitated after taking prescribed medication, 1 patient awaked, and none experienced seizures. Problems were significantly more common in physician-assisted suicide, sometimes requiring the physician to intervene and provide euthanasia.


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InternalMed_Harrison. Whether practicing in a setting where euthanasia is legal or not, over a career, 12–54% of physicians receive a request for euthanasia or physician-assisted suicide from a patient. Competency in dealing with such a request is crucial. Although challenging, the request can also provide a chance to address intense suffering. After receiving a request for euthanasia and/or physician-assisted suicide, health care providers should carefully clarify the request with empathic, open-ended questions to help elucidate the underlying cause for the request, such as “What makes you want to consider this option?” Endorsing either moral opposition or moral support for the act tends to be counterproductive, giving an impression of being judgmental or of endorsing the idea that the patient’s life is worthless. Health care providers must reassure the patient of continued care and commitment. The patient should be educated about alternative, less controversial options, such as symptom management and


InternalMed_Harrison

InternalMed_Harrison. Health care providers must reassure the patient of continued care and commitment. The patient should be educated about alternative, less controversial options, such as symptom management and withdrawing any unwanted treatments and the reality of euthanasia and/or physician-assisted suicide, because the patient may have misconceptions about their effectiveness as well as the legal implications of the choice. Depression, hopelessness, and other symptoms of psychological distress as well as physical suffering and economic burdens are likely factors motivating the request, and such factors should be assessed and treated aggressively. After these interventions and clarification of options, most patients proceed with another approach, declining life-sustaining interventions, possibly including refusal of nutrition and hydration.


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InternalMed_Harrison. Most laypersons have limited experiences with the actual dying process and death. They frequently do not know what to expect of the final hours and afterward. The family and other caregivers must be prepared, especially if the plan is for the patient to die at home.


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InternalMed_Harrison. Patients in the last days of life typically experience extreme weakness and fatigue and become bedbound; this can lead to pressure sores. The issue of turning patients who are near the end of life, however, must be balanced against the potential discomfort that movement may cause. Patients stop eating and drinking with drying of mucosal membranes and dysphagia. Careful attention to oral swabbing, lubricants for lips, and use of artificial tears can provide a form of care to substitute for attempts at feeding the patient. With loss of the gag reflex and dysphagia, patients may also experience accumulation of oral secretions, producing noises during respiration sometimes called “the death rattle.” Scopolamine can reduce the secretions. Patients also experience changes in respiration with periods of apnea or Cheyne-Stokes breathing. Decreased intravascular volume and cardiac output cause tachycardia, hypotension, peripheral coolness, and livedo reticularis (skin mottling). Patients can


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InternalMed_Harrison. of apnea or Cheyne-Stokes breathing. Decreased intravascular volume and cardiac output cause tachycardia, hypotension, peripheral coolness, and livedo reticularis (skin mottling). Patients can have urinary and, less frequently, fecal incontinence. Changes in consciousness and neurologic function generally lead to two different paths to death (Fig. 10-2).


InternalMed_Harrison

InternalMed_Harrison. Each of these terminal changes can cause patients and families distress, requiring reassurance and targeted interventions (Table 10-9). Informing families that these changes might occur and providing them with an information sheet can help preempt problems and minimize distress. Understanding that patients stop eating because they are dying, not dying because they have stopped eating, can reduce family FIgURE 10-2 Common and uncommon clinical courses in the last days of terminally ill patients. (Adapted from FD Ferris et al: Module 4: Palliative care, in Comprehensive Guide for the Care of Persons with HIV Disease. Toronto: Mt. Sinai Hospital and Casey Hospice, 1995, http://www .cpsonline.info/content/resources/hivmodule/module4complete.pdf.) and caregiver anxiety. Similarly, informing the family and caregivers that the “death rattle” may occur and that it is not indicative of suffocation, choking, or pain can reduce their worry from the breathing sounds.


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InternalMed_Harrison. Families and caregivers may also feel guilty about stopping treatments, fearing that they are “killing” the patient. This may lead to demands for interventions, such as feeding tubes, that may be ineffective. In such cases, the physician should remind the family and caregivers about the inevitability of events and the palliative goals. Interventions may prolong the dying process and cause discomfort. Physicians also should emphasize that withholding treatments is both legal and ethical and that the family members are not the cause of the patient’s death. This reassurance may have to be provided multiple times.


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InternalMed_Harrison. Hearing and touch are said to be the last senses to stop functioning. Whether this is the case or not, families and caregivers can be encouraged to communicate with the dying patient. Encouraging them to talk directly to the patient, even if he or she is unconscious, and hold the patient’s hand or demonstrate affection in other ways can be an effective way to channel their urge “to do something” for the patient. When the plan is for the patient to die at home, the physician must inform the family and caregivers how to determine that the patient has died. The cardinal signs are cessation of cardiac function and respiration; the pupils become fixed; the body becomes cool; muscles relax; and incontinence may occur. Remind the family and caregivers that the eyes may remain open even after the patient has died because Changes in the Profound fatigue Bedbound with development of pressure ulcers that are prone to infection, malodor, and pain, and joint pain


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InternalMed_Harrison. Changes in the Profound fatigue Bedbound with development of pressure ulcers that are prone to infection, malodor, and pain, and joint pain Dysphagia Inability to swallow oral medications needed for palliative care Apnea, Cheyne-Stokes respirations, dyspnea Potential transmission of infectious agents to caregivers Dry mucosal Cracked lips, mouth sores, membranes and candidiasis can also cause pain. Patient is lazy and giving up. Patient is giving up; patient will suffer from hunger and will starve to death. Patient will suffer from thirst and die of dehydration. Patient is choking and suffocating. Patient is suffocating. Patient is dirty, malodorous, and physically repellent. Patient is in horrible pain and going to have a horrible death. Patient may be malodorous or physically repellent. Reassure family and caregivers that terminal fatigue will not respond to interventions and should not be resisted. Use an air mattress if necessary.


InternalMed_Harrison

InternalMed_Harrison. Reassure family and caregivers that terminal fatigue will not respond to interventions and should not be resisted. Use an air mattress if necessary. Reassure family and caregivers that the patient is not eating because he or she is dying; not eating at the end of life does not cause suffering or death. Forced feeding, whether oral, parenteral, or enteral, does not reduce symptoms or prolong life. Reassure family and caregivers that dehydration at the end of life does not cause suffering because patients lose consciousness before any symptom distress. Intravenous hydration can worsen symptoms of dyspnea by pulmonary edema and peripheral edema as well as prolong dying process.


InternalMed_Harrison

InternalMed_Harrison. Intravenous hydration can worsen symptoms of dyspnea by pulmonary edema and peripheral edema as well as prolong dying process. Do not force oral intake. Discontinue unnecessary medications that may have been continued, including antibiotics, diuretics, antidepressants, and laxatives. If swallowing pills is difficult, convert essential medications (analgesics, antiemetics, anxiolytics, and psychotropics) to oral solutions, buccal, sublingual, or rectal administration. Reassure the family and caregivers that this is caused by secretions in the oropharynx and the patient is not choking. Reduce secretions with scopolamine (0.2–0.4 mg SC q4h or 1–3 patches q3d). Reposition patient to permit drainage of secretions. Do not suction. Suction can cause patient and family discomfort and is usually ineffective. Reassure family and caregivers that unconscious patients do not experience suffocation or air hunger. Apneic episodes are frequently a premorbid change.


InternalMed_Harrison

InternalMed_Harrison. Reassure family and caregivers that unconscious patients do not experience suffocation or air hunger. Apneic episodes are frequently a premorbid change. Opioids or anxiolytics may be used for dyspnea. Oxygen is unlikely to relieve dyspneic symptoms and may prolong the dying process. Remind family and caregivers to use universal precautions. Frequent changes of bedclothes and bedding. Use diapers, urinary catheter, or rectal tube if diarrhea or high urine output. not necessarily connote physical pain. Depending on the prognosis and goals of treatment, consider evaluating for causes of delirium and modify medications. Manage symptoms with haloperidol, chlorpromazine, diazepam, or midazolam. Use baking soda mouthwash or saliva preparation q15–30min. Use topical nystatin for candidiasis. Coat lips and nasal mucosa with petroleum jelly q60–90min. Use ophthalmic lubricants q4h or artificial tears q30min.


