Aging and Lung Disease: A Clinical Guide

By Margaret Pisani

People age 65 and older are the fastest growing segment of the U.S. population.  In the 2010 census 16% of the population, 50 million people, were age 65 and older.  That number is projected to increase to 66 million by the year 2050.  Life expectancy has also increased, with recent CDC reports indicating life expectancy at 77.9 years.  Age-adjusted death rates have decreased significantly with the largest changes occurring in older patients.  Despite these trends, the 10 leading causes of death include several pulmonary etiologies including lung cancer, chronic respiratory diseases, influenza and pneumonia.

Aging and Lung Disease: A Clinical Guide is devoted to understanding the impact of respiratory diseases in older patients.  It includes reviews of physiology of the aging lung, allergy and immunology of the aging, as well as sleep changes over the life cycle.  There are also comprehensive reviews on specific disease topics including chronic obstructive lung disease, lung cancer, atypical mycobacteria, interstitial lung disease, pulmonary hypertension, pulmonary embolism, obstructive sleep apnea, sleep disorders in older patients.  Two chapters focus on unique issues in older patients; HIV and lung transplant. Included also are important chapters on assessing functional and cognitive status and end-of-life issues in older patients with lung disease.  In addition to outlining the current state of knowledge, each chapter focuses on special considerations when caring for older patients.  Of particular interest to pulmonologists, internists, and gerontologists, other readers, such as pulmonary and geriatric nurse practitioners, as well as clinical researchers interested in both pulmonary and aging issues, willfind Aging and Lung Disease: A Clinical Guide to be a vital resource for improving their care of older patients with lung disorders.

• Language: English
• Publisher: Humana Press
• Release date: Oct 14, 2011
• ISBN: 9781607617273

Book preview

Part 1

Physiologic Changes

Margaret Pisani (ed.)Respiratory MedicineAging and Lung DiseaseA Clinical Guide10.1007/978-1-60761-727-3_1© Springer Science+Business Media, LLC 2012

1. Physiologic Changes in the Aging Lung

Carlos A. Vaz Fragoso¹  

(1)

Department of Medicine, Yale University School of Medicine and VA-CT Clinical Epidemiology Research, 950 Campbell Ave, West Haven, CT 06516, USA

Carlos A. Vaz Fragoso

Email: [e-mail]

Abstract

Aerobic cellular metabolism, a fundamental requisite for homeostasis, is dependent on oxygen delivery (O2D) and acid–base status. These, in turn, require a ventilatory response that couples gas exchange at the lung with metabolism at the cellular level. Senescence-based mechanisms adversely affect the ventilatory response, however, through reductions in respiratory physiology, termed normal aging, and through increases in the prevalence of cardiopulmonary disease, termed usual aging. Both forms of aging can lead to impairments in central respiratory drive, respiratory muscle strength, respiratory mechanics, and lung perfusion, yielding various forms of alveolar hypoventilation and the mismatch of ventilation with (lung) perfusion. Clinically, these impairments increase the risk of exercise intolerance and respiratory failure, including disturbances in O2D and acid–base status. Those at highest risk are older persons with cardiopulmonary disease, particularly if they are also obese, report the use of respiratory suppressants, or are in the midst of an episode of acute lung injury such as pneumonia. This chapter reviews the adverse effects of normal aging on respiratory physiology, at rest and with exercise. It also includes an illustrative case presentation and a discussion regarding the clinical implications of age-related reductions in respiratory physiology, relative to cardiopulmonary disease, obesity, respiratory suppressants, and acute lung injury.

Keywords

AgingRespiratory driveRespiratory musclesRespiratory mechanicsLung perfusionAging lungPhysiologic changes

Abbreviations

(A − a)DO2

Alveolar–arterial PO2 difference

CaO2

Arterial oxygen content

CvO2

Venous oxygen content

f b

Breathing frequency (respiratory rate)

FEV1

Forced expiratory volume in 1 s

[H+]

Hydrogen ion concentration

Hb

Hemoglobin

HCO3

Bicarbonate

MBC

Maximal breathing capacity

Na

Sodium

O2D

Oxygen delivery

PaCO2

Arterial carbon dioxide tension

PaO2

Arterial oxygen tension

PAO2

Alveolar partial pressure of oxygen

PIO2

Inspired oxygen tension

RQ

Respiratory quotient ( $$ {\text{V ˙CO}}_{2}/{\text{V ˙O}}_{2}$$ )

SaO2

Arterial oxygen saturation of hemoglobin

$$ {\text{V ˙CO}}_{2}$$

Production of CO2

$$ {\text{V ˙O}}_{2}$$

Consumption of oxygen

$$ {\dot{V}}_{\text{A}}$$

Alveolar minute ventilation

$$ {\dot{V}}_{\text{D}}$$

(Physiologic) dead space ventilation

$$ {\dot{V}}_{\text{E}}$$

Total minute ventilation, as measured during expiration

$$ {\dot{V}}_{\text{E}\mathrm{max}}$$

Ventilation at maximum exercise

V t

Tidal volume

V d

Dead-space volume

Aerobic cellular metabolism, a fundamental requisite for homeostasis, is dependent on oxygen delivery and acid–base status [1–3]. These, in turn, require a ventilatory response that effectively couples gas exchange at the lung with metabolism at the cellular level [3]. Senescence-based mechanisms, however, adversely affect the ventilatory response through reductions in respiratory physiology, termed normal aging, and through increases in the prevalence of cardiopulmonary disease, termed usual aging [4]. The deleterious effects of both forms of aging on the respiratory system are further exacerbated by obesity and the use of respiratory-suppressant medications, and are most evident during exercise or in the midst of an episode of acute lung injury such as pneumonia [3, 5–11].

This chapter reviews the adverse effects of normal aging on respiratory physio­logy, at rest and with exercise. It also includes an illustrative case presentation and a concluding discussion regarding the clinical implications of age-related reductions in respiratory physiology, relative to cardiopulmonary disease, obesity, medications with respiratory-suppressant properties, and acute lung injury.

