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Aspiration is a common result of stroke, and may lead to lung infections and pneumonia. Cough may prevent this aspiration and thus prevent the pneumonia. We review the four types of cough usually used to assess aspiration risk: voluntary cough (VC), reflex cough (RC), the laryngeal expiration reflex (LER), and cough on swallow (CoS). VC is easy to test but starts with an inspiration that may cause aspiration, and is controlled by cortico-brainstem pathways that may not be involved in influencing aspiration. RC also starts with an inspiration, and requires instrumental intervention, but is more relevant to protecting the lungs. The LER starts with an expiration, so is 'anti-aspiration', and is easy to test, but its neural mechanisms have not been fully analysed. CoS can be tested at the same time as direct observations of aspiration, but little is known about its neural mechanisms. Each method has its advocates, and the purpose of the review is to discuss how each may be applied and how the information from each may be assessed and valued.

Little is known about the effects of exercise on the sensory and cognitive aspects of coughing evoked by inhalation of tussigenic agents. The threshold for the cough reflex induced by inhalation of increasing nebulizer outputs of ultrasonically nebulized distilled water (fog), an index of cough reflex sensitivity, was assessed in twelve healthy humans in control conditions, during exercise and during voluntary isocapnic hyperpnea (VIH) at the same ventilatory level as the exercise. The intensity of the urge to cough (UTC), a cognitive component of coughing, was recorded throughout the trials on a linear scale. The relationships between inhaled fog nebulizer outputs and the correspondingly evoked UTC values, an index of the perceptual magnitude of the UTC sensitivity, were also calculated. Cough appearance was always assessed audiovisually. At an exercise level of 80% of anaerobic threshold, the median cough threshold was increased from a control value of 0.73 to 2.22 ml/min ( P < 0.01), i.e., cough sensitivity was downregulated. With VIH, the threshold increased from 0.73 to 2.22 ml/min ( P < 0.01), a similar downregulation. With exercise and VIH compared with control, mean UTC values at cough threshold were unchanged, i.e., control, 3.83 cm; exercise, 3.12 cm; VIH, 4.08 cm. The relationship of the fog nebulizer output/UTC value was linear in control conditions and logarithmic during both exercise and VIH. The perception of the magnitude of the UTC seems to be influenced by signals or sensations arising from exercising limb and thoracic muscles and/or by higher nervous (cortical) mechanisms. The results indicate that the adjustments brought into action by exercise-induced or voluntary hyperpnea exert inhibitory influences on the sensory and cognitive components of fog-induced cough.

Twelve distinguished scientists attended the workshop, heard three presentations, and took part in the discussions. Fontana first described his unpublished studies on cough in exercise and during hyperventilation with healthy subjects. Both activities depressed cough induced by inhalation of distilled water aerosol (fog). The possible mechanisms were discussed. Gibson then described the successful use of speech therapy to treat chronic cough, and discussed the possible mechanisms, centering on the role of the larynx and its neural control. A comparison was made with the ability of speech and laughter to precipitate cough. Widdicombe discussed the scanty literature on the effect of singing and playing wind instruments on cough, most of the evidence being anecdotal. In the discussion periods several matters for future study arose. It is usually not clear if the modulation of cough, its depression, enhancement or excitation, arose primarily at peripheral sites (reflexes from the airways), or at a cortical level, or both. Nor is it clear whether the same results would be obtained with provoked cough and with spontaneous cough. But all three aspects of 'behavioual' changes in cough sensitivity (exercise, speech and music) could be further explored, and current techniques should make this possible.

The evidence for supramedullary influences on cough is largely indirect. Cough can be voluntarily induced or inhibited, functions usually thought to reside in the cerebral cortex. A sensation of 'urge-to-cough' usually precedes cough due to an airway irritant stimulus, and this may well involve the cerebral cortex. In conditions with interruption of the pathways between the cortex and the brainstem, such as strokes and Parkinson's disease, voluntary cough may be inhibited without disruption of reflex cough from the larynx or lower airways. 'Habit cough', like Tourette's syndrome, is assumed to be cortically mediated. Placebos and many treatments based on complementary medicine are effective in inhibiting clinical cough, and the site of action is likely to be the cerebral cortex. In sleep and in anaesthesia cough is depressed and, again, this seems likely to be at a cortical level. However there are few or no experimental or clinical observation as to the localization and functions of supramedullary areas responsible for cough. It is a field of research wide open for exploration.

The Third International Symposium on Cough focused on acute and chronic cough, both clinical and basic science. Cough is a defensive and clearing mechanism, and can cause discomfort and nuisance; it is also an important symptom of many chronic airway diseases. In this Symposium, several issues concerning the relationship of cough to disease processes, different types of cough, and the concept of idiopathic cough will be discussed. Characterization of cough receptor(s) and identification of peripheral and central mechanisms for cough sensitization are current areas of investigation for delineating the cause of chronic cough. Peripheral mechanisms may be most important for acute cough such as after viral infections. The role of pathological changes at the level of the airway mucosa and of cortical pathways will be reviewed. Finally, therapeutic inhibition of the cough reflex remains an area of active research.

Although the frequency of physician consultations and the sale of over-the-counter remedies establish the high prevalence of acute cough in the elderly, epidemiological studies have tended to be imprecise. However, respiratory tract infections in nose, larynx and/or bronchi, either viral or bacterial or both, are by far the commonest cause of acute cough. These are especially frequent and hazardous in the elderly, and community living and institutionalisation may aggravate this problem. A variety of viruses and bacteria have been incriminated, with rhinovirus, influenza and respiratory syncytial viruses, and Streptococcus pneumoniae, Haemophilus influenza and Bordetella pertussis being especially important. Viral infections can readily lead to community-acquired pneumonia. Successful diagnosis should point to successful treatment, and in this respect clinical examination and patient history are paramount, supplemented by chest X-ray, viral and bacterial culture and serological testing. Depending on the results of these tests, specific antibacterial therapy may be called for, although there is dispute as to the merits of antibacterial therapy in cases of uncertain diagnosis. Prevention and prophylaxis for influenza and S. pneumoniae infections are now commendably routine in the elderly, especially those in communities. Treatment, as well as the use of antibacterials, may also be directed against the inflammatory and infective processes in the airways. Non-specific antitussive therapy is common and usually highly desirable to prevent the adverse effects of repeated coughing. There have been few advances in antitussive therapy in recent years, opioids and dextromethorphan being the most commonly used agents; they act centrally on the brainstem, but also have a large placebo effect. However they work, they are much appreciated by patients and their partners. Moreover, striking advances in our understanding of the peripheral sensory and central nervous pathways of the cough reflex in recent years should soon lead to a new and more specific choice of agents to inhibit cough.