InternalMed_Harrison

InternalMed_Harrison. the retroorbital fat pad may be depleted, permitting the orbit to fall posteriorly, which makes it difficult for the eyelids to cover the eyeball. The physician should establish a plan for who the family or caregivers will contact when the patient is dying or has died. Without a plan, they may panic and call 911, unleashing a cascade of unwanted events, from arrival of emergency personnel and resuscitation to hospital admission. The family and caregivers should be instructed to contact the hospice (if one is involved), the covering physician, or the on-call member of the palliative care team. They should also be told that the medical examiner need not be called unless the state requires it for all deaths. Unless foul play is suspected, the health care team need not contact the medical examiner either.


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InternalMed_Harrison. Just after the patient dies, even the best-prepared family may experience shock and loss and be emotionally distraught. They need time to assimilate the event and be comforted. Health care providers are likely to find it meaningful to write a bereavement card or letter to the family. The purpose is to communicate about the patient, perhaps emphasizing the patient’s virtues and the honor it was to care for the patient, and to express concern for the family’s hardship. Some physicians attend the funerals of their patients. Although this is beyond any medical obligation, the presence of the physician can be a source of support to the grieving family and provides an opportunity for closure for the physician. Death of a spouse is a strong predictor of poor health, and even mortality, for the surviving spouse. It may be important to alert the spouse’s physician about the death so that he or she is aware of symptoms that might require professional attention.


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PALLIATIVE CARE SERVICES: HoW ANd WHERE

InternalMed_Harrison. PALLIATIVE CARE SERVICES: HoW ANd WHERE


InternalMed_Harrison

InternalMed_Harrison. Determining the best approach to providing palliative care to patients will depend on patient preferences, the availability of caregivers and specialized services in close proximity, institutional resources, and reimbursement. Hospice is a leading, but not the only, model of palliative care services. In the United States, a plurality—41.5%—of hospice care is provided in residential homes. In 2012, just over 17% of hospice care was provided in nursing homes. In the United States, Medicare pays for hospice services under Part A, the hospital insurance part of reimbursement. Two physicians must certify that the patient has a prognosis of ≤6 months if the disease runs its usual course. Prognoses are probabilistic by their nature; patients are not required to die within 6 months but rather to have a condition from which half the individuals with it would not be alive within 6 months. Patients sign a hospice enrollment form that states their intent to forgo curative services related to


InternalMed_Harrison

InternalMed_Harrison. to have a condition from which half the individuals with it would not be alive within 6 months. Patients sign a hospice enrollment form that states their intent to forgo curative services related to their terminal illness, but they can still receive medical services for other comorbid conditions. Patients also can withdraw enrollment and reenroll later; the hospice Medicare benefit can be revoked later to secure traditional Medicare benefits. Payments to the hospice are per diem (or capitated), not fee-for-service. Payments are intended to cover physician services for the medical direction of the care team; regular home care visits by registered nurses and licensed practical nurses; home health aid and homemaker services; chaplain services; social work services; bereavement counseling; and medical equipment, supplies, and medications. No specific therapy is excluded, and the goal is for each therapy to be considered for its symptomatic (as opposed to disease-modifying) effect.


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InternalMed_Harrison. and medical equipment, supplies, and medications. No specific therapy is excluded, and the goal is for each therapy to be considered for its symptomatic (as opposed to disease-modifying) effect. Additional clinical care, including services of the primary physician, is covered by Medicare Part B even while the hospice Medicare benefit is in place. The health reform legislation signed into law in March 2010—the Affordable Care Act—directs the Secretary of Health and Human Services to gather data on Medicare hospice reimbursement with the goal of reforming payment rates to account for resource use over an entire episode of care. The legislation also requires additional evaluations and reviews of eligibility for hospice care by hospice physicians or nurses. Finally, the legislation establishes a demonstration project for concurrent hospice care in Medicare, which would test and evaluate allowing patients to remain eligible for regular Medicare during hospice care.


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InternalMed_Harrison. By 2012, the mean length of enrollment in a hospice was around 71.8 days, with the median being 18.7 days. Such short stays create barriers to establishing high-quality palliative services in patients’ homes and also place financial strains on hospice providers because the initial assessments are resource intensive. Physicians should initiate early referrals to the hospice to allow more time for patients to receive palliative care.


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InternalMed_Harrison. Hospice care has been the main method in the United States for securing palliative services for terminally ill patients. However, efforts rarely the primary focus of carefully developed or widely used outcome measures. Nevertheless, outcomes are as important in end-of-life care as in any other field of medical care. Specific end-of-life care instruments are being developed both for assessment, such as The Brief Hospice Inventory and NEST (needs near the end of life screening tool), and for outcome measures, such as the Palliative Care Outcomes Scale, as well as for prognosis, such as the Palliative Prognostic Index. The field of end-of-life care is entering an era of evidence-based practice and continuous improvement through clinical trials. Clinical problems of aging Luigi Ferrucci, Stephanie Studenski


InternalMed_Harrison

InternalMed_Harrison. While an in-depth understanding of internal medicine serves as a foundation, proper care of older adults should be complemented by insight into the multidimensional effects of aging on disease manifestations, consequences, and response to treatment. In younger adults, individual diseases tend to have a more distinct pathophysiology with well-defined risk factors; the same diseases in older persons may have a less distinct pathophysiology and are often the result of failed homeostatic mechanisms. Causes and clinical manifestations are less specific and can vary widely between individuals. Therefore, the care of older patients demands an understanding of the effects of aging on human physiology and a broader perspective that incorporates geriatric syndromes, disability, social contexts, and goals of care. For example, care planning for the older patient should account for the substantial portion of the wide variability in life expectancy across individuals of the same age that can be


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InternalMed_Harrison. goals of care. For example, care planning for the older patient should account for the substantial portion of the wide variability in life expectancy across individuals of the same age that can be predicted by simple and inexpensive measures such as walking speed. Estimation of the expected remaining years of life can guide recommendations about appropriate preventive and other long-term interventions and can shape discussions about treatment alternatives.


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InternalMed_Harrison. (See also Chap. 93e) Population aging emerged as a worldwide phenomenon for the first time in history within the past century. Since aging influences many facets of life, governments and societies—as well as families and communities—now face new social and economic challenges that affect health care. Fig. 11-1 highlights recent and predicted changes in U.S. population structure. are being made to ensure continuity of palliative care across settings and 25000 through time. Palliative care services are becoming available as consultative services and more rarely as palliative care units in hospitals, in day care and other outpatient settings, and in nursing homes. Palliative care consultations for nonhospice patients can be billed as for other consultations under Medicare Part B, the physician reimbursement part.


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InternalMed_Harrison. Many believe palliative care should be offered to patients regardless of their prognosis. A patient, his or her family, and physicians should not have to make a “curative versus palliative care” decision because it is rarely possible to make such a decisive switch to embracing mortality. Number of persons in thousands Care near the end of life cannot be measured by most of the available validated outcome measures because palliative care does not consider death a bad outcome. Similarly, the family and patients receiving end-of-life care may not desire the elements elicited in current qualityof-life measurements. Symptom control, enhanced family relationships, and quality of bereavement are difficult to measure and are


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InternalMed_Harrison. Many chronic diseases increase in prevalence with age. It is not unusual for older persons to have multiple chronic diseases (Fig. 11-4), although some seem more susceptible than others to co-occurring problems. Functional problems that pose difficulties or require help in performing basic activities of daily living (ADLs) (Table 11-1) increase with age and are more common among women than among


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InternalMed_Harrison. Chapter 11 Clinical Problems of Aging men. In recent decades, the age-specific prevalence of disability has declined, especially in the oldest old. Estimated rates are shown in Fig. 11-5 as the percentage of persons who reported severe difficulty or needed help in bathing, and data on other basic ADLs show similar trends. Although the age-specific prevalence of disability is decreasing, the magnitude of this decline is small compared to the overwhelming effect of population aging. Thus, the number of people with disability in the United States and other countries is rapidly expanding. Rates of cognitive impairments, such as memory problems, also increase with aging (Fig. 11-6). Chronic disease and disability lead to increased use of health care resources. Health care expenditures increase with age, increase more with disability, and are highest in the last year of life. However, new medical technologies and expensive medications are greater influences on health care costs than


InternalMed_Harrison

InternalMed_Harrison. with age, increase more with disability, and are highest in the last year of life. However, new medical technologies and expensive medications are greater influences on health care costs than population aging itself. General practitioners and internists with little specific training in geriatric medicine provide the bulk of care for older persons.