Case Presentation

Ms. K is a 70-year-old female who is hospitalized for respiratory failure, evidenced by a reduced arterial oxygen saturation of hemoglobin (SaO2) at 70%, an increased arterial carbon dioxide tension (PaCO2) at 50 mmHg, and acidemia at an arterial pH of 7.32 (on ambient air, at sea level). Symptomatically, there is a fluctuating mental status consistent with delirium, and paroxysms of a weak cough with difficulties in expectorating phlegm. On physical exam, there is extreme obesity (body mass index [BMI] at 42 kg/m²) and severe respiratory distress, with verbal dyspnea and diffuse rhonchi. A chest radiograph reveals infiltrates in the superior and posterior basal segments of the right lower lobe, suggestive of aspiration pneumonia. Past medical history is significant for chronic obstructive pulmonary disease (COPD), heart failure (HF), osteoarthritis, and insomnia. Medication history includes ongoing use of opiates for chronic pain and a bedtime hypnotic for sleep maintenance. Review of systems indicates exercise intolerance due to severe dyspnea, such as when walking on the level, bathing, or dressing.

Regarding senescence, the question addressed by this chapter is to what extent normal aging adversely affects respiratory physiology, as manifested in Ms. K’s presentation.

Respiratory Physiology

The primary physiologic function of the respiratory system is to effectively couple gas exchange at the lung (alveolar–capillary interface) with metabolism at the cellular level (tissue–capillary interface), at rest and with exercise [3]. Below, respiratory physiology is reviewed, followed thereafter by a discussion regarding age-related changes specific to the respiratory system. The physiology-based equations that are cited in this chapter are also summarized in Table 1.1.

Table 1.1

Respiratory physiology

Gas Exchange at Rest

Aerobic cellular metabolism is dependent on oxygen delivery (O2D) and acid–base status (hydrogen ion concentration or [H+]) [1, 3]. As shown below in (1.1) and (1.2), the respiratory determinants of O2D and acid–base status include the arterial oxygen content (CaO2) and PaCO2, respectively. Importantly, as shown in (1.1a) and its attached sample calculation, it is the SaO2, not the arterial oxygen tension (PaO2), that is the principle respiratory determinant of CaO2. Meaning, CaO2 is much more dependent on oxygen that is bound to hemoglobin (SaO2), than oxygen that is dissolved in blood (PaO2). As discussed later, however, PaO2 remains an important physiologic parameter, for at least two reasons. First, it reflects the matching of ventilation with lung perfusion, vis-à-vis the alveolar–arterial PO2 difference or (A − a)DO2 (1.3), and second, it is in equilibrium with SaO2— namely, the transfer of oxygen across the alveolar–capillary interface occurs sequentially from alveolar oxygen tension (PAO2) → PaO2 → SaO2.

$$ {\text{O}}_{2}\text{D }=\left[{\text{C}}_{\text{a}}{\text{O}}_{2}\right]\times \left[\text{Cardiac output}\right]$$

(1.1)

$$\begin{array}{c}{\text{C}}_{\text{a}}{\text{O}}_{2}=\left[\text{Bound oxygen}\right]+\left[\text{Dissolved oxygen}\right]\\ =\left[\text{Hb }\times {\text{S}}_{\text{a}}{\text{O}}_{2}\times 1.39\right]+\left[{\text{P}}_{\text{a}}{\text{O}}_{2}\times 0.0031\right]\end{array} $$

(1.1a)

$$\begin{array}{c}{If Hb is 15 g}/\text{dL},{\text{S}}_{\text{a}}{\text{O}}_{2}{is 98}\%,{\text{ and P}}_{\text{a}}{\text{O}}_{2}{is 8}0\text{ mmHg},\text{ then}\dots \\ =\left[15\times 0.98\times 1.39\right]+\left[80\times 0.0031\right]\\ =[20.43]+\left[0.25\right]\end{array} $$$$ [{\text{H}}^{+}]=24\left[\frac{{\text{P}}_{\text{a}}{\text{CO}}_{2}}{{\text{HCO}}_{3}}\right]$$

(1.2)

$$\left(\text{A}-\text{a}\right){\text{DO}}_{2}={\text{P}}_{\text{A}}{\text{O}}_{2}-{\text{P}}_{\text{a}}{\text{O}}_{2} $$

(1.3)

The physiologic regulation of PaCO2 and SaO2 is dependent on the ventilatory output of the respiratory system, expressed in liters/minute (total minute ventilation) and measured during expiration ( $$ {\dot{V}}_{\text{E}}$$ ) for greater diagnostic accuracy [3]. As shown below in (1.4), $$ {\dot{V}}_{\text{E}}$$ is comprised of two forms of ventilation, dead space ( $$ {\dot{V}}_{\text{D}}$$ ) and alveolar ( $$ {\dot{V}}_{\text{A}}$$ ). $$ {\dot{V}}_{\text{D}}$$ includes, in part, the volume of air that is present in the trachea, bronchi, and terminal bronchioles – collectively termed the conducting zone. Since there are no alveolar attachments, the conducting zone does not participate in gas exchange and is termed the anatomic dead space (a fixed value of about 150 mL for a 150-pound individual). By contrast, $$ {\dot{V}}_{\text{A}}$$ includes the volume of air that is available for gas exchange, namely, that which is present in the respiratory bronchioles, alveolar ducts, and alveoli – collectively termed the respiratory zone. Importantly, only regions in the respiratory zone that adequately match alveolar ventilation with perfusion ( $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ matching) can effectively participate in gas exchange. Otherwise, regions that are well ventilated but poorly perfused develop $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch, characterized by a high $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio and are referred to as the alveolar dead space. The latter when combined with the anatomic dead space constitute the physiologic dead space (total $$ {\dot{V}}_{\text{D}}$$ ) and leads to reduced CO2 elimination. Alternatively, regions that are well perfused but poorly ventilated also develop $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch, but these are instead characterized by a low $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio and lead to reduced oxygenation (increased (A − a)DO2).