Fig. 1.— Overview of the evaluation of chronic cough in an adult. ACE-I: angiotensin converting enzyme inhibitor; PEF: peak expiratory flow; PNDS: post-nasal drip syndrome; GORD: gastro-oesophageal reflux disease. Fig. 2.— Therapeutic algorithm. ACE: angiotensin-converting enzyme; GORD: gastro-oesophageal reflux disease. Fig. 3.— Investigational algorithm. CT: computed tomography. Fig. 4.— Diagnostic algorithm for the approach to children with chronic cough. ENT: ear, nose and throat; PFT: pulmonary function testing; BAL: bronchoalveolar lavage; CT: computed tomography; tbc: total blood count; CMV: cytomegalovirus; PCR: polymerase chain reaction; MRI: magnetic resonance imaging; NO: nitric oxide; BHR: bronchial hyperresponsiveness. CONTENTS Chronic cough, here defined as a cough of >8 weeks duration, is a common and frequently debilitating symptom 1, 2 that is often viewed as an intractable problem. However, theexperience of specialist cough clinics is that a very high success rate, in the order of 90%, can be achieved (table 1⇓) 3–15. The key to successful management is to establish a diagnosis and to treat the cause of cough. Truly idiopathic cough is rare and misdiagnosis common, particularly because of the failure to recognise that cough is often provoked from sites outside the airway. These guidelines aim to distil the lessons from these reports and provide a framework for a logical care pathway for patients with this highly disabling symptom. View this table: Table 1— Commonest causes of chronic cough in patients investigated in specialist clinics There are three common causes of chronic cough that arise from three different anatomical areas. This varied presentation explains the major reason for the success of multidisciplinary cough clinics compared with general clinics 16. As asthma, reflux and rhinitis are the realms of different specialists who have little experience in the diagnosis of conditions outside their expertise, a patient with chronic cough may not undergo full evaluation. This problem is exacerbated by the frequently atypical presentation of …

Objective: The laryngeal cough reflex and the laryngeal cough expiratory reflex are brainstem reflexes that protect the upper airway from significant aspiration. The purpose of this investigation was to examine the effects of tartaric acid-induced cough on pulmonary function in normal healthy and asthmatic individuals. Design: Twenty healthy and 20 asymptomatic, medicated, asthmatic volunteers engaged in a two-part evaluation of pulmonary function testing. All 40 subjects were nonsmokers. The reflex cough test, a 20% solution of prescription-grade L-tartaric acid dissolved in 0.15 M NaCI solution, initiated the laryngeal cough expiratory reflex/laryngeal cough reflex. The solution was placed in a Bennett Twin nebulizer and inhaled as a microaerosol. Pulmonary function testing was with a Spiromate AS-600. Baseline pulmonary function testing was initially performed, followed by two separate inhalations of the reflex cough test. The pulmonary function testing was repeated 5 min after the second reflex cough test. Results: Statistically significant changes seen after the reflex cough test included increases in the peak inspiratory flow in normal subjects (P = 0.004) and in the peak expiratory flow in asthmatic subjects (P = 0.014). No respiratory adverse events occurred after the reflex cough test. Conclusions: Explanations for these findings include the possibility that tartaric acid-induced cough produces central nervous system-mediated bronchodilatation, through the cough itself or by secondary mechanisms.

Objective: The purpose of this study was to trigger the laryngeal cough expiration reflex using inhaled tartaric acid aerosol and to record the latency between the time of initiation of the laryngeal cough expiration reflex component of the laryngeal cough reflex and the onset of electromyographically recorded responses in the external abdominal oblique in humans. Design: Five male subjects were tested in the seated position, and four latencies were recorded for each subject. The latencies were recorded from laryngeal stimulation to an electromyogram in the muscle belly of the left external abdominal oblique. The time line was activated by a microswitch attached to a breath-activated nebulizer. Data were analyzed using SPSS for mean latency and standard deviation. Results: The mean (standard deviation) latency to the external abdominal oblique muscle was 17.6 ± 10.6 msec. No adverse events to inhalation were reported. Conclusions: In humans, nebulized tartaric acid stimulates primarily rapid adapting receptors in the supraglottic larynx rather than C-fiber receptors. This receptor location in humans evolved neurologically to protect the airway during speech and swallowing, making the laryngeal cough expiration reflex an inseparable component of the laryngeal cough reflex, thus making it clinically significant when assessing airway protection.

To examine the means whereby dragons produce fire and steam, we have studied a related species, the desert-lizard Lacerta pyrophorus. Morphological studies showed that there were in the snout three distinctive features: (1) a dorsal swelling in the pharynx, the Organ of Feuerwerk, consisting of brown adipose tissue with an extensive sympathetic innervation; (2) greatly enlarged lachrymonasal ducts, the Ducts of Kwentsch; and (3) asbestos deposits in the nasal skin, the Bestos Bodies. Physiological studies show that the Organ of Feuerwerk can, when the animal is excited, produce extremely high temperatures. We discuss how these mechanisms can produce steam and fire, and how the snout is protected. We also discuss and offer a solution to the problem of how, since dragons are invariably male, the species can be propagated.

There have been remarkable advances recently in our understanding of the neuroregulation of cough in three areas: the properties of the sensory nerves, in particular their receptors and membrane channels; the plasticity of the pathways; and the central nervous mechanisms of cough. All these studies are relevant to our understanding of the pharmacology and therapy of cough.

This commentary describes the "deflation cough" caused by deep lung deflations. Deflation cough is a paradoxical reflex similar to that described by Henry Head in 1889 for lung inflations that probably is mediated by the same sensors and afferent fibers in the lungs and activated by gastroesophageal reflux. We discuss how this reflex must be self-limiting, the general role of paradoxical reflexes in the body, and the possible clinical significance of deflation cough.

