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Airway Physiology
UPDATE ON RESPIRATORY DISEASES
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AIRWAY PHYSIOLOGY N. Edward Robinson, BVetMed, PhD, MRCVS
Dynamic compliance, pulmonary resistance, and tidal-breathing flow-volume loops are terms that are beginning to appear in the clinical literature describing respiratory diseases of dogs and cats. To most veterinarians, these are terms heard somewhere in a physiology course but long since forgotten. Therefore, the purpose of this article is to review the physiology behind these tests of respiratory function. Because the tests primarily indicate changes in airway caliber, a second purpose is to describe factors that regulate airway diameter. The respiratory system delivers oxygen and removes carbon dioxide at rates that are matched to metabolism. This function is usually carried out at little energy cost to the animal. Respiratory diseas.e makes the respiratory system less efficient, and usually the respiratory muscles must work harder in an attempt to compensate for tl;le inefficiency. The increased effort required to breathe is noticed by the pet owner, who then seeks treatment for the animal. Alternatively, the inefficiency of the respiratory system limits oxygen delivery to the tissues, and the owner describes exercise intolerance. Efficient functioning of the respiratory system requires the delivery of adequate ventilation through a system of tubes (the airways) into the alveoli. Here, air and blood are in close proximity, and gas exchange occurs. In the blood, oxygen is bound to hemoglobin for transport to the tissues. Adequate cardiac output and distribution of blood flow to metabolizing tissue are therefore essential for gas transport. Lack of exercise tolerance or signs of respiratory distress can indicate problems in any part of the oxygen delivery system, but many of the common diseases of dogs and cats primarily affect the airways. Viruses such as distemper and adenovirus in dogs or herpesvirus and calicivirus in cats From the Department of Large Animal Clinical Sciences, Michigan State University College of Veterinary Medicine, East Lansing, Michigan
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 22 • NUMBER 5 • SEPTEMBER 1992
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and inhaled allergens and irritants have their primary effects on airways. In brachycephalic animals, selective breeding has created special airway problems.
ANATOMY OF THE AIRWAYS
During ventilation, air flows through the tubes of the upper airway and tracheobronchial tree. Flow is opposed by the frictional resistance between air molecules and the walls of the air passages. In the resting animal, air flows through the nasal cavity, pharynx, and larynx, which warm and humidify the air and provide approximately 60% of the frictional resistance to breathing (Fig. 1). When airflow rates increase during exercise or when the nasal cavity is obstructed, dogs and cats may breathe through the mouth to bypass the high resistance of the nasal cavity. The upper airway is composed of both rigid and collapsible portions. The external nares provide a collapsible valve-like structure at the entrance to the respiratory tract. Cartilages and muscles allow the animal to actively regulate the diameter of the external nares. The bony nasal cavity is quite rigid. It is lined by a ciliated epithelium that provides for the transport of mucus, which traps inhaled materials. The mucosal lining of the nasal cavity is highly vascular, so that vascular engorgement can narrow the airway considerably and thereby increase the resistance to flow. The pharynx is a collapsible tube, the patency of which is maintained by the encircling muscles attached to the bony support of the hyoid apparatus. At the entrance to the trachea, the larynx provides yet another protective valve that also functions in
50-70% Trachea 40%
Bronchi Bronchioles 40% 20%
Figure 1. Partitioning of airway resistance in the dog. When the dog breathes through its nose, the upper airway contributes over 50% of the resistance; airways caudal to the larynx contribute the remainder. Mouth breathing greatly reduces upper airway resistance. Bronchioles constitute a small fraction of the total resistance.
AIRWAY PHYSIOLOGY
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vocalization. Cartilage plates and the intrinsic laryngeal muscles control the size of the air passage; that is, the glottis. The tracheobronchial tree has up to 24 branches, which are lined by a secretory, ciliated epithelium. 33 The larger airways, trachea, and bronchi are supported by cartilage and supplied with secretory bronchial glands. All larger airways, with the exception of the trachea and the first few centimeters of the main stem bronchi, are intrapulmonary and lie within a sheath of loose connective tissue, the bronchovascular bundle, which also contains major blood vessels, lymphatics: and nerves (Fig. 2). Bronchioles are epithelial-lined tubes surrounded by smooth muscle. They lack cartilage and a connective tissue sheath. Alveoli surround the intrapulmonary airways, and the alveolar septa attach to the outer layers of the bronchovascular bundle and to the walls of bronchioles. Except before birth, when the lung contains no air, the alveolar septa are always under tension, which provides radial traction around the airways and maintains their patency. The canine and feline lung has six lobes, each supplied by a lobar bronchus, which gives rise to "daughter" bronchi. At each division of the bronchi, the diameters of the daughter airways are not equal. One daughter airway is much narrower than the parent, whereas the diameter of the other is similar to the parent. This monopodia) system of branching continues through at least the first six generations of bronchi. At the level of the bronchioles, the diameters of parent and daughter bronchioles are the same. As a result of this branching pattern, the total cross-sectional area of the tracheobronchial tree increases only a little between the trachea and the first four generations of bronchi but increases dramatically toward the periphery of the lung33 (Fig. 3). Consequently, the velocity of airflow diminishes progressively from the trachea toward the bronchioles. The high-velocity, turbulent airflow in the trachea and bronchi produces the lung sounds heard through a stethoscope in a normal animal. Laminar, low-velocity flow in the bronchioles produces no sound. As a result of the branching pattern of the tracheobronchial tree, airways greater than 2 to 5 mm diameter, that is, the trachea and bronchi, contribute 60 to 80% of tracheobronchial resistance; bronchioles contribute only 20 to 40% (see Fig. 1). The tracheobronchial tree is lined by a mucociliary system consisting of secretory and ciliated epithelial cells33 (Fig. 4). The submucosal glands also add to the tracheobronchial secretions in the bronchi and trachea. The type of epithelial lining changes along the tracheobronchial tree from pseudostratified columnar in the trachea to cuboidal in the respiratory bronchioles. Goblet cells are not normally present in the bronchioles but can develop there in response to airway disease. 40 The submucosa of the larger airways contains a plexus of blood vessels derived from the bronchial circulation. This plexus, which warms the inhaled air, can vasodilate and give rise to airway wall edema when the airways are inflamed. Also located in the submucosa are sensory and motor branches of the autonomic nervous system supplying glands, blood vessels, and the airway smooth muscle. Smooth muscle is present in the walls of airways from the trachea
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Figure 2. A, The bronchovascular bundle in which a bronchus (BR), lined by columnar epithelium and surrounded by smooth muscle, lies in a sheath of loose connective tissue that also contains cartilage (CP), blood vessels (PA), lymphatics, glands (GO), and nerves. Alveolar septa do not connect directly to the wall of the bronchus. In disease, edema and exudates accumulate in the peribronchial space. B, A bronchiole (BL) lined by cuboidal epithelium and surrounded by smooth muscle lacks the connective tissue sheath typical of bronchi. The alveolar septa are connected almost directly to the wall of the bronchiole. As the lung inflates, the tension in the alveolar septa pulls open the bronchioles. PA = blood vessels. (From Staub NC: Basic Respiratory Physiology. New York, Churchill Livingstone, 1991 , pp 16-17, with permission.)
AIRWAY PHYSIOLOGY
CROSS SECTION (CM 2 )
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DIAMETER (CM)
1.00 Diameter
Cross section
0.10 10 ~~~--~~--~~~--~~~~~~0.01
6
12 18 AIRWAY GENERATION
24
Figure 3. Airway diameter and total cross-sectional area as a function of airway generation. Generation zero represents the trachea; bronchioles begin at about the eighth generation. Although airway diameter decreases as a function of generation number, the decrease in the distal airways is small. As a result, the total cross-sectional area of each generation increases from the bronchi to the bronchioles.
BRONCHUS
BRONCHIOLE
Figure 4. Anatomy of airway wall of a bronchus and bronchiole. The bronchus has a pseudostratified columnar ciliated epithelium, which contains goblet cells (G) and is overlain by a sol and a gel layer of mucus. Mucus also is provided by submucosal glands (GL), which hypertrophy in the presence of chronic stimulation. Smooth muscle (SM) can contract and narrow the airway. Cartilage plates (CA) stiffen the airway and prevent its collapse. The bronchiole is lined by cuboidal ciliated epithelium containing Clara cells (C). There are no mucus glands, and bronchioles do not normally contain goblet cells. SM encircles the airway below the epithelium.
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to the mouths of the alveoli. It forms a band on the dorsum of the trachea, where it connects the tips of the tracheal cartilages. As the amount of cartilage diminishes from the trachea to the bronchioles, the muscle gradually encircles the airway. In the bronchioles, the muscle forms a complete sleeve around the lumen of the airway. Contraction of airway smooth muscle obstructs the airway by narrowing the lumen and increasing the frictional resistance to breathing. LUNG COMPLIANCE AND PULMONARY RESISTANCE
After the first breath of life, the lungs are never empty. Between each tidal breath, at end-exhalation, the lungs contain about 45 mL!kg bw of air, a volume known as the functional residual capacity (FRC). 29 • 34• 37• 38 This provides a reservoir of air for gas exchange between breaths and reduces the effort necessary to breathe by keeping the peripheral airways open. At FRC, the elastic recoil of the lung is acting to collapse the lung or pull it away from the thoracic wall. As a result, pleural pressure (Ppl), the pressure within the potential space between the visceral and parietal pleura, is approximately 5 em H 2 0 subatmospheric (- 5 em H 20). During inhalation, the respiratory muscles contract in order to enlarge the thorax. As this happens, Ppl decreases so that the pressure difference between the atmosphere and the pleural cavity increases. This pressure difference, which is in opposition to the elastic recoil of the lung and the frictional resistance of the airways, causes the lung to inflate. 34 The magnitude of the decrease in Ppl during inhalation is determined by four factors: the size of each breath (i.e:, tidal volume [VT]), the compliance of the lung (CL), the air flow rate (V), and the resistance of the airways (RL). ~Ppl = VT/CL
+ RLV
In clinical situations, these same four factors must be considered when a dog or cat is presented with an exaggerated breathing effort. It may have ex~rcised recently and simply be taking bigger breaths (VT) with higher V. If the animal is resting, breath size and flow rates may be bigger because the animal is hypoxic. Alternatively, the exaggerated effort may be due to an increase in RL, a decrease in CL, or both. The maximal change in pleural pressure during breathing (~PplmaJ has been used as a test of respiratory function in horses. 30 Although an exaggerated ~Pplmax may suggest a change in respiratory function, it is not specific, because it can be affected by all the factors described above. ~Pplmax can be measured in two ways: either directly by puncture of the pleural space using a cannula connected to a pressure transducer or indirectly by means of a balloon on the end of a cannula placed in the thoracic esophagus just caudal to the heart. Horses and trained dogs 7 tolerate the esophageal balloon without anesthesia, but it is unlikely that such a procedure would be possible in the majority of
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untrained dogs or cats. The excitement caused by passage of the balloon would tend to invalidate any subsequent measurements of ~Pplmax · Lung Compliance
Compliance is a measure of the ease with which a structure can be deformed. The normal lung is compliant and easily deformed, but the presence of lung disease makes it less easy to deform, that is, the lung becomes less compliant and is stiffer than normal. Measurement of. CL uses a manipulati~n of the equation shown earlier. When flow (V) ceases, the term RLV is zero, and the equation becomes LiPpi
= VT/CL
rearranging the equation CL = VT/~Ppl
In practical terms, measurement of CL requires that the dog or cat be anesthetized, because it is necessary to place an esophageal balloon to measure ~Ppl. An endotracheal tube also must be inserted and connected to a flow and/or volume measuring device in order to determine VT.
