Carl W. Peters
Rebecca J. Beyth
Miho K. Bautista
The elderly population in the United States is growing at a remarkable rate, with considerable implications for delivery of intensive care to those in the later years of life. The numbers tell the story: in the 2000 U.S. census, those 62 years of age and older represented 14.7% of the population. At that time, those 85 years of age and older numbered 4,239,587, or 1.5% of the American population, an increase of 1.2 million more than found within the similar population range 10 years earlier (1). As of 2000, the life expectancy beyond the age of 65 years was nearly 19 years for a woman and 16 years for a man. Similar predictions for those 85 years old were 7 and 6 years, respectively (2). At the dawn of the 20th century, the elderly population of the United States was a small percentage of its total, 4%, or 3.1 million people; presently, the corresponding value is 35 million people. Based on revolutionary advances in public health and the development of medications and techniques of acute medical care provided to those born in the 20 years after World War II, 70,000,000 individuals will find themselves in the population subgroup known as “elderly” by 2030 (3). At that time, those 65 years and older are forecast to compose 26% of the population of Florida, which is projected to have become the third most populous of the 50 states (4). By virtue of the diseases and natural organ aging and deterioration that accompany 65—and more—years of living and working, those who advance into this age range become increasingly voracious consumers of medical care resources, including the specialized capabilities of the intensive care unit. In 2005, spending by Medicare for those older than 65 years totaled $342 billion, representing 17.1% of the total of $2 trillion spent nationwide for health care (5). Intensive care consumes 4% of national health care expenditures (6). During the last 6 months of their lives, 11% of Medicare recipients spend 8 or more days in the ICU; various studies documenting ICU occupancy by those older than 65 years old note that this ranges from one quarter to one half of the available beds (7,8). The magnitude of these statistics portend the profound financial burden that must be borne to provide a medically sound and appropriate depth of care, a significant portion of which will be provided in the ICU. Because of the magnitude of these expenditures, which are projected to continue their slow but exponential growth, the argument has been made that, in the context of increasing demand for limited health care resources—an economically unsustainable situation—blanket cost-cutting actions such as limiting scarce ICU availability to those who would “most benefit” society and themselves in later life should be instituted. The geriatric population, in some minds, does not qualify for this category of expenditure, given their diminished physical functionality and limited life span—and therefore, less payoff in return for resource use compared to a younger population. This “logic,” however, belies reality. Although levels of functionality diminish with advancing age, albeit with a very wide bell curve contour, many individuals continue to perform both complex physical and intellectual tasks well into their eighth or ninth decades of life, bringing to bear resources of experience and problem solving not yet acquired by their descendents. Additionally, while flirting with the tactic of cost savings through measures that “cut out the expensive waste” in the ICU care of the elderly may fascinate some, thoughtful analyses argue persuasively that such a superficially derived position is misleading and inaccurate (9,10,11). Furthermore, at least in the United States, while increasingly alarmed by the financial implications of medical care costs associated with an aging population, we continue to postpone in-depth reckoning with the consequences and management of this information. Until we are ready to deal with this issue, one must maximize use of the resources available, while being mindful of the individual patient's expectations and likelihood of recovery. In the management of geriatric medical issues, recognition of the unique pathophysiology of the elderly patient may lead to streamlining of what might otherwise be a prolonged and painful ICU admission, either by recognition of the futility of the care or by amending the clinical strategy based on assessment of the distinctive clinical features, thereby extending the availability of scarce resources.
The response of the human body to physiologic insult evolves with age. A parallel with outdoor activity is useful in understanding this evolution. Imagine that a man is placed on a long ridgetop that is quite wide and smooth, and that man is told to walk down the middle of the ridge with his eyes closed. Unknown to him, as he walks, the ridge slowly becomes strewn with larger and larger rocks, and narrows inexorably as he approaches the end. Initially, the man walks quickly, with little risk of tripping or nearing the edge. As he advances farther, however, his drifting excursions off the centerline each take him closer to the treacherous rocky edge, increasing the risk of a fall. If he is careful and walks slowly, he hears the wind blowing near the cliff and is able to redirect himself away from the danger. Eventually, however, the narrowed ridgetop is completely covered with loose rocks to the very edges, and no step is possible without catastrophe. By analogy, one can think of the human body as possessing a certain amount of physiologic reserve that sustains it through times of stress brought on by disease or injury, with the maximum amount of reserve being present in young adulthood. With age, baseline organ function declines at a generally predictable rate, leaving the aging person with progressively less and less capacity to respond fully and expeditiously to stressful demands. Furthermore, there is the accumulation of permanent detrimental consequences of lifestyle decisions, such as tobacco use and lack of exercise, and of only partially controllable genetic influences, such as familial hypercholesterolemia or essential hypertension, with which the aging individual must contend, thereby increasing the likelihood of succumbing to a stressful physiologic insult. The progressive impairment of physiologic vigor is exemplified by the exponential increase in the death rate from sepsis with age, although the incidence of sepsis increases only linearly (12).
Cardiovascular Disease in the Elderly
Cardiovascular (CV) disease is pervasive in the elderly. Approximately 35% of all deaths in the United States are attributable to one of several manifestations of this pathophysiology, namely coronary artery disease and other conditions that involve the myocardium, hypertension, and arteriosclerosis of the central and peripheral arterial tree and cerebral vascular system, with three fourths of these deaths directly attributable to a cardiac cause (13). This proportion is higher in the more aged population, with CV disease manifesting itself as a complicating cofactor in the management of any older person's serious illness. For example, although only 6% of the U.S. population is 75 years of age or older, such individuals account for 30% of all myocardial infarctions and 60% of the infarction-related deaths (14).
Aging and the CV System
Studying the effect of the natural aging process on cardiovascular physiology is quite complex. From the epidemiologic standpoint, it is difficult to differentiate the basis of decline in cardiovascular function of the well-conditioned octogenarian who exercises aggressively from that of his sedentary twin who has led a life of excess, because some features and consequences of natural aging resemble those seen with disease. Although degenerative cardiovascular processes are most often looked on as what happens as you grow old, these have been demonstrated not to be the obligatory sequence of events in human aging (15,16). For all intents and purposes, the common causative elements within modern civilized existence, such as diet, minimal demands for aerobic exercise, and recurrent and ubiquitous emotional and physical stress are so intimately associated with mere existence that they may be looked on as inevitable and unchangeable. The clinical consequences to these presently unalterable processes may be perceived by the clinician or investigator as the natural process of cardiovascular aging, but the accuracy of this statement is difficult to determine. The steepness of the downward slope of this decline is increased by both a sedentary lifestyle and by the cardiovascular disease processes that are epidemic in western society's geriatric populations. Some features of cardiovascular physiology in the elderly are identical to those of younger individuals, primarily those measured in the resting state, but are affected by processes that are presently characterized as immutable in the aging process.
A degenerative process that occurs in most elderly individuals is that of stiffening of the central arterial tree with advancing age. Although the consequences of this process do not manifest in acute ways within the direct purview of the intensivist, they induce chronic progressive conditions that complicate critical illness in the elderly, warranting discussion. Oxygen- and nutrient-bearing blood is carried to organs via the conduit of the vascular arterial tree. In doing so, distensible large arteries perform transport and cushioning functions, transforming pulsatile flow into a steady stream of blood to the periphery (17). Release of the potential energy stored with each heartbeat within the stretched arterial wall elastin fibers propels the column of blood smoothly toward the muscular arterioles and capillary bed (17). With age—and likely related to both replacement of deteriorating, nonregenerating structural elastin fibers with nondistensible collagen, and to the progressive calcification of wall structural components (18)—vascular remodeling causes the progressive slow dilation and stiffening of the arterial wall, transforming the robust, pliant central vasculature typical of youth to that commonly seen in the elderly, more akin to a thick-walled, stiff, nondistensible garden hose (19,20). Augmented tensile and shear stresses related to the nonlaminar flow characteristic of fluid flow through vessels with impaired compliance contribute to progressive occlusive disease (21) that is typically found at turbulent areas of narrowing, bending, and bifurcation (22). The prominent manifestation of this progressive central arterial stiffening is that of the so-called systolic hypertension syndrome—the gradual increase in systolic blood pressure with simultaneous diastolic decline or maintenance at the same level (23). In years past, the transmission velocity of the cardiac-generated pressure impulse was discovered to change with patient age and to vary as a function of central arterial stiffness (24,25,26,27). With increased central arterial elastance—in other words, stiffness—comes an increased velocity of impulse transmission in both the forward and backward (i.e., reflected) directions. In the young, with distensible central arteries, the arrival of the reflected wave coincides with diastole, thereby augmenting coronary perfusion and modulating the magnitude of the disease-inducing tensile shear forces on the vasculature. Youthful vessels have little disease, and thus seldom display the wide pulse pressure that is the hallmark of central thickening. Aging, stiff central arteries transmit the cardiac impulse outward more rapidly and turbulently such that its reflected return arrives at the end or even the height of systole (27). In those with such vessels—the elderly—is seen isolated systolic hypertension, the term seeming to imply a benign connotation consistent with the previous generalized opinion that sustained diastolic pressure elevation was the lethal culprit (28). More recently, the insidiously destructive nature of the augmentation index—the reflected augmentation of systolic pressure at the expense of diastolic coronary perfusion, yielding an easily observed increased pulse pressure (29)—has been recognized as the true contribution of central vascular stiffness to the morbidity and mortality among the elderly. Indeed, the speed with which the cardiac impulse is propelled outward, known as pulse wave velocity (PWV), and pulse pressure (PP) are recognized as factors strongly associated with all forms of cardiovascular disease:
PP = SBP - DBP
where SBP is systolic blood pressure and DBP is diastolic blood pressure. These measurements, when elevated over time, strongly predict mortality and are indicative of vascular and cardiac pathology, even if the patient's blood pressure measurements and examination findings at a given moment, such as at the time of the initial evaluation of a geriatric patient on ICU arrival, appear benign (21,28,30,31).
Other specific processes within the cardiovascular system change with age, seen even in the most healthy and intact geriatric physiology. With myocardial aging, there is a predictable loss of myocytes, possibly from apoptosis (32,33). Since cardiac myocytes are unable to regenerate, functional “replacement” of these contractile cells occurs by hypertrophy of the remaining myocytes, with only slight overall loss of myocardial mass. With preservation of cardiac fibroblast synthetic function despite myocyte loss, cardiac tissue becomes infiltrated with an increasing proportion of noncompliant connective tissue, causing the gradual thickening and stiffening of the ventricular wall and impairment of left ventricular diastolic relaxation and filling. This appears similar to the fibrosis seen in pathologic left ventricular hypertrophy leading to congestive heart failure (34). Diastolic relaxation is an energy-requiring process, consuming ATP to recover calcium back into the sarcoplasmic reticulum after its release during systole (35). Malfunction of the calcium-sequestering mechanism, involving a dysfunctional SERCA (smooth endoplasmic reticulum calcium) pump, is felt to be at least partially responsible for the increased percentage of geriatric heart failure patients who display lusitropic dysfunction (36). As a consequence, the filling process is delayed, with a smoother—though steeper, as depicted on the left ventricular pressure–volume loop—slope of passive diastolic ventricular filling (37) into a more slowly relaxing ventricle that ends diastole with lower volume. The ventricle thereby becomes more dependent on the contribution of atrial contraction to ventricular filling for optimum systolic function. In other words, as the aging ventricle becomes progressively more and more lusitropically impaired, it fills progressively less well by virtue of thickening from age-related myocyte depletion and incomplete relaxation from SERCA pump dysfunction. The resulting dependence on volume repletion, control of heart rate, and the robust synchronous atrial contribution to ventricle filling assume increasing importance in managing geriatric cardiac issues. In the critically ill elderly patient in whom there is a very high chance of harboring occult diastolic dysfunction, if not overt congestive heart failure, the strictest attention must be paid to maintenance of both sinus rhythm and volume repletion within a narrow range. Furthermore, the reassurance of a preserved ejection fraction viewed on echocardiogram may be deceptive, since systolic function is preserved in the normal healthy geriatric heart (38) and can be maintained at greater than 50% in a very high proportion of those whose cardiac status has deteriorated to the point of being symptomatic from lusitropically deficient congestive heart failure (39,40).
Equally important is recognition of the progressive decrease in the responsiveness of myocardial and vascular tissue to adrenergic stimulation (41,42,43). This phenomenon manifests itself as an age-associated lowering of exercise-induced maximal heart rate, with a gradual shift to augmented ventricular filling to meet exercise-related demands. The stressed or exercising younger adult musters additional cardiac output by increasing contractility and heart rate and by vasodilation in the areas of maximum demand—in the case of exercise, the skeletal muscles—in response to increased levels of norepinephrine and epinephrine, with unchanged or reduced end systolic volume as output is ejected into a dilated vascular tree. The elderly, by comparison, with reduced myocardial and vasodilatory responsiveness to exercise-induced beta-1 and beta-2 stimulus (43), have increased reliance on ventricular filling (the Frank-Starling mechanism) to achieve augmented cardiac output (44,45).
Optimal care requires clinical awareness of age-related cardiovascular differences such as diastolic dysfunction. Currently, there are no medications that restore the vigor with which calcium is resequestered within the SER during diastole, nor avert the obligate loss of myocardial cells, nor restore the responsiveness of the elderly cardiovascular system to endogenous catecholamines, although supplements can be supplied via a continual infusion in the ICU setting. Meanwhile, the clinician must contend with the challenge of managing the stiff, hypertrophied ventricle perfusing a nondistensible vascular tree. With the fraction of elderly patients who harbor cardiovascular disease being as large as it is in western society, clinical manifestations of this condition may complicate the management of virtually every older patient. In those not displaying the “usual, common” symptoms of heart failure traditionally taught in medical school, one must maintain a level of suspicion to recognize the more subtle presentations of age-related lusitropic pathophysiology.
Acute Coronary Syndrome in the Elderly
Acute coronary syndrome (ACS) presents a particular challenge from the standpoints of recognition and management. Optimal management of myocardial ischemia and infarction in the elderly population is less well defined than in younger populations, since those older than 75 years are less commonly included in ischemia-related studies (46). The elderly mortality rate exceeds that found in younger individuals (47), but the elderly stand to benefit most in mortality reduction from intervention (48). In the young, acute ischemic processes are often associated with onset of classic angina or one of its common equivalents; in the elderly, symptoms may be much more subtle and nondistinguishing, but the condition is more likely to be fatal (49). Therefore, proper identification of myocardial ischemia and infarction must occur in a timely manner, as aggressive management is warranted. The diagnostic picture can be further complicated by the postoperative sedated state, when hypotension or arrhythmias may easily be attributed to hydration or electrolyte disturbances rather than to coronary insufficiency. ICU patients often have contraindications to intervention, and the risks of reperfusion therapy must be weighed thoughtfully against the benefits. While evaluating the need for intervention with the cardiologist, the patient, and family members, the intensivist must remember that only a small percentage of elderly patients warranting reperfusion therapy actually receive it (50), even when no absolute contraindication exists. This is attributable to two misperceptions: the magnitude of risk to the geriatric patient, and the likelihood of benefit (48). The cardiology literature contains studies covering enormous numbers of patients evaluating the strategies of treatment to optimize the restoration of coronary blood flow, and in-depth discussion is beyond the scope of this chapter. Nonetheless, a few generalities focusing on the management of the elderly patient can be made.
One relevant observation is the paucity of elderly individuals who have been included in many of the large trials (51), especially considering the prevalence of coronary disease in this group; for this reason, optimal management strategies may not be as well defined as those that address ACS within a younger population. ACS must be identified correctly, nonetheless, since treatment strategies of the patient subgroups within this very large category differ (52). One of the underpinnings of any strategy is that of expeditious implementation, in that the more quickly the intervention is begun, the greater the mass of myocardial tissue preserved and the greater number of lives saved (53). Rapid restoration of coronary blood flow is the major goal of treatment for STEMI (ST-segment elevation myocardial infarction). A decrease in mortality of 25% with reperfusion therapy has been demonstrated (54). From identification of STEMI, it is recommended that the infusion of thrombolytics begin within 30 minutes, or that the dilating balloon be inflated within 90 minutes (55). In general, percutaneous coronary intervention (PCI) is the preferred mode of treatment for STEMI, as long as the time constraints are met (56). Extrapolation of this analysis to the elderly population is done only with trepidation, since only small numbers of elderly patients were included in the studies covered by this meta-analysis. By examining the subgroup data, nevertheless, it appears that elderly patients in this urgent situation of evolving myocardial infarction, in which the risk of death is particularly high by virtue of the risk factors associated with advanced age (57) and by the emergent nature of the situation, are best served by PCI (47,58). PCI yielded lower mortality in the elderly population than did thrombolysis, with more benefit found as age progressively advanced, although possibly at the risk of a slightly increased rate of major bleeding events. In the management of non–ST-segment elevation MI (N-STEMI), early invasive strategy with catheterization and revascularization (when warranted) significantly benefits those older than 65 years of age (59). The early invasive strategy, however, led to a significant increase in in-hospital major bleeding (16.6% vs. 6.5%; p = 0.009) and blood transfusion (20.9% vs. 7.9%; p = 0.002) in the patients older than 75 years of age. There were no significant increases in minor bleeding or stroke in any study group. The potential benefits of PCI in the elderly patient in the elective and emergent arenas must be weighed closely against the risks incurred by this group of individuals in the form of increased bleeding and vascular complications (60).
Cardiomyopathy
Decompensated heart failure (HF) is frequently encountered in the management of the critically ill elderly. In the United States, 5,000,000 persons suffer from heart failure, with more than 50,000 new cases diagnosed yearly; over 80% of the individuals with heart failure are older than 65 years of age (61,62,63). Symptomatic heart failure by itself carries a dismal prognosis, with a median survival of 1.7 years for men and 3.2 years for women (64). Critical illness superimposed on decompensated HF is challenging for even the most adept clinical wizard. Common causes for HF in the elderly include coronary artery disease and hypertension, followed by diabetes mellitus, valvular disease (especially aortic stenosis and mitral regurgitation) and cardiomyopathies other than ischemic (65). The incidence of heart failure increases with age; Framingham Study data reveal a doubling in incidence with each decade after 45 to 54 years of age (66). Factors abound in the critical care arena that may precipitate HF decompensation, suddenly destabilizing an already tenuous orchestration of treatment modalities. These include ischemia and infarction, which is more often “silent” and subtly manifested in the elderly (67), dysrhythmias and extremes of heart rate, fever and infection, medication side effects, and rapid fluid shifts such as with bleeding and aggressive fluid resuscitation. Suspicion of cardiovascular decompensation warrants aggressive timely investigation. Marginal coronary reserve should be presumed and investigated with measurement of cardiac enzymes and documentation of electrocardiogram patterns. An echocardiogram is usually available relatively quickly and may be useful in separating those suffering from lusitropic dysfunction from those with inotropic insufficiency. Particular points of interest to be investigated include systolic ejection fraction, lusitropic state (i.e., diastolic “relaxability” between contractions, reflecting preload), valvular integrity, and wall motion abnormalities. The wary intensivist should maintain a low threshold in the use of invasive monitoring to clarify an uncertain hemodynamic state and guide infusion of vasoactive medications. In the elderly patient with heart failure, an eroded reserve may not allow more than a trivial aberration beyond the margins of physiologic compensation.
Dysrhythmias
Dysrhythmias are frequent in the elderly patient (68,69), including those who manifest no other overt cardiovascular abnormalities—for example, the so-called lone atrial fibrillation. With advancing age, sinus node and conduction system integrity deteriorate, with gradual replacement of cardiac pacemaker cells by collagen and elastic tissue (70,71,72,73,74). Such triggering events as autonomic tone disruption (75,76), ischemia or infarction (which portends worse outcome) (77,78), anatomic alterations such as fluid overload or cardiac surgery (79,80), and a host of other cardiac conditions (81) may initiate potentially injurious tachyarrhythmic events, the most common of which is atrial fibrillation.
The occurrence of atrial fibrillation (AF) increases with age (82), carrying an increased risk of stroke and death (83) in those older than 60 years, even in the absence of other cardiac abnormalities. Several issues remain unsettled in the optimal management of AF (84). Of these, the two that receive the most attention are rate control versus rhythm control, and management of anticoagulation. The AFFIRM investigators (85) found no clear survival advantage to either rate or rhythm control in AF, but the rate control strategy did appear to manifest some advantages in the area of medication side effects. All choices for chemical control of rate and rhythm in the elderly population must be made within the skewed context of the high percentage of these patients who harbor comorbid conditions, especially heart failure. Choices for immediate rate control include beta-blockers and calcium channel blockers, remaining mindful of their impact on the state of heart failure compensation. Amiodarone or digoxin may be used in those with heart failure in the absence of an accessory pathway. Digoxin is not recommended in such patients, as it may precipitate profound tachycardia via the accessory pathway, with heart rate nearing 300 beats per minute (bpm), leading to rapid cardiovascular collapse. In the case of acute hemodynamic instability, recovery of sinus rhythm with biphasic DC cardioversion after sedation is appropriate. Digoxin or amiodarone can provide rate control, but the former is not recommended for chemical cardioversion, and several medications primarily used by cardiologists surpass the latter in class of recommendation for this purpose (86).
There is no “one size fits all” solution to the question of anticoagulation, although it has been well demonstrated (87) to reduce the incidence of stroke related to AF. Equally well demonstrated (88,89) is the extent to which anticoagulation is underused in the elderly, presumably because of concern for bleeding risk in this accident- and fall-prone population, and inadequate awareness of the extent to which AF warrants anticoagulation to minimize the risk of AF-associated stroke. Although use of direct thrombin inhibitors in AF is under investigation, at present for the long-term patient, anticoagulation is best accomplished by using vitamin K antagonists for those at highest risk of severe stroke (>75 years), and aspirin for those elderly (<65) with less stroke risk; in the 65 to 75 age range, either will suffice. Target international normalized ratio (INR) of 2.0 to 3.0 is recommended for those receiving vitamin K antagonists (90). Clearly, maintenance of long-term anticoagulant regimens have limited applicability to the patient who suffers a critical injury or illness, and rapid normalization of INR may be warranted. Quickly reversible heparin may be a better choice in such a situation, if continued anticoagulation is warranted at all. AF that persists beyond 48 hours mandates anticoagulation for 2 weeks (86,90) or transesophageal echocardiogram evaluation by a cardiologist—with particular attention to the left atrium and its appendage—for the presence of clot prior to conversion to sinus rhythm. The most complete and recent American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines for management of all issues relating to atrial fibrillation appear in the references to this chapter (86).
Complex ventricular dysrhythmias and ventricular tachycardia (VT) present a difficult management problem in the elderly. Sudden cardiac death is, to a large extent, a product of untreated VT degenerating into ventricular fibrillation (VF), followed by asystole (91,92). In the elderly population as a whole, ambulatory monitoring reveals a very high instance of ventricular arrhythmias, including VT (93,94). Therefore, there is a high likelihood that any given elderly ICU patient will have worrisome ventricular ectopy, with a significant number displaying VT (95,96,97). Despite the high prevalence of ventricular ectopy in this population, only those patients with underlying heart disease have a poorer long-term prognosis by virtue of the ectopy (98). Underlying heart failure and left ventricular hypertrophy (99) associated with increased ectopy are prognostic of an increased likelihood of subsequent adverse cardiac events, including myocardial infarction and sudden death (100). Pulseless cardiac arrest due to VF or VT warrants management following current advanced cardiac life support (ACLS) guidelines, using cardiopulmonary resuscitation with chest compressions and immediate defibrillation (101). The timely recognition of these lethal arrhythmias and initiation of most recent ACLS protocols is crucial for patient welfare, since survival is a direct function of the immediacy of electrical resynchronization therapy (102). Defibrillation for VF provides the optimal chance of survival if provided within 3 minutes (103). The frequency of ventricular ectopy is increased in the geriatric ICU population where several factors, including ischemia, sepsis, extremes of heart rate, hypoxia, electrolyte imbalance, and autonomic disruption associated with recent surgery, can aggravate cardiac irritability and induce lethal arrhythmias in a marginally compensated individual. These inciting factors should be readily recognized and reversed in the constantly vigilant ICU environment. Empiric treatment of ventricular ectopy per se, however, has been demonstrated to be more proarrhythmic than beneficial (104,105), often increasing mortality and/or inducing drug-related side effects. Nonetheless, certain medications warrant closer attention. Beta-blockers after myocardial infarction have been demonstrated to reduce subsequent total mortality and sudden cardiac death (SCD) (106). After initial enthusiasm, amiodarone has not, in a recent study of cardiomyopathy patients, proven to be beneficial in reducing SCD when given prophylactically to patients with ejection fraction ≤35% and New York Heart Association (NYHA) class II or III heart failure, as compared to that achieved with a single-lead automatic implantable cardiac defibrillator (AICD) (107). With the emergence of AICD technology, there has been a gradual reduction in mortality from SCD in elderly patients, in whom there is a higher incidence than in the general population of coronary artery disease. In this situation, the AICD appears superior to medications in preventing SCD (108). Elderly individuals accrue an equal or greater benefit from AICD placement compared to younger individuals, with minimal risk involved in the actual placement of the device (109). The indications for AICD placement continue to evolve (110,111,112). Clearly, the expertise of a cardiac electrophysiologist is indicated when medications or AICD placement are considered in the management of a patient at risk for or who has survived SCD.
