Asthma: Pathophysiology and Clinical Correlates

Symposium on Pulmonary Disease

Asthma Pathophysiology and Clinical Correlates

E. R. McFadden, Jr., MD.,* and Neil T. Feldman, MD. **

The word "asthma" is derived from the Greek CY.pOf.LCY. which means "to pant." It was originally used as a synonym for breathlessness from the first millenium BC until well into the seventeenth century and as such it represented a catch-all phrase that described the symptomatic manifestations of a variety of cardiac and pulmonary diseases. In the late eighteenth and early nineteenth centuries, as knowledge advanced, sporadic efforts began to be made to try to restrict the use of the word to a specific clinical syndrome, but these efforts did not bear fruit until the early part of this century. Now the term is used exclusively to describe a respiratory illness that consists of episodic bouts of a characteristic set of signs and symptoms. Although there still is no universal agreement on a precise definition, it is useful to describe asthma as a disease that is characterized by increased responsiveness of the tracheobronchial tree to a multiplicity of stimuli which is manifested physiologically by widespread narrowing of the tracheobronchial tree that can change in severity either spontaneously or as the result of therapy, and clinically by paroxysms of cough, dyspnea, and wheezing.! Thus the physiologic hallmark is airway obstruction and the symptoms result from impedance of the movement of air into or out of the lungs. Explicit in this definition is reversibility; thus, unlike other chronic diseases with airway obstruction, fibrosis and parenchymal destruction do not occur and the impediment to flow is due to a variable combination of smooth muscle contraction, mucosal edema, and the secretion and/or lack of clearance of mucus. Also unlike other forms of airway disease, asthma usually does not have a relentlessly progressive course, but rather it is a somewhat capricious disease that is characterized by great variability of clinical expression both be"Associate Professor of Medicine, Harvard Medical School; Director, Pulmonary Function Laboratory, Peter Bent Brigham Hospital, Boston, Massachusetts '''''Assistant Professor of Medicine, Harvard Medical School; Respiratory Division, Peter Bent Brigham Hospital, Boston, Massachusetts Medical Clinics of North America- Vol. 61, No. 6, November 1977

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tween patients and in the same patients at different times. The symptomatic manifestations of asthma can be viewed as a continuum that extends from complete normalcy by both functional and clinical criteria at one extreme through status asthmaticus with respiratory failure at the other. The intermediate stages consist of an asymptomatic state with functional defects, symptomatic stages with varying degrees of airway obstruction and status asthmaticus without respiratory failure. Currently there is very little information available as to how a patient spontaneously progresses from being asymptomatic to becoming acutely ill, but recent data suggest that the baseline status of lung function plays a prime role in determining the patient's response to provocational stimuli. If one gives the identical challenge to a group of asthmatics over a period of time, there is a good direct correlation between the magnitude and severity of the induced attack and the degree of obstruction that was present before the constrictor stimulus was applied;2. 6 the more normal the patient's lung function, the less the response; the more abnormal the lung function, the greater the response. It is intriguing that this result seems to occur irrespective of the type of challenge used, suggesting that it is not a function of the stimulus, but has to do with the state of the airways themselves. Another important clinical association, but one that needs further investigation, is that there seems to be a group of individuals who do relatively well with their disease for considerable periods of time, yet when an acute exacerbation develops, it tends to be quite severe, and often these patients will have acute respiratory failure. The reasons for this type of behavior are unknown, but it is possible that these patients may have an acquired or congenital abnormality in the control of ventilation in addition to their asthma. Studies of the control of ventilation in asthma are limited, but Rebuck and Read26 have found blunted carbon dioxide responsiveness in 5 of 20 asthmatics they studied and Hudgel and Weils have shown subnormal hypoxic ventilatory drives in some of their subjects. These observations are of more than academic interest since many of the patients described in the above investigations present with disproportionately severe hypoxemia and hypercapnia when acutely ill. At present there is virtually no information available as to the frequency with which this is seen in a general asthmatic population, and clinical experience suggests that it is apt to be uncommon. Nevertheless, it is important to keep in mind, and, if one encounters an asthmatic who has repeated episodes of respiratory failure in association with acute airway obstruction, consideration should be given to evaluating the integrity of ventilatory control mechanisms. Since asthma is such a common disorder one would think that it would be possible to describe its pathophysiology, clinical course, and immunobiology with great precision. Unfortunately, this is not yet the case. Only in the last 15 years have systematic studies been undertaken in an attempt to detail the extent and type of functional abnormalities present in acute asthma. Knowledge of their mechanisms and clinical correlates and how they respond to therapy is still incomplete. We do know that when large numbers of symptomatic patients who

