Chapter 5: Pulmonary Physiology

Overview of the Respiratory System

The primary function of the respiratory (pulmonary) system is to maintain systemic arterial blood gas levels within normal range. To achieve this, the rates of O₂ uptake and CO₂ excretion at the lungs must match the respective rates of O₂ use and CO₂ production by cellular respiration. The main components of the respiratory system are the lungs, the chest wall, and the pulmonary blood vessels. Muscles of the chest wall power the movement of air into the lungs during inspiration. Distribution of the pulmonary blood flow, to match ventilation, ensures the proper gas exchange. The levels of systemic O₂ and CO₂ are monitored by chemoreceptors, allowing the pulmonary system to respond to changes in cellular respiration. Treatment of respiratory disorders requires an understanding of factors that govern ventilation (gas flow), diffusion of gases, and perfusion (blood flow) in the lungs.

Blood-Gas Interface

The lung is specialized for gas diffusion and has an internal surface area of 50–100 m². The large surface area is produced by repeated branching of the airways, which begins at the trachea and terminates in over 300 million closed air sacs called alveoli. Ventilation is the process whereby air enters the lungs and comes into contact with alveoli, which are the sites of gas exchange. Each alveolus is surrounded by a dense network of pulmonary capillaries. The blood gas interface is less than 1-μm thick and consists of the following four elements in series (Figure 5-1):

1. Thin layer of surface liquid.

2. Alveolar lining cells (type 1 pneumocytes), plus associated basement membrane.

3. Thin layer of interstitial fluid.

4. Pulmonary capillary endothelial cells, plus associated basement membrane.

Gas Laws

The volume, pressure, and temperature of gases are all closely related by physical laws (Table 5-1). These laws can be applied to help explain the mechanics of air movement into and out of alveoli as well as the diffusion of gases across the blood-gas interface.

According to Boyle's law, the volume of a gas varies inversely with its pressure at a constant temperature. For example, a gas can be compressed to a smaller volume at higher pressure. Boyle's law explains the mechanism of air flow into the lung on inspiration—lung volume is first increased when contraction of the inspiratory muscles expands the chest, which reduces the alveolar pressure below atmospheric pressure and draws air into the lung.

Dalton's law states that each gas in a mixture of gases exerts a partial pressure that is proportional to its concentration. The sum of partial pressures equals the total pressure (Figure 5-2). Dalton's law is used frequently to estimate alveolar O₂ partial pressure (Po₂) when investigating the basis of low arterial O₂ content. The term “gas tension” is used interchangeably with partial pressure.

Henry's law states that the volume of gas dissolved in a liquid is directly proportional to its partial pressure. In clinical medicine, partial pressures are reported for gases in blood as well as in air. Partial pressure in a liquid refers to gas molecules that are free in solution rather than bound to hemoglobin. At the alveolus, respiratory gases diffuse to equilibrium so that the partial pressures of O₂ (Po₂) and CO₂ (Pco₂) are the same in alveolar air and in end-pulmonary capillary blood plasma.

Units and Terminology Used in Respiratory Physiology

When describing mechanisms of gas exchange in respiratory physiology, gas quantities at various sites (e.g., inspired air, alveolar gas, and arterial blood) are referred to using standard notations (Table 5-2). Gas pressures are traditionally reported based on the height of a column of liquid; for example, mm Hg (also called Torr) or cm H₂O (1 mm Hg = 1.36 cm H₂O). The Pascal is the international unit of pressure: 1 kPa (kilopascal) = 7.5 mm Hg. Barometric pressure (Pb) is the total gas pressure in the atmosphere, and arises because of the weight of the earth's atmosphere. Therefore, Pb = 760 mm Hg at sea level and decreases at higher altitudes and increases at greater depths. Individual gas quantities can be described as fractions; therefore, a gas fraction is partial pressure divided by total pressure. Atmospheric gas is comprised of approximately 21% O₂ and 78% N₂ and very small quantities of other gases. Knowing that the fraction of O₂ in air is 21%, the Po₂ in inspired air at sea level is 21% of 760 mm Hg = 160 mm Hg.

Water Vapor

The composition of air is altered during inspiration because air is humidified in the upper respiratory tract. The water vapor pressure, or partial pressure of water (Ph₂o) in inspired air, is 47 mm Hg at 37°C. The addition of water vapor to inspired air reduces the partial pressure of other gases. For example, at sea level, inspired O₂ (Pio₂) is reduced from 160 mm Hg to 150 mm Hg[0.21 × (760 − 47)]. When gas volume is reported clinically, the standard condition of body temperature and pressure, saturated (BTPS), is used and assumes a body temperature of 37°C (310 K), a barometric pressure of 760 mm Hg, and a water vapor pressure of 47 mm Hg.

Airflow into and out of the lungs requires pressure gradients between the mouth and the alveolus, which are created by mechanical changes in lung volume. Breathing becomes difficult if the lung or the chest wall is stiff (there is low compliance) or if the resistance to gas flow along the airway is high. Resistance is a dynamic property determined during gas flow. Compliance is referred to as an elastic property and is measured without gas flow.

Lung Volumes

A spirometer is an instrument that is used during pulmonary function testing to measure lung volumes and gas flow rates. A patient breathes normally for a given period, and then inspires maximally before forcefully expiring as much air as possible. Figure 5-3 illustrates primary lung volumes and capacities and lists essential terminology necessary for describing and understanding respiratory function.

• Tidal volume (Vt) is the amount breathed in and out during normal breathing.

• Vital capacity (VC) is the maximum possible volume that can be expired following the largest breath inspired.

• Residual volume (RV) is the volume of gas remaining in the lung at the end of forceful expiration and cannot be expelled without collapsing the lung.

• Functional residual capacity (FRC) is the resting lung volume at the end of quiet expiration.

• Normal FRC is approximately 40% of total lung capacity (TLC). Many variables are optimized at normal FRC, including work of breathing, vascular resistance, and ventilation/perfusion (/) matching. Mechanical ventilation of patients is often used to correct an abnormal FRC to help restore normal respiratory function.

Certain pulmonary conditions can be divided into restrictive versus obstructive lung disease. Restrictive lung diseases (e.g., pulmonary fibrosis and acute respiratory distress syndrome) are characterized by reduced lung volumes. In contrast, obstructive lung diseases (e.g., asthma, emphysema, and chronic bronchitis) are characterized by obstruction to airflow.

Muscles of Ventilation

The diaphragm is the most important muscle of inspiration. Its contraction increases the vertical height of the thoracic cavity due to flattening of the domes of the diaphragm. The external intercostal muscles slope downward and forward between the adjacent ribs, which produces a “bucket-handle” movement of the ribs and increases the lateral and anteroposterior diameter of the chest. Expiration is passive during quiet breathing but becomes active during exercise. The most important muscles of expiration are those of the abdominal wall. The internal intercostal muscles are arranged at right angles to the external oblique muscles and assist expiration by pulling the ribs downward and inward.

Neuromuscular diseases such as Guillain-Barré syndrome can affect respiratory function by causing respiratory muscle weakness. If there is severe muscle weakness, patients may require mechanical ventilation.

Airway Anatomy

As air is drawn into the lungs, it is distributed through a highly branched airway. The first 16–17 generations of airway division comprise the conducting zone (i.e., from the trachea through the various bronchi and bronchioles to the terminal bronchioles). Gas exchange occurs in the respiratory zone of the airway and begins distal to the terminal bronchioles (Figure 5-4). A lung acinus is a functional unit formed by the division of a terminal bronchiole into the respiratory bronchioles, the alveolar ducts, and the terminal alveoli. Gas moves by diffusion within lung acini because the cross-sectional area of the respiratory zone is so large that bulk gas flow approaches zero.

When describing certain lung pathologies, it is helpful to visualize the concept of a lung acinus. Alveolar damage in patients with emphysema is either centriacinar (most common) or panacinar. In centriacinar emphysema, the primary site of damage is the respiratory bronchioles, with sparing of the distal alveoli. This type of emphysema is associated with smoking, and most damage is seen in the apical regions of the upper lobes. In panacinar emphysema, the entire acinus is damaged. Panacinar emphysema is associated with α₁-antitrypsin disease. α₁-Antitrypsin is a serum protein produced by the liver and combats damaging protease activity, particularly in the lung. α₁-Antitrypsin disease is a genetic condition in which α₁-antitrypsin accumulates in the liver (resulting in cirrhosis), causing the protein to be systemically unavailable. The panacinar emphysema that develops typically involves the entire lung, with the lung bases being most diseased.

Lung and Chest Wall Recoil

The presence of subatmospheric pressure within the chest accounts for a person's ability to draw air into the airway during inspiration. Subatmospheric pressure in the intrapleural space is created by the opposing recoil of the lungs and chest wall. When all the respiratory muscles are relaxed, the lung is at its resting lung volume (FRC), and there is equilibrium between the recoil of the lung and the chest wall. At this point, the lung tends to collapse and the chest wall tends to expand, with the two being held together by a thin layer of pleural fluid. By acting to pull the lung and chest wall apart, the opposing recoil forces create negative pressure in the intrapleural space. If the chest wall is punctured, air will flow into the pleural space (pneumothorax) until intrapleural pressure (Pip) equals atmospheric pressure; the lung will then collapse and the chest wall will spring outward (Figure 5-5).