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InternalMed_Harrison. Systemic consequences of aging are widespread but can be clustered into four main domains or processes (Fig. 11-7): (1) body composition; (2) balance between energy availability and energy demand; (3) signaling networks that maintain homeostasis; and (4) neurodegeneration. Each domain can be assessed with routine clinical tests, although more detailed research techniques are also available (Table 11-2).


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InternalMed_Harrison. Body Composition Profound changes in body composition may be the most evident and inescapable effect of aging (Fig. 11-8). Over the life span, body weight tends to increase through childhood, puberty, and adulthood until late middle age. Weight tends to decline in men between ages 65 and 70 years and in women somewhat later. Lean body mass, composed predominantly of muscle and visceral organs, decreases steadily after the third decade. In muscle, this atrophy is greater in fast-twitch than in slow-twitch fibers. The origin of this change is unknown, but several lines of evidence suggest that progressive loss of motor neurons probably plays an important role. Fat mass tends to increase in middle age and then declines in late life, reflecting the trajectory of weight change. Waist circumference continues to increase across the life span, a pattern suggesting that visceral


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InternalMed_Harrison. FIgURE 11-2 Population aging in different geographic regions. (From United Nations World Population Prospects: The 2008 Revision, http://www .un.org/esa/population/publications/wpp2008/wpp2008_highlights.pdf.) The overall number of children has remained relatively stable, but explosive growth has occurred among older populations. The percentage of growth is particularly dramatic among the oldest of the old. For example, the number of persons aged 80–89 years more than tripled between 1960 and 2010 and will increase over tenfold between 1960 and 2050. Women already outlive men by many years, and the sex discrepancy in longevity is projected to increase further in the future.


InternalMed_Harrison

InternalMed_Harrison. Population aging occurs at different rates in varying geographic regions of the world. Over the past century, Europe, Australia, and North America have had the populations with the greatest proportions of older persons, but the populations of Asia and South America are aging rapidly, and the population structure on these continents will resemble that of “older” countries by around 2050 (Fig. 11-2). Among older persons, the oldest old (those >80 years of age) are the fastest-growing segment of the population (Fig. 11-3), and the pace of population aging is projected to accelerate in most countries over the next 50 years. There is no evidence that the rate of population aging is decreasing. fat, which is responsible for most of the pathologic consequences of obesity, continues to accumulate. In some individuals, fat also accumulates inside muscle, affecting muscle quality and function. With age, fibroconnective tissue tends to increase in many organ systems. In


InternalMed_Harrison

InternalMed_Harrison. Percentage of population 80+ years old muscle, fibroconnective tissue buildup also affects muscle quality and function. In combination, the loss of muscle mass and quality result in reduced muscle strength, which ultimately affects functional capacity and mobility. Muscle strength declines with aging; this decrease not only affects functional status but also is a strong independent predictor of mortality (Fig. 11-9). Progressive demineralization and architectural modification occur in bone, resulting in a decline of bone strength. Loss of bone strength increases the risk of fracture. Sex differences in the effects of aging on bone mass are due to differences in peak bone mass and the effects of gonadal hormones on bone. Overall, compared with men, women tend to lose bone mass at a younger age and more quickly reach the threshold of low bone strength that increases fracture risk.


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InternalMed_Harrison. All of these changes in body composition can be attributed to disruptions in the links between synthesis, degradation, and repair that Years normally serve to remodel tissues. Such changes in body composition FIgURE 11-3 Percentage of the population age >80 years from are influenced not only by aging and illness but also by lifestyle factors 1950 to 2050 in representative nations. The pace of population such as physical activity and diet. Body composition can be approxiaging will accelerate. (From United Nations World Population Prospects: mated in clinical practice on the basis of weight, height, body mass The 2008 Revision, http://www.un.org/esa/population/publications/ index (BMI; weight in kilograms divided by height in meters squared), wpp2008/wpp2008_highlights.pdf.) and waist circumference or, more precisely, with dual-energy x-ray


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InternalMed_Harrison. FIgURE 11-4 Prevalence of comorbidity by age group in persons ≥65 years old living in the United States and enrolled in Medicare parts A and B in 1999. (From JL Wolff et al: Arch Intern Med 162:2269, 2002.) Basic Activities of Daily Living: Self-Care Tasks Transferring from bed to chair and back Using the toilet Moving around (as opposed to being bedridden) Instrumental Activities of Daily Living: Not Necessary for Fundamental Functioning, but Permit an Individual to Live Independently in a Percentage with memory impairment Using the telephone aWith the recognition that older persons may not be that technologically savvy since they were not as extensively exposed to technology during their lifetime.)


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InternalMed_Harrison. Using the telephone aWith the recognition that older persons may not be that technologically savvy since they were not as extensively exposed to technology during their lifetime.) FIgURE 11-6 Rates of memory impairment in different age groups. The definition of “moderate or severe memory impairment” is 4 or fewer words recalled out of 20. (Source: Health and Retirement Survey. Accessed November 15, 2013, at aoa.gov/agingstatsdotnet/Main_ Site/Data/2000_Documents/healthstatus.aspx.) FIgURE 11-5 Self-reported prevalence of disability (severe difficulty) in bathing/showering between 1992 and 2007, according to age and sex.) (From Medicare Current Beneficiary Survey 1992–2007.)


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InternalMed_Harrison. FIgURE 11-5 Self-reported prevalence of disability (severe difficulty) in bathing/showering between 1992 and 2007, according to age and sex.) (From Medicare Current Beneficiary Survey 1992–2007.) Aging Discrepancy in energy production/utilization Changes in body composition Anorexia/ malnutrition Gait disorders/ falls Disability Disease susceptibility Comorbidity Urinary incontinence Decubitus ulcers Sleep disorders Delirium Cognitive impairment Homeostatic dysregulation Neurodegeneration Domains of the aging phenotype Frailty Disease susceptibility, reduced functional reserve, reduced healing capacity, unstable health, failure to thrive Geriatric syndromes FIgURE 11-7 A unifying model of aging, frailty, and the geriatric syndromes.


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InternalMed_Harrison. Chapter 11 Clinical Problems of Aging absorptiometry, CT, or MRI. In healthy men and women in their twenties, lean body mass is, on average, 85% of body weight, with roughly 50% of lean mass represented by skeletal muscle. With aging, both the percentage of lean mass and the percentage represented by muscle decline rapidly, and these changes have important health and functional consequences.


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InternalMed_Harrison. Balance Between Energy Availability and Energy demand Release of phosphate from ATP provides every living cell with the energy required for life. However, the storage of ATP is only enough for 6 sec; therefore, ATP is constantly resynthesized. Although ATP can be resynthesized by anaerobic glycolysis, most of the energy used in the body is generated through aerobic metabolism. Therefore, energy consumption is usually estimated indirectly by oxygen consumption (indirect calorimetry). There is currently no method to measure true “fitness,” which is the maximal energy that can be produced by an organism over extended periods. Thus, fitness is estimated indirectly from peak oxygen consumption (MVo ), often during a maximal treadmill test. gressively with aging (Fig. 11-10), and the rate of decline is accelerated in persons who are sedentary and in those affected by chronic diseases.


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InternalMed_Harrison. gressively with aging (Fig. 11-10), and the rate of decline is accelerated in persons who are sedentary and in those affected by chronic diseases. A large portion of energy is consumed as the “resting metabolic rate” (RMR)—i.e., the amount of energy expended at rest in a neutral temperature environment and in a postabsorptive state. In healthy men and women, RMR declines with aging, and such decline is only partially explained by the parallel decline in the highly metabolically active tissues that make up lean body mass (Fig. 11-11). However, persons with unstable homeostasis due to illness require additional Approach to Assessment Body Composition Energetics Homeostatic Regulation Neurodegeneration Anthropometrics (weight, height, BMI, waist circumference, arm and leg circumference, skin folds) Imaging CT and MRI, DEXA Other Hydrostatic weighing Self-reported questionnaires investigating physical activity, sense of fatigue/exhaustion, exercise tolerance


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InternalMed_Harrison. Imaging CT and MRI, DEXA Other Hydrostatic weighing Self-reported questionnaires investigating physical activity, sense of fatigue/exhaustion, exercise tolerance Performance-based tests of physical function Treadmill testing of oxygen consumption during walking Objective measures of physical activity (accelerometers, double-labeled water) Nutritional biomarkers (e.g., vitamins, antioxidants) Baseline levels of biomarkers and hormone levels Inflammatory markers (e.g., ESR, CRP, IL-6, TNF-α) Response to provocative tests, such as oral glucose tolerance test, dexamethasone test, and others Objective assessment of gait, balance, reaction time, coordination Standard neurologic exam, including assessment of global cognitiona MRI, fMRI, PET, and other dynamic imaging techniques aMini Mental State; Montreal Cognitive Assessment.