$$ {\dot{V}}_{\text{E}}={\dot{V}}_{\text{A}}+{\dot{V}}_{\text{D}}$$

(1.4)

Accordingly, as shown below in (1.5), the physiologic regulation of PaCO2 relative to CO2 production ( $$ {\text{V ˙CO}}_{2}$$ ) is exclusively dependent on $$ {\dot{V}}_{\text{A}}$$ [3]. The latter is, in turn, adversely affected by a decrease in $$ {\dot{V}}_{\text{E}}$$ and/or an increase in physiologic dead space ventilation ( $$ {\dot{V}}_{\text{D}}$$ ), as shown below in a rearranged (1.4). For oxygenation, the physiologic regulation is more complex, sequentially involving PAO2, PaO2, and SaO2 [3]. First, regarding PAO2, this is most often adverely affected by an increase in PaCO2 and, to a lesser extent, by a decreased respiratory quotient (RQ) — the inspired oxygen tension (PIO2) is, otherwise, a constant value of 150 mmHg on ambient air, at sea level (1.3a). Second, regarding PaO2, this is most often adversely affected by $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch, principally involving lung regions with a low $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio (increased (A − a)DO2). Third, regarding SaO2, this in equilibrium with PaO2 as determined by the oxygen dissociation curve (Fig. 1.1) and is discussed later in this chapter.

A978-1-60761-727-3_1_Fig1_HTML.gif

Fig. 1.1

An idealized version of the oxygen dissociation curve. SaO2, arterial oxygen saturation of hemoglobin; PaO2, arterial oxygen tension

$$ {\text{P}}_{\text{A}}{\text{O}}_{2}={\text{P}}_{\text{I}}{\text{O}}_{2}-\left(\frac{{\text{P}}_{\text{a}}{\text{CO}}_{2}}{\text{RQ}}\right)$$

(1.3a)

$$ {\dot{V}}_{\text{A}}={\dot{V}}_{\text{E}}-{\dot{V}}_{\text{D}}$$

(1.4)

$$ {\text{P}}_{\text{a}}{\text{CO}}_{2}=\frac{{\text{V ˙CO}}_{2}}{{\dot{V}}_{\text{A}}}$$

(1.5)

The ventilatory output of the respiratory system and its calibration relative to cellular metabolism are dependent on multiple factors, principally central respiratory drive, respiratory muscle strength, respiratory mechanics, and lung perfusion [3]. These, if substantially impaired, can lead to abnormal ventilatory responses, including reductions in $$ {\dot{V}}_{\text{E}}$$ or $$ {\dot{V}}_{\text{A}}$$ and increases in $$ {\dot{V}}_{\text{D}}$$ or (A − a)DO2. When severe, the net effect is respiratory failure, characterized by hypercapnia (PaCO2 > 44 mmHg) and/or hypoxemia (SaO2 < 90%). A low SaO2 may subsequently decrease O2D, potentially shifting cellular metabolism to anaerobic pathways (glycolysis). This shift increases lactic acid production and leads to acidemia – see (1.2a). Similarly, a high PaCO2 may also yield an acidemia, vis-à-vis the dissociation of carbonic acid, as well as hypoxemia, due to a decreased PAO2 – see (1.2b) and prior (1.3a). Eventually, these derangements in gas exchange reduce homeostasis, with potential sequelae that include disability and reduced longevity in the affected individual [12, 13].

$$ \text{Lactic acid }\rightleftharpoons {\text{H}}^{+}+{\text{ Lactate}}^{-}$$

(1.2a)

$$ {\text{CO}}_{2}+{\text{H}}_{2}\text{O}\rightleftharpoons {\text{H}}_{2}{\text{CO}}_{3}\rightleftharpoons {\text{H}}^{+}+{\text{ HCO}}_{3}{}^{-}$$

(1.2b)

Gas Exchange During Exercise

Physical activity is also highly relevant to homeostasis [14–16]. For example, regular physical activity helps prevent obesity, hypertension, diabetes, heart disease, cancer, and premature mortality [14, 15]. Physical activity, however, mandates a substantial increase in gas exchange at the lung to meet the metabolic needs of the exercising muscle [3, 16].

During physical activity, the exercising muscle increases the level of O2 consumption ( $$ {\text{V ˙O}}_{2}$$ ) and CO2 production ( $$ {\text{V ˙CO}}_{2}$$ ), proportionate to cellular metabolism [16]. For $$ {\text{V ˙O}}_{2}$$ , this requires an increased delivery of oxygen (O2D) to the exercising muscle, as well as an increased extraction of oxygen at the tissue–capillary interface of the exercising muscle. The latter is manifested by a threefold rise in the difference between arterial and venous oxygen content (CaO2–CvO2) – see below (1.6). For $$ {\text{V ˙CO}}_{2}$$ , its increase is a byproduct of cellular metabolism and, at workloads beyond the anaerobic threshold (AT), is a consequence of the bicarbonate buffering of serum lactic acid. Meaning, beyond the AT, the exercising muscle shifts predominantly to glycolysis as its energy source, thereby increasing lactic acid production and its release into the circulation. The lactic acid in blood is then buffered by sodium bicarbonate (NaHCO3), further increasing $$ {\text{V ˙CO}}_{2}$$ – see (1.2c). The net effect of these exercise-induced metabolic changes is that the venous blood returning to the lung has a high CO2 content (the PCO2 rising to about 60 mmHg) and a low O2 content (the SO2 declining to about 40%) [17].