Pneumothorax can be spontaneous or traumatic in origin. In either case, the intrapleural air must be evacuated and is usually achieved by connecting a chest tube to suction, which restores negative intrapleural pressures and reexpands the collapsed lung.

The force acting across the wall of the lung to expand it is a transmural pressure called the transpulmonary pressure (Ptp). Ptp is calculated as the difference in pressure between the alveoli (Pa) and the intrapleural space (Pip):

Example

When the respiratory muscles are relaxed, the alveolar pressure is the same as the atmospheric pressure (given a relative value of 0 cm H₂O) and the intrapleural pressure (P_IP) is about −5 cm H₂O:

The force between the lung and the chest wall increases when the inspiratory muscles contract, causing P_IP to become more negative; for example, Pip is −10 cm H_­2O during normal quiet inspiration. The lung expands because Ptp is increased:

It is a general convention in physiology to calculate transmural pressures as the inside pressure minus the outside pressure. In the case of transpulmonary pressure, a positive value indicates a distending force for lung expansion (inspiration). A negative Ptp is a compression force on the airway as would be observed, for example, during forced expiration.

The Ventilation Cycle

Air flows into or out of the lung when there is a difference in pressure along the airway between the mouth and alveoli. Airflow is driven by changes in alveolar pressure, which in turn result from changes in intrapleural pressure. Contraction of the inspiratory muscles reduces Pip and increases Ptp_, providing a force for lung expansion. Increased lung volume decreases alveolar pressure, which drives inspiration. Note in Figure 5-6 that airflow is in phase with alveolar pressure changes. As air flows into the lung to occupy the increased volume, alveolar pressure returns to atmospheric pressure, ending inspiration. Passive recoil of the lung and chest wall during quiet expiration causes the lung volume to decrease. As a result, the alveolar pressure increases and gas flows out of the lung.

Pressure-Volume Relation of the Lung

During the cycle of ventilation, several factors contribute to the work of breathing, including lung and chest wall compliance and resistance to gas flow. Compliance is a pressure volume relation, and is defined as the transpulmonary pressure change that is required to produce a unit change in lung volume. If measurements are recorded at the start and end of a tidal breath when gas flow has stopped, static compliance is determined as:

Patients with pulmonary fibrosis or lung edema have reduced lung compliance and, therefore, have increased the work of breathing, which is sensed as dyspnea or shortness of breath. These patients tend to take small tidal breaths to minimize the change in Ptp needed to inspire. On the other hand, patients with pulmonary emphysema have increased lung compliance. They do not have difficulty breathing in but experience airway obstruction on expiration (see Dynamic Airway Compression).

Figure 5-7 shows a pressure-volume relationship of a healthy person inspiring and expiring from RV to TLC, revealing several important features of lung mechanics:

• Lung compliance is low at both high and low lung volumes.

• At high volume, lung tissue is already stretched and further distension requires more force.

• At low volume, many lung acini are collapsed and more force is needed to initiate inspiration.

• The steepest part of the pressure-volume relation, where compliance is largest, is at the point of FRC. This explains why it is easier for a person to breathe around FRC and uncomfortable to breathe at high or low lung volume.

Surfactants

Figure 5-7 shows that the pressure-volume relation for expiration is positioned to the left of that of inspiration. This phenomenon is called hysteresis and exists because of the action of lung surfactants. Surfactants are phospholipids, mainly dipalmitoyl phosphatidylcholine, secreted by type 2 pneumocytes in the alveolar walls. The surfactant molecules line up on the inner surface of the alveoli. As the lung volume decreases during expiration, adjacent surfactant molecules are forced closer together. Surfactant molecules repel each other and resist the tendency of alveoli to become smaller. The left shift of the pressure-volume relation on expiration, compared to inspiration (hysteresis), is explained by the action of surfactant to maintain alveoli open during expiration. An advantage of this phenomenon is that there is more time for gases to diffuse across the alveolar membranes.

Surface tension acts at the air-liquid interface of alveoli and tends to reduce the area of the alveolus and to generate pressure within it. Surfactants are required to counteract surface tension, which is the main reason that the lung tends to collapse. The presence of the detergent-like surfactant molecules at the air-liquid interface of the alveoli reduces surface tension, thereby maintaining normal lung compliance and preventing alveolar atelectasis (collapse).

Atelectasis is an area of collapsed lung, and is often considered the culprit that causes the mild fever that can occur within the first 24–48 hours after surgery. Atelectasis predisposes the patient to pneumonia, but can be reversed or prevented by having the patient cough or perform breathing exercises.

The law of Laplace (Equation 5-3) predicts another problem caused by surface tension (as well as the collapse of alveoli)—alveoli with small radii (r) will have higher internal pressure (P) for a given surface tension (T) than will larger alveoli. As a consequence, small alveoli will empty into larger alveoli unless lung surfactants maintain a low surface tension.

Respiratory distress syndrome of the newborn (hyaline membrane disease) is caused by a deficiency of surfactant and is associated with prematurity and with infants of diabetic mothers. Without surfactant, the infant's lungs undergo widespread alveolar collapse, producing low lung compliance. A collection of debris consisting of damaged cells, exudative necrosis, and proteins lines the alveoli and is referred to as the hyaline membrane. Treating the mother with corticosteroids 48 hours prior to the delivery of the premature infant has been shown to increase surfactant production and decrease the incidence of respiratory distress syndrome of the newborn.

Elastic Properties of the Lung and Chest Wall

Examination of the pressure-volume relation of the lung shows that compliance is optimal (largest) around FRC. A normal FRC is therefore associated with the smallest work of breathing. FRC is controlled by the relative strength of the lung and the chest wall recoil forces. Normally, there is opposition of the elastic forces of the lung and chest wall, and the lung tends to collapse and the chest wall tends to expand, as illustrated in Figure 5-8. The figure shows relaxation pressures in the airway if a patient is asked to take several breaths of different volume, and after each inspiration to then completely relax the respiratory muscles. When airway pressure is zero and all muscles are relaxed, equilibrium occurs between the lung and chest wall recoil and lung volume is at FRC. If the lung volume is increased or decreased away from this equilibrium position, effort must be applied by the respiratory muscles but the lung will return passively to FRC. In normal, quiet breathing, therefore, inspiration is active and expiration is passive.

Figure 5-8 shows how the individual elastic properties of the lung and chest wall compare to properties of the combined lung and chest wall unit (note: individual lung and chest wall properties cannot be directly measured in a living person). Lungs tend to collapse at all lung volumes from RV to TLC, shown by positive recoil pressures in the airway after the lung is inflated. The tendency of the lung to collapse is due to surface tension and also to the elastic nature of lung tissue. In contrast, the equilibrium position of the chest wall, where recoil pressure is zero, is at approximately 75% of TLC. At all volumes below 75% of TLC, recoil pressures are negative and the chest wall expands passively. At thoracic volumes above 75% of TLC, both the lung and the chest wall passively decrease their volumes. When overall compliance of the lung and chest wall unit is reduced, greater force is needed for inspiration. Low compliance has many causes, some of which are summarized in Table 5-3.

Interstitial lung disease is a general term used for many diseases that involve the lung parenchyma and cause the lung to be stiff and fibrotic with low compliance. Regardless of the cause, patients with interstitial lung disease typically present with similar manifestations of progressive exertional dyspnea, nonproductive cough, fatigue, and weight loss.

Airway Resistance

Mechanical work required for gas flow into and out of the lung requires overcoming airway resistance and the elastic properties of the lung and the chest wall. Airway resistance is referred to as a dynamic property because it is only apparent during gas flow. Airway resistance (R) determines the rate of gas flow () for a given pressure gradient from the alveolus to the mouth (ΔP). According to Ohm's law,

There are three major factors that affect resistance to air flow:

1. Airway radius is the main component of airway resistance. Figure 5-9 illustrates the resistance changes along the airway. The upper airway offers significant fixed resistance, which then declines rapidly from the fifth through the tenth generation of airway division. Because the collective cross-sectional area of lung acini is enormous, the respiratory zone of the lung has very low resistance. Bronchi and bronchioles contain smooth muscle and, therefore, are sites of variable resistance. Parasympathetic nerves release acetylcholine and cause bronchoconstriction. Catecholamines relax bronchial smooth muscle through β₂ receptors. Selective β₂-receptor agonists are used to induce bronchodilation and reduce airway resistance in patients with asthma.

Asthma is a classic, obstructive lung disease whose key differentiating feature demonstrated on spirometry is reversible bronchoconstriction following treatment with a β₂ agonist such as albuterol. Asthma is characterized by inflammatory hyperreactive airways, and triggers can include allergens (most common), infections (often viral), exercise, cold air, and drugs such as aspirin. When attempting to diagnose airway hyperreactivity, methacholine (a parasympathomimetic agent) can be given during pulmonary function testing to provoke bronchospasm.

1. Lung volume is an important determinant of airway resistance because the overall cross-sectional area of airways varies with lung volume, causing global changes in airway radius (Figure 5-10). At low lung volume, the cross-sectional area is reduced and airway resistance increases. For example, patients with pulmonary fibrosis have low lung compliance and low resting lung volume; high airway resistance contributes to their increased work of breathing.

2. Turbulent gas flow increases airway resistance. Turbulent flow occurs in the larger central airways, where flow velocity is high, and at branch points along the conducting airways. Disorganization of the gas stream requires more pressure to drive flow and effectively increases resistance. Bronchoconstriction reduces the airway diameter and increases the velocity of flow. High velocity causes turbulent flow, which generates a wheezing sound (e.g., in asthma). Table 5-4 describes different breath sounds (including wheezing) and the common causes of these sounds.