There are two ways to make V equal to zero. Following slight hyperventilation to induce apnea, the lungs can be inflated and then deflated in stepwise fashion by means of a very large syringe. 37 • 38 Brief pauses between each step allow flow to cease. Pressure is recorded at each pause, and a graph is drawn of the pressure versus volume (details are given in other references. 38 ) Lung compliance is the slope of the pressure-volume curve just above FRC (Fig. 5). Compliance calculated in this fashion is known as static lung compliance because air flow has definitely ceased when pressure is measured. Changes in static CL represent changes in the elastic behavior of the lung parenchyma, that is, the alveolar region. Normal values of static compliance have been published for dogs of various sizes. 29• 37• 38 Compliance is greater in large dogs than in small ones, because big dogs have bigger lungs. However, when compliance is divided by FRC to obtain the compliance of a unit volume of tissue, specific compliance values are independent of body size. Pneumonia with consolidation, pulmonary edema, fibrosis, and a lack of pulmonary surfactant all stiffen the lung and decrease static CL. More commonly, lung compliance is measured during tidal breathing. At the start and end of inhalation, there is a brief period when flow ceases (Fig. 6). The VT is divided by the Ppl difference between the start and end of inhalation to calculate lung compliance. 7• 13 Because compliance is measured during breathing, it is known as dynamic compliance (Cctyn)· The problem with this calculation is that the periods when flow is zero can be so transient that pressure has not equilibrated along the airways. Therefore, Cctyn is influenced by changes in airway
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VOLUME (ml) 400 300
Deflation/
200
/1'ntlation
100
0
10
20
PRESSURE (em H20)
30
Figure 5. Static pressure-volume curve of the lung of a small dog. Beginning at functional residual capacity (FRC), the lung was inflated incrementally to a transpulmonary pressure of 30 em H20 and was then deflated. The 5-cm H20 pressure at the start of inflation indicates a pleural pressure of minus 5 em H20 at FRC. Note that more pressure is required to maintain a given lung volume on inflation than on deflation. Lung compliance is the slope of the deflation limb of the pressure-volume curve over the range of tidal breathing (heavy line); that is, just above FRC.
resistance as well as in lung elasticity. A decrease in Cdyn can therefore be a result either of stiffening of the lung parenchyma or of intrapulmonary airway obstruction. Virtually all tracheobronchial diseases extending beyond the carina and all alveolar diseases can decrease c dyn• Airway Resistance
Airway resistance opposes the flow of air along the airways. Airway narrowing as a result of laryngeal paralysis, bronchospasm, or mucus accumulation can all increase RL. The measurement of RL is usually made simultaneous with measurement of Cdyn· The first equation shown is manipulated so that the term VT/CL is zero. .
= RLV
RL
.
rearranging the equation =
The various methods for setting the VT/CL equal to zero are beyond the scope of this article, but the advent of lung function computers has
AIRWAY PHYSIOLOGY
INSP Flow (ml/sec)
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EXP
100 50 0 · 50
Volume (ml)
75 50 25
Figure 6. Pleural pressure, air flow rate, and tidal volume recorded from an anesthetized cat. During inhalation, pleural pressure decreases, air flow rates increase, and air enters the lung." Toward the end of inhalation, flow rates decrease back to zero and the rate of increase of volume decreases. During exhalation, pleural pressure increases, air flow is reversed, and lung volume decreases. Because exhalation is passive in the healthy animal, flow rates peak early in exhalation.
Pressure (em H 2 0)
made the determination of both RL and Cctyn quite simple. If an endotracheal tube is in place when RL is measured, the contribution of the upper airway to RL is eliminated. To include the upper airway in measurements of RL, flow measuring devices must be attached to a face mask.
Interpretation of Changes in
Cdyn
and RL
In most diseases of the tracheobronchial tree, Cdyn decreases and increases. 7• 17• 31• 40 Occasionally, however, only one will be abnormal. The classical interpretation is that a decrease in Cctyn without an accompanying increase in RL is a result either of alveolar disease that stiffens the lung or of obstruction of the peripheral bronchioles that contribute little to the resistance to breathingY· 45 An increase in RL without a decrease in cdyn is due to obstruction of the upper airway, trachea, and large bronchi. However, a severe enough obstruction of a mainstem bronchus can decrease c dyn• It was pointed out earlier in this article that the upper airway constitutes more than 50%, and the trachea and bronchi provided another large fraction of RL (see Fig. 1). The peripheral airways provide RL
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a relatively small percentage of the total RL. 20• 27 This distribution of resistance is a result of the branching pattern of the airways and the large number of peripheral airways which are in paralleL Even though the resistance of one bronchiole is very high, thousands of bronchioles in parallel constitute only a small resistance. Extensive obstruction of the bronchioles is therefore necessary before there is a measurable increase in RL. DYNAMIC AIRWAY COLLAPSE
During both inhalation and exhalation, pressure gradients develop across the walls of the airways. These pressure gradients tend to change the size of the collapsible portions of the airways and therefore change airway resistance.
Extrathoracic Airway
The extrathoracic airways are surrounded by a relatively thin layer of tissue and skin, outside of which is ambient air at atmospheric pressure. During inhalation, pressure within the airway decreases below atmospheric pressure so that air is caused to flow into the respiratory tract (Fig. 7). The transmural pressure across the upper airway (the pressure difference between the inside and outside of the airway) therefore tends to suck the airway dosed (favors dynamic collapse). The tendency of the collapsible portions of the extrathoracic airway (the nares, pharynx, and larynx) to collapse on inhalation is normally opposed by contraction of various abductor muscles. When the abductor muscles are paralyzed, the consequences of the resulting dynamic collapse are clinically and physiologically very evident. 2• 12• 32 For example, consider a Doberman that has pulled on its choke collar for some time and has damaged the innervation of its larynx. At rest, this dog may have no apparent problem. This is because in the resting animal, the pressures necessary to generate air flow are quite small and are insufficient to cause clinically significant laryngeal collapse. Once the dog exercises, the problem becomes much more obvious: the dog begins to make an inspiratory noise, has inspiratory dyspnea, and may even collapse. To generate the increased air flow rates necessary for exercise, pressure within the airways must decrease more than in the resting animaL This decrease in pressure is now sufficient to narrow the larynx and obstruct the airway. As the larynx narrows, the velocity of airflow through the narrowed glottis must increase. Just as the higher velocity airflow over the curved upper surface of an aircraft wing reduces pressure above the wing and causes the aircraft to rise, the increased velocity of airflow through the narrowed glottis leads to a further decrease in pressure within the glottis and further narrowing. If the dog tries harder to inhale, pressures
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B
Figure 7. Pressures in the upper airway of a terrier and a dog of a brachycephalic breed. During inhalation in the terrier, (A) pressures in the airway are slightly negative (subatmospheric). During exhalation (B) the pressures are greater than atmospheric. Because the airway is well supported by the surrounding tissues and because there are no excessive folds of loose tissue, the airway diameter does not change greatly during inhalation and exhalation. In the dog of a brachycephalic breed inhaling at rest (C), pressures are more subatmospheric than in the terrier because of the resistance provided by the narrow nares and excessive tissue folds. When the dog inhales forcefully (D),' pressures decrease dramatically, and the loose folds of tissue are sucked into the airway lumen, resulting in obstruction. During forced exhalation (E), the loose tissues tend to be blown out of the air passageway by the high pressures. The brachycephalic breed is therefore demonstrating dynamic inspiratory collapse of the upper airway.
decrease further and the airway collapses more. This vicious cycle of events can continue until the glottis is completely obstructed. Air flow becomes independent of effort, because the harder the dog tries, the more the resistance to air flow increases. The dog has no problem exhaling, however, because during exhalation, pressure within the airway exceeds the surrounding atmospheric pressure. The transmural pressure therefore tends to dilate the airway. Dynamic collapse of the upper airway therefore causes inspiratory airway obstruction, inspiratory dyspnea (increased inspiratory effort and time), and abnormal sounds during inhalation. 2 Dynamic extrathoracic airway compression also occurs in dogs with collapse of the extrathoracic trachea. 1 In these animals, a normally rigid tube, the trachea, has become more compliant and is susceptible to dynamic compression during inhalation. The elliptical cross-section of the trachea of these dogs also makes it more susceptible to collapse than the more circular cross-section of the normally shaped canine trachea.
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+1
+2
A
0
+I
B
Figure B. Diagrammatic representation of pleural, alveolar, and airway pressures during quiet inhalation (A) and passive exhalation (B) in a normal dog. Alveolar pressure exceeds pleural pressure because of the elastic recoil of the lung. Pleural pressure is less than airway pressure during both inhalation and exhalation. As a result, the intrathoracic airways tend to dilate.
Brachycephalic breeds are particularly prone to dynamic obstruction of the upper airway. 1 These animals have narrow nares and excessive folds of tissue in the pharynx. 16 These obstruct the air passages, so that the dog must generate large pressure changes to move air (Fig. 7). The larynx of these animals therefore is probably chronically exposed to greater pressure changes than those occurring in the dolichocephalic breeds. The exaggerated pressure decrease during inhalation tends to draw the soft palate into the glottis and over time may lead to saccular eversion and, eventually, to laryngeal collapse. The upper airway presents fewer problems during exhalation. Pressures within the airway are greater than atmospheric pressure and therefore tend to dilate the airway (Fig. 7).
Intrathoracic Airway
Whereas dynamic airway collapse tends to occur during inhalation in the extrathoracic airway, it occurs during forced exhalation in the intrathoracic airway. 21• 22• 28 • 44 This is clinically obvious in dogs with collapsing trachea. Intrathoracic collapse occurs during cough or other forced exhalations, and extrathoracic collapse occurs during inhalation. The intrathoracic airways are surrounded by the pleural cavity or by the lung, which is itself surrounded by the pleural cavity. Therefore, the transmural pressure across the wall of the intrathoracic airway is the difference between airway and pleural pressure. To expand the lung and make air flow from the trachea to the alveoli during inhalation, pleural pressure must decrease more than airway pressure (Fig. 8). The transmural pressure across the wall of the intrathoracic airway therefore tends to cause dilation.
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During a passive exhalation, the respiratory muscles relax and the elasticity of the lung compresses the gas in the alveoli so that pressures throughout the airways increase and air flows out. Under these conditions, pressure within the airways still exceeds Ppl and dynamic collapse does not occur (Fig. 8). During a forced exhalation, the situation is very different (Fig. 9A). 28 Ppl increases well above atmospheric pressure. The pressure within the alveolus is somewhat higher than Ppl because of the elastic recoil of the alveoli. Because of frictional pressure losses, pressure decreases from the alveoli toward the larynx and, at some point in the airway, pressure within the lumen of the air passage becomes equal to Ppl. Between this equal pressure point and the thoracic inlet (downstream), the transmural pressure favors airway compression. As the airway becomes compressed, air must accelerate through the narrowed portion. As previously described, this causes a further pressure decrease and further narrowing. If the dog makes a greater effort to exhale, the airway is compressed even more and flow does not increase. Flow thus becomes independent of the effort being applied by the dog. If there is diffuse obstruction of the bronchioles, the increased resistance accentuates the pressure decrease along the airways. The point at which airway pressure equals Ppl moves closer to the alveoli and more airway is compressed (Fig. 9B). Thus, flow becomes further limited.