$$ \text{Lactic acid}\rightleftharpoons {\text{H}}^{+}+{\text{ Lactate}}^{-}\stackrel{{\text{NaHCO}}_{3}}{\rightleftharpoons }\begin{array}{c}{\text{H}}_{2}{\text{CO}}_{3}+\text{ Na}-\text{Lactate}\\ {\text{H}}_{2}{\text{CO}}_{3}\rightleftharpoons {\text{CO}}_{2}+{\text{H}}_{2}\text{O}\end{array}$$

(1.2c)

$$ {\text{V ˙O}}_{2}=\left[{\text{O}}_{2}\text{D}\right]\times \left[{\text{C}}_{\text{a}}{\text{O}}_{2}-{\text{C}}_{\text{v}}{\text{O}}_{2}\right]$$

(1.6)

$$ {\text{C}}_{\text{v}}{\text{O}}_{2}=\left[\text{Hb }\times {\text{S}}_{\text{v}}{\text{O}}_{2}\times 1.39\right]+\left[{\text{P}}_{\text{v}}{\text{O}}_{2}\times 0.0031\right]$$

In response to the returning hypoxemic and acidemic venous blood, the respiratory system increases total minute ventilation ( $$ {\dot{V}}_{\text{E}}$$ ), achieved by larger tidal breaths (V t) and higher breathing frequencies (f b) – see below (1.4a) [3, 16]. Moreover, because cardiac output increases with exercise, there is also an increase in lung perfusion that matches the increase in $$ {\dot{V}}_{\text{E}}$$ . At maximum exercise, this leads to a 30–40% reduction in the dead space ratio (V d/V t), signifying that the increased tidal breaths are largely comprised of alveolar air that is adequately perfused. The net effect is an increase in $$ {\dot{V}}_{\text{A}}$$ , as shown in (1.4b). Because the increase in $$ {\dot{V}}_{\text{A}}$$ is usually equal to or greater than the increase in $$ {\text{V ˙CO}}_{2}$$ , the PaCO2 does not rise during exercise [see prior (1.5)]. Lastly, because the exercise-induced increase in lung perfusion is concurrent with as much as a fivefold increase in V t, the capacity of the alveolar–capillary interface to effectively reoxygenate the returning venous blood is also substantially increased and, hence, PaO2 and SaO2 remain relatively normal during exercise. Thus, during physical activity, the respiratory system effectively calibrates gas exchange at the lung relative to cellular metabolism at the exercising muscle.

$$ {\dot{V}}_{\text{E}}={V}_{\text{t}}\left({f}_{\text{b}}\right)$$

(1.4a)

$$ {\dot{V}}_{\text{A}}={\dot{V}}_{\text{E}}\left(1-\frac{{V}_{\text{d}}}{{V}_{\text{t}}}\right)$$

(1.4b)

Importantly, the ventilatory response to exercise is usually nonlimiting to physical activity, but only if the breathing reserve is not compromised [16]. As shown below in (1.7), the breathing reserve is defined by the ratio of ventilatory requirement at maximal exercise ( $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ ) to maximum breathing capacity (MBC), subtracted from 1; this is normally a value of 15% or higher. In (1.7), the MBC represents the highest level of total minute ventilation that an individual can achieve. It is measured as a 12-s maximal voluntary ventilation (MVV) maneuver or is estimated from the forced expiratory volume in 1 s (FEV1), a spirometric measure of pulmonary function – see (1.7a) and (1.7b). In healthy individuals, because $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ during activities of daily living is much lower than the MBC, the breathing reserve is high (>15%).

$$ \text{Breathing reserve }=\left[1-\frac{{\dot{V}}_{\text{E}\mathrm{max}}}{\text{MBC}}\right]\times 100$$

(1.7)

$$ \text{MBC }={\text{ FEV}}_{1}\times 35\left(\text{for females}\right)$$

(1.7a)

$$ \text{MBC }={\text{ FEV}}_{1}\times 40\left(\text{for males}\right)$$

(1.7b)

As discussed later, however, impairments in respiratory physiology can lead to increased ventilatory requirements during exercise and to a decrease in MBC, thus yielding a reduced breathing reserve (<15%) [16]. This low of a breathing reserve is not sustainable, for at least two reasons. First, a low breathing reserve may be associated with expiratory flow rates during exercise that approach the maximal predicted value, meaning that the ventilatory response is flow-limited. This imposes a pulmonary mechanical limitation, with the individual likely to experience exercise intolerance and symptom-limiting dyspnea. Second, a low breathing reserve may be also associated with a mismatch of ventilation relative to lung perfusion, leading to increases in V d/V t and/or (A − a)DO2. This imposes a pulmonary vascular limitation, characterized by hypoxemia and hypercapnia, as well as severe exercise intolerance and dyspnea.

Normal Aging

As discussed below, normal aging is associated with reductions in respiratory physiology, characterized by impairments in central respiratory drive, respiratory muscle strength, respiratory mechanics, and lung perfusion. These impairments can lead to various forms of alveolar hypoventilation and the mismatch of ventilation with lung perfusion. The clinical consequences include respiratory failure (hypoxemic or hypercapnic), as well as disturbances in O2D and acid–base status. In addition, physiologic parameters related to the breathing reserve are also adversely affected, potentially contributing to exercise intolerance.

Central Respiratory Drive

This refers to the efferent output of the central respiratory controller which during quiet tidal breathing involves primarily the inspiratory neurons of the dorsal and ventral respiratory groups in the medulla [18]. It is the central respiratory controller that ultimately directs the contraction of respiratory muscles, thereby generating the ventilatory output of the respiratory system ( $$ {\dot{V}}_{\text{E}}$$ ).