With advancing age comes a parallel increase in conduction system disease, often mandating permanent pacemaker (PPM) placement. In 1990, the implantation rate for cardiac pacemakers was 329 devices per million patients; by 2002, the rate had risen to 612 per million (113). The mean age of implanted patients was 75.1 years (113). Such statistics make it likely that an elderly person with a PPM will at some time arrive in the intensive care unit for a noncardiac ailment. Furthermore, advances in engineering and microcircuitry have allowed the development of single devices that incorporate PPM and AICD capability. Although management of issues directly referable to these increasingly complex machines is more within the purview of the cardiologist, certain data can be gathered quickly that will expedite investigation of such a device's performance, as is well detailed in the recent literature (114,115,116). Considerable guidance can be formulated based on information found on the manufacturer's card carried by the patient, and on a chest radiograph, showing lead position and integrity, and an electrocardiogram with rhythm strip. Details of electrical patterns should be apparent from the rhythm strip and interrogation findings. Any ICD discharge should be investigated with interrogation.
In the instance of withdrawal or termination of unwanted medical care from a terminally ill patient, the intervention of a normally functioning ICD or PPM is directly contrary to the natural process of dying, analogous to instituting cardiopulmonary resuscitation (CPR) when “Do Not Resuscitate” orders exist. In such an instance, deactivation is indicated (117).
Pulmonary Disease
Human pulmonary function deteriorates with age, occurring on the microscopic level with resulting functional changes and on the macroscopic level from alterations of chest wall anatomy. Quantification of this age-induced deterioration is quite difficult. Measurement solely of the effects of aging on the respiratory system would require exclusion of all factors that influence respiratory function other than those relating directly to breathing and gas exchange, namely (A) chest wall mechanics, (B) lung histologic structure, and (C) neural/muscular respiratory control. The list of such influencing factors includes environmental pollution and tobacco smoke exposure, occult disease, and effects of previous nutritional deficiencies. Furthermore, these factors complicate contemporaneous comparison between different generations because of the variability of their impacts on these generations. The alternative is the longitudinal study of a rigorously screened cohort of subjects, which has been performed in a few cases (118,119). Analytic difficulties notwithstanding, it is possible, in some instances, to identify the predictable alterations in respiratory physiology that occur with age, so as to prepare the intensivist to contend with a common form of critical illness pathophysiology in the elderly—that of profound respiratory insufficiency.
Microscopic examination of tissue samples from young and older individuals reveals the basis of age-related changes in pulmonary physiology. One sees alveoli from older patients to be less fully surrounded by the elastin/collagen network (120,121), each less robustly tethered open from without, yielding an increasingly compliant lung with compromised recoil (122). Loss of cartilaginous supporting tissue in the small airways further contributes to loss of lung elasticity. The concepts of first, airway collapse, worsened in the patient with advanced emphysema, and second, the progressive stiffening of the chest wall with age allow one to forecast and better understand the evolution of geriatric respiratory function: alterations in lung volume due to gas trapping at higher residual volumes and deterioration of gas exchange. In addition, neural factors alter responsiveness to changes in PaCO2 and PaO2 (123,124). The magnitude of these changes varies from person to person.
Geriatric flow–volume curves reveal “scooping” of the expiratory limb, implying early closure of airways, and increased residual volume as seen in obstruction from airway collapse in emphysema, a similar phenomenon (125,126). Furthermore, chest wall compliance decreases from calcification of the cartilaginous rib and thoracic spine joints, with kyphotic changes stiffening the thoracic spine itself (127). Compromised compliance results in a substantial increase in the work of breathing, to be provided by deconditioned, aging muscles, likely in the face of low cardiac output and poor nutrition. Such factors yield the respiratory pattern displayed by a significant percentage of the elderly: rapid, shallow breathing at rest, with little exertional reserve. A diagram of lung volumes versus age reveals a slight increase in functional residual capacity (FRC) and residual volume, with a steep rise in closing capacity, the volume at which airway collapse takes place in the dependent airways. Thus, airway closure occurs in the upright person without pulmonary disease at a lung volume that exceeds FRC (128). In other words, airway collapse can take place in the upright healthy elderly lung even during quiet resting tidal volume during spontaneous breathing, with ventilation/perfusion (V/Q) mismatch increasing shunt fraction and alveolar-arterial partial pressure of oxygen (PO2) gradient, with relative hypoxemia for a given inspired fraction of oxygen (FiO2). Subjecting the supine elderly patient with compromised FRC to controlled positive pressure ventilation demands that meticulous attention must be paid to ventilator management to correct V/Q mismatch. The complex details of mechanical ventilation are addressed elsewhere. (Chapter 130). In general, one must use PEEP (positive end-expiratory pressure) while administering the lowest FiO2 possible, avoiding overdistention of the better aerated (more superior, nondependent) alveoli, and providing sufficient expiratory time to avoid auto-PEEP and breath stacking, as well as sufficient tidal volume into the restricted thoracic cage without exceeding peak pressure limits.
It is commonly held that healthy elderly individuals have a significantly lower PaO2 for a given FiO2, compared to equally healthy younger counterparts. Traditional teaching has proposed the following formulae (129,130):
PaO2 (mm Hg) = 104.2 - (0.27 × age)
PaO2 = 100.1 - 0.325 × age (years)
PaO2 = 109 - 0.43 (age)
More recent studies have yielded varying results (131,132), certainly not confirmatory of a pronounced “predestined” decline in oxygenation with age, and questioning the hypothesis that progressive disruption of the matching of ventilation and perfusion in the elderly is actually the cause of whatever decline actually occurs (133). The related questions of rise in (A–a) gradient with age, and “normal” age-related decline in PaO2 are, similarly, quantified by different investigators (129,130,134,135).
Nutritional Issues
Malnutrition, also known as undernutrition, is a common companion of elderly individuals and frequently a complicating factor in the efficient and successful management of an elderly ICU patient. The natural decline in energy expenditure with age begins at about age 30 and accompanies the age-related increase in body fat–to–protein ratio (136,137,138). The evolution of nutritional intake with age is one of decline that exceeds the decrease in energy expenditure (139,140) for various reasons. Thus, even the healthy individual will eat less and lose weight with time, and will be at risk for malnutrition if illness occurs or social support wanes. For example, in elderly nursing home patients, a population in whom initially minor medical problems can quickly blossom into life-threatening conditions, the incidence of undernutrition can approach 85% (141,142). Malnutrition at the onset of critical illness portends poor outcome, as does insufficient nutritional support during the course of the illness (143,144). Mortality is considerably higher in the malnourished elderly patient, compared to those who are nutritionally replete (143). Undernutrition has several common causes: (i) functional decline and social isolation from family and other support systems, (ii) anorexia associated with older age—the so-called anorexia of aging—or chronic illness, (iii) anatomic or gustatory impediments to mastication or swallowing, (iv) abuse or neglect, and (v) insufficient financial resources (145,146,147,148). Therefore, the prevalence of undernutrition in hospitalized, geriatric patients is relatively high (149,150) and is often unrecognized unless sought specifically (151). Identification of malnutrition in the elderly patient (151) may be facilitated by the routine employment of easily used physical examination and laboratory screening tools as part of an organized, proactive nutrition screening program (152). There is little literature addressing nutrition in the geriatric intensive care unit patient per se, and the principles set forth below are generally applicable to any ill elderly patient.
Undernutrition imposes a considerable burden on the marginally compensated geriatric patient. The conditions known as protein-energy malnutrition (PEM) and micronutrient deficiency complicate the treatment of several conditions seen in the ICU. These include the contribution of gastrointestinal tract nonintegrity to multiorgan system failure (153,154) and other common cardiovascular (155,156), pulmonary (157,158,159), and infectious issues (160). Wound healing is impeded by a poor nutritional state (161,162,163); in particular, development of decubitus ulcers is more common in malnourished elderly individuals, and successful management is decidedly more difficult (164). Patients with PEM are at increased risk for serious complications while in the hospital (165), with slower recovery (166), poorer functional status at discharge, and higher rates of mortality after discharge (167,168).
Malnutrition is a disorder of body composition in which macronutrient and/or micronutrient deficiencies occur when nutrient intake is insufficient, resulting in reduced organ function, abnormal blood chemistry studies, and suboptimal clinical outcomes (169). Nutritional deficiency is found in 35% to 65% of elderly hospitalized patients (170). Of the available screening techniques reflective of nutritional status, one of the most revealing is the dietary and weight loss history, as found in such structured nutritional questionnaires as the Mini Nutritional Assessment (MNA) tool and others (171,172). While probably more applicable to the long-term outpatient setting, certain pieces of information gathered from the patient or family via the MNA are helpful in providing a “snapshot” of the patient's nutritional status. Obtaining the patient's weight immediately on admission is an obvious step in assessing nutritional condition. Because of the various types of body habitus found in ICU patients, a calculation of the Quetelet body-mass index (BMI) is helpful to standardize weight to height, providing a relatively standardized estimate of body fat (173):
BMI = weight (in kg) divided by height (in m2).
The Department of Health and Human Services defines normal BMI as being within the range of 18 to 24.9, with those with BMIs less than 18 being underweight, the overweight range being 25 to 29.5, and those displaying a BMI above 30 being obese (174). These data, however, cover—in the United States—the adult population as a whole. The picture in a unique subset such as the elderly is more complex. In the geriatric population, BMI less than 20 is predictive of nearly 50% 1-year mortality (175), a stronger predictor of mortality than is diagnosis. Similar results were found among critically ill adults with a BMI less than or equal to the 15th percentile (176). Such data lead researchers to suggest that the optimal BMI lies higher in the elderly than in the general population (177); this supposition has been supported by a large study demonstrating that the detrimental effect on mortality of excess body weight declines with age (178). Furthermore, the BMI calculation does not differentiate between differences in body morphology; obese, malnourished individuals whose BMIs fall within the normal range may go unidentified using this formula (179). Since an age-associated loss of height can be significant in the geriatric population, especially in kyphotic individuals, substitution of arm span as the denominator of the BMI calculation has been suggested to give a more accurate comparison of an individual patient's BMI to the standards that were originally established in younger persons (180,181). Arm span is identical to height in younger years; although height may decline with age, arm span remains unchanged, providing more accuracy within the previously determined younger age frame of BMI reference. Knee height, as measured from plantar surface to top of patella with the ankle at 90 degrees, is another measurement (182) that can be substituted in corrected BMI calculations in those with diminished stature who are unsuitable for arm span measurement. Triceps skin fold thickness and midarm circumference can also provide an idea of body fat content (183).
In general, however, use of the BMI in the elderly is suspect, regardless of the height measurement used, as there are few normal BMI data that specifically describe those older than 65 years. The ages of geriatric patients included in nutrition studies vary, anthropometric characteristics vary in different advanced decades, and incidence of weight-changing diseases and conditions—such as cancer or the anorexia of aging—increases with age (184). These factors make the formulation of accurate statements and recommendations addressing ideal weight and BMI in the elderly difficult to formulate (137). Although the percentage of older Americans falling into the definition of obese continues to climb (185), one should not make the assumption of nutritional integrity. Age-related redistribution of caloric stores may disguise the overweight elderly patient with severe PEM (179) as one who is obese in the mind of the unwary clinician who is not familiar with the metabolism of geriatric patients, and the pathophysiologic implications of these changes (186). Misguided hypocaloric feeding, directed at mobilizing excess fat stores in the obese, but malnourished, elderly patient may worsen the situation by leaving the ongoing catabolic protein breakdown associated with critical illness uncorrected (187).
Several easily measured laboratory parameters are reflective of nutritional status on admission, and some can be followed periodically to assess the success of nutritional support. Albumin is a product of hepatic metabolism, synthesized ultimately from ingested or infused nitrogenous precursors in the presence of adequate caloric support. Although it is held that the serum albumin level is reflective of the nutritional state, various factors influencing serum albumin levels make it only vaguely reflective of overall nutritional status (188), with a ROC (receiver operating characteristic) curve rating of 0.58 compared to the clinical subjective global assessment tool. Serum albumin level does decline somewhat with age—0.8 g/L per decade for individuals older than 60 years of age—but generally remains within the numerical normal range. Significantly reduced albumin concentration, therefore, should be attributed to disease processes (189,190) and be aggressively investigated. A substantial decline in serum albumin concentration is accurately predictive of mortality and worse outcome among the elderly, both in the setting of apparent health and illness (191,192,193,194,195), possibly reflective of the presence of chronic disease- or inflammation-induced mediators that simultaneously suppress albumin gene expression (196). The half-life of albumin, 18 to 19 days (197,198,199), makes its use less than optimal in monitoring metabolic and synthetic functions, in which rapid change is significant. Alternatives include prealbumin and retinol binding protein. The former has a half-time of 2 days and is not affected by age but is elevated with steroid use. The latter has a half-time of 12 hours, decreases slightly with age, and is elevated in the setting of acute liver injury. The serum level of renally excreted retinol binding protein is artificially elevated in renal failure, which may suggest nutritional integrity (199).
As critical illness induces substantial catabolism (199,200,201), resting energy expenditure (REE) rises during the first 2 weeks of this state, with mobilization of nitrogen stores as a component of the associated inflammatory response to physiologic insult. Total energy expenditure (TEE) may rise to as high as 40 to 50 kcal/kg/day in critically ill, septic, or trauma patients, repletion of which is most difficult without correcting the underlying inciting process (202,203). In the elderly individual with marginal nutritional reserve at the onset of critical illness, early provision of caloric and protein support is warranted. The farther behind the patient starts, the more difficult is the recovery of positive nitrogen balance. Catabolic processes characteristic of critical illness are not reversible by nutrient supplementation alone; they are incited by inflammatory mediators rather than by pre-existing deficiency or inadequate repletion and are thus not forestalled by aggressive nutritional support. Traditional guidance recommends 25 kcal/kg/day of nutritional support, with an additional protein supply of 1.2 to 1.5 grams/kg/day (169), based on usual body weight. Obese individuals, defined as above (204,205), warrant feeding based on ideal, rather than usual, body weight:
Men: IBW (kg) = 50 + 2.3 kg per inch over 5 ft
Women: IBW (kg) = 45.5 + 2.3 kg per inch over 5 ft
Where IBW is ideal body weight.
Greater accuracy can be achieved using the Harris-Benedict equations to determine the estimated resting energy expenditure (REE) as a guide to calculation of nutritional needs (206):
Men: REE = 66.5 + (13.75 × weight in kg) + (5.003 × height in cm) - (6.775 × age in years)
Women: REE = 655.1 + (9.563 × weight in kg) + (1.850 × height in cm) - (4.676 × age in years)
This may be insufficient in the critically ill geriatric patient in the throes of the inflammatory response, unless the higher stress and activity factor is used (207). Resting metabolic rate may be nearly double in the critically ill or injured individual (202) compared to the healthy noninjured person. Protein supplementation at a rate of 2 g/kg is recommended for the most critically ill, catabolic patients although, in the initial stages of such a condition, the rate of catabolism may just not be ameliorable despite aggressive support in appropriate quantities (208). Initial empiric dosages should subsequently be adjusted based on indirect calorimetry and nitrogen balance studies if there is suspicion of inadequate nutritional support as revealed by following the previously noted markers of protein synthesis as surrogates of metabolic recovery (209). Enthusiastic overprovision of macronutrients in a misguided and vain attempt to thwart and correct inflammatory catabolism, on the other hand, leads to a host of complications and considerable morbidity (210) for which the geriatric patient may be unable to compensate. Furthermore, the confounding factor of obesity sometimes seen in the nutritionally deficient geriatric patient makes the recipe that provides optimal nutritional support frustratingly difficult to determine. In such situations, measurements of energy expenditure performed at frequent intervals are even more strongly advisable, since energy requirements fluctuate with time and medical condition, and vary significantly from those of younger patients, on whose metabolism nutritional recommendations are often based. In general, most, although not all, studies show that enteral nutrition is preferred because of the purported preservative effects on intestinal mucosal integrity, cost issues, and a lesser degree of risk exposure to the patient, both infectious and mechanical, associated with placement of flexible nasointestinal feeding tube versus central line for parenteral nutrition (169,211,212,213,214,215). This statement, however, is the source of endless controversy and the basis of considerable investigation and an inordinate number of publications (216,217,218). The risks and benefits of the common routes of nutritional support were recently reviewed in exquisite detail (219).
Renal Considerations
Deterioration of renal function in a critically ill patient has a dramatic impact on survival. Acute renal failure (ARF) carries a mortality of nearly 30% in a general ICU population; a decline of renal function of even lesser severity also impacts mortality significantly (220) and more so in the geriatric population. An elderly patient with compromised renal function will often succumb to the added insult of renal failure after a complex surgical intervention or traumatic injury. The chance for at least partial renal functional recovery after critical illness-related ARF is greater than 90% among those alive a year after their illness (221). Presently, there is little treatment for renal insufficiency or failure other than optimization of hemodynamics, prevention of further damage, and aggressive treatment of the complications. The intensivist holds a pivotal position in the understanding of renal physiology and principles of renal protection to minimize the impact of critical illness on renal function and its influence on outcome.
As in all physiologic systems in the elderly, there is a gradual deterioration of renal function, beginning at age 30 years (222,223). When the sixth decade is reached, this deterioration generally continues, although with a very wide bell curve of distribution (224). It is well described (225) that renal blood flow declines after the fourth decade (226). There is loss of renal—primarily cortical—mass (227) and the onset of glomerular sclerosis and involution, causing a decrease in the number of functional glomeruli (228), in turn causing a decrease in glomerular filtration rate (GFR) of 30% to 40% by age 80 (222,229). Deterioration of tubular function parallels that of the glomerulus (230). In the elderly patient, factors other than age-related deterioration may complicate renal function, including pre-existing renovascular disease, hypertensive nephrosclerosis, or hypotension associated with trauma or neglect. Clearly, accurate assessment of GFR is fundamental to the prudent management of the elderly patient's medication dosages and fluid and electrolyte status. Laboratory measurement of serum blood urea nitrogen (BUN) and creatinine (Scr), used individually or in a ratio, act as surrogates of renal function. They are, however, less accurately reflective of renal function in the elderly than in a younger person. BUN rises slightly with age over 60 years, paralleling the gradual decline in renal function. Scr reflects muscle mass and, while completely filtered (and only minimally secreted) into the tubule and therefore generally reflective of GFR, may not climb as expected despite age-related falling renal filtration (231). Age-related diminished muscle mass, often paralleling the deterioration of renal function, generates less creatine (and thus, creatinine), leading to what may erroneously be looked upon as a normal (i.e., lower than expected Scr for given GFR that is diminished from the effects of age and its associated diseases) baseline Scr.
The wary clinician will individualize each assessment of GFR by using the Cockcroft-Gault formula (232) to generate a more accurate estimate of function based on weight, age, and serum creatinine:
Creatinine clearance = [(140 - age) (weight in kg)]/(72 × Scr) (arithmetic result × 0.85 = clearance for female patients)
This formula provides a “snapshot” of function at a given time and is most useful if calculated on ICU arrival and daily thereafter. Recall that Scr may be affected (i.e., increased) by excessive muscle breakdown due to rhabdomyolysis, critical illness, or medications. Other laboratory surrogates of GFR have been devised, such as the measurement of cystatin C (233,234,235) and MDRD (modification of diet in renal disease) equations (236), but the ease with which the Cockcroft-Gault calculation is performed makes its routine replacement unlikely. If CFR remains uncertain, urine collection for measurement of creatinine clearance can be done with fair accuracy using at least an 8-hour urine collection period (237,238). However, 24-hour collection is preferred in critically ill patients and is easily done in patients with indwelling urinary catheters.
There are alterations of fluid and electrolyte handling by the aging kidney of which the intensivist must be aware, related to tubular dysfunction proportional to the decline in GFR. Although baseline electrolyte values and fluid status are likely within normal ranges in the previously healthy geriatric patient, age-related tubular dysfunction narrows the limits of correction of water and sodium aberrations that the patient can readily accomplish. Sodium excretion and reabsorption declines in efficiency, with those older than 60 years requiring considerably more time to achieve homeostasis in the face of sodium overload or deprivation (239). Similarly, the range of specific gravity and osmolarity achievable in the face of water excess or deficit is narrowed in comparison to that of a younger individual (240). Rectification of acid-base perturbations is similarly deficient (241). The stresses of critical illness or injury typical of the elderly ICU patient intensify the effects of these functional deficiencies, and must be foreseen and addressed aggressively to forestall the profound effects of deterioration of renal function on morbidity and mortality. These stresses include volume depletion from gastrointestinal (GI) bleeding, severe dehydration, diarrhea, aggressive diuresis, insensible losses in burn patients or those with drainage from wounds or fistulas, and disruption of renal blood flow from sepsis, shock, or surgical causes such as complex renovascular surgery.
Management of deteriorating renal function requires accurate diagnosis of the inciting cause, while addressing complicating or resultant metabolic derangements and preventing further insult. The details of the diagnosis of renal pathology are not specific to the geriatric patient and are addressed elsewhere in this text (Chapter 163). It is important to recognize that acute kidney injury occurs in as many as 67% of ICU admissions (220), as identified by RIFLE (risk, injury, failure, loss, end-stage) criteria (242), and that the effect of renal deterioration is quite detrimental to the elderly individual. Initial evaluation must include such fundamental steps as performance of a physical examination that may reveal an occluded urinary catheter causing an enlarged bladder. Hypovolemia, both absolute, as in severe dehydration, and relative, as in sepsis, must be aggressively corrected with appropriate fluid and blood products; invasive monitoring is warranted in this population of patients with compromised reserve. Dosage adjustment of potentially nephrotoxic medications is mandatory, using assessment of GFR as a guide. Antimicrobials such as cephalosporins and aminoglycosides, nonsteroidal anti-inflammatory medications, certain chemotherapeutic medications, and angiotensin-converting enzyme inhibitors are common offenders (243). Loop diuretics, mannitol, and natriuretic peptides have largely been demonstrated to be of no use in preventing incipient acute renal failure that may seem to be starting (244). The role of N-acetylcysteine and bicarbonate to minimize the deleterious effect of radiocontrast medium on renal function in critically ill individuals remains controversial, but it should generally be used in any elderly patient receiving contrast (245,246,247). Beyond awareness of medications that impact renal function, there is the effect of age-related diminished renal function on drug metabolism and excretion (248). Recall that common indicators of renal function, BUN and Scr, although appearing normal in the elderly, may mask a compromised GFR, risking medication-induced complications if this fact is overlooked. Early nephrology consultation is encouraged when RIFLE criteria suggest compromised renal function; similarly, a critical care pharmacologist can assist in clarifying renal-active medication issues in these complex patients.
Assessment and Management of Traumatic Injuries
Elderly individuals suffer a significant number of severe and often lethal traumatic injuries, the analysis and management of which can be frustratingly complex (249). In the 55 to 64 age group, unintentional injury was the sixth leading cause of death in 2003; in those older than 65 years, nearly 35,000 deaths were attributed to trauma (250). Most serious injuries are caused by falls, the occurrence rising dramatically as age advances into the 60s and beyond (251). Falls from a standing or even sitting position, imparting an apparently trivial amount of kinetic energy to frail tissue, may result in fatal injury, disproportionately accounting for half the trauma-related deaths when compared to those of younger people (252). Most remaining significant traumatic injuries to the elderly involve motor vehicles, either as vehicle occupants or as pedestrians (253), while there is a small but persistent incidence of injury and death from penetrating trauma in the geriatric population, declining to less than 1% in those older than 75 years (254,255). Evaluation and management of the injured elderly require familiarity with characteristic injury patterns and knowledge of comorbid diseases and particulars of geriatric physiology that impact treatment (256). Practice management guidelines for geriatric trauma (257) are helpful in this situation.
