Chapter 7: Pulmonary Function; Gas Exchange Between the Environment and Blood

Blood Gas Interface

The blood gas interface consists of the alveolar epithelium and the endothelial lining of the pulmonary capillary (see Figure 7-2). Important features of the blood gas interface include its extensive surface area (850 – 1000 cm²) and its thinness (0.3 µm). These features are ideal for the diffusion of oxygen and carbon dioxide between the air and blood, which is governed by Fick’s law of diffusion. It states that the amount of gas moving across a sheet of tissue is proportional to its surface area and inversely proportional to its thickness.

Oxygen in the air that is inhaled into the alveoli diffuses into the pulmonary capillary blood stream by crossing the alveolar epithelium, the interstitial space, the pulmonary capillary endothelium and the plasma, through the membrane and into the red blood cell. Oxygen then binds to haemoglobin, a protein found in the red blood cells. Carbon dioxide diffuses from the red blood cell or the plasma itself, across the pulmonary capillary endothelium, the interstitium, and finally the alveolar epithelium into the alveoli to be exhaled from the body.

Blood Vessels

The pulmonary blood vessels form a branching network that initially follows alongside the branching airways. Both vessels and airways bifurcate often, becoming smaller with each split. These arterioles and airways go deep within each lobe of the lung. Further downstream, a network of dense capillaries form in the region of the alveolar walls. The pulmonary veins, which return oxygenated blood to the left side of the heart, travel between the lobes of the lungs (rather than through their centres).

The pulmonary capillaries are sufficiently small in diameter (~10µm), just large enough to permit the passage of a red blood cell. This feature improves pulmonary gas exchange by reducing the distance for oxygen and carbon dioxide diffusion. Another important feature involves the vast network of the capillaries themselves, which forms nearly a complete sheet of blood in the vicinity of the alveoli. This large surface area is responsible for an amazingly small resistance to blood flow. Blood flow through each pulmonary capillary at rest is so slow that a red blood cell spends nearly 0.75 seconds in the capillary and traverses several alveoli, each with a diameter of roughly 200 µm.

These important features of the pulmonary circulation are responsible for nearly a complete equilibration of oxygen and carbon dioxide between the alveolar gas and the capillary blood. However, the thin and intricate array of the pulmonary capillaries also makes them quite weak and susceptible to damage. The entire cardiac output must travel through the pulmonary circulation. Since the cardiac output can increase above resting levels by 5 to 6 times with high-intensity exercise, the high rate of flow and pressure in addition to mechanical strain caused by increased lung volumes can be responsible for capillary stress failure. In such an instance plasma and red blood cells may enter the interstitial space or alveoli and impair pulmonary gas exchange.

In addition to the pulmonary circulation, the respiratory system also has a bronchial circulation which is responsible for delivering oxygenated blood to the airways of the conducting zone. This includes supplying blood to the primary, secondary, and lobular bronchi, and the bronchioles.

Ventilatory Muscles & Muscles of the Upper Airway

The ventilatory muscles can be categorized into three different groups. These are the muscles of the upper airway and the bronchi, inspiratory muscles, and expiratory muscles.

The muscles of the upper airway include: nasal dilator muscles, tensor muscles of the soft palate, the genioglossus, and the geniohyoid. These muscles are involved in dilating and stiffening the upper airway thereby preventing its collapse as more negative intrathoracic pressures develop during inspiration. The activity of these muscles is phasic in nature and closely related to ventilation during regular breathing or eupnea. Although the activity of upper airway muscles is not well understood during exercise, there does appear to be some relation between their activity and the magnitude of inspiratory airflow. In addition to the muscles of the upper airway, the smooth muscle of the bronchi are also involved in controlling airway resistance.

Several muscles are involved in the process of inspiration. Airflow into the lungs requires that the volume of the thoracic cavity increase thereby reducing intrathoracic pressure. The pressure gradient generated between the airways and the external environment is responsible for the mass flow of fresh air into the alveoli. Expansion of the thoracic cavity is achieved by activity in the inspiratory muscles. This includes the external intercostals (which expand the rib cage), the diaphragm, the scalene muscles, and finally the sternocleidomastoids.

At rest, elastic recoil of the lung is responsible for the process of expiration. However, during exercise, as breathing frequency and tidal volumes increase, the accessory muscles of expiration are recruited. These muscles include the rectus abdominis, the internal and external oblique muscles, the transversus abdominis, and the internal intercostals. Contraction of the abdominal muscles helps to force the diaphragm upward thereby reducing the volume of the thoracic cavity. Activity in the internal intercostals draws each individual rib together and as a result decreases the volume of the thoracic cavity. A decrease in the volume of the thoracic cavity increases intrathoracic pressure and creates the pressure gradient necessary to expel air from the lungs.

Breathing Patterns During Exercise

Breathing at rest and during exercise is more complicated than simply ventilating the lung. Ventilation must be controlled appropriately such that the work of breathing is minimized and alveolar gas partial pressures are maintained. The control of breathing system is involved in maintaining appropriate breathing patterns and is described below. Variables involved in characterizing the breathing pattern include: end-inspiratory and end-expiratory lung volumes [the difference of which is the tidal volume (V_T)], inspiratory and expiratory flow rates, and breath timing [which includes inspired time (T_I), expired time (T_E), and the frequency of breathing (f_b)], and duty cycle [T_i/(T_i+T_E)]. The simplest method of assessing breathing patterns during exercise is therefore to measure f_b and V_T. Other approaches include measuring flow volume loops as discussed below. In this section, the basic characteristics of the breathing pattern during progressive exercise and during sub maximal exercise will be described.

Breathing Patterns During Progressive Exercise

Progressive exercise involves continuously increasing work of the locomotor muscles, such as a ramp protocol maximal exercise test. Other examples include a cycle exercise test with increasing resistance and a treadmill test with increasing speed and/or incline. Figure 7-3 illustrates the ventilatory response during incremental exercise. During this type of exercise, minute ventilation (V̇E) increases with increasing intensity/(V̇O₂). At mild exercise intensities, the rise in V̇E is accomplished by increasing both f_b and V_T (see Figure 7-4). This is in contrast to moderate intensity exercise during which increases in V̇E are achieved primarily by increasing V_T while maintaining f_b. Increases in V_T are accomplished by increasing end-inspiratory lung volume and by decreasing end-expiratory lung volume. This is an ideal ventilatory exercise response because it increases V̇A and decreases dead space ventilation; it therefore has a positive effect on the quality of alveolar gases. During heavier exercise, further increases to V_T become too costly with respect to the work of breathing, therefore, V_T plateaus and increases in f_b are responsible for further increases in . At maximal exercise intensity, V_T typically reaches about 50-60% of vital capacity.

Breathing Patterns During Submaximal Exercise

Submaximal exercise is typically an intensity of exercise that can be maintained in excess of five minutes. It may involve a steady state V̇E phase if the intensity is less than 70% of V̇O₂max (in an untrained individual). Above this intensity V̇E may not reach a steady state but instead gradually increases.

V̇E during submaximal exercise can be characterized by three phases as illustrated in Figure 7-5. At exercise onset, V̇E increases abruptly and is referred to as phase I. Throughout the first 2-3 minutes of exercise V̇E slowly and gradually increases to a steady state. This slow, gradual increase in V̇E is called phase II. Finally, phase III is the steady state or the relatively constant period of V̇E. Note that these phases are not the same as the 3 phases of the rise in V̇O_2.

