Pflfigers Archiv

Pfltigers Arch. 372, 1-6 (1977)

EuropeanJournal of Physk)!ogy 9 by Springer-Verlag 1977

The Role of Augmented Breaths (Sighs) in Bronchial Asthma Attacks G. DELMOREand E. A. KOLLER* PhysiologischesInstitut der UniversitS.tZfirich, R~imistrasse69, CH-8001Zfirich, Schweiz

Summary. The study is based on plethysmographic, neurophysiological and respiratory mass-spectrographic records established during anaphylactic or histamine-induced bronchial asthma attacks in guineapigs. The frequency of occurrence of the augmented breaths (sighs) is correlated with the intensity of the lung deflation reflex (tachypnoea) which arises during the attack. In the acute phase of the asthma attack, the sighs increase in number and reinforce the uneven ventilation which underlies stimulation of the pulmonary deflation receptors. The sigh becomes an essential component of the vicious circle of uneven ventilation and vagal lung deflation reflex induced. This circle is broken in the recovery phase of the asthma attack, during which the sighs decrease in number, as the conditions underlying their occurrence subside; they now lessen the uneven ventilation and by reopening Closed lung units promote a return to normal conditions in lung mechanics. It is concluded that augmented breaths, like the asthmatic tachypnoea, are caused by uneven ventilation resulting in pulmonary self-compression and in turn stimulation of the pulmonary deflation (irritant) endings. Some factors which possibly contribute to the elicitation of augmented breaths are discussed. Key words: Augmented breath (sigh) - Bronchial asthma attack - Uneven ventilation - Vagal lung deflation (irritant) receptors.

INTRODUCTION The periodic augmented breaths (sighs) in spontaneously breathing anaesthetized animals dealt With in this paper are characterized by a deep two-phase * To whom offprint requests should be sent

inspiration usually followed by transient tachypnoea. It has been suggested that such an inspiratory effort has the function of opening spontaneously closing alveoli, thereby maintaining a healthy state of the lungs [19]. The augmented breaths thus defined are hence distinct from the repeated deep and slow breaths after vagotomy, and the gasps described by Lumsden [16]. For further discussion concerning respiratory patterns characterized by deep inspirations see Glogowska et al. [7]. Studies on the respiratory responses associated with anaphylactic or histamine-induced bronchial asthma attacks in guinea-pig [10] have revealed that sighs frequently punctuate the marked inspiratory reaction which arises at onset of increasing bronchial resistance. This inspiratory response is characterized by rapid and shallow breathing, depends on the integrity of the vagus nerves, and is due to stimulation of the "pulmonary collapse- or deflation receptors" [12]. The latter are probably identical with the "pulmonary irritant receptors" described by Widdicombe and his co-workers [17, 21]. Recent neurophysiological and respiratory massspectrometric studies [14, 2] have, in addition, shown that two different phases can be established in the course of the bronchial asthma attack: The first, the initial or "acute phase", is characterized by uneven and asynchronous ventilation, as heterogeneous pulmonary stretch receptor discharge and a delayed washout-rate have shown. There is strong experimental evidence that the uneven ventilation leads to expiratory self-compression of the lungs, which in turn leads to stimulation of the pulmonary deflation endings: The respiratory reflex response evoked sets up a vicious circle in which changes in pulmonary mechanics (bronchoconstriction, uneven distribution of air) alternate with respiratory reactions (reflex tachypnoea, increase in lung volume). This positive feedback comes to an end during the second or

2 " r e c o v e r y p h a s e " o f the bronchial a s t h m a attack, characterized by a tonic or n o r m a l discharge pattern o f the p u l m o n a r y stretch receptors in the afferent vagal n e u r o g r a m a n d m a r k e d l y hastened washoutrate in the respiratory mass-spectrogram, findings pointing to stable, " p s e u d o - h o m o g e n e o u s " ventilation (lung units concerned open or completely closed), a respiratory condition favouring reduction or even abolition o f the p u l m o n a r y deflation reflex. So far only tentatively explained [18,19,11,12,6, 21, 7, 2], however, remains the role o f the a u g m e n t e d breaths during the two phases o f the anaphylactic or histamine-induced bronchial a s t h m a attack. The aim o f the present study is to t h r o w further light on the p r o b l e m and is based on re-examination o f the d a t a assembled in previous experiments carried out by Koller and co-workers [10,11,14, 2,15].