Immediate assessment of the resuscitation status of any patient arriving in the ICU, whether from the operating room, the emergency department, or elsewhere in the hospital, is imperative. The paucity of overt physical findings of intravascular fluid deficiency that may be seen in the elderly patient adds additional urgency to its accurate analysis. The lusitropic compromise that typifies the geriatric patient demands avoidance of overgenerous fluid repletion. Although standard protocols may serve as a guide to ensure that all systems are evaluated, one must remain mindful that standard and acceptable initial hemodynamic measurements may actually conceal unsuspected injury or bleeding in the confused elderly trauma patient who may be taking medications that affect vital signs. Airway management in the elderly carries its own set of difficulties. Age-associated arthritic spinal, mandibular, and arytenoid deformities; an increased incidence of occult cervical spinal injuries (258,259,260); marginal respiratory drive; and compromised airway reflexes may warrant securing the airway preemptively, avoiding a later “crash” difficult airway emergency. A thorough and detailed physical examination is fundamental. Timely sequential measurement of routine hematology tests, even in the stable geriatric patient, may reveal unsuspected hemorrhage. Arterial blood gas analysis is a convenient tool since it is quickly performed and allows frequent measurement of hemoglobin, base deficit, and lactate. The latter two values are powerful indicators of resuscitation status and, when elevated, predict increased mortality in the elderly population (261,262). In one study of elderly trauma patients, mortality was decreased from 54% to 34% (p <0.003) by institution of a protocol of trauma team activation and early noninvasive and subsequently invasive monitoring for resuscitation of all patients older than age 70 years with an injury severity score (ISS) greater than 15, even for those with nonworrisome initial vital signs and fairly minor injuries (263). This supports the precept that achieving adequate tissue perfusion early, while often difficult to accomplish, is fundamental to successful trauma management. One must be mindful, furthermore, that while invasive monitoring carries its own risks, judicious use of these tools can improve outcome and survival in the elderly trauma patient (263,264,265).
Certain patterns of injury are found in geriatric patients. Traumatic brain injury (TBI) afflicts the elderly with extraordinary severity. High mortality leaves fewer survivors, most of whom suffer debilitating sequelae (266). In 2003, there were 90,000 emergency department visits involving TBI in those older than 65 years, of whom 38.4% died (267). Some series document mortality rates for severe TBI in those older than 55 years of age as high as 80% (268). Initial neurologic examination of an elder with significant intracranial injury may be deceptively normal (269). Suspicion of an occult central nervous system (CNS) injury must be maintained if such individuals arrive in the ICU without radiologic evaluation having been performed, warranting frequent, sequential neurologic evaluations by the same examiner and a conservative approach to ordering a cranial CT scan. Those elderly whose cause of TBI is a fall—nearly 50%, from 1988 to 1998—are likely to have three or more significant comorbid conditions complicating ICU management (270,271). Outcome after TBI is optimized by using meticulous clinical assessment, timely radiologic re-evaluation, and aggressive invasive monitoring to facilitate immediate recognition of worsening status, such as that due to recurrent intracranial hemorrhage, while minimizing secondary injury.
Secondary injury may occur when even transient episodes of hypoxia or hypotension affect cerebral perfusion pressure (CPP) (272) and, in the setting of elevated intracranial pressure (273), hyperglycemia (274), hyperthermia (275), or aggressive hyperventilation (276,277). Infusion of hypertonic saline (278) may supplement the management of elevated intracranial pressure that resists control by the usual initial measures. The cornerstone of TBI treatment is the maintenance of cerebral oxygenation by ensuring adequate oxygen content and CPP, guided by data derived via invasive intracranial monitoring devices that are inserted based on specific indications (279). Little, however, has been written specifically addressing geriatric CPP requirements. Although a CPP of 70 mm Hg is considered the standard (279), this has not been rigorously tested specifically in the elderly as it affects outcome. Cerebral autoregulation in the elderly is subject to the same influences as those that affect the younger individual. In this population, the abundance of comorbidities, such as untreated hypertension, may have acclimated the cerebral vasculature to a new baseline, making invasive cerebral monitoring even more critical in ensuring adequate perfusion for the aging brain. The profound influence of even mild TBI (280,281,282) on short- and long-term outcome in the elderly patient mandates aggressive monitoring and optimization of cerebral perfusion parameters.
Cervical spine injury is not uncommon in the geriatric trauma patient (283); plain radiographs (258,284) may be unrevealing of fracture or difficult to interpret because of age-related boney changes obscuring acute pathology (259). Fracture of the upper cervical spine is more common in the elderly than in younger individuals, especially in those who have fallen (260) and are more likely to be unstable (285). Helical CT is superior to plain radiographs to identify cervical spine injury in this population (284,285,286,287). Cervical spine pathology may exist in totally asymptomatic individuals with unremarkable examination findings, only to be discovered by a diligent clinician who takes extra steps to search for such an injury (288,289). In the cervically injured geriatric patient, the likelihood of coincident painful injury—a distracting injury in which the pain from another injury distracts the patient's attention from the perception of neck pain or a condition, such as altered mental status—that would affect the examiner's decision to forgo radiographic evaluation is so high as to make such an evaluation imperative in nearly all cases. One must be mindful of the greater likelihood that cervical injuries in the elderly often occur in the arthritis-prone superior vertebrae, which are notoriously difficult to depict on plain films (290), and consider CT evaluation of virtually all geriatric trauma patients in whom even subtle symptoms, history, or mechanism of injury suggest cervical injury, regardless of the initial examination findings or any comforting results of a protocol-based decision-assisting algorithm that suggest the safety of less aggressive investigation.
Traumatic rib fractures impose substantial morbidity. Those older than 45 years of age with more than four fractures are particularly affected (291). In a study of patients traditionally defined as elderly—those older than 64 years—rib fractures profoundly affected morbidity and mortality, with longer length of stay in the ICU, more frequent pneumonia, and overall mortality rate of 22% versus 10% (p <0.001) in those less seriously affected (292). Of note in this study was that rates of mortality and pneumonia both increased with each additional rib fracture. Epidural analgesia would appear to be the ideal technique to alleviate the pain associated with rib fractures to optimize pulmonary status and, indeed, has been found to be successful in nongeriatric adults (293,294). In one recent study, however, the opposite has been demonstrated in an elderly population when compared to parenteral analgesia (295).
The management of abdominal trauma follows pathways similar to those for younger patients, with certain caveats. As in other body systems in the elderly, findings on physical examination indicating serious abdominal pathology can be subtle, especially when complicated by distracting orthopedic or mild head injury. Liberal use of CT scanning is strongly recommended if mechanism of injury, external abdominal findings such as a seat belt mark, or laboratory evidence of hypoperfusion (elevated base deficit or serum lactate) suggest visceral injury. Nonoperative management of certain radiologically well-characterized injuries of solid organs—namely the spleen, the liver, and the pancreas—in the hemodynamically stable elderly patient is becoming increasingly accepted as evidence of the success of this approach accumulates (296,297,298).
Serious orthopedic injuries frequently befall older victims of polytrauma. Decrease in bone mineral density (BMD) with age older than about 30 years heightens the risk of fracture in general; this phenomenon is observed in varying degrees in both genders and all races, but is particularly severe in postmenopausal Caucasian women (299,300). Pelvic fracture in the aged is associated with a greater likelihood of significant blood volume transfusion and mortality (p <0.005) (301). Open pelvic fracture often has substantial associated bleeding, which is seldom treatable, with the exception of arterial bleeding, in any way other than with early stabilization, aggressive transfusion, and correction of coagulopathy in hopes of eventual tamponade of the retroperitoneal bleeding source. Arterial bleeding from lacerated pelvic vessels warrants embolization (302). The more typical scenario, however, is that of diffuse venous oozing, which, nonetheless, may render the elderly patient hemodynamically unstable, requiring large-volume transfusion of blood products as a temporizing measure until anatomic stabilization can be achieved (302,303). The presence of an open pelvic fracture, with frequent associated visceral injuries (304,305), further worsens outcome (301). Hemodynamic consequences of large-volume transfusion and frequent septic complications can drive the mortality in both younger and older adults to nearly 80% (306). Long-bone fractures, in general, warrant early immobilization and stabilization to minimize ongoing hemorrhage and generation of fat emboli; such fixation improves mortality significantly (307). Optimal timing of surgical stabilization of these quite morbid fractures, however, is a complex issue to resolve when they occur in the larger setting of the patient with severe head, chest, or abdominal injuries (308). Although postponing the operative stabilization of a femur or complex pelvic fracture to allow time to achieve hemodynamic stability in a traumatized patient is not without benefits, it is also not without risks (309,310). Prolonged immobilization of the elderly patient with such a fracture prior to stabilization forgoes the profound respiratory benefits of early mobilization, more likely exposing the patient to extended intubation, pulmonary thromboembolus, and infection.
Studies of elderly trauma patients have consistently documented the higher mortality expected in this population (254,264,310,311). The mortality rate begins to climb for those in their sixth decade, even for less severe injuries (312), when compared to younger individuals; for moderate injuries, the mortality curves diverge beginning in the fifth decade, with a steeper turn in the seventh. With advancing age, trauma-related mortality rates for those in the seventh decade and above range as high as 47% for those with an injury severity score (ISS) more than 30, compared to those 45 years old or younger (20.1%) (313). Within the context to which allusion was earlier made—that of future payoff in return for resource use—the complexity and enormity of the issue grows as health care costs rise, and as the percentage of the population represented by the elderly increases. As these rising numbers of individuals cease working, and, thereby, are no longer able to generate an income that can be taxed to finance public health care funding programs such as Medicare, or be used to pay for personal private health insurance to cover costs of traumatic injuries, the costs of providing that trauma—and, indeed, all—care will have to be borne by a source other than the patients themselves. Based on the size of these costs and the likelihood of marginally or poorly acceptable outcomes among a substantial minority of geriatric trauma patients (3,313,314,315,316), investigations have been performed that have tried to answer two important trauma outcome-related questions. These are as follows: Is it possible to identify an elderly trauma patient who will certainly die later, even if the patient survives the initial period of resuscitation, surgery, and further stabilization; and to what level of functioning will the elderly survivor of trauma-related intensive care return on discharge? To many elderly individuals, the prospect of lingering in the netherworld of prolonged posttrauma multiorgan system failure with the certainty of death pushed back “only as long as the machines keep me running,” or existing debilitated in a nonhome environment where even bowel function and bathing are at the behest of another, is worse than death itself, not really living at all, and is the basis of much concern among the elderly.
There are, however, grounds for hope. In one study of victims of penetrating trauma more than 60 years old, 91% were discharged home, most without assistance (255). The postdischarge level of functioning in elderly patients surviving blunt trauma varies widely, as would be expected in a population whose baseline physiologic attributes are so diverse. Clearly, even the healthiest octogenarian is not the physiologic equal of a two-sets-of-tennis 65-year-old and will have a significantly decreased likelihood of returning to premorbid functionality, although both individuals may be described as elderly. Nonetheless, even after significant traumatic injuries, a substantial percentage of recovering geriatric patients, even the very old, will be able to live relatively independently, albeit for some patients, in a protected environment with assistance. Many will be able to return home with or without periodic professional assistance (314,317,318,319). In one retrospective study of 38,707 elderly trauma patients with a mean ISS of 11.7 ± 0.05 (standard error of mean), in which 10.3% died in hospital, 52.2% of the survivors went home. The percentage of patients returning home after serious traumatic injuries, many requiring prolonged intensive care, varied considerably with age, from 66.7% of those 65 to 74 years to 30.5% of those 85 years of age or older (320). With aggressive rehabilitation, improvement in function and independence can continue for substantial periods of time after discharge, including in those who have suffered TBI (321). In another study, recovery of elderly trauma patients was improved by early involvement of physicians from a geriatric trauma consult service, who assisted in recognition and treatment of medical issues, and in advanced care and disposition planning (322). The likelihood of leaving the hospital after a trauma-related ICU admission can be improved from the outset, as noted earlier, by aggressive attention to adequate resuscitation to rectify suboptimal perfusion, by attention to maintenance of acceptable CPP in TBI, and by recognition and treatment of the early subtle signs of cardiac and respiratory decompensation. Finally, trauma care outcome must be scrutinized within the context of profound personal and social issues, beyond those solely of medical success, that are integral to ICU care in patients in this age group.
Outcome after a Critical Illness in the Geriatric Population
Most people die after the age of 65 years. Although life expectancy is greater at any given age now than it was even 15 years ago, with an increasing percentage of patients falling within the age range when death within a few years is a real possibility even in the most healthy of individuals, objective evaluation must be made of the appropriateness—and likelihood of successful outcome—of aggressive critical care medical services that are provided to those in this age group. At present, geriatric patients represent between 25% and 50% of all ICU admissions (8,9). In 2000, ICU costs represented 13.3% of hospital costs, 4.2% of health care expenditures, and 0.56% of the U.S. gross domestic product (323). The enormous expense associated with ICU care has prompted some analysts to raise the subject of limits on expenditures for the elderly (324,325), since, for example, an 80-year-old who is supported through a 3-week bout of sepsis is not likely to return to the revenue-generating work force for an additional 30 years as would a similarly afflicted 35-year-old. Indeed, the literature dealing with geriatric medical issues is liberally populated with articles addressing ageism in the context of delivery of services to the elderly (326,327,328), raising the concept of providing less aggressive or intensive levels of acute care to an elderly person solely on the basis of age. Meaningful discussions addressing the more philosophical issues of critical care such as the correct level of aggressiveness of care and appropriateness of withdrawal of care, to say nothing of the financial issues, simply cannot be addressed in any rational way without an accurate picture of what critical care accomplishes in these elderly patients.
A successful ICU admission is certainly defined within cultural and social, as well as personal, contexts. Although the family member's “do everything for Granddad” dictum is familiar, it often represents an unrealistic appraisal of the possible benefit from certain modalities of care that can be done, but possibly should not be done. Although the ICU is designed as a temporary environment that allows support of body functions during recovery, the complicated technology and meticulous attention to detail that characterize that environment is not the basis for such “magical” accomplishments as saving the life of a patient who has a lethal condition, despite the expectations and exhortations of some. Nonetheless, death can often skillfully be forestalled with polished and professional ICU care to such a degree that it may occur immediately after a de-escalation of such care, or later while the patient is on the general ward, in a step-down unit or rehabilitation facility, or after returning home (either early or late) to a life with varying similarity to that prior to the original serious medical occurrence (329). Meaningful discussions with elderly patients and their families, whether prior to complex morbid surgical procedures or as an ICU stay extends past the first few days, must include accurate outcome data, so as to facilitate informed decisions regarding the specifics and suitability of continued care. Studies addressing outcome in the critically ill geriatric population have produced various results that vary with the metric employed, the duration over which the outcome is monitored, and broad intrapopulation patient variability. The latter category highlights differences in age, premorbid physical status, statements of preference regarding aggressiveness of long-term medical care, and patient and family declarations addressing such subjective concepts as posthospitalization quality of life.
The term geriatric population encompasses a quite heterogeneous group of individuals from the standpoint of age, premorbid general medical health as a reflection of functional status, severity of the event that justifies ICU admission, and cultural mores as they impact interaction with the modern health care structure of the country in question. Studies assessing the results of care delivered to the elderly may or may not reflect this diversity (330), making interpretation of individual study conclusions and their application to individual clinical situations suspect. Furthermore, the term outcome must be specifically defined as to the depth of support required by the post-ICU elder and its correspondence with that autonomous person's preferences, which, again, may vary widely based on cultural, religious, national, and other parameters. Although many elders prefer a less aggressive care regimen designed around end-of-life comfort at the expense of duration of remaining life, many desire life extension in the face of critical illness by use of complex technology despite a vanishingly small or nonexistent expectation of recovery (8,331,332). Furthermore, the clinician's perceptions of the patient's desires may not be accurate, and thus may lead to withdrawal of care or withholding of a modality of treatment in a manner that would not be considered in the care of a younger patient (331). It is important to remember that while age may be associated with worse outcome from critical illness, numerous investigations have demonstrated that age, in and of itself, is less a factor than is the severity of the specific condition that warrants intensive care or the general medical condition of the patient prior to the institution of intensive care (333,334,335). Despite being subjected to procedures that are potentially morbid, the otherwise healthy patient may fare quite as well as a younger individual (335,336). In one study of outcome after intensive care in octogenarians, postdischarge survival was more accurately forecast by care dependency at the time of discharge, as a reflection of premorbid condition and severity of illness, rather than solely by length of stay (337). Quality of life (QOL) in the post-ICU elder is not necessarily inferior to that of younger individuals (338); indeed, overall QOL has been demonstrated to be similarly good across age groups ranging from middle-aged to very old (above 80 years) (339,340). It must be remembered, however, when evaluating outcome data in elderly ICU patients, that while ICU survival is less a function of age than of premorbid condition or severity of illness (30,337,338,341,342), when the aggressive ICU support is de-escalated with recovery, physiologic reserve may no longer suffice to forestall death in the few months after discharge, and thus may not be reflected in ICU outcome statistics. With the wide variability of desires for aggressiveness of care displayed by the elderly and the inaccuracy with which they are analyzed by many physicians (343), the most important function of the geriatric intensivist may be that of conducting a thorough discussion at the outset of care with the patient and involved family members so as to tailor intensiveness of care to the patient's educated and informed preferences.
Drug Dosing in the Elderly
As more patients live longer and consume a larger proportion of medications, it is necessary for health care providers to understand the risks, benefits, and consequences of drug therapy in older patients. Several important pharmacologic and nonpharmacologic issues influence the safety and effectiveness of drug therapy in this population. Pharmacokinetics, the study of the action of a drug in the body over a period of time, changes with age. The physiologic changes accompanying aging affect the pharmacologic processes of absorption, distribution, metabolism, and excretion (Table 103.1). The effects of these age-related changes are variable and difficult to predict. Some changes are related solely to aging, whereas others most likely are due to the combined effects of age, disease, and the environment. Although increasing age is often accompanied by decreased physiologic reserve in many organ systems, independent of the effects of disease, this change is not uniform. There is substantial variation from individual to individual, making some older patients more vulnerable than others. The alterations in pharmacokinetics and pharmacodynamics that occur with increasing age suggest a pharmacologic basis for concern about the vulnerability of the elderly to the effects of medications. Unfortunately, the results of epidemiologic studies that explore these relationships are unclear, in part due to the small number of older people included in premarketing studies relative to the patient population most likely to be exposed to the drug. The oldest—those aged 80 years or older—have not generally been included in clinical trials of investigational drugs, and those older subjects who do participate in such trials tend to be healthy “young-old” people. Thus, the results of these trials and the side effects reported often have limited application to the older patient with multiple illnesses, taking several medications. In general, consideration of the individual patient, his or her physiologic status—hydration, nutrition, and cardiac output, and how this status affects the pharmacology of a particular drug are more important in prescribing that drug than any specific age-related changes.
|
Table 103.1 Age-Related Changes Relevant to Drug Pharmacology |
||||||||||||||||||
|
Absorption of drugs, which occurs mainly by passive diffusion, changes little with advancing age. The changes listed in Table 105.1 could potentially affect drug absorption. More important changes result from concurrent administration of several medications. For example, antacids decrease the oral absorption of cimetidine, and alcohol accelerates the absorption of chloral hydrate.
Unlike absorption, drug distribution is affected by age in clinically meaningful ways. In older persons, the relative increase in body fat and the decrease in lean body mass alter drug distribution so that fat-soluble drugs are distributed more widely and water-soluble drugs less so (344) (Table 103.2). The increased distribution of fat-soluble drugs can delay elimination and may result in prolonged duration of action of a single dose. This effect is especially important for drugs such as hypnotics and analgesics, which may be given in single doses on an intermittent basis. For example, the volume of distribution of diazepam is increased almost twofold in older patients, and the elimination half-life is prolonged from 24 hours in young patients to approximately 90 hours in the elderly. In contrast, the volume of distribution of water-soluble compounds, such as digoxin, is decreased in older patients, and thus the dose required to reach a target plasma concentration is decreased. Likewise, due to the decreased volume of distribution, the loading dose of aminoglycosides is less in older patients.
|
Table 103.2 Volume of Distribution of Commonly Prescribed Drugs |
||||||||||||||||||||
|
||||||||||||||||||||
For drugs that bind to serum proteins, equilibrium exists between the bound or ineffective portion and the unbound (free), or effective, portion. For acidic drugs that are highly bound to albumin, the free plasma concentration may correlate best with pharmacologic effect. Although albumin levels decrease only slightly with age, they tend to decrease during periods of illnesses. This can result in elevated levels of unbound acidic drugs in older persons during episodes of illnesses, and thus in an increased potential for toxicity. These changes can be significant for drugs such as thyroid hormone, digoxin, warfarin, and phenytoin. On the other hand, some basic drugs, such as lidocaine and propranolol, bind mainly to alpha-1 acid glycoprotein, an acute phase-reactant protein. The concentration of this protein tends to rise as a person ages and is elevated following myocardial infarction and in chronic inflammatory diseases and malignant conditions (345). The plasma binding of these drugs is increased in older patients, but because these age-related changes are not great, their exact clinical relevance is uncertain.
Overall, changes in protein binding are an important consideration initially when a drug is being started, when the dosage is changed, when serum protein levels change, or when a newly administered drug displaces another protein-bound agent. Because the free portion of the drug is generally smaller than the bound portion, the normal mechanisms of metabolism and excretion ultimately eliminate the free drug. If either hepatic or renal function is impaired due to age or disease, this elimination may be slowed.
Although in vitro studies of drug-metabolizing enzyme activity from human liver biopsy samples have not demonstrated any changes with aging, some investigators speculate that the decline in liver size with age may result in decreased metabolic capacity. A significant decline in hepatic blood flow occurs with age, reductions of 25% to 47% being reported in persons between the ages of 25 and 90 years. This decrease in hepatic blood flow is clinically important because hepatic metabolism is the rate-limiting step that determines the clearance of most metabolized drugs. This change is especially relevant for drugs that undergo rapid hepatic metabolism (e.g., propranolol). Also, drugs that undergo extensive first-pass metabolism are likely to reach higher blood levels if hepatic blood flow is decreased.
The liver metabolizes drugs through two distinct systems: phase I metabolism, involving drug oxidation, reduction and hydrolysis; and phase II metabolism, involving glucuronidation, sulfation, acetylation, and methylation. Phase I metabolism is catalyzed primarily by the cytochrome P-450 system in the smooth endoplasmic reticulum of hepatocytes. Cytochrome P-450 enzymes are a superfamily of microsomal drug-metabolizing enzymes important in the biosynthesis and degradation of endogenous compounds such as steroids, lipids, and vitamins, as well as the metabolism of most commonly used drugs (346). Phase I metabolism activity decreases substantially with age. Drugs that are metabolized through phase I enzymatic activity have prolonged half-lives. Examples of some drugs whose metabolism is slowed because of these age-related changes in hepatic metabolism include meperidine, phenytoin, diazepam, propranolol, theophylline, labetalol, lidocaine, and quinidine. Age-related changes in phase I metabolism, coupled with the use of multiple medications, place older patients at increased risk for adverse drug reactions. Adverse drug reactions occur due either to inhibition or induction of cytochrome P-450 enzymes, especially CYP3A, which is thought to be involved in the metabolism of more than half of the currently prescribed drugs (347). Clinical outcomes are determined by the potency of the CYP3A inhibitor (moderate versus potent), the availability of alternative pathways, and the seriousness of the symptoms. A drug is considered a potent CYP3A inhibitor if it causes more than a fivefold increase in the plasma concentration of another drug that is primarily dependent on CYP3A for its metabolism (348). Thus, clinicians should be cognizant of potential drug interactions when they prescribe drugs from classes that include potent or moderate inhibitors of CYP3A. If a potent CYP3A inhibitor or inducer and substrate must be taken together, dosage adjustment and close clinical monitoring are warranted to avoid adverse reactions.
Phase II hepatic metabolism involves the conjugation of drugs or their metabolites to organic substrates. The elimination of drugs that undergo phase II metabolism by conjugation is generally altered less with age. Thus, drugs that require only phase II metabolism for excretion (e.g., triazolam) do not have a prolonged half-life in older people. These drugs contrast with agents such as diazepam that undergo both phases of metabolism and have active intermediate metabolites. Although the effect of aging on hepatic drug metabolism is variable, phase I metabolism is the process that is most likely to decrease in older persons. The apparent variable effect of age on drug metabolism is probably due to the fact that age is only one of many factors that affect drug metabolism. For example, cigarette smoking, alcohol intake, dietary modification, drugs, viral illness, caffeine intake, and other unknown factors also affect the rate of drug metabolism. Induction of drug metabolism can occur in older persons. The rate of elimination of theophylline is increased by smoking and by phenytoin in both young and older persons (349). Not all metabolizing isoenzymes are induced equally in the young and the old. For example, antipyrine elimination is increased after pretreatment with dichloralphenazone in younger patients but not in older patients.