Rapidly adapting receptors (RARs) occur throughout the respiratory tract from the nose to the bronchi. They have thin myelinated nerve fibres, an irregular discharge and adapt rapidly to a maintained volume stimulus, but often slowly to a chemical stimulus. They are polymodal, responding to mechanical and chemical irritant stimuli, and to many inflammatory and immunological mediators. RARs show very varied sensitivities to different stimuli, and diverse reflex responses. Those in the larynx are usually called 'irritant' receptors. They probably cause cough, the expiration reflex and other laryngeal reflexes: cardiovascular, mucus secretion, bronchoconstrictor and laryngoconstrictor. Those in the trachea and larger bronchi are very mechanosensitive; they cause cough, bronchoconstriction and airway mucus secretion. Those in the larger bronchi are more chemosensitive; they may cause cough, but also stimulate hyperventilation, augmented breaths, mucus secretion, bronchoconstriction and laryngeal closure. Most of the stimuli to RARs also affect other airway receptors, especially those with C-fibre afferents, and the total reflex response will be the additive affect of all these reflexes.

The roles of airway rapidly adapting receptors (RARs) and of C-fibre receptors in the induction of cough are reviewed. It is concluded that, while there is substantial evidence that irritant receptors in the laryngeal wall and RARs in the tracheobronchial mucosa can cause cough, the evidence for such a similar direct role for C-fibre receptors is tenuous. Indeed there is accumulating evidence that the C-fibre receptors may cause apnoea and rapid shallow breathing, and also reflexly inhibit cough. However the C-fibre receptors may release tachykinins when stimulated, and these in turn may cause plasma extravasation from mucosal postcapillary venules. RARs are excited by increases in interstitial liquid volume, so C-fibre receptors may indirectly enhance cough via the RARs.

Duneclift, S., U. Wells, and J. Widdicombe. Estimation of thickness of airway surface liquid in ferret trachea in vitro. J. Appl. Physiol. 83(3): 761–767, 1997.—The tracheae of ferrets and rabbits were mounted in vitro in organ baths. While the tracheae were liquid filled, the permeability coefficient ( P) was determined, and then while the tracheae were air filled, the percent clearance for99mTc-labeled diethylenetriaminepentaacetic acid (DTPA) was determined. The thickness of airway surface liquid (ASL) was estimated by three methods. 1) The initial concentration of99mTc-DTPA and the total amount of99mTc-DTPA (the sum of that entering the outside medium, that draining from the trachea, and that washed out at the end of 40 min) gave the initial volume of ASL and thus its thickness. Mean values were 45.7 μm for the ferret and 41.9 μm for the rabbit. 2) Estimates of ASL thickness at the end of the 40-min period, based on the final99mTc-DTPA concentration and the amount in the washout, were 42.9 μm for ferret and 45.4 μm for rabbit. 3) The ratio of Pto percent clearance gave mean ASL thickness values of 49.2 μm for the ferret and 40.3 μm for the rabbit. Thus three separate methods for determining ASL thickness give very similar results, with means in the range 40–49 μm. Administration of methacholine or atropine to ferret tracheae did not significantly change ASL thickness.

Both PAF (10 microM) and bradykinin (0.1-10 microM) increased lysozyme (from submucosal gland serous cells (+138 and +45% for PAF, 10 microM, and bradykinin, 1 microM, respectively) and albumin (mainly active epithelial transport; +387 and +108%) outputs into the ferret tracheal lumen in vitro and reduced the negativity of the potential difference (PD: -33 and -17%) across the trachea. Since PAF can cause bronchial smooth muscle hyperresponsiveness, we tested whether these effects were interactive, and if PAF would increase the actions of bradykinin. The bradykinin-induced lysozyme and albumin outputs were more than trebled and the PD change was enhanced by PAF, after the immediate secretory effects of the latter had returned to baseline. The secretory and PD responses to PAF were all prevented by the PAF-antagonist WEB 2086 and by a combination of the free-radical scavengers catalase and SOD, indicating that PAF may act on specific receptors to release free-radicals. Nedocromil sodium inhibited the increase in lysozyme and albumin outputs produced by PAF, but had no effect on the PD response. None of the tracheal responses to bradykinin was modified by WEB 2086, catalase and SOD, or nedocromil sodium. The secretory and PD hyperresponsiveness to bradykinin caused by PAF was prevented by WEB 2086 and by catalase and SOD. Nedocromil sodium greatly inhibited the lysozyme and albumin hyperresponsiveness but had no effect on the PD response. Thus PAF may release more than one type of radical which have differential effects on serous cells and albumin transport compared with PD; nedocromil sodium may act only against the radical causing the secretory effects.

Wells, U. M., S. Duneclift, and J. G. Widdicombe.H2O2increases sheep tracheal blood flow, permeability, and vascular response to luminal capsaicin. J. Appl. Physiol. 82(2): 621–631, 1997.—Exogenous hydrogen peroxide (H2O2) causes airway epithelial damage in vitro. We have studied the effects of luminal H2O2in the sheep trachea in vivo on tracheal permeability to low-molecular-weight hydrophilic (technetium-99m-labeled diethylenetriamine pentaacetic acid;99mTc-DTPA) and lipophilic ([14C]antipyrine; [14C]AP) tracers and on the tracheal vascular response to luminal capsaicin, which stimulates afferent nerve endings. A tracheal artery was perfused, and tracheal venous blood was collected. H2O2exposure (10 mM) reduced tracheal potential difference (−42.0 ± 6.4 mV) to zero. It increased arterial and venous flows (56.7 ± 6.1 and 57.3 ± 10.0%, respectively; n = 5, P < 0.01, paired t-test) but not tracheal lymph flow (unstimulated flow 5.0 ± 1.2 μl ⋅ min−1⋅ cm−1, n = 4). During H2O2exposure, permeability to99mTc-DTPA increased from −2.6 to −89.7 × 10−7cm/s ( n = 5, P < 0.05), whereas permeability to [14C]AP (−3,312.6 × 10−7cm/s, n = 4) was not altered significantly (−2,565 × 10−7cm/s). Luminal capsaicin (10 μM) increased tracheal blood flow (10.1 ± 4.1%, n = 5) and decreased venous99mTc-DTPA concentration (−19.7 ± 4.0, P < 0.01), and these effects were significantly greater after epithelial damage (28.1 ± 6.0 and −45.7 ± 4.3%, respectively, P < 0.05, unpaired t-test). Thus H2O2increases the penetration of a hydrophilic tracer into tracheal blood and lymph but has less effect on a lipophilic tracer. It also enhances the effects of luminal capsaicin on blood flow and tracer uptake.