Idiopathic pulmonary fibrosis is a specific type of interstitial lung disease. It is the most common cause of idiopathic interstitial pneumonia and has a poor prognosis. The histologic hallmark of idiopathic pulmonary fibrosis is alternating areas of a normal lung with areas of inflammation and fibrosis with architectural changes known as honeycombing. These patients have a restrictive pattern of lung disease (see Clinical Spirometry).

Dynamic Airway Compression

Airway resistance increases during forced expiration because intrapleural pressure becomes positive and the airways are compressed. Figure 5-11A shows the normal state at the end of inspiration, in which there is a positive Ptp that tends to maintain airways open. Figure 5-11B shows transmural pressures acting to compress airways during forced expiration. Forceful contraction of the expiratory muscles increases both intrapleural pressure and alveolar pressure to positive values. A positive pressure gradient between the alveolus and the mouth drives the expiratory gas flow. Notice that there is a roughly linear decline in airway pressure from the alveolus to the mouth. Because the same positive intrapleural pressure now surrounds all the airways, the transmural pressure gradient compressing the airways increases with more distance from the alveolus. The largest compression forces are applied to larger airways, which have cartilaginous support to resist collapse. The distal bronchioles do not have cartilaginous support to resist dynamic compression and, therefore, are at risk of collapsing.

The distal lung units normally resist collapse because each unit is connected to several neighboring units; therefore, if one unit collapses, other units are distorted. This mutual support is called radial traction force. Nevertheless, normal airways are compressed in forced expiration and airway resistance rises. Dynamic airway compression is a particular problem in patients with emphysema, where destruction of the lung architecture weakens the radial traction forces. Airway collapse occurs upon forced expiration, dramatically increasing airway resistance and trapping gas in the alveoli.

Air trapping is a chronic problem for patients with emphysema. The effects of air trapping can be detected through observation of the patient's respiratory pattern and by physical examination.

• Observation of the respiratory pattern. Patients with emphysema usually take large, slow tidal breaths starting from a high lung volume. They often expire through pursed lips as well. Each of these behaviors reduces dynamic airway collapse. Slow expiration requires less force so that intrapleural pressure is smaller, reducing the compression force on airways. High resting lung volume has the advantage of increasing airway diameter and reducing airway resistance. Blowing out through pursed lips creates a positive pressure in the mouth, which increases pressure inside the airways. As a result, the transmural pressure that compresses the airways is reduced.

• Clinical examination findings associated with air trapping include:

  • Physical examination. Increased anterior to posterior diameter, known as barrel chest.

  • Percussion. Hyperresonance.

  • Auscultation. Decreased breath sounds.

  • Chest radiography. Large, hyperlucent lung fields, flattened diaphragm, and increased retrosternal airspace.

Expiratory Flow Limitation

Maximal expiratory flow rate is achieved with relatively little expiratory effort due to the existence of dynamic airway compression. Figure 5-12A shows plots of expiratory flow rate as a function of lung volume when a patient uses different degrees of effort to breathe out from TLC to RV. In forced expiration from TLC, there is a rapid initial increase in flow rate to a peak, and then a steady decline in flow rate as RV is approached. The remarkable feature shown in Figure 5-12A is that, regardless of effort, the descending limb of the flow-volume loop follows the same curve.

Figure 5-12B shows that expiratory flow becomes independent of effort (measured as the size of alveolar pressure). At medium to low lung volumes, maximal expiratory flow rate is established with modest effort. Increases in voluntary force do not increase expiratory flow. Although alveolar pressure increases with effort, it cannot drive more gas flow because intrapleural pressure also becomes progressively larger. Thus, the force driving expiratory gas flow (alveolar pressure) and the force compressing the airway (intrapleural pressure) increase in parallel, and the net effect is that there is no change in expiratory flow rate. Patients with emphysema may experience expiratory flow limitation during normal quiet breathing; they attempt to breathe at even higher lung volumes, which usually lead to dyspnea, coughing, and discomfort.

Static and Dynamic Compliance

When patients are mechanically ventilated, positive pressure is used to push gas into the lung. If airway pressure is too high, there is a risk that the lung will rupture. The peak airway pressure reached when a Vt is delivered includes the pressure required to overcome both elastic forces (static compliance) and airway resistance. When static compliance is calculated, using Equation 5-2, pressure measurements are recorded at the beginning and end of inspiration, after gas flow has stopped. If measurements are recorded during gas flow, an additional component of airway pressure is present due to air flowing through a resistance (Equation 5-4). Dynamic compliance includes the pressure component due to airway resistance.

Figure 5-13A shows a protocol to determine if development of high airway pressure in a mechanically ventilated patient is due to low static compliance (e.g., the patient has developed pulmonary edema) or to increased airway resistance (e.g., bronchoconstriction). The respirator applies a positive end-expiratory pressure (PEEP) between breaths to help maintain open airways, which will reduce atelectasis in the mechanically ventilated patient. A known Vt is pushed into the lung and airway pressure is recorded. The highest pressure recorded is called peak inspiratory pressure (PIP) (note: PIP is distinct from intrapleural pressure, which is notated by P_IP). The respirator then pauses for a short period but does not allow expiration. During this pause, airway pressure decreases to a stable plateau pressure (P_PLAT). Pressure decreases because gas flow has stopped and the component of airway pressure caused by gas flow through resistance is no longer present. P_PLAT only reflects the force needed to overcome elastic (static) properties of the lung and chest wall. Static compliance can be calculated as:

Effective dynamic compliance (C_DYN) is then calculated, taking into account all components of airway pressure:

Example 1

 A patient receiving positive pressure mechanical ventilatory support has been stable for 24 hours. The following variables have been set by the ventilator:

• Breathing frequency = 12 breaths/min

• Tidal volume (Vt) = 1000 mL

• End-expiratory pressure (PEEP) = 5 cm H₂O

• Peak inspiratory airway pressure (PIP) = 25 cm H₂O

• End-inspiratory plateau pressure (Pplat) = 20 cm H₂O (determined periodically)

Calculations of static and dynamic compliance are helpful to reveal the cause of high airway pressure in a mechanically ventilated patient. Compliance is inversely proportional to pressure; thus increased airway pressures are associated with reduced compliance.

Example 2

 The patient in Example 1 has abruptly developed an increase in airway pressure due to bronchospasm. The results of his pulmonary function tests are:

• Breathing frequency = 12 breaths/min (set by respirator)

• Tidal volume (V_T) = 1000 mL (set by respirator)

• End-expiratory pressure (PEEP) = 5 cm H₂O (set by respirator)

• Peak inspiratory airway pressure (PIP) = 45 cm H₂O

• End-inspiratory plateau pressure (Pplat) = 20 cm H₂O

  
  

Figures 5-13B and 5-13C compare the two general causes of increased airway pressure in a mechanically ventilated patient. Figure 5-13B is an example of reduced static lung compliance in which both PIP and Pplat are increased (both static and dynamic compliance are reduced). Figure 5-13C is an example of high airway resistance in which PIP increases but P_PLAT does not change (dynamic compliance is reduced but static compliance is unchanged). In Example 2, the patient developed bronchospasms, the pattern shown in Figure 5-13C, and would benefit from treatment with a bronchodilator to reduce peak airway pressure when the respirator delivers a tidal breath.

Clinical Spirometry

Figure 5-14A shows the results of a forced expiration test using a spirometer, in which the patient inspires and expires maximally.

• The volume expired in the first second is called the forced expiratory volume (FEV) in 1 sec (FEV_1.0).

• The total volume expired under maximum effort is the forced vital capacity (FVC).

• FEV_1.0 is normally about 80% of FVC (FEV_1.0:FVC ratio = 0.8). FEV_1.0 represents forced expiration from high lung volume and is effort-dependent.

• Expiratory flow through the middle 50% of the expired breath (FEF_25–75) is also determined. FEF_25–75 is useful in patients who do not use maximal effort, recalling that expiratory flow becomes effort-independent at lower lung volumes (see Figure 5-12).

Two general patterns of disease can be distinguished using spirometry: obstructive and restrictive disease. Obstructive lung diseases (e.g., emphysema, chronic bronchitis, and asthma) are characterized by difficulty in moving gas out of the lung due to high airway resistance (Figure 5-14B). The FEV_1.0 and the FEV_1.0 : FVC ratios are both reduced. In restrictive lung diseases (e.g., pulmonary fibrosis), it is difficult to move gas into the lung due to low lung compliance (Figure 5-14C). Virtually all lung volumes, particularly TLC and FVC, are decreased. Expiration is not impeded because lung recoil forces are increased. The absolute value of FEV_1.0­ is low because inspired volume is initially low, but the FEV_1.0:FVC ratio is either normal or increased.

Figure 5-15 illustrates the appearance of obstructive and restrictive lung disorders using maximal expiratory flow-volume curves. Emphysema is used as an example of an obstructive disease. The flow-volume loop is displaced to the left because weak lung recoil force causes hyperinflation of the lung. Although TLC is larger, peak expiratory flow is small due to dynamic airway collapse. In Figure 5-15, the loop is displaced to the right in restrictive disorders because patients have reduced TLC and RV. Peak expiratory flow is lower than normal because the patient is not able to reach high inspiratory volumes, where flow rate is effort-dependent. The slope of the descending part of the curve may be steeper, reflecting higher lung recoil forces.

