Вы находитесь на странице: 1из 16
Respiratory Physiology & Neurobiology 152 (2006) 266–281 Cough motor mechanisms Giovanni A. Fontana ∗ ,
Respiratory Physiology & Neurobiology 152 (2006) 266–281 Cough motor mechanisms Giovanni A. Fontana ∗ ,

Respiratory Physiology & Neurobiology 152 (2006) 266–281

Physiology & Neurobiology 152 (2006) 266–281 Cough motor mechanisms Giovanni A. Fontana ∗ ,

Cough motor mechanisms

Giovanni A. Fontana , Federico Lavorini

Dipartimento di Area Critica Medico Chirurgica, Unita` Funzionale di Medicina Respiratoria, Viale G.B. Morgagni 85, 50134 Firenze, Italy

Accepted 23 February 2006

Abstract

Cough is a defensive airway mechanisms which involves the sequential activation of several laryngeal and respiratory muscles in the generation of the typical four-phase motor pattern. Activation of such muscles can be considered to represent the “primary” cough motor mechanism, and its functional significance, although complex, appears to be fairly well established. Nonetheless, the outflows of cough are numerous, and may additionally involve the reflex or mechanical activation of other respiratory and non-respiratory motor systems. These additional, or “secondary”, outflows of cough can mainly be regarded as being involved in either enhancing the defensive function of cough, or opposing the possible noxious effects exerted by the mechanical stresses of coughing. In addition, both the primary and secondary cough motor mechanisms are known to play multiple functional roles, thus considerably complicating the cough panorama. Finally, some of the secondary cough motor responses, such as the changes in the pattern of breathing, seem to be devoid of any favourable action and their functional meaning, if any, is not fully understood. Although it is well known that all patterns of cough can be produced voluntarily, the extent to which also volitional cough is accompanied by an array of motor responses similar to that of reflex cough remains to be elucidated. © 2006 Elsevier B.V. All rights reserved.

Keywords: Cough; Respiratory muscles; Laryngeal muscles; Bronchoconstriction; Mucus secretion; Perineal muscles; Lower oesophageal sphincter; Cardiovascular changes; Changes in breathing pattern

1. Introduction

Cough is a vagally mediated, defensive airway reflex consisting of a modified respiratory act aimed primar- ily at generating the high flow velocities required for

This paper is part of a special issue entitled “Cough and its Regu- lation”, guest-edited by John G. Widdicombe and Bradley J. Undem. Corresponding author. Tel.: +39 055 413183; fax: +39 055 4223 202. E-mail address: g.fontana@dac.unifi.it (G.A. Fontana).

1569-9048/$ – see front matter © 2006 Elsevier B.V. All rights reserved.

doi:10.1016/j.resp.2006.02.016

removal of mucus or any other foreign body from the lower respiratory tract. When cough is initiated voluntarily or by stimula- tion of tracheobronchial receptors, it typically begins with an inspiratory phase, characterised by an enhanced contraction of the diaphragm and abductor muscles of the larynx. However, when stimuli act at the level of the vocal folds or upper tracheal segments, the preparatory inspiration may be absent: this is considered a separate reflex, i.e., the “expiration reflex” (Korpas and Tomori, 1979). During the subsequent compressive phase, the

G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

267

laryngeal adductor muscles close the glottis, while the expiratory muscles contract. The expulsive phase of cough results from a sudden opening of the glottis and continued forceful contraction of the expiratory mus- cles. The violent muscular activity associated with the expirations of cough may have noxious effects, includ- ing trauma of the larynx and airways, rib fractures and barotrauma (Leith et al., 1986). A fourth (“cessation”) phase of cough, with some laryngeal adduction, has also been described (Leith et al., 1986). Although during coughing the above-mentioned events may replicate with minor variations, different patterns of cough which may occur in real life have been identified (Widdicombe and Fontana, in press). The neural components of the cough reflex are the receptors which sense the initial tussigenic stimulus, an afferent pathway to bulbo-pontine neuronal aggregates where interaction with other inputs may occur, and an efferent pathway connected to the effector organs. Excellent descriptions of the sensory receptors and cen- tral pathways involved in the genesis of the cough reflex can be found in the literature (e.g., Widdicombe, 2001; Shannon et al., 2004), and will be elucidated further in other sections of this issue. As briefly outlined above, the efferent arm of cough primarily involves the sequential activation of sev- eral laryngeal and respiratory muscles; however, the outflows of cough are numerous (Fontana, 2003) and they usually engage also non-respiratory muscles and organs, thus considerably complicating the cough pic- ture. In this review, we will concentrate on the motor end of the cough reflex, in an attempt to describe the most important cough motor mechanisms and their possible functional significance. In order to facilitate the understanding of the neural substrates of cough motor responses, brief accounts of the sensory and cen- tral integrative mechanisms subserving such responses will also be given (Section 2). Additional details on cough motor control mechanisms will be provided, when appropriate, within each pertinent section.

2. Neural circuits of cough

2.1. Reflex cough

The larynx and the tracheobronchial tree are the main reflexogenic zones for cough, to which we will

refer in our description of the neural circuits subserving reflex cough. However, it is now recognised that other non-respiratory areas, such as the proximal gastroin- testinal tract, innervated by vagal sensory terminals, can also initiate cough. Sensory information arising from laryngeal receptors is conveyed via the internal branch of the superior laryngeal nerve (SLN). Laryn- geal afferent fibres terminate in different regions of the nucleus tractus solitarii (nTS), where they synapse on second-order neurones (Shannon et al., 2004). Laryn- geal second-order neurones have been found in the commissural subnucleus of the nTS. Laryngeal affer- ents have also been shown to project to other nTS subnuclei, as well as to other medullary (e.g., the dorsal and ventral respiratory groups, DRG and VRG, respec- tively) and pontine regions (i.e., the pontine respiratory group) involved in control of breathing (Shannon et al.,

2004).

Also afferent signals from lower airway receptors implicated in cough mediation, conveyed by the vagus nerve, terminate mainly in the commissural subnu- cleus (Jordan, 2001), a site of possible convergence of laryngeal and lower airway sensory information. The commissural subnucleus is also the main terminus of afferent C-fibres (Jordan, 2001). Commissural second- order neurones project extensively to DRG, VRG, and pontine respiration-related neurones (Shannon et al.,

2004).

The efferent pathways of cough carry the central motor command from the pre-motoneurones of the DRG and VRG to the spinal respiratory motoneurones and, via the phrenic, intercostals and lumbar nerves, to the respiratory pump muscles. The central motor com- mand from pre-motoneurones is also transmitted via cranial motoneurones innervating the laryngeal intrin- sic muscles, and via sympathetic and parasympathetic nerves supplying the airway smooth muscle and glands.

2.2. Voluntary cough

Although human experience reveals that virtually all patterns of spontaneous cough (Widdicombe and Fontana, in press) can be reproduced voluntarily, and that both spontaneous and induced cough can volun- tarily be suppressed, only limited information is avail- able on the supramedullary mechanisms subserving the volitional control of cough. In the cat, electri- cal stimulation of the suprasylvian gyrus can initiate

268 G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

cough (Kase et al., 1984). This region appears to be related to laryngeal muscle motor control in the monkey (Simonyan and Jurgens, 2005). Conversely, stimulation of the anterior cingulate gyrus in the cat suppresses cough induced by SLN stimulation (Kase et al., 1984). Interestingly, functional magnetic resonance studies in humans have identified areas of neuronal activation by volitional inspirations which include the superior motor cortex, the premotor cortex, and the supplemen- tary motor area; additional activated areas include the inferolateral sensorymotor cortex, the prefrontal cortex and the striatum (Evans et al., 1999). It seems likely that these brain areas also participate in the production of the motor patterns of voluntary cough.

