Cardiopulmonary Response to Exercise in Health and Disease

Published on 12/06/2015 by admin

Filed under Pulmolory and Respiratory

Last modified 22/04/2025

Print this page

This article have been viewed 3985 times

Chapter 23

Cardiopulmonary Response to Exercise in Health and Disease

Objectives

After reading this chapter you will be able to:

• Describe why continual regeneration of adenosine triphosphate (ATP) is necessary to sustain exercise

• Explain how aerobic and anaerobic metabolic processes differ in their ability to generate ATP

• Explain how oxygen consumption and carbon dioxide production differ in aerobic metabolism of carbohydrates and fats

• Explain why the changes in respiratory, cardiovascular, and metabolic processes are different below than above the anaerobic threshold

• Explain how caloric expenditure is related to oxygen consumption

• Use exercise test data to differentiate cardiac and pulmonary limitations to exercise

• Explain why sedentary and athletically trained individuals differ in their ability to perform exercise

• Use exercise test data to differentiate obstructive and restrictive pulmonary limitations to physical activity

• Use exercise test data to prescribe appropriate physical activity in cardiopulmonary rehabilitation programs

Physiology of Exercise

Strenuous exercise greatly increases the body’s requirements for oxygen delivery and carbon dioxide elimination. Close coupling between increased metabolic activity and cardiopulmonary function is necessary to supply adequate oxygen to exercising muscles and maintain a normal blood acid-base balance. This coupling is schematically represented in Figure 23-1.

Figure 23-1 Ventilatory-cardiovascular-metabolic coupling. The gas-exchange pathway is a highly integrated series of steps.

Normal exchange of O₂ and CO₂ between muscle cells and the air requires the following:¹ (1) efficient alveolar ventilation, (2) pulmonary blood flow matched to ventilation, (3) adequate blood hemoglobin content, (4) adequate cardiac pump function, (5) systemic blood flow matched to tissue requirements, and (6) ventilatory control mechanisms sensitive to arterial blood gas changes. These factors normally interact in a finely coordinated fashion, responding precisely to the metabolic needs of exercising muscle.

Normally, respiratory and cardiac reserve capacities are so large that only great physiological impairment reduces daily functioning ability. Exercise testing is clinically important because it stresses all physiological systems, revealing their capacity to respond. Respiratory and cardiac impairments produce characteristically different patterns of response to exercise, allowing cardiovascular and pulmonary limitations to be differentiated. The purpose of this chapter is to provide a physiological basis for evaluating exercise performance, not to provide a definitive guide for interpreting exercise test results.

Metabolism during Exercise

The source of energy for skeletal muscle contraction is adenosine triphosphate (ATP). The structure of the ATP molecule is symbolized as follows:²

Adenosine−PO3−∼PO3−∼PO3−

The bonds between the PO3− radicals, designated by the symbol ~, are high-energy phosphate bonds. The process of metabolism breaks these bonds, releasing the energy needed to form and break cross-bridges between the muscle’s actin and myosin myofibrils, as described in Chapter 17; in this way, muscle fibers shorten and generate force. During exercise conditions, each high-energy bond stores about 7300 calories (7.3 kcal) per mole of ATP molecules.² The hydrolysis of the first PO3− bond produces 7300 calories, generating adenosine diphosphate (ADP) in the process. Hydrolysis of the remaining PO3− bond yields yet another 7300 calories and creates adenosine monophosphate (AMP) for a total energy release of about 14.6 kcal/mol.²

ATP stores in skeletal muscle are extremely small and can sustain strenuous muscular activity for only about 3 seconds.² Therefore ATP molecules must be reconstituted continuously during exercise through aerobic (with oxygen) and anaerobic (without oxygen) metabolic processes.

The energy required for sustained exercise is derived from internal and external mechanisms.³ Internal mechanisms include anaerobic production of ATP, O₂ release from hemoglobin, and dissolved O₂ uptake from plasma and tissue fluids. External mechanisms involve the delivery of atmospheric O₂ molecules to the tissues. Atmospheric O₂ is relatively unimportant for power surges of a few seconds and the first few minutes of exercise. Internal mechanisms are crucial for initiating exercise because of the delay involved in transporting atmospheric O₂ to the tissues. As exercise continues, energy production becomes primarily dependent on the adequate delivery of atmospheric O₂ to the tissues. As exercise intensity reaches maximum limits, internal anaerobic sources of energy become increasingly important.

Aerobic Metabolism

Aerobic metabolism of carbohydrates (glucose), fats (fatty acids), and proteins (amino acids) provides the major energy source for ATP synthesis.² During exercise, stored glycogen in the muscles breaks down into glucose. Glucose breaks down into pyruvic acid, which reacts with O₂ in the cell’s mitochondria, forming ATP, CO₂, and water; thus the aerobic or oxidative process of ATP synthesis consumes O₂ and generates CO₂.

Aerobic metabolism of fatty acids also produces ATP molecules. For a given rate of ATP production, fat metabolism requires more O₂ than carbohydrate metabolism (Figure 23-2). This means carbohydrate metabolism uses O₂ more efficiently and requires less cardiovascular work per mole of ATP synthesis. However, fat metabolism generates less CO₂ per mole of ATP produced than carbohydrate metabolism (see Figure 23-2); in other words, fat metabolism requires less ventilatory work than carbohydrate metabolism in generating a given amount of energy.²

Figure 23-2 Aerobic and anaerobic metabolism. About midway between resting and maximal exercise, anaerobic metabolism supplements aerobic generation of ATP. HCO3− ions buffer anaerobically generated lactic acid; this lowers the HCO3− concentration, while generating CO₂. Aerobic metabolism generates ATP much more efficiently than anaerobic metabolism.

CONCEPT QUESTION 23-1

What is the theoretical benefit of a high-fat diet in patients with advanced chronic obstructive pulmonary disease (COPD)?

Anaerobic Metabolism and Lactic Acid Production

Anaerobic metabolic processes occur in the absence of O₂. An example of anaerobic metabolism is the breakdown of creatine phosphate (CP), which, similar to the ATP molecule, possesses a high-energy phosphate bond:

Creatine∼PO3−

The breakdown of this bond supplies the immediate energy for ATP resynthesis from ADP, as shown:

Creatine∼PO3−+ADP→creatine+ATP

However, this process produces only enough ATP to fuel muscle contraction for 8 to 10 seconds during heavy exercise.²

If the cardiovascular system does not supply enough O₂ for aerobic metabolism, glucose from muscle glycogen is metabolized in a process called anaerobic glycolysis. In this process, pyruvic acid is metabolized anaerobically into lactic acid and ATP (see Figure 23-2). The lactic acid subsequently diffuses into the interstitial fluid and blood, creating lactic acidosis, a form of metabolic acidosis. Increased blood lactic acid concentration indicates the presence of anaerobic metabolism, implying inadequate O₂ delivery to the tissues.