Ventilatory Muscle Energetics

Homeostasis of respiratory gases in the blood is reliant upon the coordinated changes that link tissue metabolism, alveolar ventilation, cardiac output and peripheral blood flow. The pulmonary system in the young, healthy adult responds to dynamic exercise with remarkably precise regulation of alveolar ventilation that is matched to metabolic demand. Even during strenuous sea-level exercise the arterial partial pressures of oxygen and carbon dioxide and arterial pH remain close to resting values indicating that the neuromechanical regulation of alveolar ventilation is highly effective. Exchange of air between the atmosphere and the alveoli is dependent, in part, upon the mechanical properties and interactions between the lung, the surrounding anatomy including the chest-wall, the abdomen, and the ventilatory muscles that act upon them. The ventilation that accompanies exercise requires contraction of the ventilatory pump muscles. Contraction of these muscles permits increases in V_T and f_b during exercise and thus appropriate pulmonary gas exchange. Like the contraction of skeletal muscle there is an energy cost associated with the work of breathing. At rest, the O₂ consumption of the ventilatory muscles is approximately 3-5% of V̇O₂. At maximal exercise this can increase to 8-10% of V̇O₂max in healthy individuals and as much as 13-16% V̇O₂max in highly trained endurance athletes (Aaron et al. 1992). The work of breathing can be divided into two categories:

• elastic work, which involves altering the shape of the anatomical structures involved, and
• resistive work, which is necessary to overcome the resistance to airflow in the airways.

In general, the ventilatory response to exercise is thought to be governed by the principle of “minimal effort” (Macklem 2002). This concept is supported in two ways. First, models describing the work of breathing indicate that the ventilatory patterns naturally observed during exercise are the least costly in terms of energy expenditure. Second, ventilation during exercise occurs within a range of lung volumes for which total lung compliance is greatest. This means that the amount of work performed on the lungs and chest wall to achieve a given tidal volume is minimized compared to higher or lower lung volumes.

The total work of inspiration and expiration is substantially higher during exercise than at rest because f_b and V_T are increased. Elastic work increases substantially as tidal volume increases relative to rest. Once V_T reaches a plateau, elastic work decreases with increasing f_b because more of the elastic energy that is stored in the chest wall and lung during inspiration is recovered during expiration. The resistive work of breathing increases significantly as flow-rate increases because of increases in turbulent airflow.

As one would expect, the work of breathing will increase when V̇E increased, and therefore, the recruitment of motor units in the ventilatory muscles is increased and energy demand placed on the ventilatory muscles is increased as well. It has been shown that the metabolic and circulatory costs of a high work of breathing during maximal levels of ventilation amount to 10% of V̇O₂max in the untrained person, and up to 15-16% of V̇O₂ at maximal cardiac output in the highly-trained person (Aaron et al. 1992; Harms et al. 1997). This difference between trained and untrained individuals occurs because the trained person must achieve a greater V̇E to support the higher V̇O₂max.

The ventilatory muscle oxygen cost at similar minute ventilations is greater in females and is increased by age. An older, male, of average fitness has a higher work of breathing compared with a younger male of average fitness. Ageing is associated with a loss of lung elastic recoil and the consequences of this include a reduction in maximal expiratory flow rate and an increase in functional residual capacity. The greater oxygen cost of breathing in females compared with males occurs because women have smaller airways, lung volumes, and maximal expiratory flow rates relative to men even when matched for lung size (Mead 1980; Sheel et al. 2009). Female athletes develop expiratory flow limitation (i.e., expiratory flow during tidal breathing intersects the maximum flow-volume envelope) more frequently than male athletes and have an increase in end-expiratory and end-inspiratory lung volume at maximal exercise. This pattern of lung inflation is called dynamic hyperinflation.

Key Points

The muscles of breathing are heavily recruited during exercise and there is a significant metabolic cost associated with this muscular contraction.

Control of Exercise Ventilation

The control of exercise ventilation has been studied extensively but still remains highly controversial and poorly understood. Before undertaking our discussion of the control of exercise ventilation we must understand the components of the basic respiratory control system and normal breathing at rest (eupnea).

Overview of the Ventilatory Control System

The ventilatory control system is schematically presented in Figure 7-7. It consists of three main components: central controller, sensory input and effectors.

The first component is referred to as the central controller. The central controller is made up of groups of neurons located within the medulla and the pons that work together to integrate sensory information and to produce efferent outflow to the ventilatory muscles. These groups of neurons are therefore responsible for generating the ventilatory rhythm and pattern. They determine the length of inspiration and expiration, the rate of inspiration and expiration, and finally the volumes of inspiration and expiration. Since the ventilatory system is affected by sleep/wake state, phonation/speaking, emotion, body temperature, locomotion, learning and experience, it also receives inputs from higher brain structures such as the hypothalamus. This information allows breathing to occur automatically during a variety of activities and states, yet allows voluntary override when the need arises. We do not have to consciously alter our breathing during tasks like speaking, coughing, chewing, and swallowing which all involve the same airway and ventilatory muscles. Throughout these activities the ventilatory system is capable of regulating arterial PO₂ and PCO₂ within a narrow range (±1-2 mmHg).

Central Controller

The central controller involves neurons located throughout the ventral lateral medulla, and consists of pacemaker neurons that generate the intrinsic oscillations required for the basic pattern of breathing. An extensive neuronal network is also present and is responsible for pattern generation and fine-tuning breathing by integrating sensory and supramedullary inputs. Figure 7-8 shows a lateral view of the brainstem and highlights several distinct areas of ventilatory neurons: the pontine respiratory group (PRG), the dorsal respiratory group (DRG), the ventral respiratory group [divided into the rostral (rVRG) and caudal (cVRG) ventral respiratory group], the retrotrapezoid nucleus (RTN), the Bötzinger complex, and the preBötzinger complex. Nuclei within the PRG receive vagal afferent inputs that provide information relating to lung volume. These neurons are therefore important for limiting the rate and depth of breathing. The DRG receives bulbospinal inspiratory neurons and afferents from the peripheral chemoreceptors. It is likely an important site for sensory integration. The RTN contains both inspiratory and expiratory neurons that project to neurons within the rVRG. The importance of the RTN is not well understood but it may serve as a site of central chemoreception. The cVRG contains bulbospinal expiratory neurons that excite internal intercostals and abdominal motor neurons during expiration. The rVRG contains bulbospinal expiratory neurons that excite inspiratory muscles such as the diaphragm. The Bötzinger complex contains expiratory bulbospinal premotor neurons and excitatory interneurons. Finally, the preBötzinger complex contains pacemaker neurons that generate the basic ventilatory rhythms.

Sensory Inputs

Sensory inputs to the central controller provide information about the chemical and metabolic status of the blood and muscles, and mechanical information such as stretch of the lung. This section describes the peripheral chemoreceptors, central chemoreceptors, metaboreceptors, and mechanoreceptors.

Peripheral Chemoreceptors

The chemoreceptors are located bilaterally at the bifurcations of the common carotid arteries. They are highly vascularized and are sensitive to changes in arterial Po₂, Pco₂, and potassium ion concentration. The sensory activity from the peripheral chemoreceptors is projected to the brainstem medullary respiratory neurons through the carotid sinus nerve where it synapses with neurons located within the nucleus of the solitary tract.