METHODS The present study-as already pointed out in the introductionis based upon previous experiments [10,11,14,2,15]. In these 45 spontaneously breathing guinea-pigs anaesthetized with urethane (1-1.5 g/kg) were used. All animals were tracheotomized, and a jugular catheter was inserted for drug injections. The techniques used were standardized and can be summarized as follows:

a) Asthma Induction. Reversible asthma was induced in animals sensitized to egg albumen by inhalation of the antigen aerosol or by administration of histamine aerosol (0.5 ~ histamine dihydrochloride). The aerosol particles ranged in size from 0.5-5 mg. The aerosols were administered until the marked inspiratory reaction sets in (egg albumen up to 60 s, histamine up to 13-23 s). In ten animals asthmatic tachypnoea was compared with the tachypnoea produced by Micoren | a respiratory analeptic [9].

b) Body Plethysmography. Spontaneous breathing was recorded with a volume displacement plethysmograph. The animal breathed room air through the tracheal cannula, which was fitted into the wall of the plethysmograph. In order to avoid changes in lung volume due to changes in body temperature, the plethysmograph was placed in a water bath, the temperature of which was held constant at 28~C by means of the thermostat. Breathing frequency, tidal volume and changes in lung volume were recorded uninterruptedly. In some animals thoracic distension or compression was carried out by increasing or decreasing the intraplethysmographic pressure [51. c) Afferent VagalNeurogram.Afferent vagal activity from the left cervical nerve was recorded from single or quasi-single fibres, i.e., preparations exhibiting unit activity, but containing at the most 2 - 4 units in the otherwise intact vagus. The electrical unit activity was amplified and displayed- at the same time as the electrocardiogram, tracheal side-pressure, intraplethysmographic and pleural pressure-on a cathode-ray oscillograph and recorded in conventional manner. The discharge pattern arising from the single pulmonary vagal receptors prior to, during and after augmented breaths, throws light on the mechanical behaviour of the corresponding "lung unit", a small but so far unidentified receptor field in the lungs [13]. d) Respiratory Gas Analysis. In the 7 animals in which the mechanical situation of the entire lung was analyzed by resorting to un-

Pfliigers Arch. 372 (1977) interrupted examination of the air respired, a mass spectrometer (M 3 VARIAN MAT) was used, in which the ion currents and the four collectors can be varied in such a way that any combination of four masses-in the experiments studied: CQ, Ar, Oz and N2-can be analyzed simultaneously. The washin or washout of Ar or N2 throws light on the ventilatory pattern of the lungs, independent of changes due to perfusion or diffusion [2].

RESULTS E x a m i n a t i o n o f the plethysmograms, afferent vagal n e u r o g r a m s and respiratory m a s s - s p e c t r o g r a m s - s p e cial attention being paid to the m o m e n t o f appearance, frequency o f occurrence and effects p r o d u c e d by the s i g h - r e v e a l e d the following facts:

Augmented Breaths (Sighs) before Induction of the Bronchial Asthma Attack Sighs were rare in the anaesthetized animals prior to administration o f the aerosol. In the minute preceding administration only 1 out o f 18 animals gave a sigh. A t a breathing frequency o f 44 _+ 13 (rain - t ) a sigh occurred a b o u t once every 900 breaths. N o precursory sign ever a n n o u n c e d that a sigh was a b o u t to p u n c t u a t e the respiratory tracings. 65 ~ o f the 500 sighs recorded before administration o f the aerosol were followed by a slight transient increase in breathing frequency, a l t h o u g h no change could be clearly established in tidal volume and lung volume. Deep anaesthesia abolished the sighs. In the afferent vagal n e u r o g r a m a u g m e n t e d breaths, like r a p i d inflations, p r o d u c e d during the second phase o f the inspiratory effort m a r k e d l y increasing p u l m o n a i y stretch receptor activity, in a few o f o u r quasi-single fibre preparations also intermingled with short irregular discharge o f lung deflation receptors. D u r i n g the w a s h i n / w a s h o u t o f the reference gas the sighs were followed by a sudden rise/drop in the A r (drop/rise in the N z ) c o n c e n t r a t i o n curves.