CONCEPT QUESTION 23-2

Why would a patient experiencing severe shock be likely to have increased blood levels of lactic acid?

Anaerobic Threshold

As exercise intensity increases, energy requirements gradually increase until aerobic metabolism alone can no longer meet the demand for ATP resynthesis. Consequently, the body must rely on anaerobic metabolism to generate additional ATP. The onset of anaerobic metabolism, the anaerobic threshold, normally occurs at about 50% to 65% of the body’s maximum oxygen consumption (V˙O₂max).³ Because fat cannot be metabolized anaerobically, less fat is used as exercise intensity increases.² The major energy sources at maximal exercise are aerobic and anaerobic glucose metabolism. For this reason, the body’s glucose stores limit exercise endurance. Sustained exercise such as marathon running may totally deplete glucose stores, explaining the reason some marathon runners suddenly fatigue or “hit the wall” after about 20 miles.

Figure 23-2 shows that aerobic metabolism produces ATP far more efficiently than anaerobic metabolism. In aerobic metabolism, one molecule of glucose produces 36 molecules of ATP compared with only two molecules of ATP in anaerobic glucose metabolism. In addition, anaerobic glucose metabolism generates two lactic acid molecules. Blood bicarbonate immediately buffers newly formed lactic acid, generating more CO₂, adding to the CO₂ already produced by aerobic metabolism (see Figure 23-2). This increased CO₂ production stimulates a proportional increase in ventilation.³

Respiratory Quotient and Respiratory Exchange Ratio

The respiratory quotient (RQ) is the ratio of CO₂ molecules produced to O₂ molecules consumed by the tissues (V˙CO2/V˙O2), as shown in Figure 23-1.² (In Figure 23-2, the RQ for glucose is about 1.0, whereas for fat, it is 0.71.) The fat RQ is lower because fat metabolism generates less CO₂ per ATP molecule than carbohydrate metabolism. At rest, the body metabolizes nearly equal amounts of fats and carbohydrates, yielding an RQ of about 0.85.² As exercise intensity increases, the RQ rises toward 1.0 as the metabolic substrate changes to glucose.

The respiratory exchange ratio (R) is the ratio between CO₂ elimination and O₂ uptake, measured from inhaled and exhaled gases at the mouth (see Figure 23-1).² In steady-state conditions, R equals RQ. The steady state is characterized by a CO₂ elimination rate that matches the CO₂ production rate; likewise, the lung’s O₂ uptake rate equals the tissue’s O₂ consumption rate in steady-state conditions. During short bursts of maximal exercise such as the 100-yard dash, RQ and R are different because tissue O₂ consumption and CO₂ production momentarily exceed the lung’s O₂ uptake and CO₂ elimination. Like RQ, R increases as exercise intensity increases; the onset of anaerobic metabolism further increases R as bicarbonate reacts with lactic acid and generates more CO₂

CONCEPT QUESTION 23-3

As exercise intensity increases, CO₂ production and alveolar ventilation increase steadily. Why does the rate of alveolar ventilation rise increase abruptly after anaerobic metabolism begins?

Exercise Testing Methods

Exercise tests in the laboratory involve treadmills or bicycle ergometers that provide the subject with graded exercise over a period of time. In a graded exercise test, the workload is progressively increased in a series of stages by increasing the treadmill speed (and its angle from the floor) or by increasing the

Clinical Focus 23-1 Arterial Carbon Dioxide Pressure during Exercise

In an exercise testing laboratory, a well-trained, long-distance runner undergoes an exercise test. At rest, she has a PaCO₂ of 40 mm Hg, R of 0.8, and minute ventilation of 6.5 L per minute. After 5 minutes of running on the treadmill, the following measurements are obtained:

V˙CO₂ = 960 mL/min

V˙O₂ = 1200 mL/min

Minute ventilation = 33 L/min

From these data, do you expect her PaCO₂ to be low, normal, or high?

Discussion

Because this athlete’s V˙E increased more than five times over the resting measurement, you may be inclined to predict a low PaCO₂. However, her R remained unchanged at 0.8, as the following calculation shows:

V˙CO2/V˙O2=960/1200=0.8

The increase in V˙E perfectly matched her increased metabolic CO₂ production and V˙O₂. Although her V˙E increased greatly, it was an appropriate increase, proportional to metabolic demands. In other words, this athlete was not hyperventilating, even at a V˙E of 33 L per minute. Therefore, her PaCO₂ is expected to remain unchanged. PaCO₂ remains remarkably constant in normal individuals during mild to moderate exercise.

bicycle’s pedal resistance. For example, the subject may exercise at a certain treadmill speed and angle for 3 minutes, after which the speed and angle are increased for the next 3 minutes, and so on. The subject exercises through a well-defined series of stages, each more difficult than the last, until maximum capacity is reached. During this time, a machine called a metabolic cart measures the inhaled and exhaled O₂ and CO₂ concentrations, tidal volume (V_T), respiratory rate, and minute ventilation.

To obtain these measurements, the subject breathes through a specially designed mouthpiece attached to the metabolic cart by large-bore tubes. Nose clips prevent breathing through the nose. The lips must be sealed tightly around the mouthpiece to prevent mixing of respiratory gases with atmospheric air. An electrocardiogram (ECG) machine measures the heart rate (HR) and ECG pattern during the exercise test. Depending on the data desired, various other physiological parameters may be measured. Table 23-1 lists physiological measurements grouped according to the invasiveness of the test and the monitoring equipment needed.

TABLE 23-1

Measurements during Graded Exercise Testing

Level of Rest	Measurements
Group 1	No mouthpiece
	Patient response and symptoms
	Heart rate
	Blood pressure
	ECG
	SaO₂ by oximetry
Group 2	Mouthpiece, oxygen, and carbon dioxide analyzer
	Respiratory rate
	Tidal volume
	Minute ventilation
	End-tidal gas measurements
	V˙O₂ and O₂ pulse
	V˙CO₂
	Respiratory exchange ratio
Group 3	Arterial line
	Blood gas values: PaO₂, PaCO₂, and pH
	HCO3− and lactate
	V_D/V_T
Group 4	Right-sided heart catheter
	Pulmonary artery pressures
	Cardiac output
	Mixed venous PO₂ and SO₂

ECG, Electrocardiogram; SaO₂, arterial oxygen saturation; V˙O₂, oxygen consumption per minute; O₂ pulse, oxygen consumption per heartbeat; V˙CO₂, carbon dioxide production per minute; PaO₂, arterial oxygen pressure; PaCO₂, arterial carbon dioxide pressure; pH, measure of blood H⁺ concentration; HCO₃^–, blood bicarbonate; V_D/V_T, dead space-to-tidal volume ratio; PO₂, oxygen pressure; SO₂, oxygen saturation.

Modified from Martin L: Pulmonary physiology in clinical practice: the essentials for patient care and evaluation, St Louis, 1987, Mosby.