3. Classification of cough motor mechanisms

In functional terms, the motor mechanisms brought into action by a tussigenic stimulus acting at the level of an appropriate receptor seem to pertain to two main categories: the “primary” and the “secondary” motor mechanisms. The former are responsible for the production of the typical four-phase cough motor pattern described above (see Section 1). The “sec- ondary” motor mechanisms can be sub-categorised as those aimed to improve the effectiveness of cough as a defence mechanism, those opposing the mechani- cal stresses of cough, or as mechanisms apparently unrelated to the defensive purposes of the reflex or to counteracting its potentially noxious effects. A classifi- cation of cough motor mechanisms based on functional criteria is proposed in Table 1. Some of the cough motor mechanisms seem to play multiple functional roles:

thus, respiratory muscle activation also contributes to stabilise the chest wall, lungs and airways during the cough expulsive phase (Fontana, 2003), whereas bron- choconstriction is thought to be directed not only to improve the mechanical effectiveness of cough, but also at limiting the progression of inhaled foreign bod- ies towards the periphery of the lungs. Furthermore, bronchoconstriction and mucus secretion are consid- ered separate airway protective reflexes which can be initiated individually and may not be necessarily asso- ciated with coughing. It could be of interest to establish if and to what extent also voluntary cough is accompanied by a sim- ilar array of motor responses. For instance, it is well

Table 1 Classification of cough motor mechanisms

Primary outflows of cough Intrinsic laryngeal muscles Diaphragm Intercostal and other ribcage muscles Abdominal muscles

Secondary outflows of cough Mechanisms enhancing the defensive function of cough Bronchoconstriction Mucus secretion Mechanisms opposing the mechanical stresses of cough Perineal muscles Lower oesophageal sphincter Respiratory muscle activation Changes in breathing pattern Cardiovascular changes Changes in cardiac output and blood pressure Changes in heart rate

known that perineal muscles (Section 5.2.1) contract also during voluntary coughing, and similar consider- ations apply to cough-induced cardiovascular changes (Section 5.4); on the other hand, voluntary cough is unlikely to promote mucus secretion.

4. Primary outflows of cough

4.1. Intrinsic laryngeal muscles

In most animal species, the larynx is the site of origin of a large number of reflexes; however, the main res- piratory responses evoked by laryngeal stimulation are apnoea, coughing, expiratory efforts, and laryngeal clo- sure (Widdicombe, 1986). The organ is also implicated in complex behavioural functions such as swallowing and voice production. A number of experimental lines of evidence indicates that the glottis and the supraglot- tic region are powerful reflexogenic areas for cough (Widdicombe, 1986). At the laryngeal level, coughing requires control of the glottis by a coordinate sequence of activity in the intrinsic laryngeal muscles (Korpas and Tomori, 1979; Sant’Ambrogio et al., 1997). Recent animal studies have examined the temporal relationships between the pattern of activation of the intrinsic laryngeal muscles and the ongoing mechanical events during coughing induced by mechanical stim- ulation of the tracheobronchial tree (Sant’Ambrogio

G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

269

et al., 1997). The experiments were carried out on anaesthetised dogs by recording the electromyographic (EMG) activity of the laryngeal abductor and adduc- tor muscles, along with subglottic and intrathoracic pressure changes. The posterior cricoarytenoid (PCA) is the laryngeal abductor muscle, while the thyroary- tenoid (TA) and arytenoideus (AR) muscles are adduc- tors. The physiological role of the cricotyroid (CT) is less clearly understood. Recent experiments have shown that antidromically identified CT motoneurones in the rostral nucleus ambiguus of the rat discharge synchronously with the phrenic nerve during normal respiration (Sun et al., 2005). During the inspiratory phase of cough, contraction of the PCA and CT reduces upper airway resistance and promotes inspiratory flow. During glottal closure, the TA and AR are recruited, while both the PCA and CT display minimal activ- ity. Finally, during the expulsive phase, the PCA is recruited and the adductors are suppressed. These phe- nomena would open the glottis and, along with the activation of expiratory muscles, promote expulsion of air from the lungs. Interestingly, this pattern of motor activation turned out to be unaffected by both isolating the larynx from the intrathoracic airways and section- ing of the internal branches of the SLNs. Therefore, the well-coordinated activation of laryngeal abductor and adductor muscles during tracheobronchial cough appears to be an entirely centrally pre-programmed event that is uninfluenced by the route of breathing and laryngeal sensory feedback (Sant’Ambrogio et al.,

1997).

Further insights into the central neural mechanisms subserving intrinsic laryngeal muscle control during eupnoea and cough in the cat are provided by the results of a recent study by Poliacek et al. (2005). In these experiments, cough was induced by mechanical stim- ulation of the laryngeal and tracheobronchial mucosa prior to and after microinjections of kainic acid into discrete brainstem regions, namely the pontine respi- ratory group, the lateral tegmental field, and the raphe nuclei. Kainic acid selectively inactivates cell bodies while sparing axons of passage. In control conditions, the abductor (PCA) and adductor (TA) muscles dis- played the typical pattern of reciprocal activation dur- ing the appropriate phases of cough. Following kainic acid lesions, laryngeal and tracheobronchial mechani- cal stimulation failed to evoke cough, and the reciprocal activation of PCA and TA was replaced by the appear-

ance of irregular bursts of EMG activity (Poliacek et al., 2005). Since lesions in the selected brainstem regions caused no appreciable changes in the eupnoeic pattern of laryngeal muscle activity, such regions seem to be specifically important for laryngeal muscle control dur- ing cough and generation of the cough motor pattern (Poliacek et al., 2005). Information on intrinsic laryngeal muscle activity in human cough is relatively scarce, partly because of the difficulties in obtaining accurate EMG record- ings from these relatively inaccessible muscles. A recent cross-correlation study (Poletto et al., 2004) per- formed on normal subjects examined the relationships between EMG recordings of discrete intrinsic laryn- geal muscles and vocal folds movements during speech and various laryngeal motor activities, including voli- tional cough. The study confirmed previous observa- tions (Sant’Ambrogio et al., 1997) that TA and lateral cricoarytenoid muscles are active for vocal fold adduc- tion during the compressive phase of cough, and that adduction occurs immediately following inspiration to close off the upper airway and raise intrapulmonary pressure (Poletto et al., 2004). As in the study by Sant’Ambrogio et al. (1997), the PCA muscle activates for vocal fold abduction at the onset of the expulsive phase of cough (Poletto et al., 2004). It can be questioned whether differences exist in the pattern of activation of laryngeal and respiratory pump muscles when coughing is elicited by stimulat- ing receptors located at the level of the laryngeal or tracheobronchial mucosa, or when an expiration reflex (Korpas and Tomori, 1979) is triggered by mechani- cal stimulation of the vocal folds. By comparing the mechanical events and EMG activities of the laryn- geal and respiratory muscles during coughing induced by mechanical stimulation of the laryngopharyngeal or tracheobronchial mucosa of the cat, Poliacek et al. (2003) demonstrated longer lasting and more intense diaphragmatic and TA activity during the inspirations and expirations of a laryngeal cough, respectively. However, the pattern of activation and peak EMG activ- ity of the abdominal muscles was similar with both stimulation modalities (Poliacek et al., 2003). Dur- ing the expiration reflex, both the duration and inten- sity of abdominal muscle EMG activity were reduced compared to laryngopharyngeal and tracheobronchial coughs, as was the duration of the TA muscle dis- charge. Conversely, the intensity of peak TA muscle

270 G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

Physiology & Neurobiology 152 (2006) 266–281 cle activation by expansion of the chest wall ( Grelot´

cle activation by expansion of the chest wall (Grelot´ and Milano, 1991). At variance with the study by Tomori and Widdicombe (1969), however, diaphrag- matic activity abruptly terminated at the end of the inspiratory phase of cough (Grelot´ and Milano, 1991). Thus, in the cat, the pattern of diaphragmatic activ- ity during coughing induced by mechanical laryngeal stimulation (Tomori and Widdicombe, 1969) or by electrical SLN stimulation (Grelot´ and Milano, 1991) appear to differ, at least to some extent. In this context, it seems worthwhile to recall that the SLNs also carry

sensory information for other non-respiratory reflexes

˙

Fig. 1. Original recording of tidal volume (V T ), flow ( V ), and integrated abdominal (oblique muscle) electromyographic (IEMG) activity obtained in a normal subject during a maximum voluntary cough. The vertical line marks the onset of the IEMG activity during the late stages of the inspiratory phase of cough, suggesting coacti- vation of antagonistic muscles. Authors’ unpublished observations.

involving the activation of laryngeal and respiratory muscles, such as swallowing, retching and vomiting. In functional terms, large preparatory inspirations may serve to optimise the pre-contractile lengths of the expiratory muscle which, in turn, may facilitate

EMG activity was much higher during the expiration reflex than during cough of any origin (Poliacek et al.,

dynamic airway compression and promote high expira- tory flow velocities during the expulsive phase of cough (Fontana, 2003).

2003).