Widdicombe, John. Airway and alveolar permeability and surface liquid thickness: theory. J. Appl. Physiol. 82(1): 3–12, 1997.—The thickness of airway surface liquid (ASL) can be calculated as the ratio of the permeability coefficient of an absorbed inert tracer to the percentage rate in which it decreases in content in the airway lumen. The percentage clearance of radiolabeled diethylenetriaminepentaacetic acid (DTPA) from human airways or lungs has been measured many times, with a mean value of 1.04 ± 0.25 (SD) %/min. Rates of clearance from animal lungs of most species give values of the same order, although they are lower in the sheep and higher in the dog. Permeability coefficients have not been measured simultaneously with percentage clearances and not at all for human tissues. Values for mannitol and sucrose, of which the former gives a permeability coefficient ∼25% greater than that for sucrose and DTPA in airway tubes and isolated mucosal sheets from experimental animals, give a mean of ∼7.1 × 10−7cm/s. This corresponds to thicknesses of ASL of ∼20–150 μm for various species. The assumptions underlying this estimate are discussed. It is concluded that ASL thickness in vivo may be considerably greater than in vitro measurements involving rapid freezing of the airway wall. Estimates of alveolar permeability suggest that either it is very considerably lower than that of the airway epithelium, that methods to measure alveolar permeability mainly reflect airway permeability, or both.

The epithelium of the larynx, trachea, and larger bronchi contains sensory nerves that are responsible for cough. Their two main categories are rapidly adapting receptors (RARs) and C fiber receptors. Both types respond to a wide variety of mechanical and chemical irritants. The RARs are the main sensory complex responsible for cough. C fiber receptors cause neurogenic inflammation by the release of tachykinins such as substance P. The reflex action of C fiber receptors seems to be inhibition of cough. However, the released tachykinins can stimulate RARs and promote or enhance the cough response. The strength and pattern of cough depends on the sites of the airway that are stimulated and the local and central reflex interactions of the RARs and C fiber receptors. Tachykinins seem to be involved in cough, but their role needs further study.

Inhaled sodium metabisulphite (MBS) causes bronchoconstriction, cough and microvascular leakage. We have studied its effects on tracheal blood flow, potential difference (PD) and the permeability from tracheal lumen to venous blood of a low molecular weight hydrophilic tracer, 99mtechnetium-labelled diethylenetriamine penta-acetic acid (99mTc-DTPA) in anaesthetized sheep. Flow was measured in tracheal artery and blood from a cannulated tracheal vein collected for 5 min periods. The tracheal lumen was filled with Krebs-Henseleit solution (KH) containing 99mTc-DTPA for six to eight 15 min periods. During the third or fourth period, MBS (1, 20 or 100 mM) was washed into the tracheal lumen for 15 min. MBS increased tracheal blood flow (venous flow (Q'v), 5-10 min MBS exposure period: 1 mM -9 +/- 18% (n = 3); 20 mM +16 +/- 5% (n = 5; p < 0.05); 100 mM +43 +/- 13% (n = 5; p < 0.05). It decreased PD in a concentration-dependent way. Venous 99mTc-DTPA concentration increased progressively to +266 +/- 176 and +958 +/- 321% 25-30 min after exposure to 20 and 100 mM MBS, respectively (p < 0.05 for both). These effects were not blocked by luminal frusemide (3-7 mM) or flurbiprofen (100-500 microM). Histological sections showed changes to the epithelial cells and large intercellular spaces. Thus, luminal sodium metabisulphite increases tracheal blood flow, reduces transmural potential difference and causes tracheal epithelial damage, leading to an increase in 99mTc-labelled diethylenetriamine penta-acetic acid permeability.

For hydrophilic drugs and agents the major barrier to diffusion from the airway lumen into the mucosa is the epithelium, but for lipophilic agents epithelial permeability is high. Destruction of the epithelium increases the permeability of hydrophilic but not lipophilic agents. Changes in mucosal blood flow, induced either by vasoactive drugs or by changing the rate of arterial perfusion, lead to changes in drug uptake from the lumen to venous blood. Increases in flow decrease uptake, and vice versa for decreases in flow. The most likely explanation of this apparently paradoxical result is that increases in vascular pressure and flow result in a greater interstitial liquid volume and thus perfusion barrier, and induce solvent drag across the vascular endothelial wall, which will limit uptake of agents into the vascular lumen.

International audience; Cough is defensive airway reflex subjected to a high degree of cortical control. Not surprisingly, all cough motor patterns can be mimicked and reflex cough be inhibited up to complete suppression, at least to a certain extent. Reflex cough differentiates from other airway reflex responses for its characteristic 3-phase motor pattern, and such pattern is maintained when coughing is produced voluntarily. Despite these and some other similarities, voluntary and reflex cough differ in many important respects, suggesting different neural control of the respiratory and non-respiratory musculature implicated in the generation of the cough modalities. This paper focuses the motor features that differentiate voluntary and reflex cough efforts, and highlights the importance of functional assessment of coughing in the diagnostic workup of respiratory and extra-respiratory diseases affecting the production of voluntary and reflex cough.

Background Despite the commonality of cough and its burden, there are no published data on the relationship between atopy or sex on objectively measured cough frequency or subjective cough scores in children. In 202 children with and without cough, we determined the effect of sex and atopy on validated cough outcome measurements (cough receptor sensitivity [CRS], objective cough counts, and cough scores). We hypothesized that in contrast to adult data, sex does not influence cough outcome measures, and atopy is not a determinant of these cough measurements. Methods We combined data from four previous studies. Atopy (skin prick test), the concentration of capsaicin causing two and five or more coughs (C2 and C5, respectively), objectively measured cough frequency, and cough scores were determined and their relationship explored. The children's (93 girls, 109 boys) mean age was 10.6 years (SD 2.9), and 56% had atopy. Results In multivariate analysis, CRS was influenced by age (C2 coefficient, 5.9; P = .034; C5 coefficient, 29.1; P = .0001). Atopy and sex did not significantly influence any of the cough outcomes (cough counts, C2, C5, cough score) in control subjects and children with cough. Conclusions Atopy does not influence important cough outcome measures in children with and without chronic cough. However, age, but not sex, influences CRS in children. Unlike adult data, sex does not affect objective counts or cough score in children with and without chronic cough. Studies on cough in children should be age matched, but matching for atopic status and sex is less important.

