Clin Chest Med 26 (2005) 469 – 484

Aging of the : Impact on Pulmonary Function Tests and Adaptation to Exertion Jean-Paul Janssens, MD

Outpatient Section of the Division of Pulmonary Diseases, Geneva University Hospital, 1211 Geneva 14, Switzerland

Life expectancy has risen sharply during the past chest wall, in static elastic recoil of the lung (Fig. 1), century and is expected to continue to rise in virtually and in strength of respiratory muscles. all populations throughout the world. In the United States population, life expectancy has risen from Age-associated changes in the chest wall 47 years in 1900 to 77 in 2001 (74.4 for the male and 79.8 for the female population) [1]. The proportion of Estenne and colleagues measured age-related the population over 65 years of age currently is more changes in chest wall compliance in 50 healthy than 15% in most developed countries and is ex- subjects ages 24 to 75: aging was associated with a pected to reach 20% by the year 2020. Healthy life significant decrease (À31%) in chest wall compli- expectancy, at the age of 60, is at present 15.3 years ance, involving rib cage (upper thorax) compliance for the male population and 17.9 years for the female and compliance of the diaphragm-abdomen compart- population [2]. These demographic changes have a ment (lower thorax) [5]. Calcifications of the costal major impact on health care, financially and clini- cartilages and chondrosternal junctions and degenera- cally. Awareness of the basic changes in respiratory tive joint disease of the dorsal spine are common physiology associated with aging and their clinical radiologic observations in older subjects and contrib- implication is important for clinicians. Indeed, age- ute to chest wall stiffening [6]. Changes in the shape associated alterations of the respiratory system tend of the thorax modify chest wall mechanics; age- to diminish subjects’ reserve in cases of common related osteoporosis results in partial (wedge) or clinical diseases, such as lower respiratory tract in- complete (crush) vertebral fractures, leading to fection or heart failure [3,4]. increased dorsal kyphosis and anteroposteriordi- This review explores age-related physiologic ameter (barrel chest). Indeed, prevalence of vertebral changes in the respiratory system and their conse- fractures in the elderly population is high and quences in respiratory mechanics, gas exchange, and increases with age; in Europe, in female subjects respiratory adaptation to exertion. over 60, the prevalence of vertebral fractures is 16.8% in the 60 to 64 age group, increasing to 34.8% in the 75 to 79 age group [7]. Men also show an Structural changes in the respiratory system increase in vertebral fractures with age, but rates are related to aging approximately half those of the female population [8]. A study of 100 chest radiographs of subjects ages Most of the age-related functional changes in the 75 to 93 years, without cardiac or pulmonary dis- respiratory system result from three physiologic orders, illustrates the frequency of dorsal kyphosis events: progressive decrease in compliance of the in this age group: 25% had severe kyphosis as a consequence of vertebral wedge or crush fractures (>50), 43% had moderate kyphosis (35–50), and E-mail address: [email protected] only 23% had a normal curvature of the spine [6].

0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.05.004 chestmed.theclinics.com 470 janssens

A 100 100

80 Chest wall rs 80

60 lung 60 FRC

% TLC 40 40

RV 20 20

0 0 -40 -30 -20 -10 010203040 Pressure (cm H2O) B 100 100

80 rs 80 Chest wall 60 FRC 60 lung

% TLC 40 40 RV

20 20

0 0 -40 -30 -20 -10 010203040 Pressure (cm H2O)

Fig. 1. Static pressure-volume curves showing changes in the compliance of the chest wall, the lung, and the respiratory system between an ‘‘ideal’’ 20-year-old (A) and a 60-year-old subject (B). Note increase in RV and FRC and decrease in slope of pressure-volume curve for the respiratory system (rs) in the older subject, illustrating decreased compliance of the respiratory system. (Data from Turner J, Mead J, Wohl M. Elasticity of human lungs in relation to age. J Appl Physiol 1968;25:664–71.)

Respiratory muscle function Fig. 1) [9]. As such, during normal resting tidal , the increase in breathing-related energy Respiratory muscle performance is impaired con- expenditure (elastic work) in a 60-year-old man is comitantly by the age-related geometric modi- estimated at 20% compared with that of a 20-year- fications of the rib cage, decreased chest-wall old, placing an additional burden on the respiratory compliance, and increase in functional residual muscles [8]. capacity (FRC) resulting from decreased elastic recoil Respiratory muscle strength decreases with age of the lung (Fig. 2) [9]. The kyphotic curvature of the (Table 1). Polkey and colleagues report a significant, spine and the anteroposterior diameter of the chest although modest, decrease in the strength of the increase with aging, thereby decreasing the curvature diaphragm in elderly subjects (n = 15; mean age 73, of the diaphragm and thus its force-generating range 67–81 years) compared with a younger control capacity [6]. Changes in chest wall compliance lead group (n = 15; mean age 29, range 21–40 years): to a greater contribution to breathing from the dia- À13% for transdiaphragmatic pressure during a phragm and abdominal muscles and a lesser contri- maximal sniff (sniff transdiaphragmatic pressure bution from thoracic muscles. The age-related [Pdi]: 119 versus 136 cm H2O) and À23% during cer- reduction in chest-wall compliance is somewhat vical magnetic stimulation (twitch Pdi: 26.8 versus greater than the increase in lung compliance; thus, 35.2 cm H2O) [10]. There was, however, a consid- compliance of the respiratory system is 20% less in a erable overlap between groups, and the magnitude 60-year-old subject compared with a 20-year-old (see of the difference in this study was relatively small. aging of the respiratory system 471