 

4.3. Intercostal and other ribcage muscles

4.2. Diaphragm

Studies in cats (Van Lunteren et al., 1989; Poliacek et al., 2005) and dogs (Kobayashi et al., 1992) have demonstrated that, compared with normal breathing, the EMG diaphragmatic activity is markedly increased during the inspiratory phase of coughing. Diaphrag- matic electrical activity has also been shown to per- sist into the early stages of the expulsive phase of cough (see Section 5.2.3). In addition, Tomori and Widdicombe (1969) found that, at the onset of expi- ratory muscle activation, the intensity of diaphrag- matic activity exceeds that of the preceding inspiratory phase and terminates just prior to the attainment of peak positive pleural pressure. More recently, experi- ments performed in the anaesthetised cat also demon- strated that, during the inspiratory phase of coughing

induced by electrical SLN stimulation, the diaphragm, the rectus abdominis and the external, but not internal, oblique muscles are coactivated (Grelot´ and Milano, 1991). A small degree of oblique muscle activation may often be observed in humans during the final stages of the inspiratory phase of a voluntary cough effort (Fig. 1). Nerve recordings indicated that coactivation

is not abolished by muscular paralysis, thus excluding

a contribution of spinally mediated abdominal mus-

The understanding of the mechanical actions exerted by the intercostal muscles has represented a major challenge to many researchers over the cen- turies. Only in recent years the respiratory action of the intercostal muscles has come to a more complete elu- cidation, and the research efforts that have ultimately led to this result are the object of an excellent review published recently (De Troyer et al., 2005). Readers are therefore referred to this work for an exhaustive overview of the neural control and mechanical actions

of the intercostals during normal breathing. Here, we

will concentrate on the lesser amount of information regarding the activity of these muscles during cough. Indeed, there are few studies that have investigated intercostal muscle activity during coughing and other expulsive manoeuvres (Iscoe, 1998; De Troyer et al.,

2005).

In general terms, the external intercostals (EIC) have an inspiratory advantage, while the internal inter- costals (IIC) have an expiratory advantage. In a sim- ple machine such as a lever, mechanical advantage is

defined as the ratio of the force delivered at the load to the force applied to the lever (De Troyer et al., 2005).

A chest wall muscle in a relaxed state is thought to

have an inspiratory mechanical advantage if the muscle

G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

271

shortens during passive inflation, or to have an expira- tory advantage if the opposite is true (De Troyer et al., 2005). For the intercostal muscles, the magnitude of such mechanical advantages is such that the inspi- ratory advantage of the EIC is greatest at the rostral interspaces, and the expiratory advantage of the IEC is greatest at the ventral portion of the caudal inter- spaces (De Troyer et al., 2005). The inspiratory effect of the EIC muscles is maximal at the level of the dorsal half of the second interspace, but decreases rapidly in the ventral and caudal directions, and reverses into an expiratory effect in the ventral half of the 6th and 8th interspaces. The IIC muscles in the ventral half of the 6th and 8th interspaces have large expiratory effects that decrease dorsally and cranially (De Troyer et al., 2005). During coughing elicited by electrical stimula- tion of the SLN in the decerebrate cat, mid-thoracic EIC and IIC muscles discharged synchronously with the diaphragm and the abdominal muscles, respectively, whereas caudal EIC and IIC discharged synchronously with the abdominal muscles (Iscoe and Grelot,´ 1992). The triangularis sterni, also called the transversus thoracis, is a thin muscle that covers the paraster- nal intercostals on their inner surface, and its fibres run parallel to those of the external intercostals (De Troyer et al., 2005). In both dogs and humans, the muscle has an expiratory mechanical advantage that is particularly evident at the level of the 5th and 6th intercostals spaces. In humans, the muscle is normally silent during tidal breathing (De Troyer et al., 2005), but it is promptly activated by voluntary and invol- untary expiratory efforts, including cough (Fontana, 2003). Activation of the triangularis sterni seems to be tightly coupled with that of the abdominal muscles. The muscle function is mainly to contribute to the defla- tion of the rib cage during active expirations (Fontana,

2003).

4.4. Abdominal muscles

The principal expiratory muscles with significant respiratory function in humans lie in the ventro-lateral aspect of the abdominal wall. The abdominal muscles include the transversus abdominis muscle, the externus and internus obliquus muscles, and the rectus abdo- minis muscle (Iscoe, 1998). In humans, the abdominal muscles have an important postural function as rotators (oblique muscles) and flexors (rectus abdominis) of the

trunk. As expiratory muscles, their contraction pulls the abdominal wall inward and increases abdominal pres- sure. As a result, the diaphragm is pushed cranially, lung volume decreases and pleural pressure increases. Due to their insertions on the rib cage, contraction of the abdominal muscles contributes to expiration by lower- ing the lower ribs. Experimental lines of evidence confirm that all abdominal muscles are activated during the compres- sions and expirations of cough. However, whilst in the cat the rectus abdominis seems to contribute largely to generating the cough expulsive force (Tomori and Widdicombe, 1969), this may not be true in humans. By means of surface EMG recordings performed on humans during voluntary coughing, Floyd and Silver (1950) demonstrated substantial activation of both the internus and externus obliquus muscles that was asso- ciated with a much smaller activation of the rec- tus abdominis. A subsequent study by Strohl et al. (1981) also showed greater activation of the upper and lower ventro-lateral abdominal muscles compared with the rectus abdominis muscle during voluntary cough efforts in humans. In addition, the results of investiga- tions also involving measurement of static expiratory airway pressure during spinal cord stimulation, per- formed prior to and after ablation of different expiratory muscle groups in the anaesthetised dog (Di Marco et al., 1999) are in keeping with human studies (Floyd and Silver, 1950; Strohl et al., 1981) showing that the oblique muscles make the largest mechanical contribu- tion to pressure generation. Additional information on abdominal muscle con- trol during human cough can be inferred from the results of a study performed recently on laryngec- tomised patients (Fontana et al., 1999). As shown in Fig. 2, at threshold and suprathreshold levels for cough, patients displayed significantly lower peak abdominal (oblique muscle) EMG activity and peak expiratory flow rates than control subjects; furthermore, a much more prolonged activation of the expiratory muscles and a slower decay in expiratory flow rate was fre- quently observed in the patients during both maximum voluntary and reflex cough efforts at suprathreshold level. The reduced expiratory muscle activity observed in laryngectomised patients during the expulsive phase of reflex cough at threshold stimulus intensity is likely accounted for by the lack of sensory information car- ried by the SLN leading to an impairment in the mecha-

272 G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

Physiology & Neurobiology 152 (2006) 266–281 Fig. 2. Original recordings obtained from a control subject

Fig. 2. Original recordings obtained from a control subject (left panels) and a laryngectomised patient (right panels) during maximum voluntary coughing (upper panels), reflex cough at threshold stimulus intensity (middle panels), and cough at supra-threshold stimulus intensity (lower panels). Traces in each panel are cough expiratory flow and the integrated electromyographic activity of the abdominal muscles (IEMG). Compared with control subjects, patients commonly displayed a more prolonged activation of the expiratory muscles and a slower decay in expiratory flow rate during intense cough efforts either voluntarily or reflexly produced. Reprinted with permission from Fontana et al. (1999).

nisms subserving expiratory motoneurone recruitment and/or regulating their firing pattern (Bongianni et al., 1988; Iscoe, 1998). Conceivably, this impairment can be overcome by the more intense action of suprathresh- old stimuli (Fontana et al., 1999) and by the near maximal motor unit recruitment of maximum volun- tary cough. The mechanism(s) underlying the slower decay of abdominal muscle activity during the expiration of voli- tional and suprathreshold coughs in laryngectomised patients (Fig. 2) are presently obscure. A major factor in airway clearing and expectoration is the velocity of expiratory flow. The latter is proportional to the rate of flow and inversely related to the airway cross sectional area (Fontana, 2003). Airway cross sectional area is increased by the laryngectomy and, hence, flow veloc- ity is reduced (Fontana et al., 1999). Speculatively, prolongation of the cough expulsive phase in laryn- gectomised patients may represent a compensatory mechanism aimed at preserving the effectiveness of the cough clearing mechanism when expiratory flow velocity is diminished by laryngeal ablation. In addi- tion, it has been shown that laryngeal motor acts can influence expiratory muscle activation, possibly via a centrally programmed coordination programme and/or stretch reflexes arising from muscles of the upper air- way (Mead and Reid, 1988). Ablation of the larynx may result in a disruption of these neural mechanisms

and lead to an alteration of the expiratory motor pattern of cough. The observation of a reduced peak expiratory flow and of lower airflow velocity in laryngectomised patients casts doubts on the common assumption (Fontana et al., 1999) that ablation of the larynx has no major impact on patients’ airway clearing capac- ity. Rather, the phenomena are in keeping with the possibility of an impaired cough motor response to low- intensity stimuli such as those possibly represented by early stage respiratory infections. A weakened expul- sive capacity of cough in this clinical condition may facilitate the spreading of the initial infection and partly accounts for the increased prevalence of respiratory complications in laryngectomised patients (Fontana et al., 1999).