The peripheral chemoreceptors are the only receptors in the human body responsible for stimulating ventilation in the presence of hypoxia. There is a curvilinear relationship between ventilation and arterial Po₂ in hypoxia, as would be experienced on going to altitude (see Figure 7-9). This relationship becomes linear when ventilation is plotted against arterial oxyhemoglobin saturation, showing that the relationship between . The slope of this relationship is generally referred to as the hypoxic respiratory response. This response is blunted (i.e. slope more shallow) if the level of arterial Pco₂ is held below the resting level (hypocapnic) and augmented (i.e. steeper slope) if the arterial Pco₂ is held above the resting level (hypercapnic). This modulation of the respiratory response provides evidence that both O₂ and CO₂ are detected and impact ventilation.

Central Chemoreceptors

Central chemoreceptors are located throughout the ventral lateral surface of the medulla. Some important locations identified to contain central chemoreceptors include the rostral ventral surface of the medulla in the vicinity of the retrotrapezoid nucleus, the ventral medullary raphé, the rostral aspect of the ventral respiratory group, the nucleus of the solitary tract, and the locus ceruleus. The central chemoreceptors are sensitive to changes in of the interstitial brain fluid that result with changes in arterial Pco₂. The ionic composition of cerebral spinal fluid is closely regulated by the blood-brain barrier. However, changes can occur rapidly in the brain because CO₂ is able to quickly cross the blood brain barrier and quickly reacts with H₂O to form carbonic acid. Carbonic acid then dissociates to form bicarbonate and H⁺ ions thereby decreasing pH. The ventilatory response to hypercapnia is due to stimulation of both peripheral and central chemoreceptors. Generally, the peripheral chemoreceptors contribute the most to the initial response, as they are fast to respond while the central chemoreceptors contribute more to the steady state response.

Metaboreceptors

are located throughout the ventilatory and locomotor muscle vasculatures. Specifically they are found in the muscle interstitium in close proximity to blood vessels. Metaboreceptors provide feedback to the central controllerthrough type IV afferents regarding the metabolic state of the skeletal muscles. The firing rate of type IV afferents increases with increases in the concentration of hydrogen and potassium ions. This information has a stimulating effect on ventilation.

Mechanoreceptors

Mechanoreceptors provide feedback to the central pattern generating neurons regarding the mechanical state of the lung, airways, and locomotor muscles. Feedback is sent to the central control system through type III afferents. In the lung, mechanoreceptors are found in the parenchyma and respond to lung stretch corresponding with increased volume. The firing rate of these afferents increases with increasing lung volume and inhibits ventilation.

Mechanoreceptors are also found in airway skeletal muscle fibres and respond to pressure and airway wall deformation. This information is important for directing activity to pharyngeal and laryngeal musculatures for abducting and stiffening the airway. This is important to protect upper airway patency and prevent airflow limitation.

Efferent Output

Once the central controller has processed sensory information an appropriate response is prepared and sent to the ventilatory muscles. This efferent activity can be described during the three phases of ventilation: Inspiration, post-inspiration, and expiration. Discharge to the diaphragm through the phrenic nerve increases progressively during inspiration. During the post-inspiratory phase, phrenic neural activity dramatically drops and slowly tapers off. Phrenic discharge is silent during expiration. The 10^th and 11^th thoracic spinal motor nerves innervate the internal intercostal muscles. Excitation of the internal intercostals muscles acts to draw the ribs down and together thereby compressing the thoracic cavity. This increases pleural pressure and assists in expiration. During resting ventilation activity of the internal intercostals would be low as expiration is passive. But during exercise the activity of these muscles becomes very important to assist with expiration. The 5^th and 6^th thoracic spinal motor nerves innervate the external intercostal muscles. Excitation of the external intercostal muscles acts to lift and expand the rib cage. This has the effect of decreasing pleural pressure and thereby enhances the pressure gradient for air to enter the lungs.

Exercise Hyperpnea

Now that we have a basic understanding of the control of breathing it is possible to consider how breathing is controlled during exercise. How does the central controller know to increase ventilation during exercise? The increase in breathing with exercise is referred to as exercise hyperpnea because arterial Pco₂ is typically maintained. During strenuous exercise, ventilation may increase out of proportion to carbon dioxide production (V̇CO₂) and arterial PCO₂ decreases below resting levels. This is referred to as exercise hyperventilation.

The increase in ventilation with exercise must meet two specific demands. First, increases in V̇_A must be proportional to the increase in metabolic use of O₂ by the working muscles. Such increase in V̇_A must meet the guidelines set by the alveolar gas equation. Second, the work and metabolic cost of increasing ventilation should be minimal such that O₂ delivery and cardiac output are conserved for the locomotor muscles.

Relationship Between Alveolar Gas and Metabolic Requirements

The increase in ventilation with exercise is related to the increase in metabolic demand. The alveolar gas pressures for O₂ and CO₂ (PAO₂ and PACO₂ respectively) can be related to V̇O₂ and V̇CO₂ by variants of the alveolar gas equation. The relationship between, V̇_A, V̇O₂ and PAco₂ is:

PACO₂  = V̇CO₂ · V̇_A^-1 · K

where PAco₂ is the alveolar partial pressure for carbon dioxide (in mmHg), V̇CO₂ is carbon dioxide production (in ml·min^-1), V̇_A is alveolar ventilation (in L·min^-1) and K is a constant (equal to 0.863).

The relationship between V̇_A, V̇O₂and Pao₂ is:

PAO₂ = PIO₂ – V̇O₂ · V̇_A ^-1 · K

where Pao₂ is the alveolar partial pressure for oxygen (in mmHg), Pio₂ is the inspired partial pressure for oxygen (in mmHg, 150 mmHg at sea level), V̇O₂ is oxygen consumed (in ml·min^-1), V̇_A is alveolar ventilation (in L·min^-1) and K is a constant (equal to 0.863).

Example: An athlete has a resting oxygen consumption of 300 ml·min^-1 and a resting carbon dioxide production of 240 ml·min^-1. At sea level the athlete has normal alveolar gas pressures of 40 mmHg for CO₂ and 100 mmHg for O₂. During exercise, the athlete increases their metabolic rate six times and alveolar gas pressure for oxygen increases to about 110 mmHg. What is the alveolar ventilation at rest and during exercise? What is the Paco₂ during this exercise?

Based on the above data you should be able to determine that the alveolar ventilation at rest is 5 L·min^-1 and during exercise is 39 L·min^-1. If alveolar ventilation during exercise is 39 L·min^-1 and the carbon dioxide production is 1440 ml·min^-1 then the alveolar partial pressure for CO₂ during exercise is 32 mmHg.

The matching of metabolic demand and alveolar ventilation is essential. This is the first line of defense in the oxygen transport system. Alveolar ventilation is capable of increasing rapidly and precisely to meet the body’s oxygen demand. Alternatively, alveolar ventilation must control arterial carbon dioxide within a narrow range so as to maintain arterial blood acid base homeostasis

Exercise Hyperpnea Control Hypotheses

What drives ventilation during exercise? The mechanisms involved in controlling the ventilatory response to dynamic exercise have been studied for over a century and there remains controversy over what causes the onset of increased ventilation and what controls its level afterwards. In this section, three hypotheses will be briefly described and include:

• the central locomotor command hypothesis,
• the CO₂ flow hypothesis
• the locomotor muscle mechanoreceptor/metaboreceptor hypothesis.

It is likely that all three hypotheses are simultaneously involved during exercise. The contribution of each hypothesis to the ventilatory phases of submaximal exercise will also be described.