FLOW-VOLUME LOOPS
A common diagnostic test applied to humans is the maximal expiratory flow-volume maneuver. 4• 12• 32• 35• 39 In this procedure, an individual inhales maximally to total lung capacity (TLC) and then exhales with maximal effort as much as possible; that is, to residual Figure 9. Diagrammatic representation of pleural, alveolar, and airway pressures during forced exhalation in a normal dog and in one with peripheral airway obstruction. Pleural pressure is greater than atmospheric pressure (i.e., it is positive). When pleural pressure exceeds pressure within the intrathoracic airway, the latter is compressed (A). When the resistance of the airways close to the alveoli is increased by a peripheral airway obstruction (8), the pressure drop along the airways is increased; therefore, the point at which airway pressure equals pleural pressure moves upstream toward the alveoli. As a result, more of the intrathoracic airway is dynamically collapsed.
0
+3
+6
A
o:._ _:+_:2:__~r-'"""' B
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ROBINSON
volume (RV). The total volume of air expelled is referred to as the vital capacity (VC). This type of lung function test can only be attempted in anesthetized small animals in which maximal flow is generated by a vacuum source or by application of a positive pressure to the chest wall. Air flow rate is plotted against lung volume (Fig. 10) and it can be shown when this maneuver is conducted with increasing effort that, below 70% VC, there is a maximal expiratory flow that is independent of effort. 21 • 22• 44 The maximal flow is a result of dynamic airway compression. If more force is applied, the airway becomes more compressed and flow does not increase further. Although the equal pressure point provides a simple explanation of flow limitation, a much more complex explanation is necessary to explain all the factors affecting maximal expiratory flows. 44 Suffice it to say that maximal flow is a function of lung volume, the elastic recoil of the lung, and airway resistance. By increasing the frictional pressure losses along the airway, airway obstruction causes more airway to be subjected to compression (Fig. 9B). As a result, maximal flows are reduced. In human medicine, the maximal expiratory flow volume maneuver has gained popularity because it is noninvasive and can easily be performed by a cooperative individual who blows through a flowmeter. There is no need for measurement of Ppl. Decreases in maximal
12
Flow IIsee
10
8 6 -
2
(b)
0
100
..1._ ..-L _
~
~
_y___l______.L.....~--L__ ~
~
j____L__ _l. __ _l.__L__l.
w
0
o/o Vital capacity Figure 10. Maximal expiratory flow-volume curve. Flow is plotted as a function of lung volume expressed as percent vital capacity. During a resting tidal exhalation (curve a), the volume exhaled is small and the flow rates are low. As the dog increases the lung volume at which exhalation begins (curves b, c, and d) and increases the effort to exhale, the volume exhaled and the flow rates increase. However, curves b, c, and d merge and flow rates become independent of effort as lung volume decreases (arrows). Flow rate becomes independent of effort because of the mechanical properties of the lung; that is, the airway resistance and lung compliance are limiting flow.
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expiratory flows indicate intrathoracic airway disease. 4 • 21 • 22• 35 Similarly, maximal inspiratory flow-volume maneuvers can be used to diagnose extrathoracic airway obstructions. The problem with the use of these tests in animals is that they require patient cooperation to generate the maximal flows. Recently, however, it has been shown that useful information can be gained by examination of flow-volume loops generated during tidal breathing (Fig. 11). 1• 2 This observation brings the use of flow-volume loops into the realm of clinical usefulness for dogs and cats (see the article by McKiernan elsewhere in this issue).~
FACTORS AFFECTING AIRWAY FUNCTION Extrathoracic Airway
Extrathoracic airway obstructions can be either fixed or dynamic. 12• 13• 39 Fixed obstructions include masses such as neoplasia, foreign bodies, stenoses of the trachea, and inflammatory diseases of the nasal cavity. These obstructions are present all the time and therefore increase the resistance to breathing during both inhalation and exhalation. Respiratory distress and abnormal sounds occur during all phases of respiration. Flow-volume loops from animals with fixed upper airway obstructions show reductions in both inspiratory and expiratory flows (Fig. 11). Dynamic (nonfixed) obstructions are functional obstructions that FIXED (TYPE 3; N = 10)
NON FIXED (TYPE 2; N 17)
NORMAL (TYPE 1; N 3)
=
=
1.0 1.0
z
PEF
0
~
0.5
~a:
Cll -
:::J ~
~w
3::
0.0
0 z ...1 0 u.. ~
400
0.0
600 0.5
a:
a:
(f)
~
1.0
IF 25 PIF
IF 50
1.0
VOLUME(ml) Figure 11. Tidal-breathing flow-volume loops from a normal dog, a dog with a nonfixed upper airway obstruction, and a dog with a fixed upper airway obstruction. The various indices of loop shape are shown on the loop of the normal dog. The nonfixed obstruction is a result of dynamic compression of the upper airway and therefore limits inspiratory flow. The fixed obstruction limits both inspiratory and expiratory flow. (From Amis T, Smith MM, Gaber CE, et al: Upper airway obstruction in canine laryngeal paralysis. Am J Vet Res 47:1007, 1986; with permission.)
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ROBINSON
result from either failure of the abductor muscles of the upper airway or increased compliance of the airway, particularly the trachea. As a result of these changes, the airway collapses during inhalation, respiratory distress and abnormal sounds occur on inhalation, and the flowvolume loop reveals reduced inspiratory but normal expiratory flows (Fig. 11). The brachycephalic breeds often have a combination of fixed and dynamic obstruction. The excessive tissue folds impede both inhalation and exhalation but collapse further into the airway during inhalation (Fig. 7). 1 Intrathoracic Airway
The intrathoracic airway can be affected by fixed obstructions such as foreign bodies or stenoses that reduce both inspiratory and expiratory flow. Dynamic collapse is best exemplified by collapsing intrathoracic trachea that causes obstruction only during exhalation. The most common airway diseases, however, are accompanied by airway obstruction, increased RL, decreased c dyn' and decreased expiratory flows as a result of smooth muscle contraction, mucus accumulation, or airway wall edema. Many of these changes are a result of inflammation accompanied by the release of mediators that cause obstruction either by contracting airway smooth muscle, increasing mucus secretion, or increasing vascular permeability. In addition, some of these mediators can make the smooth muscle hyperresponsive to stimuli. A group of dogs with inherently hyperresponsive airways also has been reported. 17 The neurohumoral regulation of airway function forms the topic of the remainder of this article. Autonomic Regulation of Airways Excitatory Innervation
The major excitatory innervation to smooth muscle is the parasympathetic system (Fig. 12). 3 It reaches the lung in the vagus nerve, and its ganglia are located in the airway wall. The short postganglionic fibers release acetylcholine (Ach), which binds to muscarinic M3 receptors. In airway smooth muscle, this results in contraction and airway narrowing; in mucus glands, binding causes mucus secretion. Although muscarinic receptors are located throughout the tracheobronchial tree, the density of parasympathetic innervation is greatest in the larger airways, and stimulation of the vagus causes the greatest airway constriction in the medium-sized bronchi. In normal dogs and cats, atropine reduces RL, showing that there is always some parasympathetically mediated smooth muscle tone. 7• 15 The parasympathetic system is activated when sensory receptors in and beneath the airway epithelium are stimulated by irritants such as dusts and some gases. Inflammatory mediators, particularly histamine, also can activate
AIRWAY PHYSIOLOGY
Sensory Irritant re eptors
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Autonomic
C-fibers
NE
VIP
ACh
Smooth Muscle
Airway lumen Figure 12. Diagrammatic representation of the nerves supplying airway smooth muscle. Sensory and autonomic (motor) nerves are shown. ACh = acetylcholine, M = muscarinic receptor, NANG = nonadrenergic noncholinergic nervous system, NE = norepinephrine, SP = substance P, VIP = vasoactive intestinal peptide, ~ = beta-adrenergic receptor.
sensory receptors and cause parasympathetically mediated bronchospasm. For this reason, atropine and other parasympatholytic (anticholinergic) agents can be used as bronchodilators in animals with bronchospasm resulting from allergic responses and airway inflammation (Fig. 13).5· 7. 19, 25, 26, 42 The release of Ach from parasympathetic nerves is regulated by a variety of factors. 3 Ach apparently inhibits its own release via muscarinic M2 receptors located prejunctionally on parasympathetic nerves. Some viral infections damage M2 receptors so that this feedback inhibition is lost11 and the response of smooth muscle to parasympathetic stimulation is exaggerated. 11 • 23 Catecholamines also inhibit Ach release. Sympathetic nerves impinge on the parasympathetic system and release norepinephrine that binds to beta 1 or alpha2-receptors to cause inhibition. The alpha2 agonists, xylazine and detomidine, used for restraint can therefore have bronchodilator actions by binding to alpha2 receptors. Prostaglandin E2 , a major product of normal airway epithelium, is a potent inhibitor of Ach release. Experimentally, prolonged administration of the cyclooxygenase inhibitor, indomethacin, has been shown to cause hyperirritability of airways in dogs. 18 A second excitatory innervation, the noncholinergic system, has
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5 Resistance (em H20/lisee)
4 3
2 '+- ----- ----- --- ----+
1
Antigen 5
Time1Pmins)
15
20
Figure 13. The effect of antigen challenge on airway resistance in allergic dogs. The increase in resistance caused by antigen is reversed in the atropine-treated animal (broken line), but not in the control (solid line) animal, indicating activation of muscarinic receptors during the response to allergen.