Chronic obstructive pulmonary disease (COPD) is a term that applies to patients with either emphysema or chronic bronchitis. Patients with emphysema are known as “pink puffers” because they are able to maintain adequate O₂ saturation by hyperventilating. The classic profile of a “pink puffer” is a thin person sitting in tripod position, breathing with pursed lips. Patients with chronic bronchitis are known as “blue bloaters” because they have a blunted respiratory response to high blood CO₂ (hypercarbia), which produces an inappropriately low respiratory drive that results in hypoxemia and cyanosis. Blue bloaters are typically overweight and have red faces due to polycythemia secondary to chronic hypoxemia. They suffer from cor pulmonale (structural and functional changes in the right ventricle caused by chronic pulmonary hypertension).

Work of Breathing

Work of breathing has two major components: “elastic work” to overcome static compliance, and “resistive work” to overcome airway and tissue resistance. Patients usually adopt a pattern of breathing that minimizes work. In restrictive disease, small tidal breaths are taken more rapidly because a large amount of elastic work is needed to inflate the lungs. Patients with obstructive lung disease often expire slowly, which reduces dynamic airway collapse and resistive work of breathing.

Ventilation can be defined as mechanical events producing gas movement in the lung, which results in CO₂ elimination from the body. During this process, CO₂ diffuses readily from the pulmonary capillaries into the alveoli. CO₂ elimination depends solely on how well the alveoli are ventilated. Alveolar ventilation is reduced by the volume of dead space (wasted) ventilation. The conducting airways contribute fixed “anatomic” dead space. Alveoli that are ventilated but not perfused (“alveolar” dead space) also contribute to total “physiologic dead space. In disease states, this space can be large, resulting in inadequate CO₂ excretion. Hypoventilation is defined as inadequate CO₂ excretion, which results in an increase in arterial Pco₂. Key terminology used in the discussion of ventilation is summarized in Table 5-5.

Pulmonary embolism is a potentially fatal condition that occurs when a thromboembolism lodges in a pulmonary artery, stopping all blood flow distal to the blockage. A pulmonary embolism is a classic example of a large, total (“physiologic”) dead space in which the affected lung segment continues to have alveolar ventilation but lacks blood flow.

The Alveolar Ventilation Equation

The rate of alveolar ventilation is the sole determinant of the rate of CO₂ excretion. Because all CO₂ excretion is derived from alveolar gas, the following relationship can be written as:

The gas fraction is proportional to partial pressure, so Faco₂ can be replaced by Paco₂ multiplied by a constant (k) to produce the alveolar ventilation equation:

The blood entering the left side of the heart has equilibrated with alveolar gas. As a result, Paco₂ can be replaced by Paco₂, as shown in Equation 5-8. In addition, if CO₂ production is understood to be constant, Equation 5-8 reduces to:

This equation demonstrates a fundamentally important concept that arterial Pco₂ varies inversely with alveolar ventilation; for example, if a is doubled, arterial Pco₂ is halved. Arterial Pco₂ is influenced by the balance between CO₂ production and excretion. However, changes in CO₂ production will only change arterial Pco₂ if pulmonary function is impaired and a cannot be adjusted appropriately. For example, patients with acute respiratory depression or those with COPD are at risk of having inadequate alveolar ventilation for the rate of CO₂ production, which results in increased arterial Pco₂.

Ventilation of Dead Space

The alveolar ventilation rate is less than the expired ventilation rate because a proportion of each breath moves to areas of dead space. Expired minute ventilation is the product of tidal volume (Vt) and breathing frequency (f  ):

For each breath, about 150 mL of air remains in the anatomic dead space; there is very little additional alveolar dead space in the lungs of a healthy person. e can be divided into two functional quantities, alveolar ventilation (a) and dead space ventilation (d):

Patients who have a large total physiologic dead space waste an excessive fraction of each tidal breath to regions of the lung that do not exchange gas. There are two possible outcomes: either the patient increasese to restore a, or a is inadequate and arterial Pco₂ increases (hypoventilation). Patients with severe COPD are unable to increase e sufficiently and often have a chronically elevated arterial Pco₂.

Symptoms associated with chronic hypercapnia (elevated arterial Pco₂) differ from those associated with acute hypercapnia. Clinical manifestations of the patient with chronic hypercapnia include sleep disturbance, daytime somnolence, tremor, myoclonic jerks, and asterixis. Conversely, clinical manifestations of acute hypercapnia include anxiety, dyspnea, confusion, psychosis, and coma.

Quantifying Dead Space

Figure 5-16 shows Po₂ and Pco₂ in inspired air, in alveolar gas, and in mixed expired air. The composition of alveolar gas is fairly constant throughout the ventilatory cycle; there is a steady state between CO₂ diffusion from pulmonary capillary blood into the alveoli and from CO₂ removal by alveolar ventilation. On inspiration, the dead space is filled with inspired gas, which contains only a minimal amount of CO₂. However, the highest concentration of CO₂ is in the alveoli. On expiration, alveolar gas mixes with fresh air in the dead space, causing dilution of CO₂. Thus, the Pco₂ in mixed expired gas (Peco₂) is lower than the Pco₂ in alveolar gas (Paco₂). As dead space becomes larger, Peco₂ is reduced. The Bohr equation applies the idea that the difference between alveolar Pco₂ and expired Pco₂ is a function of the dead space volume:

In clinical practice, Paco₂ is estimated as Paco₂ and can be measured from an arterial blood sample. Equation 5-12 now becomes:

Dead space ventilation (d) is the product of expired minute ventilation (e) and the ratio of dead space to tidal volume , and because d subtracted from e equals the alveolar ventilation (a):

Example 1

The following results of pulmonary function testing were obtained in a healthy man:

• Tidal volume (Vt) = 600 mL

• Breathing frequency = 12 breaths/min

• Paco₂ (arterial) = 40 mm Hg

• Peco₂ (expired air) = 30 mm Hg

  

Example 2

The following results of pulmonary function testing were obtained in a patient with severe emphysema who had smoked two packs of cigarettes a day for 30 years:

• Tidal volume (Vt) = 1400 mL

• Breathing frequency = 8 breaths/min

• Paco₂ (arterial) = 60 mm Hg

• Peco₂ (expired air) = 20 mm Hg

  

Despite a large expired minute ventilation rate, the patient has chronic hypercapnia (excess blood CO₂) resulting from the large dead space/tidal volume ratio of 0.67, which causes a low alveolar ventilation rate.

CO₂ Production

Blood-CO₂ concentration is determined by a balance between CO₂ production from cellular metabolism and excretion via the process of alveolar ventilation. Metabolic rate is defined by O₂ consumption, and CO₂ production is related to O₂ consumption by calculating the respiratory quotient using the following equation:

The respiratory quotient is determined by the nutrients that are metabolized; for carbohydrates (RQ = 1.0); for proteins (RQ = 0.8); and for lipids (RQ = 0.7). For example, more O₂ is required to metabolize lipids because fat molecules have less O₂ atoms than do carbohydrates, and more gaseous O₂ is needed to produce CO₂ and H₂O. Under basal conditions, the average respiratory quotient is about 0.8 because more CO₂ is produced than O₂ is consumed. The respiratory quotient may change during trauma or infection, which in turn affects the rate of CO₂ production. For example, in patients with sepsis, the respiratory quotient decreases due to increased fat oxidation.

CO₂ Transport in Blood

Figure 5-17 summarizes the fate of CO₂ produced by metabolism. The figure illustrates how CO₂ diffuses as a dissolved gas along a gradient of partial pressure from cells to interstitium to systemic capillary blood plasma. CO₂ enters the red blood cells and combines with H₂O to produce H₂CO₃ in a reaction catalyzed by carbonic anhydrase. H₂CO₃ then dissociates to produce HCO₃⁻ ions inside red blood cells, which are delivered into plasma via the Cl/HCO₃ exchange (known as the “chloride shift”). The total CO₂ content of arterial blood is about 48 mL of CO₂ per dL of blood. CO₂ is carried in three forms:

1. 90% of CO₂ is carried as HCO₃^– ions in plasma.

2. 5% is carried as dissolved CO₂ molecules. CO₂ is 20 times more soluble than O₂ at body temperature, and about 2.4 mL of CO₂ is dissolved per liter of blood at a normal arterial Pco₂ of 40 mm Hg.

3. 5% of CO₂ is carried as carbamino compounds, which consist of CO₂ bound to plasma proteins or to hemoglobin within red blood cells.

Mixed venous blood contains about 52 mL of CO₂ per dL of blood, or approximately 88% HCO₃⁻, 7% carbamino compounds, and 5% dissolved CO₂. The arterial-to-venous difference in CO₂ content is small compared to that of O₂ (note: this is important for understanding the effects of the / mismatch on arterial blood gases) (see Oxygenation).

CO₂ Content Curve

Figure 5-18 compares the CO₂ and O₂ content (“dissociation”) curves, which describe the total amount of each gas present in blood as a function of its partial pressure. The O₂ content curve (see Oxygenation) plateaus because hemoglobin becomes saturated with O₂. Further increases in arterial Po₂ have little effect on total O₂ content of blood. In contrast, the CO₂ content curve is roughly linear. As a consequence, CO₂ excretion can continue to increase as a function of the alveolar ventilation rate. This explains why a patient with a large area of lung that fails to excrete CO₂ can still have a normal arterial Pco₂. Alveolar ventilation in other areas of the functional lung can increase to excrete more CO₂ and compensate for the dysfunctional areas. The same cannot occur for O₂. If poorly oxygenated blood leaves a region of the lung, other areas cannot take up more O₂ to compensate because blood from these areas is already saturated with O₂.

