Frequency dependence of capnography in anesthetized rabbits.

Aspirative capnography may be of help to diagnose early childhood asthma, but clinical usefulness in young children is limited by the relatively high respiratory rate. This study aimed to characterize the [Formula: see text] time course during airway constriction in 8 anesthetized rabbits, artificially ventilated at 30, 60 and 80breaths/min. Methacholine was inhaled to double the respiratory resistance measured at 8Hz by the forced oscillation technique. The capnogram shape changed in response to both methacholine and ventilatory frequency. Slope of phase II, the peak of first-order time derivative and trough of the second-order time derivative of the [Formula: see text] signal, were significantly attenuated after methacholine compared with baseline at all breathing rates (p<0.02). Moreover, significant correlations between respiratory reactance and resistance were observed with the phase III slope and the angle described by phase II and phase III (p<0.01). It is concluded that capnography may be useful to identify acute airway changes related to bronchoconstriction, even at high breathing frequencies.

Stimulus response latency of cough and expiration reflex depends on breathing in the rabbit.

Expiration reflex and cough may have distinct afferent pathways and/or central integrative mechanisms that may both result in different stimulus response latencies. A newly described method that uses a punctuate mechanical tracheal stimulus to provoke defensive ventilatory reflexes should allow the stimulus response latency to be calculated with reasonable accuracy. The aim of the study was to test whether cough and expiration reflex have different stimulus response latencies. Four hundred and sixty one mechanical tracheal stimulations (50-300 msec) were performed in 21 anesthetized, tracheotomized rabbits. Twenty three percent stimulations (108) provoked a cough reflex and 37% an expiration reflex (171). The individual mean stimulus response latency was computed for each reflex, calculated from stimulus onset to earliest detectable change in ventilatory flow. Cough reflex latency was significantly shorter in inspiration compared to expiration (257±19 msec vs 391±61 msec; p=0.01). In contrast, the expiration reflex latency was significantly shorter in expiration compared to inspiration (210±11 msec vs 329±29 msec, p=0.003). It is concluded that the within breath dependence of the difference in stimulus response latency between cough and expiration reflex is more likely to express different brainstem mechanisms but difference in afferent fibres may not be excluded.

Cough threshold and reactivity to mechanical stimulation of the trachea in the rabbit preliminary observations.

OBJECTIVES: The aim of the study was to characterise mechanically induced cough threshold and reactivity by exposing the trachea to stimuli of variable duration in rabbit. BACKGROUND: Long lasting mechanical stimulation is widely used in experimental protocols studying cough reflex. The cough threshold and reactivity to chemical agents is known to change due to e.g. airway inflammation but similar evidence for mechanical stimulation has not been reported. METHODS: The tracheal provocation was realized in two anesthetized tracheotomized rabbits with a rotating probe actuated by a small electrical motor with mechanical stimulus times (ST) lasting 50, 150, 300 and 600 ms. Cough reflex was evaluated from tidal volume and airflow signals. RESULTS: The incidence of cough reflex (single or multiple) increased from 8% (ST 50 ms) to 84% (ST 600 ms). With the lengthening of stimulus, the rate of multiple responses increases. CONCLUSION: The technique developed here may prove useful to standardize the protocols of mechanical cough in the experimental animal using an approach similar to chemical tussigenic agents. The cough threshold could be defined as minimal ST (STmin) capable to elicit 1 cough and cough reactivity obtained by interpolation as ST that provokes 50 % of cough responses (STso) (Tab. 1, Fig. 3, Ref. 27).

Convergence of nasal and tracheal neural pathways in modulating the cough response in guinea pigs.