5. Secondary outflows of cough

5.1. Mechanisms enhancing the effectiveness of cough

5.1.1. Bronchoconstriction An accompanying feature of cough and other res- piratory reflexes is bronchoconstriction (Korpas and Tomori, 1979). Irritation of the larynx and of the tracheobronchial tree elicits an increase in parasym-

G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

273

pathetic nerve traffic to the airways (Tomori and Widdicombe, 1969) and an increase in pulmonary resistance likely brought about by smooth muscle con- traction (Widdicombe and Nadel, 1963). Blockade of the parasympathetically induced increase in air- way resistance by atropine indicates that the motor effect depends on cholinergic muscarinic receptors (Colebatch and Halmagyi, 1963). Although cough and reflex bronchoconstriction often occur simultaneously, a large body of evidence indicates that their afferent neural pathways are sep- arate, since the reflexes can be induced individually and suppressed selectively by drugs (Karlsson et al.,

1988).

The vagal airway afferents implicated in smooth muscle control mainly include fibres originating from slowly and rapidly adapting receptors (SARs and RARs, respectively), as well as from the sensory end- ings of the unmyelinated pulmonary and bronchial C fibres (Widdicombe, 2001). All these afferents seem to convey sensory information to discrete portions of the nTS in the medulla oblongata. SARs fibres termi- nate in the ventro-lateral (Jordan, 2001) and medial (Bongianni et al., 2005) subnucleus of the nTS, and provide excitatory inputs to second order inhibitory neurones (pump cells). Fibres from RARs innervate RAR cells in the commissural portion of the nTS, located caudally to the obex; these neurones also receive inhibitory inputs from pump cells and possi- bly additional excitatory drive from C-fibre receptors. In this arrangement, increased activity from both RARs and C fibres, or reduced activity of SARs, will increase neuronal output to the airway smooth muscle, result- ing not only in bronchoconstriction but also in mucus secretion and enhanced cough. Conversely, blockade of RARs and/or C-fibre discharge, or activation of SARs, will reduce vagal outflow to the airway. The central projections of nTS neurones involved in smooth mus- cle control have not been fully elucidated but ultimately involve connections with preganglionic neurones in the nucleus ambiguus and the dorsal motor nucleus of the vagus nerve (Mazzone and Canning, 2002). The physiological meaning of cough-related airway narrowing remains uncertain and it seems doubtful that smooth muscle constriction persists during the expul- sive phase of cough, where it should exert its mechan- ical advantages (see below). In theory, however, the bronchoconstriction of cough may be advantageous in

many respects. First of all, bronchoconstriction may enhance the sensory component of cough. For instance, animal studies (Mills et al., 1970) have shown that airway RARs are stimulated or sensitised by smooth muscle contraction, and desensitised by smooth mus- cle relaxants. Some lines of evidence also suggest that the intensity of the cough response evoked by histamine inhalation in humans is related to the degree of the asso- ciate bronchoconstrictor response (Banner, 1986). Cough-related bronchoconstriction may also increase the chance that any inhaled particle will impact at the level of central airways (Richardson and Peatfield, 1981), thus limiting their progression towards the gas-exchanging regions of the lungs. Bron- choconstriction reduces the overall cross-sectional area and constricted airways are more rigid than those in the relaxed state. Therefore, a reduction in airway cross-sectional area would increase the linear velocity of the expiratory flow (see Section 4.4) and its turbulence, possibly increasing the effectiveness of cough as an airway clearing mechanism (Leith et al., 1986). Furthermore, constricted airways may remain patent when transmural pressures would otherwise collapse them (Richardson and Peatfield, 1981). This phenomenon would also shift the equal pressure point further towards the lung periphery and help the cough to clear the smaller airways. Admittedly, the beneficial effects of bronchoconstriction on the cough effectiveness may largely be counteracted by the deep inspiration that usually precedes a cough attack. Deep inspirations are known to stretch the constricted airway muscle to its resting length (Salerno et al., 1999). Therefore, the actual relevance of bronchoconstriction in cough effectiveness seems questionable, and further investigations are needed to clarify its role. Bronchoconstriction is likely to be a feature also of the so-called expiration reflex, an expulsive motor act which, at variance with cough, lacks a prepara- tory inspiration, i.e., a major factor in the genesis of the high expiratory flow rates of cough (Leith et al., 1986). Due to absence of the airway stretching effect of the preparatory inspiration, reflex bronchoconstric- tion would persist during the expulsive phase of the expiration reflex, and allow to attain higher expiratory flow velocities even in the absence of a preparatory lung inflation. Whether the central neural mechanisms subserving volitional expulsive efforts also influence airway smooth muscle tone is not known.

274 G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

5.1.2. Mucus secretion

The secretion of mucus by submucosal glands and surface epithelial goblet cells of the trachebronchial tree is an integral part of the defence mechanisms of the lungs and airways. The mucus acts as a barrier to penetration of noxious agents and limits their passage into the tissues. It also serves as the vehicle in which these noxious agents are moved up to the airways by the sweeping action of the cilia, and to be subsequently swallowed or expelled by coughing (Foster, 2002). The mucus lining forms an upper “gel” layer, that traps inhaled particles, and a lower “sol” layer, in which cilia beat to remove mucus and particles from the lungs, a process termed mucociliary clearance (Foster, 2002). It is widely recognised that excessive airway mucus secretion may induce coughing by mechanical stim- ulation of airway sensory nerves, so that stimuli that promote airway mucus secretion also provoke cough indirectly; on the other hand, there is also evidence (Phipps and Richardson, 1976) that the same mechani- cal and chemical stimuli which provoke cough may also cause reflex airway mucus secretion. Thus, since exces- sive airway mucus secretion may cause coughing, and coughing may evoke reflex airway mucus secretion, a complex mechanism of interaction between cough and airway mucus secretion exists. Reflex mucus release by tussigenic stimuli may also serve to thicken the gel mucus layer and reduce the airway cross-section, thus increasing linear velocity of airflow and produc- ing more turbulence and impaction of pollutants. Thus, cough and reflex mucus secretion can be regarded an integrated neurophysiological system of defence that limits epithelial injury from respirable irritants (Foster,

2002).

The evidence that cough may induce reflex mucus release from airway submucosal glands comes from studies performed mostly on experimental animals, due to difficulties in quantifying mucus secretion in humans. In anaesthetised cats, Phipps and Richardson (1976) investigated the effects of irritation of vari- ous parts of the airways on the mucus secretion from an isolated tracheal segment. They found that gentle rubbing of the epithelium of either the nose, nasophar- ynx or the larynx, caused cough and stimulated mucus secretion into the isolated segment. Cutting either the vagus or the sympathetic nerves to the trachea partly abolished these effects. The study by Phipps and Richardson (1976) suggests that sympathetic nerves

are part of the efferent pathways involved in the reflex mucus secretion, and this conclusion is indirectly sup- ported by the finding that laryngeal irritation excites sympathetic motor nerves to the submucosal glands (Widdicombe, 1966). On the other hand, German et al. (1980) found that vagal cooling prevented secretion from submucosal glands induced by laryngeal stimu- lation. A possible interpretation of these findings may be that the motor control of airway mucus secretion involves mainly parasympathetic pathways, although sympathetic nerves may also play a role. In keeping with this, direct stimulation of the airway surface by exogenous beta-adrenergic and anti-cholinergic agents has been shown to inhibit mucus secretion (Rogers, 2001). The possibility that these agents also exert direct regulatory influences on the cough reflex has been the object of several investigations, and the results have been evaluated collectively in recent meta-analyses (Smucny et al., 2004; Chang et al., 2004). The main conclusions from these analyses was that no current evidence supports the use of anticholinergic and beta- adrenergic agents to control the cough reflex in clinical conditions in which there is no excessive mucus pro- duction and/or airflow obstruction. Stimulation of the lower airways also initiates reflexes which cause mucus secretion into the trachea and also, by inference, into the bronchi. Inhalation of ammonia vapour into the lower airways of anaes- thetised cats causes coughing and reflexly increases mucus secretion into the upper part of the trachea not exposed to the irritant (Phipps and Richardson, 1976). In contrast, lung inflation, inhalation of histamine aerosol and intravenous injection of phenyldiguanide, which mainly excite lung stretch receptors, RARs and pulmonary C-fibres, respectively (Widdicombe, 1986), fail to induce coughing and have no consistent effect on mucus secretion (Phipps and Richardson, 1976). Based on this evidence, Phipps and Richardson (1976) con- cluded that the activity of airway receptors involved in cough has a powerful influence on mucus out- put. More recently, Davis et al. (1982) found that, in anaesthetised dogs, putatively selective stimulation of bronchial C-fibres by injection of small doses of cap- saicin or bradykinin into the bronchial arteries of dogs increases the secretory activity of the tracheal submu- cosal glands but fails to induce cough. These results indicate that chemical stimulation of vagal afferents accessible from a bronchial artery promotes secretion