Augmented Breaths (Sighs) during the Bronchial Asthma Attack I n contrast to the preliminary stage just dealt with, all the anaphylactic or histamine-induced bronchial a s t h m a attacks were a c c o m p a n i e d by frequent augm e n t e d breaths. A l t h o u g h the course o f these two types o f attacks differs, no difference Could be seen with regard to the m o m e n t o f appearance, the frequency o f occurrence o f the sighs, or the respiratory effects produced. It was evident, however, that the incidence o f the a u g m e n t e d breaths is correlated with the i n t e n s i t y - m o r e particularly the r a t e - o f the rapid and shallow breathing. In some o f the animals

G. Delmore and E. A. Koller: Sighs in Bronchial Asthma Attacks

thoracic compression or rapid distension had been applied during the attack. The respiratory response to such a manoeuvre was always augmentation of the pulmonary deflation reflex (asthmatic tachypnoea) correlated at the same time with an increase in the incidence of the sighs. Comparison of the acute and the recovery phase of the bronchial asthma attacks revealed, in addition, what follows: a) Augmented Breaths (Sighs) in the Acute Asthmatic Phase. In more than half the cases a sigh preceded the first rise in lung volume associated with onset of the marked inspiratory response, and hence appeared to initiate the acute asthmatic phase. In the (standardized) histamine-induced asthma attacks, 1 min after the asthmatic tachypnoea has set in, respiratory frequency as well as lung volume reaches maximal values. At the maximal respiratory frequency of 167 _+ 34 (rain -1) the incidence of the sighs also reaches a peak: 3.5 sighs per min, respectively 2.15 per 100 breaths. Of interest is the fact that during the non-

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Fig. 1. Frequency of occurrence of augmented breaths (sighs) in different respiratory conditions. Mean and SD. Control: Normal breathing in anaesthetized guinea-pigs before induction of bronchial asthma attack. N = 18. Micoren@: Tachypnoea induced by a respiratory analeptic. N ~ 10. Asthma I: Acute phase of the bronchial asthma attack.,~ = 18. Asthma II: Recovery phase of the bronchial asthma attack. N = ~8

. . . . . . .

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asthmatic tachypnoea induced by Micoren | 1.38 sighs per rain, respectively 0.88 sighs per 100 breaths were found, therefore at comparable breathing rates (156 _+ 32 per min) three times less than during the tachypnoea in anaphylactic or histamine-induced bronchial asthma attacks (Fig. 1: Asthma i). 82 ~ of the sighs emitted during the acute phase were followed by a marked increase in breathing frequency, followed in 34 ~ of the sighs by a decrease in tidal volume, and associated with air-trapping or permanent increase in lung volume in 56 ~ (see Fig. 2). No change in these parameters was seen in 18 ~ of the sighs recorded during the acute phase. The afferent vagal neurograms during the acute phase show that rapid and marked inflation of the lungs caused by a sigh reinforces the prevalent uneven ventilation, in otherwords, reinforces the mechanical conditions bringing about stimulation of the pulmonary deflation receptors. Figure 2-besides showing tracheal side-pressure, body plethysmogram, pleural pressure and electrocardiogram-illustrates the discharge pattern of the pulmonary stretch and the pulmonary deflation receptors during the acute phase. The graphs below the tracings represent the mechanisms which may underlie stimulation of these endings, a) before, b) during and c) after the sigh (arrow). (a) shows an increase in pulmonary stretch rec.eptor discharge (large spikes), findings pointing to overinflation of the corresponding lung unit (see graph). During the expiratory rise in intrapleural pressure (PPL), which reaches positive values, pulmonary deflation receptor activity (small spike groups) comes into play, pointing to compression or forced deflation of the corresponding lung unit (see graph). (b) The rapid inflation caused by the sigh reinforces this pulmonary overinflation and compression, since both pulmonary stretch and deflation activity have

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Fig.2. An augmented breath (arrow) in the acute asthmatic phase. From top to bottom: tracheal cannula side-pressure (P,), intraplethysmographic pressure (Pp), pleural pressure (P~,L), ECG, afferent vagal neurogram with pulmonary stretch receptor discharge (large spikes) and pulmonary deflation receptor activity (small spike groups). The sigh enhances the mechanical conditions (uneven ventilation) underlying induction of the lung deflation reflex (tachypnoea). For further explanations see text