As shown previously in (1.4), $$ {\dot{V}}_{\text{E}}$$ has two components: dead space ventilation ( $$ {\dot{V}}_{\text{D}}$$ ) and alveolar ventilation ( $$ {\dot{V}}_{\text{A}}$$ ) [3]. In an individual who has reduced central respiratory drive, but no other respiratory disturbance, the resultant decrease in $$ {\dot{V}}_{\text{E}}$$ is due to a decrease in $$ {\dot{V}}_{\text{A}}$$ , since the lower limit for $$ {\dot{V}}_{\text{D}}$$ is a fixed value (defined by the anatomic dead space). A decreased $$ {\dot{V}}_{\text{A}}$$ then leads to a rise in PaCO2, with the net effect being acidemia and hypoxemia. Because the pathophysiology initially resides in the central respiratory controller, this disturbance in gas exchange is termed central alveolar hypoventilation, uniquely characterized by an elevated PaCO2 but normal (A − a)DO2.

Several studies involving healthy older persons (awake and at rest) have shown age-related reductions in central respiratory drive. For example, based on inspiratory pressures generated at the mouth 100 ms after airway occlusion (P100) — a validated index of central respiratory drive [19], healthy persons aged 65–79 years had a 50% or greater reduction in their response to hypoxemia and hypercapnia, relative to those aged 22–29 years [20]. Similarly, based on $$ {\dot{V}}_{\text{E}}$$ , healthy men aged 64–73 years had a 41% or greater reduction in their response to hypercapnia and hypoxemia, relative to those aged 22–30 years [21]. In another study that included men and women, healthy persons aged 65–76 years had a nearly one-third reduction in the $$ {\dot{V}}_{\text{E}}$$ response to hypercapnia, relative to those aged 21–37 years [22]. Although the mechanisms underlying these age-related reductions in central respiratory drive remain unknown, recent work invokes the loss of gray matter volume in brain regions that are involved in breathing functions [23].

Other studies have failed, however, to show age-related differences in central respiratory drive, yielding P100 and $$ {\dot{V}}_{\text{E}}$$ responses to hypoxemia and hypercapnia that are similar in older versus younger persons [24–26]. Importantly, these studies may not have adequately adjusted for age-related increases in the work of breathing (WOB) and physiologic dead space ( $$ {\dot{V}}_{\text{D}}$$ ), or the age-related reduction in respiratory muscle strength. Such factors should elicit compensatory increases in central respiratory drive (P100) and $$ {\dot{V}}_{\text{E}}$$ , to maintain $$ {\dot{V}}_{\text{A}}$$ [see (1.4b)] [3, 19, 27, 28]. [Age-related changes in WOB, $$ {\dot{V}}_{\text{D}}$$ , and respiratory muscle strength are discussed later in this chapter.] It is, thus, postulated that, when P100 and $$ {\dot{V}}_{\text{E}}$$ responses to hypoxemia and hypercapnia are reported as similar in older versus younger persons, these may instead indicate a relative age-related reduction in central respiratory drive.

The conflicting results of prior studies on central respiratory drive may also reflect methodological differences regarding techniques for testing chemoreceptor function [24, 25], and small sample sizes. Concerning the latter, each of the above cited studies on central respiratory drive enrolled less than 20 participants aged 65 years or older. A small sample size diminishes the power to discriminate differences in central respiratory drive. This is particularly relevant in older persons because advancing age is characterized by increased variability in respiratory physiology [29]. Increased variability confers greater heterogeneity, necessitating larger study populations to conclusively determine differences in central respiratory drive. Nonetheless, despite the stated limitations, it is opined that prior work is consistent with older persons having an absolute or relative reduction in central respiratory drive, an impression that is in agreement with other age-related reductions in ­respiratory physiology (e.g., decreased respiratory muscle strength).

An additional factor to consider is the age-related reduction in perceptual awareness of breathing discomfort, implying a decreased afferent input to the central respiratory controller [30, 31]. Prior research comparing older persons aged 60–80 years with those aged 20–46 years has shown an age-related reduction in the awareness of methacholine-provoked bronchoconstriction, characterized by less severe respiratory symptoms despite greater reductions in FEV1 [30]. The mechanism underlying this reduced perceptual awareness is unknown but could involve the central nervous system, and peripheral mechanoreceptors or chemoreceptors [30].

Despite the age-related reduction in central respiratory drive, the PaCO2 does not rise in healthy older adults [32, 33]. This is likely a consequence of the large physiologic reserve capacity that is intrinsic to the respiratory system [34–36], meaning that more severe reductions in central respiratory drive are required before gas exchange abnormalities become evident. Hence, it is postulated that the age-related reduction in central respiratory drive may serve instead as a predisposing factor for the development of respiratory failure. As discussed later in this chapter, the most vulnerable individuals are older persons with cardiopulmonary disease, particularly those who are also obese, report the use of respiratory-suppressant medications (opiates or sedative-hypnotics), or are in the midst of an episode of acute lung injury.

Because older age is an independent risk factor for respiratory failure [10, 11], future work should evaluate whether the P100 and $$ {\dot{V}}_{\text{E}}$$ responses to hypoxemia and hypercapnia are associated with subsequent respiratory failure, in otherwise healthy older persons who are never-smokers. If proven true, strategies that mitigate the age-related reduction in central respiratory drive may lead to lower rates of respiratory failure in older persons, particularly in the setting of acute lung injury (pneumonia) [10, 11].

Respiratory Muscles

The tidal volume (V t), defined as the volume of air that is moved into and out of the lung per breath taken, is dependent on respiratory muscle strength, principally diaphragmatic [37]. Consequently, a reduction in respiratory muscle strength may lead to a decrease in V t and, in turn, a decrease in the total minute ventilation ( $$ {\dot{V}}_{\text{E}}$$ ) – see (1.4a). Moreover, because the anatomic dead space is a fixed volume, the decrease in V t leads to an increase in the dead space ratio (V d/V t). The sum effect of a concurrent decrease in $$ {\dot{V}}_{\text{E}}$$ and an increase in V d/V t is for a substantial reduction in alveolar ventilation ( $$ {\dot{V}}_{\text{A}}$$ ) – see (1.4b).

