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Water Aerosols and Cough
Pulmonary Pharmacology & Therapeutics (2002) 15, 205±211 doi:10.1006/pupt.2002.0359, available online at http://www.idealibrary.com on
1
PULMONARY PHARMACOLOGY
& THERAPEUTICS
Review Water Aerosols and Cough Giovanni A. Fontana, Federico Lavorini, Massimo Pistolesi UnitaÁ Funzionale di Medicina Respiratoria UniversitaÁ degli Studi di Firenze, Italia SUMMARY: Inhalation of ultrasonically nebulised distilled water (fog) induces cough; however, the receptor type(s) mediating this reflex are poorly defined. In humans, cough threshold can be determined by inhalation of progressively increasing fog concentrations; the intensity of the associated motor response can be indexed in terms of flow-related variables as well as of the peak and slope of the integrated electromyographic activity of the abdominal muscles. We have evaluated coughing in patients with Parkinson's disease who show a high incidence of serious chest infections. These patients turned out to have a normal cough threshold but reduced expiratory muscle force during reflex coughing; this suggests an impairment in the central mechanisms subserving muscle activation possibly leading to inefficient airway clearing. Recurrent chest infections also affect laryngectomised patients. These patients have a normal cough threshold but reduced muscle force during coughing in response to threshold stimuli. Voluntary coughing is preserved in these patients, and this should be used to facilitate mucus removal. In normal subjects, fog inhalation causes cough and increases in respiratory drive and minute ventilation, mainly accounted for by increases in tidal volume, possibly due to activation of airway rapidly adapting receptors. Nedocromil sodium administration increases cough threshold and attenuates the ventilatory responses. The assessment of sensory and motor components of coughing may represent a useful tool for those investigating cough in # 2002 Published by Elsevier Science Ltd. humans. KEY WORDS:
Cough threshold, Parkinson's disease, Laryngectomy, Electromyography, Nedocromil sodium.
ASSESSING THE SENSORY COMPONENT OF COUGH
INTRODUCTION Cough is a defence mechanism initiated by appropriate chemical and/or mechanical stimulation of sensory endings located in the larynx and the proximal respiratory tract. The aim of the reflex is removal of mucus and/or foreign bodies from the airways by the generation of high expiratory flow rates. The assessment of the sensory and motor components of coughing may be important to evaluate the mechanisms implicated in the genesis of cough responses, as well as to investigate the effects of antitussive agents.
In human cough studies, cough sensitivity is best assessed in terms of cough threshold. Although several nebulised agents may be used to assess cough sensitivity,1±5 inhalation of ultrasonically nebulised distilled water (fog) represents a potent cough stimulus, with the advantage of being particularly well accepted by both normal subjects and patients. In addition, the short- and long-term repeatability of cough threshold values determined by using this tussigenic agent has recently been demonstrated in humans.6 In the clinical setting, fog is produced by means of an ultrasonic nebuliser whose output can be adjusted by means of a potentiometer and monitored as a direct current (DC) signal on an oscilloscope.7 The nebuliser output can be progressively increased in steps corresponding to 5% of the maximum attainable DC signal. As shown in Fig. 1, the relation between
Author for correspondence: Giovanni A. Fontana, M. D., Dipartimento di Area Critica Medico Chirurgica, UnitaÁ Funzionale di Medicina Respiratoria, Viale G. B. Morgagni, 85, 50134 Firenze, Italia. Tel: 30-055-413183; Fax: 39-055-4223202; E-mail: [email protected] 1094±5539/02/$ ± see front matter
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peak flow to the time to peak.8±10 Cough peak flow, however, may be influenced not only by the intensity of the muscle effort produced during coughing, but also by the mechanical properties of the respiratory system, particularly airway resistance.
Electromyographic activity of the expiratory muscles
Fig. 1 Relationship of fog output (ml/min) vs. the nebuliser's operation frequency expressed as a direct current (DC). Each data point represents the mean (SD) of 5 separate measurements.
DC signal and the actual nebuliser output in ml/min fits with the linear model; mean nebuliser output (ml/min) can be calculated according to the equation reported in Fig. 1. To assess cough threshold, subjects are connected to the nebuliser via a mouthpiece and a two-way nonrebreathing shutter valve, and tidally inhale progressively increasing fog concentrations obtained by adjusting the nebuliser output.6,7 With this method, cough threshold is taken as the lowest fog output capable of evoking at least one cough during two distinct challenges separated by a time interval of approximately 30 min. This procedure ensures that the recorded cough response was actually evoked by fog inhalation and not a random event.6 A valuable aspect of cough threshold to fog inhalation as assessed with the method described above is its short- and long-term reproducibility.6 In normal subjects, re-assessment of cough threshold following a 3 h and a 6±9 month interval showed that cough threshold values were highly repeatable, suggesting that this variable represents a useful and reliable tool for quantification of subject's cough sensitivity.6
ASSESSING THE MOTOR COMPONENT COUGH Cough flow The airflow generated by a subject during voluntary and reflex cough efforts can easily be recorded by means of a large-size pneumotachograph. Several variables that may be relevant for assessing the intensity of a cough effort can easily be measured or calculated from a cough flow tracing. These include the cough peak flow, the time that elapses from the onset of flow to peak flow, i.e., the so-called time to peak, and volume acceleration, that is the ratio of cough
The intensity of voluntary and reflex cough efforts can conveniently be assessed by means of the integrated electromyographic activity of the abdominal muscles (IEMG). In the mid eighties, Cox et al2 were the first to use the IEMG of the abdominal muscle, namely the obliquus externus muscle, in the assessment of cough motor responses. These authors, however, proposed the use of the `true' integrated activity, that is the sum of the electrical activity generated during each muscle contraction, rather than the `moving average' of the activity, which provides the real time course of each electromyographic event. The `moving average' of the IEMG is proportional to the actual tension (force) developed by the contacting muscles during both isometric and isotonic conditions.11 From IEMG recordings obtained during coughing, it is possible to measure the peak amplitude of the IEMG activity (IEMGP), and the time duration of the expiratory ramp, i.e. the cough expiratory time (TEC). The ratio between these two variables (IEMGP/TEC) represents the rate of rise or `slope' of the IEMG activity. The IEMGP is an expression of the total number of recruited motor units and of their maximal frequency of discharge, while IEMGP/TEC reflects the rate of motor units recruitment as well as the rate of increase in firing frequency.12 As fully described elsewhere,13 to allow comparisons of IEMG-related variables obtained in different subjects or in different experimental conditions, IEMG amplitudes need to be normalised. In normal subjects, or in patients with normal central mechanisms of muscle activation, this can easily be achieved by expressing each recorded IEMGP as a fraction of the maximum recorded IEMG amplitude (absolute maximum). Absolute maximum IEMGP amplitudes are usually attained, in our experimental conditions, during maximum voluntary coughing (MVC). In patients with a central deficit of motor activation, the maximum recorded abdominal IEMG amplitude cannot be taken per se as the real absolute maximum, since it does not account for the actual loss in expiratory muscle force in these patients.14 The latter can reliably be expressed as the ratio of measuredto-predicted maximum expiratory pressure.13 Since the relationship between muscle force and IEMG activity is maintained also in patients with a central
Water Aerosols and Cough
deficit of motor activation, it can be assumed that measured PEmax maximum recorded IEMGP AU predicted PEmax absolute maximum IEMGP AU Then, absolute maximum IEMGP maximum recorded IEMGP predicted PEmax measured PEmax This estimated absolute maximum IEMG amplitude can then be used to scale all other recorded IEMGP values. PATIENTS WITH PARKINSON'S DISEASE Parkinson's disease is a clinical syndrome dominated by a disorder of movement consisting of tremor, rigidity and slowness of movements (bradykinesia). One of the most prominent features contributing to bradykinesia is a failure to energise muscles up to the level necessary to perform fast or ballistic movements.15±17 Respiratory problems are a common feature of the disease and respiratory complications, particularly aspiration pneumonia, are the most common cause of death.18 Indirect lines of evidence14,19 seem to indicate that not only swallowing disturbances,19 but also a defective cough reflex, may contribute to predisposing patients with Parkinson's disease to chest infection. Thus, we have evaluated the sensory and motor components of reflex and voluntary coughing both in patients with Parkinson's disease with normal or nearnormal lung function tests and in age-matched control subjects. As shown in Fig. 2A, patients with Parkinson's disease displayed a significant reduction in expiratory muscle force.14 Noticeably, patients' cough threshold to fog inhalation turned out to be similar to that of
Fig. 2 Comparisons of mean maximum expiratory pressure (PEmax) values recorded in control subjects and in patients with Parkinson's disease (A) as well as in control subjects and laryngectomised patients (B). C, control subjects; P, patients. *, P < 0.01 by unpaired t-tests.