G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

275

by tracheal submucosal glands without coughing. Simi-

lar results were obtained by Schultz et al. (1985) when capsaicin was injected into the right atrium to selec- tively stimulate pulmonary C fibres. Collectively, the

results of these two latter studies seem to indicate that stimulation of both bronchial and pulmonary C fibres are involved in the mucus secretion but not directly in cough mediation. These results are somewhat at variance with those

of Phipps and Richardson (1976) who found that stim-

ulation of pulmonary C-fibre endings by injection of phenildiguanide has little effects on mucus secretion. Differences related to the species studied and/or to the different techniques used to measure secretory activ-

ity may account for the discrepancy. Furthermore, the fact that stimulation of both bronchial and pulmonary

C fibres is a powerful stimulus for submucosal gland

secretion in the trachea, but not for cough, suggests that, similarly to cough and bronchoconstriction (see above), separate afferent pathways are involved in coughing and reflex mucus secretion. It is likely that C-fibre activity, although not primarily causing cough, may cause reflex secretion of mucus, which produces cough by a secondary mechanical action (Widdicombe, 2003). Furthermore, the sensory nerve endings in the lungs are thought to mediate axon reflexes in response to tissue damage or the released inflammatory or immunological mediators, a phenomenon termed neurogenic inflammation (Widdicombe, 2003). These axon reflexes are conducted along the nerve branches that release sensory neuropeptides; the latter, in turn, may promote mucus secretions, stimulate mechano- sensitive receptors in the airway, and promote cough (Widdicombe, 2003). Neurogenic inflammation, how- ever, seems well established for rodents, which have an abundance of neuropeptides in the airway sensory nerves; whether this phenomenon also occurs in human airways remains controversial.

5.2. Mechanisms opposing the mechanical

stresses of cough

5.2.1. Perineal muscles It has long been known that cough, Valsalva manoeuvres and more generally abdominal strain determine reflex contraction of the perineal muscles (e.g., Amarenco et al., 2005). Expiration-related bul- bospinal neurones located in the caudal region of the

VRG (cVRG) convey central drive to expiratory inter- costal and abdominal motoneurones during normal res- piration and expulsive manoeuvres (Bongianni et al., 2005). Some cVRG neurones have also been found to project more caudally beyond the ends of the major respiratory motor pools (Miller et al., 1995), to at least the 5th lumbar segment. Anatomical tracing (Holstege and Tan, 1987) and electrophysiological (Sasaki et al., 1991) studies have identified expiratory cVRG neu- rones projecting to the lumbar and sacral cord to the region of the nucleus of Onuf (Bongianni et al., 1998), which contains pudendal motoneurones innervating the external urethral and anal sphincters. Urethral and anal sphinteric muscle contraction is a major mechanism maintaining continence (Amarenco et al., 2005). During cough or other stresses lead- ing to an increase in abdominal pressure, specifically in the bladder and rectum, a simultaneous increase in sphincter pressures is required to prevent leakage. This increase is brought about by a tonic contrac- tion of the striated urethral and external anal muscles (Amarenco et al., 2005). The activity of other pelvic floor muscles, such as the bulbocavernosus, ischio- cavernosus, and pubococcygeus, also increases during coughing (Amarenco et al., 2005). It has recently been demonstrated that the intensity of pelvic floor mus- cles contraction is proportional to the magnitude of the increase in abdominal pressure caused by cough efforts (Amarenco et al., 2005). The finding also suggests that pelvic floor muscle activation is centrally programmed to maintain continence during cough and other abdom- inal stresses, and that alteration of the pelvic floor muscles response to raised abdominal pressure may be a key factor in incontinence pathophysiology. The fact that perineal muscle contracts also during voluntary cough suggests that commands to these muscles may originate from the central neural network of cough even in the absence of afferent inputs.

5.2.2. Lower oesophageal sphincter

Gastro-oesophageal reflux (GOR) has long been associated with a number of respiratory symptoms, including cough. The possible pathophysiological mechanisms implicated in the genesis of GOR-related cough have been reviewed (Fontana and Pistolesi, 2003). Several investigations have proposed a self- perpetuating positive feedback cycle between cough and GOR, whereby cough from any cause may precip-

276 G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

itate further reflux (Ing, 1997). Several factors, includ- ing the lower oesophageal sphincter (LOS) smooth muscle control mechanisms, the crural diaphragm and the phreno-oesophageal ligament are claimed to be the major neurological and anatomical determinants of oesophageal competence (Shafik et al., 2004). The con- tribution of the LOS smooth muscle in the prevention of GOR and its role in gastro-oesophageal competence is not fully understood (Shafik et al., 2004). It has been proposed that the mechanical events of cough may trigger LOS relaxations which, on the back- ground of a raised abdominal pressure, would promote GOR (Ing, 1997). This possibility, however, has not been definitely proven and, in patients with normal LOS basal tone, increases in abdominal pressure dur- ing coughing does not seem to promote reflux (Ing, 1997). Furthermore, human and animal experiments have actually documented an increase in LOS muscle tone and, hence, in LOS competence, when abdom- inal pressure is increased by straining or coughing (Shafik et al., 2004). In patients scheduled for surgi- cal repair of abdominal hernia, Shafik et al. (2004) recorded LOS pressure and EMG activity during condi- tions leading to an increase in abdominal pressure such as straining and coughing evoked reflexly by mechan- ical stimulation of the larynx and trachea. Measure- ments were performed with the abdomen closed after hernia reconstruction and after waning of the muscle relaxant. Both straining and coughing provoked simi- lar increases in LOS muscle tone and EMG activity, indicating LOS smooth muscle contraction possibly evoked reflexly by increases in abdominal pressure (Shafik et al., 2004). The neural substrate of the puta- tive “straining-oesophageal reflex” remains to be elu- cidated.

5.2.3. Respiratory muscle activation

As illustrated above, the respiratory muscles are primarily engaged in generating the motor patterns of cough. However, some lines of evidence seem to suggest that their activity during cough also plays a pos- sible role in preventing the potentially harmful effects (Leith et al., 1986) of the reflex. Coactivation of antag- onistic muscles, as well as the antagonistic activity of some expiratory muscles, may be taken as exam- ples of this phenomenon. For instance, it has long been known that the diaphragmatic electrical activity which characterises the inspiratory phase of cough also

extends into the compressive and expulsive phases of cough (Tomori and Widdicombe, 1969; Van Lunteren et al., 1989). This phenomenon may serve to counter- balance the mechanical effect of intense activation of the expiratory musculature or delay the transmission of pressure from the abdomen to the thorax (Tomori and Widdicombe, 1969). Furthermore, during the late

inspiratory phase, a certain degree of electrical activity arises from the abdominal muscles (see Section 4.2), also suggesting coactivation. An anticipated recruit- ment of expiratory motor units may serve as a braking mechanism aimed at controlling the inspiratory volume

of cough or as a flow limiting mechanisms, which may

also prevent the progression of debris towards the lung periphery.

A study in rabbits examined the separate contribu-

tions of the abdominal and expiratory intercostals in expiratory reserve volume generation following com- pression of either the chest wall or abdomen (D’Angelo et al., 2003). Isolated compression of the rib cage decreased lung volume and pushed the diaphragm cau- dad, causing an increase in abdominal pressure and expansion of the abdominal walls. Conversely, isolated abdominal compression also decreased lung volume but expanded the rib cage. Of note, the sum volume generated by separate compressions of the chest and abdominal walls turned out to be significantly greater than the control expiratory reserve volume, suggesting an antagonistic action of the intercostals and abdomi- nal muscles (De Troyer et al., 2005) in lung deflation. The antagonistic action of the expiratory intercostals and abdominals is thought to counteract the chest wall distortion caused by the isolated contraction of either muscle group.