Both sides of the nasal vasculature of the dog in vivo were perfused separately, with measurement of vascular resistance responses to stimulation of various nerves. Stimulation of the central end of a cut superior laryngeal nerve caused an ipsilateral vasodilation (-4.98%) and a contralateral vasoconstriction (+3.96%), the difference being statistically significant (P < 0.01). Stimulation of a glossopharyngeal nerve caused vasodilation on both sides, the ipsilateral (-17.52%) being greater than the contralateral (-6.33%) response (P < 0.05). Mechanical stimulation of the nasal mucosa caused little ipsilateral change (+0.47%) and a weak contralateral vasoconstriction (+3.78%; P < 0.01). Stimulation of the central end of a cervical vagus nerve caused vasodilations on both sides, the ipsilateral (-9.75%) being greater than the contralateral (-5.73%) change (P < 0.05). With bilateral perfusions of the cervical tracheal arteries, stimulation of a superior laryngeal nerve caused vasodilation on both sides, the ipsilateral (-10.1%) being greater than the contralateral (-7.4%) response (P < 0.05). Stimulation of the central end of a vagus nerve caused vasoconstrictions on both the sides, the ipsilateral (+37.4%) being greater than the contralateral (+10.8%) change (P < 0.05). Thus various nervous inputs from the nose, pharynx, larynx, and vagal distribution cause asymmetric vascular responses both in the nose and in the cervical trachea.

The possible existence of arteriovenous anastomoses (AVAs) in the tracheobronchial circulation has been largely ignored; however, their presence would have many implications. Here we have searched for AVAs in the tracheal circulation of seven anesthetized sheep that were ventilated through a low cervical tracheostomy. Arteries to the midcervical trachea were isolated and perfused in situ at systemic blood pressure; blood flow was measured with an electromagnetic flow probe. A vein draining the perfused segment was cannulated. Radiolabeled microspheres (16 microns diam) injected into the arterial inflow of the perfusion indicated the distribution of blood flow (cervical trachea, 69.9 +/- 4.55% (SE); esophagus, 15.1 +/- 3.9%; connective tissue and blood vessels near trachea, 9.5 +/- 1.8%; lymph nodes, 4.0 +/- 2.2%; skeletal muscle, 0.17 +/- 0.07%; trachea below intubation, 0.00%; larynx, 0.00%; other tissues 0.81 +/- 0.32%). Less than 0.6% of the activity was detected in the tracheal venous blood and lungs, indicating little shunting via AVAs. Within the trachea, blood flow (per wet weight of tissue) to the mucosa overlying smooth muscle was approximately 25% of that to the mucosa overlying cartilage. Intra-arterial infusion of methacholine doubled perfusion blood flow without altering the proportion of shunted blood. Within the trachea, blood flow increased most to the mucosa overlying smooth muscle and to smooth muscle. In conclusion the contribution of AVAs to total blood flow in the cervical trachea is < 1%.

Although in the clinic the presence of mucus in the airways is known to be an important factor influencing the sound of coughing in pathological conditions, this observation has not been established experimentally. We have substituted mucus in the airways of anaesthetized cats with 0.5 ml of natural undiluted egg albumin (EA) from hens' eggs, or with 1 ml of 10% pig gastric mucin (PGM) in saline. There were obvious changes in the character of cough sounds and significant increases in the intensity of the sounds (+76% with EA, +36% with PGM). The intensity of cough efforts significantly increased but only in the cats with addition of PGM (mean 30%). Removal of EA or PGM caused the opposite effects, a decrease in cough sounds (-41%) and intensity of cough effort (-52%), with simultaneous changes in the character of the cough sounds. There were no clear-cut patterns of cough sounds as has been described for humans. The cough sounds were often present not only during the expiratory phase of cough but also during the inspiratory phase. The results establish an important role of mucus in the airways in the creation of cough sounds.

We have assessed the importance of changes in lung structure on the pattern of cough sound and its creation with 13 anaesthetized cats. Acute lung injury with oedema was induced by i.v. administration of a mixture of fatty acids. Cough was elicited by mechanical stimulation of the mucous membranes of the airways and was evaluated by its intensities of effort and sound before and up to 2 h after administration of the fatty acids. Changes of cough sound pattern were not definitive, there being no typical alterations. The cough effort and sound intensities, induced from the trachea, consistently decreased (by 70-80% in both cases). The cough efforts immediately after induction of oedema were transiently abolished in some cats. The cough values induced from the larynx similarly decreased at 5 min (51-57%) but subsequently gradually returned to control values. There were significant correlations, both for coughs induced from the trachea and from the larynx, and for changes in intensity of efforts compared with sounds. Thus, pathological changes in the lungs modify the intensities both of cough efforts and their associated sounds.

Some patients exhibit cough-like expiratory efforts ("deflation cough") during slow vital capacity (SVC) and/or FVC maneuver. The cause and motor features of these expulsive efforts are unknown.Of 1,720 consecutive patients, 43 displayed deflation cough during SVC or FVC, and 18 agreed to participate in additional examinations involving radiologic and clinical assessments. Variables of the motor pattern of deflation cough, as well as its intensity and frequency, were recorded by means of a pneumotachograph; the "integrated" surface abdominal electromyographic activity (IEMG) was recorded as well. On different occasions, participants were randomly administered either an antacid or salbutamol or matched placebos. Comparisons between deflation cough variables prior to and after drug administration were performed by means of the analysis of variance and post hoc tests.Fourteen patients (77.8%) were affected by a respiratory disease, and all of them also reported esophageal and/or extraesophageal symptom(s) of reflux. In control conditions, maximal lung emptying was consistently accompanied by the appearance of deflation cough. Peak IEMG and peak expiratory flow rates of deflation cough correlated (r = 0.53, P.05). Inhaled agents had no effect. Antacid abolished deflation cough in 11 patients, reduced its frequency in four, and was ineffective in three. Matched placebo was significantly less effective.All patients with deflation cough present symptoms of gastroesophageal reflux; acidic reflux, possibly evoked by the efforts of lung emptying, may be the causative factor. Receptors sensitive to lung collapse may also contribute to deflation cough when antacid administration fails.