Pneumonia is an infection of the airspaces and results in pus-filled alveoli, which effectively reduces alveolar ventilation in the affected areas. Other healthy areas of the lung can compensate to eliminate CO₂, but patients can become hypoxemic (low arterial Po₂) and require supplemental O₂.

The Haldane Effect

The Haldane effect refers to changes in the position of the CO₂ content curve that occur with oxygenation of the blood and which affect diffusion gradients for CO₂. The only form of CO₂ that can diffuse from cells to plasma at the tissues and from plasma to alveolar gas at the lung is free CO₂ molecules.

Gases obey Fick's law of diffusion (see Chapter 1). The rate of diffusion is proportional to the surface area and inversely proportional to the thickness of the diffusion barrier, making the lung ideally suited for gas diffusion. The rate of diffusion is proportional to the diffusion constant. CO₂ has a high diffusion constant and diffuses about 20 times more rapidly than O₂. For this reason, CO₂ diffusion is almost never a clinical concern. However, diseases that increase the thickness of the diffusion barrier, such as pulmonary fibrosis or pulmonary edema, can affect O₂ uptake. The diffusion rate is also proportional to the partial pressure gradient. CO₂ excretion at the lung occurs because Pco₂ is higher in mixed venous blood than in alveolar gas. The partial pressure gradient is reversed in the tissues, where CO₂ is generated by cells and diffuses into the systemic capillary blood.

The Haldane effect describes variations in plasma Pco₂ with oxygenation, which promote CO₂ diffusion at both the lung and tissues. The basis of the Haldane effect is redistribution of CO₂ between carbamino hemoglobin and dissolved CO₂. In the pulmonary capillaries, O₂ binding to hemoglobin liberates free CO₂ from carbamino hemoglobin. As a result, the pulmonary capillary partial pressure of CO₂ (Pcco₂) increases (shown by a right shift in the CO₂ dissociation curve), resulting in more CO₂ excretion (Figure 5-19). The reverse process occurs at the tissues—O₂ unloading from hemoglobin allows more carbamino hemoglobin to form. This decreases the plasma Pco₂ in the systemic capillaries and increases the partial pressure gradient for CO₂ diffusion from tissues into blood.

Regional Differences in Ventilation

As a result of gravity, ventilation is higher at the base of the lung than at the apex in a person who is standing (Figure 5-20). The weight of the lung compresses alveoli at the base of the lung. When the lung is at FRC, alveoli at the base of the lung have optimal compliance and are more easily ventilated, whereas alveoli at the apex have a high resting volume and are more difficult to ventilate due to lower compliance. In addition, basal alveoli have a larger range of volume through which they can expand during inspiration. It is important to consider the effects of gravity on the distribution of ventilation and perfusion when considering / matching (see Oxygenation).

The pulmonary circulation receives the entire cardiac output from the right ventricle. Deoxygenated blood flows through a network of vessels, which branch in concert with the airways. Alveoli are enveloped by interconnecting pulmonary capillaries. Blood flows in “sheets” around the alveoli rather than through discrete capillaries, thereby maximizing gas exchange. Oxygenated blood is returned to the left atrium via the pulmonary venous system.

Pulmonary Blood Pressure

Mean pulmonary artery pressure is only about 10 mm Hg, and systolic and diastolic pressures are about 25 mm Hg and 8 mm Hg, respectively. Outlet pressure from the pulmonary circulation into the left atrium is about 5 mm Hg. Therefore, the driving pressure for blood flow through the pulmonary circulation is only about 10% to that of the systemic circulation. The lower blood pressure in the pulmonary circulation is reflected in the thin walls of the right ventricle and pulmonary arteries. A lower pressure blood circulation has the advantage of reducing workload on the right ventricle and also reduces the risk of excessive interstitial fluid formation, which would interfere with O₂ diffusion.

Cor pulmonale is right ventricular failure due to excessively high pulmonary artery pressures that can arise from pulmonary emboli (either massive or multiple emboli), pulmonary vascular disease (e.g., collagen vascular disease such as scleroderma), or parenchymal disease (e.g., COPD; pulmonary fibrosis).

Pulmonary Vascular Resistance

Low perfusion pressure is able to drive the entire cardiac output through the pulmonary circulation because pulmonary vascular resistance is very low. In the systemic circulation, arterioles offer most vascular resistance. In the pulmonary circulation, resistance is shared between arterioles, capillaries, and venules. The behavior of capillaries and larger vessels is very different, giving rise to the concept of alveolar and extraalveolar vessels. Alveolar vessels are influenced by alveolar pressure and are compressed if the alveolar pressure increases above the vascular pressure. Extraalveolar vessels are affected most by lung volume. As the lungs expand, radial forces increase. The increased radial traction causes the extraalveolar vessels to open, which reduces their resistance. When lung volume decreases, extraalveolar vessels are compressed.

The pulmonary circulation is forced to accommodate large increases in blood flow whenever cardiac output increases (e.g., exercise). Increased cardiac output through the pulmonary circulation can be accommodated because pulmonary vascular resistance decreases as cardiac output increases (Figure 5-21A). The decrease in pulmonary vascular resistance that is observed when cardiac output increases occurs because of the distention of the pulmonary capillaries and by recruitment of capillaries that were not perfused at rest. In contrast, most systemic vascular beds actively autoregulate blood flow in response to increased blood pressure.

Lung volume is an important passive determinant of pulmonary vascular resistance. Figure 5-21B shows that pulmonary vascular resistance is optimal around FRC. Vascular resistance increases at either high or low lung volume. At low lung volumes (patients with restrictive lung disease), compression of the extraalveolar vessels predominates to increase resistance. At high lung volumes (e.g., patients with emphysema), the pulmonary capillaries are stretched, resulting in reduced capillary diameter and increased pulmonary vascular resistance.

Smoking destroys the alveolar membranes and their corresponding pulmonary capillaries, significantly decreasing the pulmonary capillary cross-sectional area and therefore contributing to increased pulmonary artery pressure.

Hypoxic Pulmonary Vasoconstriction

Active control of pulmonary vascular resistance occurs in response to alveolar hypoxia (low Po₂). Figure 5-22 shows decreased pulmonary blood flow when the alveolar Po₂ decreases below 60 mm Hg. A rapid ascent to a high altitude, where atmospheric Po₂ is low, causes pulmonary vasoconstriction and may cause pulmonary hypertension. This mechanism is the opposite response to most systemic vascular beds, which vasodilate in response to hypoxia. Hypoxic pulmonary vasoconstriction has two important physiologic roles:

1. In fetal life, the lungs are not necessary for gas exchange. Before a breath is taken, hypoxic pulmonary vasoconstriction shunts blood away from the lungs. Immediately after birth, when the first inspiration occurs, the pulmonary arterioles dilate, pulmonary vascular resistance decreases, and normal lung perfusion is established.

2. After birth, hypoxic pulmonary vasoconstriction shunts blood away from poorly ventilated regions of the lung, thereby improving ventilation-to-perfusion matching.

Nitric oxide and the drug sildenafil (Viagra) are both substances that cause vasodilation in the lung and can be used to relieve pulmonary hypertension. Nitric oxide results in vasodilation by directly activating a soluble guanylate cyclase, thereby increasing cyclic guanosine monophosphate (cGMP) levels. Sildenafil inhibits the breakdown of cGMP by blocking phosphodiesterase type-5 and allowing cGMP to activate protein kinase G, which results in vasodilation.

Regional Differences in Perfusion

The distribution of pulmonary blood flow within the lungs is significantly affected by gravity, which has a more marked effect on regional perfusion than on ventilation. Blood flow is significantly greater at the base of the lung than at the apex. Within this gradient of perfusion, there are three lung zones based on interaction between alveolar and vascular pressure (Figure 5-23):

• Zone 1. Arterial and venous pressures are both less than alveolar pressure, resulting in compression of the pulmonary capillaries and no perfusion. Pressure developed by the right ventricle is normally just large enough to prevent zone 1 from occurring at the apex of the lung. Zone 1 is alveolar dead space, which is ventilated but not perfused. If blood pressure decreases (e.g., hemorrhage) or if alveolar pressure increases (e.g., mechanical ventilation), zone 1 may become a significant fraction of total perfusion.

• Zone 2. Alveolar pressure is between arterial and venous pressure. The perfusion pressure in zone 2 is the difference between arterial and alveolar pressure. Vessels are partially constricted, and blood flow is more limited.

• Zone 3. Arterial and venous pressures both exceed alveolar pressure. Perfusion pressure is the arterial-to-venous pressure difference. Zone 3 represents the areas of the lung with the largest rate of blood flow (i.e., the base of the upright lung).

A Swan-Ganz catheter is used to obtain pulmonary capillary wedge pressure, an estimate of left atrial pressure and left ventricular end-diastolic pressure. The balloon-tipped catheter is inserted into a central vein and allowed to float along the path through the right atrium, the right ventricle, the pulmonary artery, and down to a pulmonary capillary. The inflated balloon will “wedge” into place, occluding the small pulmonary vessel. To estimate the left atrial and left ventricular pressures, the sensor on the tip of the catheter must have a continuous column of blood from the pulmonary capillary to the left atrium and ventricle. To achieve this, the catheter must be placed in lung zone 3 because capillary collapse is present in zones 1 and 2, which prevents direct connection with the left atrium.