5.3. Changes in breathing pattern

In this section we refer to a motor mechanism which,

based on present knowledge, does not seem to play

a definite role in supporting the defensive function

of cough, nor to represent a motor action aimed at protecting the body from the mechanical stresses of cough. Nonetheless, ventilatory adjustments consis- tently accompany the appearance of cough and seem therefore worth mentioning. The afferent nerve fibres from the lower respiratory tract are not only implicated in the genesis of protective and defensive reflexes, but also exert potent regulatory

G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

277

influences that are also known to participate in the shaping of the pattern of breathing (Coleridge and Coleridge, 1986). For instance, animal experiments have shown that the reflex ventilatory adjustments elicited by the stimulation of RARs mainly consist of an increase in respiratory drive, possibly associated with a lengthening in inspiratory time (Coleridge and Coleridge, 1986). More recently, activation of rabbit peripheral airway RARs has been shown to stimulate increases in ventilation by augmenting both the rate and the depth of breathing ( Yu et al., 1998 ). Also activation of C fibres can stimulate breathing (Coleridge and Coleridge, 1986). However, the reflex ventilatory response evoked by C-fibre stimulation is rapid shallow breathing, often preceded by a period of apnoea (Coleridge and Coleridge, 1986). Animal studies have revealed that non-isotonic solutions can stimulate both the RARs and C-fibre receptors (Pisarri et al., 1992), and a number of clinical trials have demonstrated that ultrasonically nebulised distilled water (fog) is a potent tussigenic agent in humans (Fontana et al., 2005). By simultaneously recording the cough response and changes in the pattern of breathing provoked by inhalation of progressively increasing fog concentrations in humans, Lavorini et al. (2001) attempted to get insights into the receptor type(s) prevailingly stimulated by fog inhalation in humans. Fog concentrations too low to elicit cough caused no ventilatory changes, whereas concentrations of thresh- old intensity for the cough reflex caused increases in minute ventilation that preceded, accompanied and followed the appearance of cough (Fig. 3). The fact that the ventilatory changes consisted of selective increases in the volume components of the breathing pattern (Lavorini et al., 2001) points to a prevailing stimulation of the RARs, initially causing hyperpnoea and then also cough. Simultaneous activation of the C-fibre receptors could have contributed by sensitising the neural pathway for the cough reflex. It is also possi- ble, but it remains to be ascertained, that fog inhalation could first have produced respiratory sensations, par- ticularly an “urge-to cough” (Davenport et al., 2002) which, in turn, could have stimulated breathing and facilitated the onset of cough, possibly via a cortical pathway. It remains, however, to be ascertained if other chemical stimuli such as, for instance, citric acid and capsaicin, also produce similar ventilatory adjustments.

and capsaicin, also produce similar ventilatory adjustments. Fig. 3. Original recordings of tidal volume ( V

Fig. 3. Original recordings of tidal volume (V T ) and integrated elec- tromyographic activity of the abdominal muscles (IEMG) in one normal subject obtained prior to (left panel) and during inhalation of the threshold concentration of ultrasonically nebulised distilled water for the cough reflex. Note the increases in V T and inspiratory drive that precede, accompany and follow the appearance of cough in the absence of significant changes in respiratory timing. Reprinted with permission from Lavorini et al. (2001).

5.4. Cardiovascular changes

In most animals, mechanical probing of the laryn- geal and tracheobronchial mucosa also elicits cardio- vascular changes, mainly consisting of bradycardia and hypertension (Tomori and Widdicombe, 1969). In humans, however, selective laryngeal stimulation by

distilled water results in hypertension with tachycardia (Nishino et al., 1996). Although these studies indi- cate that cough-associated cardiovascular adjustments are reflexly mediated, at least to some extent, the car- diovascular phenomena associated with coughing in humans seem to descend mainly from the large tho- racic and abdominal pressure swings provoked by the mechanical events of cough. Indeed, during the inspi- ratory phase, intrathoracic pressure falls to values as low as 13 kPa; during the compressive and expulsive phases, intrathoracic pressure may rise to over +13 kPa and attain values up to 40 kPa during very pronounced cough efforts. Pressure within the abdomen varies in

a reciprocal fashion (Sharpey-Shafer, 1953a). Once

transmitted to the systemic and pulmonary circulation,

the large pressure swings of cough may exert profound influences on cardiovascular activity. Although mostly

of only short duration, such influences can be clinically

very important.

5.4.1. Changes in cardiac output and blood pressure During the inspiratory phase, pressure in the abdom- inal cavity rises owing to the contraction of the

278 G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

diaphragm, while it falls in the thoracic cavity. As a result, blood is abruptly drawn in from the vena cava, so that the right atrium and right ventricle fill to capac- ity. Consequently, the cardiac output increases. During the compressive phase, intrathoracic pressure rises and blood is squeezed out from the intra-thoracic organs and forced to the periphery, thus increasing systemic blood pressure. The drop in intrathoracic pressure that occurs at the end of the expulsive phase of cough has the reverse effects: cardiac output and systemic blood pressure markedly decrease, while systemic venous pressure rises (Sharpey-Shafer, 1953a). The increase in venous pressure and the reduction in blood pressure may result in a decreased cerebral perfusion pressure that may eventually cause loss of consciousness i.e., the so-called “cough syncope”. The cough syncope is an infrequent but well- recognised clinical condition whose pathophysiology remains controversial. Sharpey-Shafer (1953b) sug- gested that continuous coughing impaired venous return to the heart, resulting in decreased cardiac out- put and systemic pressure. However, the same author (Sharpey-Shafer, 1953b) also showed that, in patients in whom syncope apparently was caused by inter- mittent, single cough efforts, the forearm blood flow was actually increased. Based on this observation, the author concluded that a baroreflex mechanism must be partly responsible for the cough-induced syncope. Alternatively, McIntosh et al. (1956) proposed that, during a paroxysm of cough, the high intra-thoracic pressure transmitted to the cerebrospinal fluid may squeeze blood out of the cranial vascular space, thereby causing loss of consciousness by an ill-defined cerebral ischemia mechanism. Currently, cough-induced syncope is considered a form of neurally mediated reflex syncope (Hainsworth, 2004) in which baroreceptor responses play a key role (Sharpey-Shafer, 1953b). In this view, the most likely trigger sites for the cough-induced syncope are though to be the arterial receptors responding to sudden increases in arterial pressure with cough, and/or venous stretch receptors responding to the abrupt reduction of venous return with cough (Benditt et al., 2005). Alter- native trigger mechanisms, such as a laryngovagal or a bronchopulmonary reflex, have also been proposed (Hainsworth, 2004). In our experience, intense and prolonged cough- ing is generally accompanied by ventilatory increase

also leading to an appreciable reduction in end tidal CO 2 . This latter phenomenon is known to cause cere- bral vasoconstriction and might therefore contribute to cough syncope.

5.4.2. Changes in heart rate

Cough may also cause reflex changes in heart rate, since arterial baroreceptors are sensitive to the transient intrathoracic pressure fluctuations induced by cough- ing (Sharpey-Shafer, 1953a). Wei and Harris (1982) investigated the amplitude and the time course of heart rate changes in response to three forceful intermit- tent cough efforts in healthy humans. They found that, in addition to arterial hypotension and periph- eral vasodilation, a consistent and reproducible reflex tachycardia occurred in response to the large intratho- racic pressure transients generated by cough. Gener- ally, the heart rate rose quickly, usually reaching a peak 2–3 s following cough, and returned to base- line values within 15–20 s after cough. The increase in heart rate following cough likely represents, at least in part, a baroreceptor mediated response to the decreases in mean arterial and pulse pressure that occur after coughing in conjunction with both periph- eral vasodilation and a possible increase in venous return (Sharpey-Shafer, 1953a). Whether other recep- tors that may be stimulated by cough or induce cough also have an effect on cardiac acceleration is unclear. It has been shown that stimulation of stretch receptors situated at the junction of the superior vena cava and the right atrium results in tachycar- dia (Shepherd, 1981). However, other receptors, both cardiac and pulmonary, mediate bradycardic response when stimulated by increased intrathoracic pressure (Shepherd, 1981). Finally, in the anaesthetised cat, activation of SAR by stepwise increases in lung vol- ume markedly reduces the cardio-inhibitory effects provoked by carotid body chemoreceptor stimulation (Daly and Kirkman, 1989), suggesting that SARs can reflexly increase heart rate. Cardone et al. (1987) have investigated the auto- nomic and mechanical components involved in the heart rate response to cough. They found that the cardio-acceleratory response to cough was completely abolished by prior administration of atropine while -adrenergic blockade with propanolol failed to affect it. Thus, the authors suggested that the tachycardic response to cough is essentially under cholinergic

G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

279

control, with an immediate vagal withdrawal fol- lowed by vagal reactivation that decreased heart rate after 5–6 s (Cardone et al., 1987). However, the influence of intrathoracic and arterial fluctuations, causing a reduced venous return and an increased right atrial pressure, could have also contributed directly to the cough-induced cardio-acceleratory response. The changes in cardiovascular activity caused by coughing may also have beneficial effects. For instance, Criley et al. (1976) have shown that patients developing ventricular fibrillation during cardiac catheterisation may carry out their own positive intrathoracic pressure resuscitation and maintain consciousness by cough- ing in a forceful, rhythmic fashion, and these authors proposed voluntary coughing as a form of cardiopul- monary resuscitation.