Central Locomotor Command Hypothesis

Unlike the CO₂ flow and muscle afferents hypotheses, the central command hypothesis is a feed-forward pathway rather than a feed-back pathway. With this hypothesis ventilation is stimulated directly by supramedullary locomotor centre neurons. These neurons are found in regions of the hypothalamus, the diencephalons of the midbrain, and in the premotor cortex. Excitation of exercise and respiratory circuits is parallel and simultaneous and ventilation would therefore increase concurrently with the beginning of locomotion (Eldridge et al. 1985). This hypothesis likely contributes extensively to the phase 1 ventilatory response to exercise.

CO2 Flow Hypothesis

The CO₂ flow hypothesis states that exercise ventilation is influenced by afferents sensing CO₂ flow in the lung or in the right side of the pulmonary circulation. This hypothesis is represented by the equation:

            CO₂Flow = Q̇ · CvCO₂

where Q̇ is pulmonary blood flow in L·min^-1 and CvCO₂ is the CO₂ content of mixed venous blood in mL CO₂ per 100mL of blood. A close relationship exists between increases in alveolar ventilation to CO₂ production with steady-state exercise (Phillipson et al. 1981). Also, for this reason, this hypothesis is thought to contribute the most to the control of ventilation during the third phase of sub maximal exercise. This hypothesis is attractive because typically during exercise there is no change in arterial Pco₂ and increases by only a small amount. Therefore, it is otherwise unlikely that the peripheral chemoreceptors could be involved in exercise ventilation. However, CO₂ flow to the lung is not the sole contributor to exercise ventilation. Contribution from locomotor receptors and central command is also important.

Locomotor Muscle Mechanoreceptor/Metaboreceptor Hypothesis

Feedback from working locomotor muscles is another hypothesis thought to contribute to the control of exercise hyperpnea. With this hypothesis, mechanical stimuli such as stretch, pressure, and tension of skeletal muscle and tendons is sensed by type III nerve afferents and metabolic stimuli such as and bradykinin is sensed by type IV afferents (Kaufman and Forster 2011). This information is sent to the central controller and influences ventilation. Information from type III and IV afferents plays an important role in stimulating the initial phase 1 ventilatory response to exercise and also is involved in the slower increase in ventilation toward steady state or the phase 2 response.

Regulation of Ventilation During High-Intensity Exercise

The regulation of ventilation during high-intensity exercise remains a topic of debate. During submaximal exercise blood is near-normal but with heavier exercise there is significant lactacidosis and increases in other blood substances (e.g., potassium, catecholamines). Exercise-induced changes in these substances within arterial blood are known to excite the carotid chemoreceptors suggesting that they contribute to the hyperpnea of heavy exercise. Indeed many experimental approaches have yielded impressive correlative data linking a given humoral stimuli and exercise ventilation. On the other hand, when the carotid body is removed in experimental animals the ventilator response to exercise remains intact (Pan et al. 1986). The general consensus is that the carotid bodies are not the primary transducer of the hyperventilatory response. Rather, they may serve to ‘fine tune’ the regulation of ventilation during heavy exercise.

Key Points

Our understanding of the mechanisms that control ventilation during exercise remains incomplete. It is difficult, if not impossible, to identify a given mechanism as the ‘primary driver’ of exercise hyperpnea. It is likely that in the intact state (i.e., whole organism) the integrated ventilator response incorporates both feed-forward and feed-back mechanisms and that there is considerable redundancy in control mechanisms.

Pulmonary Gas Exchange

Demands of Exercise

 As mentioned in the introduction to this chapter, exercise places unique demands on the body that must be accommodated by the ventilatory system. During exercise, the metabolic rate can increase 10-20 fold over resting values. As such, both oxygen delivery and carbon dioxide elimination must increase to meet these demands. It is the job of the ventilatory system (in conjunction with the cardiovascular system) to ensure adequate oxygen delivery and removal of waste CO₂ at all intensities of exercise. In the healthy exercising human, even at maximal exercise, CO₂ levels in the blood do not rise and in the majority of people O₂ levels remain constant, demonstrating the effectiveness of the ventilatory system in meeting these demands.

When we talk about the amount of physiological work done by the exercising human we talk about metabolic rate.  Metabolic rate is typically expressed as a measure of oxygen consumption.  Physiologists usually express oxygen consumption in L·min^-1 or mL·kg^-1·min^-1. The former unit is used for absolute oxygen consumption, whereas the latter is used for relative oxygen consumption, taking body mass into account. It is appropriate to use absolute when the energy cost of the exercise is independent of body mass (like swimming or cycling on an ergometer) and relative when the exercise is dependent on body mass (like running and walking). In contrast clinicians use a different unit (called the MET) to measure metabolic rate. One MET approximates resting metabolic rate and is equivalent to 3.5 mL·kg^-1·min^-1. During exercise if an individual is exercising at 10 METs, then their oxygen consumption is equivalent to 10 times their resting metabolic rate. Very fit athletes will be able to perform up to 20 METs of work at maximal exercise (the intensity that elicits maximal oxygen uptake).

To interpret gas exchange during exercise, we not only assess oxygen consumption, (V̇O₂), but also carbon dioxide production (V̇CO₂). The ratio of carbon dioxide production to oxygen consumption depends on the fuels being utilized. Each of the primary fuels for exercise (carbohydrate, protein and fat) produce slightly different amounts of carbon dioxide for a given amount of oxygen consumed. This ratio of carbon dioxide production to oxygen consumption ( V̇CO₂/V̇O₂) is called the respiratory quotient (RQ) when it represents the true metabolic gas exchange. For example in the metabolism of glucose we see the following reaction:

C₆H₁₂O₆ + 6 O₂ 6 CO₂ + 6 H₂O

Six molecules of O₂ are consumed, and 6 molecules of CO₂ are produced, giving a of 6/6 or 1.0. Conversely, when palmitic acid (a fatty acid) is metabolized we get the following equation:

C₁₆H₃₂O₂ + 23 O₂ 16 CO₂ + 16 H₂O

Twenty-three molecules of O₂ are consumed and only 16 molecules of CO₂ are produced, giving us a of 0.7. By comparison, the RQ of protein metabolism is typically in the range of 0.8-0.9. When we calculate the RQ, we are using it to reflect the specific gas exchange that is occurring at the tissue level. In exercising humans, we cannot easily measure these tissue values, so instead we look at the ratio of whole body V̇CO₂ and V̇O₂ measured across the pulmonary system. This whole body ratio is called the respiratory exchange ratio (RER), and represents the ratio of whole body V̇Co₂/V̇o₂. During rest and low and moderate intensity exercise we can use the RER to estimate the relative contributions of and carbohydrate to oxygen consumption. For example, we notice at lower intensities, that individuals typically have values below 0.85, reflecting a relative preference for lipid metabolism. As exercise intensity increases, RER gets closer to 1.0, indicating a transition to carbohydrates as the predominant fuel source.

