Conscious Perception of Bronchospasm as a Protective Phenomenon in Asthma

Conscious Perception of Bronchospasm as a Protective Phenomenon in Asthma* A. R. Rubinfeld, M.B., B.S., • • and M. C. F. Pain, M .D., F.C.C.P.t

Ten bdtlally asymptomatic lllfhmatk subjects underwent metbac:hollne-lndnced attacks of asthma on a nwnber of occasions, to the point when tightness in the chest Will jnst sensed (threshold point). As baseline long volumes Increased and the caliber of the airways decreased, the relldive changes needed to attain a tbresbold point gen-

Jt has been commonly accepted but poorly docu-

mented that in the presence of chronic asthma, patients may become adapted to the presence of their pulmonary dysfunction. They may, for instance, remain asymptomatic but taper their activities to a lower level; their degree of pulmonary dysfunction might possibly be grossly underestimated and their therapy less than optimal. 1 In keeping with this apparent blunting of perceptive ability with longstanding dysfunction, one might expect the perception of further acute fluctuations in the caliber of the airways to be similarly affected; however, the subjective nature of breathlessness has left the quantitation of this clinical impression essentially undocumented Studies utilizing externally applied loads to breathing and defining thresholds for detection of these loads have allowed quantitation of some sensations associated with breathing;2.3 however, external loading, while valuable in defining physiologic loadcompensating mechanisms, is far from an ideal model of the pulmonary dysfunction seen in states of disease. The present study was an attempt to further define the relationship between an intrinsic load to breathing (methacholine-induced asthma) and the subjective detection of this load. The study ex•From the Respiratory Laboratory, Royal Melbourne Hospital, Parkville, Victoria, Australia. Supported by grants-in-aid from the National Health and Medical Research Council of Australia and the Asthma Foundation of Victoria. This study was performed with the informed consent of each subject and with the approval of the Ethics Committee of the Royal Melbourne Hospital. ••Research Fellow. t Respiratory Specialist. Manuscript received August 3; revision accepted October 21. Reprint requests: Dr. Paln, Respiratory Laboratory, Royol Melbourne Hospital, Victoria 3052, Australia

154 RUBINFRD, PAIN

erally became smaller. Although pulmonary function can deteriorate chronically without increasing dyspnea, it is possible that a mechanism exists at the level of consciousness to protect a subject's breathing at times when pulmonary function is acutely Impaired.

amines the sensitivity of individual asthmatic subjects in detecting acute fluctuations in pulmonary function on a number of occasions. MATERIALS AND METIIODS

Ten subjects, each with asthma since childhood, agreed to undertake bronchoprovocation tests on a number of occasions. Our intention was to compare the changes in pulmonary function required to produce just noticeable symptoms on two specific occasions, once when initial pulmonary function was close to normal, and once when initial pulmonary function was modestly impaired, the subject being initially asymptomatic on each occasion. Testing was performed in a 900-L variable-pressure plethysmograph. After initial indices of pulmonary function were measured, bronchoprovocation was continued until the subject indicated that tightness in the chest was just barely discernible (threshold point). Indices of pulmonary function were again measured, and the test ceased. The threshold point was thus a subjective determination. An attempt at standardization was made by the use of a visual analogue scale ( unpublished data) . If the subject felt more than "just noticeably tight," the procedure was completed, but the results were not included for analysis. The technique of bronchoprovocation was as follows: Aerosols were sequentially generated from freshly prepared solutions of methacholine hydrochloride ( 0.5, 1.25, 2.5, 5.0, and 10.0 mg/ml) in isotonic saline solution. Aerosols were generated by nebulizers ( Bennett Vaponephrin) driven with an oxygen How of 5 L/min. The subjects took a s ingle vital capacity ( VC) inhalation of the aerosol through a tube 1 inch in diameter in the wall of the plethysmograph (so as not to contaminate their environment) at three-minute intervals, until tightness in the chest was just sensed. Despite the standard method of administration, the subjects were instructed that the aerosols were randomized and that they might be given an aerosol of either isotonic saline solution or active drug. Lung volumes and indices of airway caliber were measured in the following manner. Two slow expirations from functional residual capacity ( FRC) to residual volume ( RV) were followed by two slow vital capacity ( VC) maneuvers at 30-second intervals. The greatest value of each