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control subjects (Fig. 3A), thus indicating that cough sensitivity is not affected by the disease. The motor characteristics of voluntary and reflex coughing in the two study groups, as assessed by using the IEMG activity of the abdominal muscles, are diagrammatically depicted in Fig. 4A. In normal subjects, corrected values of peak and slope of the IEMG activity observed during maximum voluntary cough efforts (MVC) slightly but significantly exceeded those attained during reflex cough (RC) evoked by a fog stimulus of threshold intensity. In the patients, TEC during MVC did not significantly differ from that recorded in control subjects during both MVC and RC. However, patients TEC values during RC were substantially increased when compared with those recorded during MVC, as well as with TEC values recorded in control subject during both MVC and RC. In addition, mean corrected peak IEMG values turned out to be significantly depressed in the patients, both during MVC and RC (Fig. 4A). In the patients, the reduction in IEMGP values during MVC and RC, along with the lengthening of TEC during RC, accounted for the marked reduction in the slope of IEMG activity during both MVC and RC (Fig. 4A). The reduction observed in IEMGP and IEMGP/ TEC during cough efforts, that also correlated with the degree of motor impairment,13 probably reflects bradykinesia, one of the most prominent functional disturbances in patients with Parkinson's disease. A contributing feature of bradykinesia is a failure to energise muscles up to a level necessary for the execution of rapid or ballistic movements.16,17,20 Since cough can conceivably be regarded as a fast or ballistic-like motor act, the same pathophysiological mechanism could account for impaired motor cough responses in
Fig. 3 Box and whiskers plots comparing cough threshold values observed in control subjects and in patients with Parkinson's disease (A), in control subjects and laryngectomised patients (B), and in normal subjects following placebo (PL) and nedocromil sodium (NCS) administration (C). Each box extends from the 25th to the 75th percentile and contains the median value; whiskers extend from the lowest to the highest recorded value. *, P < 0.01 by Mann±Whitney tests.
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Fig. 4 Diagrammatic representation of average IEMG patterns. In A, comparison between maximum voluntary cough (solid lines), and reflex cough at threshold level (dotted lines) in control subjects (upper panel) and Parkinson's disease patients (lower panel). In B, comparison between maximum voluntary cough (solid lines), reflex cough at threshold level (dotted lines) and suprathreshold (1.8 threshold, dashed lines) levels in control subjects (upper panel) and in laryngectomised patients (lower panel). Values are means SD for peak IEMG activity and duration of expiratory IEMG ramp activity (TEC). Horizontal bars represent standard deviations for mean duration of expiratory IEMG ramp activity; standard deviations for peak IEMG amplitudes are represented by vertical bars. For statistical significance see text.
Parkinson's disease. This motor deficit may account for the observed expiratory muscle weakness and suggests a reduction of expiratory flow during coughing, possibly leading to an impairment of airway clearing mechanisms. The latter may explain, along with the well known swallowing disturbances, the high incidence of potentially lethal pulmonary infections that characterise the late stages of Parkinson's disease.
LARYNGECTOMISED PATIENTS Respiratory tract infections are commonly observed also in laryngectomised patients. This may be due not only to the loss of the protective shield represented by the nose and the upper airway, but also to an impairment in cough sensory and motor components following laryngeal ablation. Indeed, tussigenic stimuli have been shown to activate the `irritant' receptors located in the laryngeal mucosa as well as the `irritant' receptors of the tracheobronchial tree. Both these receptors are believed to be mainly responsible for reflex cough responses,21±23 even if recent lines of evidence seem to indicate that signals arising from
the larynx are not crucial for triggering cough.3 Although evidence exists22 that tracheostomised and intubated patients still `cough', suggesting that airway clearing may still be possible even in the absence of glottis closure, laryngectomy may limit cough effectiveness and represents an indication for bronchial hygiene therapy, particularly directed towards cough.24 Whether ablation of the larynx has an impact on respiratory muscle activity during voluntary and reflex expiratory thrusts remains unclear; however, it has been reported that signals of laryngeal origin may have a role in regulating the strength of the inspiratory and expiratory efforts during coughing,25±27 suggesting that ablation of the larynx interferes with the physiological mechanisms implicated in the control of the intensity of expiratory muscle activity during coughing. We have assessed cough threshold to fog inhalation in a group of laryngectomised patients and in an agematched control group.28 The intensity of cough efforts during MVC, reflex cough at threshold level (RCT), and reflex cough at suprathreshold stimulus intensity corresponding to 1.8 the threshold intensity (RCST), was indexed in terms of IEMGP, IEMGP/TEC, peak expiratory flow, and volume acceleration. Static expiratory muscle force was also measured.