An important pharmacokinetic change that occurs in persons of advanced age is that of reduced renal drug elimination. This change results from the age-related decline in both glomerular filtration rate and tubular function. Drugs that depend on glomerular function (e.g., gentamicin) and/or on tubular secretion (e.g., penicillin) for elimination both exhibit reduced excretion in older patients. Because drug elimination is correlated with creatinine clearance, measurement of creatinine clearance is helpful in determining the maintenance dose. As noted earlier, the average creatinine clearance declines by 50% from age 25 to age 85 despite a serum creatinine level that remains unchanged at approximately 1.0 mg/dL. The Cockroft-Gault formula (see earlier discussion) is useful in the accurate assessment of renal function when planning administration of renally excreted drugs. Although helpful in adjusting for age, weight, and the measured serum creatinine level, it does not account for individual variation.
Altered renal clearance leads to two clinically relevant consequences: the half-lives of renally excreted drugs are prolonged, and the serum levels of these drugs are increased. For drugs with large therapeutic indices (e.g., penicillin), this is of little clinical importance, but for drugs with a narrower therapeutic index (e.g., digoxin, cimetidine, aminoglycosides), side effects may occur in older patients if dose reductions are not made. Thus, it is not surprising that digoxin is the drug that most often causes side effects in the elderly, especially if the dose exceeds 0.125 mg daily (350). To define dose requirements further, therapeutic drug monitoring should be performed for drugs with a low therapeutic index.
In addition to the factors that determine the drug concentration at the site of action—the pharmacokinetics—the effect of a drug also depends on the sensitivity of the target organ to the drug. The biochemical and physiologic effects of drugs and their mechanisms of action—pharmacodynamics—and the effects of aging are not clearly known. Pharmacodynamics has been even less extensively studied in older patients than has been pharmacokinetics. Generalizations are not straightforward, and the effect of age on sensitivity to drugs varies with the drug studied and the response measured. These differences in sensitivity occur in the absence of marked reductions in the metabolism of the drug and its related compounds. Thus, sensitivity to drug effects may either increase or decrease with increasing age. For example, older patients seem to be more sensitive to the sedative effects of given blood levels of benzodiazepine drugs (e.g., diazepam) but less sensitive to the effects of drugs mediated by beta-adrenergic receptors (e.g., isoproterenol, propranolol). Although an age-related decline in hormone receptor affinity or number (e.g., in beta-adrenergic receptors) is suspected, definitive data demonstrating such an alteration are sparse. Other possible explanations offered for these differences are alterations in second-messenger function and alterations in cellular and nuclear responses.
Since the response of older patients to any given medication is variable and cannot be foreseen, all drugs should be used appropriately, but judiciously, in older patients. The physician should resist the temptation to apply protocol medicine. In general, knowledge of the pharmacology of the drugs prescribed, limits on the number used, determination of the preparation and dosage based on the patient's general condition and ability to handle the drug, combined with downward adjustment of the dose in the presence of known hepatic or renal impairment, in concert with surveillance for untoward effects, will minimize the risks of medication use in the elderly.
Special Problems of the Elderly
As has been briefly addressed above, more people are living longer with chronic diseases, thus increasingly older patients are being admitted to the ICU. Over one half of all ICU admissions are patients older than 65 years of age, and they account for almost 60% of all ICU days (7,341,351,352). Unfortunately, many of these older patients' final days before death are spent in the ICU; 40% of Medicare patients who die are admitted to an ICU during their terminal illness, accounting for 25% of all Medicare expenditures (353,354). Additionally, of those who survive, many are discharged to a subacute facility with persistent organ failure where they eventually die. Dardaine et al. (355) reported a 6-month post-ICU survival of 53% in 116 patients over 70 years of age who had required mechanical ventilation for more than 24 hours. Compared to their younger counterparts, octogenarians have a higher ICU mortality rate (10% vs. 6%, p <0.01) and higher discharge rate to a subacute care facility (35% vs. 18%, p <0.01) (337). Furthermore, those discharged to a subacute care facility had a higher mortality rate compared to those discharged home (31% vs. 17%). Preadmission comorbidities and severity of illness were independent predictors of discharge to a subacute care facility. Degenerative brain disease, cerebrovascular disease, chronic heart failure, chronic pulmonary disease, diabetes mellitus, and malnutrition were more commonly associated with care dependency. Thus, the decision to admit an elderly patient to an ICU should be based not only on their comorbidities, acuity of illness, prehospital functional status, including quality of life, but also on their preference for the use of life-sustaining treatments if it is known. The underlying disease process is not altered despite the use of invasive procedures in terminally ill patients (356,357), and potential harm or discomfort can occur if invasive procedures are used inappropriately. To avoid such unintended consequences and enhance optimal end-of-life decision making, health care providers need to identify, explain, and negotiate consensus therapeutic goals (358).
Neurologic Disorders
Neurologic problems common among older adults in the critical care setting are delirium, stroke, and sleep disorders.
Delirium
Background and Risk Factors
Delirium is an acute mental disorder common among elderly patients. Fourteen percent to 56% of the hospitalized elderly develop delirium (359), increasing the 6-month mortality rate among these patients to 10% to 26% (360,361). Recognition is difficult, with only 25% of cases being diagnosed using standard screening tools (362,363). Delirium-associated morbidity complicates the hospitalization of 2.3 million older people annually, adding 17.5 million inpatient days and $4 billion to Medicare expenditures to cover increased lengths of stay and greater need for postdischarge institutionalization, rehabilitation, and home care (364,365,366,367). Older adults with multiple comorbidities, particularly pre-existing cognitive deficits, are predisposed (368,369,370), with a prevalence rate surpassing 50% during intensive care. Symptoms persist in nearly that number after ICU departure (371). Particularly at risk are those with a history of hypertension, smoking, elevated bilirubin level, recent epidural analgesia, and recent administration of morphine (369,370,372). Other predictors of delirium include respiratory disease, infection, fever, hypotension, hypocalcemia, and hyperamylasemia (373). Invasive devices, sensory alteration, and inadequate or overaggressive pain control likely aggravate delirium-inducing medication effects in the critically ill patient (369,372,374).
Pathophysiology
Specific pathophysiologic mechanisms are not well understood. The phenomenon can be viewed as a final pathway of various causes of acute brain dysfunction. These include the following: (a) direct brain injury from trauma, cerebrovascular disease, or central nervous system infection; (b) systemic disturbances such as hypoxemia, hypotension, renal failure, hepatic failure, sepsis, and endocrine dysfunction; (c) effects of toxic or pharmacologic agents such as anticholinergics, narcotics, and sedative-hypnotics; and (d) the consequences of withdrawal of substances to which the brain has developed tolerance (e.g., alcohol or benzodiazepines). Delirium is more likely to occur when these factors coexist in patients with pre-existing comorbidities (375,376,377,378,379,380,381,382,383,384,385,386,387,388). Current theory proposes alteration of central nervous system neurotransmitter levels and metabolism by age, medication, or illness as paramount in producing the mental status that characterizes delirium, particularly acetylcholine and dopamine pathways, and serotonin, GABA, histamine, glutamine, and norepinephrine systems (389,390,391,392).
Diagnosis
Criteria defining delirium are detailed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) of the American Psychiatric Association, specifically (a) a disturbance of consciousness with impaired ability to focus, sustain, or shift attention; (b) a change in cognitive function (in terms of memory, orientation, and language) or a perceptual disturbance that is not better explained by pre-existing or evolving dementia; (c) disturbance development over a short period of time in hours or days, fluctuating through the day; and (d) history, physical examination, or laboratory data suggestive of the abnormalities caused by a general medical condition (393). Additional features include alteration of sleep/awake cycle and psychomotor activities. Various instruments have been developed that allow accurate and timely diagnosis using these criteria (370,394,395,396) when the diagnosis is specifically sought. Patterns of psychomotor symptoms are termed hyperactive and hypoactive (397,398,399). Hyperactive patients are agitated and combative, with loud, inappropriately boisterous outbursts and motor activity that can be harmful to self or a caregiver. Those termed hypoactive alternate between calm, appropriate behavior and a minimally interactive, withdrawn state, making this variant easy to overlook. Delirium may erroneously be attributed to such conditions as dementia or depression (indeed, the three may coexist) or simply not be recognized (400), delaying the diagnosis. Delays may be explained by the following: (a) the fluctuating nature of the signs and symptoms, (b) inadequate or insufficiently detailed scheduled neurologic and cognitive assessments of patients at risk for delirium, (c) avoidance of interactions with patients displaying altered mental status, or (d) misperception of mental status changes “expected” in critically ill patients (401,402). Altered mental status in any patient suggests delirium; an organized approach to its investigation (403) that focuses on known risk factors is paramount to avoid overlooking the condition.
Of particular interest to the intensivist who manages elderly patients are alterations of mental status temporally related to surgical procedure, specifically delerium developing within the immediate (minutes to days) postoperative time, and the more indolent neurocognitive decline that may appear days to weeks to months later, termed postoperative cognitive dysfunction (POCD). The uniqueness of these conditions lies in their association with the postoperative period. Emergence delirium, the transitory restlessness and disorientation often apparent in the postanesthesia care unit or an ICU that receives patients directly from the operating room, is familiar to all anesthesiologists and often resolves within a brief period of time. More worrisome is interval delirium, appearing 2 to 7 days after operation, the patient manifesting disorientation and agitation and being at risk for suboptimal outcome by virtue of its appearance. Risk factors for postoperative delirium are additive to those menacing the nonoperated elderly patient, including perioperative hypoxemia and hypotension, exposure to medications that are used in the operating room—anticholinergics such as atropine, volatile inhalational anesthetics, neuromuscular blocking agents, and potent opioids—and high-volume blood transfusion and rapid fluid shifts associated with surgery. Procedures using cardiopulmonary bypass raise the possibility of microscopic atheromatous or air emboli as contributors. The incidence of postoperative delirium ranges from 0 to 74%, varying with age group, type of surgery, variability of diagnostic criteria, and preoperative and postoperative cognitive status (404). POCD was first identified in 1955 (405), characterized by the appearance weeks to months after a surgical procedure of impairment of memory, concentration, comprehension of language, and social integration (406). Although the intensivist is seldom charged with management of POCD, she or he is instrumental in its prevention, in that delirium in the early postoperative period may forecast its later appearance (407). One well-designed investigation of elderly patients undergoing noncardiac surgery reported the incidence of delirium to be 25% at 1 week after operation, with symptoms of POCD being present in 9.9% of patients at 3 months, significantly worse than controls at both intervals (406), and revealing advancing age as the only factor significantly predictive of POCD. Similarly, abundant literature (408,409,410) exists addressing this syndrome in cardiac surgery patients following both on- and off-pump procedures, most of whom were older than 60 years of age. Although most cardiac surgery patients suffer various concurrent confounding medical conditions that make the specific effects solely of cardiac surgery on subsequent mental status difficult to isolate, meticulous attention to statistical and study control issues allows identification of a substantial incidence (53%) of coronary artery bypass graft (CABG) patients (average age, 60.9 years ± 10.6 years) showing cognitive deterioration consistent with POCD at time of discharge, and 42% at 5 years (411), with age being a univariate predictor of decline. The specific cause of POCD is obscure. Suggested causes are those noted above as well as more abstract considerations such as brain inflammation, genetic factors, cerebral edema, and blood–brain barrier dysfunction (412,413,414).
Timely recognition of the onset of delirium is required for optimal treatment, facilitating rapid identification of reversible precipitating factors. Beyond that, treatment is supportive, with aggressive treatment of symptoms and protection of the patient from the sequelae of his or her delirious state. Prevention is central, requiring a multicomponent approach that includes modification of environmental factors and provision of supportive measures, as demonstrated in a prospective, although nonrandomized, study of 852 patients over 70 years old admitted to a general medicine service in which a multicomponent delirium prevention strategy achieved a one-third reduction in the incidence of delirium, compared to those who received standard care (364). Although this study included patients in a general ward, one may extrapolate the findings to profoundly at-risk ICU patients. Symptomatic treatment uses both pharmacologic and nonpharmacologic strategies. Instrumental are the use of repeated reorientation, cognitive stimulating activities, promotion of adequate sleep on a normal sleep/wake cycle, physical therapy and mobilization, early removal of catheters and physical restraints, and provision of eyeglasses and hearing aids, combined with the judicious use of medications particularly targeted at calming agitation. All potentially neuroactive medications such as benzodiazepines, opioids, or those with anticholinergic effects that are not absolutely fundamental to the patient's treatment plan and improvement should be discontinued (370,372,373). Butyrophenone haloperidol is often used in the management of delirium-induced agitation, having few active metabolites and minimal anticholinergic, sedative, and hypotensive effects (415). A recent retrospective analysis suggested that haloperidol use was independently associated with lower mortality in 989 critically ill patients (416). For POCD, there is no management other than prevention; no therapy has been identified that is curative once the syndrome had developed. In all cases, contributing problems must be identified and corrected and the patient protected. Support must also be provided to family members, who likely will be affected by their loved one's distressing symptoms and by the prospect of additional responsibilities for caring for that person.
Stroke
Incidence and Risk Factors
Stroke is the third leading cause of death and the leading cause of disability in the elderly. Approximately 500,000 individuals in this age group suffer strokes annually in the United States, corresponding to one event every 45 seconds and leading to one death every 3 minutes. Among those 55 years and older, the incidence of stroke doubles with each additional decade of life (417), despite a decline in the United States, Canada, and Western Europe through the later part of the 20th century to the present, attributable to improved management of modifiable risk factors. Among these factors, hypertension is by far the most powerful; aggressive blood pressure control can reduce the risk of stroke by 40% (417). Coronary atherosclerosis, left ventricular hypertrophy, and atrial fibrillation contribute to stroke risk. Diabetes mellitus may increase likelihood of stroke by a factor of two to four; tight glucose control significantly reduces this risk, and may postpone such vascular complications as retinopathy and nephropathy (418,419). Modifiable factors also include cigarette smoking, hyperlipidemia, and excessive alcohol consumption.
Classification
Stroke classification can be based on location, cause, and time course. Prior to routine availability of CT, history and clinical findings provided the sole method of neurologic lesion identification. Today, rapid CT localization supplemented by the time-sensitive history and clinical examination findings allow much more rapid formulation of a treatment plan. Although the details of stroke syndromes are addressed elsewhere in this textbook (see Chapter 84), discussion of some issues as they affect the elderly is warranted.
Location
The most common location in which a stroke occurs, representing approximately two thirds of ischemic strokes (420), is in the distribution of the middle cerebral artery (MCA). Findings include contralateral hemiplegia and hemianesthesia. Proximal MCA occlusion produces profound symptoms: homonymous hemianopsia, or deviation of the head and eyes toward the side of the lesion. Involvement of the dominant MCA distribution may cause aphasia, expressive or receptive. Dominant hemisphere MCA lesions may induce depression in the elderly, whereas those in the nondominant hemisphere produce visuospatial deficits, unilateral neglect, and emotional lability that can mimic depression, sometimes delaying correct diagnosis. Anterior cerebral artery (ACA) stroke, the least common variety, accounting for about 2% of ischemic infarcts (420), most profoundly affects the contralateral leg and foot, generally with lesser impact on the arm and little involvement of the face. Very proximal ACA occlusion, however, may affect the entire contralateral side. Abundant collateral flow in ACA territory yields various symptoms associated with anterior circulation stroke. One may observe frontal lobe features such as emotional lability, mood impairment, personality changes, and intellectual deficits; aphasia is uncommon. Stroke-related paraplegia and incontinence may leave the elderly victim wheelchair-bound and unable to control critical body functions, greatly complicating rehabilitation and subsequent independent living. Strokes in the distribution of the posterior cerebral artery (PCA) manifest a diversity of findings due to the variability of anatomic origin, namely partial or complete origin from the basilar artery or internal carotid arteries. Neurologic consequences of PCA stroke include contralateral hemianesthesia and hemianopsia with sparing of central macular vision, difficulty with reading and calculations, and hemiballismus from subthalamic involvement (420). With vertebrobasilar atherothrombotic disease, cerebellar dysfunction predominates. Common symptoms include vomiting, dizziness, ataxia, nystagmus, and double vision. Vertigo can be profound, causing an already tenuously balanced elderly person to sustain a fatal fall. Other symptoms include weakness of the face and the opposite side of the body, with dysarthria or dysphasia. Facial numbness may occur. Brain stem involvement may be revealed by altered mental status or quadriplegia (420). Lacunar strokes—small occlusions of the penetrating and subcortical arteries—tend to occur in the basal ganglia, internal capsule, thalamus, or pons. Depending on the specific sites of lesions, a wide variety of presentation may occur, including pure motor or sensory findings, symptoms that appear parkinsonian, or a mixture of presenting abnormalities.
Cause
Strokes are either ischemic or hemorrhagic. Those that are ischemic, about 85% of the total, involve occlusion of the cerebral vessel by embolus or thrombosis; the remaining 15% include hemorrhage into the brain parenchyma or its surrounding spaces (420). Rapid identification of the specific cause of the stroke is fundamental to its management, since modalities of treatment vary with cause. Embolic phenomena most often originate from the heart, commonly associated with atrial fibrillation, which is frequent in the elderly population. Atherosclerotic disease of the aortic arch is emerging as an increasingly important and recognized risk factor for recurrent stroke when the wall thickness exceeds 4 mm (421). Atheroma-associated clot formation may produce neurologic syndromes known as thrombotic stroke. Subintimal vascular disease is the ultimate inciting event, inducing arterial narrowing with ulcerated plaque formation in areas of more turbulent flow, such as the carotid bifurcation, leading ultimately to symptoms ranging from a temporary deficit (i.e., a transient ischemic attack, or TIA) to complete arterial occlusion caused by clot formation.
Time Course
Stroke phases are termed acute, subacute, and chronic, each with its unique needs and goals of care. Time spans are generally said to extend from symptom onset to 48 hours, 48 hours to 3 months, and past 3 months, respectively.
The intensivist is little involved in direct management of stroke-related symptoms after the first few days, although elderly patients who fall within the later stages of recovery may certainly require intensive care for recurrent stroke, a stroke-related complication, or other critical illness.
Acute phase of stroke (admission to 48 hours)
Management of the acute phase involves, first and foremost, ensuring airway and hemodynamic stability. Thereafter, the goals of care are (i) identification of the stroke as ischemic or hemorrhagic, (ii) initiation of thrombolytic therapy when indicated, and (iii) recognition and therapy of medical or neurologic complications. The first goal is most easily achieved by obtaining a noncontrast-enhanced CT scan of the brain as quickly as possible when stroke is suspected. Hemorrhage is usually obvious on this scan, although early in the course of ischemic stroke there may be no visible abnormality. Early CT may reveal one of the many mimics of stroke: subarachnoid hemorrhage, subdural hematoma, neoplasm, or hydrocephalus. Contrast enhancement may improve yield if tumor or infection are likely. Recall that comorbid conditions abound in the elderly; cardiac arrhythmias or infarction may provoke or result from a cerebrovascular event, mandating 12-lead electrocardiogram (ECG) and continuous cardiac monitoring in all stroke patients. Questions of the numerous other causes of altered mental status in the geriatric patient must be investigated and settled quickly. For those in whom, with the assistance of expert consultation, it is decided that ischemic stroke is present, the risks and benefits of thrombolytic therapy must be weighed. Current recommendations for management include initiation of intravenous thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) as soon as possible, within 180 minutes of onset of stroke, in the absence of contraindications (422,423). Intra-arterial thrombolysis is an option for those with occlusion of the middle cerebral artery. Of note is that rt-PA is approved by the Food and Drug Administration (FDA) for intravenous administration, but not for intra-arterial use. Use of rt-PA appears to improve outcome from stroke at 3 months. There is a relative paucity of data documenting treatment of older patients, similar to those studies addressing thrombolysis for myocardial infarction. It does appear, however, that while there may be poorer outcome from stroke in the elderly population, there is no increased likelihood of rt-PA–induced severe intracranial hemorrhage (424,425). A number of stroke scales, including the National Institutes of Health Stroke Scale (NIHSS), have been devised to assist in quantification of severity of stroke-related symptoms, as a guide to optimal management. Important issues such as blood pressure management and anticoagulation are best addressed in concert with expert consultation (426).
Subacute and chronic phases of stroke management
The acute events and aggressive treatment related to stroke often stabilize a patient's condition within 48 hours. Thereafter, close attention to complications or neurologic decompensation is warranted. Early extubation is advisable, with meticulous attention to the return of intact airway reflexes and sufficient recovery of mental status. Otherwise, tracheostomy for airway protection allows withdrawal of sedation, early mobilization, and more robust participation in physical and occupational therapy, with the long-term goal of rehabilitation to maximal recovery. The common companions of those with compromised mental status, namely pulmonary aspiration, skin breakdown, infections, and limitation of extremity range of movement, can be ameliorated by aggressive rehabilitation efforts. Early nutritional support via feeding tube is sometimes overlooked in the flurry of initial management activity but must be initiated as early as possible. Formal rehabilitation programs may be organized in the setting of the acute inpatient rehabilitation unit, or in long-term rehabilitation hospitals, skilled nursing facilities, outpatient rehabilitation centers, or home. Optimal programs incorporate comprehensive assessment and treatment by a multidisciplinary team that includes physical, occupational, and speech therapists, and a geriatrician, physiatrist, psychologist, nurse, and social worker during this first few months during which most neurologic recovery occurs. A pre-existing state of debilitation, however, may limit the 3-hour period of active participation traditional to inpatient environments, mandating alternate plans. General goals of rehabilitation include restoration of motor and sensory function, and strengthening of intact functions to facilitate compensation for residual deficits. Beyond the first few months, while neurologic function likely plateaus, functional recovery continues when encouraged and supported by family presence, social interaction, and adequate nutrition. The stroke recurrence rate of 30% within 10 years warrants continued attention to chronic medical conditions. Framingham Study data documents survival in stroke victims of 50% in 5 years (427,428,429). Preservation of functional gains, avoidance of complications, and aggressive management of contributing comorbid conditions may well forestall the decline that often follows a stroke in an elderly patient.
Sleep Disorders
Background
Insomnia plagues the elderly, afflicting nearly 50% of older adults (430); the genders are generally equally affected, although sleepless men predominate after 85 years of age. Prevalence increases in the elderly with the number of coincident medical conditions (431,432). Common sleep complaints among the community-dwelling elderly are difficulty in initiation of sleep, and nighttime and early morning awakening (433). Sequelae of insomnia include physical and mental fatigue, anxiety, and irritability, which worsen as bedtime approaches and personal worries re-emerge without the protective diversion of normal daytime activities (434). Chronic dysfunctional sleep induces a state of endless fatigue, affecting memory and concentration (431,435). The elderly are particularly affected, with steepened cognitive decline and risk of falls, with associated morbidity and mortality (436,437,438). Hospitalization amplifies the morbidity of sleep disturbances; ICU admission likely subverts any semblance of a normal sleep pattern. Sedation to facilitate mechanical ventilation subdues consciousness but disrupts normal variation in sleep stages, preventing rest. Circadian rhythms are disrupted, with dyssynchrony with anticipated light/dark time cycles and adequate daily morning exposure to sufficient bright light (439). Many elderly patients become disoriented at night, exhausted and confused by constant alarms, noises, dressing changes, unscheduled diagnostic procedures, and the impact of acute severe illness, producing delirium in nearly two thirds of elderly ICU patients (372). Dementia contributes to this phenomenon.