Both for the nose and the lower airways there is an extensive subepithelial capillary network. That for the nose is fenestrated, and this is true for the tracheobronchial tree of rats, guinea pigs, and hamsters, and for that of human asthmatics. However, healthy humans, dogs, and sheep have capillaries without fenestrations except for those close to neuroepithelial bodies and submucosal glands. Deeper in the mucosa there is a capacitance system of vessels, conspicuous in the nose but present also in the lower airways of rabbits and sheep and, to a lesser extent, in those of dogs and humans. Both for the nose and the lower airways, parasympathetic nerves are vasodilator, sympathetic nerves are vasoconstrictor, and sensory nerves are able to release dilator neuropeptides. Most inflammatory and immunologic mediators are vasodilator. A conspicuous difference between the nasal and lower airway vasculatures is the presence of arteriovenous anastomoses only in the former. Countercurrent mechanisms also exist in ...

Tracheal blood flow and 99mTc-labeled diethylenetriamine pentaacetic acid (DTPA) clearance were measured in the sheep trachea in vivo. The tracheal arteries were isolated and perfused. An isolated segment of tracheal lumen was filled with Krebs-Henseleit solution containing 99mTc-DTPA, and radioactivity was measured in blood from a catheterized tracheal vein. Infusions at constant pressure of methacholine (n = 5), albuterol (n = 6), and histamine (n = 5) increased arterial inflow [+250 +/- 73.0, +74.2 +/- 22.9, +68.9 +/- 39.2% (SE), respectively] and venous outflow (+49.5 +/- 13.8, +11.6 +/- 4.5, +6.2 +/- 13.9%) but decreased 99mTc-DTPA output (-36.8 +/- 8.4, -20.4 +/- 6.2, -58.1 +/- 11.7%) and concentration (-53.9 +/- 10.1, -27.3 +/- 7.5, -49.3 +/- 14.4%). Phenylephrine (n = 9) decreased arterial inflow (-49.4 +/- 10.0%) and venous outflow (-4.1 +/- 5.9%) but increased 99mTc-DTPA output (+74.6 +/- 44.2%) and concentration (+94.4 +/- 56.6%). When the tracheal arteries were initially perfused at constant flow and the flow rate was then changed, 50% increases in flow (n = 5) increased perfusion pressure (+35.9 +/- 2.2%) and venous outflow (+10.5 +/- 3.8%) but decreased 99mTc-DTPA output (-24.4 +/- 7.8%) and concentration (-30.4 +/- 8.8%). Decreases in flow of 50% (n = 3) and 100% (n = 10) decreased perfusion pressure (-34.2 +/- 4.2, -80.1 +/- 3.5%, respectively) and venous outflow (-11.0 +/- 4.8, -29.7 +/- 7.2%) but increased 99mTc-DTPA output (+45.9 +/- 27.5, +167.4 +/- 70.4%) and concentration (+64.7 +/- 26.7, +305.7 +/- 110.2%).(ABSTRACT TRUNCATED AT 250 WORDS)

With the ferret liquid-filled trachea in vitro, intraluminal methacholine (MCh), phenylephrine (PE) and histamine (Hist) increased smooth muscle tone and salbutamol (Salb) decreased tone. Lysozyme output was increased by intraluminal MCh and PE. Albumin transport into the lumen was not altered by intraluminal Hist, Salb or PE. The concentration-response curves for smooth muscle contraction and for lysozyme output to extraluminal MCh lay to the left of those for intraluminal MCh. Indomethacin shifted the smooth-muscle response curves to MCh significantly to the left but did not significantly alter lysozyme output. Extraluminal MCh produced a concentration-dependent increase in albumin output whilst intraluminal MCh did so in one of three studies. Albumin output in response to MCh was not significantly altered by indomethacin. Thus, MCh has a less potent effect on smooth muscle and lysozyme secretion and, to a lesser extent, on epithelial albumin transport when given intraluminally. This may be because the epithelium restricts diffusion of the drug or due to the production of a non-prostanoid factor which inhibits smooth muscle responsiveness. Smooth muscle responsiveness is enhanced by blocking cyclooxygenase activity, suggesting MCh-induced release of a prostanoid with relaxant activity.

The tracheobronchial vasculature consists of a subepithelial capillary network and a deeper system of blood sinuses or capacitance vessels. There seem to be no arteriovenous anastomoses. Sympathetic nerves constrict the vasculature by the transmitters noradrenaline and neuropeptide-Y, parasympathetic nerves dilate it by acetylcholine and vasoactive intestinal polypeptide, and sensory nerves release neuropeptides including substance P that are dilator. Most inflammatory mediators are also vasodilator. In asthma there is mucosal vasodilation due to the direct action of mediators on vascular smooth muscle, neuropeptides released by axon reflexes in sensory nerve receptors, and possibly reflex vasodilation due to stimulation of sensory nerves. The vasodilation increases the thickness of the mucosa, both by vascular engorgement and by increased interstitial liquid volume. This mucosal thickening will narrow the airways and increase the rigidity of their walls. The vascular bed is also dilated by cold and hyperosmolality, and this change may be a component of the bronchoconstriction due to hyperventilation, inhalation of cold air and exercise. Changes in mucosal blood flow influence the uptake of chemical agents from the lumen, and the success of aerosol therapy in asthma may to some extent depend upon the influence of mucosal blood flow.

We review the actions of complementary and alternative medicines (CAMs) in the treatment of cough and of the conditions associated with it; in particular asthma and upper respiratory tract infections. These therapies may work (1) peripherally, at the sites in the airways and lungs at which cough is being activated, (2) in the brainstem, where the neural "cough center" is situated, or (3) at the cerebral cortex, where cough can be initiated, suppressed or modified by conscious or unconscious controls. Of the large number of trials of CAMs against cough, most are inadequate in design. It may be difficult to randomize selection. Blinding is often impossible both for the patient and the therapist, and adequate placebo controls may be difficult to devise. The patient can usually identify the "active" treatment by the taste or smell of a medicine, or from the approach and apparatus being used. Pure chemicals can be extracted from many of the herbs used as antitussives, and can be shown to be effective in randomized, blind, and controlled trials, but it does not follow that the herb itself, used in the recommended formula and shown to be antitussive, acts by this agency unless a placebo effect is ruled out. A few herbs are identified where the evidence points to a true antitussive action. Of nonherbal treatments, the few positive results are usually outweighed by the larger number of negative ones. Thus, in general, CAMs for cough are welcomed enthusiastically by the patient but lack sound evidence for their efficacy. Antitussive chemicals can be extracted from many herbs, but it is no more than a reasonable hypothesis that the herb itself acts through this pathway.