Water Aerosols and Cough
Maximum expiratory pressure (Fig. 2B) and cough threshold (Fig. 3B) values were similar in patients and controls, as were IEMGP, IEMGP/TEC recorded during MVC and RCST. In contrast, during RCT, patients' IEMGP was significantly reduced, thus leading to a significant decrease in IEMGP/TEC even in the absence of significant differences in TEC (Fig. 4B). In all experimental conditions, cough volume acceleration was also significantly reduced in the patients, especially during RCT. The observation that cough threshold to fog inhalation is not significantly influenced by surgical ablation of the larynx is in keeping with previous finding,3,29 whilst IEMG data are consistent with the possibility that, in the absence of afferent information from the larynx, the mechanisms subserving motor unit recruitment and/or regulating their firing rate are impaired at cough threshold level. In this connection, it is worth recalling that signals conveyed by the superior laryngeal nerve affect the discharge of expiratory bulbospinal neurones and, hence, the activity of the abdominal motoneurones.26,27 Furthermore, repetitive expiratory flow interruptions performed in humans by voluntary glottal closure, and functionally similar to low-intensity cough efforts, consistently evoked bursts of activity in the expiratory muscles during the periods of no flow.30 This observation indicates that laryngeal motor acts are coupled with expiratory motor activation, possibly via a centrally programmed coordination programme and/or stretch reflexes arising from upper airway muscles.30 Disruption of these neural mechanisms following laryngeal ablation may result in a weakened cough response to low intensity (threshold) stimuli. On the other hand, this impairment may be overcome following more intense airway receptor stimulation such as that represented by ST fog concentrations.28 In all experimental conditions, patients' volume acceleration values proved to be lower than those of control subjects.28 This phenomenon is mainly accounted for by a lengthening in time to peak during MVC and RCST, while during RCT a reduction in cough peak flow also plays a significant role.28 The lengthening in time to peak suggests a reduction in flow velocity during voluntary and reflex coughing. In fact, laryngeal ablation may determine both an increase in airway cross sectional area and a reduction in expiratory muscle force caused by the lack of the compressive (isometric) phase of coughing. Both these factors may concur in decreasing flow velocity and, hence, volume acceleration. Since flow velocity is crucial for effective expectoration, laryngectomised patients need to participate in bronchial hygiene therapy programmes, particularly directed cough, to minimise the mechanical impact of laryngeal ablation, thus facilitating removal of airway secretions
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and preventing the occurrence or worsening of respiratory tract infections.31 VENTILATORY REFLEX RESPONSES TO FOG INHALATION: EFFECTS OF NEDOCROMIL SODIUM The vagally innervated airway receptors implicated in the mediation of cough include the rapidly adapting `irritant' receptors and the sensory endings of the pulmonary and bronchial C fibres.32 All these receptor types also appear to be involved, with different modalities, in the shaping of the breathing pattern, since animal studies have suggested that their stimulation by various agents, including nonisosmolar water solutions injected directly in the blood supply to the endings33 or directly applied into the airway lumen,34 cause reflex increases in ventilation. We aimed at ascertaining whether inhalation of a tussigenic fog concentration also influences the pattern of breathing in normal subjects. Furthermore, we attempted to evaluate if coughing and the possibly associated changes in the pattern of breathing are influenced by prior administration of nedocromil sodium (NCS), a drug capable of interfering with the transduction of sensory inputs from the lungs.35 We have therefore evaluated the effects of no drug, placebo, and NCS administration on the cough threshold and changes in the pattern of breathing during fog inhalation in a group of healthy subjects.36 Normal subjects were preferred to avoid the confounding effects on coughing and respiratory activity caused by inhalation of a potentially bronchoconstrictor agent in patients with respiratory diseases.37 Measurements of tidal volume (VT), duration of inspiratory and expiratory times (TI and TE, respectively), total duration of the respiratory cycle (TT), mean inspiratory flow (VT/TI), duty cycle (TI/TT), respiratory frequency (f, 60/TT), and minute ventilation (VI) were obtained by inductive plethysmography. As shown in Fig. 3C, median cough threshold values were unaffected by placebo, but were significantly increased (P < 0.01) by NCS administration. Individual mean values of baseline breathing pattern variables observed on each study day were similar and not significantly influenced by placebo and nedocromil sodium administration. In no-drug and placebo trials, inhalation of fog concentrations lower than cough threshold caused only slight and nonsignificant changes in the pattern of breathing, while inhalation of the threshold fog concentration consistently provoked a progressive rise in VT, VT/TI, and VI (Fig. 5) accompanying the appearance of cough. The increase in VT/TI and VI was mainly due to a rise in VT; no significant changes were
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ACKNOWLEDGEMENTS This study was supported by grants from the Ministero dell'Istruzione, UniversitaÁe Ricerca of Italy.
REFERENCES
Fig. 5 Average spirograms demonstrating changes in the pattern of breathing during inhalation of the threshold fog concentration prior to (solid lines) and following (dotted lines) nedocromil sodium (NCS) administration. Values are mean SD for tidal volume. *, P < 0.01 by unpaired t tests.
detected in the time component of the breathing pattern. Following NCS administration, fog-induced increases in VT, VT/TI, and VI were markedly attenuated (Fig. 5). Since it is well known that fog inhalation does not cause bronchoconstriction in normal subjects,37 these reflex changes in the pattern of breathing do not represent a response to an increase in mechanical load; more likely, they reflect fog-induced activation of airway receptors implicated both in the mediation of coughing and in the control of the breathing pattern. Fog-induced changes in the pattern of breathing observed in our subjects are probably due to stimulation of rapidly adapting receptors. In fact, the reflex ventilatory adjustments elicited by these receptors mainly consist of increases in tidal volume, possibly associated with a lengthening in TI,38 while activation of pulmonary and bronchial C fibre endings induces apnoea followed by rapid, shallow breathing.39 Due to its effect on cough threshold, NCS administration may be useful for treating cough, especially when the use of centrally acting antitussive drugs should be avoided.
CONCLUSIONS We believe that the assessment of cough threshold and evaluation of IEMG activity of expiratory muscles may provide valuable information on the sensory and motor mechanisms subserving cough in the clinical setting and therefore represent useful tools for cough researches. The simultaneous analysis of the respiratory adjustments evoked by fog inhalation may provide insights into the functional role of airway receptors.