In the present study we investigated the possibility of central convergence of neural pathways coming from distant anatomical regions in modulating the cough response. We addressed this issue by inducing cough from the tracheo-bronchial region on the background of capsaicin-stimulated and mesocain-blocked nasal mucosa in 14 anesthetized guinea pigs. The control group consisted of 6 guinea pigs in which the active agents, capsaicin and mesocain, were substituted for by inert physiological saline. All animals were tracheostomized, and the larynx was disconnected from the proximal part of the trachea with preserved innervations, and all were subjected to the same protocol. Cough, induced by mechanical irritation of the tracheo-bronchial mucosa, was elicited three times: in the control condition, after intranasal capsaicin challenge, and after another capsaicin challenge preceded by intranasal instillation of a local anesthetic, mesocain. The main finding of the study was that the number of cough efforts per bout, assessed from positive deflections on the intrapleural pressure recordings, was significantly enhanced by intranasal capsaicin challenge and this effect was reversed by intranasal pretreatment with the anesthetic mesocain [2.1 +/-0.2 (control) vs. 3.5 +/-0.4 (capsaicin) vs. 2.2 +/-0.2 (capsaicin after mesocain) (P<0.01)], with no appreciable changes in the magnitude of cough efforts. The cough response in the control group remained unchanged. We conclude that tracheo-bronchial cough may be modified by neural sensory input to the brain coming from nasal mucosa. Therefore, cough reflex is subject to central convergence of peripheral neural pathways originating at distant anatomical locations.

Role of gender and pubertal stage on cough sensitivity in childhood and adolescence.

Studies in healthy adult volunteers and patients with chronic cough have shown that women have increased cough sensitivity to inhaled tussigenic stimuli, including capsaicin. The explanation for this phenomenon remains unknown, although the influence of pubertal changes (dimensional, hormonal) may play a role. In the present study we set out to examine the effect of the pubertal status on cough reflex sensitivity in a population of male and female children and adolescents. The study consisted of cough reflex sensitivity (CRS) testing, spirometry, and a children-completed pubertal status questionnaire. The inclusion criteria were no current symptoms of respiratory disease, no respiratory infection in the preceding 2 weeks, no allergic disease, and no other disease that could modulate CRS. All children were non-smokers. For assessing the CRS we used a compressed air-driven nebuliser controlled by a dosimeter with an inspiratory flow regulator valve. Each subject inhaled up to 12 capsaicin aerosol concentrations (0.61-1250 micromol/l) during 400 ms at 1 min intervals. CRS was defined as the lowest capsaicin concentration that evoked minimally 2 coughs. 225 children (median age 13 yr, 103 girls/122 boys) were divided according to the pubertal status (prepubertal, early pubertal, and late pubertal) and gender. We found that CRS [geometric mean (95%CI)] was similar in prepubertal and early pubertal girls and boys. However, CRS was significantly higher in late pubertal girls (n=56) than in boys (n=26) [53.57 (35.62-80.64) micromol/l vs. 119.7 (70.74-208.55) micromol/l; respectively; P=0.017]. We conclude that puberty and gender have a significant influence on the cough threshold to capsaicin. It seems, however, hard to determine what factors are responsible for the observed gender differences in cough reactivity adolescents.

Acidification of the oesophagus acutely increases the cough sensitivity in patients with gastro-oesophageal reflux and chronic cough.

Gastro-oesophageal reflux disease (GORD) is one of the most common causes of chronic cough; however, the mechanisms by which GOR initiates coughing are incompletely understood. We address the hypothesis that acidification of oesophagus acutely increases the cough reflex sensitivity in patients with GORD and chronic cough. Nine patients with GORD with chronic cough and 16 patients with GORD without cough were recruited. In a randomized double blind study, saline and acid (HCl, 0.1 mol L(-1)) were separately infused into oesophagus via naso-oesophageal catheter. Cough reflex sensitivity to inhaled capsaicin was determined immediately after completion of each infusion. Infusion of acid into oesophagus increased capsaicin cough reflex sensitivity in patients with GORD and chronic cough. In contrast, acid had no effect on the cough sensitivity in patients with GORD without cough. In a separate study, acid infusion into oesophagus did not affect the cough sensitivity in 18 healthy subjects. We conclude that acid in the oesophagus acutely increases the cough reflex sensitivity to capsaicin in patients with GORD and chronic cough. This phenomenon may contribute to the pathogenesis of cough due to GORD.

Cough reflex sensitivity in children with suspected and confirmed gastroesophageal reflux disease.