70 grip) [13]. Peripheral muscle strength declines with aging. Bassey and Harries report a 2% annual 60 FRC decrease in handgrip strength in 620 healthy subjects 50 over age 65 [20]. Decrease in muscle strength results from a decrease in cross-sectional muscle fiber area 40 (process referred to as sarcopenia), a decrease in the RV number of muscle fibers (especially type II fast- 30 % TLC twitch fibers and motor units), alterations in neuro- muscular junctions, and loss of peripheral motor 20 neurons with selective denervation of type II muscle fibers [21–26]. Other proposed mechanisms of age- 10 related muscular dysfunction include impairment of ++ 0 the sarcoplasmic reticulum Ca pump resulting from 10 20 30 40 50 60 70 uncoupling of ATP hydrolysis from Ca++ transport Age (years) (which may reduce maximal shortening velocity and relaxation), loss of muscle proteins resulting from Fig. 2. Progressive and linear increase in RVand FRC decreased synthesis (ie, decreased ‘‘repair’’ ability between the ages of 20 and 60 years. Gray zones represent and protein turnover), and a decline in mitochondrial ± 1 SD. (Data from Turner J, Mead J, Wohl M. Elasticity of oxidative capacity [27–31]. human lungs in relation to age. J Appl Physiol 1968;25: Respiratory muscle function also is dependent on 664–71.) energy availability (ie, blood flow, content, and carbohydrate or lipid levels) [32]. Decreased Similarly, Tolep and coworkers report maximal respiratory muscle strength is described in patients Pdi values in healthy elderly subjects (n = 10; ages who have chronic heart failure (CHF). Mancini and 65–75, 128 ± 9 cm H2O), which were 25% lower colleagues show that CHF has a highly significant than values obtained in young adults (n = 9; ages impact on respiratory muscle strength and on the 19–28, 171 ± 8 cm H2O) [11]. Although one cross- tension-time index [33]. The tension-time index de- sectional study fails to demonstrate any relationship scribes the relationship between force of contraction between age and maximal static respiratory pressures (Pdi/Pdimax) and duration of contraction (ratio of in 104 subjects over 55 [12], larger studies—also inspiratory time to total respiratory cycle duration based on noninvasive measurements (maximal inspir- [TI/TTOT]) and is related inversely to respiratory atory and expiratory pressures [MIP and MEP] at the muscle endurance. In elderly subjects who have heart mouth and sniff nasal inspiratory pressure [SNIP])— document an age-related decrease in respiratory muscle performance [13–16]. Table 1 Respiratory muscle strength is related to nutri- Maximal inspiratory and expiratory pressures measured at tional status, often deficient in the elderly. Enright the mouth in older subjects, by age group and sex and colleagues demonstrate significant correlations MIP (cm H2O) MEP (cm H2O) between MIP or MEP pressures and lean body mass Age group (y) n = 5201 n = 756 (measured by bioelectric impedance), body weight, or Women body mass index [14]. Arora and Rochester show the 65–69 59 125 deleterious impact of undernourishment on respira- 70–74 56 121 tory muscle strength or maximal voluntary ventila- 75–79 49 102 tion: the decrease in respiratory muscle strength and 80–84 45 84 maximal voluntary ventilation was highly significant >85 40 94 Men in undernourished subjects (71 ± 6% of ideal body 65–69 84 188 weight) compared with control subjects (104 ± 10% 70–74 81 179 of ideal body weight) [17]. Necropsy studies confirm 75–79 74 161 the correlation between body weight and diaphragm 80–84 64 142 muscle mass further [18]. >85 56 131 Age-associated alterations in skeletal muscles also Data from Enright PL, Kronmal RA, Manolio TA, et al. affect respiratory muscle function [19]. MIP and Respiratory muscle strength in the elderly: correlates and MEP in elderly subjects are correlated strongly and reference values. Am J Respir Crit Care Med 1994;149: independently with peripheral muscle strength (hand- 430–8. 472 janssens failure, the tension-time index increases, primarily enlargement is remarkably homogeneous as opposed because of an increase in Pdi/Pdimax and, during to the irregular distribution of airspace enlargement in , approaches values shown to generate fatigue emphysema. Morphometric studies consistently find [34]. Evans and coworkers show a significant corre- an increase in the average distance between airspace lation between cardiac index and sniff Pdi [35]. walls (mean linear intercept) and a decrease in the Nishimura and coworkers make a similar observation surface area of airspace wall per unit of lung volume in subjects who have CHF, showing significant cor- beginning in the third decade of life. The decrease in relations between MIP and cardiac index or maximal surface area of airspace wall per unit of lung volume oxygen consumption (Vo2max) per body weight, as approximately is linear and continues throughout life, an index of cardiovascular performance [36]. resulting in a 25% to 30% decrease in nonagenarians Other frequent clinical situations that produce [46,47]. Although these changes are histologically diminished respiratory muscle function in the elderly different from emphysema (no destruction of alveolar include Parkinson’s disease and sequelae of cerebral walls), they result in similar changes in lung vascular disease [37,38]. Myasthenia gravis is an- compliance. Thus, as described by Turner coworkers other cause of respiratory muscle weakness, although in subjects ages 20 to 60, static elastic recoil pressure encountered less commonly. of the lung decreases as a part of normal aging (0.1– À1 0.2 cm H2O Á year ), and the static pressure-volume Changes in the lung parenchyma and peripheral curve for the lung is shifted to the left and has a airways steeper slope [9,48]. Verbeken and coworkers pro- pose that the changes in structural and functional The human respiratory system is exposed con- characteristics caused by isolated airspace enlarge- tinuously to air and a variety of inhaled pollutants. ment that are seen in the elderly be differentiated This creates a challenge for physiologists and cli- from emphysema by the absence of alveolar wall de- nicians, namely to differentiate—in studies of human struction and inflammation and designated as senile lungs—the true impact of normal aging (ie, physio- lung [45]. logic aging) from that of environmental exposure. In a postmortem study, mean bronchiolar diame- Environmental tobacco smoke and particulate air ter also decreased significantly after age 40 [49]. pollution have measurable and well-documented ef- Bronchiolar narrowing and increased resistance were fects on respiratory symptoms and disease in the independent of any emphysematous changes or of elderly [39–41]. Appropriate animal models, there- previous bronchiolar injury. This decline in small fore, are needed to study pathologic changes that airway diameter may contribute to the decrement in occur with aging per se. Senescence-accelerated mice expiratory flow noted with aging [49]. Reduction in (SAM; a murine model of accelerated senescence) is supporting tissues around the airways further in- proposed as such a model, permitting investigation of creases the tendency for the small airways (<2 mm) the differences between the aging lung and cigarette to collapse. smoke–related airspace enlargement [42,43]. Mor- phometric studies of SAM show a notable homoge- neous enlargement of alveolar duct size with aging. Pulmonary function tests Cellular infiltrates in the alveoli rarely are seen, sug- gesting that the airspace enlargement does not result Specifics of pulmonary function testing in an older from inflammation, as opposed to what is seen in population emphysema. The ratio of lung weight to body weight does not decrease with aging, suggesting little or no The application of conventional quality control lung destruction [42]. Elastic fibers of the lung in standards to objective assessment of pulmonary SAM have a reduced recoil pressure, causing function in older subjects may prove difficult because distention of the alveolar spaces and increased lung of mood alterations, fatigability, lack of cooperation, volume [43]. Age-related changes in the pressure- or cognitive impairment. Indeed, prevalence of volume curves show a shift leftwards and upwards dementia increases with aging, reaching 5.6% after (ie, loss of elastic recoil of the lung) (see Fig. 1). age 75, 22% after age 80, and 30% as of age 90 [50]. These changes are similar to those described in senile The relationship between ability to perform spirome- hyperinflation of the lung in humans [9,44]. try and cognitive function in the elderly is reported by As noted in SAM during the course of aging, several investigators [51–54]. The feasibility of high- alveolar ducts in humans increase in diameter and quality spirometry in elderly subjects who do not alveoli become wider and shallower [45].This have cognitive impairment is confirmed in a large aging of the respiratory system 473