1. Morice A H, Higgins K S, Yeo W W. Adaptation of cough reflex with different types of stimulation. Eur Respir J 1992; 5: 841±847. 2. Cox I D, Wallis P J W, Apps M C P, Hughes D T D, Empey D W, Osman R C A, Burke C A. An electromyographic method of objectively assessing cough intensity and use of the method to assess effects of codeine on the dose-response curve to citric acid. Br J Clin Pharmac 1984; 8: 377±382. 3. Stockwell M, Lang S, Yip R, Zintel T, White C, Gallagher C G. Lack of importance of the superior laryngeal nerves in citric acid cough in humans. J Appl Physiol 1993; 75: 613±617. 4. Pounsford J C, Birch M J, Saunders K B. Effects of bronchodilators on the cough response to inhaled citric acid in normal and asthmatic subjects. Thorax 1985; 40: 662±667. 5. Choudry N B, Fuller R W, Pride N B. Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin, and histamine. Am Rev Respir Dis 1989; 140: 137±141. 6. Fontana G A, Pantaleo T, Lavorini F, Maluccio N M, Mutolo D, Pistolesi M. Repeatability of cough-related variables during fog challenges at threshold and suprathreshold stimulus intensity in humans. Eur Respir J 1999; 13: 1447±1450. 7. Fontana G A, Pantaleo T, Lavorini F, Boddi V, Panuccio P. A noninvasive electromyographic study on threshold and cough intensity in humans. Eur Respir J 1997; 10: 983±989. 8. Knudson R J, Mead J, Knudson D E. Contribution of airway collapse to supramaximal expiratory flows. J Appl Physiol 1974; 36: 653±667. 9. Murty G E, Smith M C F, Lancaster P. Cough intensity in the laryngectomee. Clin Otolaryngol 1991; 16: 25±28. 10. Yanagihara N, von Leden H, Werner-Kukuk E. The physical parameters of cough: the larynx in a normal single cough. Acta Otolaryngol 1966; 61: 495±510. 11. Bigland B, Lippold O C J. The relation between force, velocity and integrated electrical activity in human muscles. J Physiol 1954; 123: 214±224. 12. Desmedt J E, Godaux E. Ballistic contractions in man: characteristic recruitment pattern of single motor units in the tibialis anterior muscle. J Physiol 1977; 264: 673±693. 13. Fontana G A, Pantaleo T, Lavorini F, Benvenuti F, Gangemi S. Defective motor control of coughing in Parkinson's disease. Am J Respir Crit Care Med 1998; 158: 458±464. 14. De Bruin P F C, De Bruin V M S, Lees A J, Pride N B. Effects of treatment on airway dynamics and respiratory muscle strength in Parkinson's disease. Am Rev Respir Dis 1993; 148: 1576±1580. 15. Hallet M. Physiology of basal ganglia disorders: an overview. Can J Neurol Sci 1993; 20: 177±183. 16. Hallett M, Khosbhin S. A physiological mechanism of bradykinesia. Brain 1980; 103: 301±314. 17. Baroni A, Benvenuti F, Fantini L, Pantaleo T, Urbani F. Human ballistic arm abduction movements: effects of L-Dopa treatment in Parkinson's disease. Neurology 1984; 34: 868±876. 18. Hoehn M, Yahr M D. Parkinsonism: onset, progression, and mortality. Neurology 1967; 17: 427±442. 19. Robbins J A, Logemann J A, Kirshner H S. Swallowing and speech production in Parkinson's disease. Ann Neurol 1986; 19: 283±287. 20. Hallett M. Clinical neurophysiology of akinesia. Rev Neurol (Paris) 1990; 146: 585±590. 21. Sant'Ambrogio G. Afferent pathways for the cough reflex. Clin Respir Physiol 1987; 23(Suppl 10): 19s±23s.
Water Aerosols and Cough 22. Mathew O P, Sant'Ambrogio F B. Laryngeal reflexes. In: Mathew O P, Sant'Ambrogio G eds. Respiratory function of the upper airway. New York: Marcel Dekker, 1988: 259±302. 23. Sant'Ambrogio G, Sant'Ambrogio F B. Role of larynx in cough. Pulm Pharmacol 1996; 9: 379±382. 24. American Association for Respiratory Care. AARC Clinical Practice Guidelines. Directed cough. Respir Care 1993; 38: 495±499. 25. Korpas J, Tomori Z. Progress in respiratory research. Cough and other respiratory reflexes. Basel: Karger 1979, vol. 12. 26. Bongianni F, Corda M, Fontana G, Pantaleo T. Influences of superior laryngeal afferent stimulation on expiratory activity in cats. J Appl Physiol 1988; 65: 385±392. 27. Jodkowski J S, Berger A J. Influences from laryngeal afferents on expiratory bulbospinal neurons and motoneurons. J Appl Physiol 1988; 64: 1337±1345. 28. Fontana G A, Pantaleo T, Lavorini F, Mutolo D, Polli G, Pistolesi M. Coughing in laryngectomized patients. Am J Respir Crit Care Med 1999; 160: 1578±1584. 29. Higenbottam T, Jackson T M, Woolman P, Lowry R, Wallwork J. The cough response to ultrasonically nebulized distilled water in heart-lung transplantation patients. Am Rev Respir Dis 1989; 140: 58±61. 30. Mead J, Reid M B. Respiratory muscle activity during repeated airflow interruption. J Appl Physiol 1988; 64: 2314±2317. 31. Gleeson M, Jani P. Long term care of patients who have had a laryngectomy. Br Med J 1994; 308: 1452±1453. 32. Widdicombe J G. Sensory neurophysiology of the cough reflex. J Allergy Clin Immunol 1996; 98: S84±S90. 33. Pisarri T E, Jonzon A, Coleridge H M, Coleridge J C G. Vagal afferents and reflex responses to changes in surface
34.
35.
36.
37.
38.
39.
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osmolarity in lower airways of dogs. J Appl Physiol 1992; 73: 2305±2313. Pisarri T E, Jonzon A, Coleridge H M, Coleridge J C J. Intravenous injection of hypertonic NaCl solution stimulates pulmonary C-fibres in dogs. Am J Physiol 1991; 260 (Heart Circ Physiol 29): H1522±H1530. Alton E W, Kingsleigh-Smith D J, Munkonge F M, Smith S N, Lindsay A R G, Gruenert D C, Jeffery P K, Norris A, Geddes D M, Williams A J. Asthma prophylaxis agents alter the function of an airway epithelial chloride channel. Am J Respir Cell Mol Biol 1996; 14: 380±387. Lavorini F, Fontana G A, Pantaleo T, Camiciottoli G, Castellani W, Maluccio N M, Pistolesi M. Fog-induced respiratory responses are attenuated by nedocromil sodium in humans. Am J Respir Crit Care Med 2001; 163: 117±1120. Sheppard D, Rizk N W, Bouishey H A, Bethel R A. Mechanism of cough and bronchoconstriction induced by distilled water aerosol. Am Rev Respir Dis 1983; l27: 691±694. Coleridge H M, Coleridge J C G. Reflexes evoked from tracheobronchial tree and lungs. In: Handbook of physiology. The respiratory system. Control of breathing. Am Physiol Soc, sect. 3, vol. II, part 1, chapt. 12, Bethesda, MD 1986: 395±429. Tatar M, Webber S E, Widdicombe J G. Lung C-fibre receptor activation and defensive reflexes in anaesthetized cats. J Physiol 1988; 402: 411±420.