Oxygen Transport

 Oxygen is relatively insoluble in bodily fluids. For example for a partial pressure of oxygen in the alveolus (Po₂) of 100 mmHg, only 3 mL of oxygen dissolves in the blood for each litre of blood. With this oxygen carrying capacity, the cardiac output would have to be (3.5 ml·min^-1* 60 kg·(3ml·litre^-1) ^-1 =70 litres·min^-1 for a 60 kg person (assuming total extraction). The capacity of dissolved oxygen in fluids is clearly inadequate. Instead, humans use haemoglobin (Hb) to boost the oxygen carrying capacity of the blood. Haemoglobin is an iron-containing metalloprotein pigment in the erythrocytes (red blood cells) that enhances oxygen carrying capacity of the blood by approximately 70-fold. At rest, the 60 kg individual mentioned above would have a cardiac output of about 4 litres·min^-1 with extraction of only 25% of the available O₂. Each haemoglobin molecule can bind up to 4 oxygen molecules and the binding of Hb to O₂ is directly related to PO₂. At a high arterial PO₂ (100 mmHg for example) the saturation of Hb is nearly 100%. As PO₂ drops, then the number of O₂ binding sites that are occupied by O₂ decreases. Typically Hb is 50% saturated with O₂ at a PO₂ of 60 mmHg. When haemoglobin is saturated with oxygen molecules, it is called oxyhaemoglobin, conversely, desaturated Hb is referred to as deoxyhaemoglobin. The binding of oxygen to haemoglobin demonstrates cooperative binding. This means that each oxygen molecule that binds to one of the four sites on the haemoglobin increases the affinity for binding of subsequent oxygen molecules. This behaviour explains the sigmoidal shape of the haemoglobin oxygen dissociation curve (Figure 7-11).

 The affinity of Hb for O₂ also varies based on tissue conditions. Circumstances influence binding of O₂ to Hb; 2,3 diphosphoglycerate (2,3 DPG), CO₂, and temperature affect binding. These circumstances allow a higher Hb-O₂ affinity at the lung where is preferred, and enhanced dissociation at the level of exercising tissue where the O₂ unloading is preferred. The factors that favour enhanced dissociation are all present in exercising muscle. These are a low pH, a high PCO₂, high temperature, and an increase in the concentration of 2,3 DPG. 2,3 DPG is a 3-carbon molecule that is present within the erythrocytes due to glycolysis. It acts by binding to deoxyhaemoglobin and stabilizing it in its deoxygenated state, thus promoting oxygen dissociation. Conversely when the haemoglobin returns to the lung, these conditions are reversed, favouring enhanced binding of O₂ to Hb. This shifting of the Hb-O₂ dissociation curve is termed the Bohr effect (Figure 7-11).

 Within the muscle cells, oxygen transport is facilitated by myoglobin, another iron-containing globular protein, with a similar function to haemoglobin. In contrast, each molecule of myoglobin can only bind one molecule of oxygen instead of four. Since each myoglobin only binds to a single oxygen molecule it does not exhibit cooperative binding, and therefore it has neither a sigmoid dissociation curve like haemoglobin, nor does it exhibit the Bohr effect.

Ventilation-Perfusion

 Gas transport relies on adequate lung ventilation to bring new oxygen to the alveoli and to remove CO₂. Likewise, blood has to be pumped to these same alveoli in order to take up the oxygen and transfer the CO₂ to the alveoli. Matching of these two processes (ventilation and perfusion) is key to effective gas exchange. When ventilation and perfusion are not adequately matched the phenomena of shunt and dead space occur. Shunting refers to blood that travels from the right side of the heart to the left side of the heart without exposure to ventilated alveoli, whereas dead space refers to inspired air that is exhaled without exposure to perfused alveoli. Shunt and dead space will now be described in detail.

Shunt

Shunt can occur within the pulmonary system or the heart. Intracardiac shunting occurs when blood travels directly from the right side of the heart to the left side of the heart through a direct communication such as a patent foramen ovale, or a ventricular septal defect. The foramen ovale is a portal between the right and left atria which is open during embryonic development, but which is meant to close soon after birth. However, in 25% of the population the foramen ovale fails to close completely, allowing some shunting from the right atrium to the left atrium. A ventricular septal defect is a direct communication between the ventricles that remains open due to an abnormality during development. Ventricular septal defects occur much less frequently than patent foramina ovale and cause more substantial shunts.

 Shunt can also occur in the pulmonary circulation. Certain individuals with a condition called hereditary haemorrhagic telangiectasia (also called Osler-Weber-Rendu Syndrome) have direct interfaces between the arterial and venous circulations within the lung. These connections are called arteriovenous malformations. One of the clinical findings in people with pulmonary arteriovenous malformations (AVMs) is that they demonstrate platypnea, which means that when they sit up they become more short of breath. This platypnea occurs because as they sit up, a greater proportion of their cardiac output is shunted through the lower regions of the lung where the AVMs occur, leading to low levels of arterial oxygen (hypoxaemia) and increased levels of arterial carbon dioxide (hypercarbia). The hypoxaemia and the hypercarbia cause the sensation of shortness of breath (dyspnea).

 A potential intrapulmonary shunt has also been demonstrated in athletic individuals without any medical condition. Termed exercise-induced intrapulmonary shunt, researchers have shown that an intrapulmonary shunt seems to occur in the majority of athletic individuals during exercise. Using a technique called contrast echocardiography, researchers inject agitated saline that contains small bubbles (called microbubbles) that are easily visualised with a cardiac ultrasound (echocardiogram). To look for shunt, these microbubbles are injected on the venous side of the vascular system and visualised as they travel through the right side of the heart. If the microbubbles are immediately visible on the left side at the same time or soon after they appear on the right side of the heart, an intracardiac shunt is suspected. If instead, the bubbles appear on the left side after a delay, then it is suggested that the shunting occurred outside the heart but somewhere in the pulmonary vascular system (an intrapulmonary shunt). This intrapulmonary shunt has been shown to be more common during exercise in hypoxic conditions, and seems to be preventable with hyperoxia.

Dead Space

Anatomic dead space has already been discussed previously in the chapter and is different from physiologic dead space. Instead of referring to an anatomic subsection of the lung in which no gas exchange takes place, physiologic dead space is a functional definition. It includes parts of the lung that are not perfused at all, but will also comprise areas that are poorly perfused, providing an assessment of the gas exchange capacity of the lung. In healthy individuals, anatomic and physiologic dead space are very close in value, whereas individuals with lung disease can have a much larger physiologic than dead space.

Physiologic dead space is calculated using Bohr’s method:

V_D · V_T ^-1= (Paco₂ – Peco₂ ) · Paco₂^-1

Where V_D and V_T represent dead space and tidal volume, respectively. PAco₂ and PEco₂ represent alveolar and mixed expired partial pressures of CO₂, respectively. Often arterial Pco₂ is substituted for alveolar Pco₂ in this equation, because they are nearly equivalent in healthy individuals. The partial pressure of end-tidal CO₂ (PETCO₂) can be used as a measure of PAco₂ and eliminate the need for arterial puncture or catheterization.

Distribution of Ventilation

Ventilation is not homogenous across the lung. There are regional differences in ventilation of the lung, mostly due to the effects of gravity. Because of the weight of the lung, the intrapleural pressures are more negative in the upper parts of the lung than in the lower parts of the lung. This difference causes the alveoli in the lower parts of the lung to have a smaller resting volume than the upper parts of the lung. Said differently, this means that the base of the lung is relatively compressed in the resting state but expands more on inspiration than the apex. During inspiration, the lower parts of the lung take up a greater proportion of the inspired air than the upper areas. This relationship varies depending on the degree of lung inflation. In fact, at very low lung volumes, the upper regions of the lung are better ventilated than the lower regions.

 At the end of expiration when the volume in the lung is low, not all of the air is allowed to leave the alveoli. Respiratory bronchioles can close before the alveoli are empty, leading to gas trapping or airway closure. This occurs at only very low lung volumes (not normally found during exercise) in healthy young people. With age, healthy people slowly lose the elastic recoil in their lungs. This loss of elasticity causes intrapleural pressures to be less negative, and lead to airway closure at higher lung volumes. As the loss of elastic recoil becomes more apparent, airway closure can occur above functional residual capacity, leading to impairment in gas exchange.