Identification and Management of Sleep Disorders
The sleep/wake cycle is regulated by a complex neurochemical interaction subserved by the brainstem, hypothalamus, pons, and preoptic areas of the brain (440). Aberrations of sleep patterns produce dysfunctional sleep (441), disrupting daytime functioning. Sleep architecture is determined for an individual by performance of a sleep study displayed on a hypnogram. Normal sleep architecture displays three segments: light sleep (stages one and two); deep (delta or slow wave) sleep (stages three and four), which is the most restorative segment; and rapid eye movement, or REM, sleep (stages one and four) (442). In nonelderly adults, typical cycle time between REM and non-REM sleep is 90 to 120 minutes (442). Advanced age alters sleep by shortening sleep latency and total sleep time, preserving REM sleep, decreasing the delta segment, and advancing the natural onset of sleepiness to an earlier time in the evening (433). Nocturnal sleep fragmentation worsens, with daytime somnolence and frequent napping being commonplace, sometimes causing reversal of the sleep/wake cycle. Acute insomnia in the geriatric patient may be precipitated by a host of issues, including the critical illness itself. Metabolic derangements related to sepsis or trauma, recent exposure to potent anesthetic agents, and the unfamiliar ICU environment filled with off-schedule and frequent disruptions effectively prevent restful sleep. Although not generally within the purview of the intensivist, investigation of the cause of insomnia may be initiated for the ICU patient by meticulous history gathering, discussion with family members, use of sleep-related questionnaires such as the Multiple Sleep Latency Test (441) and the Epworth sleepiness scale screening tool (443), and observation of the patient for evidence of any of the primary sleep disorders that respond to specific treatment modalities. These include a spectrum of conditions collectively termed sleep-disordered breathing (SDB), periodic limb movements in sleep/restless legs syndrome, and REM sleep behavior disorder. Some causes of SDB (obstructive sleep apnea, specifically) respond to continuous positive airway pressure (CPAP) (444), and the latter two respond to medications (445,446). Secondary causes are legion, including medications, sleep-disruptive behavioral habits (such as prolonged daytime naps, sedentary lifestyle, overindulgence in tobacco or alcohol, late evening meals), numerous medical conditions (heart failure with orthopnea, incomplete bladder emptying with nocturia, gastric reflux, dementia), or environmental deficiencies (insufficient daytime sunlight exposure, inadequate climate control) (442).
Effective treatment obviously requires an accurate diagnosis. Evidence of primary causes should be relayed to the patient, family members, and the physician responsible for long-term management of the patient after transfer. All possible accommodations should be made to minimize interruption of the older patient's restful nighttime sleep periods, minimizing noise, procedures, and cycling of lights on and off. Daily exposure to bright sunlight through nearby windows is beneficial (447,448). Pharmacologic treatments are best addressed on an individual basis, and within certain guidelines (449). Various medications are available (442); each, however, may provoke delirium in elderly patients. In-depth guidelines for the evaluation and treatment of sleep disorders are available (435,450,451,452,453,454,455).
Rehabilitation after Acute Illness
The impact of critical illness on the lives of elderly patients is profound. Beyond the associated death rates, level of functioning is compromised in a substantial percentage of survivors (456). Increasing vulnerability to long-term dependence increases with age (457). Medical intervention in the critically ill or injured patient has evolved to a level of sophistication and capability that allows a previously unsalvageable patient to survive. Thoughtful and comprehensive discharge planning, initiated at the time of admission, can shorten length of stay (LOS) (458) and provide the springboard for return to a reasonable, though often compromised, level of functional autonomy (459). Many of these elderly individuals, after considerable improvement, may nevertheless linger for a prolonged period, requiring a single isolated critical intervention such as mechanical ventilation, further risking the decline of inactivity. The deleterious effects of such a prolonged hospital confinement can be ameliorated by early use of the expertise of rehabilitation professionals. Furthermore, optimal recovery from certain common medical occurrences and conditions simply is not possible without active patient participation, which can be assisted and promoted by the physical medicine team. It is being increasingly recognized that early institution of rehabilitation planning and execution by such a team of specialists can reduce health care costs, length of stay, and severity of disability after discharge (460). Shortening of hospitalization decreases the exposure of the marginally compensated patient to its debilitating risks (461). Avoidance of postillness disability is of paramount importance in that it is associated with higher mortality and greater dependence on family and other caregivers (462,463).
Rehabilitation, as a general concept, encompasses several basic tenets that meld smoothly with the critical care frame of reference (464). Fundamental to any rehabilitation plan is stabilization of the primary inciting disorder; such a precept is the essence of the practice of critical care medicine, and thus is accomplished by virtue of the administration of ICU care. The unique jeopardy in which the elderly exist by virtue of their frailty and vulnerability to complications warrants the most meticulous attention to routine ICU precautions, which must be recognized by the intensivist (465). These include frequent turning, early nutrition, appropriate deep venous thrombosis (DVT) prophylaxis, semirecumbent positioning, and maintenance of day–night cycle of auditory and visual stimulation. Early evaluation by a multidisciplinary team of specialists facilitates identification of evolving and anticipated functional deficits that are amenable to treatment, whether preventive or corrective. Integrated rehabilitation treatment and planning should occur in both the immediate and long-term settings by involvement of the physiatry team. Admission of a frail elder to a specialized unit designed around and attentive to specific features of geriatric pathophysiology has been demonstrated to improve functional outcomes (466).
The fundamental tool available to the geriatrician with which to organize the management and treatment of medical issues, including problems warranting formal rehabilitation, is the comprehensive geriatric assessment (CGA) (467). The integrated, patient-centered concept of treatment implicit in CGA is often accomplished in specialized hospital units or within the framework of treatment considerations peculiar to the elderly, managed by a devoted multidisciplinary team. Such units include the geriatric evaluation and management (GEM) unit, as found in some Veterans Administration hospitals (468), or a specifically formulated management plan termed Acute Care for Elders (ACE) (469), or a construct of aggressive hospitalwide screening and treatment for at-risk patients by specialists and volunteers in an organization such as the Hospital Elder Life Program (HELP) (470). An alternative for the intensivist, whose patients are clearly unavailable for transfer to such a location remote from the ICU, is consultation by an in-patient geriatric consultation service team including individuals knowledgeable in rehabilitation issues (471). To date, the success of CGA in improving functionality and decreasing disability in the elderly after discharge seems clear, although improvement in mortality with this approach, as documented by several studies, seems less so (466,468,472,473,474).
Several specific medical issues mandating ICU admission require active rehabilitation activities to achieve successful treatment. These include cardiac events related both to ACS and cardiac surgery, stroke, serious injury, various debilitating musculoskeletal conditions, and such morbid orthopedic procedures as lower extremity amputation and hip fracture repair.
Although large studies and reviews (475) document the success of aggressive rehabilitation in reducing cardiac mortality, its success specifically in the elderly appears mostly in small, nonrandomized, or uncontrolled studies. Nevertheless, it appears that an aggressive program of cardiac rehabilitation conducted for elderly patients, although often limited by arthritis or coexistent peripheral vascular or pulmonary disease, is safe, able to improve aerobic capacity, and favorably affects body fat percentage, lipid profiles, and physical function scores (476,477,478). Less enthusiastic referral habits by physicians may explain lower participation among elderly cardiac patients, especially women, compared to younger people (479,480,481).
Recovery from acute stroke presents a complex challenge to victim and physician alike. Whereas the cardiac patient may see improvement after surgery that continues during rehabilitation, the stroke patient often must endure compromised mental status and motor/sensory capabilities from the initial insult, yielding a debilitated individual with little motivational reserve with which to sustain himself or herself during recovery. Survival beyond the first few days likely mandates prolonged assistance that may be required for months to achieve optimal improvement. The extent of this improvement hinges on several issues. These include age (482), the nature and severity of the initial deficit (483,484), presence of intracranial hemorrhage-related rather than infarction-related stroke—a patient with the former improves more than one with the latter for a given initial severity (485)—and early initiation of the rehabilitation activities, preferably within 7 days (486). The plasticity of injured and unaffected normal brain tissue allows gradual improvement over the subsequent several months (487). Specific stroke-related rehabilitation issues include the following: (a) optimal location for therapy, (b) speech and swallowing, (c) recovery of upper extremity function, (d) balance and walking, and (e) strengthening exercises (483). Evaluation tools such as the Barthel Index and the Stroke Impact Scale (488) are used to quantify a stroke patient's recovery, which may continue for as long as six months of recovery in the absence of another complication (489,490). Success of recovery from stroke varies over a large population (491) based on aforementioned variables and, to some extent, social status (492).
Rehabilitation of an injured elderly patient often involves continued long-term supportive therapy of conditions from which a younger individual may well recover quickly, namely mild traumatic brain injury and extremity fracture. Indeed, continuity of specialized geriatrician involvement may facilitate continued attention to several issues during a prolonged trauma-ICU admission: comorbid problems, functional abilities and family support, formulation and continuous assessment of an itemized management plan toward realistic goals, and early initiation of planning for discharge and follow-up care (493,494). Of particular concern to intensivists managing elderly patients is hip fracture, of which more than 250,000 occur annually (495), with most patients being older than 50 years of age. Such fractures increase mortality—compared to that of similar patients without fracture—in those older than 65 years of age by 12% to 36% (496), as well as the likelihood of subsequent institutionalization (497) and functional dependence (498). Those whose course is complicated by pre-existing cognitive dysfunction or delirium fare more poorly (497,499). Successful management requires identification and correction/stabilization of comorbid conditions, appropriate surgical treatment, and early initiation of important precepts of rehabilitation (495,500). These include early mobilization, initially to chair followed by standing and walking with weight bearing; prolonged bed rest fosters deconditioning and is to be avoided. The intensivist who manages a particularly ill elder must address the potential for thromboembolic complications by encouraging early mobilization to minimize venous stasis, and by using prophylactic anticoagulant medication; regimens differ according to the exact situation (501,502,503,504). Functionality can be profoundly affected after hip fracture (505,506) and is further impacted by a high level of comorbidity (507). Although more men than women die initially after hip fracture, those who survive after the first year experience comparable functional recovery regardless of gender (508). Very advanced age is not necessarily a contraindication to hip fracture surgery in the absence of a prohibitive comorbidity; those older than 90 years often do quite well, returning, with aggressive rehabilitation and social support, to independent living (509).
About 50,000 amputations are performed annually in the United States, most on patients who are older than 60 years (510). Rates of lower extremity amputation declined from the 1980s to the mid 1990s, paralleling the improvement in arterial bypass and angioplasty techniques and the heightened attention to control of risk factors for vascular disease. Rates since then seem to have stabilized (511). Eighty percent of amputations are performed as a result of arteriosclerotic occlusive disease and complications of diabetes mellitus (512), coincident with common comorbidities that may direct an elderly patient to the ICU. Nearly half of lower extremity amputees die within 2 years (513); a substantial percentage of survivors go on to lose the other leg (514) within a few years. Despite the attention paid to morbid consequences of amputation during the immediate postoperative period, this procedure profoundly impacts the patient's entire remaining life span. Optimal therapy for the amputee is achievable only with the early involvement and assistance of a rehabilitation team of physicians, technologists, and therapists skilled specifically in management of amputation-related issues and familiar with prosthetic devices. Level of amputation varies with severity of lower extremity involvement; although medically sound judgement is the pre-eminent guide in this decision, it is important to note that the more joints and muscles are replaced by a prosthesis, the greater the associated forfeiture of mobility and increase in energy cost of ambulation. The transmetatarsal amputee requires fairly trivial energy supplement to return to ambulation; the similar requirement for a transfemoral amputation patient can balloon by nearly 100% (512,513,514,515). Such cardiovascular and energy demands are considerable, even in an otherwise healthy amputee (515,516), and may not be achievable in the debilitated geriatric vascular or traumatized patient without risk of further decompensation. Nonetheless, early mobilization is to be encouraged. Prolonged bed rest further compromises balance and endurance, inviting the onset of contractures and loss of strength in compensatory muscle groups during prosthesis introduction. In the past, elderly amputees were seldom offered prosthesis; this picture has reversed with the more modern approach to elderly amputee care (517), in which such an offering is made to nearly 90% of elderly. An early visit from the physiatrist to the amputee's bedside facilitates initiation of an organized rehabilitation care plan to formulate future prosthetic, physical therapy, wound care, and emotional support needs. Parts of these recovery plan components may be initiated by the intensivist while the patient is still critically ill and more fully conducted on a regular hospital ward, a specialty rehabilitation facility, or even at home. Follow-up must be long term; medical, emotional, and physical needs continue long after the amputee's surgical stump has completely healed (518,519).
Summary
The health care needs of the elderly members of the community represent enormous challenges to all members of the medical profession. The aspirations and personal convictions of such individuals are as fundamental to the well-being and fruitfulness of their lives as are those of any other segment of the population. While years of living bring elderly patients with the most complex illnesses and comorbid conditions to the door of the hospital and intensive care unit, it is to be remembered that the elderly often recover fully, or almost so, from profoundly serious illness despite numerous worrisome impediments that would discourage all but the most optimistic clinician. In general, vigilance and dispatch in investigations and treatment of critically ill geriatric patients, using the guidelines listed in this chapter, will facilitate recognition of the subtleties of such conditions. Although a substantial percentage of the elderly cannot be brought back to an independent level of functioning, every effort should be expended to achieve accurate diagnosis and expeditious treatment, providing full intensive support to conditions that are correctable and recognition when reasonable limits have been reached.
References
1. United States Census 2000. www.census.gov/main/www/cen2000.html. Accessed April 1, 2007.
2. CDC National Vital Statistics Report, Vol 54; No. 14, April 19, 2006, Report revised as of 28 March, 2007. www.cdc.gov/nchs/data/nvsr/nvsr54/nvsr54_14.pdf. Accessed April 1, 2007.
3. Rice DP, Fineman N. Economic implications of increased longevity in the United States. Annu Rev Public Health. 2004;25:457–473.
4. Office of Demographic and Economic Research; The Florida Legislature. http://edr.state.fl.us/population.htm. AccessedApril 1, 2007.
5. U.S. Department of Health & Human Services: Centers for Medicare & Medicaid Services. www.cms.hhs.gov/NationalHealthExpendData. Accessed April 1, 2007.
6. Alsarraf AA, Fowler R. Health, economic evaluation, and critical care. J Crit Care. 2005;20:194–197.
7. Angus DC, Kelley MA, Schmitz RJ, et al. Committee on Manpower for Pulmonary and Critical Care Societies (COMPACCS). Caring for the critically ill patient. Current and projected workforce requirements for care of the critically ill and patients with pulmonary disease: can we meet the requirements of an aging population? JAMA. 2000;284:2762–2770.
8. Rockwood K, Noseworthy TW, Gibney RT, et al. One-year outcome of elderly and young patients admitted to intensive care units. Crit Care Med. 1993;21:687–691.
9. Luce JM, Rubenfeld GD. Can health care costs be reduced by limiting intensive care at the end of life? Am J Respir Crit Care Med. 2002;165:750–754.
10. Fries JF, Koop CE, Beadle CE, et al. Reducing health care costs by reducing the need and demand for medical services. The Health Project Consortium. N Engl J Med. 1993;329:321–325.
11. Emanuel EJ, Emanuel LL. The economics of dying. The illusion of cost savings at the end of life. N Engl J Med. 1994;330:540–544.
12. Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med. 2006;34:15–21.
13. CDC/National Center for Health Statistic. Cardiovascular disease in the elderly. www.cdc.gov/nchs/. Accessed April 1, 2007.
14. Crispell KA. Common cardiovascular issues encountered in geriatric critical care. Crit Care Clin. 2003;19:677–691.
15. Timio M. Blood pressure trend and psychosocial factors: the case of the nuns in a secluded order. Acta Physiol Scand Suppl. 1997;640:137–139.
16. Poulter NR, Khaw KT, Mugambi M, et al. Blood pressure patterns in relation to age, weight and urinary electrolytes in three Kenyan communities. Trans R Soc Trop Med Hyg. 1985;79:389–392.
17. Nichols WW, O'Rourke MF. McDonald's Blood Flow in Arteries. London, England: Edward Arnold Publishers; 1990.
18. Greenwald SE; Ageing of the conduit arteries. J Pathol. 2007;211:157–172.
19. London GM, Marchais SJ, Guerin AP, et al. Arterial stiffness: pathophysiology and clinical impact. Clin Exp Hypertens. 2004;26:689–699.
20. Dao HH, Essalihi R, Bouvet C, et al. Evolution and modulation of age-related medial elastocalcinosis: impact on large artery stiffness and isolated systolic hypertension. Cardiovasc Res. 2005;66:307–317.
21. Avolio A, Jones D, Tafazzoli-Shadpour M. Quantification of alterations in structure and function of elastin in the arterial media. Hypertension. 1998;32:170–175.
22. O'Rourke M. Mechanical principles in arterial disease. Hypertension. 1995;26:2–9.
23. Izzo JL Jr. Arterial stiffness and the systolic hypertension syndrome. Curr Opin Cardiol. 2004;19:341–352.
24. Bramwell JC, Hill AV. Velocity of tansmission of the Pulse Wave. Lancet. 1922;1:891–892.
25. O'Rourke MF, Blazek JV, Morreels CL Jr, et al. Pressure wave transmission along the human aorta. Changes with age and in arterial degenerative disease. Circ Res. 1968;23:567–579.
26. Nichols WW, O'Rourke MF, Avolio AP, et al. Effects of age on ventricular-vascular coupling. Am J Cardiol. 1985;55:1179–1184.
27. Nichols WW, Edwards DG. Arterial elastance and wave reflection augmentation of systolic blood pressure: deleterious effects and implications for therapy. J Cardiovasc Pharmacol Ther. 2001;6:5–21.
28. Strandberg TE, Pitkala K. What is the most important component of blood pressure: systolic, diastolic or pulse pressure? Curr Opin Nephrol Hypertens. 2003;12:293–297.
29. Nichols WW, Singh BM. Augmentation index as a measure of peripheral vascular disease state. Curr Opin Cardiol. 2002;17:543–551.
30. Safar ME. Systolic blood pressure, pulse pressure and arterial stiffness as cardiovascular risk factors. Curr Opin Nephrol Hypertens. 2001;10:257–261.
31. Franklin SS, Gustin W 4th, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation. 1997;96:308–315.
32. Olivetti G, Melissari M, Capasso JM, et al. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991;68:1560–1568.
33. Wei JY. Age and the cardiovascular system. N Engl J Med. 1992;327:1735–1739.
34. Weber KT, Brilla CG. Structural basis for pathologic left ventricular hypertrophy. Clin Cardiol. 1993;16(5 Suppl 2):II10–II14.
35. Kass DA, Bronzwaer JG, Paulus WJ. What mechanisms underlie diastolic dysfunction in heart failure? Circ Res. 2004;94:1533–1542.
36. Periasamy M, Kalyanasundaram A. SERCA pump isoforms: their role in calcium transport and disease. Muscle Nerve. 2007;35:430–442.
37. Aurigemma GP, Gaasch WH. Clinical practice. Diastolic heart failure. N Engl J Med. 2004;351:1097–1105.
38. Mandinov L, Eberli FR, Seiler C, et al. Diastolic heart failure. Cardiovasc Res. 2000;45:813–825.
39. Kitzman DW, Gardin JM, Gottdiener JS, et al.; Cardiovascular Health Study Research Group. Importance of heart failure with preserved systolic function in patients > or = 65 years of age. CHS Research Group. Cardiovascular Health Study. Am J Cardiol. 2001;87:413–419.
40. Brucks S, Little WC, Chao T, et al. Contribution of left ventricular diastolic dysfunction to heart failure regardless of ejection fraction. Am J Cardiol. 2005;95:603–606.
41. Lakatta EG. Diminished beta-adrenergic modulation of cardiovascular function in advanced age. Cardiol Clin. 1986;4:185–200.
42. Lakatta EG, Sollott SJ. Perspectives on mammalian cardiovascular aging: humans to molecules. Comp Biochem Physiol A Mol Integr Physiol. 2002;132:699–721.
43. Lakatta EG. Catecholamines and cardiovascular function in aging. Endocrinol Metab Clin North Am. 1987;16:877–891.
44. Rodeheffer RJ, Gerstenblith G, Becker LC, et al. Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac dilatation and increased stroke volume compensate for a diminished heart rate. Circulation. 1984;69:203–213.
45. Stratton JR, Levy WC, Cerqueira MD, et al. Cardiovascular responses to exercise. Effects of aging and exercise training in healthy men. Circulation. 1994;89:1648–1655.
46. Mehta RH, Granger CB, Alexander KP, et al. Reperfusion strategies for acute myocardial infarction in the elderly: benefits and risks. J Am Coll Cardiol. 2005;45:471–478.
47. Goldberg RJ, McCormick D, Gurwitz JH, et al. Age-related trends in short- and long-term survival after acute myocardial infarction: a 20-year population-based perspective (1975–1995). Am J Cardiol. 1998;82:1311–1317.
48. Angeja BG, Gibson CM, Chin R, et al. Use of reperfusion therapies in elderly patients with acute myocardial infarction. Drugs Aging. 2001;18:587–596.
49. Canto JG, Shlipak MG, Rogers WJ, et al. Prevalence, clinical characteristics, and mortality among patients with myocardial infarction presenting without chest pain. JAMA. 2000;283:3223–3229.
50. Giugliano RP, Camargo CA Jr, Lloyd-Jones DM, et al. Elderly patients receive less aggressive medical and invasive management of unstable angina: potential impact of practice guidelines. Arch Intern Med. 1998;158:1113–1120.
51. Lee PY, Alexander KP, Hammill BG, et al. Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA. 2001;286(6):708–713.
52. Antman EM, Braunwald E. Acute myocardial infarction. In: Braunwald EB, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia, PA: WB Saunders; 1997
53. Gersh BJ, Anderson JL. Thrombolysis and myocardial salvage. Results of clinical trials and the animal paradigm—paradoxic or predictable? Circulation. 1993;88(1):296–306.
54. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Lancet. 1994;343(8893):311–322.
55. Antman EM, Anbe DT, Armstrong PW, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation. 2004;110(5):588–636.
56. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361(9351):13–20.
57. Guagliumi G, Stone GW, Cox DA, et al. Outcome in elderly patients undergoing primary coronary intervention for acute myocardial infarction: results from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. Circulation. 2004;110(12):1598–1604.
58. Zahn R, Schiele R, Schneider S, et al. Primary angioplasty versus intravenous thrombolysis in acute myocardial infarction: can we define subgroups of patients benefiting most from primary angioplasty? Results from the pooled data of the Maximal Individual Therapy in Acute Myocardial Infarction Registry and the Myocardial Infarction Registry. J Am Coll Cardiol. 2001;37(7):1827–1835.
59. Bach RG, Cannon CP, Weintraub WS, et al. The effect of routine, early invasive management on outcome for elderly patients with non-ST-segment elevation acute coronary syndromes. Ann Intern Med. 2004;141(3):186–195.
60. Assali AR, Moustapha A, Sdringola S, et al. The dilemma of success: percutaneous coronary interventions in patients > or = 75 years of age-successful but associated with higher vascular complications and cardiac mortality. Catheter Cardiovasc Interv. 2003;59(2):195–199.
61. Hunt SA, Abraham WT, Chin MH, et al. American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112(12):e154–235. Epub 2005 Sep 13.
62. Masoudi FA, Havranek EP, Krumholz HM. The burden of chronic congestive heart failure in older persons: magnitude and implications for policy and research. Heart Fail Rev. 2002;7(1):9–16.
63. Kannel WB, Belanger AJ. Epidemiology of heart failure. Am Heart J. 1991;121(3 Pt 1):951–957.
64. Kannel WB, Ho K, Thom T. Changing epidemiological features of cardiac failure. Br Heart J. 1994;72(2 Suppl):S3–9.
65. Aronow WS. Epidemiology, pathophysiology, prognosis, and treatment of systolic and diastolic heart failure in elderly patients. Heart Dis. 2003;5(4):279–294.
66. Kannel WB. Incidence and epidemiology of heart failure. Heart Fail Rev. 2000;5(2):167–173.
67. Aronow WS, Tresch DD. Management of the older patient with acute myocardial infarction: difference in clinical presentations between older and younger patients. J Am Geriatr Soc. 1998; 46(9):1157–1162.
68. Marinchak RA, Friehling TD, Kowey PR. Diagnosis and treatment of cardiac rhythm disorders in the elderly. Clin Geriatr Med. 1988;4(1):83–110.
69. Rials SJ, Marinchak RA, Kowey PR. Arrhythmias in the elderly. Cardiovasc Clin. 1992;22(2):139–157.
70. Falk RH. Etiology and complications of atrial fibrillation: insights from pathology studies. Am J Cardiol. 1998;82(8A):10N–17N.
71. Fujino M, Okada R, Arakawa K. The relationship of aging to histological changes in the conduction system of the normal human heart. Jpn Heart J. 1983;24(1):13–20.
72. Lev M. Aging changes in the human sinoatrial node. J Gerontol. 1954;9(1):1–9.
73. Roberts WC. The aging heart. Mayo Clin Proc. 1988;63(2):205–206.
74. Thery C, Gosselin B, Lekieffre J, et al. Pathology of sinoatrial node. Correlations with electrocardiographic findings in 111 patients. Am Heart J. 1977;93(6):735–740.
75. Tai CT, Chiou CW, Chen SA. Interaction between the autonomic nervous system and atrial tachyarrhythmias. J Cardiovasc Electrophysiol. 2002;13(1):83–87.