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InternalMed_Harrison. MRI, fMRI, PET, and other dynamic imaging techniques aMini Mental State; Montreal Cognitive Assessment. Abbreviations: BMI, body mass index; CRP, C-reactive protein; DEXA, dual-energy x-ray absorptiometry; ESR, erythrocyte sedimentation rate; fMRI, functional MRI; IL-6, interleukin 6; PET, positron emission tomography; TNFα, tumor necrosis factor α. FIgURE 11-8 Longitudinal changes of weight, body composition, and waist circumference over the life span, estimated in 1167 participants in the Baltimore Longitudinal Study of Aging. Lean body mass (LBM) and fat mass were estimated with dual-energy x-ray absorptiometry. (Source: The Baltimore Longitudinal study of Aging 2010; unpublished data.) Survivors, n = 3680 Non-survivors, n = 3680


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InternalMed_Harrison. (Source: The Baltimore Longitudinal study of Aging 2010; unpublished data.) Survivors, n = 3680 Non-survivors, n = 3680 FIgURE 11-9 Cross-sectional differences and longitudinal changes in muscle strength over a 27-year follow-up. Note that persons who died during the follow-up had lower baseline muscle strength. (From T Rantanen et al: J Appl Physiol 85:2047, 1998.) 1.8 1.6 1.4 1.2 1.0 0.8 0.6 FIgURE 11-10 Longitudinal changes in aerobic capacity in participants in the Baltimore Longitudinal Study of Aging. (From JL Fleg: FIgURE 11-11 Changes in resting metabolic rate with aging. Circulation 112:674, 2005.) (Unpublished data from the Baltimore Longitudinal Study of Aging.) taBLe 11-3 horMones that deCrease, reMaIn staBLe, and InCrease WIth aGInG Chapter 11 Clinical Problems of Aging


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InternalMed_Harrison. FIgURE 11-12 Longitudinal trajectory of bioavailable testosterone plasma concentration in the Baltimore Longitudinal Study of Aging (BLSA). The plot is based on 584 men who were 50 years or older with a total of 1455 data points. The average follow up for each subject was 3.2 years. (Figure created using unpublished data from the BLSA.) energy for compensatory mechanisms. Indeed, observational studies have demonstrated (1) that older persons with poor health status and substantial morbidity have a higher RMR than healthier individuals of the same age and sex and (2) that a high RMR is an independent risk factor for mortality and may contribute to the weight loss that often accompanies severe illness. Finally, for reasons that are not yet completely clear but certainly involve changes in the biomechanical characteristics of movement, older age, pathology, and physical impairment increase the energy cost of motor activities such as walking. Overall, older individuals with multiple


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InternalMed_Harrison. in the biomechanical characteristics of movement, older age, pathology, and physical impairment increase the energy cost of motor activities such as walking. Overall, older individuals with multiple chronic conditions have low available energy levels and require more energy both at rest and during physical activity. Thus, sick older people may consume all their available energy performing the most basic ADLs, and consequent fatigue and restriction may lead to a sedentary existence. Energy status can be assessed clinically by simply asking patients about their perceived level of fatigue during daily activities such as walking or dressing. Energy capacity can be assessed more precisely by exercise tolerance during a walking test or a treadmill test coupled with spirometry.


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InternalMed_Harrison. The main signaling pathways that control homeostasis involve hormones, inflammatory mediators, and antioxidants; all are profoundly affected by aging. Sex hormone levels, such as testosterone in men (Fig. 11-12) and estrogen in women, decrease with age, while other hormone systems may change more subtly (Table 11-3). Most aging individuals, even those who remain healthy and fully functional, tend to dysregulation. For example, taken one at a time, levels of testosterone, dehydroepiandrosterone (DHEA), and insulin-like growth factor 1 (IGF-1) do not predict mortality, but in combination they are highly predictive of longevity. This combination effect is especially strong in the setting of congestive heart failure. Similarly, several micronutrients, such as vitamins (especially vitamin D), minerals (selenium and magnesium), and antioxidants (vitamins D and E), also regulate aspects of metabolism. Low levels of these micronutrients have been associated with accelerated aging and a high


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InternalMed_Harrison. minerals (selenium and magnesium), and antioxidants (vitamins D and E), also regulate aspects of metabolism. Low levels of these micronutrients have been associated with accelerated aging and a high risk of adverse outcomes. However, except for vitamin D, no clear evidence suggests that supplementation has positive effects on health. Unfortunately, no standard criteria exist that allow the detection and quantification of homeostatic dysregulation as a general phenomenon.


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InternalMed_Harrison. Neurodegeneration It was long generally believed that neurons stop reproducing shortly after birth and that their number declines throughout life. However, results from animal models and even some studies in humans suggest that neurogenesis in the hippocampus continues at low levels throughout life. Brain atrophy occurs with aging after the age of 60 years. Atrophy proceeds at varying rates in different parts of the brain (Fig. 11-14) and is often accompanied by an inflammatory response and microglial activation. Age-associated brain atrophy may contribute to age-related declines in cognitive and motor function. Atrophy may also be a factor in some brain diseases that can occur with aging, such as mild cognitive impairment, in which persons have mild but detectable impairments on tests of cognition but no severe disability in daily activities. In mild cognitive impairment, atrophy has been found mostly in the prefrontal cortex and hippocampus, develop a mild proinflammatory state


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InternalMed_Harrison. of cognition but no severe disability in daily activities. In mild cognitive impairment, atrophy has been found mostly in the prefrontal cortex and hippocampus, develop a mild proinflammatory state characterized by high levels of proinflammatory markers, including interleukin 6 (IL-6) and C-reactive protein (CRP) (Fig. 11-13). Aging is also thought to be associated with increased oxidative stress damage, either because the production of reactive oxygen species increases or because antioxidant buffers are less effective. Since hormones, inflammatory markers, and antioxidants are integrated into complex signaling networks, levels


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InternalMed_Harrison. FIgURE 11-13 Change in interleukin 6 (IL-6) and C-reactive protein (CRP) with aging. Values are expressed as Z-scores to make them comparable. (From L Ferrucci et al: Blood 105:2294, 2005.) 1.5 1 0.5 0 –0.5 –1 20-39 40-49 50-64 65-74 Age groups Age groups 75-84 85+ 20-39 40-49 50-64 65-74 75-84 n of SD from the sex-specific meanMenIL-6 CRP causative factors. Thus, the therapeutic strategy of sin gle-molecule replacement may be ineffective or even 85+counterproductive. The presence of such signaling networks and feedback loops may help explain why single-hormone “replacement therapy” for problems of aging has demonstrated little benefit. The focus of research in this area is now on multiple-hormone 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Five-year decrease in regional cortical size (SD)


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InternalMed_Harrison. FIgURE 11-14 Five-year decline in mean volumes of different brain regions, measured in standard deviation (SD) units (Cohen’s d ). The primary visual cortex shows the least average shrinkage, and the prefrontal and inferior parietal cortex and hippocampus show the most average shrinkage. (From N Raz et al: Ann N Y Acad Sci 1097:84, 2007.) in number at a rate of ∼1% per year, starting after the third decade. These larger motor units contribute to reductions in fine-motor control and manual dexterity. Age-related changes also occur in the autonomic nervous system, affecting cardiovascular and splanchnic function.