Date received: 4 January 2002 Date accepted: 19 February 2002
1
PULMONARY PHARMACOLOGY
& THERAPEUTICS
Review Water Aerosols and Cough Giovanni A. Fontana, Federico Lavorini, Massimo Pistolesi UnitaÁ Funzionale di Medicina Respiratoria UniversitaÁ degli Studi di Firenze, Italia SUMMARY: Inhalation of ultrasonically nebulised distilled water (fog) induces cough; however, the receptor type(s) mediating this reflex are poorly defined. In humans, cough threshold can be determined by inhalation of progressively increasing fog concentrations; the intensity of the associated motor response can be indexed in terms of flow-related variables as well as of the peak and slope of the integrated electromyographic activity of the abdominal muscles. We have evaluated coughing in patients with Parkinson's disease who show a high incidence of serious chest infections. These patients turned out to have a normal cough threshold but reduced expiratory muscle force during reflex coughing; this suggests an impairment in the central mechanisms subserving muscle activation possibly leading to inefficient airway clearing. Recurrent chest infections also affect laryngectomised patients. These patients have a normal cough threshold but reduced muscle force during coughing in response to threshold stimuli. Voluntary coughing is preserved in these patients, and this should be used to facilitate mucus removal. In normal subjects, fog inhalation causes cough and increases in respiratory drive and minute ventilation, mainly accounted for by increases in tidal volume, possibly due to activation of airway rapidly adapting receptors. Nedocromil sodium administration increases cough threshold and attenuates the ventilatory responses. The assessment of sensory and motor components of coughing may represent a useful tool for those investigating cough in # 2002 Published by Elsevier Science Ltd. humans. KEY WORDS:
Cough threshold, Parkinson's disease, Laryngectomy, Electromyography, Nedocromil sodium.
ASSESSING THE SENSORY COMPONENT OF COUGH
INTRODUCTION Cough is a defence mechanism initiated by appropriate chemical and/or mechanical stimulation of sensory endings located in the larynx and the proximal respiratory tract. The aim of the reflex is removal of mucus and/or foreign bodies from the airways by the generation of high expiratory flow rates. The assessment of the sensory and motor components of coughing may be important to evaluate the mechanisms implicated in the genesis of cough responses, as well as to investigate the effects of antitussive agents.
In human cough studies, cough sensitivity is best assessed in terms of cough threshold. Although several nebulised agents may be used to assess cough sensitivity,1±5 inhalation of ultrasonically nebulised distilled water (fog) represents a potent cough stimulus, with the advantage of being particularly well accepted by both normal subjects and patients. In addition, the short- and long-term repeatability of cough threshold values determined by using this tussigenic agent has recently been demonstrated in humans.6 In the clinical setting, fog is produced by means of an ultrasonic nebuliser whose output can be adjusted by means of a potentiometer and monitored as a direct current (DC) signal on an oscilloscope.7 The nebuliser output can be progressively increased in steps corresponding to 5% of the maximum attainable DC signal. As shown in Fig. 1, the relation between
Author for correspondence: Giovanni A. Fontana, M. D., Dipartimento di Area Critica Medico Chirurgica, UnitaÁ Funzionale di Medicina Respiratoria, Viale G. B. Morgagni, 85, 50134 Firenze, Italia. Tel: 30-055-413183; Fax: 39-055-4223202; E-mail: [email protected] 1094±5539/02/$ ± see front matter
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#
2002 Published by Elsevier Science Ltd.
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peak flow to the time to peak.8±10 Cough peak flow, however, may be influenced not only by the intensity of the muscle effort produced during coughing, but also by the mechanical properties of the respiratory system, particularly airway resistance.
Electromyographic activity of the expiratory muscles
Fig. 1 Relationship of fog output (ml/min) vs. the nebuliser's operation frequency expressed as a direct current (DC). Each data point represents the mean (SD) of 5 separate measurements.
DC signal and the actual nebuliser output in ml/min fits with the linear model; mean nebuliser output (ml/min) can be calculated according to the equation reported in Fig. 1. To assess cough threshold, subjects are connected to the nebuliser via a mouthpiece and a two-way nonrebreathing shutter valve, and tidally inhale progressively increasing fog concentrations obtained by adjusting the nebuliser output.6,7 With this method, cough threshold is taken as the lowest fog output capable of evoking at least one cough during two distinct challenges separated by a time interval of approximately 30 min. This procedure ensures that the recorded cough response was actually evoked by fog inhalation and not a random event.6 A valuable aspect of cough threshold to fog inhalation as assessed with the method described above is its short- and long-term reproducibility.6 In normal subjects, re-assessment of cough threshold following a 3 h and a 6±9 month interval showed that cough threshold values were highly repeatable, suggesting that this variable represents a useful and reliable tool for quantification of subject's cough sensitivity.6
ASSESSING THE MOTOR COMPONENT COUGH Cough flow The airflow generated by a subject during voluntary and reflex cough efforts can easily be recorded by means of a large-size pneumotachograph. Several variables that may be relevant for assessing the intensity of a cough effort can easily be measured or calculated from a cough flow tracing. These include the cough peak flow, the time that elapses from the onset of flow to peak flow, i.e., the so-called time to peak, and volume acceleration, that is the ratio of cough
The intensity of voluntary and reflex cough efforts can conveniently be assessed by means of the integrated electromyographic activity of the abdominal muscles (IEMG). In the mid eighties, Cox et al2 were the first to use the IEMG of the abdominal muscle, namely the obliquus externus muscle, in the assessment of cough motor responses. These authors, however, proposed the use of the `true' integrated activity, that is the sum of the electrical activity generated during each muscle contraction, rather than the `moving average' of the activity, which provides the real time course of each electromyographic event. The `moving average' of the IEMG is proportional to the actual tension (force) developed by the contacting muscles during both isometric and isotonic conditions.11 From IEMG recordings obtained during coughing, it is possible to measure the peak amplitude of the IEMG activity (IEMGP), and the time duration of the expiratory ramp, i.e. the cough expiratory time (TEC). The ratio between these two variables (IEMGP/TEC) represents the rate of rise or `slope' of the IEMG activity. The IEMGP is an expression of the total number of recruited motor units and of their maximal frequency of discharge, while IEMGP/TEC reflects the rate of motor units recruitment as well as the rate of increase in firing frequency.12 As fully described elsewhere,13 to allow comparisons of IEMG-related variables obtained in different subjects or in different experimental conditions, IEMG amplitudes need to be normalised. In normal subjects, or in patients with normal central mechanisms of muscle activation, this can easily be achieved by expressing each recorded IEMGP as a fraction of the maximum recorded IEMG amplitude (absolute maximum). Absolute maximum IEMGP amplitudes are usually attained, in our experimental conditions, during maximum voluntary coughing (MVC). In patients with a central deficit of motor activation, the maximum recorded abdominal IEMG amplitude cannot be taken per se as the real absolute maximum, since it does not account for the actual loss in expiratory muscle force in these patients.14 The latter can reliably be expressed as the ratio of measuredto-predicted maximum expiratory pressure.13 Since the relationship between muscle force and IEMG activity is maintained also in patients with a central
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deficit of motor activation, it can be assumed that measured PEmax maximum recorded IEMGP AU predicted PEmax absolute maximum IEMGP AU Then, absolute maximum IEMGP maximum recorded IEMGP predicted PEmax measured PEmax This estimated absolute maximum IEMG amplitude can then be used to scale all other recorded IEMGP values. PATIENTS WITH PARKINSON'S DISEASE Parkinson's disease is a clinical syndrome dominated by a disorder of movement consisting of tremor, rigidity and slowness of movements (bradykinesia). One of the most prominent features contributing to bradykinesia is a failure to energise muscles up to the level necessary to perform fast or ballistic movements.15±17 Respiratory problems are a common feature of the disease and respiratory complications, particularly aspiration pneumonia, are the most common cause of death.18 Indirect lines of evidence14,19 seem to indicate that not only swallowing disturbances,19 but also a defective cough reflex, may contribute to predisposing patients with Parkinson's disease to chest infection. Thus, we have evaluated the sensory and motor components of reflex and voluntary coughing both in patients with Parkinson's disease with normal or nearnormal lung function tests and in age-matched control subjects. As shown in Fig. 2A, patients with Parkinson's disease displayed a significant reduction in expiratory muscle force.14 Noticeably, patients' cough threshold to fog inhalation turned out to be similar to that of
Fig. 2 Comparisons of mean maximum expiratory pressure (PEmax) values recorded in control subjects and in patients with Parkinson's disease (A) as well as in control subjects and laryngectomised patients (B). C, control subjects; P, patients. *, P < 0.01 by unpaired t-tests.