76. Coumel P. Autonomic influences in atrial tachyarrhythmias. J Cardiovasc Electrophysiol. 1996;7(10):999–1007.
77. Wong CK, White HD, Wilcox RG, et al. Significance of atrial fibrillation during acute myocardial infarction, and its current management: insights from the GUSTO-3 trial. Card Electrophysiol Rev. 2003;7(3):201–207.
78. Wong CK, White HD, Wilcox RG, et al. New atrial fibrillation after acute myocardial infarction independently predicts death: the GUSTO-III experience. Am Heart J. 2000;140(6):878–885.
79. Kailasam R, Palin CA, Hogue CW Jr. Atrial fibrillation after cardiac surgery: an evidence-based approach to prevention. Semin Cardiothorac Vasc Anesth. 2005;9(1):77–85.
80. McMurry SA, Hogue CW Jr. Atrial fibrillation and cardiac surgery. Curr Opin Anaesthesiol. 2004;17(1):63–70.
81. Chatap G, Giraud K, Vincent JP. Atrial fibrillation in the elderly: facts and management. Drugs Aging. 2002;19(11):819–846.
82. Hersi A, Wyse DG. Management of atrial fibrillation. Curr Probl Cardiol. 2005;30(4):175–233.
83. Kopecky SL, Gersh BJ, McGoon MD, et al. Lone atrial fibrillation in elderly persons: a marker for cardiovascular risk. Arch Intern Med. 1999;159(10):1118–1122.
84. Nattel S, Opie LH. Controversies in atrial fibrillation. Lancet. 2006;367(9506):262–272.
85. Wyse DG, Waldo AL, DiMarco JP, et al. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347(23):1825–1833.
86. Fuster V, Ryden LE, Cannom DS, et al: American College of Cardiology; American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 guidelines for the management of patients with atrial fibrillation) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace. 2006;8(9):651–745.
87. Snow V, Weiss KB, LeFevre M, et al. AAFP Panel on Atrial Fibrillation; ACP Panel on Atrial Fibrillation. Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med. 2003;139(12):1009–1017.
88. Monette J, Gurwitz JH, Rochon PA, et al. Physician attitudes concerning warfarin for stroke prevention in atrial fibrillation: results of a survey of long-term care practitioners. J Am Geriatr Soc. 1997;45(9):1060–1065.
89. Vasishta S, Toor F, Johansen A, et al. Stroke prevention in atrial fibrillation: physicians' attitudes to anticoagulation in older people. Arch Gerontol Geriatr. 2001;33(3):219–226.
90. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):429S–456S.
91. Zipes DP, Wellens HJ. Sudden cardiac death. Circulation. 1998;98(21):2334–2351.
92. Bayes de Luna A, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J. 1989;117(1):151–159.
93. Fleg JL, Kennedy HL. Cardiac arrhythmias in a healthy elderly population: detection by 24-hour ambulatory electrocardiography. Chest. 1982;81(3):302–307.
94. Fleg JL, Kennedy HL. Long-term prognostic significance of ambulatory electrocardiographic findings in apparently healthy subjects greater than or equal to 60 years of age. Am J Cardiol. 1992;70(7):748–751.
95. Sajadieh A, Nielsen OW, Rasmussen V, et al. Ventricular arrhythmias and risk of death and acute myocardial infarction in apparently healthy subjects of age > or =55 years. Am J Cardiol. 2006;97(9):1351–1357.
96. Manolio TA, Furberg CD, Rautaharju PM, et al. Cardiac arrhythmias on 24-h ambulatory electrocardiography in older women and men: the Cardiovascular Health Study. J Am Coll Cardiol. 1994;23(4):916–925.
97. Hedblad B, Janzon L, Johansson BW, et al. Survival and incidence of myocardial infarction in men with ambulatory ECG-detected frequent and complex ventricular arrhythmias. 10-year follow-up of the ‘Men born 1914’ study in Malmo, Sweden. Eur Heart J. 1997;18(11):1787–1795.
98. Kennedy HL, Whitlock JA, Sprague MK, et al. Long-term follow-up of asymptomatic healthy subjects with frequent and complex ventricular ectopy. N Engl J Med. 1985;312(4):193–197.
99. Kahan T, Bergfeldt L. Left ventricular hypertrophy in hypertension: its arrhythmogenic potential. Heart. 2005;91(2):250–256.
100. Aronow WS, Epstein S, Koenigsberg M, et al. Usefulness of echocardiographic left ventricular hypertrophy, ventricular tachycardia and complex ventricular arrhythmias in predicting ventricular fibrillation or sudden cardiac death in elderly patients. Am J Cardiol. 1988;62(16):1124–1125.
101. ECC Committee, Subcommittees and Task Forces of the American Heart Association. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2005;112(24 Suppl):IV1–203.
102. Valenzuela TD, Roe DJ, Nichol G, et al. Outcomes of rapid defibrillation by security officers after cardiac arrest in casinos. N Engl J Med. 2000;343(17):1206–1209.
103. Eisenberg MS, Mengert TJ. Cardiac resuscitation. N Engl J Med. 2001;344(17):1304–1313.
104. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction. An overview of results from randomized controlled trials. JAMA. 1993;270(13):1589–1595.
105. Aronow WS, Mercando AD, Epstein S, et al. Effect of quinidine or procainamide versus no antiarrhythmic drug on sudden cardiac death, total cardiac death, and total death in elderly patients with heart disease and complex ventricular arrhythmias. Am J Cardiol. 1990;66(4):423–428.
106. Hilleman DE, Bauman AL. Role of antiarrhythmic therapy in patients at risk for sudden cardiac death: an evidence-based review. Pharmacotherapy. 2001;21(5):556–575.
107. Bardy GH, Lee KL, Mark DB, et al. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352(3):225–237.
108. Siddiqui A, Kowey PR. Sudden death secondary to cardiac arrhythmias: mechanisms and treatment strategies. Curr Opin Cardiol. 2006;21(5):517–525.
109. Tresch DD, Troup PJ, Thakur RK, et al. Comparison of efficacy of automatic implantable cardioverter defibrillator in patients older and younger than 65 years of age. Am J Med. 1991;90(6):717–724.
110. Goldberger Z, Lampert R. Implantable cardioverter-defibrillators: expanding indications and technologies. JAMA. 2006;295(7):809–818.
111. Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices–summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). J Am Coll Cardiol. 2002;40(9):1703–1719.
112. Prystowsky EN. Prevention of sudden cardiac death. Clin Cardiol. 2005;28(11 Suppl 1):I12–I18.
113. Birnie D, Williams K, Guo A, et al. Reasons for escalating pacemaker implants. Am J Cardiol. 2006;98(1):93–97.
114. McPherson CA, Manthous C. Permanent pacemakers and implantable defibrillators: considerations for intensivists. Am J Respir Crit Care Med. 2004;170(9):933–940.
115. Stone KR, McPherson CA. Assessment and management of patients with pacemakers and implantable cardioverter defibrillators. Crit Care Med. 2004;32(4 Suppl):S155–165.
116. Trohman RG, Kim MH, Pinski SL. Cardiac pacing: the state of the art. Lancet. 2004;364(9446):1701–1719.
117. Mueller PS, Hook CC, Hayes DL. Ethical analysis of withdrawal of pacemaker or implantable cardioverter-defibrillator support at the end of life. Mayo Clin Proc. 2003;78(8):959–963.
118. Ware JH, Dockery DW, Louis TA, et al. Longitudinal and cross-sectional estimates of pulmonary function decline in never-smoking adults. Am J Epidemiol. 1990;132(4):685–700.
119. van Pelt W, Borsboom GJ, Rijcken B, et al. Discrepancies between longitudinal and cross-sectional change in ventilatory function in 12 years of follow-up. Am J Respir Crit Care Med. 1994;149(5):1218–1826.
120. Lang MR, Fiaux GW, Gillooly M, et al. Collagen content of alveolar wall tissue in emphysematous and non-emphysematous lungs. Thorax. 1994;49(4):319–326.
121. Andreotti L, Bussotti A, Cammelli D, et al. Connective tissue in aging lung. Gerontology. 1983;29(6):377–387.
122. Turner JM, Mead J, Wohl ME. Elasticity of human lungs in relation to age. J Appl Physiol. 1968;25(6):664–671.
123. Kronenberg RS, Drage CW. Attenuation of the ventilatory and heart rate responses to hypoxia and hypercapnia with aging in normal men. J Clin Invest. 1973;52(8):1812–1819.
124. Brischetto MJ, Millman RP, Peterson DD, et al. Effect of aging on ventilatory response to exercise and CO2. J Appl Physiol. 1984;56(5):1143–1150.
125. Babb TG, Rodarte JR. Mechanism of reduced maximal expiratory flow with aging. J Appl Physiol. 2000;89(2):505–511.
126. Fowler RW, Pluck RA, Hetzel MR. Maximal expiratory flow-volume curves in Londoners aged 60 years and over. Thorax. 1987;42(3):173–182.
127. Mittman C, Edelman NH, Norris AH, et al. Relationship between chest wall and pulmonary compliance and age. J Appl Physiol. 1965; 20:1211–1216.
128. Levitzky MG. Effects of aging on the respiratory system. Physiologist. 1984;27(2):102–107.
129. Mellemgaard K. The alveolar-arterial oxygen difference: its size and components in normal man. Acta Physiol Scand. 1966;67(1):10–20.
130. Sorbini CA, Grassi V, Solinas E, et al. Arterial oxygen tension in relation to age in healthy subjects. Respiration. 1968;25(1):3–13.
131. Cardus J, Burgos F, Diaz O, et al. Increase in pulmonary ventilation-perfusion inequality with age in healthy individuals. Am J Respir Crit Care Med. 1997;156(2 Pt 1):648–653.
132. Delclaux B, Orcel B, Housset B, et al. Arterial blood gases in elderly persons with chronic obstructive pulmonary disease (COPD). Eur Respir J. 1994;7(5):856–861.
133. Janssens JP. Aging of the respiratory system: impact on pulmonary function tests and adaptation to exertion. Clin Chest Med. 2005;26(3):469–484, vi–vii.
134. Knudson RJ. How aging affects the normal lung. J Respir Dis. 1981;2:74–84.
135. Skorodin MS. Respiratory disease and A-a gradient measurement. JAMA. 1984;252:1344. (letter).
136. Prentice AM, Jebb SA. Beyond body mass index. Obes Rev. 2001;2(3):141–147.
137. Ritz P. Factors affecting energy and macronutrient requirements in elderly people. Public Health Nutr. 2001;4(2B):561–568.
138. Steen B. Body composition and aging. Nutr Rev. 1988;46(2):45–51.
139. Wurtman JJ, Lieberman H, Tsay R, et al. Calorie and nutrient intakes of elderly and young subjects measured under identical conditions. J Gerontol. 1988;43(6):B174–B180.
140. Rolls BJ, Dimeo KA, Shide DJ. Age-related impairments in the regulation of food intake. Am J Clin Nutr. 1995;62(5):923–931.
141. Mowe M, Bohmer T. The prevalence of undiagnosed protein-calorie undernutrition in a population of hospitalized elderly patients. J Am Geriatr Soc. 1991;39(11):1089–1092.
142. Visvanathan R. Under-nutrition in older people: a serious and growing global problem! J Postgrad Med. 2003;49(4):352–360.
143. Cederholm T, Jagren C, Hellstrom K. Outcome of protein-energy malnutrition in elderly medical patients. Am J Med. 1995;98(1):67–74.
144. Constans T, Bacq Y, Brechot JF, Guilmot JL, et al. Protein-energy malnutrition in elderly medical patients. J Am Geriatr Soc. 1992;40(3):263–268.
145. Brownie S. Why are elderly individuals at risk of nutritional deficiency? Int J Nurs Pract. 2006;12(2):110–118.
146. Deschamps V, Astier X, Ferry M, et al. Nutritional status of healthy elderly persons living in Dordogne, France, and relation with mortality and cognitive or functional decline. Eur J Clin Nutr. 2002;56(4):305–312.
147. Pearson JM, Schlettwein-Gsell D, Brzozowska A, et al. Life style characteristics associated with nutritional risk in elderly subjects aged 80-85 years. J Nutr Health Aging. 2001;5(4):278–283.
148. Hays NP, Roberts SB. The anorexia of aging in humans. Physiol Behav. 2006;88(3):257–266.
149. Omran ML, Morley JE. Assessment of protein energy malnutrition in older persons, part I: history, examination, body composition, and screening tools. Nutrition. 2000;16(1):50–63.
150. Omran ML, Morley JE. Assessment of protein energy malnutrition in older persons, Part II: laboratory evaluation. Nutrition. 2000;16(2):131–140.
151. van Bokhorst-de van der Schueren MA, Klinkenberg M, Thijs A. Profile of the malnourished patient. Eur J Clin Nutr. 2005;59(10):1129–1135.
152. Harris D, Haboubi N. Malnutrition screening in the elderly population. J R Soc Med. 2005;98(9):411–414.
153. Schmidt H, Martindale R. The gastrointestinal tract in critical illness. Curr Opin Clin Nutr Metab Care. 2001;4(6):547–551.
154. Nieuwenhuijzen GA, Deitch EA, Goris RJ. Infection, the gut and the development of the multiple organ dysfunction syndrome. Eur J Surg. 1996;162(4):259–273.
155. Witte KK, Nikitin NP, Parker AC, et al. The effect of micronutrient supplementation on quality-of-life and left ventricular function in elderly patients with chronic heart failure. Eur Heart J. 2005;26(21):2238–2244.
156. Webb JG, Kiess MC, Chan-Yan CC. Malnutrition and the heart. CMAJ. 1986;135(7):753–758.
157. Creutzberg EC, Wouters EF, Mostert R, et al. Efficacy of nutritional supplementation therapy in depleted patients with chronic obstructive pulmonary disease. Nutrition. 2003;19(2):120–127.
158. Schols AM. Nutrition in chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2000;6(2):110–115.
159. Schols AM. Pulmonary cachexia. Int J Cardiol. 2002;85(1):101–110.
160. Lesourd B. Nutrition: a major factor influencing immunity in the elderly. J Nutr Health Aging. 2004;8(1):28–37.
161. Hollington P, Mawdsley J, Lim W, et al. An 11-year experience of enterocutaneous fistula. Br J Surg. 2004;91(12):1646–1651.
162. Demling RH. The incidence and impact of pre-existing protein energy malnutrition on outcome in the elderly burn patient population. J Burn Care Rehabil. 2005;26(1):94–100.
163. Witte MB, Barbul A. Repair of full-thickness bowel injury. Crit Care Med. 2003;31(8 Suppl):S538–S546.
164. Mathus-Vliegen EM. Old age, malnutrition, and pressure sores: an ill-fated alliance. J Gerontol A Biol Sci Med Sci. 2004;59(4):355–360.
165. Sullivan DH, Bopp MM, Roberson PK. Protein-energy undernutrition and life-threatening complications among the hospitalized elderly. J Gen Intern Med. 2002;17(12):923–932.
166. Johansen N, Kondrup J, Plum LM, et al. Effect of nutritional support on clinical outcome in patients at nutritional risk. Clin Nutr. 2004;23(4):539–550.
167. Covinsky KE, Martin GE, Beyth RJ, et al. The relationship between clinical assessments of nutritional status and adverse outcomes in older hospitalized medical patients. J Am Geriatr Soc. 1999;47(5):532–538.
168. Giner M, Laviano A, Meguid MM, et al. In 1995 a correlation between malnutrition and poor outcome in critically ill patients still exists. Nutrition. 1996;12(1):23–29.
169. Cerra FB, Benitez MR, Blackburn GL, et al. Applied nutrition in ICU patients. A consensus statement of the American College of Chest Physicians. Chest. 1997;111(3):769–778.
170. Sullivan DH, Sun S, Walls RC. Protein-energy undernutrition among elderly hospitalized patients: a prospective study. JAMA. 1999;281(21):2013–2019.
171. Guigoz Y, Vellas B, Garry PJ. Assessing the nutritional status of the elderly: the Mini Nutritional Assessment as part of the geriatric evaluation. Nutr Rev. 1996;54(1 Pt 2):S59–S65.
172. Omran ML, Salem P. Diagnosing undernutrition. Clin Geriatr Med. 2002;18(4):719–736.
173. Garrow JS, Webster J. Quetelet's index (W/H2) as a measure of fatness. Int J Obes. 1985;9(2):147–153.
174. US Department of Health and Human Services; National Institutes of Health: http://www.nhlbi.nih.gov/health/public/heart/obesity/lose_wt/risk.htm (last accessed on 20 April 2007)
175. Flodin L, Svensson S, Cederholm T. Body mass index as a predictor of 1 year mortality in geriatric patients. Clin Nutr. 2000;19(2):121–125.
176. Galanos AN, Pieper CF, Kussin PS, et al. Relationship of body mass index to subsequent mortality among seriously ill hospitalized patients. SUPPORT Investigators. The Study to Understand Prognoses and Preferences for Outcome and Risks of Treatments. Crit Care Med. 1997;25(12):1962–1968.
177. Beck AM, Ovesen L. At which body mass index and degree of weight loss should hospitalized elderly patients be considered at nutritional risk? Clin Nutr. 1998;17(5):195–198.
178. Stevens J, Cai J, Pamuk ER, et al. The effect of age on the association between body-mass index and mortality. N Engl J Med. 1998;338(1):1–7.
179. Davidson I, Smith S. Nutritional screening: pitfalls of nutritional screening in the injured obese patient. Proc Nutr Soc. 2004;63(3):421–425.
180. Kalliomaki JL, Siltavuori L, Virtama P. Stature and aging. J Am Geriatr Soc. 1973;21(11):504–506.
181. Dequeker JV, Baeyens JP, Claessens J. The significance of stature as a clinical measurement of aging. J Am Geriatr Soc. 1969;17(2):169–179.
182. Han TS, Lean ME. Lower leg length as an index of stature in adults. Int J Obes Relat Metab Disord. 1996;20(1):21–27.
183. Noppa H, Andersson M, Bengtsson C, et al. Body composition in middle-aged women with special reference to the correlation between body fat mass and anthropometric data. Am J Clin Nutr. 1979;32(7):1388–1395.
184. Rossner S. Obesity in the elderly—a future matter of concern? Obes Rev. 2001;2(3):183–188.
185. Villareal DT, Apovian CM, Kushner RF, et al: NAASO, The Obesity Society. Obesity in older adults: technical review and position statement of the American Society for Nutrition and NAASO, The Obesity Society. Am J Clin Nutr. 2005;82(5):923–934.
186. Zamboni M, Mazzali G, Zoico E, et al. Health consequences of obesity in the elderly: a review of four unresolved questions. Int J Obes (Lond). 2005;29(9):1011–1029.
187. Liu KJ, Cho MJ, Atten MJ, et al. Hypocaloric parenteral nutrition support in elderly obese patients. Am Surg. 2000;66(4):394–399.
188. Covinsky KE, Covinsky MH, Palmer RM, et al. Serum albumin concentration and clinical assessments of nutritional status in hospitalized older people: different sides of different coins? J Am Geriatr Soc. 2002;50(4):631–637.
189. Campion EW, deLabry LO, Glynn RJ. The effect of age on serum albumin in healthy males: report from the Normative Aging Study. J Gerontol. 1988;43(1):M18–M20.
190. Cooper JK, Gardner C. Effect of aging on serum albumin. J Am Geriatr Soc. 1989;37(11):1039–1042.
191. Fuhrman MP, Charney P, Mueller CM. Hepatic proteins and nutrition assessment. J Am Diet Assoc. 2004;104(8):1258–1264.
192. Goldwasser P, Feldman J. Association of serum albumin and mortality risk. J Clin Epidemiol. 1997;50(6):693–703.
193. Don BR, Kaysen G. Serum albumin: relationship to inflammation and nutrition. Semin Dial. 2004;17(6):432–437.
194. Sung J, Bochicchio GV, Joshi M, et al. Admission serum albumin is predicitve of outcome in critically ill trauma patients. Am Surg. 2004;70(12):1099–1102.
195. Corti MC, Guralnik JM, Salive ME, et al. Serum albumin level and physical disability as predictors of mortality in older persons. JAMA. 1994;272(13):1036–1042.
196. Chojkier M. Inhibition of albumin synthesis in chronic diseases: molecular mechanisms. J Clin Gastroenterol. 2005;39(4 Suppl 2):S143–S146.
197. Nicholson JP, Wolmarans MR, Park GR. The role of albumin in critical illness. Br J Anaesth. 2000;85(4):599–610.
198. Rothschild MA, Oratz M, Schreiber SS. Albumin synthesis. 1. N Engl J Med. 1972;286(14):748–757.
199. Rothschild MA, Oratz M, Schreiber SS. Albumin synthesis (second of two parts). N Engl J Med. 1972;286(15):816–821.
200. Cerra FB. Hypermetabolism, organ failure, and metabolic support. Surgery. 1987;101(1):1–14.
201. Wernerman J, Hammarqvist F, Gamrin L, et al. Protein metabolism in critical illness. Baillieres Clin Endocrinol Metab. 1996;10(4):603–615.
202. Plank LD, Hill GL. Energy balance in critical illness. Proc Nutr Soc. 2003;62(2):545–552.
203. Uehara M, Plank LD, Hill GL. Components of energy expenditure in patients with severe sepsis and major trauma: a basis for clinical care. Crit Care Med. 1999;27(7):1295–1302.
204. Heiat A, Vaccarino V, Krumholz HM. An evidence-based assessment of federal guidelines for overweight and obesity as they apply to elderly persons. Arch Intern Med. 2001;161(9):1194–1203.
205. Executive summary of the clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Arch Intern Med. 1998;158(17):1855–1867.
206. Harris J, Benedict F. A biometric study of basal metabolism in man. Washington D.C. Carnegie Institute of Washington. 1919.
207. Cheng CH, Chen CH, Wong Y, et al. Measured versus estimated energy expenditure in mechanically ventilated critically ill patients. Clin Nutr. 2002;21(2):165–172.
208. Frankenfield DC, Smith JS, Cooney RN. Accelerated nitrogen loss after traumatic injury is not attenuated by achievement of energy balance. JPEN J Parenter Enteral Nutr. 1997;21(6):324–329.
209. Long CL, Schaffel N, Geiger JW, et al. Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorimetry and nitrogen balance. JPEN J Parenter Enteral Nutr. 1979;3(6):452–456.
210. Klein CJ, Stanek GS, Wiles CE 3rd. Overfeeding macronutrients to critically ill adults: metabolic complications. J Am Diet Assoc. 1998;98(7):795–806.
211. Heyland DK, Dhaliwal R, Drover JW, et al: Canadian Critical Care Clinical Practice Guidelines Committee. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr. 2003;27(5):355–373.
212. Woodcock NP, Zeigler D, Palmer MD, et al. Enteral versus parenteral nutrition: a pragmatic study. Nutrition. 2001;17(1):1–12.
213. Heyland DK, Dhaliwal R, Day A, et al. Validation of the Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients: results of a prospective observational study. Crit Care Med. 2004;32(11):2260–2266.
214. Wernerman J. Guidelines for nutritional support in intensive care unit patients: a critical analysis. Curr Opin Clin Nutr Metab Care. 2005;8(2):171–175.
215. Kreymann KG, Berger MM, Deutz NE, et al; ESPEN (European Society for Parenteral and Enteral Nutrition). ESPEN Guidelines on Enteral Nutrition: intensive care. Clin Nutr. 2006;25(2):210–223. Epub 2006 May 11.
216. Bistrian BR, McCowen KC. Nutritional and metabolic support in the adult intensive care unit: key controversies. Crit Care Med. 2006;34(5):1525–1531.
217. Griffiths RD, Bongers T. Nutrition support for patients in the intensive care unit. Postgrad Med J. 2005;81(960):629–636.
218. Griffiths RD. Is parenteral nutrition really that risky in the intensive care unit? Curr Opin Clin Nutr Metab Care. 2004;7(2):175–181.
219. Debaveye Y, Van den Berghe G. Risks and benefits of nutritional support during critical illness. Annu Rev Nutr. 2006;26:513–538.
220. Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care. 2006;10(3):R73. Epub 2006 May 12.
221. Schiffl H. Renal recovery from acute tubular necrosis requiring renal replacement therapy: a prospective study in critically ill patients. Nephrol Dial Transplant. 2006;21(5):1248–1252. Epub 2006 Jan 31.
222. Lindeman RD. Overview: renal physiology and pathophysiology of aging. Am J Kidney Dis. 1990;16(4):275–282.
223. Epstein M. Aging and the kidney. J Am Soc Nephrol. 1996;7(8):1106–1122.
224. Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc. 1985;33(4):278–285.