Distribution of Perfusion

As with ventilation, perfusion is also not uniformly distributed. The pressures exerted on the arterial and venous components of the pulmonary vasculature vary in different regions of the lung. Gravity affects the perfusion pressure of the lung such that perfusion pressures are higher in the dependent (lower) regions of the lung, and lower in the upper regions of the lung. These pressure differentials are affected by posture and body position during exercise. For example, during supine exercise such as recumbent cycling the posterior parts of the lung would be dependent and demonstrate higher perfusion pressures whereas during road cycling (leaning forward) these same areas would show a relative decrease in perfusion pressure. In certain situations there may be a region in the lung where arterial pressure is lower than alveolar pressure. In this situation, the alveolar pressure occludes the pulmonary capillary and there is no perfusion at that alveolus. This particular phenomenon leads to dead space. Figure 7-11 displays the regional differences in lung perfusion.

Ventilation-Perfusion Matching

To strive for optimal gas exchange, the body attempts to match ventilation-perfusion ratio to perfusion. The relationship between ventilation and perfusion on a whole body level is described by the ventilation-perfusion ratio. For example, at rest, average ventilation would be 4.2 L·min^-1, while perfusion (cardiac output from the right ventricle) would be 5 L·min^-1. This situation gives us a ventilation-perfusion ratio of 0.84. This ratio remains essentially unchanged during light exercise, but during heavy exercise, as ventilation increases disproportionately to oxygen consumption, the ventilation-perfusion ratio can increase substantially. It is not uncommon for ventilation during heavy exercise to be in the range of 150 L·min^-1 for a corresponding perfusion of about 30 L·min^-1, giving a ventilation-perfusion ratio of 5.

We have already covered the regional differences in both ventilation-perfusion ratio and perfusion as a result of the effects of gravity and lung mechanics on various areas of the lung. Typically, ventilation increases as you move from the top of the lung to the bottom of the lung. Similarly, perfusion also increases but in a much greater magnitude of change. This situation can lead to significant variation in ventilation-perfusion ratio in different regions of the lung. One strategy used to somewhat mitigate this potential for variation is hypoxic pulmonary vasoconstriction (HPV). The smooth muscle in the walls of the small pulmonary arterioles can constrict in response to hypoxic conditions, increasing pulmonary vascular resistance by up to 300%. Interestingly, this phenomenon occurs primarily in response to alveolar and not arterial hypoxia. Alveolar hypoxia presumably causes vessel wall hypoxia, which is sensed in the vessel smooth muscle wall, causing contraction and vasoconstriction. The effect of this response is to decrease blood flow to poorly ventilated areas of the lung, diverting it to the better-perfused areas. In contrast, at high altitude the entire lung becomes hypoxic, leading to a global hypoxic pulmonary vasoconstriction and resultant rise in pulmonary artery pressure. High altitude pulmonary oedema (HAPE) is a potentially lethal condition that can develop in highly sensitive visitors to high altitude (approximately 2500 meters above sea level or higher). These susceptible individuals develop a form of exaggerated hypoxic pulmonary vasoconstriction, which is presumed to cause leakage of fluid from the pulmonary capillaries into the alveoli. This build-up of fluid in the alveoli leads to impairment in gas exchange, causing significant hypoxaemia, illness, and often death. HAPE is exacerbated by exercise, presumably as it increases cardiac output, and therefore pulmonary artery pressure, which would increase the potential for leakage of fluid into the lung. The ultimate treatment for HAPE is descent back to a lower altitude that has higher partial pressure for O₂, where the condition resolves spontaneously within a couple of days.

Diffusion

 Diffusion of a gas through a tissue is governed by Fick’s law (see below). Diffusion is the process where a substance goes from an area of higher concentration to an area of lower concentration. It is a passive process that that does not require energy. In respiratory physiology, diffusion refers to the movement of gas across the distance and barriers between the alveoli and the blood. The rate of diffusion is proportionate to the area of the membrane, and the difference in partial pressure of the gas across the membrane. Diffusion is inversely proportional to the thickness of the membrane. The area of the blood gas interface in the lung is approximately 70 square metres, and it is as thin as 0.3 m. Solubility of each particular gas is also important. For example CO₂ diffuses about 20 times more rapidly than O₂ across the blood alveolar interface due to its much higher solubility in body fluids.

 The rate of transfer of gas across the barrier between the alveolus and the capillary is not only modulated by the direct tissue barrier. Resistance to diffusion also comes from the path that the gas molecule (such as O₂ or CO₂) takes through the capillary plasma and erythrocyte cytoplasm to ultimately bind with the haemoglobin molecule. Resistance comes from both the distance of diffusion through the blood as well as the rate of reaction between the CO₂ and O₂ molecules with the haemoglobin molecule. Typically the process of diffusion is regarded as a two-component process, with the two components being the membrane component and the blood component. The membrane component comprises the process of diffusion from the alveolus, across the respiratory membrane (including the diffusion through the plasma and the erythrocyte cytoplasm). The blood component comprises the reaction between the gas molecules and the Hb molecule.

The diffusing capacity of the lung is described by the equation:

                                D_L = V̇gas · (P₁-P₂)^-1

Where D_L represents the diffusing capacity of both lungs, V̇_GAS represents the flow of the gas, and P₁-P₂ represents the difference in partial pressure from one side of the tissue to the other (i.e., alveoli-to-blood).

The diffusing capacity can be subdivided into it’s constituent components as:

                               1·DL^-1 = 1 · DM^-1 + 1 · Θ^-1 · V_C

Where D_L represents the diffusing capacity of both lungs, D_M represents the membrane component, and represents the blood component with V_C as the capillary blood flow, and as the rate of reaction of O₂ with Hb. We can therefore see that diffusing capacity can be affected by changes in the membrane or in the blood component. Examples of membrane changes would be pulmonary fibrosis (where scarring increases the resistance to diffusion across the membrane) or pulmonary oedema (where water impairs the transmission by increasing the distance). Examples of blood component changes that affect diffusing capacity would include anaemia. Anaemia is a term describing a number of conditions that cause a decrease in the red cell content of blood. Anaemia is one potential medical cause of poor performance in the athlete, and it is one of the first conditions to be screened for in the athlete presenting to medical care for unexplained poor performance or fatigue. Conversely, some people can develop a rare condition called polycythaemia, which causes an increase in the number of red blood cells, and thus Hb in the pulmonary vasculature, leading to an increase in diffusing capacity. Athletes can also cause spurious polycythaemia by blood doping or taking erythropoietin (EPO). In blood doping, an athlete increases their red cell mass by adding extra blood to their vascular system, either their own blood that has been previously removed and stored, or blood from a compatible donor. Erythropoietin is a hormone that signals the body to make more red blood cells.

 During exercise, pulmonary blood flow increases dramatically, causing diffusing capacity to rise proportionately. Following intense exercise, this elevated diffusing capacity may take some time to return to baseline levels, due to an increase in post-exercise cardiac output.