The tracheobronchial vasculature is controlled by adrenergic, cholinergic, and peptidergic nervous mechanisms. Sympathetic nerves release norepinephrine and neuropeptide Y (NPY), which are both constrictor agents, the latter being long-lasting. Parasympathetic nerves release acetylcholine and usually vasoactive intestinal polypeptide (VIP), both of which are vasodilators, VIP being the longer lasting. These motor nerves are controlled by many reflex inputs. Activation of pulmonary C-fiber receptors by irritants and inflammatory mediators causes a powerful vasodilatation, mainly via sympathetic motor nerves. Cardiac and chemoreceptor reflexes also influence airway vascular tone. Sensory nerves in the airway mucosa are responsible for local axon reflexes in response to irritants and inflammatory mediators. These nerves contain neuropeptides such as substance P (SP), neurokinins A and B (NKA, NKB), and calcitonin gene-related peptide (CGRP). All these neuropeptides are powerful vasodilators. Thus, inflammatory conditions in the lungs such as asthma cause vasodilation by local direct action of mediators, by axon reflexes, and by central nervous reflexes. The vasodilation could lead to mucosal edema. Thus, airway vascular responses have to be added to bronchoconstriction and mucus secretion as part of the mucosal pathology of asthma.

Blood flow in the tracheal mucosa (Qm) has been measured by laser-Doppler flowmetry in anesthetized sheep and dogs. The values have been compared with tracheal arterial inflow (Qtr) by use of an electromagnetic flow probe and with tracheal arterial perfusion pressure (Ptr) produced by mechanical perfusion. Changes in blood flow were caused by injections of methacholine, phenylephrine, and histamine into the perfusion circuit. These interventions produced a range of measurements for each animal. Correlations of Qm against Qtr were significant in two of five animals (R = 0.03–0.93); correlations of Qm against Ptr were significant in two of four animals (R = 0.56–0.96). Percent changes in Qtr were generally much larger than those of Qm, and there was considerable variability between Qm and either Qtr or Ptr. Qm reflected the same vascular changes as Ptr or Qtr in 28 interventions and showed an opposing change in 4 cases. In 11 interventions, changes measured by Ptr or Qtr were not reflected by any changes in Qm. Thus qualitative changes in tracheal perfusion measured with these methods were usually the same; quantitatively the three methods showed great differences. These differences may reflect different regulatory mechanisms in various components of the tracheal vasculature or different technical aspects of the methods used.

1. We have examined the effect of calcitonin gene-related peptide (CGRP) on basal mucus volume, lysozyme and albumin outputs from the ferret whole trachea in vitro, and on the outputs produced by methacholine and substance P (SP). We have also examined the effect of inhibiting neutral enkephalinase with thiorphan on the responses to CGRP. 2. CGRP (1-100 nM) produced small concentration-dependent increases in basal mucus volume, lysozyme and albumin outputs. These effect of CGRP were enhanced by thiorphan. The increases in basal outputs with CGRP and the potentiation by thiorphan were considerably less than previously observed with SP and neurokinin A (NKA). CGRP had no significant effect on potential difference (PD) across the trachea. 3. CGRP produced a concentration-dependent inhibition of methacholine- and SP-induced lysozyme output but a concentration-dependent increase in methacholine- and SP-induced albumin output. The effects of CGRP on methacholine-induced lysozyme and albumin outputs were enhanced by thiorphan. CGRP weakly inhibited methacholine-induced mucus volume output and weakly enhanced SP-induced mucus volume output. 4. Thus, CGRP weakly stimulates basal serous cell secretion and epithelial albumin transport, but does not alter epithelial integrity. CGRP inhibits the serous cell secretion due to methacholine or SP, but potentiates the epithelial albumin transport produced by these agents. The interaction between CGRP and other sensory neuropeptides or muscarinic agonists on airway submucosal glands and epithelium may be important in the normal airway and in inflammatory airway diseases where release of sensory neuropeptides is enhanced.

With cats anaesthetized with sodium pentobarbital we studied how veratrine-induced reflexes interact with cough. Cough was elicited by mechanical stimulation of tracheobronchial mucosa and its intensity was evaluated from the changes in oesophageal pressure. Veratrine injected intravenously produced apnoea, bradycardia and long-lasting hypotension. With each dose the intensity of cough was significantly decreased during the apnoea. When the mechanical stimulus was repeated during the breathing following apnoea with remaining hypotension, cough intensity parameters were not changed from control. Veratrine injected intracardially caused bradycardia, hypotension, and decreases in respiratory rate and tidal volume. The intensity of cough elicited just after injection of veratrine was also significantly decreased. We suggest that veratrine-induced reflexes depress the cough reflex mainly by inhibitory reflexes arising from cardiac receptors. The inhibition of cough is probably mediated indirectly via the inhibition of medullary respiratory neurons.

The panel considered the different types of cough in terms of basic mechanisms and clinical manifestations; both experimentally and clinically cough could occur in single efforts and as 'bouts' or 'epochs'. There were different definitions of cough but, provided the definition used was clear, this did not seem to be a major concern. The methods available for determining the nature or type of clinical cough were discussed, in particular automated cough counting in the clinic and more sophisticated methods available in the laboratory. With regard to semantics, there has been great variation in the names used; this applies to nervous sensors for cough, to cough reflexes and epochs, to clinical names for cough, and to cough sounds. Some simplification and uniformity of nomenclature seemed desirable although, provided the use of a name was clear, little confusion probably existed. The panel felt that the cough nomenclature would evolve with time and would prove to be useful for investigators, clinicians and coughers.

Stimuli within the lung can cause the sensations of pain, ache, irritation and urge-to-cough. In general these are abolished or inhibited by vagal section or vagal anaesthesia, or local anaesthesia within the airways. They are present in patients with functional high cervical spinal cord transaction and after general neuromuscular paralysis. There are at least nine sensors in the bronchopulmonary system, studied almost entirely in animals. It is at present impossible to link any one sensor with any one pattern of sensation. It is reasonable to suppose that urge-to-cough arises from sensors what mediate cough, but there are at least five sensors involved in this reflex, and how they relate to unpleasant sensation is unknown. The problem is that sensation can almost only be studied in humans, and the vagal neural mechanisms almost only in other species. Vagal sensors can also ameliorate the sensation of air hunger, and this is probably due to the action of slowly adapting pulmonary stretch receptors (SARs). The same sensors may give rise to the awareness of lung volume and its changes. Many sensors in the lungs can be sensitized or desensitized by natural or imposed conditions, and this could underlie the sensitization and desensitization of dyspnoeic sensations that have been described.