To compensate for a reduced V t, the efferent output of the central respiratory controller increases (central respiratory drive, [P100]), thereby yielding a more rapid breathing frequency (f b) and, as a result, $$ {\dot{V}}_{\text{E}}$$ is maintained or even increased – see (1.4a) [38]. When respiratory muscle weakness becomes progressively severe (<30% of normal) [36], the compensatory response becomes incomplete, for two reasons. First, V d/V t remains elevated, and second, the decrement in V t is much greater than the increase in f b. Thus, despite the increase in central respiratory drive, the net effect of progressively severe respiratory muscle weakness is a decline in $$ {\dot{V}}_{\text{A}}$$ , followed by a rise in PaCO2 and, thereafter, acidemia and hypoxemia. Because the pathophysio­logy initially resides in the respiratory muscles, this disturbance in gas exchange is termed peripheral alveolar hypoventilation.

Another important function of respiratory muscles is their role in the clearance of airway secretions by cough-based mechanisms [39]. This becomes especially relevant when respiratory muscle weakness develops. In this setting, there can be substantial difficulties in the clearance of secretions, potentially leading to airways obstruction, atelectasis, and pneumonia. These yield $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatching, mainly due to reduced alveolar ventilation relative to lung perfusion (low $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio), as well as an increase in the work of breathing (WOB) [39, 40]. The net effect is reduced oxygenation (increased (A − a)DO2) and the imposition of a fatiguing WOB on already weakened respiratory muscles (further reducing V t). Thus, in addition to the noted increase in PaCO2, peripheral alveolar hypoventilation that is due to respiratory muscle weakness may be also characterized by an increased (A − a)DO2.

Several large studies have shown that advancing age is independently associated with a decrease in the maximal inspiratory pressure (MIP), a measure of inspiratory muscle strength, and a decrease in the maximal expiratory pressure (MEP), a measure of expiratory muscle strength [41–43]. To illustrate, for a male of average height and weight, the MIP is 111 and 70 cm H2O at age 50 and 80 years, respectively [43]. The age-related reductions in MIP and MEP are likely a consequence of sarcopenia and impaired respiratory mechanics [44–47]. The sarcopenia refers to a quantitative and qualitative loss of muscle mass, potentially due to reductions in muscle protein synthesis [46]. The impaired respiratory mechanics refers to thoracic kyphosis and hyperinflation, factors that decrease the curvature of the diaphragm, thus adversely affecting length–tension relationships and, in turn, leading to reduced muscle strength [44, 45, 47]. Moreover, impaired respiratory mechanics also include an increase in the stiffness of the chest wall, thereby imposing a greater WOB that could further compromise diaphragmatic endurance (fatigue) [44, 45, 47].

Despite the age-related reduction in respiratory muscle strength, the PaCO2 does not rise in healthy older adults [32, 33]. This again reflects the large physiologic reserve capacity that is intrinsic to the respiratory system, such that more severe reductions in respiratory muscle strength are likely required before gas exchange abnormalities become evident [36]. Hence, it is postulated that the age-related reduction in respiratory muscle strength may serve instead as a predisposing factor for the development of respiratory failure. As discussed later in this chapter, the most vulnerable individuals are older persons with cardiopulmonary disease, particularly those who are also obese, report the use of respiratory-suppressant medications (opiates or sedative-hypnotics), or are in the midst of an episode of acute lung injury.

Because older age is an independent risk factor for respiratory failure [10, 11], future work should evaluate whether physiologic measures related to respiratory muscle strength (MIP and MEP) are associated with subsequent respiratory failure, in otherwise healthy older persons who are never-smokers. If proven true, strategies that mitigate the age-related reduction in respiratory muscle strength may lead to lower rates of respiratory failure in older persons, particularly in the setting of acute lung injury [10, 11].

Respiratory Mechanics

In order to achieve effective levels of gas exchange, ventilation in the respiratory zone must be matched with lung perfusion ( $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ matching). Normally, the efficiency of the respiratory zone is less than maximal, yielding a small degree of $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch [3]. Specifically, in the sitting position, there is an increase in ventilation and perfusion from top to bottom, but perfusion increases more rapidly. This results in a $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio that is higher at the apex but lower at the base. These regional ­differences mitigate a full equilibration between PAO2 and PaO2 (PAO2 > PaO2), and hence, the (A − a)DO2 is normally slightly greater than 0 [33]. This has an insignificant effect on O2D, however, because the PaO2 remains well above 60 mmHg. As shown on the oxygen dissociation curve (Fig. 1.1) [3], the SaO2 only declines substantially at PaO2 levels <60 mmHg. Nonetheless, the $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch that is intrinsic to the respiratory system, although small, suggests a vulnerability for developing impaired gas exchange.

Normal aging is associated with an increase in $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch [48–50]. Using a multiple inert gas technique in 64 healthy never-smokers aged 18–71 years, Cardus et al. have shown a small age-related increase in $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch, principally characterized by a low $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio [50]. The net effect is an age-related increase in (A − a)DO2, from a value of about 2 for adults aged 18–24 years (corresponding to an average PaO2 of 99.9 mmHg) to a value of 15 for those aged 65 years or older (corresponding to an average PaO2 of 88.7 mmHg) – on ambient air, at sea level [33].