Delivery of O₂ from the atmosphere to cells involves several steps. Successful oxygenation requires:

• Ventilation of perfused alveoli with atmospheric O₂.

• Diffusion of O₂ across the blood-gas barrier and binding of O₂ to hemoglobin in the erythrocytes.

• A balance between ventilation and perfusion to prevent desaturated venous blood from entering the systemic arterial circulation (i.e., venous admixture).

• Adequate blood flow to the tissues in relation to metabolic demand.

• Unloading of O₂ from hemoglobin at the tissues.

O₂ diffuses down a cascade of partial pressure from atmospheric gas (which has a Po₂ of about 150 mm Hg at sea level) to mitochondria (which can have a Po₂ of less than 5 mm Hg) (Figure 5-24). The gradient for O₂ diffusion along this cascade can be varied by the external conditions applied. For example, the Po₂ of inspired air for a patient at sea level on 100% O₂, via non-rebreather face mask, is approximately 700 mm Hg, whereas the inspired Po₂ at the top of Mt. Everest is about 40 mm Hg!

Tissue O₂ Delivery and Consumption

The body has very limited stores of O₂; therefore interruptions to cardiac output or pulmonary oxygenation are fatal within a few minutes. To avoid cellular hypoxia, matching between tissue O₂ consumption and O₂ delivery in arterial blood must be continuous. The rate of O₂ delivery is the product of cardiac output and arterial O₂ content:

The rate of O₂ consumption is the product of cardiac output and the arteriovenous difference in O₂ content:

Typical values for a resting adult are t = 5 L/min, Cao₂ = 20 mL/dL, and Cvo₂ = 15 mL/dL. From Equation 5-16B, basal o₂ = 250 mL/min.

Vo_2 max is a measure of peak O₂ consumption at maximal aerobic exercise and is used as a measure of aerobic fitness. As such, it can vary from 20 mL/kg/min for a sedentary person, to 40 mL/kg/min for the average untrained person, to 85 mL/kg/min for an elite trained athlete.

O₂ Transport in Blood

Despite the relatively low solubility of O₂ in plasma, the volume of gaseous O₂ per liter of blood remarkably is almost the same as that in air. This is possible because red blood cells contain a large quantity of the O₂-binding protein hemoglobin. Only 2% of O₂ in arterial blood is present as dissolved O₂. At an arterial Po₂ of 100 mm Hg, only 0.3 mL of O₂ is dissolved in every 100 mL of blood. Ninety-eight percent of O₂ in blood is carried bound to hemoglobin within red blood cells. One gram of hemoglobin carries approximately 1.35 mL of O₂ when 100% saturated.

The total O₂ content of arterial blood is calculated as:

The function of the pulmonary system is to provide an adequate arterial Po₂. This pressure is crucial because hemoglobin saturation depends on adequate arterial Po₂, and oxyhemoglobin is the primary O₂ carrier in blood. As illustrated by Equation 5-17, O₂ content will be inadequate if hemoglobin concentration is low (anemia) or if Sao₂ is low. Low Sao₂ results from hypoxemia (low arterial Po₂). Potential causes of hypoxemia include inadequate ventilation, diffusion, and / mismatch.

When caring for a critically ill patient (e.g., shock from significant trauma), it is imperative to maximize O₂ content. This can be accomplished by careful assessment and correction of the hemoglobin concentration, the arterial Po₂, and the Sao₂.

The Oxyhemoglobin Dissociation Curve

Figure 5-25 shows the normal relationship between percent hemoglobin saturation and Po₂. Each hemoglobin molecule can bind four O₂ molecules. There is cooperative binding of O₂ so that each additional O₂ binds more easily, producing the sigmoidal shape of the O₂ dissociation curve. In healthy lungs with an alveolar partial pressure of O₂ of 100 mm Hg, pulmonary capillary blood is 100% saturated with O₂. When Po₂ decreases below 60 mm Hg, there is a rapid decline in hemoglobin saturation. Mechanisms that control breathing strongly increase ventilation if arterial Po₂ decreases below 60 mm Hg.

A general rule of thumb concerning oxygenation is the “4-5-6:7-8-9” rule. An arterial Po₂ of 40 mm Hg, 50 mm Hg, or 60 mm Hg roughly corresponds to Sao₂ of 70%, 80%, or 90%, respectively. Due to the rapid decline in hemoglobin saturation at an arterial Po₂ <60 mm Hg (or Sao₂ <90%), the therapeutic goals for oxygenation (with a few exceptions) are typically arterial Po₂ > 60 mm Hg (or Sao₂ > 90%), which corresponds with the flat portion of the O₂ dissociation curve.

Figure 5-26 shows that the position of the O₂ dissociation curve can shift, affecting the ability to take up O₂ at the lung and alter the amount of O₂ unloaded from hemoglobin at the tissues. The O₂ affinity of hemoglobin is described using a P₅₀ value, which is the Po₂ resulting in 50% saturation. A normal P₅₀ is about 27 mm Hg; lower P₅₀ indicates an increase in O₂ affinity and a left shift in the dissociation curve, whereas a higher P₅₀ indicates a decrease in O₂ affinity and a right shift in the dissociation curve.

A left shift in the oxyhemoglobin dissociation curve causes hemoglobin to become saturated at lower Po₂. Therefore, loading O₂ into blood at the lung is easier, but it is more difficult to unload O₂ at the tissues. The O₂ dissociation curve for fetal hemoglobin lies to the left of the curve for adult (maternal) hemoglobin; higher O₂ affinity of fetal hemoglobin aids in O₂ transfer across the placenta. If the curve shifts right, O₂ loading at the lungs is reduced and the proportion of hemoglobin saturated with O₂ (Sao₂) may be reduced, but O₂ is unloaded more readily at the tissues.

In clinical management of acutely ill patients, it is preferable to retain some right shift in the curve to increase O₂ availability at the tissues. This can be achieved by accepting a slightly lower blood pH because an acidic environment will cause a right shift, enhancing O₂ delivery to the tissues.

Several factors cause a right shift in the O₂ dissociation curve, including:

• Increased temperature (e.g., exercise). Higher temperature increases O₂ unloading in working muscle.

• Increased CO₂. High levels of CO₂ in metabolically active tissues indicate high O₂ demand, and more O₂ unloading is desirable.

• Increased [H⁺]. Buffering of H⁺ by hemoglobin reduces its O₂ affinity (known as the Bohr effect). For example, anaerobic metabolism produces lactic acid, indicating that more O₂ delivery to the tissue is needed.

• Increased concentration of 2,3-bisphosphoglycerate (BPG) in erythrocytes. BPG is an end product of metabolism in erythrocytes. Hypoxemia increases BPG formation, causing more unloading of O₂ from hemoglobin. If blood is stored in blood banks for a long period, BPG levels are reduced. A transfusion with blood that has been stored for a long period causes an unwanted left shift in the O₂ dissociation curve.

Carbon monoxide (CO) is a product of incomplete combustion and is a colorless, odorless, tasteless, nonirritating gas. CO is a poisonous gas because it binds irreversibly to hemoglobin and prevents O₂ binding. It binds to hemoglobin with very high affinity to produce carboxyhemoglobin. Figure 5-27 shows the effect of CO poisoning on the O₂ dissociation curve. In the example shown, the amount of hemoglobin available to bind O₂ is reduced by 50%. CO also causes a decrease in P₅₀, which reduces O₂ unloading at the tissues.

A pulse oximeter is used in many clinical situations to measure the ratio of deoxyhemoglobin to oxyhemoglobin (functional saturation). A pulse oximeter is unable to detect carboxyhemoglobin and, as a result, it does not detect the decrease in true O₂ saturation caused by CO poisoning. It is a common misconception that arterial Po₂ is reduced in CO poisoning. The arterial Po₂ is normal in CO poisoning unless there is another pulmonary abnormality present.

CO poisoning occurs when a person inspires toxic levels of CO, which can result in brain damage or even death. Symptoms are very nonspecific and often mimic viral illness, with headache, malaise, nausea, vomiting, and drowsiness. Classic findings associated with CO poisoning are cherry-red skin and bilateral necrosis of the basal ganglia, particularly the globus pallidus.

Alveolar O₂ Transfer

Before O₂ can bind to hemoglobin, it must first diffuse across the blood-gas barrier. A red blood cell is in transit only 0.75 seconds through a pulmonary capillary at rest. In extreme exercise, when cardiac output is increased, the transit time may be less than 0.25 seconds. In healthy persons, the equilibration of the partial pressure of O₂ occurs between alveolar gas and pulmonary capillary blood in this brief amount of time (Figure 5-28A). Patients with lung disease (e.g., pulmonary fibrosis) may have reduced diffusion capacity, and equilibration of O₂ across the alveolus may be incomplete. Diffusion defects are unmasked when the blood transit time is low (e.g., exercise) or if the driving force for O₂ diffusion is reduced (e.g., low inspired O₂ partial pressure at high altitude).