6. Conclusions

The appearance of cough, either voluntarily or reflexly produced, also implies the simultaneous acti- vation of additional motor mechanisms involving res- piratory and non-respiratory organs, thus considerably complicating the classical view of cough as an air- way defensive motor act. Cough motor mechanisms may be classified as “primary”, i.e., those mainly responsible for the production of the motor patterns of cough, and as “secondary”, i.e., those involved in enhancing the defensive function of cough, or oppos- ing its potentially harmful effects. Other secondary outflows of cough, such the changes in the pattern of breathing and the cardiovascular adjustments, are of uncertain functional significance. The proposed clas- sification needs to be taken with caution, however, since several cough motor mechanisms appear to play multiple functional roles. Other aspects regarding the cough motor mechanisms remain to be elucidated. For instance, whereas it seems clear that the motor pat- tern of cough may differ when it is reflexly evoked by stimuli acting at the level of different areas within the respiratory tract, it is not known if coughing elicited from non-respiratory regions (e.g., the oesophagus) has any distinctive motor feature. Whether voluntary coughing is also accompanied by a similar array of secondary outflows has not yet been firmly estab- lished.

Acknowledgment

This work was supported by grants from the Italian Department of Education.

References

Amarenco, G., Ismael, S.S., Lagauche, D., Raibaut, P., Rene-Corail, P., Wolff, N., Thoumie, P., Haab, F., 2005. Cough anal reflex:

strict relationship between intravesical pressure and pelvic floor muscle electromyographic activity during cough. Urodynamic and electrophysiological study. J. Urol. 1, 149–152. Banner, A.S., 1986. Cough: physiology, evaluation, and treatment. Lung 164, 79–92. Benditt, D.G., Samniah, N., Pham, S., Sakaguchi, S., Lu, F., Lurie, K.G., Ermis, C., 2005. Effect of cough on heart rate and blood pressure in patients with cough syncope. Heart Rhythm 2,

807–813.

Bongianni, F., Corda, M., Fontana, G.A., Pantaleo, T., 1988. Influ- ences of superior laryngeal afferent stimulation on expiratory activity in cats. J. Appl. Physiol. 65, 385–392. Bongianni, F., Mutolo, D., Fontana, G.A., Pantaleo, T., 1998. Dis-

charge patterns of Botzinger complex neurons during cough in the cat. Am. J. Physiol. 274, R1015–R1024. Bongianni, F., Mutolo, D., Nardone, F., Pantaleo, T., 2005. Ionotropic glutamate receptors mediate excitatory drive to caudal medullary expiratory neurons in the rabbit. Brain Res. 1056, 145–

157.

Cardone, C., Bellavere, F., Ferri, M., Fedele, D., 1987. Autonomic mechanisms in the heart response to coughing. Clin. Sci. 72,

55–60.

Chang, A.B., McKean, M., Morris, P., 2004. Inhaled anti- cholinergics for prolonged non-specific cough in children. Cochrane Database Syst. Rev., CD004358. Colebatch, H.J.H., Halmagyi, D.F.J., 1963. Effect of vagotomy and vagal stimulation on lung mechanics and circulation. J. Appl. Physiol. 18, 881–887. Coleridge, H.M., Coleridge, J.C.G., 1986. Reflexes evoked from tracheobronchial tree and lungs. In: Cherniack, N.S., Widdi- combe, J.G. (Eds.), Handbook of Physiology. Section 3: The Respiratory System, vol. II: Control of Breathing, Part 1. American Physiological Society, Washington, DC, pp. 395–

429.

Criley, J.M., Bloufuss, A.H., Kissell, G.K., 1976. Cough-induced car-

diac compression. Self-administered from of cardiopulmonary resuscitation. J. Am. Med. Assoc. 263, 1246–1250. Daly, M.B., Kirkman, E., 1989. Differential modulation by pulmonary stretch afferents of some reflex cardioinhibitory responses in the cat. J. Physiol. 417, 323–341. D’Angelo, E., Prandi, E., D’Angelo, E., Pecchiari, M., 2003. Lung- deflating ability of rib cage and abdominal muscles in rabbits. Respir. Physiol. Neurobiol. 135, 17–24. Davenport, P.W., Sapienza, C.M., Bolser, D.C., 2002. Psychophys- ical assessment of the urge-to-cough. Eur. Respir. Rev. 12,

249–253.

280 G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

Davis, B., Roberts, A.M., Coleridge, H.M., Coleridge, J.C., 1982. Reflex tracheal gland secretion evoked by stimulation of bronchial C-fibers in dogs. J. Appl. Physiol. 53, 985–

991.

De Troyer, A., Kirkwood, P.A., Wilson, T.A., 2005. Respiratory action of the intercostals muscles. Physiol. Rev. 85, 717–

756.

Di Marco, A.F., Romaniuk, J.R., Kowalski, K.E., Supinski, G., 1999. Mechanical contribution of expiratory muscles to pressure gen- eration during spinal cord stimulation. J. Appl. Physiol. 87,

1433–1439.

Evans, K.C., Shea, S.A., Saykin, A.J., 1999. Functional MRI localisa- tion of central nervous system regions associated with volitional inspiration in humans. J. Physiol. 520, 383–392. Floyd, W.F., Silver, P.H.S., 1950. Electromyographic study of pat- terns of activity of the anterior abdominal wall muscles in man. J. Anat. 84, 132–145. Fontana, G.A., Pantaleo, T., Lavorini, F., Mutolo, D., Polli, G., Pis- tolesi, M., 1999. Coughing in laryngectomized patients. Am. J. Respir. Crit. Care Med. 160, 1578–1584. Fontana, G.A., Pistolesi, M., 2003. Cough 3: chronic cough and gastro-oesophageal reflux. Thorax 58, 1092–1095. Fontana, G.A., 2003. Motor mechanisms and the mechanics of cough. In: Chung, K.F., Widdicombe, J.G., Boushey, H. (Eds.), Cough: Causes, Mechanisms and Therapy. Blackwell Publishing, pp. 193–205. Fontana, G.A., Lavorini, F., Pistolesi, M., 2005. Water aerosols and cough. In: Redington, A.E., Morice, A.H. (Eds.), Acute and Chronic Cough. Taylor & Francis Group, pp. 195–214. Foster, W.M., 2002. Mucociliary transport and cough in humans. Pulm. Pharmacol. 15, 277–282. German, V.F., Ueki, I.F., Nadel, J.A., 1980. Micropipette measure- ments of airway submucosal glands secretion: laryngeal reflex. Am. Rev. Respir. Dis. 122, 413–416. Grelot,´ L., Milano, S., 1991. Diaphragmatic and abdominal muscle activity during coughing in the decerebrate cat. Neuroreport 2,

165–168.

Hainsworth, R., 2004. Pathophysiology of syncope. Clin. Autonom. Res. 14 (Suppl. 1), 18–24. Holstege, G., Tan, J., 1987. Supraspinal control of motoneurons innervating the striated muscles of the pelvic floor including ure- thral and anal sphincters in the cat. Brain 110, 1323–1344. Ing, A.J., 1997. Cough and gastroesophageal reflux. Am. J. Med. 103, 91S–96S. Iscoe, S., Grelot,´ L., 1992. Regional intercostal activity during cough- ing and vomiting in decerebrate cats. Can. J. Physiol. Pharmacol. 70, 1195–1199. Iscoe, S., 1998. Control of abdominal muscles. Prog. Neurobiol. 56,

433–506.