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present for treatment of acute episodes are studied, their lung function is apt to show the following derangements in a statistical sense. Forced expiratory volume and flow rates will all be depressed. The forced vital capacity (FVC) will tend to be the best preserved index on a spirogram and can be expected to range between 80 per cent and 20 per cent predicted with an average of 50 per cent.14 One second forced expiratory volumes (FEV J) will average around 30 per cent of the predicted value and the mean for various flow rates will be less than 20 per cent of the predicted value. 14 Hyperinflation is invariably present. The most abnormal lung volume will be residual volume (RV) which tends to be between 300 and 600 per cent of normal with the average being around 400 per cenU 4 Functional residual capacity (FRC) is usually double normal and total lung capacity (TLC) is usually normal or only slightly elevated. 12 ,11 Occasionally, with very severe and prolonged obstruction, residual volume can truly become gigantic and total lung capacity can increase by as much as 2 liters. 12 , 14, 3J When arterial blood gases are examined, the commonest finding is a combination of moderate arterial hypoxemia (Po 2 = 50 to 70 mm Hg at sea level), hypocapnia and respiratory alkalosis.1 6 , 29 If the FEV, is less than 25 per cent predicted, arterial CO 2 tends to normalize; if the obstruction is very severe (FEVIless than 15 per cent of predicted), modest degrees of hypercapnia occur. In terms of frequencies of each pattern, the literature suggests that approximately 75 per cent of untreated acutely ill asthmatics will have respiratory alkalosis, 15 per cent will have normal pH and arterial carbon dioxide tensions, and 10 per cent or less will have respiratory acidosis. It should be emphasized that a normal carbon dioxide tension in an acu tely ill asthmatic is a serious finding and should be viewed as impending respiratory failure. All sick asthmatics will have hypoxemia, but in 90 per cent or so the arterial saturation will be only mildly disturbed because of the leftward shift of the oxyhemoglobin association-dissociation curve produced by alkalosis.'s Metabolic acidosis is very uncommon in uncomplicated asthma in adults, but is seen more frequently in children30 for reasons not yet completely understood, but that presumably relate to compromised cardiac function. Usually there are no clinical counterparts to the derangements in blood gases. Cyanosis is a very late sign. Consequently, dangerous levels of hypoxia can go undetected. Similarly, the signs of acute hypercapnia, such as wide pulse pressure, tachycardia, restlessness, and agitation, are present far too frequently in mild episodes of asthma to be of much use clinically. Thus, the only way of reliably determining the integrity of an asthmatic's gas exchanging ability is to examine arterial oxygen and carbon dioxide tensions and pH. Although the mechanisms for the changes in mechanics listed above have not been completely worked out, it is known that a physical reduction in airway dimensions, because of smooth muscle contraction, dynamic collapsibility of airways, and loss of elastic recoil all play a part in producing the defects that can be measured. 5 , J6, 2:' Airway closure without reabsorption of trapped gas plus a loss of lung elasticity have been incriminated as the mechanisms for hyperinflation. 5 • 14 However, the precise mechanisms are as yet undefined.