Cardio-Pulmonary Interactions

The respiratory and cardiovascular systems interact extensively with each other. Not only do they share close quarters within the thoracic cavity, but also, they must work together to support oxygen delivery and carbon dioxide transport. There are two types of interactions that occur between the cardiovascular and respiratory systems. The first is mechanical interactions. Mechanical interactions occur due to the pressure changes that occur within the thoracic cavity due to breathing. Mechanical interactions can affect cardiac preload, afterload, and venous return. The second type of interaction is reflexive in nature and results from an integration of the cardiovascular and ventilatory control systems in the medulla. Such reflexes affect heart rate (ventilatory sinus arrhythmia), muscle sympathetic nerve outflow, and blood flow to the ventilatory muscles and limb muscles (metaboreflex). These mechanical and reflexive interactions will be described in the following section.

Mechanical Interactions between the Cardiovascular and Pulmonary Systems

Inspiration generates substantial negative pressures (with respect to pressure measured outside the body) within the thoracic space. This increases the transmural pressure gradient across the walls of the ventricles, increases cardiac preload, and improves ventricular filling. During inspiration, right atrial pressure is reduced and the pressure gradient for returning venous blood to the heart is increased. With expiration, the opposite effects impede ventricular filling. During expiration the pressures within the thoracic space are increased and the pressure gradient responsible for ventricular filling. is reduced. Similarly, the return of venous blood is reduced because its pressure gradient is also reduced. There is an effect of lung surface pressure upon the heart that can limit the facilitating effects of inspiration on ventricular filling. This occurs during exercise when larger lung volumes result and the cardiac fossa becomes less compliant.

Increases in venous return during inspiration and reductions in intrathoracic pressure can also be countered by an increase in abdominal cavity pressure caused by the descent of the diaphragm. Diaphragm descent can compress the abdominal inferior vena cava and hinder venous return from the lower extremities (Miller et al. 2005a, 2005b).

Although, negative thoracic pressure during inspiration increases venous return to the right heart, it does not necessarily lead to increased stroke volume from the left ventricle. There are two forces opposing left ventricular output during inspiration. The first is a reduction of left ventricular volume due to ventricular interdependence. The increased volume of the right ventricle shifts the interventricular septum and encroaches upon the left ventricle thereby reducing its compliance and its volume. Left heart output is also reduced during inspiration because of an increase in afterload. Afterload is increased because the pressure gradient that the left ventricle must overcome to eject blood is much greater during inspiration.

Reflexive Interactions between the Cardiovascular and Pulmonary Systems

Breathing has significant influences on sympathetic vasoconstrictor outflow. Sympathetic nervous system activity in a resting muscle vascular bed is reduced during the late inspiration and early expiration. It rises and peaks during mid expiration. This reflex is controlled by a neural pathway that senses stretch of the lung parenchyma providing feedback to the nucleus of the solitary tract, where input is integrated by a group of cardiopulmonary interneurons and efferent sympathetic nerves. The lung stretch is sensed by pulmonary stretch receptors found in the lung parenchyma.

Another reflex pathway dependent upon ventilation is the within-breath variation in heart rate. This is commonly referred to as ventilatory-sinus arrhythmia. This pathway is vagally mediated and is dependent upon tidal volume. Pulmonary stretch receptors sense the stretch of the lung and during inspiration as lung stretch increases there is an increase in heart rate. Alternatively, during expiration as lung stretch decreases the heart rate also decreases. Ventilatory sinus arrhythmia may improve ventilation-perfusion matching and/or minimize cardiac work (Ben-Tal et al. 2012). During inspiration when good air is entering the lungs the heart rate increases to increase perfusion of the lung. During expiration there is a lack of useful ventilation, heart rate decreases, and lung perfusion decreases.

The ventilatory muscle metaboreflex is important because it causes blood to preferentially perfuse the ventilatory muscles over exercising muscles as the ventilatory muscles become fatigued (Dempsey et al. 2003). Metaboreceptors within the ventilatory muscles sense the accumulation of metabolic byproducts and this reflexively increases sympathetic nervous system output to muscle vascular beds. The ensuing vasoconstriction diverts blood away from the exercising muscles to the fatiguing ventilatory muscles. In terms of exercise performance this limits the delivery of oxygen to the working peripheral muscles and limits overall performance.

Key Points

During exercise there are important cardiorespiratory interactions whereby the act of breathing can influence venous return, cardiac output and blood flow distribution.

Lessons from Elite Athletes

To this point we have presented the pulmonary system as a complex system but one that is capable of meeting the ‘challenges’ of exercise. The maintenance of homeostasis of oxygen in arterial blood is generally not a problem because of a lung and chest wall that are generally “overbuilt” with respect to maximum metabolic demands for gas transport. On the other hand, evidence is accumulating that the healthy pulmonary system in some humans may not be so “overbuilt” as fitness level increases, because the lung diffusion surface and airways, and perhaps even ventilatory muscles, do not adapt to the “training stimulus” anywhere near to the same extent as do other links in the oxygen transport scheme. The result is that the now relatively “underbuilt” pulmonary system in the fit subject contributes significantly to the limitations of exercise performance for two specific reasons: (i) diaphragm and (ii) exercise-induced arterial hypoxaemia (EIAH).

Diaphragm Fatigue

The human diaphragm is a large dome-shaped muscle that separates the abdominal and thoracic cavities and is the primary muscle driving active inspiration. Other muscles of inspiration include the external intercostals and accessory muscles (i.e., scalenes and sternocleidomastoid), which become recruited to a greater degree as ventilation increases. The diaphragm must sustain extremely high levels of force output and requires a high proportion of cardiac output during intense exercise. Given the significant demand for O₂ and the high work of breathing that occurs during maximal exercise, it seems possible that the diaphragm, like other skeletal muscle, can be susceptible to (Johnson et al. 1993).

Fatigue has been defined as any exercise-induced reduction in the ability to exert muscle force or power, regardless of whether or not the task can be sustained. However, due to the potential clinical significance of ventilatory muscle fatigue, a more appropriate definition is a loss in the capacity for developing force and/or velocity of a muscle, resulting from muscle activity under load and which is reversible by rest. Although the techniques used in the assessment of diaphragm fatigue are indirect, there is sufficient evidence to suggest that the muscles of inspiration (primarily diaphragm) can be fatigued with high levels of ventilatory muscle work. For fatigue to occur, the diaphragm must sustain extremely high levels of force output and during heavy endurance exercise, the magnitude of fatigue and the likelihood of its occurrence increases as the relative intensity exceeds 85% of V̇O₂max. Measurement of diaphragm fatigue is done by stimulating the phrenic nerves via electrical or magnetic stimulation while measuring the pressure difference between gastric and esophageal pressure (i.e., transdiaphragmatic pressure) before and after exercise. Several studies utilizing this technique in healthy individuals have shown that the diaphragm fatigues during heavy endurance-type exercise.

Does diaphragm fatigue influence V̇O₂max and exercise performance? To test this hypothesis, cyclists performed time to exhaustion cycle exercise at 90% of V̇O₂max work of breathing was increased or decreased by ventilatory muscle loading and unloading respectively. The increased work of breathing by ventilatory muscle loading caused a 15% reduction in time to exhaustion performance compared to controls. This detrimental effect on exercise performance was attributed to the associated reduction in leg blood flow, which enhances the onset of leg and also the intensity of leg and ventilatory muscle effort perceptions. When the ventilatory muscles were unloaded, there was a reduction in V̇O₂ a reduced rate of change in dyspneic and limb discomfort sensations, and improvements in time to exhaustion performance by 14%. Exercise-induced diaphragmatic has important relevance to the athlete and causative mechanisms relate to interactions among the ventilatory muscles, the autonomic nervous system and the cardiovascular system.