4 increased. (c) After the sigh, the rapid and shallow breathing is enhanced. The pulmonary stretch receptor discharge is transiently decreased, still outlasts, however, both respiratory phases. This indicates that the lung unit concerned (see graph) i s - p a r a d o x i c a l l y relaxed owing to the sigh, but that expiratory relaxation is still hampered: Increasing stretch receptor activity shows that renewed air-trapping and overinflation set in ( c - a ' ) . As positive expiratory pleural pressure and expiratory pulmonary deflation receptor activity-and hence the asthmatic tachypnoea-increase after the sigh, the expiratory self-compression of the lungs brought about by uneven ventilation is reinforced. The elimination of the reference gas during the acute phase of the asthma attack is always delayed and occurs in successive stages, giving rise to a deformed expiratory Ar or N2 concentration curve. These results point to uneven and asynchronous ventilation. In the records examined, sighs do not influence the rate of washout/washin of the reference gas during this asthmatic phase. It is of interest that the respiratory results produced by the sigh during the acute phase are essentially similar to those produced by rapid (passive) inflations of the lungs.

b) Augmented Breaths (Sighs) in the Recovery Phase of the Asthma Attack. The recovery phase in the histamine-induced asthma attack sets in approximately 1 min after the respiratory rate in the acute phase has reached its peak. During the recovery phase a general decrease in breathing frequency and lung volume tends to occur and the frequency of occurrence of the sighs decreases too. At the respiratory rate of 81 +_ 31 (rain -1) 0.6 sighs per rain, respectively 0.75 sighs per 100 breaths are found (see Fig. 1 : Asthma II). During the gradual return to normal breathing the sighs followed by inspiratory drives, so typical for the acute phase, gradually give way to augmented breaths followed by a decrease in breathing frequency and lung volume in 64 % of the sighs, an increase in tidal volume in 75 % (see Fig. 3). In the afferent vagal neurogram 75 % of the sighs recorded were followed by normalized pulmonary stretch receptor and decreased pulmonary deflation receptor discharge, indicating normalization in lung mechanics. 49 ~ of the sighs in the washin/washout of the reference gas induced a sudden decrease/increase in the Ar (rise/drop in the N2) concentration, findings which are the reverse of those established before induction of the attack or during the acute phase. Furthermore the augmented breaths had apparently no effect on the normal or hastened washout-rate.

Pfliigers Arch. 372 (1977) ~----15 sec

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Fig. 3. An augmented breath (arrow) in the recoveryphase of the bronchial asthma attack. Washin (Ar)/washout(N2)curvescombined with plethysmogram. The sigh promotes the return to normal breathing (breathing frequency and tidal volume) by reopening closed lung units. For further explanations see text Figure 3 is a typical example of the effects produced by the sigh on ventilatory pattern in the recovery phase of the asthma attack. The sigh causes a decrease in breathing frequency combined with an increase in tidal volume (see above). During the washin of Ar as reference gas, the N2 concentration is suddenly increased by the augmented breath, which suggests that lung units excluded from ventilation have been reopened by the sigh and that the N2 washout in this lung unit has begun (see graph). These findings indicate that augmented breaths in the recovery phase of the asthma attack play a part in the return to normal conditions in lung mechanics, a fact which also holds true for passive inflations.

DISCUSSION Our study indicates that the augmented breaths in the bronchial asthma attacks studied are closely correlated with the marked inspiratory response (rapid and shallow breathing associated with increase in lung volume) which sets in at onset of increasing bronchial resis-

G. Delmore and E. A. Koller: Sighsin Bronchial Asthma Attacks

5

tance. The sighs punctuate and often also precede in increasing number the marked inspiratory response as the latter gradually reaches its peak, and they then decrease in frequency as the respiratory rate and the lung volume return to normal values. The results lend support to the conclusion that the rate of occurrence of the sighs appears to reflect the intensity of the asthmatic attack [10]. It has been shown that the augmented breaths are dependent on intact vagi and are mediated by afferent fibres in response to pulmonary overinflation or collapse [19,20,1,10,11,6,17,7] and as such differ from the "sighs" caused by mechanical stimulation of the laryngeal mucosa (see Glogowska et al. [7]). The augmented breaths are characteristic in conditions in which the respiratory effects due to pulmonary deflation (irritant) receptor activity overrule those due to pulmonary stretch receptor discharge (see below). This is the case during asthmatic tachypnoea as well as during hyperpnoea induced by chemical irritants. It is therefore not surprising that the mechanical conditions which underlie stimulation of the pulmonary deflation receptors are reflected by the frequency of occurrence of the sighs as well as by the influence exerted by the latter on breathing during the two phases of the bronchial asthma attack. In the initial or acute asthmatic phase, the augmented breaths, like passive inflations [10], enhance the mechanical conditions underlying the stimulation of the pulmonary deflation receptors and hence the increase in breathing frequency and lung volume. The mechanisms responsible for this enhancement have been explained by Koller and Kbhl [15]: Uneven distribution of the inspired air during the acute phase of the asthma attack produces air-trapping and regional overinflation of the lungs. The greater the latter, the greater the expiratory rise in intrathoracic pressure, conditions leading to expiratory self-compression of the lungs and in turn to stimulation of the pulmonary deflation (irritant) endings. The lung deflation reflex, however, overrules the heterogeneous respiratory effects of the pulmonary stretch receptors (see above). The sighs during the acute phase become an essential component of the vicious circle of uneven ventilation and reflex induced tachypnoea: they reinforce the deflation reflex brought about by uneven ventilation and overinftation-conditions incidentally recalling the inspiratory effort of the paradoxical reflex of Head [8]: The resultant tachypnoea lowers the dynamic compliance (see Caro et al. [3]). The lowered compliance, however, as suggested by Reynolds [19], favours the occurrence of the sighs by stimulation of the pulmonary deflation (irritant) endings [6, 21 ]. In the recovery phase, the phase of return to normal breathing rate, the frequency of occurrence of the