Physiological Changes during Exercise

Oxygen Consumption, Cardiac Output, and Blood Pressure

Figure 23-3 represents the exercise performance of a normal person. V˙O₂ increases linearly with the work rate from rest to maximal exercise. The slope of V˙O₂ increase is about the same for all normal people; it is unaffected by training, age, or gender.¹ Because V˙O₂ depends primarily on the amount of work done by exercising muscle, V˙O₂ can be predicted from the work rate.^2,3

Figure 23-3 Breath-by-breath physiological changes during exercise from rest to maximal exertion in minute ventilation (V˙E), carbon output (V˙CO₂), oxygen uptake (V˙O₂), ventilatory equivalent for carbon dioxide (V˙E/V˙CO₂), ventilatory equivalent for oxygen (V˙E/V˙O₂), end-tidal PCO₂ (P_ETCO₂), end-tidal PO₂ (P_ETO₂), arterial blood lactate, bicarbonate, and pH. *BTPS,* Body temperature and pressure, saturated; *STPD,* standard temperature and pressure, dry. (From Mason RJ, et al, editors: *Textbook of respiratory medicine,* ed 4, St Louis, 2005, Saunders.)

As exercise intensifies, contracting muscles consume ever greater amounts of ATP, which means aerobic ATP regeneration requires an increasingly greater O₂ supply from the blood flow. Cardiac output rises to meet this demand by increasing stroke volume (SV) and heart rate. SV increases to its maximum value within the first half of the tolerable work rate range (at about 45% of the maximum V˙O₂).³ From that point on, SV remains fairly constant; the only way the heart can increase its output further is to increase its rate of contraction. The early increase in SV is the result of an increased ejection fraction rather than greater diastolic filling; sympathetic nervous stimulation and circulating epinephrine increase systolic ejection.³ Heart rate increases linearly with O₂ requirements until the maximum heart rate (HR_max) is achieved (Figure 23-4).

Figure 23-4 Changes in heart rate, systemic blood pressure, and SaO₂ during exercise from rest to maximal exertion. *AT,* Aerobic threshold. (From Martin L: *Pulmonary physiology in clinical practice: the essentials for patient care and evaluation,* St Louis, 1987, Mosby.)

As cardiac output increases with exercise, systolic blood pressure rises significantly (often ≥200 mm Hg). Diastolic pressure changes little, if at all, in normal, healthy people because the peripheral vasculature dilates significantly in response to increased O₂ demand, which greatly reduces vascular resistance.2,3 Thus, the pulse pressure (systolic – diastolic) increases significantly, forcing open all of the capillaries in working skeletal muscle. In heavy exercise, up to 80% of the cardiac output is diverted to skeletal muscle, making possible greatly increased O₂ delivery and V˙O₂ rates.

HR_max is age related and does not change with fitness. The predicted HR_max for adults is as follows:⁴

HRmax=220−Age(years)

HR_max, and thus, cardiac output are reduced in older persons because their hearts are less responsive to beta-adrenergic stimulation.⁴ An unconditioned person and a conditioned athlete of the same age have the same HR_max, but the conditioned athlete has a much greater SV and therefore a much higher cardiac output at HR_max. For a given amount of submaximal exercise, a conditioned person’s HR is much lower than the HR of a sedentary person. This explains why a sedentary person reaches the HR_max sooner and at much lower exercise intensity than an athlete. Because the unconditioned person’s cardiac output is lower at the HR_max, maximum O₂ delivery and V˙O₂ are also lower.

Carbon Dioxide Production, Respiratory Exchange Ratio, and Minute Ventilation

The increased metabolic activity of exercising muscles raises not only the V˙O₂ but also the V˙CO₂. Before the anaerobic threshold is reached, V˙CO₂ increases linearly and parallel with V˙O₂. Thus, R remains constant. The ventilation rate and depth rise to accommodate the increase in V˙CO₂, producing a linear increase in V˙E parallel with V˙CO₂ and V˙O₂ (see Figure 23-3, before anaerobic threshold).

Although it is generally accepted that increased V˙CO₂ during exercise is the stimulus for the higher V˙E, some evidence suggests that a neurally mediated, muscle-derived signal plays a role. Apparently, peripheral muscle receptors send signals to the central nervous system, increasing blood pressure, HR, and ventilation. These signals are enhanced by muscle ischemia but are not present in ischemia alone without exercise.⁵ Thus, muscle movement appears to be partly responsible for the increased V˙E of exercise.

The ventilatory response to exercise was discussed in Chapter 11. The immediate hyperpnea of exercise has long been a controversial subject and remains incompletely understood.³ The abrupt increase in V˙E at the onset of exercise (phase I) occurs long before any chemical or humoral change can occur in the body. Rather than being geared to a chemoreceptor reflex mechanism, the abrupt increase in ventilation appears to be a response to anticipated future metabolic demand. Evidence points to a sophisticated internal respiratory controller that integrates multiple afferent and efferent signals to predict the level of metabolic activity that will occur and then adjusts ventilation before the fact.⁶ A study of children with congenital central hypoventilation syndrome revealed that passive leg motion induced by a motor-driven ergocycle increased V˙E, although these children had no V˙E response to inhaled CO₂.⁷ Increased V˙E occurred immediately with the first breath after the onset of pedaling motion in children with congenital central hypoventilation syndrome and normal controls. This study supports the idea that muscle or joint receptors play a role in exercise hyperpnea.

Normal people increase V˙E by increasing both V_T and respiratory rate. Early in exercise, a higher V_T produces most of the increase in V˙E. After about 60% to 70% of the vital capacity is reached, V_T plateaus, and increased respiratory rate is responsible for additional V˙E increases.⁸

Figure 23-5 shows that dead space-to-tidal volume ratio (V_D/V_T) decreases as exercise progresses. The initial steep reduction in V_D/V_T reflects early increases in V_T with respect to the fixed anatomical dead space. V_D/V_T decreases from normal values of 0.3 to 0.4 at rest to 0.15 to 0.2 in exercise, in part due to a larger V_T but also because of significant blood flow diversion to previously underperfused upper lung zones.^3,8 As the respiratory rate begins to account for more of the increase in V˙E, the decline in V_D/V_T is less steep.

Figure 23-5 Changes in arterial blood gases, blood lactate, and V_D/V_T ratio during exercise from rest to maximal exertion. (From Martin L: *Pulmonary physiology in clinical practice: the essentials for patient care and evaluation,* St Louis, 1987, Mosby.)