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control subjects (Fig. 3A), thus indicating that cough sensitivity is not affected by the disease. The motor characteristics of voluntary and reflex coughing in the two study groups, as assessed by using the IEMG activity of the abdominal muscles, are diagrammatically depicted in Fig. 4A. In normal subjects, corrected values of peak and slope of the IEMG activity observed during maximum voluntary cough efforts (MVC) slightly but significantly exceeded those attained during reflex cough (RC) evoked by a fog stimulus of threshold intensity. In the patients, TEC during MVC did not significantly differ from that recorded in control subjects during both MVC and RC. However, patients TEC values during RC were substantially increased when compared with those recorded during MVC, as well as with TEC values recorded in control subject during both MVC and RC. In addition, mean corrected peak IEMG values turned out to be significantly depressed in the patients, both during MVC and RC (Fig. 4A). In the patients, the reduction in IEMGP values during MVC and RC, along with the lengthening of TEC during RC, accounted for the marked reduction in the slope of IEMG activity during both MVC and RC (Fig. 4A). The reduction observed in IEMGP and IEMGP/ TEC during cough efforts, that also correlated with the degree of motor impairment,13 probably reflects bradykinesia, one of the most prominent functional disturbances in patients with Parkinson's disease. A contributing feature of bradykinesia is a failure to energise muscles up to a level necessary for the execution of rapid or ballistic movements.16,17,20 Since cough can conceivably be regarded as a fast or ballistic-like motor act, the same pathophysiological mechanism could account for impaired motor cough responses in
Fig. 3 Box and whiskers plots comparing cough threshold values observed in control subjects and in patients with Parkinson's disease (A), in control subjects and laryngectomised patients (B), and in normal subjects following placebo (PL) and nedocromil sodium (NCS) administration (C). Each box extends from the 25th to the 75th percentile and contains the median value; whiskers extend from the lowest to the highest recorded value. *, P < 0.01 by Mann±Whitney tests.
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Fig. 4 Diagrammatic representation of average IEMG patterns. In A, comparison between maximum voluntary cough (solid lines), and reflex cough at threshold level (dotted lines) in control subjects (upper panel) and Parkinson's disease patients (lower panel). In B, comparison between maximum voluntary cough (solid lines), reflex cough at threshold level (dotted lines) and suprathreshold (1.8 threshold, dashed lines) levels in control subjects (upper panel) and in laryngectomised patients (lower panel). Values are means SD for peak IEMG activity and duration of expiratory IEMG ramp activity (TEC). Horizontal bars represent standard deviations for mean duration of expiratory IEMG ramp activity; standard deviations for peak IEMG amplitudes are represented by vertical bars. For statistical significance see text.
Parkinson's disease. This motor deficit may account for the observed expiratory muscle weakness and suggests a reduction of expiratory flow during coughing, possibly leading to an impairment of airway clearing mechanisms. The latter may explain, along with the well known swallowing disturbances, the high incidence of potentially lethal pulmonary infections that characterise the late stages of Parkinson's disease.
LARYNGECTOMISED PATIENTS Respiratory tract infections are commonly observed also in laryngectomised patients. This may be due not only to the loss of the protective shield represented by the nose and the upper airway, but also to an impairment in cough sensory and motor components following laryngeal ablation. Indeed, tussigenic stimuli have been shown to activate the `irritant' receptors located in the laryngeal mucosa as well as the `irritant' receptors of the tracheobronchial tree. Both these receptors are believed to be mainly responsible for reflex cough responses,21±23 even if recent lines of evidence seem to indicate that signals arising from
the larynx are not crucial for triggering cough.3 Although evidence exists22 that tracheostomised and intubated patients still `cough', suggesting that airway clearing may still be possible even in the absence of glottis closure, laryngectomy may limit cough effectiveness and represents an indication for bronchial hygiene therapy, particularly directed towards cough.24 Whether ablation of the larynx has an impact on respiratory muscle activity during voluntary and reflex expiratory thrusts remains unclear; however, it has been reported that signals of laryngeal origin may have a role in regulating the strength of the inspiratory and expiratory efforts during coughing,25±27 suggesting that ablation of the larynx interferes with the physiological mechanisms implicated in the control of the intensity of expiratory muscle activity during coughing. We have assessed cough threshold to fog inhalation in a group of laryngectomised patients and in an agematched control group.28 The intensity of cough efforts during MVC, reflex cough at threshold level (RCT), and reflex cough at suprathreshold stimulus intensity corresponding to 1.8 the threshold intensity (RCST), was indexed in terms of IEMGP, IEMGP/TEC, peak expiratory flow, and volume acceleration. Static expiratory muscle force was also measured.