Diffusion and Perfusion Limited Gas Transfer

Uptake of gas from the alveolus can be described as “diffusion limited” or “perfusion limited.” Extreme examples of these concepts are shown in Figure 5-28B. Nitrous oxide (N₂O) is a poorly soluble gas that does not bind to anything in blood. N₂O is perfusion limited because Pn₂o arrives at equilibrium very rapidly across the alveolus; N₂O uptake is only limited by the rate that blood arrives in pulmonary capillaries. In contrast, CO uptake is diffusion limited. Pco does not equilibrate across the alveolus because almost all CO that diffuses into the pulmonary capillaries binds to hemoglobin. As a result, the partial pressure of CO in the pulmonary capillaries remains at approximately zero.

O₂ uptake is normally perfusion limited because blood equilibrates fully with alveolar Po₂ in transit through pulmonary capillaries. There is a reserve for more O₂ uptake, demonstrated during exercise when perfusion increases and equilibration across the alveolus still occurs. O₂ uptake can become diffusion limited in lung disease (e.g., pulmonary fibrosis) when the partial pressure of O₂ is unable to equilibrate between the alveoli and the pulmonary capillary blood. In healthy individuals, this is also possible under extreme conditions such as heavy exercise at a high altitude.

Lung Diffusion Capacity

Small nontoxic doses of CO can be administered to measure lung diffusion capacity. Even at low blood flow rates, the capacity for CO binding is so large that its uptake is only limited by the rate of diffusion:

Diffusion capacity can be measured to assess for diseases that impair the alveolar-capillary membrane. Decreased diffusion capacity can be seen in interstitial lung disease, emphysema, and pulmonary vascular disease. (Note: diffusion capacity is normal in patients with asthma.)

/ Matching

The most common cause of hypoxemia (low arterial O₂ partial pressure) is mismatch between the distribution of ventilation and pulmonary blood flow. Expired minute ventilation and cardiac output are both about 5–6 L/min at rest, yielding an overall / ratio of about 1. Even when overall / = 1, abnormalities in gas exchange result if there are regional differences in the distribution of ventilation and perfusion. The two most extreme situations are intrapulmonary shunt (/ = 0), where lung units are perfused with blood but receive no ventilation (e.g., complete airway obstruction), and dead space (/ = ∞), where lung units are ventilated but not perfused (e.g., pulmonary embolism). Figure 5-29 shows the spectrum of alveolar Po₂ and Pco₂ as / deviates from normal toward these extreme positions. Perfusion without ventilation results in an alveolar gas composition in equilibrium with mixed venous blood. Ventilation without perfusion results in alveoli containing inspired air.

A / scan is a nuclear medicine study that can be used in the diagnosis of pulmonary emboli and illustrates the concept of matching ventilation to perfusion. Pulmonary emboli will show a reduced blood flow in an area of normal ventilation. In cases of multiple pulmonary emboli, the perfusion scan can show a “moth-eaten” appearance in areas of normal ventilation.

Characteristics of High /

Regions of the lung that are ventilated but not perfused contribute to physiologic dead space. A patient with areas of high / will experience a decrease in useful alveolar ventilation unless total ventilation can be adequately increased. This decrease results in less CO₂ excretion and a buildup of the arterial partial pressure of CO₂, a common finding in patients with COPD. In acute situations when hypoxemia occurs, the arterial Pco₂ is often normal or may even be reduced. This occurs because lung units that are well perfused can increase CO₂ excretion if ventilation is increased. Similarly, loss of CO₂ excretion in a region of high / can be compensated by increasing ventilation of well-perfused lung units. Oxygenation is not directly affected by high /.

Intrapulmonary Shunt

Intrapulmonary (right-to-left) shunt mixes deoxygenated blood directly into arterial blood and, as a result, the arterial Po₂ may be dramatically reduced. Figure 5-30 shows an example where 50% of blood delivered to the left atrium is from a normal lung and 50% is shunted blood flow (/ = 0). Pulmonary capillary blood from the normal lung has a partial pressure of O₂ (Pco₂) = 100 mm Hg, yielding a hemoglobin saturation of 100%. Shunted blood is the same composition as venous blood, in which the partial pressure of O₂ is about 40 mm Hg and hemoglobin saturation is about 75%. When equal volumes of oxygenated and deoxygenated blood are mixed, the resulting Po₂ is less than the average of the individual Po₂ values. Nonlinearity of the O₂ dissociation curve accounts for the low arterial O₂ partial pressure produced by shunt. The law of mass conservation allows the total O₂ content of two samples to be averaged; therefore hemoglobin saturation can be averaged because the O₂ content is 98% oxyhemoglobin. Po₂ must then be read from the O₂ dissociation curve.

In contrast to the effect of shunt to produce hypoxemia, there is little direct change in the arterial partial pressure of CO₂ because the venous CO₂ content is not much larger than the arterial CO₂ content. When mixed venous blood is combined with oxygenated blood, the resulting arterial Pco₂ is only slightly increased (Figure 5-30). In contrast to O₂, partial pressures of CO₂ can be averaged because the CO₂ dissociation curve is linear and differences in Pco₂ reflect differences in total CO₂ content. The physiologic response to the hypoxemia caused by intrapulmonary shunt is to increase ventilation. Increased ventilation would increase CO₂ excretion, but would not add more O₂ because pulmonary capillary blood leaving ventilated lung units is already saturated with O₂.

Treatment of hypoxemia caused by an intrapulmonary shunt is difficult because the hypoxemia is refractory to supplemental O₂. Figure 5-31 shows the effect of breathing 100% O₂ using an example of 50% shunt. Because nonventilated areas cannot receive supplemental O₂, they continue to deliver deoxygenated blood to the arterial circulation. There is a large increase in the alveolar and pulmonary capillary Po₂ in well-ventilated alveoli. However, the O₂ content of blood from these lung units increases only minimally because hemoglobin is already saturated with O₂. Note that the amount of extra dissolved O₂ in pulmonary capillary blood is small, even at very high partial pressure of O_2.

Quantifying Right-to-Left Shunt

The amount of right-to-left shunt, as a fraction of cardiac output, can be calculated using the principle of mass conservation. This calculation can be used clinically to determine the extent of right-to-left shunt in patients with arterial hypoxemia. The total amount of O₂ delivered to the systemic circulation is the product of cardiac output and arterial O₂ content (  t × Cao₂). This amount must equal the sum of O₂ from shunted blood (   s × Cvo₂) and pulmonary capillary blood (t s) × Cco₂. Rearranging for the shunt fraction s/t:

Example

A 36-year-old man has severe viral pneumonia and is admitted to the hospital. The results of his arterial blood gas analysis show hypoxemia with an arterial Po₂ of 58 mm Hg and hemoglobin saturation (Sao₂) of 88%:

• Cco₂ = 19.2 mL O₂/dL of blood

• Cao₂ = 16.8 mL O₂/dL of blood

• Cvo₂ = 15.0 mL O₂/dL of blood

Shunt fraction s/t  = (19.2−16.8)/(19.2−15.0)

= 0.57 = 57% (normal 2−5%)

A high shunt ratio (s/t) can result from either intracardiac or intrapulmonary shunting. Intracardiac shunting is an example of a cyanotic congenital heart disease caused by a ventriculoseptal defect, with pulmonary hypertension causing a right to left shunt (Eisenmenger syndrome). Intrapulmonary shunting can occur as a result of atelectasis, pulmonary edema, or pneumonia.

Alveolar-Arterial Po₂ Gradient

Despite equilibration between alveolar gas and pulmonary capillary blood (alveolar Po₂ = pulmonary capillary Po₂), arterial Po₂ is always less than alveolar Po₂. This P(a-a)o₂ gradient is calculated clinically to identify the cause of hypoxemia (Figure 5-32). Diffusion abnormality and intrapulmonary shunt are examples where the P(a-a)o₂ gradient is increased. To calculate a P(a-a)o₂ gradient, the alveolar Po₂ must first be calculated, using the alveolar gas equation:

Another form of the alveolar gas equation that is used clinically:

After alveolar Po₂ is calculated using Equation 5-21, and arterial Po₂ is measured in an arterial blood sample, the P(a-a)o₂

gradient can then be calculated:

A person breathing atmospheric air at sea level has a normal P(a-a)o₂ gradient of about 5–10 mm Hg. A small P(a-a)o₂ gradient is normally present for two reasons:

1. Anatomic right-to-left shunting of blood. Bronchial blood vessels from the systemic circulation deliver O₂ and nutrients to lung tissue. Some of the bronchial venous blood drains directly into the pulmonary vein. A small amount of coronary venous blood also drains directly into the left ventricle via the thebesian veins.

2. / mismatch. / inequalities exist in the lung of a person standing due to the effects of gravity. Figure 5-33 shows that there is both higher ventilation and perfusion at the base of the lung than at the apex; however, the gradient for perfusion is steeper than the gradient for ventilation. As a result, the / ratio is high at the apex of the lung and slightly low at the base of the lung. Areas with low / at the base of the lung deliver blood that is not perfectly oxygenated.

When breathing 100% O₂, a healthy person has an alveolar-arterial O₂ tension gradient of up to 100 mm Hg. A larger P(a-a)o₂ gradient indicates oxygenation problems.

Example

A patient with pneumonia was breathing 100% O₂ at sea level via a non-rebreather oxygen mask. This information, together with the results of an arterial blood gas analysis, provided the following data to calculate alveolar Po₂:

• Fio₂ = 100% (1.0)

• Pb = 760 mm Hg

• Ph₂o = 47 mm Hg

• Paco₂ = 36 mm Hg (measured from an arterial blood gas sample)

• RQ = 0.8 (standard respiratory quotient used clinically)

• Pao₂ = 168 mm Hg (measured from an arterial blood gas sample)

The presence of such a large difference between O₂ tension in alveoli compared to O₂ tension in arterial blood indicates a severe oxygenation defect.