The age-related increase in $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch, specifically that which is due to a low $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio, is likely the consequence of impaired respiratory mechanics. Developmentally, after achieving peak pulmonary function at 18–25 years of age, there is an increase in the rigidity of the chest wall and a decrease in the elastic recoil of the lung, across the lifespan [29, 44, 45]. These age-related changes lead to airflow limitation [29, 51], defined by a decreased ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC), and to hyperinflation (increased functional residual capacity [FRC]) and air trapping (increased residual volume [RV]). In addition, because of losses in supporting elastic tissue, there is an increase in the closing volume, defined as the lung volume above which there is dynamic collapse of small airways, most evident in the gravity-dependent regions of the lung [49]. To illustrate, the lower limit of normal for FEV1/FVC will decrease from about 0.75 and 0.85 at age 20 years to less than 0.60 and 0.70 at age 80 years, in males and females, respectively [29]. This increase in airflow limitation is associated with an annual decline in FEV1 of about 30 mL/year, a 50% increase in RV between ages 20 and 70 years, and an increase in the closing volume such that by age 65 years it approaches the sitting FRC [29, 45, 51]. The latter is problematic because it leads to reduced ventilation, particularly in the gravity-dependent regions of the lung (even during normal tidal breathing) [45, 49]. The net effect of these age-related changes in respiratory mechanics is a reduction in alveolar ventilation relative to lung perfusion, namely, $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch due to a low $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio [50].

As discussed earlier, the age-related changes in respiratory mechanics may have an adverse effect on respiratory muscle strength and endurance. First, because hyperinflation decreases the curvature of the diaphragm, length–tension relationships are adversely affected (reducing muscle strength), and second, because increased stiffness of the chest wall imparts a greater work of breathing (WOB), the expanding pressures that are generated by the diaphragm must increase to maintain tidal volume.

Despite the age-related changes in respiratory mechanics, the PaO2 remains well above 60 mmHg and PaCO2 does not rise in healthy older persons [32, 33]. This again reflects the large physiologic reserve capacity that is intrinsic to the respiratory system, meaning that more severe impairments in respiratory mechanics are required before gas exchange abnormalities become evident [34–36]. Hence, it is postulated that age-related changes in respiratory mechanics may serve instead as a predisposing factor for developing respiratory failure.

Lung Perfusion

$$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch is often a heterogeneous process that includes some regions within the respiratory zone having high $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratios, while others have low $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratios [3]. In contrast to impaired respiratory mechanics, wherein $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch is largely a consequence of a low $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio, a reduction in lung perfusion will instead confer a high $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio, meaning a lung region having relatively normal ventilation but reduced perfusion [3].

As discussed earlier, lung regions that have a high $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio lead to impaired CO2 elimination and are collectively termed the alveolar dead space [3]. When the latter is added to the anatomic dead space, this combined volume of air is termed the physiologic dead space. Under normal conditions, the alveolar dead space is minimal (being predominantly located at the lung apices), and as a result, the physiologic dead space is only slightly greater than the anatomic dead space. However, factors that impart reductions in lung perfusion in otherwise well-ventilated regions of the respiratory zone will substantially increase the physiologic dead space. The net effect is an increase in the dead space ratio (V d/V t) and dead space ventilation ( $$ {\dot{V}}_{\text{D}}$$ ) that, in turn, yield a decrease in alveolar ventilation ( $$ {\dot{V}}_{\text{A}}$$ ) – see (1.4) and (1.4b). Consequently, gas exchange derangements that are principally due to reduced lung perfusion represent an alternative form of peripheral alveolar hypoventilation, also characterized by an elevated PaCO2. Moreover, because lung regions with a high $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio often coexist with those having a low $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio, peripheral alveolar hypoventilation that is due to reduced lung perfusion may be additionally characterized by an increased (A − a)DO2.

Normal aging may impart a reduction in lung perfusion. Using magnetic ­resonance imaging, Levin et al. have demonstrated age-related increases in lung perfusion heterogeneity in a study population of 56 healthy, nonsmoking participants, aged 21–76 years [52]. Increased heterogeneity denotes less uniform perfusion, including regions that have decreased perfusion (high $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio) [53, 54]. The reduction in lung perfusion is likely a consequence of age-related changes in the pulmonary circulation [54, 55]. In a large study involving 3,790 participants aged 1–89 years who had normal echocardiograms, the pulmonary arterial systolic pressure (PASP) rose an average of about 1 mmHg per decade of age, yielding an upper limit for the PASP of 40 mmHg in those older than 50 years [55]. This rise in pulmonary arterial systolic pressure has been attributed in part to an increase in pulmonary vascular resistance [55], and may coexist with age-related declines in the density of lung capillaries [56].

The age-related reduction in lung perfusion may be also complicated by a decrease in the diffusion capacity of the lung for carbon monoxide (DLCO), a physiologic measure of the transfer capacity of oxygen across the alveolar–capillary interface. In a study involving 74 healthy participants aged 69–104 years and 55 healthy participants aged 26 ± 4 years, Guénard and Marthan have demonstrated an age-related decrease in the DLCO [57]. This corresponded to about a 50% reduction in the DLCO for older persons (65 years or older), relative to younger persons (20–40 years) [57]. It has been postulated that this reduction in DLCO may be due to declines in the density of lung capillaries and alveolar surface area [45, 56, 57].

When considered together, the above studies suggest that gas exchange is adversely affected by age-related changes in the pulmonary vasculature, manifested as reductions in lung perfusion and diffusion (DLCO). However, because PaO2 remains well above 60 mmHg and PaCO2 does not rise in healthy older persons [32 33], the age-related reductions in lung perfusion and diffusion are not severe enough to limit gas exchange to levels of respiratory failure. This again likely reflects the large physiologic reserve capacity that is intrinsic to the respiratory ­system [34–36]. Nonetheless, in the setting of cardiopulmonary disease, extreme obesity, use of respiratory-suppressant medications (opiates and sedative-­hypnotics), or in the midst of an episode of acute lung injury (pneumonia), it is postulated that age-related reductions in lung perfusion and diffusion could increase the ­vulnerability for developing respiratory failure.

Breathing Reserve (Exercise)

Older persons are the most sedentary of any age group, with only 17.4% of those aged 75 years or older reporting any regular leisure-type physical activity [58]. Because dyspnea is prevalent in older persons [59], an impairment in respiratory physiology could prove to be an important contributor to exercise intolerance and, hence, physical inactivity.