CHEST, 72: 2, AUGUST, 1977

expired volume was used for calculations. After a one-minute rest, airway resistance ( Raw) and thoracic gas volume at FRC were measured• between two and five times, the average being used for calculations. Duplicate maneuvers for forced vital capacity ( FVC) were then performed, allowing onesecond forced expiratory volume ( FEV 1 ) to be measured and maximal expiratory flow-volume curves to be stored and photographed (the greatest of each was used for calculations). The maximal expiratory flow-volume curves were obtained by plotting expired flow against its electronically integrated signal (expired volume) on a storage oscilloscope (Tektronix 5310 N) and photographing the tracing. Maximal expiratory flow at 50 percent of the VC ( Vmax50) and an index of the time constant of the lung (V/V25-75) were obtained from the maximal expiratory flow-volume curves. The V/V25-75 was taken as the slope of the straight line joining the points at 25 percent and 75 percent of VC on the maximal expiratory flow-volume curve. Expiratory flow was measured with a Fleisch No. 4 pneumotachygraph and a pressure transducer (Hewlett-Packard P270), airway pressure with a pressure transducer (HewlettPackard 1280B), and plethysmographic pressure with a pressure transducer (Hewlett-Packard P270). All signals were recorded on a six-channel recorder ( S. E. Laboratories 2005 U .V . ).

Bronchoprovocation was commenced two minutes after the final baseline maneuver for FVC, in order to allow for possible changes after forced expirations.5-7 Predicted values for lung volumes, Raw, and Vmax50 were taken from the data of Goldman and Becklake,8 Pelzer and Thomson,v and Cherniack and Raber,'0 respectively. The changes in pulmonary function needed to produce a threshold were compared on two occasions. Comparisons were. made only if initial indices differed by an order ( arbitrarily) of 25 percent or more. REsULTS

Table 1 represents comparisons for the following indices of pulmonary function: total lung capacity (TLC), FRC, RV, FEV,, Raw, Vmax50 (uncorrected for lung volume), and V /V25-75. Comparisons were made in the following fashion. Consider the values of Raw for subject 1. On the first occasion ·listed, subject 1 was asymptomatic, the Raw being 76 percent of predicted. A change of 127 percent from that baseline level was seen when symptoms first became apparent On the second occasion listed, subject 1 again initially was asymptomatic, but her baseline value of Raw was somewhat impaired ( 166 percent of predicted). On this occasion, only a 93 percent increase from this baseline level was required for her to reach a threshold point. Subject 1 was thus considered to be relatively more sensitive to acute fluctuation on the occasion when she commenced with already impaired pulmonary function. Such a comparison was not possible in every subject, since baseline indices did not necessarily diHer by 25 percent or more. Thus, only those tests when baseline fluctuation allowed such comparisons are tabulated.

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Seven of the ten subjects demonstrated sufficient fluctuation in baseline values for static lung volumes (TLC, FRC, or RV) to allow comparisons. In each case, as the baseline value for static lung volume increased, the relative change ( ie, further increase) needed to attain a threshold point became less. A 25 percent fluctuation in baseline FEV 1 was not seen in any subject. When Raw was considered, comparisons of sensitivity to internal loading were possible in six subjects. In four of these six subjects, as baseline Raw became impaired, the subject appeared relatively more sensitive to further acute deterioration. Similar trends were seen in four of the seven subjects in whom comparisons of Vmax50 were possible and in six of the seven subjects in whom comparisons of V/V25-75 were made. Thus, only a minority of subjects had a relative blunting in their perception of acute "bronchospasm" as their baseline pulmonary function deteriorated. DISCUSSION

Both neural and chemically mediated events contribute to the ventilatory responses seen when external loads are added to a subject's breathing." The responses to internally loaded breathiilg cannot yet be studied in such a pure form. Thus, in our attempts to quantify the relationships between an internally added load and a subject's awareness of the load, a number of compromises were accepted. - · The subjects were part of a well-motivated group of outpatients and hospital staff, agreeing to undertake bronchoprovocation tests on a number of occasions. They were not apprehensive about the procedures, and while a conditioned response12 could not be ruled out, emphasis was placed on the explanation that the sequence of aerosol administration was randomized (although in practice, it was not). Experiments utilizing externally loaded breathing,3 have defined threshold loads as those detected on only 50 percent of the occasions presented. The present study has the disadvantage (?) of a purely subjective determination of threshold, that of the asthmatic subject undergoing an attack; however, we have confirmed that the degree of pulmonary dysfunction during such induced thresholds is comparable to that when symptoms of similar degree arise spontaneously (unpublished data). We believe, then, that study of such internal loading is more appropriate to clinical extrapolation than study of external loading. Furthermore, while we describe an "internal load,"' we are aware that our measurements of pulmonary function give only