Events Occurring after Anaerobic Threshold

As shown in Figure 23-3, the anaerobic threshold is the point at which the V˙CO₂ slope becomes steeper than the V˙O₂ slope, indicating an increase in CO₂ generation rate. This increase in CO₂ generation is due to the bicarbonate buffering of anaerobically produced lactic acid.^3,4 The increased generation of CO₂ stimulates ventilation, and the V˙E slope rises in parallel with the V˙CO₂ slope, maintaining a constant PaCO₂. In the end, the amount of CO₂ exhaled per minute increases with respect to the amount of O₂ taken up by the lungs, and R increases. The new V˙E slope has two phases. For some time, immediately after an aerobic threshold (AT) appears, the V˙E slope rises to match the increased V˙CO₂ slope. This short phase is referred to as isocapnic buffering, in which ventilation increases in concert with CO₂, momentarily compensating for the evolving lactic acidosis (see Figure 23-3).

As bicarbonate stores diminish and arterial pH falls, ventilation is stimulated more intensely, causing a second-phase increase in V˙E, out of proportion with the V˙CO₂ increase. (See the steeper V˙E slope after the second dotted vertical line in Figure 23-3.) The sharper rise in V˙E relative to V˙CO₂ represents hyperventilation; thus, PaCO₂ falls, as is reflected by the decrease in P_ETCO₂. (Recall that P_ETCO₂ is normally about equal to PaCO₂.) At the same time, P_ETO₂ also increases because the increase in V˙E supplies O₂ to the lungs more rapidly than it can be taken up.

As exercise intensity progresses to maximum levels, arterial pH falls further as blood lactate increases and bicarbonate concentration falls (see Figure 23-5). In other words, at maximal exercise, hyperventilation fails to compensate adequately for the lactic acidosis of anaerobic metabolism.

The increased ventilation with respect to V˙CO₂ and V˙O₂ at AT causes V˙E/V˙CO2 and V˙E/V˙O2 to increase. These two ratios are called ventilatory equivalents for carbon dioxide and oxygen respectively. V˙E/V˙O₂ begins to increase soon after AT is reached because the increased CO₂ produced by lactic acid buffering adds to the ventilatory drive. V˙E/V˙CO₂ does not increase until after the isocapnic buffering period. At this point, metabolic acidosis drives V˙E further, increasing it out of proportion to the increase in V˙CO₂ (see Figure 23-3).

A commonly accepted noninvasive method for determining AT is the V-slope method, which relates V˙CO₂ to V˙O₂.⁴ At the anaerobic threshold, the V˙CO₂ slope becomes steeper than the V˙O₂ slope, signaling the onset of lactic acid buffering. Values for R, V˙E/V˙O₂, and P_ETO₂ also increase at AT. Table 23-2 summarizes changes during progressive exercise.

TABLE 23-2

Physiological Changes during Exercise as Work Rate Increases

Measured Value	Reason for Change
Before Anaerobic Threshold
Expired Gas
V˙O₂ rate increases linearly	Need for aerobic ATP regeneration increases linearly
V˙CO₂ rate increases at the same rate as V˙O₂	CO₂ is a by-product of aerobic ATP regeneration
V˙E rate increases at the same rate as V˙CO₂	V˙E matches CO₂ production to maintain acid-base homeostasis
R (V˙CO₂/V˙O₂) is constant	V˙O₂ and V˙CO₂ rates increase equally
P_ETO₂ is constant	O₂ uptake from the lungs equals inspired O₂
P_ETCO₂ is constant	CO₂ exhaled equals CO₂ produced
V˙E/V˙O₂ is constant	V˙E and V˙O₂ rates increase equally
V˙E/V˙CO₂ is constant	V˙E and V˙CO₂ rates increase equally
Blood
Lactic acid concentration is constant	Metabolism is mainly aerobic
Heart Rate and Cardiac Output
Rates of increase are linear	O₂ delivery keeps pace with V˙O₂
At Anaerobic Threshold
Expired Gas
V˙O₂ rate increases linearly	Aerobic ATP regeneration needs continue to increase linearly
V˙CO₂ increases at a greater rate than V˙O₂	Lactic acid buffering by HCO3− accelerates V˙CO₂
V˙E increases at a greater rate than V˙O₂	V˙E responds proportionately to V˙CO₂ increase
R increases	Increased V˙E causes CO₂ elimination rate to exceed O₂ uptake rate
P_ETO₂ and V˙E/V˙O₂ increase	V˙E increases more than V˙O₂
P_ETCO₂ and V˙E/V˙CO₂ are constant	V˙E matches CO₂ production (isocapnic buffering)
Blood
Lactic acid concentration increases	Anaerobic metabolism begins to supplement aerobic ATP regeneration
Heart Rate and Cardiac Output
Rates of increase are linear	O₂ delivery keeps pace with V˙O₂ requirements
Anaerobic Threshold to Maximal Exercise
Expired Gas
V˙O₂ increases linearly to plateau (V˙O₂max)	O₂ needs continue to increase linearly
	V˙O₂max is limited by maximum heart rate
V˙CO₂ increases at a greater rate than V˙O₂	Lactic acid buffering and CO₂ generation rate continue to increase
V˙E increases at a greater rate than V˙CO₂	Development of metabolic (lactic) acidosis stimulates V˙E further (respiratory compensation)
R continues to increase	CO₂ elimination rate continues to increase more than O₂ uptake rate
P_ETO₂ and V˙E/V˙O₂ increase more sharply	Added stimulation from metabolic acidosis increases V˙E disproportionately to V˙O₂
P_ETCO₂ decreases and V˙E/V˙CO₂ increases	Added stimulation from metabolic acidosis increases V˙E disproportionately relative to V˙CO₂ (compensatory hyperventilation)
Blood
Lactic acid concentration increases	Continued increase in anaerobic metabolism supplements aerobic ATP regeneration
[HCO3−] decreases	HCO3− is used up in lactic acid buffering
Heart Rate and Cardiac Output
Linear rates increase to plateau (HR_max)	O₂ delivery keeps pace with O₂ requirements until age-determined HR_max is achieved

V˙O₂, Oxygen consumption per minute; V˙CO₂, carbon dioxide production per minute; ATP, adenosine triphosphate; V˙E, minute ventilation; R, respiratory exchange ratio in the lungs; P_ETO₂, end-tidal gas oxygen pressure; P_ETCO₂, end-tidal gas carbon dioxide pressure; HCO₃^–, blood bicarbonate; V˙O₂max, maximum attainable oxygen consumption; HR_max, maximum attainable heart rate.