been described more recently. 3 The mediators of this system are neuropeptides (tachykinins) such as substance P. They are apparently released locally, probably through axon reflexes, when sensory nerves are stimulated by irritants. The release of tachykinins results in prolonged bronchospasm and edema of the airway wall. Tachykinins also can increase the release of Ach. These substances are metabolized by proteases on the epithelium and elsewhere. Damage to the epithelium by viruses and some industrial pollutants can therefore prolong the actions of tachykinins. At present, there is no commercially available blocker of tachykinin receptors. Inhibitory Innervation
There are two inhibitory nervous systems supplying the airways: the sympathetic system and the nonadrenergic-noncholinergic (NANC) system. 3 Airway smooth muscle and epithelium is richly supplied with beta-adrenergic (primarily beta2) receptors. These receptors are activated either by the release of norepinephrine from sympathetic nerves or by circulating catecholamines from the adrenal medulla. In both the dog and the cat, there is direct sympathetic innervation of bronchial smooth muscle. The tracheal smooth muscle receives sympathetic innervation in the cat but not in the dog.6• 24 Sympathetic nerves are activated during flight and fight reactions and, presumably, the small amount of resting airway tone is abolished when the beta receptors are activated. Whether the sympathetic system is activated in the presence of airway disease is not clear. The observation that beta-adrenergic blockade enhances airway obstruction in humans and animals with airway
AIRWAY PHYSIOLOGY
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disease suggests that the normal circulating levels of catechola.mines may be sufficient to activate airway beta receptors. The extensive presence of betaz receptors is made use of in the treatment of bronchospasm by administration of specific betaz agonists. The NANC inhibitory system runs in the vagus nerve and the mediator, probably vasoactive intestinal peptide (VIP) may be coreleased with Ach. The NANC system has been clearly demonstrated in cats8 but not in dogs. Because the mediator is a peptide, it is easily broken down by the proteases that are released from mast and, other cells during the inflammatory response. The NANC system therefore may not be functional in the presence of airway inflammation. The stimuli that activate the NANC system have not been well defined. Mediators in Airway Disease
The list of mediators released from and produced by cells in the allergic and other inflammatory response increases almost daily. No one mediator is responsible for all the changes observed in a particular disease. Mediators are released in a cascade and interact with one another. Mediators produced by one cell may even be taken up and modified by another cell. The mediators thought to be important in airway disease include histamine, the leukotrienes, and some of the prostanoids. Their effects vary in intensity at different levels of the tracheobronchial tree. 41 Histamine is a preformed mediator that is released from mast cells when antigen binds to IgE on mast cell surface during the immediate allergic response. 43 Histamine binds to either H 1 or Hz receptors on a variety of tissues. Activation of the H 1 receptors on muscle causes bronchospasm. Activation of the same receptor type stimulates irritant receptors and causes cough and reflexly mediated bronchospasm. 9 The activation of H 1 receptors also is responsible for vasodilation, airway wall edema, and pruritis. The Hz receptors are responsible for airway mucus secretion and may act to inhibit smooth muscle contraction in some species. Histamine probably is only important in the immediate hypersensitivity reaction, that is, the bronchospasm that occurs within 15 minutes of antigen challenge. Antihistamines (H1 blockers) prevent bronchospasm in this reaction but not in the more delayed responses that are accompanied by airway inflammation. The delayed response occurs several hours after antigen challenge, when neutrophils migrate into the airway wall and lumen. Airways become obstructed by smooth muscle contraction, mucus secretion, and airway wall edema. Feline asthma is most likely a delayed response. Leukotrienes are products of the lipoxygenase pathway of the arachidonic acid cascade (Fig. 14). 10 Leukotrienes are produced by neutrophils, eosinophils, mast cells, macrophages, airway epithelium, and vascular endothelium. There are a variety of biologically active leukotrienes but particularly potent in the lung are the sulfidopeptide leukotrienes (LTC4 , LTD4 , and LTE4), formerly known as slow-reacting substance of anaphylaxis. The sulfidopeptide leukotrienes are very
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Membrane phospholipids
I
Arachidonic acid Cyclooxygenase I
I
I
I
5-LipoXjgenase I
I
PG~ PG~ PGD2 PGF2 TXA 2
LTA4 I
I
5-HETE
I
Figure 14. The arachidonic acid cascade. PG = prostaglandin; LT = leukotriene; TX = thromboxane; HETE = hydroxyeicosatetraenoic acid.
potent bronchoconstrictors. with a much longer duration of action than histamine. Leukotrienes also increase the permeability of blood vessels. The recent advent of potent, specific antagonists is allowing investigation of the role of leukotrienes in airway disease. There is increasing evidence that leukotrienes play an important role in human asthma and in some experimentally induced delayed hypersensitivity responses in animals. Prostanoids are products of the cyclooxygenase pathway of arachidonic acid metabolism (Fig. 14). 36 There are prostanoids such as PGE2 that are bronchodilators; others such as PGF2aiph• and thromboxane are bronchoconstrictors. Some of the actions of both histamine and leukotrienes are mediated through secondary production of prostanoids. Because prostanoids can modulate release of Ach, they may be responsible for some of the airway hyperresponsiveness that occurs in inflammatory airway disease. 5· 26 However, the role of prostanoids in airway disease appears to be secondary, because cyclooxygenase inhibitors such as aspirin do not provide a major therapeutic benefit. SUMMARY
The understanding of the mechanisms of dog and cat airway disease is in its infancy, because the clinical tools necessary to measure airway function in patients have not been readily available. The advent of lung function computers that can rapidly analyze flow-volume loops and calculate Cdyn and RL will make it easier to evaluate airway function in disease and to detect the effects of the newer specific receptor blockers. In the not-too-distant future, measurements of lung function will be used to prove the efficacy of new therapeutic agents for canine and feline airway disease and to guide the clinician in the use of these agents. References 1. Amis T, Kurpershoek C: Tidal breathing flow-volume loop analysis for clinical assessment of airway obstruction in conscious dogs. Am J Vet Res 47:1002, 1986
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2. Amis T, Smith MM, Gaber CE, et a!: Upper airway obstruction in canine laryngeal paralysis. Am J Vet Res 47:1007, 1986 3. Barnes PJ: Neural control of airway smooth muscle. In Crystal RG, West JB (eds): The Lung: Scientific Foundations. New York, Raven, 1991, p 903 4. Berend N, Woolcock AJ, Marlin GE: Correlation between the function and structure of the lung in smokers. Am Rev Respir Dis 119:695, 1979 5. Chung KF, Becker AB, Lazarus SC, et a!: Antigen-induced airway hyperresponsiveness and pulmonary inflammation in allergic dogs. J Appl Physiol 58:1347, 1985 6. Dahlstrom A, Fuxe K, Hokfelt T, et a!: Adrenergic innervation of the bronchial • muscle of the cat. Acta Physiol Scand 66:507, 1966 7. Dain D, Gold WM: Mechanical properties of the lungs and experimental a?thma in conscious allergic dogs. J Appl Physiol 38:96, 1975 8. Diamond L, O'Donnell M: A nonadrenergic vagal inhibitory pathway to feline airways. Science 207:185, 1980 9. Dixon M, Jackson OM, Richards IM: The effects of H 1 and H 2 receptor agonists on total lung resistance, dynamic lung compliance and irritant receptor discharge in the anaesthetized dog. Br J Pharmacol 66:203, 1979 10. Drazen JM: Regulation by leukotrienes. In Crystal RG, West JB (eds): The Lung: Scientific Foundations. New York, Raven, 1991, p 917 11. Fryer AD, Jacoby DB: Parainfluenza virus infection damages inhibitory M2 muscarinic receptors on pulmonary parasympathetic nerves in the guinea-pig. Br J Pharmacal 102:267, 1990 12. Gibson GJ, Pride NB, Emprey DW: The role of inspiratory dynamic compression in upper airway obstruction. Am ·Rev Respir Dis 108:1352, 1973 13. Gould WM, Boushey HA: Pulmonary function testing. In Murray JF, Nadel JA (eds): Textbook of Respiratory Medicine. Philadelphia, WB Saunders, 1988, p 611 14. Gould WM, Kessler G-F, Yu DYC: Role of vagus nerves in experimental asthma in allergic dogs. J Appl Physiol 33:719, 1972 15. Hahn HL, Graf PO, Nadel JA: Effect of vagal tone on airway diameters and on lung volume in anesthetized dogs. J Appl Physiol 41 :581, 1976 16. Hendricks JC, Kline LR, Kovalski RJ, et a!: The english bulldog: A natural model of sleep-disordered breathing. J Appl Physiol 63:1344, 1987 17. Hirshman C, Malley A, Downes H: Basenji-greyhound dog model of asthma: Reactivity to Ascaris suum, citric acid, and methacholine. J Appl Physiol 49:953, 1980 18. Ito Y: Prejunctional control of excitatory neuroeffector transmission by prostaglandins in the airway smooth muscle tissue. Am Rev Respir Dis 143:56, 1991 19. Holtzman MJ, Fabbri LM, O'Byrne PM, eta!: Importance of airway inflammation for hyperresponsiveness induced by ozone. Am Rev Respir Dis 127:686, 1983 20. Hoppin FG, Green M, Morgan MS: Relationship of central and peripheral airway resistance to lung volume in dogs. J Appl Physiol 44:728, 1978 21. Hyatt RE: Expiratory flow limitation. J Appl Physiol 55:1, 1983 22. Hyatt RE, Black LF: The flow-volume curve: a current perspective. Am Rev Respir Dis 107:191, 1973 23. Killingsworth CR, Robinson NE, Adams T, et al: Cholinergic reactivity of tracheal smooth muscle after infection with feline herpesvirus I. J Appl Physiol 69:1953, 1990 24. Knight OS, Hyman AL, Kadowitz PJ: Innervation of intrapulmonary airway smooth muscle of the dog, monkey and baboon. J Auton Nerv Syst 3:31, 1981 25. Krell RD, Chakrin LW, Wardell JR: The effect of cholinergic agents on a canine model of allergic asthma. J Allergy Clin Immunol 58:19, 1976 26. Lee L-Y, Bleecker ER, Nadel JA: Effect of ozone on bronchomotor response to inhaled histamine aerosol in dogs. J Appl Physiol 43:626, 1977 27. Macklem PT, Mead J: Resistance of central and peripheral airways measured by a retrograde catheter. J Appl Physiol 22:395, 1967 28. Macklem PT, Mead J: Factors determining maximal expiratory flow in dogs. J Appl Physiol 25:159, 1968 29. Mauderly JL, Hahn FF: The effects of age on lung function and structure in adult animals. Adv Vet Sci Comp Med 26:35, 1982. 30. McPherson EA, Lawson GHK, Murphy J, et al: Chronic obstructive pulmonary disease (COPD): Identification of affected horses. Equine Vet J 10:47- 53, 1978
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31. Miller JE, Eyster G, DeYoung B, et al: Pulmonary function in dogs with mitral valve regurgitation. Am J Vet Res 47:2498, 1986 32. Miller A, Hyatt RE: Evaluation of obstructing lesions of the trachea and larynx by flow-volume loops. Am Rev Respir Dis 108:475, 1973 33. Murray JF: Postnatal growth and development of the lung. In The Normal Lung. Philadelphia, WB Saunders, 1986, p 23 . 34. Murray JF: Ventilation. In The Normal Lung. Philadelphia, WB Saunders, 1986, p 83 35. Pride NB: The assessment of airflow obstruction- role of measurements of airways resistance and tests of forced expiration. Br J Dis Chest 65:135, 1971 36. Robinson C, Holgate ST: Regulation by prostanoids. In Crystal RG, West JB (eds): The Lung: Scientific Foundations. New York, Raven, 1991, p 941 37. Robinson NE, Gillespie JR: Lung volumes in aging beagle dogs. J Appl Physiol 35:317, 1973 38. Robinson NE, Gillespie JR, Berry JD, et al: Lung compliance, lung volumes, and single-breath diffusing capacity in dogs. J Appl Physiol 33:808, 1972 39. Rotman HH, Liss HP, Weg JG: Diagnosis of upper airway obstruction by lung function testing. Chest 58:796, 1975 40. Scanlon PD, Seltzer J, Ingram RH, et al: Chronic exposure to sulfur dioxide: Physiologic and histologic evaluation of dogs exposed to 50 or 15 ppm. Am Rev Respir Dis 135:831, 1987 41. Shioya T, Solway J, Munoz NM, et a!: Distribution of airway contractile responses within the major diameter bronchi during exogenous bronchoconstriction. Am Rev Respir Dis 135, 1105, 1987 42. Shore SA, Bai TR, Wang CG, et al: Central and local cholinergic components of histamine-induced bronchoconstriction in dogs. JAppl Physiol 58:533, 1985 43. White MV, Kalliner MA: Regulation by histamine. In Crystal RG, West JB (eds): The Lung: Scientific Foundations. New York, Raven, 1991, p 927 44. Wilson TA, Hyatt RE: Forced expiration. In Crystal RG, West JB (eds): The Lung: Scientific Foundations. New York, Raven, 1991, p 1021 45. Woolcock AJ, Vincent NJ, Macklem PT. Frequency dependence of compliance as a test for obstruction in the small airways. J Clin Invest 48:1097, 1969
Address reprint requests to N. Edward Robinson, BVetMed, PhD, MRCVS Department of Large Animal Clinical Sciences G-321 Veterinary Medical Center Michigan State University East Lansing, Ml 48824-1314
0195-5616/92 $0.00 + .20
AIRWAY PHYSIOLOGY N. Edward Robinson, BVetMed, PhD, MRCVS
Dynamic compliance, pulmonary resistance, and tidal-breathing flow-volume loops are terms that are beginning to appear in the clinical literature describing respiratory diseases of dogs and cats. To most veterinarians, these are terms heard somewhere in a physiology course but long since forgotten. Therefore, the purpose of this article is to review the physiology behind these tests of respiratory function. Because the tests primarily indicate changes in airway caliber, a second purpose is to describe factors that regulate airway diameter. The respiratory system delivers oxygen and removes carbon dioxide at rates that are matched to metabolism. This function is usually carried out at little energy cost to the animal. Respiratory diseas.e makes the respiratory system less efficient, and usually the respiratory muscles must work harder in an attempt to compensate for tl;le inefficiency. The increased effort required to breathe is noticed by the pet owner, who then seeks treatment for the animal. Alternatively, the inefficiency of the respiratory system limits oxygen delivery to the tissues, and the owner describes exercise intolerance. Efficient functioning of the respiratory system requires the delivery of adequate ventilation through a system of tubes (the airways) into the alveoli. Here, air and blood are in close proximity, and gas exchange occurs. In the blood, oxygen is bound to hemoglobin for transport to the tissues. Adequate cardiac output and distribution of blood flow to metabolizing tissue are therefore essential for gas transport. Lack of exercise tolerance or signs of respiratory distress can indicate problems in any part of the oxygen delivery system, but many of the common diseases of dogs and cats primarily affect the airways. Viruses such as distemper and adenovirus in dogs or herpesvirus and calicivirus in cats From the Department of Large Animal Clinical Sciences, Michigan State University College of Veterinary Medicine, East Lansing, Michigan
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 22 • NUMBER 5 • SEPTEMBER 1992
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and inhaled allergens and irritants have their primary effects on airways. In brachycephalic animals, selective breeding has created special airway problems.