Experimental and clinical studies performed in adults revealed that gastresophageal reflux disease (GORD) is associated with an appreciable increase in cough reflex sensitivity (CRS). The association between respiratory diseases and GORD is also present in children, but there is little evidence that GORD without aspiration of refluxate (proximal reflux) is a frequent cause of cough in children. The aim of this study was to find out whether CRS in children with GORD will be changed compared with healthy children, and if so, to determine the role of proximal vs. distal reflux in these changes. CRS and 24-h esophageal pH monitoring were performed in 20 children of whom 13 had confirmed GORD and 7 were suspected to have GORD. The control group consisted of 27 healthy children. For assessing the CRS, each subject inhaled 12 capsaicin aerosol concentrations (0.61-1250 micromol/l) at 1 min intervals. CRS was defined as the lowest capsaicin concentration that evoked minimally 2 coughs (C2). CRS in the group of children with suspected GORD [C2: 17.0 micromol/l (6.4-45.6 micromol/l)] and with confirmed GORD [C2: 13.4 micromol/l (3.6-50.9 micromol/l)] were significantly elevated (P<0.05) compared with healthy children [C2: 72.1 micromol/l (25.5-203.9 micromol/l)]. According to the parameters of 24-h pH monitoring, a significantly higher exposure to acid was present in the distal compared with proximal oesophagus. CRS changes correlated negatively with the distal, but not proximal, esophageal acid exposure. In conclusion, CRS changes in children suffering from GORD are similar to those described in adult patients with GORD. It is plausible that the main role in increased CRS in children with GORD play episodes of distal acid refluxes.

The influence of autonomic neuropathy on cough reflex sensitivity in children with diabetes mellitus type 1.

Diabetic autonomic neuropathy (DAN) is manifested by dysfunction of one or more organ systems. Its subclinical form (sDAN) can be recognized with the use of noninvasive cardiovascular reflex tests. As the cough reflex is mediated via autonomic nervous system, there is a reason to suppose that it can also be changed due to presence of sDAN. The aim of the present study was to assess cough reflex sensitivity (CRS) in diabetic children with and without sDAN. A CRS test was performed in 35 children suffering from diabetes mellitus type 1 and the results were compared with those from age-matched 27 healthy children. Cough was induced by inhalation of capsaicin aerosol in doubling concentrations (0.61-1250 micromol/l) for 400 ms each. CRS was defined as the lowest capsaicin concentration that evoked 2 or more coughs (C2 parameter) and 5 or more coughs (C5 parameter). We found that CRS in the whole group of diabetic children was not significantly different from that in healthy children [diabetic children--C2: 75.1 micromol/l (95% CI: 42.0-134.2 micromol/l)] vs. healthy children--C2: 72.4 micromol/l (95% CI: 75.7-644.8 micromol/l)]. However, a significant decrease (P=0.005) in CRS was found in diabetic children with sDAN [n=12; C2: 221.0 micromol/l (95% CI: 75.7-644.8 micromol/l)] compared with diabetic children without sDAN [(n=23; C2: 42.7 micromol/l (95% CI: 23.1-79.0 micromol/l)]. We conclude that testing cough reflex sensitivity might be a way to establish the presence of diabetic neuropathy.

Testing of cough reflex sensitivity in children suffering from allergic rhinitis and common cold.

Cough associated with upper respiratory tract disorders is a common and troublesome problem in children and little is known about the etiology of this type of cough. This study examined the capsaicin cough sensitivity (CS) in children suffering from allergic rhinitis (AR) and upper respiratory tract infection (URI), comparing it with that in healthy children taken as controls (C). CS to capsaicin, spirometry, skin prick tests, and nose-throat examination were performed in 61 children grouped by the diagnosis of AR, URI, and C. The results, in order of C vs. AR vs. URI, expressed as a geometric mean (+/-95% CI) log(10) muM of capsaicin for C2 (the lowest concentration of capsaicin in mumol/l required to induce >or=2 coughs) were: 1.8 (1.6-1.9) vs. 1.0 (0.8-1.2) vs. 0.48 (0.2-0.8), P<0.001 and for C5 (the lowest concentration of capsaicin in mumol/l required to induce >or=5 coughs) 2.9 (2.8-2.9) vs. 2.6 (2.5-2.6) vs. 2.1 (2.0-2.3), P<0.05. We found that CS in children with AR, even when tested out of pollen season, was significantly heightened compared with controls. CS in children with URI was extremely high compared with both C and AR groups. We conclude that pathological processes in the nose of any etiology could cause a sensitization of the cough reflex with decreased cough threshold during asymptomatic period of AR. Cough also is enhanced by acute inflammation in the upper airways in nonatopic children.