Italian study of 1612 ambulatory subjects ages 65 and NEP, they are considered flow limited. This technique older who did nor did not have chronic airflow has significant limitations, as it underestimated the limitation: tests with at least three acceptable curves presence of COPD without resting flow limitation in were obtained in 82% of normal subjects and in 84% a study of 26 adults ages 42 to 87 (mean 65 ± of patients who have chronic airflow limitation [55]. 10 years) and, therefore, cannot be considered a sub- Cognitive impairment, however, lower educational stitute for spirometric screening for COPD [59]. level, and shorter 6-minute walking distance levels For assessment of respiratory muscle perfor- were found to be independent predictors of a poor mance, SNIP and MIP and MEP are feasible in older acceptability rate [55]. Pezzoli and colleagues per- subjects, although SNIP tends to be easier to perform formed spirometric testing in 715 subjects who and better tolerated than MIP; these tests show an had respiratory symptoms and reported a feasibility important learning effect and must be repeated at least rate (according to ATS criteria) of 82%; low Mini– five (MIP and MEP) to 10 (SNIP) times [60,61]. Mental State Examination and activities of daily Reported coefficients of variation for MIP and MEP living scores were associated with poor spirometric in healthy elderly subjects are, respectively, 10.2% performance [56]. Lower feasibility rates for spirome- and 12.8% [62]. try are reported in elderly patients who were in- Plethysmographic measurement of lung volumes stitutionalized (41%) and hospitalized (50%), with a seldom is required in this age group and, to the clear relationship between the degree of cognitive author’s knowledge, no specific reference values are impairment and feasibility of testing [53,54]. The available for subjects over age 70. prevalence of delirium in older people on hospital admission ranges from 10% to 24%, whereas de- Lung volumes lirium develops in 5% to 32% of older patients after admission [57]. Underdiagnosis, therefore undertreat- The major determinants of static lung volumes are ment, of chronic obstructive pulmonary disease the elastic recoil of the chest wall and that of the lung (COPD) in older subjects may be related to difficul- parenchyma. Loss of elastic recoil of the lung pa- ties encountered in performing spirometry adequately renchyma and, to a lesser degree, decrease in re- in this population. spiratory muscle performance result in an increase in Alternative tests for the measurment of COPD in residual volume (RV): RV increases (air-trapping) the elderly have been explored to find methods that by approximately 50% between ages 20 and 70 (see may be less cooperation dependent for test subjects. Fig. 2). Conversely, there is a progressive decrease in Measurement of airway resistance using the forced vital capacity to approximately 75% of best values. oscillation technique (FOT) is applied more easily Because of the increased stiffness of the chest wall, than spirometry in older patients who have cogni- the age-related diminished elastic recoil of the lungs tive disorders [53,54]. In elderly patients who are is counterbalanced by an increased elastic load hospitalized or institutionalized, measurement of from the chest wall; total lung capacity (TLC) airway resistance by FOT was successful in 74% to thus remains fairly constant throughout life [63]. 76% of patients tested. The reported sensitivity and Increased elastic recoil of the chest wall and dimin- specificity for the detection of COPD in older sub- ished elastic recoil of the lung parenchyma also jects were 76% and 78%, respectively; thus, FOT is explain the increase in FRC (ie, elderly subjects useful in this population [54]. Conversely, assessment breathe at higher lung volumes than younger sub- of airway resistance using the interrupter technique, jects) (see Figs. 1 and 2) [63]. widely used in epidemiologic and pediatric studies, in The closing volume (ie, the volume at which small spite of its attractive simplicity, performed poorly in airways in dependent regions of the lung begin to the detection of COPD in older subjects compared close during expiration) increases with age. Prema- with FOT or spirometry, with a higher coefficient ture closure of terminal airways is related to a loss of of variation than FOT [58]. The negative expiratory supporting tissues around the airways. The closing pressure technique (NEP), which does not require a volume begins to exceed the supine FRC at approxi- forced expiratory maneuver, is useful to detect flow mately 44 years of age and to exceed the sitting limitation [59]. The test involves applying negative FRC at approximately 65 years of age [64]. Closing pressure at the mouth during a tidal expiration. When volume may reach 55% to 60% of TLC and equal the NEP elicits an increase in flow throughout the FRC; as such, normal tidal breathing may occur expiration, patients are not flow limited. In contrast, with a significant proportion of peripheral airways when patients do not have an increase in flow during not contributing to gas exchange (low ventilation- most or part of the tidal expiration