CONSCIOUS PERCEPTION OF BRONCHOSPASM 155

Table 1--Ce...,....uon. o/ B....U-Irulka o/ J>lllrn-.ry F•nedon .,.., c....,... ReqlllreU s,....,.,..,. • Subject and Me&8Urement

TLC

Subject 1 (F, 21 yr) Determination 1 Initial value, percent of predicted Percent change to threshold Determination 2 Initial value, percent of predicted Percent change to threshold

FEV,

Raw

RV

66 13

99 84

76 127

121 40

114t St

173t 4t

166t 93t

71 43

Subject 2 (M, 23 yr) Determination 1 Initial value, percent of predicted Percent change to threshold Determination 2 Initial value, percent of predicted Percent change to threshold Subject 3 (F, 22 yr) Determination 1 Initial value, percent of predicted Percent change to threshold Determination 2 Initial value, percent of predicted Percent change to threshold

71 66

168

121 t 30t

162t 6lt

Subject 6 (F, 25 yr) Determination 1 Initial value, percent of predicted Percent change to threshold Determination2 Initial value, percent of predicted Percent change to threehold

1.9t St

82 31

2.9 28

63 53

2.0t 13t

93 79

46 43

4.1 37

143t 72t

32t 35t

2.8t llt

76 53

83 151

101 79

46 43

1.8 38

mt 1St

181 t 59t

263t 72t

32t 35t

1.4t 27t

87

121 21

81 21

179t 2t

39 37

87 63

116 49

~

123t lOt

Subject 7 (M, 23 yr) Determination 1 Initial value, percent of predicted Percent change to threshold Determination2 Initial value, percent of predicted Percent change to threshold

68t 24t

155t 19t

Subject 8 (F, 31 yr) Determination 1 Initial value, percent of predicted Percent change to threshold Determination 2 Initial value, percent of predicted Percent change to threshold Subject 9 (M, 23 yr) Determination 1 Initial value, percent of predicted Percent change to threshold Determination 2 Initial value, percent of predicted Percent change to threshold

3.4 16

66

Subject 4 (M, 24 yr) Determination 1 Initial value, percent of predicted Percent change to threshold Determination 2 Initial value, percent of predicted Percent change to threshold Subject 5 (M, 22 yr) Determination 1 Initial value, percent of predicted Percent change to threshold Determination2 Initial value, percent of predicted Percent change to threshold

Vmax50 'I /V25-75**

FRC

1.4t 12t

130 141

74 194

2.5 25

172t 116t

286 334

1.7 50

86 27

60 152

86

49

68 2

114t 5t

172t 17t

166t 34t

44t Ot

Subject 10 (M, 22 yr) Determination 1 Initial value, percent of predicted Percent change to threshold Determination2 Initial value, percent of predicted Percent change to threshold

2.4 28

2.2 27 1.6t 6t

139 151 238 426

•If initial status on two occasions was comparable, compariaon was not made (indicated by ellipsis) .

..V/V25-75 is elope of maximal expiratory flow-volume curve (see·•).

tPair of data where relatively 1- change in pulmonary function was needed to attain threshold point on occasion when initial baseline index was relatively impaired .

.156 RUBINFELD, PAIN

CHEST, 72: 2, AUGUST, 1977

a limited indication of the mechanical changes seen during the attacks. The lack of data obtainable with · more invasive procedures was offset by the advantages of having our subjects available for repeated studies. Given these limitations, our results reveal the following trends. H the baseline pairs of data are considered, each subject remained asymptomatic, despite fluctuation of at least 25 percent in some indices of airway caliber or lung volume. It seems, then, that such gradual deterioration in pulmonary function need not necessarily be associated with the development of symptoms. The data do not allow us to define limits to the degree of gradual deterioration beyond which symptoms become apparent; however, it may be relevant that fluctuations of 25 percent or more in the baseline FEV1 were not seen in these subjects in the absence of symptoms. It is possible that this degree of gradual deterioration approximates the limits of change in pulmonary or airway mechanics beyond which symptoms will develop. A general pattern also emerges after consideration of the changes in percentages in the indices of pulmonary function needed to attain a threshold point from the asymptomatic state. The majority of pairs of data suggested that as baseline static lung volume increased and indices of airway caliber revealed greater airway obstruction, relatively smaller acute fluctuations were required to produce just noticeable symptoms. We interpret these trends as confirming the clinical impression that gradual deterioration in pulmonary function need not necessarily be associated with the development of symptoms; however, superimposed on this adaption to gradual change is a greater awareness of acute deterioration in pulmonary function. Nevertheless, these conclusions should be considered in the light of the following two points. First, in our comparisons of pairs of data, we have used absolute Raw, rather than the more common index specific airway resistance ( ie, Raw I thoracic gas volume). We have also considered absolute Vmax50 uncorrected for alterations in lung volume. Our reasons are these. The FRC and Raw were the indices measured at the lung volume present when symptoms developed. These measurements, furthermore, did not require forced or maximal respiratory maneuvers. Since each independently provides information about the resistive and elastic components of the induced load, we considered that each should be compared in isolation. Our reasoning was similar in our use of Vmax50 as an index of resistive load, rather than the more commonly CHEST, 72: 2, AUGUST, 1977