As discussed earlier in the section on Respiratory Physiology, a low breathing reserve may lead to exercise intolerance. The breathing reserve is defined by the ratio of ventilatory requirement at maximal exercise ( $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ ) to maximum breathing capacity (MBC), subtracted from 1; this is normally a value of 15% or higher [see (1.7)] [16]. As described below, however, normal aging may reduce the breathing reserve to levels less than 15%, by increasing $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ (relative to workload) and by decreasing MBC [16, 60, 61].

The age-related increase in $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ is likely due to $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch vis-à-vis two possible mechanisms. First, the typical pattern of an exercise-induced increase in pulmonary vascular recruitment (increased lung perfusion) may be reduced in older persons, as aging is associated with a decline in pulmonary capillary density, an increase in pulmonary vascular resistance, and an attenuated cardiac output response to exercise [16, 52–57]. The reduced lung perfusion could thus lead to increased $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch, characterized by a high $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio and, as a result, an increase in V d/V t and $$ {\dot{V}}_{\text{D}}$$ . In this setting, as a compensatory response, ventilation, especially at maximal exercise ( $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ ), is increased to maintain adequate levels of CO2 elimination [ $$ {\dot{V}}_{\text{A}}$$ ; see (1.4b)]. Second, because aging is also associated with impaired respiratory mechanics, the exercise response may be additionally characterized by $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ mismatch that is due to a low $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio, thus yielding a reduction in oxygenation capacity (increased (A − a)DO2) [16, 29, 44–51]. The compensatory response is also an increase in ventilation, especially at maximal exercise ( $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ ).

Less likely, but still a potential contributor to an increased $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ , is the age-related defect in oxygen diffusion across the alveolar–capillary interface [56, 57]. The latter may limit the gas exchange capacity of the lung, particularly at maximal exercise, as follows; since the transit of the red blood cell in the pulmonary capillary bed is rapid at maximal exercise due to an increased cardiac output, the time required for equilibration of oxygen across the alveolar–capillary interface may be inadequate in the setting of a diffusion defect (PAO2 → PaO2 → SaO2). This may then contribute to further exercise-induced reductions in oxygenation capacity, thus leading to the compensatory response of an increase in ventilation, especially at maximal exercise $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ .

The MBC is known to decline across the adult lifespan, a consequence of age-related changes in respiratory mechanics but also potentially due to reductions in respiratory muscle strength and central respiratory drive. To illustrate, as shown in (1.7b) [16], a 30-year-old male who has an FEV1 of 4.20 L will have an MBC of 168 L/min. At age 70 years, however, assuming a normal annual decline of about 30 mL, the FEV1 will have decreased to 3 L, thus yielding an MBC of only 120 L/min. Consequently, an age-related decrease in MBC, together with an increase in $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ , may result in a reduced breathing reserve (<15%).

The age-related reduction in breathing reserve may be further associated with a pulmonary mechanical limitation (flow-limited) and a pulmonary vascular limitation (gas exchange limited), as illustrated in Fig. 1.2 [16, 62, 63]. In the example given, at a similar level of maximal oxygen consumption (max $$ {\text{V ˙O}}_{2}$$ ), an older person aged 70 years, in comparison with a younger person aged 30 years, had more than twice the dead space at maximal exercise (V d/V t of 0.28 versus 0.12; $$ {\dot{V}}_{\text{D}}$$ of 32 L/min versus 14 L/min, respectively), yielding a greater ventilatory requirement at maximal exercise ( $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ of 120 L/min versus 100 L/min, respectively). Despite the higher $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ , the older person had the same PaCO2 and a lower PaO2, indicating that the excess ventilation was wasted (physiologic dead space) and associated with lung regions having a low $$ {\dot{V}}_{\text{A}}/\dot{Q}$$ ratio (increased (A − a)DO2), respectively. Moreover, the higher $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ in the older person was associated with expiratory flow rates that were flow-limited, evidenced by flow–volume curves during exercise (solid lines) approaching the maximal predicted flow-rate (dotted line). Lastly, the higher $$ {\dot{V}}_{\text{E}\mathrm{max}}$$ in the older person likely occurred in the setting of a decreased MBC, potentially yielding a lower breathing reserve (<15%).

A978-1-60761-727-3_1_Fig2_HTML.gif

Fig. 1.2

Ventilatory response to exercise in young and older adults, as measured by flow–volume loops and gas exchange. Flow–volume loops in younger (left) and older (right) adults at rest and during exercise; (+) flows indicate expiration, while (−) flows indicate inspiration. The flow–volume loop with the dotted line represents maximal expiratory and inspiratory flow rates, as measured during a forced vital capacity (FVC) maneuver (spirometry). The solid lines represent flow–volume loops during exercise, with increasing flows and volumes occurring at progressively higher workloads. In this study, participants were matched for max $$ {\text{V ˙O}}_{2}$$ ; see text for discussion. max $$ {\text{V ˙O}}_{2}$$ , oxygen consumption at maximal exercise; V d/V t, dead-space ratio; PaO2, arterial oxygen tension; PaCO2, arterial carbon dioxide tension; $$ {\dot{V}}_{\text{A}}$$ , alveolar minute ventilation; $$ {\dot{V}}_{\text{D}}$$ , dead space ventilation; L, liter; s, second (reproduced with permission from [16])

Nonetheless, despite age-related reductions in respiratory physiology, the predominant limitation to maximal exercise in healthy older persons remains the cardiovascular and musculoskeletal systems, as it is in younger persons [16]. Specifically, in response to maximal exercise, an individual reaches age-specific maxima in heart rate and stroke volume, and hence cardiac output (cardiac output = heart rate × stroke volume), concurrent with anaerobic metabolism at the exercising muscle. By contrast, the noted age-related reduction in respiratory physiology is more likely to be a secondary phenomenon, typically occurring after the anaerobic threshold. However, as discussed below in the section