on application of perfusion ratio [V/Q] zones). Although this is sug- 474 janssens gested as an important mechanism for the age-related Enright and colleagues selected 777 healthy non- decrease in Pao2, increase in alveolar-arterial differ- obese, never-smokers ages 65 to 85 who had no ence in partial pressure of oxygen (Pao2 À Pao2), history of lung disease from 5201 ambulatory elderly and decrease in carbon monoxide transfer, measure- participants of the Cardiovascular Health Study; ment of V/Q inequality using the multiple inert gas estimation of annual decline for FEV1 was 32 mL/ elimination technique (MIGET) fails to show a year in women and 27 mL/year for men and, for significant increase in low V/Q areas with aging in FVC, 33 mL/year in women and 20 mL/year in men 64 subjects ages 18 to 71 [65]. (Box 1) [13,74,108,113,117]. Regression equations suggest a linear relationship between age and decline Spirometry in FEV1 and FVC in this study [73]. In summary, the average yearly decline of FEV1 and FVC is approx- Forced expiratory volumes increase with growth imately 30 mL/year, although it may be overesti- up to the age of approximately 18. According to mated by cross-sectional studies. Whether or not European Community for Coal and Steel data, no decline of forced expiratory volumes with age is significant changes occur in forced expiratory volume linear remains controversial, and longitudinal studies in 1 second (FEV1) or forced vital capacity (FVC) of older nonsmoking subjects are required to clarify between the ages of 18 and 25 [66]. After this pla- this issue. teau, FEV1 and FVC start to decrease, although more According to published reference values for recent studies excluding smokers suggest a later start FEV1/FVC, using a threshold value of FEV1/FVC of FEV1 and FVC decline in nonsmokers [67]. Cross- less than 70% for defining the presence of airway sectional and longitudinal studies show an acceler- obstruction, as suggested by the Global Initiative for ated decline in FEV1 and FVC with age; the rate of Chronic Lung Diseases (GOLD) Workshop Sum- decline is greater in cross-sectional versus longitudi- mary, may lead to overdiagnosis of COPD. This is nal studies and in men versus women and more rapid illustrated by a Norwegian study of forced expiratory in patients who have increased airway reactivity [63]. volumes in 71 asymptomatic never-smokers, ages 70 The age-related decrease in FEV1 and FVC initially or older; according to GOLD criteria, 25% had stage I was considered linear, but more recent studies— COPD and 10% stage II; for subjects older than 80, including subjects ages 18 to 74—suggest that the results were, respectively, 32% and 18% [76]. Using decline may be nonlinear and accelerates with ag- the regression equations published by Enright and ing [68–71]. colleagues, normal values for FEV1/FVC are less Regression equations, based on extrapolations than 70% for men ages 80 and older and women ages from groups of younger subjects, tend to overestimate 92 and older (see Box 1) [74]. predicted values for FEV1, FVC, and FEV1/FVC in elderly subjects [67]. Few studies report results ob- Flow-volume curves and peak expiratory flow tained in large samples of elderly subjects. Ericsson and Irnell, for example, report measurements per- Fowler and colleagues report characteristic modi- formed on 264 normal ‘‘elderly’’ subjects, none of fications in the expiratory flow-volume curve with whom was older than 71 years of age [72]. Fowler aging (Fig. 3) [73]. The changes in expiratory flow- and colleagues studied 182 Londoners over age 60, volume suggested alterations in the small peripheral but only 44 subjects were over age 75 and 23 were airways, with an obstructive pattern present even in over 80 [73]. The three largest studies (all cross- lifetime nonsmokers, suggesting that this pattern may be sectional) reporting spirometric data from healthy normal in old age. Similar results are reported by Babb elderly subjects were published by Milne and Wil- and Rodarte, who compared expiratory flow rates in 17 liamson, Enright and colleagues, and DuWayne younger adults (ages 35–45) with those of 19 older Schmidt and colleagues[52,74,75]. DuWayne adults (ages 65–75); in this study, decline in peak Schmidt and colleagues included patients ages 20 to expiratory flow (PEF) in the older group is proportional 94 and found that decline in FEV1 and FVC with age to loss of lung elastic recoil [77]. Changes in peripheral was linear (À31 mL/year in men and À27 mL/year in airways and loss of supporting tissue around the airways women). Values for FEV1/FVC were stable in young (‘‘senile lung’’) (discussed previously) are plausible adults and decreased in women over age 55 and in explanations for these findings. men over age 60 to 70 to 75% range [75]. The study Although PEF rates tend to decrease with age, the by Milne and Williamson includes a large number of variability in predicted peak flow values is large, and active or former smokers, and 20% of subjects had prediction equations are, therefore, not reliable regular cough and phlegm; thus, it is unreliable [52]. [78,79]. PEF lability (maximal difference in PEF aging of the respiratory system 475