reported indices of Vmax at a nominated lung volume. Consider the following hypothetic example: A subject, initially asymptomatic and with normal pulmonary function, develops acute asthma, with his FRC increasing to the level of his recently normal TLC. Let us assume also that Vmax is important to the subject as an indicator of whether pulmonary dysfunction is present. During the attack, VmaxFRC is sensed and may well be compared to a similar index recently remembered as being normal (VmaxFRG prior to the attack), not to a volume-corrected comparison ( eg, VmaxTLC before the attack). Secondly, we have assumed that the percentage of change from baseline is an indicator of a subject's "sensitivity to change in pulmonary function." This may not be biologically appropriate. It may be that a subject's "sensitivity" should be considered in relationship to his maximal tolerable level of pulmonary dysfunction, ie, the nearer this limit is approached in the absence of symptoms, the less sensitive the subject (quite a different scale to our assessment using only one extreme of a '1oad spectrum"). While this approach is possible in some situations, the present study certainly precludes such an approach; however, we are able to compare our results to prior studies quantifying some respiratory sensations. Some studies13·14 have suggested that respiratory sensations behave in accord with the Power law. 15 This concept, validated for a variety of sensory modalities, compares the intensity of the stimulus to intensity of response. The log-linear relationship between the two seems generally accepted; however, our method does not allow comparisons with this concept. Other authors have suggested that respiratory sensations may behave in accord with the WeberFechner law. 18 Wiley and Zechman 17 found that regardless of subjects' initial level of pulmonary resistance, the addition of a constant proportion of this value was required in order to produce a threshold awareness of loading; however, comparisons were not made in the one subject with fluctuating baseline values for pulmonary function. Other studies, using yet different methods, contrast to both of the previously discussed concepts.18·19 Perhaps the closest comparison to the present study was that of Aitken et al, as discussed by Wood. 18 Their asthmatic subjects complained of more severe symptoms than did a group of normal subjects after the addition of a standard resistive load to breathing. Wood 18 considered that the asthmatic subjects whose pulmonary function was already impaired were more sensitive to the added CONSCIOUS PERCEPnON OF BRONCHOSPASM 157

load than the normal subjects, a finding interpreted as contrasting to the expectations of the WeberFechner law, since the added load was a smaller proportion of the baseline load in the asthmatic subjects. Our results similarly contrast to the form of analysis described by the Weber-Fechner law. In attempting to separately analyze various mechanical components of our ·total "internal load," we suggested that in any one subject, perception of added load was not constant; ie, there was a tendency for "greater sensitivity" to acute deterioration in pulmonary function at times when baseline pulmonary function was already impaired. It may be that such conscious awareness of acute deterioration in pulmonary function serves as a protective mechanism. Hudgel and Weil20 have documented a tendency for reduced ventilatory responses to hypoxia and hypercapnia in subjects during intervals of remission of severe asthma. If this depressed ventilatory response is of importance in the development of respiratory failure precipitated by acute air.way obstruction, a protective phenomenon at the level of consciousness might assume significance. This conscious perception of disease should certainly not be compromised by the practice, now sufficiently condemned, of administering sedatives to subjects suffering from acute asthma.

1 McNicol KN, Williams HB: Spectrum of asthma in childhood: 1. Clinical and physiological components. Br Med J 4:7, 1973 2 Campbell EJM, Freedman S, Smith PS, et al: The ability of man to detect added elastic loads to breathing. Clin Sci 20:223, 1961 3 Bennett ED, Jayson MIV, Rubenstein D, et al: The ability of man to detect added non-elastic loads to breathing. Clin Sci 23: 155, 1962 4 DuBois AB, Botelho SY, Comroe JH: A new method for measuring airway resistance in man using a body plethys-

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5 6 7

8 9 10 11 12 13 14 15 16

17 18 19 20

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