Causes of Arterial Hypoxemia

Table 5-6 summarizes the major causes of hypoxemia and characterizes the P(a-a)o₂ gradient and response to supplemental o₂ for each. An interpretation of low arterial Po₂ requires a calculation of the P(a-a)o₂ gradient and measurement of arterial Pco₂.

Table Graphic Jump Location

Table 5-6Major Causes of Arterial Hypoxemia and Response to Supplemental Oxygen

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Table 5-6Major Causes of Arterial Hypoxemia and Response to Supplemental Oxygen

Cause	P(a-a)o2 Gradient	Responds to Supplemental O2
Low Pio2	Normal	Yes
Global hypoventilation	Normal	Yes
Diffusion abnormality	Increased	Yes
/ mismatch (low /)	Increased	Yes
Intrapulmonary shunt	Increased	No

• Low Pio₂ is an effect of high altitude but can also result from incorrect air mixtures used in scuba diving. Low alveolar Po₂ is the cause of low arterial Po₂. The P(a-a)o₂ gradient is normal, and the treatment is to restore alveolar Po₂ with supplemental O₂.

• Global hypoventilation occurs when total minute ventilation is low. This condition may be due to defective central control of breathing, such as narcotic overdose or from paralysis of ventilatory muscles. High arterial Pco₂ is always present. High alveolar Pco₂ develops because the venous blood Pco₂ is increased, and CO₂ diffuses readily into alveoli. CO₂ displaces O₂ in the alveolus, decreasing the alveolar Po₂. The P(a-a)o₂ gradient is normal. Low arterial Po₂ responds to supplemental O_2; ventilatory support is needed to restore alveolar ventilation.

• Diffusion abnormality (e.g., pulmonary fibrosis) is a rare cause of hypoxemia. Alveolar Po₂ is normal, but a P(a-a)o₂ gradient develops. Supplemental O₂ is an effective treatment because it increases the driving force of O₂ diffusion.

• Regional / imbalance (e.g., pneumonia) is the most common cause of hypoxemia. Unlike global hypoventilation, arterial Pco₂ is not increased because total alveolar ventilation is normal, or it may even be increased. Regions of the lung with low / deliver poorly oxygenated blood and cause the development of a P(a-a)o₂ gradient. Hypoxemia responds to supplemental O₂ because affected lung units have some ventilation that can be enriched with O₂.

• Intrapulmonary shunt is the most dangerous cause of hypoxemia because, as shown in Figure 5-31, no compensation is possible by normal lung units, even when 100% O₂ is given. The effect of shunt is magnified if venous desaturation (low Svo₂) develops. The Svo₂ is determined by the balance between O₂ delivery and consumption. O₂ delivery is too low in conditions such as low cardiac output or severe anemia. The causes of shunt and low Svo₂ must be addressed to treat these causes of hypoxemia (e.g., acute respiratory distress syndrome).

A central pattern generator in the medulla and pons initiates the basic rhythmic pattern of breathing, which proceeds without the need for conscious control (e.g., during sleep). There are many inputs to the central pattern generator that influence breathing; for example:

• Negative feedback responses to maintain the arterial Pco₂ and Po₂ and pH.

• Sensory feedback relating to the mechanical state of the lung and chest wall to minimize work of breathing, to prevent overinflation of the lung, and to respond to irritants.

• Sensory feedback from receptors in the joints and muscles to increase ventilation in response to exercise.

• Integration with the sympathetic nervous system to increase ventilation during “fight or flight” responses, and with other stress responses such as a high body temperature or a low arterial blood pressure.

• Integration to allow speech and swallowing.

• Conscious control to allow hyperventilation or breath holding.

The Central Nervous System Neural Controller

Figure 5-34 illustrates the main components of the central nervous system controller for ventilation. The basic rhythm of breathing is controlled by groups of neurons in the medulla and pons. The medullary center has a dorsal respiratory group of neurons in the nucleus of the tractus solitarius and a ventral respiratory group in the nucleus ambiguous and nucleus retroambiguus. The dorsal respiratory group generates the basic inspiratory pattern. Stimulation of the ventral respiratory group increases the breathing rate and causes active expiration. Outflow from the medullary centers reaches the muscles of ventilation via somatic motor neurons. Control of the diaphragm via the phrenic nerves (C3–C5) is most important. Two pontine centers provide fine-tuning to the dorsal respiratory group—the apneustic center promotes inspiration, and the pneumotaxic center inhibits inspiration.

Hangman's fracture results in a spinal cord injury at the level of C2. The fracture causes apnea (cessation of breathing) because the spinal cord is interrupted proximal to the origin of the phrenic nerve roots. In contrast, a spinal cord injury at the level of C4 will result in quadriplegia (motor dysfunction of the upper and lower extremities) but only weakened ventilatory muscles because part of the phrenic nerve remains functional.

Table 5-7 summarizes some abnormal breathing patterns and their causes. The activity of the central pattern generator is modified by multiple inputs:

• Descending cortical inputs allow voluntary control of breathing.

• Hypothalamic and limbic system inputs account for breathing patterns seen in emotional states such as rage or fear.

• Input from neural receptors in the lung and chest wall is conveyed to the central nervous system via the vagus nerves. Changes in the mechanical state of the lung and chest wall can cause reflex changes in the breathing pattern. For example, stretch receptors in the airway initiate the Hering-Breuer reflex, which increases breathing frequency and prevents hyperinflation of the lungs. Pulmonary J receptors surround blood vessels and initiate increased ventilation associated with edema in the lung.

• Ascending spinal inputs from neural receptors in working muscles and joints provide information about the workload of exercise. Ventilation is stimulated as a function of workload to match O₂ demand. Ventilation also matches increased cardiac output during exercise to ensure / matching and preservation of normal arterial blood gas tensions.

Negative Feedback Control of Ventilation by CO₂, O₂, and pH

Ventilation is increased if the arterial Pco₂ increases or if the arterial Po₂ decreases. These negative feedback responses assist in maintaining blood gases within a normal range. Under normal conditions, maintenance of arterial Pco₂ predominates. Ventilation is also stimulated by reduced arterial blood pH, representing the pulmonary contribution to acid-base balance (see Chapter 6).

Figure 5-35 shows increased ventilation in response to high arterial Pco₂, which represents a negative feedback response to increase CO₂ excretion and thereby to restore the arterial Pco₂ to normal. The predominance of arterial Pco₂ in control of ventilation is indicated by the steepness of the curves shown in Figure 5-35, although the ventilatory response to hypercapnia is blunted by increased arterial Po₂ and stimulated by a coexisting hypoxemia.

Figure 5-36 shows increased ventilation in response to reduced arterial Po₂. This response accounts for a presentation of low arterial Pco₂ in patients with hypoxemia. A marked increase in ventilation does not occur until arterial Po₂ is below 60 mm Hg, corresponding with the region of steep decline in oxyhemoglobin saturation on the O₂ dissociation curve. The response to hypoxemia is blunted if arterial Pco₂ is reduced, but stimulated if arterial Pco₂ is increased. Many patients with COPD have hypercapnia; they often adapt to tolerate high arterial Pco₂ but rely on hypoxemia to drive ventilation. Treatment with supplemental O₂ may cause these patients to stop breathing because arterial Po₂ is increased abruptly, removing their drive to breathe.

Patients with acidemia (e.g., lactic acidosis) usually have reduced arterial Pco₂ due to the stimulation of ventilation by low pH (Figure 5-37). The equilibrium CO₂ + H₂O ↔ H₂CO₃ ↔ H⁺ + HCO₃⁻ shifts to the left when the arterial Pco₂ is reduced, which reduces [H⁺] and moves pH back toward the normal range. Ventilation is affected only slightly by alkalemia. If ventilation were to be reduced to return pH to normal, it would be at the cost of increased arterial Pco₂, which is prevented by the powerful feedback control of arterial Pco₂.

Chemoreceptors

Changes in ventilation due to altered blood gases and pH are initiated by chemoreceptors. Central chemoreceptors are located on the ventral surface of the medulla and respond to changes in arterial Pco₂. Figure 5-38 shows how altered arterial Pco₂ is sensed through changes in cerebrospinal fluid (CSF) pH:

• CO₂ diffuses readily across the blood-brain barrier.

• CSF pH decreases because the CSF is poorly buffered due to its low protein content.

• Decreased CSF pH (increased [H⁺]) stimulates central chemoreceptors.

Changes in blood pH are not sensed by the central chemoreceptors because the blood-brain barrier prevents H⁺ from crossing into the brain. Arterial Po₂ as well as arterial pH are not sensed by the brain and rely on input from peripheral chemoreceptors.

Peripheral chemoreceptors are located in the carotid bodies at the bifurcation of the common carotid arteries and in the aortic bodies in the aortic arch. Glomus cells within the carotid body are able to sense changes in O₂, H⁺, and CO₂, and relay signals to the central pattern generator via the glossopharyngeal and vagus nerves. The control of ventilation by O₂ and pH is initiated in peripheral chemoreceptors. Control of ventilation by CO₂ is mainly through central chemoreceptors (Figure 5-39).