Box 1. Regression equations for pulmonary function test variables in older subjects

Spirometry: men

FEV1 (liters) = (0.0378 Â heightcm) À (0.0271 Â ageyears) À 1.73; LLN = À0.84 FVC = (0.0567 Â heightcm) À (0.0206 Â ageyears) À 4.37; LLN = À1.12 FEV1/FVC% = (À0.294 Â ageyears) + 93.8; LLN = À11.7

Spirometry: women

FEV1 (liters) = (0.0281 Â heightcm) À (0.0325 Â ageyears) À 0.09; LLN = À0.48 FVC = (0.0365 Â heightcm) À (0.0330 Â ageyears) À 0.70; LLN = À0.64 FEV1/FVC% = (À0.242 Â ageyears) + 92.3; LLN = À9.3

Maximal mouth inspiratory and maximal mouth expiratory pressures: men

MIP (cm H2O) = (0.131 Â weightlb) À (1.27 Â ageyears) + 153; LLN = À41 MEP (cm H2O) = (0.25 Â weightlb) À (2.95 Â ageyears)+347;LLN=À71

Maximal mouth inspiratory and maximal mouth expiratory pressures: women

MIP (cm H2O) = (0.133 Â weightlb) À (0.805 Â ageyears)+96;LLN=À32 MIP (cm H2O) = (0.344 Â weightlb) À (2.12 Â ageyears) + 219; LLN = À52

6-minute walk test: men (n = 117; ages 40 to 80)

6MWDmeters = (7.57 Â heightcm) À (5.02 Â ageyears) À 309 m; LLN = À153 m

6-minute walk test: women (n = 173, ages 40 to 80)

6MWDmeters = (2.11 Â heightcm) À (2.29 Â weightkg) À (5.78 Â ageyears) + 667 m; LLN = À139 m

Maximal heart rate (n = 18712)

Maximal heart rate = 208 À (0.7 Â age)

Maximal oxygen consumption (n = 100; ages 15 to 71)

Vo2max (L/min) = (0.046 Â heightcm) À (0.021 Â ageyears) À 0.62 (0: male; 1: female) À 4.31 L; LLN = À.89 L

Abbreviations: LLN, lower limit of normal (mean À 1.96 SD); 6MWD, distance walked during a 6-minute test. per mean PEF) is shown to correlate with a diagnosis monitoring of ambulatory PEF (independent predic- of asthma in younger subjects. Although middle-aged tor of higher PEF lability) [80]. In a study of 1223 and older persons seem to be successful in providing subjects (mean age 66, range 43–80), Enright and a measure of PEF reliably at home, older age per se colleagues report an upper limit of normal of 16% was a factor of increased variability in longitudinal for PEF lability in older patients [80]. Another study 476 janssens