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Maximum expiratory pressure (Fig. 2B) and cough threshold (Fig. 3B) values were similar in patients and controls, as were IEMGP, IEMGP/TEC recorded during MVC and RCST. In contrast, during RCT, patients' IEMGP was significantly reduced, thus leading to a significant decrease in IEMGP/TEC even in the absence of significant differences in TEC (Fig. 4B). In all experimental conditions, cough volume acceleration was also significantly reduced in the patients, especially during RCT. The observation that cough threshold to fog inhalation is not significantly influenced by surgical ablation of the larynx is in keeping with previous finding,3,29 whilst IEMG data are consistent with the possibility that, in the absence of afferent information from the larynx, the mechanisms subserving motor unit recruitment and/or regulating their firing rate are impaired at cough threshold level. In this connection, it is worth recalling that signals conveyed by the superior laryngeal nerve affect the discharge of expiratory bulbospinal neurones and, hence, the activity of the abdominal motoneurones.26,27 Furthermore, repetitive expiratory flow interruptions performed in humans by voluntary glottal closure, and functionally similar to low-intensity cough efforts, consistently evoked bursts of activity in the expiratory muscles during the periods of no flow.30 This observation indicates that laryngeal motor acts are coupled with expiratory motor activation, possibly via a centrally programmed coordination programme and/or stretch reflexes arising from upper airway muscles.30 Disruption of these neural mechanisms following laryngeal ablation may result in a weakened cough response to low intensity (threshold) stimuli. On the other hand, this impairment may be overcome following more intense airway receptor stimulation such as that represented by ST fog concentrations.28 In all experimental conditions, patients' volume acceleration values proved to be lower than those of control subjects.28 This phenomenon is mainly accounted for by a lengthening in time to peak during MVC and RCST, while during RCT a reduction in cough peak flow also plays a significant role.28 The lengthening in time to peak suggests a reduction in flow velocity during voluntary and reflex coughing. In fact, laryngeal ablation may determine both an increase in airway cross sectional area and a reduction in expiratory muscle force caused by the lack of the compressive (isometric) phase of coughing. Both these factors may concur in decreasing flow velocity and, hence, volume acceleration. Since flow velocity is crucial for effective expectoration, laryngectomised patients need to participate in bronchial hygiene therapy programmes, particularly directed cough, to minimise the mechanical impact of laryngeal ablation, thus facilitating removal of airway secretions
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and preventing the occurrence or worsening of respiratory tract infections.31 VENTILATORY REFLEX RESPONSES TO FOG INHALATION: EFFECTS OF NEDOCROMIL SODIUM The vagally innervated airway receptors implicated in the mediation of cough include the rapidly adapting `irritant' receptors and the sensory endings of the pulmonary and bronchial C fibres.32 All these receptor types also appear to be involved, with different modalities, in the shaping of the breathing pattern, since animal studies have suggested that their stimulation by various agents, including nonisosmolar water solutions injected directly in the blood supply to the endings33 or directly applied into the airway lumen,34 cause reflex increases in ventilation. We aimed at ascertaining whether inhalation of a tussigenic fog concentration also influences the pattern of breathing in normal subjects. Furthermore, we attempted to evaluate if coughing and the possibly associated changes in the pattern of breathing are influenced by prior administration of nedocromil sodium (NCS), a drug capable of interfering with the transduction of sensory inputs from the lungs.35 We have therefore evaluated the effects of no drug, placebo, and NCS administration on the cough threshold and changes in the pattern of breathing during fog inhalation in a group of healthy subjects.36 Normal subjects were preferred to avoid the confounding effects on coughing and respiratory activity caused by inhalation of a potentially bronchoconstrictor agent in patients with respiratory diseases.37 Measurements of tidal volume (VT), duration of inspiratory and expiratory times (TI and TE, respectively), total duration of the respiratory cycle (TT), mean inspiratory flow (VT/TI), duty cycle (TI/TT), respiratory frequency (f, 60/TT), and minute ventilation (VI) were obtained by inductive plethysmography. As shown in Fig. 3C, median cough threshold values were unaffected by placebo, but were significantly increased (P < 0.01) by NCS administration. Individual mean values of baseline breathing pattern variables observed on each study day were similar and not significantly influenced by placebo and nedocromil sodium administration. In no-drug and placebo trials, inhalation of fog concentrations lower than cough threshold caused only slight and nonsignificant changes in the pattern of breathing, while inhalation of the threshold fog concentration consistently provoked a progressive rise in VT, VT/TI, and VI (Fig. 5) accompanying the appearance of cough. The increase in VT/TI and VI was mainly due to a rise in VT; no significant changes were
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ACKNOWLEDGEMENTS This study was supported by grants from the Ministero dell'Istruzione, UniversitaÁe Ricerca of Italy.
REFERENCES
Fig. 5 Average spirograms demonstrating changes in the pattern of breathing during inhalation of the threshold fog concentration prior to (solid lines) and following (dotted lines) nedocromil sodium (NCS) administration. Values are mean SD for tidal volume. *, P < 0.01 by unpaired t tests.
detected in the time component of the breathing pattern. Following NCS administration, fog-induced increases in VT, VT/TI, and VI were markedly attenuated (Fig. 5). Since it is well known that fog inhalation does not cause bronchoconstriction in normal subjects,37 these reflex changes in the pattern of breathing do not represent a response to an increase in mechanical load; more likely, they reflect fog-induced activation of airway receptors implicated both in the mediation of coughing and in the control of the breathing pattern. Fog-induced changes in the pattern of breathing observed in our subjects are probably due to stimulation of rapidly adapting receptors. In fact, the reflex ventilatory adjustments elicited by these receptors mainly consist of increases in tidal volume, possibly associated with a lengthening in TI,38 while activation of pulmonary and bronchial C fibre endings induces apnoea followed by rapid, shallow breathing.39 Due to its effect on cough threshold, NCS administration may be useful for treating cough, especially when the use of centrally acting antitussive drugs should be avoided.
CONCLUSIONS We believe that the assessment of cough threshold and evaluation of IEMG activity of expiratory muscles may provide valuable information on the sensory and motor mechanisms subserving cough in the clinical setting and therefore represent useful tools for cough researches. The simultaneous analysis of the respiratory adjustments evoked by fog inhalation may provide insights into the functional role of airway receptors.