225. Lindeman RD, Goldman R. Anatomic and physiologic age changes in the kidney. Exp Gerontol. 1986;21(4-5):379–406.
226. Davies DF, Shock NW. Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest. 1950;29(5):496–507.
227. Hollenberg NK, Adams DF, Solomon HS, et al. Senescence and the renal vasculature in normal man. Circ Res. 1974;34(3):309–316.
228. Cortes P, Zhao X, Dumler F, et al. Age-related changes in glomerular volume and hydroxyproline content in rat and human. J Am Soc Nephrol. 1992;2(12):1716–1725.
229. Meyer BR. Renal function in aging. J Am Geriatr Soc. 1989;37(8):791–800.
230. Wharton WW 3rd, Sondeen JL, McBiles M, et al. Measurement of glomerular filtration rate in ICU patients using 99mTc-DTPA and inulin. Kidney Int. 1992;42(1):174–178.
231. Tietz NW, Shuey DF, Wekstein DR. Laboratory values in fit aging individuals—sexagenarians through centenarians. Clin Chem. 1992;38(6):1167–1185.
232. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.
233. Burkhardt H, Bojarsky G, Gretz N, et al. Creatinine clearance, Cockcroft-Gault formula and cystatin C: estimators of true glomerular filtration rate in the elderly? Gerontology. 2002;48(3):140–146.
234. Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant. 2003;18(10):2024–2031.
235. Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis. 2002;40(2):221–226.
236. Kuan Y, Hossain M, Surman J, et al. GFR prediction using the MDRD and Cockcroft and Gault equations in patients with end-stage renal disease. Nephrol Dial Transplant. 2005;20(11):2394–2401. Epub 2005 Aug 22.
237. O'Connell MB, Wong MO, Bannick-Mohrland SD, et al. Accuracy of 2- and 8-hour urine collections for measuring creatinine clearance in the hospitalized elderly. Pharmacotherapy. 1993;13(2):135–142.
238. Baumann TJ, Staddon JE, Horst HM, et al. Minimum urine collection periods for accurate determination of creatinine clearance in critically ill patients. Clin Pharm. 1987;6(5):393–398.
239. Luft FC, Weinberger MH, Fineberg NS, et al. Effects of age on renal sodium homeostasis and its relevance to sodium sensitivity. Am J Med. 1987;82(1B):9–15.
240. Rowe JW, Shock NW, DeFronzo RA. The influence of age on the renal response to water deprivation in man. Nephron. 1976;17(4):270–278.
241. Agarwal BN, Cabebe FG. Renal acidification in elderly subjects. Nephron. 1980;26(6):291–295.
242. Bellomo R, Ronco C, Kellum JA, et al: Acute Dialysis Quality Initiative workgroup. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204–R212.
243. Taber SS, Mueller BA. Drug-associated renal dysfunction. Crit Care Clin. 2006;22(2):357–374, viii.
244. Leblanc M, Kellum JA, Gibney RT, et al. Risk factors for acute renal failure: inherent and modifiable risks. Curr Opin Crit Care. 2005;11(6):533–536.
245. van den Berk G, Tonino S, de Fijter C, et al. Bench-to-bedside review: preventive measures for contrast-induced nephropathy in critically ill patients. Crit Care. 2005;9(4):361–370. Epub 2005 Jan 7.
246. Meschi M, Detrenis S, Musini S, et al. Facts and fallacies concerning the prevention of contrast medium-induced nephropathy. Crit Care Med. 2006;34(8):2060–2068.
247. Bagshaw SM, McAlister FA, Manns BJ, et al. Acetylcysteine in the prevention of contrast-induced nephropathy: a case study of the pitfalls in the evolution of evidence. Arch Intern Med. 2006;166(2):161–166.
248. Muhlberg W, Platt D. Age-dependent changes of the kidneys: pharmacological implications. Gerontology. 1999;45(5):243–253.
249. Lonner JH, Koval KJ. Polytrauma in the elderly. Clin Orthop Relat Res. 1995;(318):136–143.
250. Center for Disease Control: National Center for Injury Control and Prevention: http://www.cdc.gov/ncipc/fact_book/factbook.htm (Last accessed on 20 April, 2007)
251. Hogue CC. Injury in late life: part I. Epidemiology. J Am Geriatr Soc. 1982;30(3):183–190.
252. Mosenthal AC, Livingston DH, Elcavage J, et al. Falls: epidemiology and strategies for prevention. J Trauma. 1995;38(5):753–756.
253. Spaite DW, Criss EA, Valenzuela TD, et al. Geriatric injury: an analysis of prehospital demographics, mechanisms, and patterns. Ann Emerg Med. 1990;19(12):1418–1421.
254. Hannan EL, Waller CH, Farrell LS, et al. Elderly trauma inpatients in New York state: 1994–1998. J Trauma. 2004;56(6):1297–1304.
255. Nagy KK, Smith RF, Roberts RR, et al. Prognosis of penetrating trauma in elderly patients: a comparison with younger patients. J Trauma. 2000;49(2):190–193; discussion 193–194.
256. McMahon DJ, Shapiro MB, et al. The injured elderly in the trauma intensive care unit. Surg Clin North Am. 2000;80(3):1005–1019.
257. Jacobs DG, Plaisier BR, Barie PS, et al. EAST Practice Management Guidelines Work Group. Practice management guidelines for geriatric trauma: the EAST Practice Management Guidelines Work Group. J Trauma. 2003;54(2):391–416.
258. Mann FA, Kubal WS, Blackmore CC. Improving the imaging diagnosis of cervical spine injury in the very elderly: implications of the epidemiology of injury. Emergency Radiol. 2000; 7(1):36–41.
259. Ehara S, Shimamura T. Cervical spine injury in the elderly: imaging features. Skeletal Radiol. 2001;30(1):1–7.
260. Prasad VS, Schwartz A, Bhutani R, et al. Characteristics of injuries to the cervical spine and spinal cord in polytrauma patient population: experience from a regional trauma unit. Spinal Cord. 1999;37(8):560–568.
261. MacLeod J, Lynn M, McKenney MG, et al. Predictors of mortality in trauma patients. Am Surg. 2004;70(9):805–810.
262. Davis JW, Kaups KL. Base deficit in the elderly: a marker of severe injury and death. J Trauma. 1998;45(5):873–877.
263. Demetriades D, Karaiskakis M, Velmahos G, et al. Effect on outcome of early intensive management of geriatric trauma patients. Br J Surg. 2002;89(10):1319–1322.
264. McKinley BA, Marvin RG, Cocanour CS, et al. Blunt trauma resuscitation: the old can respond. Arch Surg. 2000;135(6):688–693; discussion 694–695.
265. Scalea TM, Simon HM, Duncan AO, et al. Geriatric blunt multiple trauma: improved survival with early invasive monitoring. J Trauma. 1990;30(2):129–34; discussion 134–136.
266. Flanagan SR, Hibbard MR, Riordan B, et al. Traumatic brain injury in the elderly: diagnostic and treatment challenges. Clin Geriatr Med. 2006;22(2):449–468; x.
267. Rutland-Brown W, Langlois JA, Thomas KE, et al. Incidence of traumatic brain injury in the United States, 2003. J Head Trauma Rehabil. 2006;21(6):544–548.
268. Thompson HJ, McCormick WC, Kagan SH. Traumatic brain injury in older adults: epidemiology, outcomes, and future implications. J Am Geriatr Soc. 2006;54(10):1590–1595.
269. Rathlev NK, Medzon R, Lowery D, et al. Intracranial pathology in elders with blunt head trauma. Acad Emerg Med. 2006;13(3):302–307.
270. Adekoya N, Thurman DJ, White DD, et al. Surveillance for traumatic brain injury deaths—United States, 1989–1998. MMWR Surveill Summ. 2002;51(10):1–14.
271. Coronado VG, Thomas KE, Sattin RW, et al. The CDC traumatic brain injury surveillance system: characteristics of persons aged 65 years and older hospitalized with a TBI. J Head Trauma Rehabil. 2005;20(3):215–228.
272. Stocchetti N, Furlan A, Volta F. Hypoxemia and arterial hypotension at the accident scene in head injury. J Trauma. 1996;40(5):764–767.
273. Eisenberg HM, Frankowski RF, Contant CF, et al. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg. 1988;69(1):15–23.
274. Jeremitsky E, Omert LA, Dunham CM, et al. The impact of hyperglycemia on patients with severe brain injury. J Trauma. 2005;58(1):47–50.
275. Cairns CJ, Andrews PJ. Management of hyperthermia in traumatic brain injury. Curr Opin Crit Care. 2002;8(2):106–110.
276. Coles JP, Fryer TD, Coleman MR, et al. Hyperventilation following head injury: effect on ischemic burden and cerebral oxidative metabolism. Crit Care Med. 2007;35(2):568–578.
277. Muizelaar JP, Marmarou A, Ward JD, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. J Neurosurg. 1991;75(5):731–739.
278. Doyle JA, Davis DP, Hoyt DB. The use of hypertonic saline in the treatment of traumatic brain injury. J Trauma. 2001;50(2):367–383.
279. Bullock R, Chesnut RM, Clifton G, et al. Guidelines for the management of severe head injury. Brain Trauma Foundation. Eur J Emerg Med. 1996;3(2):109–127.
280. Mosenthal AC, Lavery RF, Addis M, et al. Isolated traumatic brain injury: age is an independent predictor of mortality and early outcome. J Trauma. 2002;52(5):907–911.
281. LeBlanc J, de Guise E, Gosselin N, et al. Comparison of functional outcome following acute care in young, middle-aged and elderly patients with traumatic brain injury. Brain Inj. 2006;20(8):779–790.
282. Hukkelhoven CW, Steyerberg EW, Rampen AJ, et al. Patient age and outcome following severe traumatic brain injury: an analysis of 5,600 patients. J Neurosurg. 2003;99(4):666–673.
283. Hu R, Mustard CA, Burns C. Epidemiology of incident spinal fracture in a complete population. Spine. 1996;21(4):492–499.
284. Gale SC, Gracias VH, Reilly PM, et al. The inefficiency of plain radiography to evaluate the cervical spine after blunt trauma. J Trauma. 2005;59(5):1121–1125.
285. Lomoschitz FM, Blackmore CC, Mirza SK, et al. Cervical spine injuries in patients 65 years old and older: epidemiologic analysis regarding the effects of age and injury mechanism on distribution, type, and stability of injuries. AJR Am J Roentgenol. 2002;178(3):573–577.
286. Widder S, Doig C, Burrowes P, et al. Prospective evaluation of computed tomographic scanning for the spinal clearance of obtunded trauma patients: preliminary results. J Trauma. 2004;56(6):1179–1184.
287. Schenarts PJ, Diaz J, Kaiser C, et al. Prospective comparison of admission computed tomographic scan and plain films of the upper cervical spine in trauma patients with altered mental status. J Trauma. 2001;51(4):663–668.
288. Mace SE. The unstable occult cervical spine fracture: a review. Am J Emerg Med. 1992;10(2):136–142.
289. Barry TB, McNamara RM. Clinical decision rules and cervical spine injury in an elderly patient: a word of caution. J Emerg Med. 2005;29(4):433–436.
290. Heffernan DS, Schermer CR, Lu SW. What defines a distracting injury in cervical spine assessment? J Trauma. 2005;59(6):1396–1399.
291. Holcomb JB, McMullin NR, Kozar RA, et al. Morbidity from rib fractures increases after age 45. J Am Coll Surg. 2003;196(4):549–555.
292. Bulger EM, Arneson MA, Mock CN, et al. Rib fractures in the elderly. J Trauma. 2000;48(6):1040–1046.
293. Karmakar MK, Critchley LA, Ho AM, et al. Continuous thoracic paravertebral infusion of bupivacaine for pain management in patients with multiple fractured ribs. Chest. 2003;123(2):424–431.
294. Bulger EM, Edwards T, Klotz P, et al. Epidural analgesia improves outcome after multiple rib fractures. Surgery. 2004;136(2):426–430.
295. Kieninger AN, Bair HA, Bendick PJ, et al. Epidural versus intravenous pain control in elderly patients with rib fractures. Am J Surg. 2005;189(3):327–330.
296. Falimirski ME, Provost D. Nonsurgical management of solid abdominal organ injury in patients over 55 years of age. Am Surg. 2000;66(7):631–635.
297. Krause KR, Howells GA, Bair HA, et al. Nonoperative management of blunt splenic injury in adults 55 years and older: a twenty-year experience. Am Surg. 2000;66(7):636–640.
298. Franklin GA, Casos SR. Current advances in the surgical approach to abdominal trauma. Injury. 2006;37(12):1143–1156. Epub 2006 Nov 7.
299. Looker AC, Johnston CC Jr, Wahner HW, et al. Prevalence of low femoral bone density in older U.S. women from NHANES III. J Bone Miner Res. 1995;10(5):796–802.
300. Wehren LE. The epidemiology of osteoporosis and fractures in geriatric medicine. Clin Geriatr Med. 2003;19(2):245–258.
301. Henry SM, Pollak AN, Jones AL, et al. Pelvic fracture in geriatric patients: a distinct clinical entity. J Trauma. 2002;53(1):15–20.
302. Dyer GS, Vrahas MS. Review of the pathophysiology and acute management of haemorrhage in pelvic fracture. Injury. 2006;37(7):602–613.
303. Pohlemann T, Bosch U, Gansslen A, et al. The Hannover experience in management of pelvic fractures. Clin Orthop Relat Res. 1994;(305):69–80.
304. Perry JF Jr. Pelvic open fractures. Clin Orthop Relat Res. 1980;(151):41–45.
305. Hanson PB, Milne JC, Chapman MW. Open fractures of the pelvis. Review of 43 cases. J Bone Joint Surg Br. 1991;73(2):325–329.
306. Dente CJ, Feliciano DV, Rozycki GS, et al. The outcome of open pelvic fractures in the modern era. Am J Surg. 2005;190(6):830–835.
307. Bone LB, McNamara K, Shine B, et al. Mortality in multiple trauma patients with fractures. J Trauma. 1994;37(2):262–264; discussion 264–265.
308. Dunham CM, Bosse MJ, Clancy TV, et al. EAST Practice Management Guidelines Work Group. Practice management guidelines for the optimal timing of long-bone fracture stabilization in polytrauma patients: the EAST Practice Management Guidelines Work Group. J Trauma. 2001;50(5):958–967.
309. Crowl AC, Young JS, Kahler DM, et al. Occult hypoperfusion is associated with increased morbidity in patients undergoing early femur fracture fixation. J Trauma. 2000;48(2):260–267.
310. Grossman MD, Miller D, Scaff DW, et al. When is an elder old? Effect of preexisting conditions on mortality in geriatric trauma. J Trauma. 2002;52(2):242–246.
311. Perdue PW, Watts DD, Kaufmann CR, et al. Differences in mortality between elderly and younger adult trauma patients: geriatric status increases risk of delayed death. J Trauma. 1998;45(4):805–810.
312. Morris JA Jr, MacKenzie EJ, Damiano AM, et al. Mortality in trauma patients: the interaction between host factors and severity. J Trauma. 1990;30(12):1476–1482.
313. Taylor MD, Tracy JK, Meyer W, et al. Trauma in the elderly: intensive care unit resource use and outcome. J Trauma. 2002;53(3):407–414.
314. McKevitt EC, Calvert E, Ng A, et al. Geriatric trauma: resource use and patient outcomes. Can J Surg. 2003;46(3):211–215.
315. Ross N, Timberlake GA, Rubino LJ, et al. High cost of trauma care in the elderly. South Med J. 1989;82(7):857–859.
316. Young JS, Cephas GA, Blow O. Outcome and cost of trauma among the elderly: a real-life model of a single-payer reimbursement system. J Trauma. 1998;45(4):800–804.
317. Grossman M, Scaff DW, Miller D, et al. Functional outcomes in octogenarian trauma. J Trauma. 2003;55(1):26–32.
318. van Aalst JA, Morris JA Jr, Yates HK, et al. Severely injured geriatric patients return to independent living: a study of factors influencing function and independence. J Trauma. 1991;31(8):1096–1101.
319. Carrillo EH, Richardson JD, Malias MA, et al. Long term outcome of blunt trauma care in the elderly. Surg Gynecol Obstet. 1993;176(6):559–564.
320. Richmond TS, Kauder D, Strumpf N, et al. Characteristics and outcomes of serious traumatic injury in older adults. J Am Geriatr Soc. 2002;50(2):215–222.
321. Mosenthal AC, Livingston DH, Lavery RF, et al. The effect of age on functional outcome in mild traumatic brain injury: 6-month report of a prospective multicenter trial. J Trauma. 2004;56(5):1042–1048.
322. Fallon WF Jr, Rader E, Zyzanski S, et al. Geriatric outcomes are improved by a geriatric trauma consultation service. J Trauma. 2006;61(5):1040–1046.
323. Halpern NA, Pastores SM, Greenstein RJ. Critical care medicine in the United States 1985–2000: an analysis of bed numbers, use, and costs. Crit Care Med. 2004;32(6):1254–1259.
324. Callahan D. Old age and new policy. JAMA. 1989;261(6):905–906.
325. Levinsky NG. Age as a criterion for rationing health care. N Engl J Med. 1990;322(25):1813–1816.
326. Hubbard RE, Lyons RA, Woodhouse KW, et al. Absence of ageism in access to critical care: a cross-sectional study. Age Ageing. 2003;32(4):382–387.
327. Nuckton TJ, List ND. Age as a factor in critical care unit admissions. Arch Intern Med. 1995;155(10):1087–1092.
328. Attitudes of critical care medicine professionals concerning distribution of intensive care resources. The Society of Critical Care Medicine Ethics Committee. Crit Care Med. 1994;22(2):358–362.
329. Somme D, Maillet JM, Gisselbrecht M, et al. Critically ill old and the oldest-old patients in intensive care: short- and long-term outcomes. Intensive Care Med. 2003;29(12):2137–2143. Epub 2003 Nov 12.
330. Hennessy D, Juzwishin K, Yergens D, et al. Outcomes of elderly survivors of intensive care: a review of the literature. Chest. 2005;127(5):1764–1774.
331. Hamel MB, Teno JM, Goldman L, Lynn J, et al. Patient age and decisions to withhold life-sustaining treatments from seriously ill, hospitalized adults. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. Ann Intern Med. 1999;130(2):116–125.
332. Somogyi-Zalud E, Zhong Z, Hamel MB, et al. The use of life-sustaining treatments in hospitalized persons aged 80 and older. J Am Geriatr Soc. 2002;50(5):930–934.
333. Hamel MB, Davis RB, Teno JM, et al. Older age, aggressiveness of care, and survival for seriously ill, hospitalized adults. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments. Ann Intern Med. 1999;131(10):721–728.
334. Kleinpell RM. Exploring outcomes after critical illness in the elderly. Outcomes Manag. 2003;7(4):159–169.
335. Layon AJ, George BE, Hamby B, et al. Do elderly patients overutilize healthcare resources and benefit less from them than younger patients? A study of patients who underwent craniotomy for treatment of neoplasm. Crit Care Med. 1995;23(5):829–834.
336. Blair SL, Schwarz RE. Advanced age does not contribute to increased risks or poor outcome after major abdominal operations. Am Surg. 2001;67(12):1123–1127.
337. Rady MY, Johnson DJ. Hospital discharge to care facility: a patient-centered outcome for the evaluation of intensive care for octogenarians. Chest. 2004;126(5):1583–1591.
338. Wehler M, Geise A, Hadzionerovic D, et al. Health-related quality of life of patients with multiple organ dysfunction: individual changes and comparison with normative population. Crit Care Med. 2003;31(4):1094–1101.
339. Kleinpell RM, Ferrans CE. Quality of life of elderly patients after treatment in the ICU. Res Nurs Health. 2002;25(3):212–221.
340. Eddleston JM, White P, Guthrie E. Survival, morbidity, and quality of life after discharge from intensive care. Crit Care Med. 2000;28(7):2293–2299.
341. Chelluri L, Pinsky MR, Donahoe MP, et al. Long-term outcome of critically ill elderly patients requiring intensive care. JAMA. 1993;269(24):3119–3123.
342. Wu AW, Rubin HR, Rosen MJ. Are elderly people less responsive to intensive care? J Am Geriatr Soc. 1990;38(6):621–627.
343. Teno JM, Fisher E, Hamel MB, et al. Decision-making and outcomes of prolonged ICU stays in seriously ill patients. J Am Geriatr Soc. 2000; 48(5 Suppl):S70–S74.
344. Vestal RE, Norris AH, Tobin JD, et al. Antipyrine metabolism in man: influence of age, alcohol, caffeine, and smoking. Clin Pharmacol Ther. 1975;18(4):425–432.
345. Abernethy DR, Kerzner L. Age effects on alpha-1-acid glycoprotein concentration and imipramine plasma protein binding. J Am Geriatr Soc. 1984;32(10):705–708.
346. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352(21):2211–2221.
347. Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet. 2002;360(9340):1155–1162.
348. CYP3A and Drug Interactions. The Medical Letter 2005;47(1212):54–55.
349. Crowley JJ, Cusack BJ, Jue SG, et al. Aging and drug interactions. II. Effect of phenytoin and smoking on the oxidation of theophylline and cortisol in healthy men. J Pharmacol Exp Ther. 1988;245(2):513–523.
350. Nolan L, O'Malley K. Prescribing for the elderly. Part I: Sensitivity of the elderly to adverse drug reactions. J Am Geriatr Soc. 1988;36(2):142–149.
351. Knaus WA, Wagner DP, Draper EA, et al. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest. 1991;100(6):1619–1636.
352. Suresh R, Kupfer YY, Tessler S. The graying of the intensive care unit: demographic changes 1988–1998. Crit Care Med 1999:27(Suppl):A27.
353. Barnato AE, McClellan MB, Kagay CR, et al. Trends in inpatient treatment intensity among Medicare beneficiaries at the end of life. Health Serv Res. 2004;39(2):363–375.
354. Lubitz JD, Riley GF. Trends in Medicare payments in the last year of life. N Engl J Med. 1993;328(15):1092–1096.
355. Dardaine V, Dequin PF, Ripault H, et al. Outcome of older patients requiring ventilatory support in intensive care: impact of nutritional status. J Am Geriatr Soc. 2001;49(5):564–570.
356. Baker R, Wu AW, Teno JM, et al. Family satisfaction with end-of-life care in seriously ill hospitalized adults. J Am Geriatr Soc. 2000;48(5 Suppl):S61–S69.
357. Borum ML, Lynn J, Zhong Z. The effects of patient race on outcomes in seriously ill patients in SUPPORT: an overview of economic impact, medical intervention, and end-of-life decisions. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments. J Am Geriatr Soc. 2000;48(5 Suppl):S194–S198.
358. Braun UK, Beyth RJ, Ford ME, et al. Defining limits in care of terminally ill patients. BMJ. 2007;334(7587):239–241.
359. Fick DM, Agostini JV, Inouye SK. Delirium superimposed on dementia: a systematic review. J Am Geriatr Soc. 2002;50(10):1723–1732.
360. Kakuma R, du Fort GG, Arsenault L, et al. Delirium in older emergency department patients discharged home: effect on survival. J Am Geriatr Soc. 2003;51(4):443–450.
361. O'Keeffe S, Lavan J. The prognostic significance of delirium in older hospital patients. J Am Geriatr Soc. 1997;45(2):174–178.
362. Cameron DJ, Thomas RI, Mulvihill M, et al. Delirium: a test of the Diagnostic and Statistical Manual III criteria on medical inpatients. J Am Geriatr Soc. 1987;35(11):1007–1010.
363. Foreman MD, Wakefield B, Culp K, et al. Delirium in elderly patients: an overview of the state of the Science. J Gerontol Nurs. 2001;27(4):12–20.
364. Inouye SK, Bogardus ST Jr, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med. 1999;340(9):669–676.
365. Inouye SK, Viscoli CM, Horwitz RI, et al. A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med. 1993;119(6):474–481.
366. McCusker J, Cole MG, Dendukuri N, et al. Does delirium increase hospital stay? J Am Geriatr Soc. 2003;51(11):1539–1546.
367. Cole MG, Primeau FJ. Prognosis of delirium in elderly hospital patients. CMAJ. 1993;149(1):41–46.
368. Cole MG. Delirium in elderly patients. Am J Geriatr Psychiatry. 2004;12(1):7–21.
369. Cole MG, Primeau FJ, Elie LM. Delirium: prevention, treatment, and outcome studies. J Geriatr Psychiatry Neurol. 1998;11(3):126–137.
370. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291(14):1753–1762.
371. McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc. 2003;51(5):591–598.
372. Dubois MJ, Bergeron N, Dumont M, et al. Delirium in an intensive care unit: a study of risk factors. Intensive Care Med. 2001;27(8):1297–1304.