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InternalMed_Harrison. Systemic Changes Coexisting with and Affecting one Another • the phenotype of agIng: the fInal common pathway of systemIc InteractIon While age-related system changes have been described individually, in reality, these changes develop in parallel and affect one another through many feed-forward and feedback loops. Some systemic interactions are well understood, while others are under investigation. For example, body composition interacts with energy balance and signaling. Higher lean body mass increases energy consumption and improves insulin sensitivity and carbohydrate metabolism. Higher fat mass, especially visceral fat mass, is the culprit in the metabolic syndrome and is associated with low testosterone levels, high sex hormone–binding globulin levels, and increased levels of proinflammatory markers such as


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InternalMed_Harrison. CRP and IL-6. Altered signaling can affect neurode generation; insulin resistance and adipokines such as leptin and adiponectin are associated with declines in but these findings are not specific and their diagnostic utility is unclear (Fig. 11-15). Other neurophysiologic changes in the brain frequently occur with aging and may contribute to cognitive decline. Functional imaging studies have shown that some older people have diminished coordination between the brain regions responsible for higher-order cognitive functions and that such diminished coordination is correlated with poor cognitive performance. In young healthy individuals, the brain activity associated with executive cognitive functions (e.g., problem-solving, decision-making) is very well localized; in contrast, in healthy older individuals, the pattern of cortical activation is more diffuse. Brain pathology has typically been associated with specific diseases; amyloid plaques and neurofibrillary tangles are considered


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InternalMed_Harrison. older individuals, the pattern of cortical activation is more diffuse. Brain pathology has typically been associated with specific diseases; amyloid plaques and neurofibrillary tangles are considered the pathologic hallmarks of Alzheimer’s disease. However, these pathologic markers have been found at autopsy in many older individuals who had normal cognition, as assessed by extensive testing in the year before death.


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InternalMed_Harrison. Taken together, trends in brain changes with aging suggest that some neurophysiologic manifestations are compensatory adaptations rather than primary contributors to age-related declines. Because the brain is capable of reorganization and compensation, extensive neurodegeneration may not be clinically evident. Therefore, early detection requires careful testing. Clinically, cortical and subcortical changes are reflected in the high prevalence of “soft,” nonspecific neurologic signs, often reflected in slow and unstable gait, poor balance, and slow reaction times. These movement changes can be elicited more overtly with “dual tasks,” in which a 1050 cognitive function. Combined with loss of motor neurons and dysfunction of the motor unit, a state of inflammation and reduced levels of testosterone and IGF-1 have been linked to accelerated decline of muscle mass and strength. Normal intersystem coordination is also affected by aging. The hypothalamus normally functions as a central


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InternalMed_Harrison. testosterone and IGF-1 have been linked to accelerated decline of muscle mass and strength. Normal intersystem coordination is also affected by aging. The hypothalamus normally functions as a central regulator of metabolism and energy use and coordinates physiologic responses of the entire organism through hormonal signaling; aging-related changes in the hypothalamus alter this control. The central nervous system (CNS) also controls adaptive sympathetic/parasympathetic activity, so that age-related CNS degeneration may have implications for autonomic function.


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InternalMed_Harrison. The phenotype that results from the aging process is characterized by increased susceptibility to diseases, high risk of multiple coexisting diseases, impaired response to stress (including limited ability to heal or recover after an acute disease), emergence of “geriatric syndromes” (characterized by stereotyped clinical manifestations but multifactorial causes), altered response to treatment, high risk of disability, and loss of personal autonomy with all its psychological and social consequences. In addition, these key aging processes may interfere with the typical pathophysiology of specific diseases, thereby altering expected clinical manifestations and confounding diagnosis. Clinically, patients may present with obvious problems within only one of these domains, but, since systems interact, all four main domains should be evaluated 7.5 cognitive and a motor task are performed simultaneously. In a simple version of a dual task, when an older adult has to stop walking in order to


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InternalMed_Harrison. all four main domains should be evaluated 7.5 cognitive and a motor task are performed simultaneously. In a simple version of a dual task, when an older adult has to stop walking in order to talk, an increased risk of falls can be predicted. Poor dual-task per formance has been interpreted as a marker cessing, so that simultaneous processing 7.0 6.5 6.0 5.5 is more constrained. Beyond the brain, 5.0 4.5 the spinal cord also experiences changes after the age of 60 years, including reduced numbers of motor neurons and damage to myelin. The motor neurons that survive plexity and by service to larger motor units. FIgURE 11-15 Longitudinal changes of regional brain volumes in normal aging and mild As motor units become larger, they decline cognitive impairment (MCI). (From I Driscoll et al: Neurology 72:1906, 2009.) and considered potential therapeutic targets. When patients present with obvious problems in multiple main systems affected by aging, they tend toward extreme degrees of


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InternalMed_Harrison. al: Neurology 72:1906, 2009.) and considered potential therapeutic targets. When patients present with obvious problems in multiple main systems affected by aging, they tend toward extreme degrees of susceptibility and loss of resilience, a condition that is globally referred to as frailty.


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InternalMed_Harrison. bIologIc underpInnIngs of the domaIns of the agIng phenotype The changes that occur with aging encompass multiple physiologic systems. Although they are often described in isolation, they are likely attributable to the progressive dysfunction of a unique mechanism that affects some fundamental housekeeping mechanism of cellular physiology. An important goal of future research is to connect the aging phenotype in humans to theories of aging that have largely been developed from studies in cell or animal models. If the main theories of aging could be operationalized into assessments that are feasible in humans, it would be possible to test the hypothesis that some of these processes are correlated with all the domains of the aging phenotype, above and beyond chronologic age. Review of the biologic theories (hallmarks) of aging provides an excellent template for a working hypothesis that, at least theoretically, could be tested in longitudinal studies. Candidate mechanisms of mammalian


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InternalMed_Harrison. biologic theories (hallmarks) of aging provides an excellent template for a working hypothesis that, at least theoretically, could be tested in longitudinal studies. Candidate mechanisms of mammalian aging include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.


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InternalMed_Harrison. Frailty Frailty has been described as a physiologic syndrome that is characterized by decreased reserve and diminished resistance to stressors, that results from cumulative decline across multiple physiologic systems, and that causes vulnerability to adverse outcomes and a high risk of death. A proposed “phenotype” definition characterized by weight loss, fatigue, impaired grip strength, diminished physical activity, and slow gait has shown good internal consistency and strong predictive validity and has been used in many clinical and epidemiologic studies. An alternative approach, the Frailty Index, assesses cumulative physiologic and functional burden. When combined with a structured clinical assessment (the Comprehensive Geriatric Assessment), the Frailty Index can be applied in clinical settings and has low rates of missing data; it predicts survival in community-dwelling older people as well as survival, length of stay and discharge location in acute-care settings. Regardless of


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InternalMed_Harrison. settings and has low rates of missing data; it predicts survival in community-dwelling older people as well as survival, length of stay and discharge location in acute-care settings. Regardless of the definition, an extensive body of literature shows that older persons who are considered frail by any definition have overt changes in the same four main processes: body composition, homeostatic dysregulation, energetic failure, and neurodegeneration—the characteristics of the aging phenotype. A classic clinical case would be an older woman with sarcopenic obesity characterized by increased body fat and decreased muscle (body composition changes); extremely low exercise tolerance and extreme fatigue (energetic failure); high insulin levels, low IGF-1 levels, inadequate intake of calories, and low levels of vitamins D and E and carotenoids (signal dysregulation); and memory problems, slow gait, and unstable balance (neurodegeneration). This woman is likely to exhibit all the manifestations


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InternalMed_Harrison. low levels of vitamins D and E and carotenoids (signal dysregulation); and memory problems, slow gait, and unstable balance (neurodegeneration). This woman is likely to exhibit all the manifestations of frailty, including a high risk of multiple diseases, disability, urinary incontinence, falls, delirium, depression, and other geriatric syndromes. It is expected that the biologic process underlying a particular “aging theory” would be more advanced in this woman than would be expected on the basis of chronologic age.