Jordan, D., 2001. Central nervous pathways and control of the air- ways. Respir. Physiol. 125, 67–81. Karlsson, J.-A., Sant’Ambrogio, G., Widdicombe, J.G., 1988. Affer- ent neural pathways in cough and reflex bronchoconstriction. J. Appl. Physiol. 65, 1007–1023. Kase, Y., Kito, G., Miyata, T., Takahama, K., 1984. Influence of cere- bral cortex stimulation upon cough-like spasmodic expiratory responses (SER) and cough in the cat. Brain Res. 306, 293–298.

Kobayashi, I., Kondo, T., Suzuki, H., Ohta, Y., Yamabayashi, H., 1992. Expiratory activity of the inspiratory muscles during cough. Jpn. J. Physiol. 42, 905–916. Korpas, J., Tomori, Z., 1979. Cough and other respiratory reflexes. In: Herzog, H. (Ed.), Progress in Respiratory Research, vol. 12.

Karger, Basel. Lavorini, F., Fontana, G.A., Pantaleo, T., Camiciottoli, G., Castellani, W., Maluccio, N.M., Pistolesi, M., 2001. Fog-induced respiratory responses are attenuated by nedocromil sodium in humans. Am.

J. Respir. Crit. Care Med. 163, 1117–1120.

Leith, D.E., Butler, J., Sneddon, P., Brain, S.L., Cough, J.D., 1986. In:

Macklem, P.T., Mead, J. (Eds.), Handbook of Physiology, Section 3: The Respiratory System, vol. III: Mechanics of Breathing, Part 1. American Physiological Society, Washington, DC, pp.

315–336.

Mazzone, S.B., Canning, B.J., 2002. Central nervous system con- trol of the airways: pharmacological implications. Curr. Opin. Pharmacol. 2, 220–228. Mead, J., Reid, M.B., 1988. Respiratory muscle activity during repeated airflow interruption. J. Appl. Physiol. 64, 2314–2317. McIntosh, H.D., Estes, E.H., Warren, J.V., 1956. The mechanism of cough syncope. Am. Heart J. 52, 70–82. Miller, A.D., Nonaka, S., Siniaia, M.S., Jakus, J., 1995. Multifunc- tional ventral respiratory group: bulbospinal expiratory neurons play a role in pudendal discharge during vomiting. J. Auton. Nerv. Syst. 54, 253–260. Mills, J.E., Sellick, H., Widdicombe, J.G., 1970. Epithelial irritant receptors in the lungs. In: Porter, R. (Ed.), Breathing, Hering- Breuer Centenary Symposium. Churchill, London, pp. 77–92. Nishino, T., Tagaito, Y., Isono, S., 1996. Cough and other reflexes on

irritation of airway mucosa in man. Pulm. Pharmacol. 9, 285–292. Phipps, R.J., Richardson, P.S., 1976. The effects of irritation at vari- ous levels of the airway upon tracheal mucus secretion in the cat.

J. Physiol. 261, 563–581.

Pisarri, T.E., Jonzon, A., Coleridge, H.M., Coleridge, J.C.G., 1992. Vagal afferents and reflex responses to changes in surface osmo- larity in lower airways of dogs. J. Appl. Physiol. 73, 2305–

2313.

Poletto, C.J., Verdun, L.P., Strominger, R., Ludlow, C.L., 2004. Cor- respondence between laryngeal vocal fold movement and muscle activity during speech and nonspeech gestures. J. Appl. Physiol. 97, 858–866. Poliacek, I., Stransky, A., Jakus, J., Barani, H., Tomori, Z., Halasova, E., 2003. Activity of the laryngeal abductor and adductor muscles during cough, expiration and aspiration reflexes in cats. Physiol Res. 52, 749–762. Poliacek, I., Stransky, A., Szereda-Przestaszewska, M., Akus, J., Barani, H., Tomori, Z., Halasova, E., 2005. Cough and laryn- geal muscle discharges in brainstem lesioned anesthetized cats. Physiol Res. [Epub ahead of print]. Richardson, P.S., Peatfield, A.C., 1981. Reflexes concerned in the defence of the lungs. Bull. Eur. Physiopat. Resp. 17, 979–1012. Rogers, D.F., 2001. Motor control of airway goblet cells and glands. Respir. Physiol. 125, 129–144. Salerno, F.G., Shinozuka, N., Fredberg, J.J., Ludwig, M.S., 1999. Tidal volume amplitude affects the degree of induced bron- choconstriction in dogs. J. Appl. Physiol. 87, 1674–1677.

G.A. Fontana, F. Lavorini / Respiratory Physiology & Neurobiology 152 (2006) 266–281

281

Sant’Ambrogio, G., Kuna, S.T., Vanoye, C.R., Sant’Ambrogio, F.,

1997. Activation of intrinsic laryngeal muscles during cough.

Am. J. Respir. Crit. Care Med. 155, 637–641. Sasaki, S.I., Uchino, H., Imagawa, M., Miyake, T., Uchino, Y., 1991. Lower lumbar branching of caudal medullary expiratory neurons of the cat. Brain Res. 553, 159–162. Schultz, H.D., Roberts, A.M., Bratcher, C., Coleridge, H.M., Coleridge, J.C.G., Davis, B., 1985. Pulmonary C-fibres reflexly increase secretion by tracheal submucosal glands in dogs. J. Appl. Physiol. 58, 907–910. Shafik, A., El-Sibai, O., Shafik, A.A., Mostafa, R., Shafik, I., 2004. Effect of straining on the lower esophageal sphincter: identifica- tion of the “straining-esophageal reflex” and its role in gastroe-

sophageal competence mechanism. J. Invest. Surg. 17, 191–196. Shannon, R., Beakey, D.M., Morris, K.F., Nuding, S.C., Segers, L.S., Lindsey, B.G., 2004. Production of reflex cough by brainstem respiratory networks. Pulm. Pharmacol. Ther. 17, 369–376. Sharpey-Shafer, E.P., 1953a. Effects of coughing on intrathoracic pressure, arterial pressure and peripheral blood flow. J. Physiol. 122, 351–357. Sharpey-Shafer, E.P., 1953b. The mechanism of syncope after cough- ing. Br. Med. J. 2, 860–863. Shepherd, J.T., 1981. The lungs as receptor sites for cardiovascular regulation. Circulation 63, 1–10. Simonyan, K., Jurgens, U., 2005. Afferent subcortical connections into the motor cortical larynx area in the rhesus monkey. Neuro- science 130, 119–131. Smucny, J., Flynn, C., Becker, L., Glazier, R., 2004. Beta2-agonists for acute bronchitis. Cochrane Database Syst. Rev., CD001726. Strohl, K.P., Mead, J., Banzett, R.B., Loring, S., Kosch, P.,

1981. Regional differences in abdominal muscle activity dur-

ing various maneuvres in humans. J. Appl. Physiol. 51, 1471–

1476.

Sun, Q.J., Berkowitz, R.G., Pilowsky, P.M., 2005. Response of laryn- geal motoneurons to hyperventilation induced apnea in the rat. Respir. Physiol. Neurobiol. 146, 155–163. Tomori, Z., Widdicombe, J.G., 1969. Muscular, bronchomotor and cardiovascular reflexes elicited by mechanical stimulation of the respiratory tract. J. Physiol. 200, 25–49. Van Lunteren, E., Daniels, R., Chandler Deal, R., Haxhiou, M., 1989. Role of costal and crural diaphragm and parasternal intercostals during coughing in cats. J. Appl. Physiol. 66, 135–141. Wei, J.W., Harris, W.S., 1982. Heart rate response to cough. J. Appl. Physiol. 53, 1039–1043. Widdicombe, J.G., Nadel, J.A., 1963. Reflex effects of lung inflation on tracheal volume. J. Appl. Physiol. 18, 681–686. Widdicombe, J.G., 1966. Action potentials in parasympathetic and sympathetic efferent fibers to the trachea and lungs in dogs and cats. J. Physiol. 186, 56–88. Widdicombe, J.G., 1986. Reflexes from the upper respiratory tract. In: Handbook of Physiology. The Respiratory System. Control of Breathing. Section 3, vol. II, Part 1. American Physiological Society, Washington, DC, pp. 363–394 (Chapter 11). Widdicombe, J.G., 2001. Airway receptors. Respir. Physiol. 125,

3–15.

Widdicombe, J.G., 2003. Overview of neural pathways in allergy and asthma. Pulm. Pharmacol. Ther. 16, 23–30. Widdicombe, J.G., Fontana, G.A., in press. Cough: what is in a name? Eur. Respir. J. Yu, J., Zhang, J.F., Fletcher, E.C., 1998. Stimulation of breathing by activation of pulmonary peripheral afferents in rabbits. J. Appl. Physiol. 85, 1485–1492.