373. Aldemir M, Ozen S, Kara IH, et al. Predisposing factors for delirium in the surgical intensive care unit. Crit Care. 2001;5(5):265–270.
374. Morrison RS, Magaziner J, Gilbert M, et al. Relationship between pain and opioid analgesics on the development of delirium following hip fracture. J Gerontol A Biol Sci Med Sci. 2003;58(1):76–81.
375. Mesulam MM, Waxman SG, Geschwind N, et al. Acute confusional states with right middle cerebral artery infarctions. J Neurol Neurosurg Psychiatry. 1976;39(1):84–89.
376. Teasdale E, Cardoso E, Galbraith S, et al. CT scan in severe diffuse head injury: physiological and clinical correlations. J Neurol Neurosurg Psychiatry. 1984;47(6):600–603.
377. Noldy NE, Carlen PL. Acute, withdrawal, and chronic alcohol effects in man: event-related potential and quantitative EEG techniques. Ann Med. 1990;22(5):333–339.
378. van Sweden B, Mellerio F. Toxic ictal delirium. Biol Psychiatry. 1989;25(4):449–458.
379. Trzepacz PT, Sclabassi RJ, Van Thiel DH. Delirium: a subcortical phenomenon? J Neuropsychiatry Clin Neurosci. 1989;1(3):283–290.
380. Woods JC, Mion LC, Connor JT, et al. Agitation among ventilated medical intensive care unit patients: frequency, characteristics and outcomes. Intensive Care Med. 2004;30(6):1066–1072.
381. Konsman JP, Parnet P, Dantzer R. Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci. 2002;25(3):154–159.
382. Allan SM. The role of pro- and antiinflammatory cytokines in neurodegeneration. Ann N Y Acad Sci. 2000;917:84–93.
383. Young GB, Bolton CF, Austin TW, et al. The encephalopathy associated with septic illness. Clin Invest Med. 1990;13(6):297–304.
384. Sprung CL, Peduzzi PN, Shatney CH, et al. Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study Group. Crit Care Med. 1990;18(8):801–806.
385. Moller K, Strauss GI, Qvist J, et al. Cerebral blood flow and oxidative metabolism during human endotoxemia. J Cereb Blood Flow Metab. 2002;22(10):1262–1270.
386. Wong ML, Bongiorno PB, Rettori V, et al. Interleukin (IL) 1beta, IL-1 receptor antagonist, IL-10, and IL-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: pathophysiological implications. Proc Natl Acad Sci U S A. 1997;94(1):227–232.
387. Sharshar T, Gray F, Poron F, et al. Multifocal necrotizing leukoencephalopathy in septic shock. Crit Care Med. 2002;30(10):2371–2375.
388. Sharshar T, Annane D, de la Grandmaison GL, et al. The neuropathology of septic shock. Brain Pathol. 2004;14(1):21–33.
389. van der Mast RC, Fekkes D. Serotonin and amino acids: partners in delirium pathophysiology? Semin Clin Neuropsychiatry. 2000;5(2):125–131.
390. Mussi C, Ferrari R, Ascari S, et al. Importance of serum anticholinergic activity in the assessment of elderly patients with delirium. J Geriatr Psychiatry Neurol. 1999;12(2):82–86.
391. Tune LE, Egeli S. Acetylcholine and delirium. Dement Geriatr Cogn Disord. 1999;10(5):342–344.
392. Roche V. Southwestern Internal Medicine Conference. Etiology and management of delirium. Am J Med Sci. 2003;325(1):20–30.
393. American Psychiatric Association. Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. 4th ed. Washington DC: 2000.
394. Trzepacz PT, Mittal D, Torres R, et al. Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium. J Neuropsychiatry Clin Neurosci. 2001;13(2):229–242.
395. Bergeron N, Dubois MJ, Dumont M, et al. Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive Care Med. 2001;27(5):859–864.
396. Inouye SK, van Dyck CH, Alessi CA, et al. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990;113(12):941–948.
397. Meagher DJ, O'Hanlon D, O'Mahony E, et al. Relationship between symptoms and motoric subtype of delirium. J Neuropsychiatry Clin Neurosci. 2000;12(1):51–56.
398. Lipowski ZJ. Delirium in the elderly patient. N Engl J Med. 1989;320(9):578–582.
399. Ross CA, Peyser CE, Shapiro I, et al. Delirium: phenomenologic and etiologic subtypes. Int Psychogeriatr. 1991;3(2):135–147.
400. Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. JAMA. 1990;263(8):1097–1101.
401. Ely EW, Siegel MD, Inouye SK. Delirium in the intensive care unit: an under-recognized syndrome of organ dysfunction. Semin Respir Crit Care Med. 2001;22(2):115–126.
402. Ely EW, Stephens RK, Jackson JC, et al. Current opinions regarding the importance, diagnosis, and management of delirium in the intensive care unit: a survey of 912 healthcare professionals. Crit Care Med. 2004;32(1):106–112.
403. Inouye SK. Delirium in older persons. N Engl J Med. 2006;354(11):1157–1165.
404. Dyer CB, Ashton CM, Teasdale TA. Postoperative delirium. A review of 80 primary data-collection studies. Arch Intern Med. 1995;155(5):461–465.
405. Bedford PD. Adverse cerebral effects of anaesthesia on old people. Lancet. 1955;269(6884):259–263.
406. Moller JT. Cerebral dysfunction after anaesthesia. Acta Anaesthesiol Scand Suppl. 1997;110:13–16.
407. Rogers MP, Liang MH, Daltroy LH, et al. Delirium after elective orthopedic surgery: risk factors and natural history. Int J Psychiatry Med. 1989;19(2):109–121.
408. Selnes OA, Goldsborough MA, Borowicz LM Jr, et al. Determinants of cognitive change after coronary artery bypass surgery: a multifactorial problem. Ann Thorac Surg. 1999;67(6):1669–1676.
409. Selnes OA, Royall RM, Grega MA, et al. Cognitive changes 5 years after coronary artery bypass grafting: is there evidence of late decline? Arch Neurol. 2001;58(4):598–604.
410. Stroobant N, Van Nooten G, Van Belleghem Y, et al. Relation between neurocognitive impairment, embolic load, and cerebrovascular reactivity following on- and off-pump coronary artery bypass grafting. Chest. 2005;127(6):1967–1976.
411. Newman MF, Kirchner JL, Phillips-Bute B, et al: Neurological Outcome Research Group and the Cardiothoracic Anesthesiology Research Endeavors Investigators. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med. 2001;344(6):395–402.
412. Dodds C, Allison J. Postoperative cognitive deficit in the elderly surgical patient. Br J Anaesth. 1998;81(3):449–462.
413. Bryson GL, Wyand A. Evidence-based clinical update: general anesthesia and the risk of delirium and postoperative cognitive dysfunction. Can J Anaesth. 2006;53(7):669–677.
414. Bekker AY, Weeks EJ. Cognitive function after anaesthesia in the elderly. Best Pract Res Clin Anaesthesiol. 2003;17(2):259–272.
415. Jacobi J, Fraser GL, Coursin DB, et al. Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), American Society of Health-System Pharmacists (ASHP), American College of Chest Physicians. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30(1):119–141.
416. Milbrandt EB, Kersten A, Kong L, et al. Haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. Crit Care Med. 2005;33(1):226–229.
417. Thom T, Haase N, Rosamond W, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113(6):e85–e151.
418. Sacco RL. Risk factors, outcomes, and stroke subtypes for ischemic stroke. Neurology. 1997; 49(5 Suppl 4):S39–S44.
419. Sacco RL. Reducing the risk of stroke in diabetes: what have we learned that is new? Diabetes Obes Metab. 2002;4 Suppl 1:S27–S34.
420. Zivin JA. Approach to cerebrovascular diseases. In: Goldman L, Ausiello D, eds. Cecil Textbook of Medicine. Philadelphia, PA: WB Saunders, 2004.
421. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. The French Study of Aortic Plaques in Stroke Group. N Engl J Med. 1996;334(19):1216–1221.
422. Adams HP Jr, Adams RJ, Brott T, et al. Stroke Council of the American Stroke Association. Guidelines for the early management of patients with ischemic stroke: A Scientific statement from the Stroke Council of the American Stroke Association. Stroke. 2003;34(4):1056–1083.
423. Adams H, Adams R, Del Zoppo G, et al. Stroke Council of the American Heart Association; American Stroke Association. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a Scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke. 2005;36(4):916–923.
424. Berrouschot J, Rother J, Glahn J, et al. Outcome and severe hemorrhagic complications of intravenous thrombolysis with tissue plasminogen activator in very old (> or =80 years) stroke patients. Stroke. 2005;36(11):2421–2425.
425. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581–1587.
426. Kasner SE. Clinical interpretation and use of stroke scales. Lancet Neurol. 2006;5(7):603–612.
427. Gresham GE, Fitzpatrick TE, Wolf PA, et al. Residual disability in survivors of stroke–the Framingham study. N Engl J Med. 1975;293(19):954–956.
428. Kelly-Hayes M, Wolf PA, Kannel WB, et al. Factors influencing survival and need for institutionalization following stroke: The Framingham Study. Arch Phys Med Rehabil. 1988;69(6):415–418.
429. Sacco RL, Wolf PA, Kannel WB, et al. Survival and recurrence following stroke. The Framingham study. Stroke. 1982;13(3):290–295.
430. Cooke JR, Ancoli-Israel S. Sleep and its disorders in older adults. Psychiatr Clin North Am. 2006;29(4):1077–1093.
431. Foley DJ, Monjan A, Simonsick EM, et al. Incidence and remission of insomnia among elderly adults: an epidemiologic study of 6,800 persons over three years. Sleep. 1999;22 Suppl 2:S366–S372.
432. Foley D, Ancoli-Israel S, Britz P, et al. Sleep disturbances and chronic disease in older adults: results of the 2003 National Sleep Foundation Sleep in America Survey. J Psychosom Res. 2004;56(5):497–502.
433. Neubauer DN. Sleep problems in the elderly. Am Fam Physician. 1999;59(9):2551–2558, 2559–2560.
434. Vgontzas AN, Kales A. Sleep and its disorders. Annu Rev Med. 1999;50:387–400.
435. Schubert CR, Cruickshanks KJ, Dalton DS, et al. Prevalence of sleep problems and quality of life in an older population. Sleep. 2002;25(8):889–893.
436. Brassington GS, King AC, Bliwise DL. Sleep problems as a risk factor for falls in a sample of community-dwelling adults aged 64–99 years. J Am Geriatr Soc. 2000;48(10):1234–1240.
437. Cricco M, Simonsick EM, Foley DJ. The impact of insomnia on cognitive functioning in older adults. J Am Geriatr Soc. 2001;49(9):1185–1189.
438. Manabe K, Matsui T, Yamaya M, et al. Sleep patterns and mortality among elderly patients in a geriatric hospital. Gerontology. 2000;46(6):318–322.
439. Shochat T, Martin J, Marler M, et al. Illumination levels in nursing home patients: effects on sleep and activity rhythms. J Sleep Res. 2000;9(4):373–379.
440. Espana RA, Scammell TE. Sleep neurobiology for the clinician. Sleep. 2004;27(4):811–820.
441. Feinsilver SH. Sleep in the elderly. What is normal? Clin Geriatr Med. 2003;19(1):177–188, viii.
442. Kamel NS, Gammack JK. Insomnia in the elderly: cause, approach, and treatment. Am J Med. 2006;119(6):463–469.
443. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540–545.
444. Shochat T, Pillar G. Sleep apnoea in the older adult: pathophysiology, epidemiology, consequences and management. Drugs Aging. 2003;20(8):551–560.
445. Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain. 2000;123 (Pt 2):331–339.
446. Littner MR, Kushida C, Anderson WM, et al. Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 2004;27(3):557–559.
447. Kobayashi R, Kohsaka M, Fukuda N, et al. Effects of morning bright light on sleep in healthy elderly women. Psychiatry Clin Neurosci. 1999;53(2):237–238.
448. Fetveit A, Skjerve A, Bjorvatn B. Bright light treatment improves sleep in institutionalised elderly—an open trial. Int J Geriatr Psychiatry. 2003;18(6):520–526.
449. Kupfer DJ, Reynolds CF 3rd. Management of insomnia. N Engl J Med. 1997;336(5):341–346.
450. Chesson A Jr, Hartse K, Anderson WM, et al. Practice parameters for the evaluation of chronic insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 2000;23(2):237–241.
451. Howes JB, Ryan J, Fairbrother G, et al. Benzodiazepine prescribing in a Sydney teaching hospital. Med J Aust. 1996;165(6):305–308.
452. Kripke DF. Chronic hypnotic use: deadly risks, doubtful benefit. REVIEW ARTICLE. Sleep Med Rev. 2000;4(1):5–20.
453. Morin CM, Colecchi C, Stone J, et al. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA. 1999;281(11):991–999.
454. Obermeyer WH, Benca RM. Effects of drugs on sleep. Neurol Clin. 1996;14(4):827–840.
455. Smith MT, Perlis ML, Park A, et al. Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry. 2002;159(1):5–11.
456. Sager MA, Franke T, Inouye SK, et al. Functional outcomes of acute medical illness and hospitalization in older persons. Arch Intern Med. 1996;156(6):645–652.
457. Covinsky KE, Palmer RM, Fortinsky RH, et al. Loss of independence in activities of daily living in older adults hospitalized with medical illnesses: increased vulnerability with age. J Am Geriatr Soc. 2003;51(4):451–458.
458. Nasraway SA, Button GJ, Rand WM, et al. Survivors of catastrophic illness: outcome after direct transfer from intensive care to extended care facilities. Crit Care Med. 2000;28(1):19–25.
459. Montuclard L, Garrouste-Orgeas M, Timsit JF, et al. Outcome, functional autonomy, and quality of life of elderly patients with a long-term intensive care unit stay. Crit Care Med. 2000;28(10):3389–3395.
460. Stucki G, Stier-Jarmer M, Grill E, et al. Rationale and principles of early rehabilitation care after an acute injury or illness. Disabil Rehabil. 2005;27(7-8):353–359.
461. Creditor MC. Hazards of hospitalization of the elderly. Ann Intern Med. 1993;118(3):219–223.
462. Manton KG. A longitudinal study of functional change and mortality in the United States. J Gerontol. 1988;43(5):S153–S161.
463. Gill TM, Allore HG, Holford TR, et al. Hospitalization, restricted activity, and the development of disability among older persons. JAMA. 2004;292(17):2115–2124.
464. Brummel-Smith K. Rehabilitation. In: Cassel CK, Leipzig RM, Cohen HJ, Larson EB, Meier DE, ed. Geriatric Medicine: An evidence based approach. New York, New York: Springer-Verlag, 2003
465. Hoenig H, Nusbaum N, Brummel-Smith K. Geriatric rehabilitation: state of the art. J Am Geriatr Soc. 1997;45(11):1371–1381.
466. Landefeld CS, Palmer RM, Kresevic DM, et al. A randomized trial of care in a hospital medical unit especially designed to improve the functional outcomes of acutely ill older patients. N Engl J Med. 1995;332(20):1338–1344.
467. Ellis G, Langhorne P. Comprehensive geriatric assessment for older hospital patients. Br Med Bull. 2005;71:45–59.
468. Cohen HJ, Feussner JR, Weinberger M, et al. A controlled trial of inpatient and outpatient geriatric evaluation and management. N Engl J Med. 2002;346(12):905–912.
469. Counsell SR, Holder CM, Liebenauer LL, et al. Effects of a multicomponent intervention on functional outcomes and process of care in hospitalized older patients: a randomized controlled trial of Acute Care for Elders (ACE) in a community hospital. J Am Geriatr Soc. 2000;48(12):1572–1581.
470. Inouye SK, Bogardus ST Jr, Baker DI, et al. The Hospital Elder Life Program: a model of care to prevent cognitive and functional decline in older hospitalized patients. Hospital Elder Life Program. J Am Geriatr Soc. 2000;48(12):1697–1706.
471. Winograd CH. Inpatient geriatric consultation. Clin Geriatr Med. 1987;3(1):193–202.
472. Stuck AE, Siu AL, Wieland GD, et al. Comprehensive geriatric assessment: a meta-analysis of controlled trials. Lancet. 1993;342(8878):1032–1036.
473. Miller DK. Effectiveness of acute rehabilitation services in geriatric evaluation and management units. Clin Geriatr Med. 2000;16(4):775–782.
474. Reuben DB, Borok GM, Wolde-Tsadik G, et al. A randomized trial of comprehensive geriatric assessment in the care of hospitalized patients. N Engl J Med. 1995;332(20):1345–1350.
475. Jolliffe JA, Rees K, Taylor RS, et al. Exercise-based rehabilitation for coronary heart disease. Cochrane Database Syst Rev. 2000;(4):CD001800.
476. Pasquali SK, Alexander KP, Peterson ED. Cardiac rehabilitation in the elderly. Am Heart J. 2001;142(5):748–755.
477. Lavie CJ, Milani RV, Littman AB. Benefits of cardiac rehabilitation and exercise training in secondary coronary prevention in the elderly. J Am Coll Cardiol. 1993;22(3):678–683.
478. Kreizman IJ, Allen D. Aging with cardiopulmonary disease: the rehab perspective. Phys Med Rehabil Clin N Am. 2005;16(1):251–265, x.
479. Lavie CJ, Milani RV. Effects of cardiac rehabilitation programs on exercise capacity, coronary risk factors, behavioral characteristics, and quality of life in a large elderly cohort. Am J Cardiol. 1995;76(3):177–179.
480. Ades PA, Waldmann ML, Polk DM, et al. Referral patterns and exercise response in the rehabilitation of female coronary patients aged greater than or equal to 62 years. Am J Cardiol. 1992;69(17):1422–1425.
481. Cottin Y, Cambou JP, Casillas JM, et al. Specific profile and referral bias of rehabilitated patients after an acute coronary syndrome. J Cardiopulm Rehabil. 2004;24(1):38–44.
482. Arboix A, Garcia-Eroles L, Massons J, et al. Acute stroke in very old people: clinical features and predictors of in-hospital mortality. J Am Geriatr Soc. 2000;48(1):36–41.
483. Dobkin BH. Clinical practice. Rehabilitation after stroke. N Engl J Med. 2005;352(16):1677–1684.
484. Macciocchi SN, Diamond PT, Alves WM, et al. Ischemic stroke: relation of age, lesion location, and initial neurologic deficit to functional outcome. Arch Phys Med Rehabil. 1998;79(10):1255–1257.
485. Kelly PJ, Furie KL, Shafqat S, et al. Functional recovery following rehabilitation after hemorrhagic and ischemic stroke. Arch Phys Med Rehabil. 2003;84(7):968–972.
486. Musicco M, Emberti L, Nappi G, et al: Italian Multicenter Study on Outcomes of Rehabilitation of Neurological Patients. Early and long-term outcome of rehabilitation in stroke patients: the role of patient characteristics, time of initiation, and duration of interventions. Arch Phys Med Rehabil. 2003;84(4):551–558.
487. Hallett M. Plasticity of the human motor cortex and recovery from stroke. Brain Res Brain Res Rev. 2001;36(2–3):169–174.
488. Duncan PW, Wallace D, Lai SM, et al. The Stroke Impact Scale version 2.0. Evaluation of reliability, validity, and sensitivity to change. Stroke. 1999;30(10):2131–2140.
489. Lai SM, Studenski S, Duncan PW, et al. Persisting consequences of stroke measured by the Stroke Impact Scale. Stroke. 2002;33(7):1840–1844.
490. Jorgensen HS, Nakayama H, Raaschou HO, et al. Outcome and time course of recovery in stroke. Part II: time course of recovery. The Copenhagen Stroke Study. Arch Phys Med Rehabil. 1995;76(5):406–412.
491. Jorgensen HS, Nakayama H, Raaschou HO, et al. Outcome and time course of recovery in stroke. Part I: outcome. The Copenhagen Stroke Study. Arch Phys Med Rehabil. 1995;76(5):399–405.
492. Weir NU, Gunkel A, McDowall M, et al. Study of the relationship between social deprivation and outcome after stroke. Stroke. 2005;36(4):815–819.
493. Barnes MP. Rehabilitation after traumatic brain injury. Br Med Bull. 1999;55(4):927–943.
494. Horan MA, Clague JE. Injury in the aging: recovery and rehabilitation. Br Med Bull. 1999;55(4):895–909.
495. Zuckerman JD. Hip fracture. N Engl J Med. 1996;334(23):1519–1525.
496. Richmond J, Aharonoff GB, Zuckerman JD, et al. Mortality risk after hip fracture. J Orthop Trauma. 2003;17(1):53–56.
497. Cree M, Soskolne CL, Belseck E, et al. Mortality and institutionalization following hip fracture. J Am Geriatr Soc. 2000;48(3):283–288.
498. Cree M, Carriere KC, Soskolne CL, et al. Functional dependence after hip fracture. Am J Phys Med Rehabil. 2001;80(10):736–743.
499. Marcantonio ER, Flacker JM, Michaels M, et al. Delirium is independently associated with poor functional recovery after hip fracture. J Am Geriatr Soc. 2000;48(6):618–624.
500. Koval KJ, Sala DA, Kummer FJ, et al. Postoperative weight-bearing after a fracture of the femoral neck or an intertrochanteric fracture. J Bone Joint Surg Am. 1998;80(3):352–356.
501. Handoll HH, Farrar MJ, McBirnie J, et al. Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures. Cochrane Database Syst Rev. 2002;(4):CD000305.
502. Bergqvist D, Benoni G, Bjorgell O, et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med. 1996;335(10):696–700.
503. Dahl OE, Bergqvist D. Current controversies in deep vein thrombosis prophylaxis after orthopaedic surgery. Curr Opin Pulm Med. 2002;8(5):394–397.
504. Freedman KB, Brookenthal KR, Fitzgerald RH Jr, et al. A meta-analysis of thromboembolic prophylaxis following elective total hip arthroplasty. J Bone Joint Surg Am. 2000;82-A(7):929–938.
505. Rosell PA, Parker MJ. Functional outcome after hip fracture. A 1-year prospective outcome study of 275 patients. Injury. 2003;34(7):529–532.
506. Lin PC, Chang SY. Functional recovery among elderly people one year after hip fracture surgery. J Nurs Res. 2004;12(1):72–82.
507. Press Y, Grinshpun Y, Berzak A, et al. The effect of co-morbidity on the rehabilitation process in elderly patients after hip fracture. Arch Gerontol Geriatr. 2007; [Epub ahead of print]
508. Hawkes WG, Wehren L, Orwig D, et al. Gender differences in functioning after hip fracture. J Gerontol A Biol Sci Med Sci. 2006;61(5):495–499.
509. Shah MR, Aharonoff GB, Wolinsky P, et al. Outcome after hip fracture in individuals ninety years of age and older. J Orthop Trauma. 2001;15(1):34–39.
510. Cutson TM, Bongiorni DR. Rehabilitation of the older lower limb amputee: a brief review. J Am Geriatr Soc. 1996;44(11):1388–1393.
511. Feinglass J, Brown JL, LoSasso A, et al. Rates of lower-extremity amputation and arterial reconstruction in the United States, 1979 to 1996. Am J Public Health. 1999;89(8):1222–1227.
512. Esquenazi A. Geriatric amputee rehabilitation. Clin Geriatr Med. 1993;9(4):731–743.
513. Cruz CP, Eidt JF, Capps C, et al. Major lower extremity amputations at a Veterans Affairs hospital. Am J Surg. 2003;186(5):449–454.
514. Waters RL, Perry J, Antonelli D, et al. Energy cost of walking of amputees: the influence of level of amputation. J Bone Joint Surg Am. 1976;58(1):42–46.
515. Fisher SV, Gullickson G Jr. Energy cost of ambulation in health and disability: a literature review. Arch Phys Med Rehabil. 1978;59(3):124–133.
516. Pagliarulo MA, Waters R, Hislop HJ. Energy cost of walking of below-knee amputees having no vascular disease. Phys Ther. 1979;59(5):538–543.
517. Harris KA, van Schie L, Carroll SE, et al. Rehabilitation potential of elderly patients with major amputations. J Cardiovasc Surg (Torino). 1991;32(4):463–467.
518. Legro MW, Reiber G, del Aguila M, et al. Issues of importance reported by persons with lower limb amputations and prostheses. J Rehabil Res Dev. 1999;36(3):155–163.
519. Esquenazi A, DiGiacomo R. Rehabilitation after amputation. J Am Podiatr Med Assoc. 2001;91(1):13–22.