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InternalMed_Harrison. A goal of future research in geriatric medicine that has strong potential for clinical translation is to demonstrate that the hypothetical patient described above is biologically older, according to some robust biomarkers of biologic aging, than would be estimated from chronologic age alone. Conceptualizing frailty through the four main underlying processes is a step in this direction that stems from accumulated evidence and recognizes the heterogeneity and dynamic nature of the aging phenotype. Aging is universal but proceeds at highly variable rates, with wide heterogeneity in the emergence of the aging phenotype. Thus, the question is not whether an older patient is frail, but rather whether the severity of frailty is beyond the threshold of clinical and behavioral relevance. Understanding frailty through the lens of four interacting underlying processes also provides an interface with diseases that, like aging itself, affect the aging phenotype. For example, congestive heart


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InternalMed_Harrison. frailty through the lens of four interacting underlying processes also provides an interface with diseases that, like aging itself, affect the aging phenotype. For example, congestive heart failure is associated with low energy availability, multiple hormonal derangements, and a proinflammatory state, thereby contributing to frailty severity. Parkinson’s disease provides an example of neurodegeneration that, in an advanced state, affects body composition, energy metabolism, and homeostatic signaling, resulting in a syndrome that closely resembles frailty. Diabetes is especially important to aging and frailty because it harms body composition, energy metabolism, homeostatic dysregulation, and neuronal integrity. Accordingly, a number of studies have found that type 2 diabetes is a strong risk factor for frailty and for many of its consequences. Since disease and aging interact, careful and appropriate treatment of disease is critical to prevent or reduce frailty.


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InternalMed_Harrison. CoNSEQUENCES oF AgINg PRoCESSES, THE AgINg PHENoTYPE, ANd FRAILTY While the pathophysiology of frailty is still being elucidated, its consequences have been well characterized in prospective studies. Four main consequences are important for clinical practice: (1) ineffective or incomplete homeostatic response to stress, (2) multiple coexisting diseases (multior comorbidity) and polypharmacy, (3) physical disability, and (4) the so-called geriatric syndromes. We will briefly address each one of these consequences.


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InternalMed_Harrison. Low Resistance to Stress Frailty can be considered a progressive loss of reserve in multiple physiologic functions. At an early stage and in the absence of stress, mildly frail older individuals may appear to be normal. However, they have reduced ability to cope with challenges, such as acute diseases, traumas, surgical procedures, or chemotherapy. Acute illness involving a hospital stay is associated with undernutrition and inactivity, which sometimes may be of such magnitude that the residual muscle mass fails to meet the minimal requirement for walking. Even when nutrition is reinstated, energy reserves may be insufficient to adequately rebuild muscle mass. Older persons have a reduced ability to tolerate infections, in part because they are less able than younger people to build a dynamic inflammatory response to vaccination or infectious exposure; thus, infections are more likely to become severe and systemic and to resolve more slowly. In the context of tolerance to stress,


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InternalMed_Harrison. dynamic inflammatory response to vaccination or infectious exposure; thus, infections are more likely to become severe and systemic and to resolve more slowly. In the context of tolerance to stress, assessing aspects of frailty can help estimate the individual’s ability to withstand the rigors of aggressive treatments and to respond to interventions aimed at infection as well as the caregiver’s ability to anticipate and prevent complications of hospitalization and generally to estimate prognosis. Accordingly, treatment plans may be adjusted to improve tolerance and safety; bed rest and hospitalization should be used sparingly; and infections should be prevented, anticipated, and managed assertively.


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InternalMed_Harrison. Comorbidity and Polypharmacy Older age is associated with high rates of many chronic diseases (Fig. 11-4). Thus, not unexpectedly, the percentage of individuals affected by multiple medical conditions (coor multimorbidity) also increases with age. In frail older individuals, comorbidity occurs at higher rates than would be expected from the combined probability of the component conditions. It is likely that frailty and comorbidity affect each other, so that multiple diseases contribute to frailty and frailty increases susceptibility to diseases.


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InternalMed_Harrison. Clinically, patients with multiple conditions present unique diagnostic and treatment challenges. Standard diagnostic criteria may not be informative because there are additional confusing signs and symptoms. A classic example is the coexistence of deficiencies in iron and vitamin B12, creating an apparently normocytic anemia. The risk/ benefit ratio for many medical and surgical treatment options may be reduced in the face of other diseases. Drug treatment planning is made more complex because comorbid diseases may affect the absorption, volume of distribution, protein binding, and, especially, elimination of many drugs, leading to fluctuation in therapeutic levels and increased risk of underor overdosing. Drug excretion is affected by renal and hepatic changes with aging that may not be detectable with the usual clinical tests. Formulas for estimating glomerular filtration rate in older patients are available, whereas the estimation of changes in hepatic excretion remains a


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InternalMed_Harrison. not be detectable with the usual clinical tests. Formulas for estimating glomerular filtration rate in older patients are available, whereas the estimation of changes in hepatic excretion remains a challenge.


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InternalMed_Harrison. Patients with many diseases are usually prescribed multiple drugs, especially when they are cared for by multiple specialists who do not communicate. The risk of adverse drug reactions, drug–drug interactions, and poor compliance increases geometrically with the number


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InternalMed_Harrison. Chapter 11 Clinical Problems of Aging of drugs prescribed and with the severity of frailty. Some general rules to minimize the chances of adverse drug events are as follows: (1) Always ask patients to bring in all medications, including prescription drugs, over-the-counter products, vitamin supplements, and herbal preparations (the “brown bag test”). (2) Screen for unnecessary drugs; those without a clear indication should be discontinued. (3) Simplify the regimen in terms of number of agents and schedules, try to avoid frequent changes, and use single-daily-dose regimens whenever possible. (4) Avoid drugs that are expensive or not covered by insurance whenever possible. (5) Minimize the number of drugs to those that are absolutely essential, and always check for possible interactions. (6) Make sure that the patient or an available caregiver understands the administered regimen, and provide legible written instructions. (7) Schedule periodic medication reviews.


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InternalMed_Harrison. disability and Impaired Recovery from Acute-onset disability The prevalence of disability in self-care and home management increases steeply with aging and tends to be higher among women than among men (Fig. 11-5). Physical and cognitive function in older persons reflects overall health status and predicts health care utilization, institutionalization, and mortality more accurately than any other known biomedical measure. Thus, assessment of function and disability and prediction of the risk of disability are cornerstones of geriatric medicine. Frailty, regardless of the criteria used for its definition, is a robust and powerful risk factor for disability. Because of this strong relationship, measures of physical function and mobility have been proposed as standard criteria for frailty. However, disability occurs late in the frailty process, after reserve and compensation are exhausted. Early in the development of frailty, body composition changes, reductions in fitness, homeostatic


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InternalMed_Harrison. However, disability occurs late in the frailty process, after reserve and compensation are exhausted. Early in the development of frailty, body composition changes, reductions in fitness, homeostatic deregulation, and neurodegeneration can begin without affecting daily function. As opposed to disability in younger persons, in which the rule is to look for a clear dominant cause, disability in frail older persons is almost always multifactorial. Multiple disrupted aging processes are usually involved, even when the precipitating cause seems unique. Excess fat mass, poor muscle strength, reduced lean body mass, poor fitness, reduced energy efficiency, poor nutritional intake, low circulating levels of antioxidant micronutrients, high levels of proinflammatory markers, objective signs of neurologic dysfunction, and cognitive impairment all contribute to disability. The multifactorial nature of disability in frail older persons reduces the capacity for compensation and interferes with


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InternalMed_Harrison. neurologic dysfunction, and cognitive impairment all contribute to disability. The multifactorial nature of disability in frail older persons reduces the capacity for compensation and interferes with functional recovery. For example, a small lacunar stroke that causes problems with balance in a young hypertensive individual can be overcome by standing and walking with the feet further apart, a strategy that requires brain adaptation, strong muscles, and a high energy capacity. The same small lacunar stroke may cause catastrophic disability in an older person already affected by neurodegeneration and weakness, who is less able to compensate. As a consequence, interventions aimed at preventing and reducing disability in older persons should have a dual focus on both the precipitating cause and the systems needed for compensation. In the case of the lacunar stroke, interventions to promote mobility function might include stroke prevention, balance rehabilitation, and strength training.