12 sistance [63]. Using the FOT, Pasker and colleagues find a weak impact of age on resistance and re- 8 actance, with opposite effects according to sex; the investigators consider the relationship between FOT measurements and age clinically irrelevant [83]. 4 Respiratory muscle testing 0 Respiratory muscle weakness may lead to short- Flow (L/sec) -4 ness of breath, reduced exercise tolerance, and, in more severe cases, alveolar hypoventilation and re- spiratory failure. The overall strength of respiratory -8 muscles can be measured noninvasively by recording TLCVolume RV MIP and MEP or by measuring SNIP [61,84]. These measurements can be performed easily at bedside Fig. 3. Changes in the expiratory flow-volume curve with [61,84]. Inspiratory pressures are measured at FRC or aging, suggesting obstruction to airflow. Curves from an at RV. Expiratory pressures usually are measured at older (dashed line) and a younger subject (solid line), normalized to percentage of vital capacity. (Data from Babb TLC. As discussed previously, the learning effect for TG, Rodarte JR. Mechanism of reduced maximal expiratory MIP, MEP, and SNIP measurements is important, flow with aging. J Appl Physiol 2000;89:505–11; and with significant increases over at least five consecu- Fowler RW, Pluck RA, Hetzel MR. Maximal expiratory tive maneuvers [13,61]. Values greater than or equal flow-volume curves in Londeners aged 60 years and over. to 80 cm H2O (in men) or 70 cm H2O (in women) for Thorax 1987;42:173–82.) MIP or greater than or equal to 70 cm H2O in men and 60 cm H2O in women for SNIP exclude clinically by the same group, based on a larger community relevant respiratory muscle weakness [85]. sample of 4581 persons ages 65 and older, reports an Available reference values for these measurements upper limit of normal of 29% for PEF lability. A cut- show a decrease with age of respiratory muscle off value of 30% for PEF lability, therefore, is strength (see Table 1 and Box 1) [13–16]. Enright recommended in older subjects for the diagnosis of and colleagues measured MIP and MEP in ambula- asthma [78]. tory subjects ages greater than or equal to 65; normal No specific changes are noted regarding the values for women ages greater than or equal to 65 and inspiratory flow curves, although maximal inspiratory males ages greater than or equal to 75 are below the flow values decrease with aging. Because lung aforementioned threshold for clinically relevant res- deposition of inhaled drugs is flow dependent with piratory muscle dysfunction [13]. Nutritional status available powder-inhaling devices, determination of (body weight, bioelectric impedance, and body mass maximal inspiratory flow in older subjects may be index) and peripheral muscle strength (handgrip) relevant when considering topical bronchodilator or correlate significantly with MIP and MEP values anti-inflammatory treatment with a powder inhaler [13]. Other investigators find values in the same [81,82]. Some powder-inhaling devices require min- range for MIP, MEP, or SNIP [15,16,86]. The de- imal inspiratory flows (through the device) of up to crease in respiratory muscle strength likely is relevant 60 L Á minÀ1 and these values may not be attained in in elderly patients in clinical situations where an very elderly patients. With the Turbuhaler, for additional load is placed on the respiratory muscles, instance, lung deposition at an inspirator flow of such as pneumonia or left ventricular failure [35,36]. 30 L Á minÀ1 is approximately half that obtained at The effects of poor nutritional status and CHF on 60 L Á minÀ1, although equivalent to that obtained respiratory muscle strength are discussed previously. with a metered-dose inhaler [82].