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The mechanisms at work in producing the alterations in arterial blood gas are better understood and relate to mismatched ventilation perfusion ratios. 16. 19,20.33 Because the obstruction in the lungs is nonuniformly distributed, the incoming air will tend to go preferentially to the areas with the least involvement. This sets up the situation in which a small number of alveoli receive almost all the ventilation while the majority of the obstructed areas markedly hypoventilate in relation to their volumeP These factors result in local changes in alveolar gas tensions which in turn cause hypoxic vasoconstriction with topographical inequalities of blood flow. 4 ,33 Therefore, the lung can be thought of as being composed of two units, one of which is markedly hyperventilated in relation to its perfusion, giving rise to hypocarbia, and the other with a very low ventilation-perfusion relationship, yielding hypoxemia. The resultant blood gases then represent the algebraic sums of the oxygen and the carbon dioxide content of the blood leaving these two areas. With respect to the signs and symptoms of asthma, one tends to think only in terms of the classic triad of cough, dyspnea and wheezing, but other signs such as the use of accessory muscles and pulsus paradoxicus can be present under certain circumstances. Analysis of the time course of the clinical variables indicates that a dry cough tends to occur early in an attack, often in association with a sense of constriction in the chest, followed thereafter by wheezing and dyspnea. If the attack becomes severe, cough frequency may then decrease until the obstruction begins to abate and then it increases again and now becomes productive of various amounts of white mucoid sputum. Frequently in severe attacks the sputum can appear yellow to green in color and look purulent. This should not necessarily be interpreted as evidence of pyogenic infection, for the sputum of asthmatics contains eosinophils that can cause the change in consistency and they possess enzymatic systems capable of causing discoloration. If one is in a position to treat the first stages of the attack, the progression is often completely interrupted and the patient quickly returns to an asymptomatic state. The mechanism for the cough is unknown, but it probably is related initially to inflammation or irritation of the airway mucosa in the area of subepithelial vagal receptors. Increased firing rate of vagal afferents could readily result from airway deformation secondary to the smooth muscle contraction; thus, although cough is often the first symptom, it is unlikely that it initiates the obstruction de novo in most patients. However, it can accentuate that already present by inducing further bronchoconstriction via reflex mechanisms. The wheezing heard in asthma is a continuous musical sound and when analyzed it can be shown to be composed of fundamental frequencies with harmonics. 21 The production of a wheeze in the airway is dependent essentially upon the same factors that produce sound in tubes, that is, the velocity of air and the development of turbulence. Thus it is probable that these sounds develop by partial obstruction in areas of the lung that have relatively high flow rates, and are not produced in very small distal airways where the movement of gas is by molecular diffusion. The intensity (loudness) and pitch of the wheeze will change as

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a function of the geometry and cross-sectional area of the site of the obstruction and the pressure drop across it at a given volume flow. Therefore, both of these characteristics of the sound will vary during the development and remission of an acute episode of asthma, and useful clinical information can be obtained by observing the quality and intensity of the wheeze. Unlike cough, the respiratory sounds of asthma tend not to be biphasic. In the typical situation, as the attack begins, wheezing develops, progresses until it is audible to the unaided ear and then fades until the patient's lungs again become quiet during normal tidal respiration. If maximum forced exhalations are performed at this stage, an occasional scattered wheeze can be elicited in both lung fields. This pattern has given rise to the concept that a loss of wheezing means the cessation of the attack and vice versa. However, there are circumstances in which this is not true. For example, in situations associated with very severe asthma, wheezing often tends to be quite high pitched, musical, and of relatively low intensity. When the patient is treated, the intensity of the wheeze often increases markedly and its character changes from a relatively pure note to a lower pitched, coarser, more discontinuous noise with multiple components. Although we know of no direct measurements, it seems reasonable to assume that in the untreated state the airways were so obstructed that insufficient velocity could be achieved to produce much sound, and the increase in wheezing and noisy respirations with therapy does not mean worsening of the patient's condition, but rather an improvement, in that as the obstruction is dissipated, the patient becomes more able to mobilize secretions as well as to move air with sufficient velocity so as to produce more intense sounds. The converse also occurs. Noisy respirations moving toward high pitched, low intensity musical sounds in association with an increased frequency of respiration means a deterioration in lung function and should alert those in attendance to the possibility of impending suffocation. The mechanism for the sensation of dyspnea is unknown. It is undoubtedly related to the magnitude of the obstruction and the degree of hyperinflation present but the precise interactions which produce dyspnea have yet to be determined. Similarly, the precise mechanism by which patients begin to use their accessory muscles of respiration and develop pulsus paradoxicus has not been explained. Here, too, the amount of obstruction and hyperinflation probably plays some role. It is known that functional residual capacity and residual volume are markedly altered in acute asthma and that the diaphragms become flattened on chest radiographs. In fact, they can even bow toward the abdomen in the area of their lateral insertions on the rib cage. As air trapping progresses, the ribs are moved upward and out and the chest is held in the inspiratory position. It may be that the patient is forced into the situation of having to lift his entire rib cage cephalad to inspire tidal air and brings his accessory muscles into play in order to do it. The development of pulsus paradoxicus tends to occur temporally with the use of accessory muscles, suggesting that there is some com-