Reliability of the capsaicin cough reflex sensitivity test in healthy children.

Testing cough reflex sensitivity (CRS) in children requires suitable methodology. A CRS test performed under control of inspiratory flow rate (IFR) shows excellent reliability in children, but it is difficult to perform, especially in younger children. The aim of the present study was to find whether the capsaicin CRS test performed without direct control of constant IFR in healthy children is reliable enough for practical use. The CRS test was performed in 27 healthy children, aged 7-17 yr three times within 8 days. Cough was induced by inhalation of capsaicin aerosol in doubling concentrations (0.61-1250 micromol/l) for 400 ms each. CRS was defined as the lowest capsaicin concentration that evoked 2 or more coughs (C2). Although the intraclass correlation coefficient values showed good to excellent reliability of this test, the within-subject standard deviation values revealed lower reliability of this method compared to the CRS test performed under control of IFR. From the results obtained it is reasonable to conclude that the method using uncontrolled IFR in CRS testing provides acceptable precision only when a bigger sample size is used or more tests are performed. Good to excellent reliability of this method was found in children with higher values of C2 and in those aged 13-17 yr.

The effect of chemical stimulation of esophageal mucosa on citric acid induced cough and specific airway resistance in guinea pig.

BACKGROUND: Gastroesophageal reflux disease is one of the most common causes of chronic cough. The mechanism of the cough initiation in these patients remains unresolved. OBJECTIVES: This study was designed to investigate the effect of intraesophageal (IE) administration of capsaicin on cough and specific airway resistance (Saw) in guinea pigs. METHODS: Male TRIK strain guinea pigs were used. In the first experiment 12 controls received IE saline, 9 animals (group 1) received IE capsaicin (400 microM, 0.2 ml) and 12 guinea pigs (group 2) received IE capsaicin (400 microM, 0.2 ml) 24 hours after IE administration of hydrochloric acid (3 M, 0.2 ml). Cough induced by inhalation of citric acid (CA) and Saw was determined after IE administration of saline in controls and capsaicin in groups 1 a 2. In the second experiment, CA induced cough was determined in guinea pigs (n=13) in the beginning of the study (control response), after NaOH (1 M, 0.2 ml) was administered IE. One week later in conditions of corrosive esophagitis CA induced cough was determined after IE administration of capsaicin (cough during esophageal stimulation). RESULTS: There was no difference in CA induced cough between controls, group 1 and 2 (p=0.98). Saw was hot affected by IE capsaicin stimulation and CA inhalation in group 1 and group 2. There was no difference found between control cough response and those induced after IE capsaicin in animals with corrosive esophagitis (p=0.75). CONCLUSION: Esophageal stimulation with capsaicin did not trigger and/or modulate CA induced cough and Saw in guinea pigs models. (Fig. 5, Ref. 22.)

Modulation of experimentally-induced cough by stimulation of nasal mucosa in cats and guinea pigs.

Stimulation of afferent nerves in upper airways may contribute to the pathogenesis of chronic cough in chronic disorders of nose and/or sinuses. We tested the hypothesis that stimulation of the nasal afferent nerves enhances experimentally-induced cough. Intranasal administration of capsaicin (50 microM, 25 microl) did not evoke cough in anaesthetized cats, but enhanced cough induced by mechanical stimulation of the tracheobronchial mucosa (number of coughs, median [IQR]) (6.5 [5.5-8.5] versus 10 [7-14]; P = 0.028, n = 13). In contrast, intranasal histamine (16 mM, 25 microl) had no effect. Intranasal capsaicin (50 microM, 15 microl) did not evoke cough, but enhanced cough evoked by mechanical stimulation of the tracheobronchial mucosa (1 [1-3] versus 3 [2-4]; P = 0.0037, n = 15) in anaesthetized guinea pigs and cough induced by inhalation of citric acid (0.3M, 2 min) in awake guinea pigs (3 [2-5] versus 5 [3-7], P ? 0.0026, n = 23). We conclude that stimulation of nasal afferent nerves with capsaicin enhances experimentally-induced cough. Our results suggest that afferent inputs from the nose interact with the cough reflex pathways in a manner that enhances cough.