Airway resistance and conductance Gas exchange

When adjusted for lung volume, age has no sig- Changes in arterial oxygen tension and nificant effect on airway resistance. Peripheral air- ventilation-perfusion relationships ways contribute marginally to the total resistance of the airways and, therefore, changes in the peripheral Wagner and coworkers, using the MIGET, report airways are not reflected by changes in airway re- an increase, with aging, in V/Q imbalance, with a rise aging of the respiratory system 477 in units with a high V/Q (wasted ventilation or decline in Pao2 up to 70 to 74 years of age, followed physiologic dead space) and in units with a low V/Q by a slight rise in Pao2 from ages 75 to 90. For (shunt or venous admixture) [87,88]. The decrease in healthy patients older than 75, Pao2 was not Pao2 with age is described a consequence of this correlated with age; mean values reported were increased heterogeneity of V/Q and, in particular, of 83 ± 9 mm Hg (11.1 ± 1.2 kPa), and fifth percentile the increase in units with a low V/Q (dependent parts was at 68.4 mm Hg (9.2 kPa) [93]. of the lung, poorly ventilated during tidal breathing, A modest increase in the Pao2 À Pao2 with age is as reflected by an increased closing volume) [87]. expected because of the previously described increase These conclusions are based, however, on a small in V/Q heterogeneity. According to Sorbini and number of observations. More recently, Cardus and coworkers [92], the highest normal value for the coworkers described the age-related changes in V/Q Pao2 À Pao2 at a certain age is given by the distribution in 64 healthy subjects ages 18 to 71 [65]. equation: Pao2 À Pao2 (mm Hg)  1.4 ± 0.43  age Although there was a slight increase in V/Q mismatch (years). High values obtained by this equation (ie, in older patients, shunt and low V/Q areas did not 4.8 kPa [36 mm Hg] for 80 years of age) also may exceed 3% of total cardiac output, and decrease in result from the supine position of subjects at time Pao2 with age was minimal (6 mm Hg). Most of the of sampling. More recent studies find no significant variance of V/Q mismatch was not a result of aging relationship between age and Pao2 À Pao2; however, and remained unexplained; the role of an increase in values reported are well above normal values for closing volume with aging was not supported by younger adults (ie, 3.2 ± 1.4 kPa [24 ± 10 mm Hg] these data. This elegant study included, unfortunately, [90] and 4.4 ± 0.6 kPa [33 ± 4.5 mm Hg] [91]). a small number of older patients (only 4 were older than 60) and may not reflect changes in V/Q distribution occurring in the very old. Indeed, closing Carbon monoxide transfer factor volume increases with age but may equal FRC only when subjects reach approximately 65 years of age Flattening of the internal surface of the alveoli (according to Leblanc and coworkers [89], FRC À (ductectasia) in the elderly is associated with a re- closing volume = 1.95 À [0.03  age]). duction in alveolar surface (75 m2 at the age of 2 Regressions proposed for the computing of Pao2 30 years versus 60 m at age 70 years, a reduction of as a function of age vary widely, mainly in relation to 0.27 m2 Á yearÀ1) [63]. Because of loss of alveolar the coefficient attributed to age [90]. Indeed, for an surface area, decreased density of lung capillaries, 82-year-old man, predicted values for Pao2 range decline in pulmonary capillary blood volume, and from 8.4 to 11.3 kPa (63–84 mm Hg). Delclaux and increased V/Q heterogeneity, it is estimated that, even colleagues measured arterial blood gases in 274 sub- in healthy nonsmokers, there is a yearly decline in jects ages 65 to 100 (mean 82 years) with and without the diffusing capacity of the lung for carbon mon- À1 À1 airway obstruction; mean Pao2 was 10 ± 1.4 kPa oxide (Dlco) of 0.2 to 0.32 mL Á min Á mmHg (75 ± 11 mm Hg) [90]. These investigators suggest from middle ages and onward in men and a decrease À1 À1 accepting as normal a Pao2 of 10.6 to 11.3 kPa of 0.06 to 0.18 mL Á min Á mmHg in women (80–85 mm Hg) for subjects 65 years of age and [91,94]. Gue´nard and Marthan determined, in a popu- older [90]. Guenard and coworkers find no significant lation of 74 healthy subjects aged 69 to 104, the correlation between Pao2 and age in 74 subjects ages following regression equation for transfer capacity of 69 to 104; mean values reported were 11.2 ± 1.0 kPa the lung for carbon monoxide (Tlco) versus age (84 ± 7.5 mm Hg) [91]. Conversely, Sorbini and (age explaining 29% of the variance of Tlco): Tlco colleagues showed that there was a linear, but re- (mL Á minÀ1 Á kPaÀ1) = 126 – 0.9  age (years; ciprocal, relationship between age and Pao2 in non- r = 0.54, P < 0.001) [91]. smoking healthy subjects, with the following regression equation: Pao2 = 109 À (0.43  age) (the fact that patients were supine during arterial sampling probably explains lower Pao2 values ob- Regulation of breathing tained from this regression) [92]. More recently, Cerveri and coworkers suggest that the decrease in Aging and ventilatory responses Pao2 with aging is not linear [93]. In their study, arterial blood gas tests were analyzed in 194 non- Aging is associated with a marked attenuation smoking subjects ages 40 to 90. Stratifying the results in ventilatory responses to hypoxia and hypercap- by 5-year age intervals, the investigators found a clear nia [95–97]. Kronenberg and Drage compared the 478 janssens responses to hypercapnia and hypoxia in eight During sleep healthy young men (22–30 years old) with those of eight older men (64–73 years old) [95]. In the older The prevalence of sleep-disordered breathing subjects, ventilatory response to hypoxia was four increases in elderly subjects. In middle-aged popula- times less than that of the younger group; response to tions, the prevalence of the obstructive sleep apnea hypercapnia was decreased by 58%. Mouth occlusion syndrome (OSAS), using an apnea/hypopnea index À1 pressure (P0.1), an index of respiratory drive, is the (AHI) of 15 events Á h as a cut-off value, is ap- inspiratory pressure generated at the mouth when proximately 4% in women and 9% in men [103].In occluding the airway 0.1 second after the beginning older subjects, however, 13% to 62% of elderly of inspiration. Peterson and colleagues describe, in subjects suffer from OSAS with an AHI greater than subjects ages 65 to 79, a 50% reduction in the re- 10 events per hour [104]. Sleep-disordered breathing sponse to isocapnic hypoxia and a 60% reduction in may be associated with impairment in cognitive that to hyperoxic hypercapnia measured by P0.1 com- function and is reported to be more frequent in Alz- pared with younger subjects [97]. More recently, heimer’s disease [105]. As discussed previously, however, two studies cast doubt on the age-related aging is associated with a diminished perception of decrease in hypoxic ventilatory response. Smith and added resistive loads, such as that generated by colleagues studied two groups of nonsmoking male bronchoconstriction or upper airway collapse. Indeed, subjects, ages 30 ± 7 and 73 ± 3, who were submitted respiratory effort in response to upper airway oc- to 20 minutes of acute isocapnic hypoxia; ventilatory clusion in elderly patients is decreased compared with responses and increment in neuromuscular drive were younger subjects. Krieger and coworkers recorded similar in both groups [98]. Similarly, Pokorski and esophageal pressure during sleep in 116 patients who Marczak compare the ventilatory response to iso- had OSAS (AHI > 20) and showed that indexes of capnic hypoxia in 19 women ages 71 ± 1 to respiratory effort were reduced significantly in older 16 younger women and find no