ANATOMY OF THE AIRWAYS
During ventilation, air flows through the tubes of the upper airway and tracheobronchial tree. Flow is opposed by the frictional resistance between air molecules and the walls of the air passages. In the resting animal, air flows through the nasal cavity, pharynx, and larynx, which warm and humidify the air and provide approximately 60% of the frictional resistance to breathing (Fig. 1). When airflow rates increase during exercise or when the nasal cavity is obstructed, dogs and cats may breathe through the mouth to bypass the high resistance of the nasal cavity. The upper airway is composed of both rigid and collapsible portions. The external nares provide a collapsible valve-like structure at the entrance to the respiratory tract. Cartilages and muscles allow the animal to actively regulate the diameter of the external nares. The bony nasal cavity is quite rigid. It is lined by a ciliated epithelium that provides for the transport of mucus, which traps inhaled materials. The mucosal lining of the nasal cavity is highly vascular, so that vascular engorgement can narrow the airway considerably and thereby increase the resistance to flow. The pharynx is a collapsible tube, the patency of which is maintained by the encircling muscles attached to the bony support of the hyoid apparatus. At the entrance to the trachea, the larynx provides yet another protective valve that also functions in
50-70% Trachea 40%
Bronchi Bronchioles 40% 20%
Figure 1. Partitioning of airway resistance in the dog. When the dog breathes through its nose, the upper airway contributes over 50% of the resistance; airways caudal to the larynx contribute the remainder. Mouth breathing greatly reduces upper airway resistance. Bronchioles constitute a small fraction of the total resistance.
AIRWAY PHYSIOLOGY
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vocalization. Cartilage plates and the intrinsic laryngeal muscles control the size of the air passage; that is, the glottis. The tracheobronchial tree has up to 24 branches, which are lined by a secretory, ciliated epithelium. 33 The larger airways, trachea, and bronchi are supported by cartilage and supplied with secretory bronchial glands. All larger airways, with the exception of the trachea and the first few centimeters of the main stem bronchi, are intrapulmonary and lie within a sheath of loose connective tissue, the bronchovascular bundle, which also contains major blood vessels, lymphatics: and nerves (Fig. 2). Bronchioles are epithelial-lined tubes surrounded by smooth muscle. They lack cartilage and a connective tissue sheath. Alveoli surround the intrapulmonary airways, and the alveolar septa attach to the outer layers of the bronchovascular bundle and to the walls of bronchioles. Except before birth, when the lung contains no air, the alveolar septa are always under tension, which provides radial traction around the airways and maintains their patency. The canine and feline lung has six lobes, each supplied by a lobar bronchus, which gives rise to "daughter" bronchi. At each division of the bronchi, the diameters of the daughter airways are not equal. One daughter airway is much narrower than the parent, whereas the diameter of the other is similar to the parent. This monopodia) system of branching continues through at least the first six generations of bronchi. At the level of the bronchioles, the diameters of parent and daughter bronchioles are the same. As a result of this branching pattern, the total cross-sectional area of the tracheobronchial tree increases only a little between the trachea and the first four generations of bronchi but increases dramatically toward the periphery of the lung33 (Fig. 3). Consequently, the velocity of airflow diminishes progressively from the trachea toward the bronchioles. The high-velocity, turbulent airflow in the trachea and bronchi produces the lung sounds heard through a stethoscope in a normal animal. Laminar, low-velocity flow in the bronchioles produces no sound. As a result of the branching pattern of the tracheobronchial tree, airways greater than 2 to 5 mm diameter, that is, the trachea and bronchi, contribute 60 to 80% of tracheobronchial resistance; bronchioles contribute only 20 to 40% (see Fig. 1). The tracheobronchial tree is lined by a mucociliary system consisting of secretory and ciliated epithelial cells33 (Fig. 4). The submucosal glands also add to the tracheobronchial secretions in the bronchi and trachea. The type of epithelial lining changes along the tracheobronchial tree from pseudostratified columnar in the trachea to cuboidal in the respiratory bronchioles. Goblet cells are not normally present in the bronchioles but can develop there in response to airway disease. 40 The submucosa of the larger airways contains a plexus of blood vessels derived from the bronchial circulation. This plexus, which warms the inhaled air, can vasodilate and give rise to airway wall edema when the airways are inflamed. Also located in the submucosa are sensory and motor branches of the autonomic nervous system supplying glands, blood vessels, and the airway smooth muscle. Smooth muscle is present in the walls of airways from the trachea
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Figure 2. A, The bronchovascular bundle in which a bronchus (BR), lined by columnar epithelium and surrounded by smooth muscle, lies in a sheath of loose connective tissue that also contains cartilage (CP), blood vessels (PA), lymphatics, glands (GO), and nerves. Alveolar septa do not connect directly to the wall of the bronchus. In disease, edema and exudates accumulate in the peribronchial space. B, A bronchiole (BL) lined by cuboidal epithelium and surrounded by smooth muscle lacks the connective tissue sheath typical of bronchi. The alveolar septa are connected almost directly to the wall of the bronchiole. As the lung inflates, the tension in the alveolar septa pulls open the bronchioles. PA = blood vessels. (From Staub NC: Basic Respiratory Physiology. New York, Churchill Livingstone, 1991 , pp 16-17, with permission.)
AIRWAY PHYSIOLOGY
CROSS SECTION (CM 2 )
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DIAMETER (CM)
1.00 Diameter
Cross section
0.10 10 ~~~--~~--~~~--~~~~~~0.01
6
12 18 AIRWAY GENERATION
24
Figure 3. Airway diameter and total cross-sectional area as a function of airway generation. Generation zero represents the trachea; bronchioles begin at about the eighth generation. Although airway diameter decreases as a function of generation number, the decrease in the distal airways is small. As a result, the total cross-sectional area of each generation increases from the bronchi to the bronchioles.
BRONCHUS
BRONCHIOLE
Figure 4. Anatomy of airway wall of a bronchus and bronchiole. The bronchus has a pseudostratified columnar ciliated epithelium, which contains goblet cells (G) and is overlain by a sol and a gel layer of mucus. Mucus also is provided by submucosal glands (GL), which hypertrophy in the presence of chronic stimulation. Smooth muscle (SM) can contract and narrow the airway. Cartilage plates (CA) stiffen the airway and prevent its collapse. The bronchiole is lined by cuboidal ciliated epithelium containing Clara cells (C). There are no mucus glands, and bronchioles do not normally contain goblet cells. SM encircles the airway below the epithelium.
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to the mouths of the alveoli. It forms a band on the dorsum of the trachea, where it connects the tips of the tracheal cartilages. As the amount of cartilage diminishes from the trachea to the bronchioles, the muscle gradually encircles the airway. In the bronchioles, the muscle forms a complete sleeve around the lumen of the airway. Contraction of airway smooth muscle obstructs the airway by narrowing the lumen and increasing the frictional resistance to breathing. LUNG COMPLIANCE AND PULMONARY RESISTANCE
After the first breath of life, the lungs are never empty. Between each tidal breath, at end-exhalation, the lungs contain about 45 mL!kg bw of air, a volume known as the functional residual capacity (FRC). 29 • 34• 37• 38 This provides a reservoir of air for gas exchange between breaths and reduces the effort necessary to breathe by keeping the peripheral airways open. At FRC, the elastic recoil of the lung is acting to collapse the lung or pull it away from the thoracic wall. As a result, pleural pressure (Ppl), the pressure within the potential space between the visceral and parietal pleura, is approximately 5 em H 2 0 subatmospheric (- 5 em H 20). During inhalation, the respiratory muscles contract in order to enlarge the thorax. As this happens, Ppl decreases so that the pressure difference between the atmosphere and the pleural cavity increases. This pressure difference, which is in opposition to the elastic recoil of the lung and the frictional resistance of the airways, causes the lung to inflate. 34 The magnitude of the decrease in Ppl during inhalation is determined by four factors: the size of each breath (i.e:, tidal volume [VT]), the compliance of the lung (CL), the air flow rate (V), and the resistance of the airways (RL). ~Ppl = VT/CL
+ RLV
In clinical situations, these same four factors must be considered when a dog or cat is presented with an exaggerated breathing effort. It may have ex~rcised recently and simply be taking bigger breaths (VT) with higher V. If the animal is resting, breath size and flow rates may be bigger because the animal is hypoxic. Alternatively, the exaggerated effort may be due to an increase in RL, a decrease in CL, or both. The maximal change in pleural pressure during breathing (~PplmaJ has been used as a test of respiratory function in horses. 30 Although an exaggerated ~Pplmax may suggest a change in respiratory function, it is not specific, because it can be affected by all the factors described above. ~Pplmax can be measured in two ways: either directly by puncture of the pleural space using a cannula connected to a pressure transducer or indirectly by means of a balloon on the end of a cannula placed in the thoracic esophagus just caudal to the heart. Horses and trained dogs 7 tolerate the esophageal balloon without anesthesia, but it is unlikely that such a procedure would be possible in the majority of
AIRWAY PHYSIOLOGY
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untrained dogs or cats. The excitement caused by passage of the balloon would tend to invalidate any subsequent measurements of ~Pplmax · Lung Compliance
Compliance is a measure of the ease with which a structure can be deformed. The normal lung is compliant and easily deformed, but the presence of lung disease makes it less easy to deform, that is, the lung becomes less compliant and is stiffer than normal. Measurement of. CL uses a manipulati~n of the equation shown earlier. When flow (V) ceases, the term RLV is zero, and the equation becomes LiPpi
= VT/CL
rearranging the equation CL = VT/~Ppl
In practical terms, measurement of CL requires that the dog or cat be anesthetized, because it is necessary to place an esophageal balloon to measure ~Ppl. An endotracheal tube also must be inserted and connected to a flow and/or volume measuring device in order to determine VT.