1. Morice A H, Higgins K S, Yeo W W. Adaptation of cough reflex with different types of stimulation. Eur Respir J 1992; 5: 841±847. 2. Cox I D, Wallis P J W, Apps M C P, Hughes D T D, Empey D W, Osman R C A, Burke C A. An electromyographic method of objectively assessing cough intensity and use of the method to assess effects of codeine on the dose-response curve to citric acid. Br J Clin Pharmac 1984; 8: 377±382. 3. Stockwell M, Lang S, Yip R, Zintel T, White C, Gallagher C G. Lack of importance of the superior laryngeal nerves in citric acid cough in humans. J Appl Physiol 1993; 75: 613±617. 4. Pounsford J C, Birch M J, Saunders K B. Effects of bronchodilators on the cough response to inhaled citric acid in normal and asthmatic subjects. Thorax 1985; 40: 662±667. 5. Choudry N B, Fuller R W, Pride N B. Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin, and histamine. Am Rev Respir Dis 1989; 140: 137±141. 6. Fontana G A, Pantaleo T, Lavorini F, Maluccio N M, Mutolo D, Pistolesi M. Repeatability of cough-related variables during fog challenges at threshold and suprathreshold stimulus intensity in humans. Eur Respir J 1999; 13: 1447±1450. 7. Fontana G A, Pantaleo T, Lavorini F, Boddi V, Panuccio P. A noninvasive electromyographic study on threshold and cough intensity in humans. Eur Respir J 1997; 10: 983±989. 8. Knudson R J, Mead J, Knudson D E. Contribution of airway collapse to supramaximal expiratory flows. J Appl Physiol 1974; 36: 653±667. 9. Murty G E, Smith M C F, Lancaster P. Cough intensity in the laryngectomee. Clin Otolaryngol 1991; 16: 25±28. 10. Yanagihara N, von Leden H, Werner-Kukuk E. The physical parameters of cough: the larynx in a normal single cough. Acta Otolaryngol 1966; 61: 495±510. 11. Bigland B, Lippold O C J. The relation between force, velocity and integrated electrical activity in human muscles. J Physiol 1954; 123: 214±224. 12. Desmedt J E, Godaux E. Ballistic contractions in man: characteristic recruitment pattern of single motor units in the tibialis anterior muscle. J Physiol 1977; 264: 673±693. 13. Fontana G A, Pantaleo T, Lavorini F, Benvenuti F, Gangemi S. Defective motor control of coughing in Parkinson's disease. Am J Respir Crit Care Med 1998; 158: 458±464. 14. De Bruin P F C, De Bruin V M S, Lees A J, Pride N B. Effects of treatment on airway dynamics and respiratory muscle strength in Parkinson's disease. Am Rev Respir Dis 1993; 148: 1576±1580. 15. Hallet M. Physiology of basal ganglia disorders: an overview. Can J Neurol Sci 1993; 20: 177±183. 16. Hallett M, Khosbhin S. A physiological mechanism of bradykinesia. Brain 1980; 103: 301±314. 17. Baroni A, Benvenuti F, Fantini L, Pantaleo T, Urbani F. Human ballistic arm abduction movements: effects of L-Dopa treatment in Parkinson's disease. Neurology 1984; 34: 868±876. 18. Hoehn M, Yahr M D. Parkinsonism: onset, progression, and mortality. Neurology 1967; 17: 427±442. 19. Robbins J A, Logemann J A, Kirshner H S. Swallowing and speech production in Parkinson's disease. Ann Neurol 1986; 19: 283±287. 20. Hallett M. Clinical neurophysiology of akinesia. Rev Neurol (Paris) 1990; 146: 585±590. 21. Sant'Ambrogio G. Afferent pathways for the cough reflex. Clin Respir Physiol 1987; 23(Suppl 10): 19s±23s.
Water Aerosols and Cough 22. Mathew O P, Sant'Ambrogio F B. Laryngeal reflexes. In: Mathew O P, Sant'Ambrogio G eds. Respiratory function of the upper airway. New York: Marcel Dekker, 1988: 259±302. 23. Sant'Ambrogio G, Sant'Ambrogio F B. Role of larynx in cough. Pulm Pharmacol 1996; 9: 379±382. 24. American Association for Respiratory Care. AARC Clinical Practice Guidelines. Directed cough. Respir Care 1993; 38: 495±499. 25. Korpas J, Tomori Z. Progress in respiratory research. Cough and other respiratory reflexes. Basel: Karger 1979, vol. 12. 26. Bongianni F, Corda M, Fontana G, Pantaleo T. Influences of superior laryngeal afferent stimulation on expiratory activity in cats. J Appl Physiol 1988; 65: 385±392. 27. Jodkowski J S, Berger A J. Influences from laryngeal afferents on expiratory bulbospinal neurons and motoneurons. J Appl Physiol 1988; 64: 1337±1345. 28. Fontana G A, Pantaleo T, Lavorini F, Mutolo D, Polli G, Pistolesi M. Coughing in laryngectomized patients. Am J Respir Crit Care Med 1999; 160: 1578±1584. 29. Higenbottam T, Jackson T M, Woolman P, Lowry R, Wallwork J. The cough response to ultrasonically nebulized distilled water in heart-lung transplantation patients. Am Rev Respir Dis 1989; 140: 58±61. 30. Mead J, Reid M B. Respiratory muscle activity during repeated airflow interruption. J Appl Physiol 1988; 64: 2314±2317. 31. Gleeson M, Jani P. Long term care of patients who have had a laryngectomy. Br Med J 1994; 308: 1452±1453. 32. Widdicombe J G. Sensory neurophysiology of the cough reflex. J Allergy Clin Immunol 1996; 98: S84±S90. 33. Pisarri T E, Jonzon A, Coleridge H M, Coleridge J C G. Vagal afferents and reflex responses to changes in surface
34.
35.
36.
37.
38.
39.
211
osmolarity in lower airways of dogs. J Appl Physiol 1992; 73: 2305±2313. Pisarri T E, Jonzon A, Coleridge H M, Coleridge J C J. Intravenous injection of hypertonic NaCl solution stimulates pulmonary C-fibres in dogs. Am J Physiol 1991; 260 (Heart Circ Physiol 29): H1522±H1530. Alton E W, Kingsleigh-Smith D J, Munkonge F M, Smith S N, Lindsay A R G, Gruenert D C, Jeffery P K, Norris A, Geddes D M, Williams A J. Asthma prophylaxis agents alter the function of an airway epithelial chloride channel. Am J Respir Cell Mol Biol 1996; 14: 380±387. Lavorini F, Fontana G A, Pantaleo T, Camiciottoli G, Castellani W, Maluccio N M, Pistolesi M. Fog-induced respiratory responses are attenuated by nedocromil sodium in humans. Am J Respir Crit Care Med 2001; 163: 117±1120. Sheppard D, Rizk N W, Bouishey H A, Bethel R A. Mechanism of cough and bronchoconstriction induced by distilled water aerosol. Am Rev Respir Dis 1983; l27: 691±694. Coleridge H M, Coleridge J C G. Reflexes evoked from tracheobronchial tree and lungs. In: Handbook of physiology. The respiratory system. Control of breathing. Am Physiol Soc, sect. 3, vol. II, part 1, chapt. 12, Bethesda, MD 1986: 395±429. Tatar M, Webber S E, Widdicombe J G. Lung C-fibre receptor activation and defensive reflexes in anaesthetized cats. J Physiol 1988; 402: 411±420.
Date received: 4 January 2002 Date accepted: 19 February 2002