significant difference compared with younger patients (inspiratory effort at between groups in slopes of the DVe (ventilation) end of apnea: maximal esophageal pressure 40 ± 2 to DSao2 (arterial oxygen saturation) ratio and DP0.1/ versus 56 ± 3 cm H2O) [106]. The lesser increase in DSao2 [99]. respiratory effort in older patients may result from a The importance of the decrease in ventilatory re- decrease in respiratory drive and respiratory muscle sponse to hypercapnia in older subjects also is performance. In spite of the fact that indexes of unsettled: as in the study by Kronenberg and respiratory effort during apneic episodes were lower Drage, Brischetto and colleagues report a reduction in older individuals, mean apnea duration was not in the slope of the ventilatory response to hyper- prolonged significantly in older patients (28.3 ± 0.7 s capnia in older subjects (À67%) versus a younger versus 30.4 ± 0.9 s), and postapneic Sao2 was higher control group [95,96]. Rubin and coworkers, how- in older individuals. ever, in a comparative study of ventilatory response and P0.1 response to hypercapnia, fail to disclose significant differences between older (n = 10, ages Ventilatory response to exercise over 60) versus younger adults (n = 18, ages under 30) [100]. Performance during the 6-minute walk test Thus, although some studies suggest that there is an age-related decline in the ability to integrate In subjects who do not have significant osteo- information received from sensors (peripheral and articular or neuromuscular limitation, the 6-minute central chemoreceptors and mechanoreceptors) and walk test is a widely used standardized measurement generate appropriate neural activity, further inves- for evaluating physical function; results of a 6-minute tigations are needed to clarify this issue. walk test are useful to quantify physical limitation Agingalsoisassociatedwithadecreasedpercep- and monitor progression of disease in chronic tion of added resistive or elastic loads [57,101,102]. obstructive or restrictive disorders, CHF, or pulmo- Older subjects have a lower perception of methacholine- nary vascular diseases; performance is correlated with induced bronchoconstriction than younger subjects. health-related quality-of-life scores and predictive of Although available evidence yields conflicting results, morbidity and mortality in disorders, such as pulmo- blunting of the response to hypoxia and hypercapnia and nary hypertension or CHF [107]. There is a 15% lower ability to perceive bronchoconstriction may rep- learning effect when tests are performed on two resent a partial loss of important protective mechanisms successive days. Coefficient of variation is 8%. (alarm signals). Enright and Sherrill established reference equations aging of the respiratory system 479 for the 6-minute walk test from results collected in decline in Vo2max was explained by the loss of 290 healthy subjects ages 40 to 80 (see Box 1) muscle mass [118]. [108]. Predicted values for distance walked decrease linearly with age, with a difference of approximately Ventilation and exercise 200 meters between the ages of 40 and 80 years. Mean baseline Sao2 was stable at 96%. The 6-minute Ventilation during exercise in the elderly is asso- walk test is a submaximal exercise test (peak Vo2max ciated with more abdominal contribution than in during a 6-minute walk is approximately 80% of young adults and a concomitant change in respiratory Vo2max during maximal exercise testing); thus, pattern (higher rate and lower tidal volume), which potentially it is less sensitive for the detection of may result from increased stiffness of the tho- cardiac or pulmonary disorders. racic cage. When compared with younger subjects, initial Maximal oxygen consumption and aging ventilatory (and circulatory) responses to exercise are slowed in the elderly. Although respiratory frequency The ability to perform physical tasks declines with increases rapidly, rise in tidal volume and total À1 advancing age. Vo2max, expressed in L Á min , ventilation is delayed [119]. reaches a peak between 20 and 30 years of age. In contrast to the previously discussed decreased Longitudinal and cross-sectional studies thereafter response to hypercapnia at rest, elderly subjects seem show a decrease in Vo2max at an estimated rate of 9% more responsive than younger subjects to carbon to 10% per decade or À0.37 to À1.32 mL/kg/min/ dioxide during exercise. Poulin and colleagues year (see Box 1) [109–114]. The ventilatory thresh- demonstrate, in a sample of 224 subjects aged 56 to old also decreases with age, although less rapidly 85, that, for a given production than Vo2max [115]. The decrease in Vo2max is more (Vco2), the ventilatory response (Ve/Vco2)in- pronounced in sedentary subjects than in those creases with aging [120]. Similarly, Inbar and co- remaining physically active [109]. In fact, loss in workers find a 14% increase in Ve/Vco2 and a 13% Vo2max is attenuated in fit elderly individuals and increase in Ve/Vo2 between the ages of 20 and 70, in may not be significant clinically. Vo2max of older a large cross-sectional study of 1424 healthy subjects trained athletes is shown to be higher than that of [114]. This also was reported by Brischetto and middle-aged untrained men [116]. Thigh muscular colleagues [95]. In both of these studies, this response mass also has a positive impact on Vo2max [113]. The was related neither to oxygen desaturation nor to Fick equation gives the relationship between cardiac increased metabolic acidosis; Prioux and colleagues, output, peripheral oxygen extraction ([Ca À Cv]o2), however, show that, above the anaerobic threshold, and oxygen consumption per unit time (Vo2): Vo2 = older subjects had, for a given carbon dioxide pro- cardiac output  [Ca À Cv]o2. Maximal heart rate duction, higher lactate concentrations [121]. A higher (HR) in healthy adults decreases with age: Tanaka dead space–to–tidal volume ratio in elderly subjects and colleagues, in a recent a meta-analysis compiling most probably is contributive to the higher Ve/Vco2 data from 18,712 subjects, show that maximal HR is ratio. In agreement with this hypothesis is the independent of sex and level of physical activity and observation of a higher difference between end-tidal is predicted mainly by age alone; they computed the and arterial carbon dioxide tensions (Paco2) in older equation, maximal HR = 208 À 0.7  age (r = À 0.90 subjects and the increase in V/Q heterogeneity with versus age), which gives slightly higher values than aging (described previously) [65,114]. In itself, this the commonly used predictive equation, maximal may increase dyspnea for a given workload. Indeed, HR = 220 À age [117]. Factors limiting Vo2 in older for a given Ve, the oxygen cost of breathing is higher subjects are reduced maximal HR (resulting from a in elderly subjects. decrease in sensitivity of cardiac b-adrenergic recep- tors), decreased left ventricular ejection fraction, Response to exercise training reduced maximal cardiac output, and reduced periph- eral muscle mass. Fleg and Lakatta measured 24-hour Pulmonary rehabilitation programs are shown to urinary creatinine excretion, an index of muscle mass, improve exercise capacity in older patients who have in 184 healthy nonobese volunteers, aged 22 to 87, COPD. A retrospective study by Couser and co- who performed a maximal treadmill exercise [118]. workers compares the impact of a 2-month rehabili- Vo2max showed a strong negative linear relationship tation program in 28 subjects ages 75 years and with age. When Vo2max was normalized for creati- older versus 56 subjects aged less than 75. 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