Exercise-Induced Arterial Hypoxaemia (EIAH)

The level of oxygenation in arterial blood during exercise is defined by measures of PaO₂, SaO₂, and CaO₂. Traditionally, all three measurements were thought to be maintained at all levels of exercise. However, an SaO₂ of 3-15% below resting levels have been observed to occur at or near maximum exercise intensities. EIAH has been reported most frequently in fit young males, as sedentary males do not experience EIAH. It has been estimated that approximately 50% of very fit endurance athletes develop EIAH when exercising at sea level whereas untrained individuals do not. Studies of smaller numbers of fit females claim higher prevalence of EIAH and that it occurs at lower levels of V̇O₂max than in young adult males. In our view, there is insufficient data to know the true prevalence of EIAH and the effects of fitness level or gender. Larger studies with direct blood gas measurements are required. Furthermore, it is not known if the mechanisms mediating EIAH are the same between men and women; nor is it known why some untrained (but healthy) women develop EIAH while their male counterparts do not.

What causes EIAH? Mechanisms to explain EIAH remain controversial.  Pao₂ is reduced below resting levels due to a widened alveolar-arterial O₂ difference (AaDO₂) and/or an insufficient increase in PAO₂. Decreases in SaO₂ are further exaggerated by a rightward shift of the HbO₂ dissociation curve due to metabolic acidosis and increased temperature. An excessively widened AaDO₂ during exercise is the most consistent contributor to EIAH. Hyperventilation in heavy exercise is a major compensatory mechanism—not only to minimize the degree of metabolic acidosis but also to prevent arterial hypoxemia. Thus this compensatory ventilatory response is often insufficient in the face of a widened AaDO₂ and therefore contributes to EIAH. The precise causes of either of these deficiencies are not known but some promising mechanisms are currently under study. For example, exercise-induced ventilation-perfusion (V̇_A/Q̇) inequality most likely contributes to a widened AaDO₂; especially in view of the onset of EIAH during sub maximal exercise in some subjects. At least some of this proposed V̇_A/Q̇ inequality may be due to the release of inflammatory mediators in the lung and their effects on the small airways and/or arterioles in the lung periphery. At maximum exercise, a diffusion limitation and perhaps even “stress-failure” of the alveolar-capillary interface remain plausible, but evidence for their existence is indirect in exercising humans. Recent studies imply that exercise-induced intrapulmonary arteriovenous shunting may play a role in EIAH but this has not yet been directly tested. This could simply be due to the fast transit time of the blood. The time needed for equilibration between alveolar and capillary blood PO₂ is greater than the time that a drop of blood is in the capillary.

Does EIAH affect V̇O₂max and exercise performance? Preventing O₂ desaturation by having athletes breathe a mildly hyperoxic gas (F_IO₂: 26%) shows that there is a 1% drop in V˙ o₂max for every 1% drop in SaO₂ at any SaO₂ beyond 92-93%. Although EIAH affects V̇O₂max, it is important to recognize that an individual’s maximal aerobic capacity is simply one of many factors that influences endurance performance. Recent work in male subjects has shown that peripheral muscle during strenuous exercise is greater when arterial O₂ content is reduced by breathing hypoxic gas versus normoxic and hyperoxic gases, lending support to the idea that gas exchange impairment may adversely influence exercise performance.

Summary

The primary purpose of the pulmonary system is to provide the body with oxygen and dispose of CO₂. The oxygen cascade illustrates the pathway for oxygen delivery to the muscles. Partial pressure of O₂ decreases as you move from ambient air (PO₂=159 mm Hg) to alveolae (PO₂ = 105 mm Hg), to arterial blood (PO₂=98 mmHg to tissue (PO₂ =2-40 mm Hg and venous blood (PO₂=20-40 mmHg. Our ventilation responds during exercise by increasing quickly at the onset of exercise, and levelling off at a rate that is proportional to the exercise demand for O₂. As exercise intensity approaches V̇O₂max, ventilation increases disproportionately. This hyperventilation assists with buffering H⁺ by ridding the body of CO₂. The control of ventilation is complex and includes both feedforward ad feedback mechanisms. Feedforward involves output from the motor cortex directly into the ventilatory control system. Feedback involves central and peripheral chemoreceptors and mechanoreceptors providing input to the ventilatory control system.

For most of us, our lungs are overbuilt for the demand that we can place on them; able to ventilate more than is needed even at maximal oxygen uptake. For highly trained athletes, however, this may not be the case. The inability to fully saturate arterial blood for those with exceptionally high V̇O₂max is an indication that the lungs do not adapt to training.

Assignments

1. Using the terminology from this chapter, describe an example of the process by which the brain receives information from the body, process the information, and initiates changes in breathing. Place your example in the context of a real-world scenario.

2. Consider the idea of physiologic dead space. a) How does it differ from dead space? b) How is it calculated? c) How is physiologic dead space affected in a person with respiratory illness?

3. Using the categories discussed in this chapter, place the following muscles into the correct group of ventilatory muscles. Also, briefly touch on their function.

Nasal dilator muscles

External intercostals

Sternocleidomastoids

The genioglossus

Tensor muscles of the soft palate

Rectus abdominis

Scalenes

Internal and external oblique muscles

The diaphragm

Transversus abdominis

Internal intercostals

Geniohyoid

4. Describe how the ventilatory system meets the demands of rising minute ventilation during a) light, b) moderate, and c) intense exercise.

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About the Authors

Glen E. Foster, School of Health and Exercise Science, The University of British Columbia – Okanagan

Dr. Foster completed his education at the University of British Columbia and University of Calgary. He is currently an Associate Professor in the School of Health and Exercise Sciences at the University of British Columbia’s Okanagan campus. In addition to undergraduate teaching and mentoring graduate students, Dr. Foster serves on the editorial board for several scientific journals in the area of exercise and environmental physiology.

Michael S. Koehle, School of Kinesiology, The University of British Columbia – Vancouver and Division of Sports Medicine, The University of British Columbia – Vancouver

Michael Koehle MD PhD, is the  Director of Sport & Exercise Medicine at the University of British Columbia.  He is a Professor in the both the School of Kinesiology and the Faculty of Medicine at UBC.  His research focusses on the interaction between the human body and its environment, specifically how the body is affected by environmental stresses such as high altitude, heat, and air pollution.  He practices Sport and Exercise Medicine at the UBC Sport & Exercise Medicine Centre and as a Physician for Athletics Canada..  His research program combines exercise and environmental physiology ranging from basic mechanistic research to clinical field studies in remote environments and applied research for high-performance sport.

Anne Lasinsky, School of Kinesiology, The University of British Columbia – Vancouver

Dr. Anne Lasinsky has received degrees from the Universities of Pittsburgh, Connecticut, and Pennsylvania followed by doctoral and postdoctoral training at the University of British Columbia (UBC) in Vancouver. She currently teaches courses and conducts research in the UBC School of Kinesiology.

A. William Sheel, School of Kinesiology, The University of British Columbia – Vancouver

Dr. Sheel (Bill) completed his education at Canadian institutions (University of New Brunswick, University of British Columbia) followed by postdoctoral training at the University of Wisconsin-Madison. He is currently a Professor in the School of Kinesiology and Adjunct Professor in the Faculty of Medicine at UBC. In addition to teaching undergraduate courses and supervising graduate students, he performs several editorial duties for scientific journals and is a Past Chair for the Canadian Society for Exercise Physiology (CSEP).