Controversy exists over whether unavailability of O₂ causes the increased blood lactate measured during progressive exercise.³ If tissue cells do not use O₂, anaerobic metabolism sustains ATP synthesis, generating lactate in the process. However, O₂ unavailability is not necessarily the cause of an increased blood lactate concentration. An elevated blood lactate concentration means its production rate exceeds its metabolism rate. In other words, an increase in blood lactate may simply reflect that its metabolism rate cannot keep up with its production, not that O₂ is unavailable. Therefore, blood lactate concentration may not accurately reflect the degree of O₂ limitation.³ Nevertheless, the onset of lactic acidosis is delayed in exercising subjects breathing high O₂ concentrations. In addition, high workloads elicit lower than normal blood lactate concentrations when patients are breathing supplemental O₂. Conversely, the lactate threshold is reached sooner and maximum lactate concentration is higher when a patient is breathing a low fractional concentration of oxygen in inspired gas (F_IO₂). These findings provide strong evidence that anaerobic threshold is an O₂-dependent mechanism.⁹

Arterial Blood Gases

Figure 23-5 shows that arterial blood gases remain remarkably constant up to the anaerobic threshold. As discussed earlier, [HCO3−] and pH decrease after reaching AT as HCO3− buffers lactic acid; about 22 mEq of CO₂ are evolved for each 1 mEq of lactic acid buffered.³ Hyperventilation does little to raise PaO₂ and has even less effect on SaO₂ (see Figure 23-4); that is, room air F_IO₂ limits the increase in PaO₂, and SaO₂ is already near its maximum level under normal resting conditions (refer to the oxygen-hemoglobin equilibrium curve in Chapter 8). Thus, arterial oxygen content does not increase significantly from rest to maximal exercise. For these reasons, increased O₂ delivery to the tissues depends entirely on the increase in cardiac output in normal individuals.

Oxygen Diffusion Capacity

O₂ diffusion capacity almost triples with exercise.² At rest, blood flow through many pulmonary capillaries is extremely slow or even stopped. During exercise, increased cardiac output perfuses all capillaries to their maximum capacities, greatly increasing the surface area for diffusion. In addition, increased pulmonary vascular pressure produces a more uniform vertical distribution of pulmonary blood flow, greatly improving apical perfusion and increasing the diffusion surface area.⁸

Oxygen Cost of Work

After a steady state is reached during exercise, V˙O₂ can be predicted from the work rate (watts) whether the exercising individual is trained or untrained, old or young, male or female.⁹ The linear relationship between V˙O₂ and work rate (Figure 23-6) has a slope of about 10 mL V˙O₂/watt. This relationship reflects the fact that the same number of O₂ molecules is always used to generate the specific number of ATP molecules needed to produce a particular muscular contraction force. For this reason, the terms V˙O₂ and work rate can be used interchangeably. In other words, work efficiency is relatively constant in people in steady-state exercise. Work efficiency is expressed as follows:⁹

Figure 23-6 V˙O₂ increases linearly with the work rate until V˙O₂max is reached. V˙O₂ can be predicted from the work rate.

Efficiency=Externalworkdone/minBody’s energy cost/min

In this calculation, the external work and energy cost of performing the work are converted to their caloric equivalents. V˙O₂ can be converted to its caloric equivalent if the following information is known: (1) the number of calories produced when the body metabolizes 1 g of carbohydrate, fat, or protein and (2) the amount of O₂ used in the process. (Such conversions are the basis for indirect calorimetry, a process for determining the resting energy expenditure and caloric nutritional needs in critically ill patients.) Likewise, the work rate (watts) can be converted to caloric equivalents from its relationship with V˙O₂. The normal work efficiency for lower extremity bicycle work is about 0.30, or 30%.⁹

CONCEPT QUESTION 23-4

A physically conditioned person and a sedentary, unconditioned person pedal a bicycle ergometer for the same time at the same pedal resistance. Compare V˙O₂ in these two people.

In clinical practice, work is generally not measured in watts; instead, it is measured in milliliters per minute of V˙O₂ per kilogram of body weight. The average resting V˙O₂/kg for a 70-kg, 40-year-old man is about 3.5 mL O₂/min/kg, a value known as a metabolic equivalent (MET).⁴ The number of METs associated with a given level of work is calculated by first measuring the total O₂ consumed per minute and dividing by body weight (kg); the result is then divided by 3.5. For example, 35 mL O₂/min/kg is equal to 10 METs. However, estimating V˙O₂ from the work rate is inaccurate if the exercising subject fails to reach a steady state—a state in which tissue V˙O₂ and O₂ uptake in the lungs are equal. In addition, V˙O₂ may not increase linearly with the work rate in patients with cardiovascular disease.

Oxygen Debt

The body cannot store much O₂. During heavy exercise of short duration, the body consumes most of the stored O₂ in the lungs, blood, and muscle fibers within about one minute, and the lungs cannot take up O₂ fast enough to meet the body’s requirements; this creates an O₂ debt. The debt is repaid in the immediate recovery period as the subject hyperventilates, and the lungs take up much greater amounts of O₂ than the muscles normally require at rest. O₂ taken up during the recovery phase is used to reconstitute the high-energy ATP system and to metabolize lactic acid.²

Normal Exercise-Limiting Factors

Cardiac Factors

At maximal exercise, HR may triple compared with rest, and SV may double, producing a cardiac output up to six times above normal.3,4 O₂ delivery and V˙O₂ increase to the same degree. Nevertheless, cardiac capacity is the factor that normally limits exercise; ventilatory capacity does not limit the ability of normal, healthy people to perform work.^1,2

Cardiac capacity is determined chiefly by the maximum attainable HR. Early in exercise, SV reaches a maximum value, whereas HR continues to increase. O₂ delivery and V˙O₂ reach maximum limits because HR does so. Because healthy individuals can generally attain their predicted HR_max, the heart rate reserve (HRR) is normally zero during maximal exercise.¹ HRR is calculated as shown:

HRR=PredictedHRmax−ObservedHRmax

If SV is abnormally low, HR_max is reached prematurely, limiting the maximum amount of O₂ that can be delivered and consumed.

A measure of the heart’s efficiency in terms of O₂ delivered or consumed is the O₂ pulse, measured in milliliters of O₂ consumed per heart beat, as the following shows:

O2pulse=V˙O2/HR

The O₂ pulse increases only when work rate increases, theoretically because blood flow distribution to working tissues improves, allowing for greater O₂ extraction per unit of blood. An increase in O₂ pulse is thus a marker for improved blood flow distribution.³ Fick’s equation (see Chapter 8) can be rearranged as follows to show that the O₂ pulse is equal to SV multiplied by the arterial-venous O₂ content difference:

CO×C(a−v¯)O2=V˙O2

Substituting SV × HR for CO:

SV×HR×C(a−v¯)O2=V˙O2

Rearranging for the O₂ pulse gives the following:

V˙O2/HR=SV×C(a−v¯)O2

The O₂ pulse (left side of the preceding equation) increases early in exercise as SV increases. As SV peaks, increased tissue O₂ extraction (i.e., increased C[a-v¯]O₂) accounts for further O₂ pulse increases. The O₂ pulse plateaus as HR_max is approached. A low SV produces a low O₂ pulse because the heart rate is high in relation to V˙O₂

CONCEPT QUESTION 23-5

Explain why the O₂ pulse of a sedentary, unconditioned person is lower than the O₂ pulse of a trained athlete.