The expiration reflex (ER) is a forced expiratory effort against a closed glottis that subsequently opens to eject laryngeal debris and prevent aspiration of material. It is distinct from the cough reflex. Its source is usually assumed to be restricted to the larynx and vocal folds, and its possible origin from the tracheobronchial (TB) tree has been suggested but never studied. The current authors re-analysed previous records with mechanical or chemical stimulation of the TB tree to see if an ER can consistently be elicited, and to see whether it has properties similar to that from the larynx and vocal folds. A random review was made of some of the extensive literature on TB "cough" to see if it confirmed the authors' conclusions. The TBER was consistently seen in cats and rabbits, either alone or followed by cough. These results are consistent with many studies in other species, including humans. It was enhanced, relative to cough, by inflation of the lungs and by general anaesthesia. Tracheobronchial expiration reflex occurs frequently with mechanical stimulation of the tracheobronchial tree. It differs fundamentally from many of the properties of "true" cough. Its features similar to the laryngeal expiration reflex suggest that both should be labelled "expiration reflexes" and not cough. Its existence should be taken into account in experimental, and possibly clinical, studies on tracheobronchial cough.

Congenital central hypoventilation syndrome (CCHS) is a genetic disorder mainly characterized by failure of automatic control of breathing, causing alveolar hypoventilation. Little is known regarding cough in CCHS. Parental reports indicate that patients cough normally during airway infections; however, previous studies have demonstrated no cough response to fog inhalation.To evaluate the sensory and motor components of cough, respiratory sensations, and changes in ventilation evoked by fog inhalation in children with CCHS and in sex- and age-matched control subjects.Cough threshold was measured and cough intensity was indexed in terms of cough peak expiratory flow and integrated abdominal electromyographic activity. The pattern of breathing was recorded by inductive plethysmography. Respiratory sensations were also investigated.All control subjects and six of seven patients coughed in response to fog inhalation. The seventh coughed with citric acid aerosol inhalation. Cough threshold values were similar in control subjects (range, 0.40-2.22 ml/min) and patients (range, 0.40-3.26 ml/min). Mean values of cough peak expiratory flow and of integrated abdominal electromyographic activity-related variables during coughing were also similar and corresponded to 80% of those recorded during maximum voluntary cough. Cough appearance was preceded by respiratory sensations and increases (P0.01) in ventilation in the control subjects but not in the patients.Children with CCHS have normal cough threshold and motor responses to fog inhalation. However, the lack of respiratory sensations and the likely related ventilatory changes typically elicited by tussigenic fog concentrations suggest a neural sensory deficit that may increase the risk of respiratory disease in these patients.

Cough 1) All basic scientific articles should refer to cough as a three-phase motor act. For the purposes of acoustic recordings in clinical studies, however, cough should be described as a forced expulsive manoeuvre or manoeuvres against a closed glottis that are associated with a characteristic sound or sounds. 2) All scientific articles should include a clear definition of what the authors have used as their definition of cough. ### Capsaicin and citric acid inhalation cough challenge 1) The methodology for the performance of inhalation cough challenge should be standardised so as to facilitate universal interpretation and comparison of data generated by different laboratories. 2) Comprehensive normal ranges need to be developed using the standardised methodology advocated in the present document. 3) The single-breath concentration–response method using a flow-limited dosimeter is recommended for most experimental protocols. 4) Both C2 and C5 should be recorded. 5) Since there is wide inter-individual variation, cough challenge data have no intrinsic significance, but may usefully be used to follow change in cough reflex sensitivity in an individual. ### Cough induced by inhalation of aqueous solutions 1) Aerosolised aqueous solutions represent a useful experimental tool in cough research. 2) The cough challenge with ultrasonic distilled water (fog) is difficult to standardise since it is highly dependent upon nebuliser output. 3) Consideration should be given to potential adverse events, such as bronchoconstriction and cross-infection. ### Cough monitors 1) No cough monitor is currently the gold standard. 2) Monitors should be developed that are ambulatory, are capable of being digitally processed and permit prolonged (24-h) recording. 3) There is little to commend any particular method of quantifying cough over any other. ### Assessment of quality of life of patients with chronic cough 1) Cough can have profound effects on health status, which can be assessed by cough-specific health status questionnaires. 2) Cough visual analogue scale (VAS, 0–100 mm) should be used to assess cough severity in patients with chronic cough. 3) Patients with chronic cough should be assessed with cough-specific quality-of-life questionnaires in clinical studies. ### Animal models of cough 1) The most useful animal model of cough is …

We review cough from premature birth, mature neonatal life, in childhood and adult life, and in old age. There is a regrettable lack of definitive studies, but many clues in the literature. The cough reflex seems weak in premature infants, but develops with maturity. It is pronounced in childhood, but there seem to be no studies comparing its strength then with that in adulthood. In old age the cough may weaken, as indicated by the prevalence of aspiration pneumonia. These changes are presumably related to the development and degeneration of the afferent and central nervous pathways for cough, which may be reflected in the changes in laryngeal muscle function with age. There is much evidence that age influences the development of the respiratory system in general, and of the immune system which would affect the degree, frequency and clinical issues of cough. Other factors that limit our understanding of the changes in cough with age include the reporting of cough by parents in infants and carers in old age and the use of different diagnostic criteria throughout life. Age-related variation in cough sensitivity seems to be well established, but its quantitation and mechanisms require much further research.

Cough is usually defined as a three-phase event, although for convenience clinicians may prefer to define it as only the expiratory expulsive efforts. Cough may occur as a single event or as a cough ‘epoch’ (or ‘bout’ or ‘attack’) that includes several or many expiratory efforts in a single episode. The distinction between a single cough and a cough epoch is important, both in mechanistic and clinical implications, since the latter may include many ‘expiration reflexes’ (ERs), for which the functions and neural mechanisms are different from those of the cough reflex. We describe the various ways in which cough can be assessed. For simplicity in clinical work the main methods are patient scores or automated cough counters; these assess only one aspect of the complex changes in cough. For analytical and basic medical studies other facets of cough need to be included: expiratory EMGs, respiratory pressures, airflows and lung volume changes. Cough ‘intensity’, a much used expression, needs to be defined in terms of the facets of cough which are being measured.