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mon mechanical phenomenon underlying both. Given the pulmonary mechanical derangements of acute asthma, it seems probable that the afterload of both the right and left ventricles is increased. They both share an increased transmural pressure in their major outflow vessels (pulmonary artery and aorta) because of the large pleural pressure swings associated with inspiration. 5. 22 In addition the right ventricle afterload is increased by the effects of lung volume on pulmonary vascular resistance 7 ,28 and possibly hypoxic vasoconstriction. 4 The net effect of these changes is a decrease in stroke volume during inspiration despite the fact that venous return into the thorax is undoubtedly augmented. When the relationship between the signs and symptoms and physiology of acute asthma is examined serially as the patients improve, it becomes apparent that there is a large functional reserve in the lungs and that the clinical variables imperfectly reflect the degree of obstruction. In one study!5 it was found that within 30 minutes after the first treatment, approximately 80 per cent of the patients lost the sensation of dyspnea and their perception of stridulous breathing. After two treatments, 92 per cent were asymptomatic and by the third treatment all felt completely well. The use of accessory muscles was alleviated in 90 per cent of the patients with one treatment and in all by two. Wheezing on physical examination took longer to remit and did not seem to bear any constant relation to the patients' symptoms. In fact, when over 90 per cent of the subjects considered themselves asymptomatic, 40 per cent were still wheezing when examined. From a physiologic point of view it was found that when the patients considered their attacks to have ended, although significant improvements had occurred in lung function over pretreatment values, the mean airway resistance and residual volume were still over 200 per cent of predicted, and the FEV! and maximum mid-expiratory flow rate were only 43 and 22 per cent of normal respectively. When the physicians in attendance considered the patients to be well on the basis of physical examination, residual volume was still around 200 per cent of predicted, FEV! was 60 per cent of normal, and flow rates in the mid-vital capacity range were 30 per cent of expected values. These data demonstrate that if loss of subjective complaints or even of signs like wheezing were relied upon as definitive therapeutic endpoints that one could not detect or would seriously underestimate a large reservoir of residual disease. Although these residual abnormalities may not be sufficient to cause symptoms at rest initially, they can last for considerable periods of time27 and as indicated earlier in this review they may eventually serve as a base upon which future attacks may form. 2 ,6 These observations help to explain why some patients with asthma are prone to relapses of progressive severity within a relatively short period of time after emergency therapy of their disease. Very often these individuals are originally treated for only short periods until their symptoms disappear, and given the above information on the state of lung function at this stage of the disease, it is easy to see how relatively small amounts of additional obstruction could again produce acute symptoms. For these

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reasons it has been suggested that the treatment of any given acute episode should be maintained until there is objective evidence that forced expiratory volumes or flow rates have moved into or near their predicted values before discharging the patient from the emergency room. Evidence is beginning to accumulate that indicates that when this approach is taken, and when therapy is continued further on an outpatient basis, the frequency and severity of subsequent exacerbations can be substantially reduced by maintaining the patient's lung function as close to normal as possible.1 3 The information presented thus far demonstrates that it is unreliable, and on occasion even hazardous, to rely solely on the patient's perceptions, or on one's clinical acumen, in determining the severity of an acute attack of asthma. The only way to make this determination reliably is to measure some aspect of mechanics such as a forced expiratory volume as well as arterial blood gases. However, if one is in a busy emergency room or other such setting and is dealing with large numbers of asthmatics, it may be impractical from both logistical and financial standpoints to make these measurements on every patient. Who, then, should receive them? Obviously it should be those asthmatics who are the sickest and who are least likely to respond to simple therapeutic maneuvers; but how can they be detected? A useful way of making this distinction is to record the presence or absence of pulsus paradoxicus and use of the accessory muscles of respiration in addition to the other routine data on vital signs, and so forth, that one typically obtains, for it has been shown that when either of these signs is present, lung function is severely compromised. lo • 15.24.25 Typically, FE VI is less than a liter, there is marked hyperinflation, pulse rates are faster and arterial carbon dioxide tensions are higher in the presence of either or both of these signs. lo • 15 Thus, one can identify the sickest asthmatics from physical examination. But this only answers part of the question raised above: what of the response to therapy? Data obtained from serial studies of the pattern of remission indicate that the expected order of recovery is that pulsus paradoxus and the use of accessory muscles should disappear quickly followed thereafter by other symptoms such as dyspnea and then by wheezing. 15 Consequently, failure of the patient to lose these signs within 30 minutes or so of receiving appropriate therapy now makes objective monitoring mandatory. Arterial gases and some simple spirometric measurements of the degree of obstruction, such as the FEV I, should now be obtained.':' If the carbon dioxide tension is less than normal, therapy can continue in the emergency room and only spirometric parameters need be followed, provided they show progressive improvement. If, however, they ':The peak flow meter is a relatively inexpensive, portable instrument which provides rapid, reproducible measurements of peak expiratory flow rate (PEFR). This measurement has been shown to correlate well with other expiratory flow measurements and with the severity of asthma. In many hospitals, it is used as the index of severity of the disease, as an indication of response to therapy, and as a guide to the need for hospitalization. In general, a PEFR less than 100 L per minute signifies severe asthma requiring constant attention and treatment. -Editor.