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InternalMed_Harrison. As a rule of thumb, the assessment of contributing causes and the design of intervention strategies for disability in older persons should always consider the four main aging processes that contribute to frailty. One of the most popular approaches to disability measurement is a modification of the International Classification of Impairments, Disabilities and Handicaps (World Health Organization, 1980) proposed by the Institute of Medicine (1992). This classification infers a causal pathway in four steps: pathology (diseases), impairment (the physical manifestation of diseases), functional limitation (global functions such as walking, grasping, climbing stairs), and disability (ability to fulfill social roles in the environment). In practice, the assessment of functional limitation and disability is performed either by (1) self-reported questionnaire concerning the degree of ability to perform basic self-care or more complex ADLs or by (2) performance-based measures of physical


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InternalMed_Harrison. and disability is performed either by (1) self-reported questionnaire concerning the degree of ability to perform basic self-care or more complex ADLs or by (2) performance-based measures of physical function that assess specific domains, such as balance, gait, manual dexterity, coordination, flexibility, and endurance. A concise list of standard tools that can be used to assess physical function in older persons is provided in Table 11-4. In 2001, the WHO officially endorsed a new classification system, the International Classification of Functioning, Disability and Health, known more commonly as the ICF. In the ICF, health measures are classified from bodily, individual, and societal perspectives by means of two lists: a list of body functions and structure and a list of domains of activity and participation. Since an individual’s functioning and disability occur in a context, the ICF also includes a list of environmental factors. A detailed list of codes that allow the


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InternalMed_Harrison. of activity and participation. Since an individual’s functioning and disability occur in a context, the ICF also includes a list of environmental factors. A detailed list of codes that allow the classification of body functions, activities, and participation is being developed. The ICF system is widely implemented in Europe and is gaining popularity in the United States. Whatever classification system is used, the health care provider should try to identify factors that can be modified to minimize disability. Many of these factors are discussed in this chapter. Important issues related to aging that are not addressed in this chapter but are covered elsewhere include dementia (Chap. 35) and other cognitive disorders including aphasia, memory loss, and other focal cerebral disorders (Chap. 36).


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InternalMed_Harrison. geriatric Syndromes The term geriatric syndrome encompasses clinical conditions that are frequently encountered in older persons; have a deleterious effect on function and quality of life; have a multifactorial pathophysiology, often involving systems unrelated to the apparent chief symptom; and are manifested by stereotypical clinical presentations. The list of geriatric syndromes includes incontinence, delirium, falls, pressure ulcers, sleep disorders, problems with eating or feeding, pain, and depressed mood. In addition, dementia and physical disability are sometimes considered to be geriatric syndromes. The term syndrome is somewhat misleading in this context since it is most commonly used to describe a pattern of symptoms and signs that have a single underlying cause. The term geriatric syndromes, by contrast, refers to “multifactorial health conditions that occur when the accumulated effects of impairments in multiple systems render an older person vulnerable to situational


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InternalMed_Harrison. syndromes, by contrast, refers to “multifactorial health conditions that occur when the accumulated effects of impairments in multiple systems render an older person vulnerable to situational challenges.” According to this definition, geriatric syndromes reflect the complex interactions between an individual’s vulnerabilities and exposure to stressors or challenges. This definition aligns well with the concept that geriatric syndromes should be considered as phenotypic consequences of frailty and that a limited number of shared risk factors contribute to their etiology. Indeed, in various combinations and frequencies, virtually all geriatric syndromes are characterized by body composition changes, energy gaps, signaling disequilibria, and neurodegeneration. For example, detrusor (bladder) underactivity is a multifactorial geriatric condition that contributes to urinary retention in the frail elderly. It is characterized by detrusor muscle loss, fibrosis, and axonal degeneration. A


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InternalMed_Harrison. underactivity is a multifactorial geriatric condition that contributes to urinary retention in the frail elderly. It is characterized by detrusor muscle loss, fibrosis, and axonal degeneration. A proinflammatory state and a lack of estrogen signaling cause bladder muscle loss and detrusor underactivity, while a chronic urinary tract infection may cause detrusor hyperactivity; all of these factors may contribute to urinary incontinence.


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InternalMed_Harrison. Because of limited space, only delirium, falls, chronic pain, incontinence, and anorexia are addressed here. Interested readers are referred to textbooks on geriatric medicine for a discussion of other geriatric syndromes.


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InternalMed_Harrison. delirium (See also Chap. 34) Delirium is an acute disorder of disturbed attention that fluctuates with time. It affects 15–55% of hospitalized older patients. Delirium has previously been considered to be transient and reversible and a normal consequence of surgery, chronic disease, or infections in older people. Delirium may be associated with a substantially increased risk for dementia and is an independent risk factor for morbidity, prolonged hospitalization, and death. These associations are particularly strong in the oldest old. Fig. 11-16 shows an algorithm for assessment and management of delirium in hospitalized older patients. The clinical presentation of delirium is heterogeneous, but frequent features are (1) a rapid decline in the level of consciousness, with difficulty focusing, shifting, or sustaining attention; (2) cognitive change (rumbling incoherent speech, memory gaps, disorientation, hallucinations) not explained by dementia; and (3) a medical history suggestive of


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InternalMed_Harrison. shifting, or sustaining attention; (2) cognitive change (rumbling incoherent speech, memory gaps, disorientation, hallucinations) not explained by dementia; and (3) a medical history suggestive of preexisting cognitive impairment, frailty, and comorbidity. The strongest predisposing factors for delirium are dementia, any other condition associated with chronic or transient neurologic dysfunction (neurologic diseases, dehydration, alcohol consumption, psychoactive drugs), and sensory (visual and hearing) deprivation; these associations suggest that delirium is a condition of brain function susceptibility (neurodegeneration or transient neuronal impairment) that precludes the avoidance of decompensation in the face of a stressful event. Many stressful conditions have been implicated as precipitating factors, including surgery; anesthesia; persistent pain; treatment with opiates, narcotics, or anticholinergics; sleep deprivation, immobilization; hypoxia; malnutrition; and metabolic and


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InternalMed_Harrison. factors, including surgery; anesthesia; persistent pain; treatment with opiates, narcotics, or anticholinergics; sleep deprivation, immobilization; hypoxia; malnutrition; and metabolic and electrolyte derangements. Both the occurrence and the severity of delirium can be reduced by anticipatory screening and preventive strategies targeting the precipitating causes. The Confusion Assessment Method is a simple, validated tool for screening in the hospital setting. The three pillars of treatment are (1) immediate identification and treatment of precipitating factors, (2) withdrawal of drugs that may have promoted the onset of delirium, and (3) supportive care, including management of hypoxia, hydration and nutrition, mobilization, and environmental modifications. Whether patients who are cared for in special delirium units have better outcomes than those who are not is still in question. Physical restraints should be avoided because they tend to increase agitation and injury. Whenever


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InternalMed_Harrison. for in special delirium units have better outcomes than those who are not is still in question. Physical restraints should be avoided because they tend to increase agitation and injury. Whenever possible, drug treatment should be avoided because it may prolong or aggravate delirium in some cases. The treatment of choice is low-dose haloperidol. It remains difficult to reduce delirium in patients with acute illness or other stressful conditions. Interventions based on dietary supplementation or careful use of pain medications and sedatives in preand postoperative older patients have been only partially successful.


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InternalMed_Harrison. Chapter 11 Clinical Problems of Aging FIgURE 11-16 Algorithm depicting assessment and management of delirium in hospitalized older patients. (Modified from SK Inouye: N Engl J Med 354:1157, 2006.) Hospital admission Assess current and recent changes in mental status Monitor mental status Prevention Address risk factors Improve communication Improve environment Early discharge Avoid psychotropic drugs Acute Impaired mental status Cognitive assessment and delirium evaluation Identify and address predisposing and precipitating risk factors Provide supportive care and prevent complications Manage symptoms of delirium Rule out depression, mania and psychosis Delirium confirmed


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InternalMed_Harrison. Falls and Balance disorders Unstable gait and falls are serious concerns in the older adult because they lead not only to injury but also to restricted activity, increased health care utilization, and even death. Like all geriatric syndromes, problems with balance and falls tend to be multifactorial and are strongly connected with the disrupted aging systems that contribute to frailty. Poor muscle strength, neural damage in the basal ganglia and cerebellum, diabetes, and peripheral neuropathy are all recognized risk factors for falls. Therefore, evaluation and management require a structured multisystem approach that spans the entire frailty spectrum and beyond. Accordingly, interventions to prevent or reduce instability and falls usually require a mix of medical, rehabilitative, and environmental modification approaches. Guidelines for the evaluation and management of falls, released by the American Geriatrics Society, recommend asking all older adults about falls and perceived gait


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InternalMed_Harrison. modification approaches. Guidelines for the evaluation and management of falls, released by the American Geriatrics Society, recommend asking all older adults about falls and perceived gait instability (Fig. 11-17). Patients with a positive history of multiple falls as well as persons who have sustained one or more injurious falls should undergo an evaluation of gait and balance as well as a targeted history and physical examination to detect