Pulmonary Factors

During maximal exercise, V˙E may be as high as 150 L per minute, about 25 times resting V˙E. The respiratory rate approximately triples, whereas the V_T increases about sixfold, up to about 60% or 70% of the vital capacity.⁸ Despite these large increases, normal, healthy people still do not attain their measured maximum voluntary ventilation (MVV) during maximal exercise.⁸ The breathing reserve (BR) is usually defined as the difference between MVV and maximum exercise ventilation (V˙Emax),⁸ as the following equation shows:

BR=MVV−V˙Emax

BR represents a theoretical potential for increasing ventilation further once the point of maximum exercise is reached. MVV (measured over 12 to 15 seconds) is normally 20% to 50% larger than the ventilation an individual attains during maximal exercise.8,10–12 MVV is commonly estimated by multiplying the forced expiratory volume in 1 second (FEV₁) by 40 (MVV = FEV₁ × 40).¹³ Does this mean normal people have the potential to increase their ventilation by an additional 20% to 50% once they reach the point of maximum exercise? They probably cannot. The maximum ventilation that can be voluntarily sustained for 15 minutes or longer corresponds to 55% to 80% of the MVV in normal people.^10,12 Electromyographic studies show signs of diaphragmatic fatigue in normal people who are ventilating at greater than 70% of the MVV, a level commonly attained during maximal exercise. If V˙Emax is compared with the maximal sustainable ventilation over the same time frame, BR is quite small, even in normal subjects. Nevertheless, BR calculated in the traditional way (MVV − V˙Emax) is an important quantitative indicator of ventilatory reserve; it is higher in normal people and lower in people with pulmonary disease. Although respiratory muscle fatigue may occur during maximal exercise in normal subjects, it is not clear that this fatigue actually limits exercise.¹⁰

Some studies show that maximum ventilatory capacity may be an exercise-limiting factor in elite, world-class athletes.13,14 Trained athletes in these studies were able to exercise at intensities beyond levels that elicited V˙O₂max. This supramaximal exercise was predicted to require 115% of the measured V˙O₂max. These athletes were able to sustain supramaximal exercise to the extent that they could increase their minute ventilation. In other words, although they reached their maximum cardiac capacity, these athletes were able to use their remaining ventilatory capacity to exercise further. In this sense, ventilatory capacity was the factor that determined maximal exercise intensity.

Physically Conditioned versus Physically Unconditioned

The maximum heart rates of physically fit and unfit people of the same age are the same. Physically conditioned and unconditioned people performing the same amount of work consume the same amounts of O₂ because V˙O₂ is linearly related to the work rate regardless of conditioning, age, or gender. What then is the defining difference between physically conditioned and unconditioned people?

These differences have been mentioned in previous sections. A physically conditioned person has a much greater SV than an unconditioned person. For this reason, a physically fit person generates a much higher cardiac output during maximal exercise, although HR_max is the same for both people if they are the same age. This means the conditioned person delivers adequate O₂ to the muscles at a lower HR than the unconditioned person.

At a given work rate, the unconditioned individual has a higher HR than the conditioned person (Figure 23-7). Although the same amount of O₂ is required to perform the work, the lower SV of the unconditioned person requires a faster HR. During maximal exercise, determined by HR_max, the unconditioned person has a relatively low work output, cardiac output, oxygen-delivery rate, and V˙O₂max. For these reasons, V˙O₂max is an indicator of fitness. The average V˙O₂max of an untrained 20-year-old person is about 40 to 50 mL/min/kg and that of a 60-year-old person is about 28 to 35 mL/min/kg. The V˙O₂max of highly trained athletes is 1.5 to 1.7 times greater than that of nonathletes.^13,15

Figure 23-7 A given work rate elicits a faster heart rate in an unfit person than in a fit person. An unfit person achieves a maximum heart rate sooner and at a relatively low work rate.

Physical training programs raise V˙O₂max by increasing the heart’s muscle mass, SV, and cardiac output. Such cardiac hypertrophy and increased pumping effectiveness occur only with aerobic, endurance types of training, not with short, high-energy sprint types of training.² Training increases the amount of O₂ the muscles can extract from the blood, partly because muscle capillary density is increased and distribution of blood flow to working muscles is improved and partly because of an enhanced capacity of trained muscles to use O₂.³ At the cellular level, trained muscles have larger and more numerous mitochondria and increased levels of aerobic enzymes; these factors combined with an increased capillary density enhance carbohydrate metabolism and ATP production.³

CONCEPT QUESTION 23-6

After a 12-week exercise conditioning program, your resting HR decreases from 72 beats per minute to 58 beats per minute. What is the physiological explanation?

Physiological Basis for Clinical Exercise Testing

Differentiating Cardiac and Pulmonary Causes of Exercise Intolerance

Cardiopulmonary exercise testing is widely used to distinguish between circulatory and ventilatory exercise limitations.¹⁶ Cardiac and pulmonary defects produce their own unique kinds of abnormal test results, allowing the contribution of each system to exercise intolerance to be evaluated.

Cardiac Disease

The heart limits exercise when it fails to pump enough blood to meet the body’s O₂ needs and the ventilatory reserve is not yet exhausted. Low cardiac output means either HR or SV fail to increase adequately. Most commonly, cardiac diseases limit increases in SV, causing the body to rely on a higher HR to keep pace with increasing O₂ requirements. As a result, HR rises at an ever-increasing pace in a nonlinear fashion with respect to V˙O₂; HR is abnormally high for a given cardiac output (Figure 23-8). This produces a low O₂ pulse (V˙O₂/HR). Because HR increases more rapidly than V˙O₂ increases, the O₂ pulse reaches a maximum value early and plateaus (Figure 23-9). Although cardiac output increases during exercise, it cannot keep pace with increasing tissue O₂ needs. This inadequate increase in cardiac output means O₂ delivery increases at an inadequate rate, which limits the increase in V˙O₂. Consequently, the relationship between V˙O₂ and work rate is not linear, as it is in healthy people (Figure 23-10).¹

Figure 23-9 Abnormally low stroke volume in cardiac disease causes the maximum heart rate and maximum V˙O₂ to be reached early during exercise. This produces a low O₂ pulse that plateaus early.

Figure 23-10 In cardiac disease, the inadequate increase in cardiac output during exercise means O₂ delivery increases inadequately, which limits the increase in V˙O₂.

Low cardiac output and O₂ delivery cause people to reach anaerobic threshold and generate lactic acid at low work rates. The subsequent buffering of this acid by bicarbonate increases CO₂ generation. Consequently, V˙E requirements increase, and the patient develops dyspnea early in exercise. Low cardiac output also reduces pulmonary blood flow with respect to ventilation, increasing alveolar dead space and V_D/V_T. This further increases the V˙E required to maintain CO₂ homeostasis. Figure 23-11 summarizes the typical consequences of exercise in a patient with cardiac disease.

Figure 23-11 Flow diagram illustrating the typical consequences of exercise in cardiac disease.