sighs decreases significantly. The augmented breaths promote the normalization of lung mechanics to the same extent as the mechanical conditions underlying their occurrence subside. During this phase, characterized by pseudohomogeneous ventilation, the sighs increase the ventilated part of the alveolar space by reopening lung units which were excluded from ventilation during the bronchial asthma attack (see Fig. 3) or during the hyperpnoea induced by chemical irritants [2]. Careful passive inflation or thoracic distension in this stage of the asthma attack evokes the same effects as do sighs [10,12,13]. This has also been demonstrated in man [18], in cat [47] and rabbit [21]. The return to stable conditions in lung mechanics occurring in this phase of the asthma attack allows the activity of the rapidly adapting pulmonary deflation endings to subside, so that the return to normal breathing is rendered possible. The normal animal or the healthy human being also emits augmented breaths, although relatively seldom. If sighs are dependent on the activation of pulmonary deflation receptors, this would mean that the lung deflation reflex also occurs sporadically during normal breathing. Unevenness of ventilation caused by regional differences in intrapleural pressure is a normal phenomenon. The compressed region of the lung at the base in man (see West [22]), particularly when sitting, or in general when intermittent ventilation occurs as a result of shallow breathing, could very well lead to mechanical conditions which activate lung deflation endings and thus cause augmented breaths. The frequency of sighs could therefore be increased in man by any factor able to reinforce the latent uneven ventilation (see below). Glogowska et al. [7] in a careful study described the role of the vagi, the peripheral chemoreceptors and other afferent pathways in the genesis of augmented breaths in cats and rabbits. They state: "There is evidence that vagal and chemoreceptor inspiratory drives sum in the C.N.S. to cause augmented breaths, although a positive feedback (peripheral chemoreceptor activity increasing breathing and thus increasing lung irritant [deflation] receptor activity) may be involved too." Although the chemoreceptor drive may contribute to the elicitation of sighs, it should be pointed out that augmented breaths also occur in the chemoreceptor-denervated rabbit [9] or guineapig (unpublished observation). Hyperthemia (including panting) may also contribute to the elicitation of augmented breaths. On the one hand, the rapid and shallow breathing due to hyperthermia reinforces physiological or pathological uneven ventilation and therefore the conditions promoting the occurrence of sighs (see above), on the other, the sigh may be facilitated by hyperthermic influences on central

Pflfigers Arch. 372 (1977)

mechanisms. The importance of the C.N.S. for the genesis of augmented breaths is moreover supported by the fact that in deep anaesthesia (urethane) sighs no longer appear, whereas analeptics (Micoren | increase the frequency of their occurrence. In conclusion, augmented breaths in the bronchial asthma a t t a c k - and possibly during normal breathing t o o - a r e caused by uneven ventilation and mediated by vagal fibres arising from the pulmonary deflation endings. Several factors may be involved in the genesis of the augmented breaths: either the reinforcement of mechanical conditions underlying stimulation of the pulmonary deflation endings (tachypnoea, pulmonary or thoracic compression, chemical irritants), or the facilitation of the pulmonary deflation reflex (hypoxemia, hyperthermia, analeptics), or, an interplay of both peripheral and central mechanisms.

8. 9. 10.

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13. 14.

Acknowledgements. We are greatly indebted to Miss V. Bucher for critically reviewing the manuscript and also grateful to Mrs. S. Meier for much skilled technical help.

15. 16.

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Received August 9, 1976