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InternalMed_Harrison. Recommend fall prevention, education and exercise program that includes balance, gait and coordination training and strength training Ask all patients about falls in the past year No falls One fall past 6 months Gait or balance problem Report >1 fall, or difficulty with gait or balance, or seeking medical attention because of fall Multifactorial fall risk assessment Check for gait or balance problems History of falls Medications Gait and balance Cognition Visual acuity Lower limb joint function Neurological impairment Muscle strength HR and rhythm Postural hypotension Feet and footwear Environmental hazards Intervene with identified risks Modify medications Prescribe individualized exercise program Treat vision impairment Manage postural hypotension Manage HR and rhythm abnormalities Supplement vitamin D Address foot/shoe problems Reduce environmental hazards Education/ training in self-management and behavioral changes


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InternalMed_Harrison. FIgURE 11-17 Algorithm depicting assessment and management of falls in older patients. HR, heart rate. (From American Geriatrics Society and British Geriatrics Society: Clinical Practice Guideline for the Prevention of Falls in Older Persons. New York, American Geriatric Society, 2010.) sensory, nervous system, brain, cardiovascular, and musculoskeletal contributors. Interventions depend on the factors identified but often include medication adjustment, physical therapy, and home modifications. Meta-analyses of strategies to reduce the risk of falls have found that multifactorial risk assessment and management as well as individually targeted therapeutic exercise are effective. Supplementation with vitamin D at 800 IU daily may also help reduce falls, especially in older persons with low vitamin D levels.


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InternalMed_Harrison. Persistent Pain Pain from multiple sources is the most common symptom reported by older adults in primary care settings and is also common in acute-care, long-term-care, and palliative-care settings. Acute pain and cancer pain are beyond the scope of this chapter. Persistent pain results in restricted activity, depression, sleep disorders, and social isolation and increases the risk of adverse events due to medication. The most common causes of persistent pain are musculoskeletal problems, but neuropathic pain and ischemic pain occur frequently, and multiple concurrent causes are often found. Alterations in mechanical and structural elements of the skeleton commonly lead to secondary problems in other parts of the body, especially soft tissue or myofascial components. A structured history should elicit information about the quality, severity, and temporal patterns of pain. Physical examination should focus on the back and joints, on trigger points and periarticular areas, and on


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InternalMed_Harrison. should elicit information about the quality, severity, and temporal patterns of pain. Physical examination should focus on the back and joints, on trigger points and periarticular areas, and on possible evidence of radicular neurologic patterns and peripheral vascular disease. Pharmacologic management should follow standard progressions, as recommended by the World Health Organization (Chap. 18), and adverse effects on the CNS, which are especially likely in this population, must be monitored. For persistent pain, regular analgesic schedules are appropriate and should be combined with nonpharmacologic approaches such as splints, physical exercise, heat, and other modalities. A variety of adjuvant analgesics such as antidepressants and anticonvulsants may be used; again, however, effects on reaction time and alertness may be dose limiting, especially in older persons with cognitive impairment. Joint or soft tissue injections may be helpful. Education of the patient and mutually


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InternalMed_Harrison. on reaction time and alertness may be dose limiting, especially in older persons with cognitive impairment. Joint or soft tissue injections may be helpful. Education of the patient and mutually agreed-upon goal setting are important since pain usually is not fully eliminated but rather is controlled to a tolerable level that maximizes function while minimizing adverse effects.


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InternalMed_Harrison. Urinary Incontinence Urinary incontinence—the involuntary leakage of urine—is highly prevalent among older persons (especially women) and has a profound negative impact on quality of life. Approximately 50% of American women will experience some form of urinary incontinence over a lifetime. Increasing age, white race, childbirth, obesity, and medical comorbidity are all risk factors for urinary incontinence. The three main clinical forms of urinary incontinence are as follows: (1) Stress incontinence is the failure of the sphincteric mechanism to remain closed when there is a sudden increase in intraabdominal pressure, such as a cough or sneeze. In women this condition is due to insufficient strength of the pelvic floor muscles, while in men it is almost exclusively secondary to prostate surgery. (2) Urge incontinence is the loss of urine accompanied by a sudden sensation of need to urinate and inability to control it and is due to detrusor muscle overactivity (lack of inhibition)


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InternalMed_Harrison. surgery. (2) Urge incontinence is the loss of urine accompanied by a sudden sensation of need to urinate and inability to control it and is due to detrusor muscle overactivity (lack of inhibition) caused by loss of neurologic control or local irritation. (3) Overflow incontinence is characterized by urinary dribbling, either constantly or for some period after urination. This condition is due to impaired detrusor contractility (due usually to denervation, for example, in


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Prevalence of urinary incontinence*

InternalMed_Harrison. Prevalence of urinary incontinence*


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InternalMed_Harrison. FIgURE 11-18 Rates of urge, stress, and mixed incontinence, by age group, in a sample of 3552 women. *Based on a sample of 3553 participants. (From JL Melville et al: Arch Intern Med 165:537, 2005.) diabetes) or bladder outlet obstruction (prostate hypertrophy in men and cystocele in women). Thus, it is not surprising that the pathogenesis of urinary incontinence is connected to the disrupted aging systems that contribute to frailty, body composition changes (atrophy of the bladder and pelvic floor muscle), and neurodegeneration (both central and peripheral nervous systems). Frailty is a strong risk factor for urinary incontinence. Indeed, older women are more likely to have mixed (urge + stress) incontinence than any pure form (Fig. 11-18). In analogy with the other geriatric syndromes, urinary incontinence derives from a predisposing condition superimposed on a stressful precipitating factor. Accordingly, treatment of urinary incontinence should address both. The first line of


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InternalMed_Harrison. urinary incontinence derives from a predisposing condition superimposed on a stressful precipitating factor. Accordingly, treatment of urinary incontinence should address both. The first line of treatment is bladder training associated with pelvic muscle exercise (Kegel exercises) that sometimes should be associated with electrical stimulation. Women with possible vaginal or uterine prolapse should be referred to a specialist. Urinary tract infections should be investigated and eventually treated. A long list of medications can precipitate urinary incontinence, including diuretics, antidepressants, sedative hypnotics, adrenergic agonists or blockers, anticholinergics, and calcium channel blockers. Whenever possible, these medications should be discontinued. Until recently, it was believed that oral or local estrogen treatment alleviated the symptoms of urinary incontinence in postmenopausal women, but this notion is now controversial. Antimuscarinic drugs such as tolterodine,


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InternalMed_Harrison. believed that oral or local estrogen treatment alleviated the symptoms of urinary incontinence in postmenopausal women, but this notion is now controversial. Antimuscarinic drugs such as tolterodine, darifenacin, and fesoterodine are modestly effective for mixed-etiology incontinence, but all of these drugs can affect cognition and so must be used with caution and with monitoring of cognitive status. In some cases, surgical treatment should be considered. Chronic catheterization has many adverse effects and should be limited to chronic urinary retention that cannot be managed in any other way. Bacteriuria always occurs and should be treated only if it is symptomatic. Bacterial communities isolated from the urine of women with urinary incontinence appear to differ with the type of incontinence; this observation suggests that the bladder microbiota may play a role in urinary incontinence. If so, this microbial population would be a potential target for treatment.


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InternalMed_Harrison. Undernutrition and Anorexia There is strong evidence that the healthy mammalian life span is greatly affected by changes in the activity of central nutrient-sensing mechanisms, especially those that involve the rapamycin (mTOR) network. Polymorphic variations in the gene that encodes mTOR in humans are associated with longevity; this association suggests that the role of nutrient signaling in healthy aging may be conserved in humans. Normal aging is associated with a decline in food intake that is more marked in men than in women. To some extent, food intake is reduced because energy demand declines as a result of the combination of a lower level of physical activity, a decline in lean body mass, and slowed rates of protein turnover. Other contributors to decreased food intake include losses of taste sensation, reduced stomach compliance, higher circulating levels of cholecystokinin, and, in men, low testosterone levels associated with increased leptin. When food intake decreases to a


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InternalMed_Harrison. of taste sensation, reduced stomach compliance, higher circulating levels of cholecystokinin, and, in men, low testosterone levels associated with increased leptin. When food intake decreases to a level below the reduced energy demand, the result is energy malnutrition.