Pulmonary Disease

The lungs limit exercise when they cannot provide the increased V˙E required to do more work, while the cardiovascular system is still functioning below maximum capacity. In the following sections, the discussion of pulmonary problems is limited to obstructive and restrictive lung diseases.

Severe airflow obstruction greatly reduces MVV because high airway resistance slows maximum expiratory flow during rapid respiratory rates. This increased resistance prevents the lungs from emptying to normal resting levels during exercise. As a result, the lungs develop increased end expiratory volumes; this decreases inspiratory capacity (IC), further limiting ventilatory capacity.¹⁷ MVV may be so low that it is matched or exceeded by V˙Emax.⁸ Individuals with severe obstruction reach their ventilation limits before they reach their maximum HR or predicted V˙O₂max. In other words, they are more limited in their ability to eliminate CO₂ than in their ability to make O₂ available to the tissues. The mechanical pulmonary apparatus simply cannot move air fast enough to satisfy ventilatory demands of exercise.

Abnormal ventilatory mechanics in obstructive disease produces significant ventilation-perfusion (V˙/Q˙) mismatches. Certain lung regions are hypoventilated, whereas others are hyperventilated. In COPD, the degree to which alveolar ventilation is reduced is less than the degree to which dead space ventilation is increased, which results in a greater than normal V_D/V_T. A greater V_D/V_T decreases ventilatory efficiency, requiring a higher total V˙E to maintain a normal V˙A and CO₂ elimination rate. Consequently, V˙E/V˙CO₂ and V˙E/V˙O₂ are increased. Patients with COPD usually have a higher resting V˙E than healthy people for the same metabolic rate.¹⁸ The higher resting V˙E combined with a lower MVV leaves less ventilatory reserve available to accommodate the demands of exercise. The BR (MVV − V˙Emax) remaining at maximal exercise is often zero in patients with advanced COPD (Figure 23-12).

Figure 23-12 Ventilatory limitation to exercise. In lung disease, resting minute ventilation is high, and MVV is low, decreasing the ventilatory capacity. Ventilation at maximal exertion is near or equal to MVV, leaving little or no breathing reserve. Severe dyspnea stops exercise at a low work rate and submaximum heart rate. This limits V˙O₂max.

Because MVV depends on patient effort and motivation, it is often indirectly estimated from FEV₁. Various studies show that MVV in normal subjects and patients with COPD is accurately estimated by the following formula:19–21

MVV=FEV1×40

If ventilatory capacity alone limits exercise, low breathing reserve and high HR reserve are expected at the point of maximal exercise. Also, a low V˙O₂max is expected because HR_max is not achieved, limiting O₂ delivery. V_D/V_T remains elevated and relatively constant with increasing exercise rather than decreasing, as in normal people.¹⁸ (This is manifested as a relatively constant difference between PaCO₂ and P_ETCO₂.) A patient with pulmonary limitations stops exercising because of severe dyspnea as BR approaches zero (see Figure 23-12).

During pulmonary-limited exercise, the anaerobic threshold generally occurs in the normal range, about midway between resting V˙O₂ and predicted V˙O₂max. However, ventilatory capacity may limit obstructed patients so severely that dyspnea prevents them from exercising to levels necessary for anaerobic metabolism.¹ Nevertheless, studies show that most patients with COPD reach the anaerobic threshold and develop metabolic acidosis during maximal exercise.¹⁸ Abnormal lung mechanics prevent V˙E from responding adequately to the subsequent decrease in pH and increase in CO₂. Consequently, acidosis worsens rapidly after anaerobic metabolism begins.

Depending on the disease severity, PaO₂ may increase, remain constant, or decrease with exercise.¹⁸ Exercise improves V˙/Q˙ in some instances (because of improved lung perfusion), increasing the PaO₂. A decreasing PaO₂ during exercise distinguishes emphysema from chronic bronchitis. Emphysema is characterized by a destruction of the capillary vascular bed. High blood flow during exercise exceeds the alveolar capillary membrane O₂ diffusion capacity, causing PaO₂ to decrease. PaO₂ remains constant or increases with exercise in pure chronic bronchitis because the membrane surface area is not affected in this disease.

Restrictive disease such as pulmonary fibrosis is characterized by a nonuniform distribution of inflammatory scar tissue throughout the alveoli, creating alternating areas of low and normal compliance. Scar tissue may replace the capillary bed in severely involved units or merely thicken the alveolar capillary membrane. The result is a high V_D/V_T, a reduced surface area for gas exchange, impaired diffusion, and overall low lung compliance. Low lung compliance decreases all lung volumes and capacities, especially IC. The small IC limits the patient’s ability to increase the V_T during exercise. Consequently, the breathing rate increases earlier in exercise and to a much greater extent than normal. As a result, the V_T/IC ratio increases and approaches 1.0. During maximal exercise in restrictive disease, the breathing rate usually exceeds 50 breaths per minute.¹ As with obstructive disease, V˙E max often nearly equals MVV, reducing BR.

As exercise progresses in patients with restrictive diseases, the limited diffusion capacity leads to a decrease in PaO₂. This occurs because an increased cardiac output decreases the time that capillary blood is in contact with alveolar gas; there is not enough time for alveolar O₂ to diffuse into the capillary blood. As with obstructive disease, dyspnea usually causes the patient to stop exercising before HR_max is reached, lowering the V˙O₂max. Box 23-1 summarizes exercise test abnormalities in patients who have obstructive and restrictive lung diseases.

BOX 23-1 Typical Exercise Test Abnormalities in Pulmonary Disease

Obstructive and Restrictive Disease

Low breathing reserve

Low maximum V˙O₂

High V_D/V_T

High heart rate reserve

Inadequate V˙E response to lactic acidosis

High (PaCO₂ − P_ETCO₂)

High P(A-a)O₂

High V˙E/V˙CO₂ and V˙E/V˙O₂

Restrictive Disease

High V_T/IC ratio

Breathing rate >50 breaths/min during maximal exercise

Systematic decreases in PaO₂ and increases in P(A-a)O₂ as work rate increases

V˙O₂, Oxygen consumption per minute; V_D/V_T, dead space-to-tidal volume ratio; V˙E, minute ventilation; P_ACO₂, alveolar carbon dioxide pressure; P_ETCO₂, end-tidal gas carbon dioxide pressure; P(A-a)O₂, alveolar-arterial oxygen pressure difference; V˙CO₂, carbon dioxide production per minute; V_T, tidal volume; IC, inspiratory capacity; PaO₂, arterial oxygen pressure.

Exercise Tests and Prescription in Cardiopulmonary Rehabilitation

Exercise is an essential component of cardiopulmonary rehabilitation programs. The major benefit of exercise in this setting is that exercise leads to decreased myocardial work (HR) for a given level of activity. Exercise test results identify appropriate training heart rates. Patients can then monitor their own HR and choose appropriate exercise intensities.