There are two ways to make V equal to zero. Following slight hyperventilation to induce apnea, the lungs can be inflated and then deflated in stepwise fashion by means of a very large syringe. 37 • 38 Brief pauses between each step allow flow to cease. Pressure is recorded at each pause, and a graph is drawn of the pressure versus volume (details are given in other references. 38 ) Lung compliance is the slope of the pressure-volume curve just above FRC (Fig. 5). Compliance calculated in this fashion is known as static lung compliance because air flow has definitely ceased when pressure is measured. Changes in static CL represent changes in the elastic behavior of the lung parenchyma, that is, the alveolar region. Normal values of static compliance have been published for dogs of various sizes. 29• 37• 38 Compliance is greater in large dogs than in small ones, because big dogs have bigger lungs. However, when compliance is divided by FRC to obtain the compliance of a unit volume of tissue, specific compliance values are independent of body size. Pneumonia with consolidation, pulmonary edema, fibrosis, and a lack of pulmonary surfactant all stiffen the lung and decrease static CL. More commonly, lung compliance is measured during tidal breathing. At the start and end of inhalation, there is a brief period when flow ceases (Fig. 6). The VT is divided by the Ppl difference between the start and end of inhalation to calculate lung compliance. 7• 13 Because compliance is measured during breathing, it is known as dynamic compliance (Cctyn)· The problem with this calculation is that the periods when flow is zero can be so transient that pressure has not equilibrated along the airways. Therefore, Cctyn is influenced by changes in airway
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VOLUME (ml) 400 300
Deflation/
200
/1'ntlation
100
0
10
20
PRESSURE (em H20)
30
Figure 5. Static pressure-volume curve of the lung of a small dog. Beginning at functional residual capacity (FRC), the lung was inflated incrementally to a transpulmonary pressure of 30 em H20 and was then deflated. The 5-cm H20 pressure at the start of inflation indicates a pleural pressure of minus 5 em H20 at FRC. Note that more pressure is required to maintain a given lung volume on inflation than on deflation. Lung compliance is the slope of the deflation limb of the pressure-volume curve over the range of tidal breathing (heavy line); that is, just above FRC.
resistance as well as in lung elasticity. A decrease in Cdyn can therefore be a result either of stiffening of the lung parenchyma or of intrapulmonary airway obstruction. Virtually all tracheobronchial diseases extending beyond the carina and all alveolar diseases can decrease c dyn• Airway Resistance
Airway resistance opposes the flow of air along the airways. Airway narrowing as a result of laryngeal paralysis, bronchospasm, or mucus accumulation can all increase RL. The measurement of RL is usually made simultaneous with measurement of Cdyn· The first equation shown is manipulated so that the term VT/CL is zero. .
= RLV
RL
.
rearranging the equation =
The various methods for setting the VT/CL equal to zero are beyond the scope of this article, but the advent of lung function computers has
AIRWAY PHYSIOLOGY
INSP Flow (ml/sec)
1051
EXP
100 50 0 · 50
Volume (ml)
75 50 25
Figure 6. Pleural pressure, air flow rate, and tidal volume recorded from an anesthetized cat. During inhalation, pleural pressure decreases, air flow rates increase, and air enters the lung." Toward the end of inhalation, flow rates decrease back to zero and the rate of increase of volume decreases. During exhalation, pleural pressure increases, air flow is reversed, and lung volume decreases. Because exhalation is passive in the healthy animal, flow rates peak early in exhalation.
Pressure (em H 2 0)
made the determination of both RL and Cctyn quite simple. If an endotracheal tube is in place when RL is measured, the contribution of the upper airway to RL is eliminated. To include the upper airway in measurements of RL, flow measuring devices must be attached to a face mask.
Interpretation of Changes in
Cdyn
and RL
In most diseases of the tracheobronchial tree, Cdyn decreases and increases. 7• 17• 31• 40 Occasionally, however, only one will be abnormal. The classical interpretation is that a decrease in Cctyn without an accompanying increase in RL is a result either of alveolar disease that stiffens the lung or of obstruction of the peripheral bronchioles that contribute little to the resistance to breathingY· 45 An increase in RL without a decrease in cdyn is due to obstruction of the upper airway, trachea, and large bronchi. However, a severe enough obstruction of a mainstem bronchus can decrease c dyn• It was pointed out earlier in this article that the upper airway constitutes more than 50%, and the trachea and bronchi provided another large fraction of RL (see Fig. 1). The peripheral airways provide RL
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a relatively small percentage of the total RL. 20• 27 This distribution of resistance is a result of the branching pattern of the airways and the large number of peripheral airways which are in paralleL Even though the resistance of one bronchiole is very high, thousands of bronchioles in parallel constitute only a small resistance. Extensive obstruction of the bronchioles is therefore necessary before there is a measurable increase in RL. DYNAMIC AIRWAY COLLAPSE
During both inhalation and exhalation, pressure gradients develop across the walls of the airways. These pressure gradients tend to change the size of the collapsible portions of the airways and therefore change airway resistance.
Extrathoracic Airway
The extrathoracic airways are surrounded by a relatively thin layer of tissue and skin, outside of which is ambient air at atmospheric pressure. During inhalation, pressure within the airway decreases below atmospheric pressure so that air is caused to flow into the respiratory tract (Fig. 7). The transmural pressure across the upper airway (the pressure difference between the inside and outside of the airway) therefore tends to suck the airway dosed (favors dynamic collapse). The tendency of the collapsible portions of the extrathoracic airway (the nares, pharynx, and larynx) to collapse on inhalation is normally opposed by contraction of various abductor muscles. When the abductor muscles are paralyzed, the consequences of the resulting dynamic collapse are clinically and physiologically very evident. 2• 12• 32 For example, consider a Doberman that has pulled on its choke collar for some time and has damaged the innervation of its larynx. At rest, this dog may have no apparent problem. This is because in the resting animal, the pressures necessary to generate air flow are quite small and are insufficient to cause clinically significant laryngeal collapse. Once the dog exercises, the problem becomes much more obvious: the dog begins to make an inspiratory noise, has inspiratory dyspnea, and may even collapse. To generate the increased air flow rates necessary for exercise, pressure within the airways must decrease more than in the resting animaL This decrease in pressure is now sufficient to narrow the larynx and obstruct the airway. As the larynx narrows, the velocity of airflow through the narrowed glottis must increase. Just as the higher velocity airflow over the curved upper surface of an aircraft wing reduces pressure above the wing and causes the aircraft to rise, the increased velocity of airflow through the narrowed glottis leads to a further decrease in pressure within the glottis and further narrowing. If the dog tries harder to inhale, pressures
AIRWAY PHYSIOLOGY
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B
Figure 7. Pressures in the upper airway of a terrier and a dog of a brachycephalic breed. During inhalation in the terrier, (A) pressures in the airway are slightly negative (subatmospheric). During exhalation (B) the pressures are greater than atmospheric. Because the airway is well supported by the surrounding tissues and because there are no excessive folds of loose tissue, the airway diameter does not change greatly during inhalation and exhalation. In the dog of a brachycephalic breed inhaling at rest (C), pressures are more subatmospheric than in the terrier because of the resistance provided by the narrow nares and excessive tissue folds. When the dog inhales forcefully (D),' pressures decrease dramatically, and the loose folds of tissue are sucked into the airway lumen, resulting in obstruction. During forced exhalation (E), the loose tissues tend to be blown out of the air passageway by the high pressures. The brachycephalic breed is therefore demonstrating dynamic inspiratory collapse of the upper airway.
decrease further and the airway collapses more. This vicious cycle of events can continue until the glottis is completely obstructed. Air flow becomes independent of effort, because the harder the dog tries, the more the resistance to air flow increases. The dog has no problem exhaling, however, because during exhalation, pressure within the airway exceeds the surrounding atmospheric pressure. The transmural pressure therefore tends to dilate the airway. Dynamic collapse of the upper airway therefore causes inspiratory airway obstruction, inspiratory dyspnea (increased inspiratory effort and time), and abnormal sounds during inhalation. 2 Dynamic extrathoracic airway compression also occurs in dogs with collapse of the extrathoracic trachea. 1 In these animals, a normally rigid tube, the trachea, has become more compliant and is susceptible to dynamic compression during inhalation. The elliptical cross-section of the trachea of these dogs also makes it more susceptible to collapse than the more circular cross-section of the normally shaped canine trachea.
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+1
+2
A
0
+I
B
Figure B. Diagrammatic representation of pleural, alveolar, and airway pressures during quiet inhalation (A) and passive exhalation (B) in a normal dog. Alveolar pressure exceeds pleural pressure because of the elastic recoil of the lung. Pleural pressure is less than airway pressure during both inhalation and exhalation. As a result, the intrathoracic airways tend to dilate.
Brachycephalic breeds are particularly prone to dynamic obstruction of the upper airway. 1 These animals have narrow nares and excessive folds of tissue in the pharynx. 16 These obstruct the air passages, so that the dog must generate large pressure changes to move air (Fig. 7). The larynx of these animals therefore is probably chronically exposed to greater pressure changes than those occurring in the dolichocephalic breeds. The exaggerated pressure decrease during inhalation tends to draw the soft palate into the glottis and over time may lead to saccular eversion and, eventually, to laryngeal collapse. The upper airway presents fewer problems during exhalation. Pressures within the airway are greater than atmospheric pressure and therefore tend to dilate the airway (Fig. 7).
Intrathoracic Airway
Whereas dynamic airway collapse tends to occur during inhalation in the extrathoracic airway, it occurs during forced exhalation in the intrathoracic airway. 21• 22• 28 • 44 This is clinically obvious in dogs with collapsing trachea. Intrathoracic collapse occurs during cough or other forced exhalations, and extrathoracic collapse occurs during inhalation. The intrathoracic airways are surrounded by the pleural cavity or by the lung, which is itself surrounded by the pleural cavity. Therefore, the transmural pressure across the wall of the intrathoracic airway is the difference between airway and pleural pressure. To expand the lung and make air flow from the trachea to the alveoli during inhalation, pleural pressure must decrease more than airway pressure (Fig. 8). The transmural pressure across the wall of the intrathoracic airway therefore tends to cause dilation.
AIRWAY PHYSIOLOGY
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During a passive exhalation, the respiratory muscles relax and the elasticity of the lung compresses the gas in the alveoli so that pressures throughout the airways increase and air flows out. Under these conditions, pressure within the airways still exceeds Ppl and dynamic collapse does not occur (Fig. 8). During a forced exhalation, the situation is very different (Fig. 9A). 28 Ppl increases well above atmospheric pressure. The pressure within the alveolus is somewhat higher than Ppl because of the elastic recoil of the alveoli. Because of frictional pressure losses, pressure decreases from the alveoli toward the larynx and, at some point in the airway, pressure within the lumen of the air passage becomes equal to Ppl. Between this equal pressure point and the thoracic inlet (downstream), the transmural pressure favors airway compression. As the airway becomes compressed, air must accelerate through the narrowed portion. As previously described, this causes a further pressure decrease and further narrowing. If the dog makes a greater effort to exhale, the airway is compressed even more and flow does not increase. Flow thus becomes independent of the effort being applied by the dog. If there is diffuse obstruction of the bronchioles, the increased resistance accentuates the pressure decrease along the airways. The point at which airway pressure equals Ppl moves closer to the alveoli and more airway is compressed (Fig. 9B). Thus, flow becomes further limited.