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remain relatively stable over the next several hours despite repeated medications, arterial gases should be serially obtained as well, for the probability of the development of incipient or frank respiratory failure is increasing. If the initial blood gas shows eucapnia or mild hypercapnia, therapy should be quite vigorous and multiple drug modalities including steroids should be started or intensified. Under these circumstances, arterial blood gases should be watched quite closely and if the CO 2 does not fall to hypocapnic ranges within a few hours, the patient should be admitted. Of course if the follow-up gases show an increasing CO 2 tension, further emergency room treatment is unadvisable, and the patient should be immediately placed in an environment where ventilatory support capabilities exist. In certain situations more detailed lung function testing may need to be performed. This usually occurs in status asthmaticus without respiratory failure, where the patient is undergoing optimal treatment seemingly without much success. Typically, what one finds physiologically is that there is marked hyperinflation with residual volumes tending to approach the predicted values for total lung capacity and TLC often is 140 to 160 per cent of predicted. When the response to acute therapy is studied under these circumstances, the FEV 1 , which tends to be quite low, may not improve its absolute value initially, but concomitant measures of total lung capacity (TLC) show that gas trapping is diminished so that the FEV 1 /TLC ratio is improving. 32 Eventually, as TLC normalizes, FEV 1 will also begin to do so. Another feature of acute asthma that should be pointed out is that when one is following the course of treatment with serial measures of arterial oxygen tensions (P a02), hypoxemia will frequently worsen for short periods following the administration. of sympathomimetics.3 , 9, 11 Usually the fall in P a02 is only a few millimeters of mercury and is of little significance. It does not mean that the patient is getting sicker but rather that there has been a transient decrease in ventilation-perfusion ratios because of shifts in the distribution of either ventilation or perfusion. 3 , 9, 11, 17 In our experience supplemental oxygen has never been required to combat this, and it is of far more physiologic than clinical interest.

SUMMARY Sufficient data has now accumulated that demonstrates that a careful analysis of the presenting signs and symptoms of a patient with acute asthma will permit clinically useful conclusions to be drawn regarding the magnitude and severity of the underlying airway obstruction and the expected response to therapy. If a patient with severe obstruction deviates from this expected course, objective measurements of mechanical function and gas exchange should be obtained. In our current state of knowledge, these measurements should then be used as the prime indices of therapeutic

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effectiveness and less reliance should be placed on traditional clinical approaches.

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29. Tai, E., and Reed, J.: Blood gas tension in bronchial asthma. Lancet, 1 :644, 1967. 30. Weng, T. R, Langer, H. M., Featherby, E. A., et al.: Arterial blood gas tensions and acidbase balance in symptomatic and asymptomatic asthma in childhood. Amer. Rev. Resp. Dis., 101 :274,1970. 31. Woolcock, A. J., and Read, J.: Lung volumes in exacerbations of asthma. Amer. J. Med., 41 :259, 1966. 32. Woolcock, A. J., and Read, J.: Improvement in bronchial asthma not reflected in forced expiratory volume. Lancet, 1 :1323, 1965. 33. Woolcock, A. J., McRae, J., Morris, J. G., et al.: Abnormal pulmonary blood flow distribution in bronchial asthma. Aust. Ann. Int. Med., 15:196,1966. Pulmonary Function Laboratory Peter Bent Brigham Hospital Boston, Massachusetts 02115