Depending on the factor that limits exercise, patients may benefit from endurance training, controlled breathing and relaxation exercises, and exercises while breathing supplemental O₂.²² For endurance training such as walking or bicycling, exercise intensity should be high enough to produce a HR greater than 60% but less than 80% of the predicted HR_max. About 30 minutes of exercise at this intensity every other day is needed to achieve the classic training effect (i.e., decreased HR for a given submaximal workload). The Karvonen equation is commonly used to compute a target HR range for endurance training in cardiac patients; this method adds from 45% to 85% of the difference between HR_max and resting HR to the resting heart rate as follows:²³

TargetHRrange=0.45to0.85(HRmax−HRrest)+HRrest

Exercise testing is valuable for assessing the effectiveness of cardiopulmonary rehabilitation programs; initial test results establish a physiological baseline that can be compared with test results obtained after a rehabilitation program is completed. Such comparative quantitative data objectively demonstrates patient outcome and progress, which helps justify the medical necessity of rehabilitation programs to third-party payers such as Medicare and private insurance companies.

For example, if the resting HR is 60 beats per minute and HR_max obtained during an exercise stress test is 130 beats per minute, the difference is 70 beats per minute (130 − 60 = 70). This difference is then multiplied by 0.45 and 0.85 and added to the resting HR to define the target HR range:

0.45(70)=32+60=92

0.85(70)=60+60=120

Target HR range for endurance training is 92 to 120 beats per minute.

Clinical Focus 23-2 Origin of Exercise Limitation

Case 1

A 58-year-old woman with a history of cigarette smoking undergoes an exercise test to evaluate dyspnea on exertion. She weighs 70 kg. Pulmonary function tests reveal moderate airway obstruction and MVV of 42 L per minute. ECGs show no ischemic abnormalities. Treadmill exercise test data are obtained and show the following:

	At Rest	0% Grade—1.7 mph	5% Grade—1.7 mph	10% Grade—1.7 mph	12% Grade—2.5 mph
V˙O₂ (mL/min)	340	825	985	1130	1372
V˙CO₂ (mL/min)	295	660	808	949	1180
V˙E(L/min)	10	27	33	38	40
P(A-a)O₂ (mm Hg)	16	13	12	19	21
HR (beats/min)	75	96	100	113	120

Further measurements were not made because the patient became severely dyspneic and could not continue exercising. Did this patient achieve the anaerobic threshold or the maximum heart rate, or both? Did cardiac or pulmonary factors limit exercise?

Discussion

The AT marks the onset of lactic acid production. The subsequent decrease in pH is normally expected to stimulate ventilation, causing V˙E to increase more rapidly than V˙CO₂. Also, V˙CO₂ is expected to increase more rapidly than V˙O₂ at AT. Examination of the data indicates this did not happen; V˙CO₂ and V˙E increased fourfold, and RQ did not rise above 1.0. (In the last stage, RQ = 1180 ÷ 1372, which equals 0.86.) Therefore, the anaerobic threshold apparently was not reached.

This patient’s maximum predicted heart rate is as follows: 220 − 58 = 162 beats/min. A significant HRR exists at maximal exercise capacity. Normally, HRR is about zero during maximal exercise. Conversely, little BR exists during maximal exercise; V˙E max is about 95% of MVV (40 ÷ 42 = 0.95), leaving a BR of 5%. Normally, a BR between 20% and 50% of MVV exists during maximal exercise. This patient’s exercise is limited by pulmonary, not cardiac, factors. The following factors support this conclusion: (1) failure to reach the anaerobic threshold, (2) large HRR, and (3) extremely small BR. The appropriate increase in the heart rate and O₂ pulse (V˙O₂/HR) during exercise rules out cardiac limitation. This woman’s complaint of dyspnea on exertion must be related to pulmonary disease.

Case 2

A 60-year-old man with a history of smoking undergoes an exercise test to evaluate dyspnea and substernal chest pain on exertion. A resting 12-lead ECG reveals no abnormalities. Pulmonary function tests show a mildly obstructive pattern. MVV is 130 L per minute. The patient exercises on a bicycle ergometer for about 3 minutes, with no added workload. The workload is then gradually increased in 1-minute increments. The patient stops exercising after 7 minutes because of chest pains. ST segment depression occurs on the ECG in the last 2 minutes of exercise. The following results are obtained during maximal exercise:

	Predicted	Measured
V˙O₂max (mL/min)	2250	1485
HR_max (beats/min)	160	149
V˙O₂ at AT (mL/min)	>900	550
V˙Emax (L/min)	—	91

Following are resting versus maximal exercise data:

	Resting	Maximal Exercise
PaO₂ (mm Hg)	85	113
P(A-a)O₂ (mm Hg)	16	9

Is cardiac disease or pulmonary disease responsible for this patient’s exertional dyspnea and exercise limitation?

Discussion

Data relevant to cardiac (see Figure 23-11) and pulmonary function (see Box 23-1) are as follows:

Cardiac	Pulmonary
HR_max = 92% of predicted: 149/160 = 0.92	V˙Emax = 70% of MVV: 91/130 = 0.7 (BR = 30%)
V˙O₂max = 66% of predicted: 1485/2250 = 0.66	PaO₂ increased with exercise
Predicted O₂ pulse = 2250/160 = 13.9 mL O₂/beat	P(A-a)O₂ decreased with exercise
Actual O₂ pulse = 1485/149 = 9.97 mL O₂/beat
Anaerobic threshold at V˙O₂ = 550 mL/min (37% of V˙O₂max)
Heart rate reserve = 8%

Evidence for a low SV includes the following: (1) predicted HR_max almost reached early in exercise at a low V˙O₂max and (2) O₂ pulse lower than predicted. Achieving the anaerobic threshold at only 37% of the measured V˙O₂max means O₂ delivery to the muscles is too low to meet the workload’s requirement. ST segment depression indicates myocardial ischemia, which further decreases contractility and SV.

Conversely, V˙E max is only 70% of MVV. Considerable potential exists for increasing V˙E further during maximal exercise. The increasing PaO₂ and decreasing P(A-a)O₂ mean that V˙/Q˙ improves with exercise (a normal phenomenon).

The combined evidence suggests an oxygen-delivery problem not related to lung function. In other words, inappropriately low cardiac output causes anaerobic metabolism and lactic acid production at low work rates. Lactic acid increases the V˙E requirement, accounting for the exertional dyspnea. Normal BR and normal response of PaO₂ and P(A-a)O₂ to exercise confirm the absence of pulmonary limitation.

It is more accurate to use the actual HR_max obtained from an exercise test rather than the predicted HR_max.²³ An alternative, even more accurate method (recommended for both cardiac patients and healthy adults) is based on oxygen consumption reserve (V˙O₂R), which is the difference between V˙O₂max measured during a stress test and the resting O₂ consumption:²³