FLOW-VOLUME LOOPS
A common diagnostic test applied to humans is the maximal expiratory flow-volume maneuver. 4• 12• 32• 35• 39 In this procedure, an individual inhales maximally to total lung capacity (TLC) and then exhales with maximal effort as much as possible; that is, to residual Figure 9. Diagrammatic representation of pleural, alveolar, and airway pressures during forced exhalation in a normal dog and in one with peripheral airway obstruction. Pleural pressure is greater than atmospheric pressure (i.e., it is positive). When pleural pressure exceeds pressure within the intrathoracic airway, the latter is compressed (A). When the resistance of the airways close to the alveoli is increased by a peripheral airway obstruction (8), the pressure drop along the airways is increased; therefore, the point at which airway pressure equals pleural pressure moves upstream toward the alveoli. As a result, more of the intrathoracic airway is dynamically collapsed.
0
+3
+6
A
o:._ _:+_:2:__~r-'"""' B
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volume (RV). The total volume of air expelled is referred to as the vital capacity (VC). This type of lung function test can only be attempted in anesthetized small animals in which maximal flow is generated by a vacuum source or by application of a positive pressure to the chest wall. Air flow rate is plotted against lung volume (Fig. 10) and it can be shown when this maneuver is conducted with increasing effort that, below 70% VC, there is a maximal expiratory flow that is independent of effort. 21 • 22• 44 The maximal flow is a result of dynamic airway compression. If more force is applied, the airway becomes more compressed and flow does not increase further. Although the equal pressure point provides a simple explanation of flow limitation, a much more complex explanation is necessary to explain all the factors affecting maximal expiratory flows. 44 Suffice it to say that maximal flow is a function of lung volume, the elastic recoil of the lung, and airway resistance. By increasing the frictional pressure losses along the airway, airway obstruction causes more airway to be subjected to compression (Fig. 9B). As a result, maximal flows are reduced. In human medicine, the maximal expiratory flow volume maneuver has gained popularity because it is noninvasive and can easily be performed by a cooperative individual who blows through a flowmeter. There is no need for measurement of Ppl. Decreases in maximal
12
Flow IIsee
10
8 6 -
2
(b)
0
100
..1._ ..-L _
~
~
_y___l______.L.....~--L__ ~
~
j____L__ _l. __ _l.__L__l.
w
0
o/o Vital capacity Figure 10. Maximal expiratory flow-volume curve. Flow is plotted as a function of lung volume expressed as percent vital capacity. During a resting tidal exhalation (curve a), the volume exhaled is small and the flow rates are low. As the dog increases the lung volume at which exhalation begins (curves b, c, and d) and increases the effort to exhale, the volume exhaled and the flow rates increase. However, curves b, c, and d merge and flow rates become independent of effort as lung volume decreases (arrows). Flow rate becomes independent of effort because of the mechanical properties of the lung; that is, the airway resistance and lung compliance are limiting flow.
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expiratory flows indicate intrathoracic airway disease. 4 • 21 • 22• 35 Similarly, maximal inspiratory flow-volume maneuvers can be used to diagnose extrathoracic airway obstructions. The problem with the use of these tests in animals is that they require patient cooperation to generate the maximal flows. Recently, however, it has been shown that useful information can be gained by examination of flow-volume loops generated during tidal breathing (Fig. 11). 1• 2 This observation brings the use of flow-volume loops into the realm of clinical usefulness for dogs and cats (see the article by McKiernan elsewhere in this issue).~
FACTORS AFFECTING AIRWAY FUNCTION Extrathoracic Airway
Extrathoracic airway obstructions can be either fixed or dynamic. 12• 13• 39 Fixed obstructions include masses such as neoplasia, foreign bodies, stenoses of the trachea, and inflammatory diseases of the nasal cavity. These obstructions are present all the time and therefore increase the resistance to breathing during both inhalation and exhalation. Respiratory distress and abnormal sounds occur during all phases of respiration. Flow-volume loops from animals with fixed upper airway obstructions show reductions in both inspiratory and expiratory flows (Fig. 11). Dynamic (nonfixed) obstructions are functional obstructions that FIXED (TYPE 3; N = 10)
NON FIXED (TYPE 2; N 17)
NORMAL (TYPE 1; N 3)
=
=
1.0 1.0
z
PEF
0
~
0.5
~a:
Cll -
:::J ~
~w
3::
0.0
0 z ...1 0 u.. ~
400
0.0
600 0.5
a:
a:
(f)
~
1.0
IF 25 PIF
IF 50
1.0
VOLUME(ml) Figure 11. Tidal-breathing flow-volume loops from a normal dog, a dog with a nonfixed upper airway obstruction, and a dog with a fixed upper airway obstruction. The various indices of loop shape are shown on the loop of the normal dog. The nonfixed obstruction is a result of dynamic compression of the upper airway and therefore limits inspiratory flow. The fixed obstruction limits both inspiratory and expiratory flow. (From Amis T, Smith MM, Gaber CE, et al: Upper airway obstruction in canine laryngeal paralysis. Am J Vet Res 47:1007, 1986; with permission.)
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result from either failure of the abductor muscles of the upper airway or increased compliance of the airway, particularly the trachea. As a result of these changes, the airway collapses during inhalation, respiratory distress and abnormal sounds occur on inhalation, and the flowvolume loop reveals reduced inspiratory but normal expiratory flows (Fig. 11). The brachycephalic breeds often have a combination of fixed and dynamic obstruction. The excessive tissue folds impede both inhalation and exhalation but collapse further into the airway during inhalation (Fig. 7). 1 Intrathoracic Airway
The intrathoracic airway can be affected by fixed obstructions such as foreign bodies or stenoses that reduce both inspiratory and expiratory flow. Dynamic collapse is best exemplified by collapsing intrathoracic trachea that causes obstruction only during exhalation. The most common airway diseases, however, are accompanied by airway obstruction, increased RL, decreased c dyn' and decreased expiratory flows as a result of smooth muscle contraction, mucus accumulation, or airway wall edema. Many of these changes are a result of inflammation accompanied by the release of mediators that cause obstruction either by contracting airway smooth muscle, increasing mucus secretion, or increasing vascular permeability. In addition, some of these mediators can make the smooth muscle hyperresponsive to stimuli. A group of dogs with inherently hyperresponsive airways also has been reported. 17 The neurohumoral regulation of airway function forms the topic of the remainder of this article. Autonomic Regulation of Airways Excitatory Innervation
The major excitatory innervation to smooth muscle is the parasympathetic system (Fig. 12). 3 It reaches the lung in the vagus nerve, and its ganglia are located in the airway wall. The short postganglionic fibers release acetylcholine (Ach), which binds to muscarinic M3 receptors. In airway smooth muscle, this results in contraction and airway narrowing; in mucus glands, binding causes mucus secretion. Although muscarinic receptors are located throughout the tracheobronchial tree, the density of parasympathetic innervation is greatest in the larger airways, and stimulation of the vagus causes the greatest airway constriction in the medium-sized bronchi. In normal dogs and cats, atropine reduces RL, showing that there is always some parasympathetically mediated smooth muscle tone. 7• 15 The parasympathetic system is activated when sensory receptors in and beneath the airway epithelium are stimulated by irritants such as dusts and some gases. Inflammatory mediators, particularly histamine, also can activate
AIRWAY PHYSIOLOGY
Sensory Irritant re eptors
1059
Autonomic
C-fibers
NE
VIP
ACh
Smooth Muscle
Airway lumen Figure 12. Diagrammatic representation of the nerves supplying airway smooth muscle. Sensory and autonomic (motor) nerves are shown. ACh = acetylcholine, M = muscarinic receptor, NANG = nonadrenergic noncholinergic nervous system, NE = norepinephrine, SP = substance P, VIP = vasoactive intestinal peptide, ~ = beta-adrenergic receptor.
sensory receptors and cause parasympathetically mediated bronchospasm. For this reason, atropine and other parasympatholytic (anticholinergic) agents can be used as bronchodilators in animals with bronchospasm resulting from allergic responses and airway inflammation (Fig. 13).5· 7. 19, 25, 26, 42 The release of Ach from parasympathetic nerves is regulated by a variety of factors. 3 Ach apparently inhibits its own release via muscarinic M2 receptors located prejunctionally on parasympathetic nerves. Some viral infections damage M2 receptors so that this feedback inhibition is lost11 and the response of smooth muscle to parasympathetic stimulation is exaggerated. 11 • 23 Catecholamines also inhibit Ach release. Sympathetic nerves impinge on the parasympathetic system and release norepinephrine that binds to beta 1 or alpha2-receptors to cause inhibition. The alpha2 agonists, xylazine and detomidine, used for restraint can therefore have bronchodilator actions by binding to alpha2 receptors. Prostaglandin E2 , a major product of normal airway epithelium, is a potent inhibitor of Ach release. Experimentally, prolonged administration of the cyclooxygenase inhibitor, indomethacin, has been shown to cause hyperirritability of airways in dogs. 18 A second excitatory innervation, the noncholinergic system, has
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5 Resistance (em H20/lisee)
4 3
2 '+- ----- ----- --- ----+
1
Antigen 5
Time1Pmins)
15
20
Figure 13. The effect of antigen challenge on airway resistance in allergic dogs. The increase in resistance caused by antigen is reversed in the atropine-treated animal (broken line), but not in the control (solid line) animal, indicating activation of muscarinic receptors during the response to allergen.
been described more recently. 3 The mediators of this system are neuropeptides (tachykinins) such as substance P. They are apparently released locally, probably through axon reflexes, when sensory nerves are stimulated by irritants. The release of tachykinins results in prolonged bronchospasm and edema of the airway wall. Tachykinins also can increase the release of Ach. These substances are metabolized by proteases on the epithelium and elsewhere. Damage to the epithelium by viruses and some industrial pollutants can therefore prolong the actions of tachykinins. At present, there is no commercially available blocker of tachykinin receptors. Inhibitory Innervation
There are two inhibitory nervous systems supplying the airways: the sympathetic system and the nonadrenergic-noncholinergic (NANC) system. 3 Airway smooth muscle and epithelium is richly supplied with beta-adrenergic (primarily beta2) receptors. These receptors are activated either by the release of norepinephrine from sympathetic nerves or by circulating catecholamines from the adrenal medulla. In both the dog and the cat, there is direct sympathetic innervation of bronchial smooth muscle. The tracheal smooth muscle receives sympathetic innervation in the cat but not in the dog.6• 24 Sympathetic nerves are activated during flight and fight reactions and, presumably, the small amount of resting airway tone is abolished when the beta receptors are activated. Whether the sympathetic system is activated in the presence of airway disease is not clear. The observation that beta-adrenergic blockade enhances airway obstruction in humans and animals with airway
AIRWAY PHYSIOLOGY
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disease suggests that the normal circulating levels of catechola.mines may be sufficient to activate airway beta receptors. The extensive presence of betaz receptors is made use of in the treatment of bronchospasm by administration of specific betaz agonists. The NANC inhibitory system runs in the vagus nerve and the mediator, probably vasoactive intestinal peptide (VIP) may be coreleased with Ach. The NANC system has been clearly demonstrated in cats8 but not in dogs. Because the mediator is a peptide, it is easily broken down by the proteases that are released from mast and, other cells during the inflammatory response. The NANC system therefore may not be functional in the presence of airway inflammation. The stimuli that activate the NANC system have not been well defined. Mediators in Airway Disease
The list of mediators released from and produced by cells in the allergic and other inflammatory response increases almost daily. No one mediator is responsible for all the changes observed in a particular disease. Mediators are released in a cascade and interact with one another. Mediators produced by one cell may even be taken up and modified by another cell. The mediators thought to be important in airway disease include histamine, the leukotrienes, and some of the prostanoids. Their effects vary in intensity at different levels of the tracheobronchial tree. 41 Histamine is a preformed mediator that is released from mast cells when antigen binds to IgE on mast cell surface during the immediate allergic response. 43 Histamine binds to either H 1 or Hz receptors on a variety of tissues. Activation of the H 1 receptors on muscle causes bronchospasm. Activation of the same receptor type stimulates irritant receptors and causes cough and reflexly mediated bronchospasm. 9 The activation of H 1 receptors also is responsible for vasodilation, airway wall edema, and pruritis. The Hz receptors are responsible for airway mucus secretion and may act to inhibit smooth muscle contraction in some species. Histamine probably is only important in the immediate hypersensitivity reaction, that is, the bronchospasm that occurs within 15 minutes of antigen challenge. Antihistamines (H1 blockers) prevent bronchospasm in this reaction but not in the more delayed responses that are accompanied by airway inflammation. The delayed response occurs several hours after antigen challenge, when neutrophils migrate into the airway wall and lumen. Airways become obstructed by smooth muscle contraction, mucus secretion, and airway wall edema. Feline asthma is most likely a delayed response. Leukotrienes are products of the lipoxygenase pathway of the arachidonic acid cascade (Fig. 14). 10 Leukotrienes are produced by neutrophils, eosinophils, mast cells, macrophages, airway epithelium, and vascular endothelium. There are a variety of biologically active leukotrienes but particularly potent in the lung are the sulfidopeptide leukotrienes (LTC4 , LTD4 , and LTE4), formerly known as slow-reacting substance of anaphylaxis. The sulfidopeptide leukotrienes are very
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Membrane phospholipids
I
Arachidonic acid Cyclooxygenase I
I
I
I
5-LipoXjgenase I
I
PG~ PG~ PGD2 PGF2 TXA 2
LTA4 I
I
5-HETE
I
Figure 14. The arachidonic acid cascade. PG = prostaglandin; LT = leukotriene; TX = thromboxane; HETE = hydroxyeicosatetraenoic acid.
potent bronchoconstrictors. with a much longer duration of action than histamine. Leukotrienes also increase the permeability of blood vessels. The recent advent of potent, specific antagonists is allowing investigation of the role of leukotrienes in airway disease. There is increasing evidence that leukotrienes play an important role in human asthma and in some experimentally induced delayed hypersensitivity responses in animals. Prostanoids are products of the cyclooxygenase pathway of arachidonic acid metabolism (Fig. 14). 36 There are prostanoids such as PGE2 that are bronchodilators; others such as PGF2aiph• and thromboxane are bronchoconstrictors. Some of the actions of both histamine and leukotrienes are mediated through secondary production of prostanoids. Because prostanoids can modulate release of Ach, they may be responsible for some of the airway hyperresponsiveness that occurs in inflammatory airway disease. 5· 26 However, the role of prostanoids in airway disease appears to be secondary, because cyclooxygenase inhibitors such as aspirin do not provide a major therapeutic benefit. SUMMARY
The understanding of the mechanisms of dog and cat airway disease is in its infancy, because the clinical tools necessary to measure airway function in patients have not been readily available. The advent of lung function computers that can rapidly analyze flow-volume loops and calculate Cdyn and RL will make it easier to evaluate airway function in disease and to detect the effects of the newer specific receptor blockers. In the not-too-distant future, measurements of lung function will be used to prove the efficacy of new therapeutic agents for canine and feline airway disease and to guide the clinician in the use of these agents. References 1. Amis T, Kurpershoek C: Tidal breathing flow-volume loop analysis for clinical assessment of airway obstruction in conscious dogs. Am J Vet Res 47:1002, 1986
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2. Amis T, Smith MM, Gaber CE, et a!: Upper airway obstruction in canine laryngeal paralysis. Am J Vet Res 47:1007, 1986 3. Barnes PJ: Neural control of airway smooth muscle. In Crystal RG, West JB (eds): The Lung: Scientific Foundations. New York, Raven, 1991, p 903 4. Berend N, Woolcock AJ, Marlin GE: Correlation between the function and structure of the lung in smokers. Am Rev Respir Dis 119:695, 1979 5. Chung KF, Becker AB, Lazarus SC, et a!: Antigen-induced airway hyperresponsiveness and pulmonary inflammation in allergic dogs. J Appl Physiol 58:1347, 1985 6. Dahlstrom A, Fuxe K, Hokfelt T, et a!: Adrenergic innervation of the bronchial • muscle of the cat. Acta Physiol Scand 66:507, 1966 7. Dain D, Gold WM: Mechanical properties of the lungs and experimental a?thma in conscious allergic dogs. J Appl Physiol 38:96, 1975 8. Diamond L, O'Donnell M: A nonadrenergic vagal inhibitory pathway to feline airways. Science 207:185, 1980 9. Dixon M, Jackson OM, Richards IM: The effects of H 1 and H 2 receptor agonists on total lung resistance, dynamic lung compliance and irritant receptor discharge in the anaesthetized dog. Br J Pharmacol 66:203, 1979 10. Drazen JM: Regulation by leukotrienes. In Crystal RG, West JB (eds): The Lung: Scientific Foundations. New York, Raven, 1991, p 917 11. Fryer AD, Jacoby DB: Parainfluenza virus infection damages inhibitory M2 muscarinic receptors on pulmonary parasympathetic nerves in the guinea-pig. Br J Pharmacal 102:267, 1990 12. Gibson GJ, Pride NB, Emprey DW: The role of inspiratory dynamic compression in upper airway obstruction. Am ·Rev Respir Dis 108:1352, 1973 13. Gould WM, Boushey HA: Pulmonary function testing. In Murray JF, Nadel JA (eds): Textbook of Respiratory Medicine. Philadelphia, WB Saunders, 1988, p 611 14. Gould WM, Kessler G-F, Yu DYC: Role of vagus nerves in experimental asthma in allergic dogs. J Appl Physiol 33:719, 1972 15. Hahn HL, Graf PO, Nadel JA: Effect of vagal tone on airway diameters and on lung volume in anesthetized dogs. J Appl Physiol 41 :581, 1976 16. Hendricks JC, Kline LR, Kovalski RJ, et a!: The english bulldog: A natural model of sleep-disordered breathing. J Appl Physiol 63:1344, 1987 17. Hirshman C, Malley A, Downes H: Basenji-greyhound dog model of asthma: Reactivity to Ascaris suum, citric acid, and methacholine. J Appl Physiol 49:953, 1980 18. Ito Y: Prejunctional control of excitatory neuroeffector transmission by prostaglandins in the airway smooth muscle tissue. Am Rev Respir Dis 143:56, 1991 19. Holtzman MJ, Fabbri LM, O'Byrne PM, eta!: Importance of airway inflammation for hyperresponsiveness induced by ozone. Am Rev Respir Dis 127:686, 1983 20. Hoppin FG, Green M, Morgan MS: Relationship of central and peripheral airway resistance to lung volume in dogs. J Appl Physiol 44:728, 1978 21. Hyatt RE: Expiratory flow limitation. J Appl Physiol 55:1, 1983 22. Hyatt RE, Black LF: The flow-volume curve: a current perspective. Am Rev Respir Dis 107:191, 1973 23. Killingsworth CR, Robinson NE, Adams T, et al: Cholinergic reactivity of tracheal smooth muscle after infection with feline herpesvirus I. J Appl Physiol 69:1953, 1990 24. Knight OS, Hyman AL, Kadowitz PJ: Innervation of intrapulmonary airway smooth muscle of the dog, monkey and baboon. J Auton Nerv Syst 3:31, 1981 25. Krell RD, Chakrin LW, Wardell JR: The effect of cholinergic agents on a canine model of allergic asthma. J Allergy Clin Immunol 58:19, 1976 26. Lee L-Y, Bleecker ER, Nadel JA: Effect of ozone on bronchomotor response to inhaled histamine aerosol in dogs. J Appl Physiol 43:626, 1977 27. Macklem PT, Mead J: Resistance of central and peripheral airways measured by a retrograde catheter. J Appl Physiol 22:395, 1967 28. Macklem PT, Mead J: Factors determining maximal expiratory flow in dogs. J Appl Physiol 25:159, 1968 29. Mauderly JL, Hahn FF: The effects of age on lung function and structure in adult animals. Adv Vet Sci Comp Med 26:35, 1982. 30. McPherson EA, Lawson GHK, Murphy J, et al: Chronic obstructive pulmonary disease (COPD): Identification of affected horses. Equine Vet J 10:47- 53, 1978
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31. Miller JE, Eyster G, DeYoung B, et al: Pulmonary function in dogs with mitral valve regurgitation. Am J Vet Res 47:2498, 1986 32. Miller A, Hyatt RE: Evaluation of obstructing lesions of the trachea and larynx by flow-volume loops. Am Rev Respir Dis 108:475, 1973 33. Murray JF: Postnatal growth and development of the lung. In The Normal Lung. Philadelphia, WB Saunders, 1986, p 23 . 34. Murray JF: Ventilation. In The Normal Lung. Philadelphia, WB Saunders, 1986, p 83 35. Pride NB: The assessment of airflow obstruction- role of measurements of airways resistance and tests of forced expiration. Br J Dis Chest 65:135, 1971 36. Robinson C, Holgate ST: Regulation by prostanoids. In Crystal RG, West JB (eds): The Lung: Scientific Foundations. New York, Raven, 1991, p 941 37. Robinson NE, Gillespie JR: Lung volumes in aging beagle dogs. J Appl Physiol 35:317, 1973 38. Robinson NE, Gillespie JR, Berry JD, et al: Lung compliance, lung volumes, and single-breath diffusing capacity in dogs. J Appl Physiol 33:808, 1972 39. Rotman HH, Liss HP, Weg JG: Diagnosis of upper airway obstruction by lung function testing. Chest 58:796, 1975 40. Scanlon PD, Seltzer J, Ingram RH, et al: Chronic exposure to sulfur dioxide: Physiologic and histologic evaluation of dogs exposed to 50 or 15 ppm. Am Rev Respir Dis 135:831, 1987 41. Shioya T, Solway J, Munoz NM, et a!: Distribution of airway contractile responses within the major diameter bronchi during exogenous bronchoconstriction. Am Rev Respir Dis 135, 1105, 1987 42. Shore SA, Bai TR, Wang CG, et al: Central and local cholinergic components of histamine-induced bronchoconstriction in dogs. JAppl Physiol 58:533, 1985 43. White MV, Kalliner MA: Regulation by histamine. In Crystal RG, West JB (eds): The Lung: Scientific Foundations. New York, Raven, 1991, p 927 44. Wilson TA, Hyatt RE: Forced expiration. In Crystal RG, West JB (eds): The Lung: Scientific Foundations. New York, Raven, 1991, p 1021 45. Woolcock AJ, Vincent NJ, Macklem PT. Frequency dependence of compliance as a test for obstruction in the small airways. J Clin Invest 48:1097, 1969
Address reprint requests to N. Edward Robinson, BVetMed, PhD, MRCVS Department of Large Animal Clinical Sciences G-321 Veterinary Medical Center Michigan State University East Lansing, Ml 48824-1314