Expiration Reflex Research Articles

Ventrolateral medullary respiratory network participation in the expiration reflex in the cat.

The expiration reflex is a distinct airway defensive response characterized by a brief, intense expiratory effort and coordinated adduction and abduction of the laryngeal folds. This study addressed the hypothesis that the ventrolateral medullary respiratory network participates in the reflex. Extracellular neuron activity was recorded with microelectrode arrays in decerebrated, neuromuscular-blocked, ventilated cats. In 32 recordings (17 cats), 232 neurons were monitored in the rostral (including Bötzinger and pre-Bötzinger complexes) and caudal ventral respiratory group. Neurons were classified by firing pattern, evaluated for spinal projections, functional associations with recurrent laryngeal and lumbar nerves, and firing rate changes during brief, large increases in lumbar motor nerve discharge (fictive expiration reflex, FER) elicited during mechanical stimulation of the vocal folds. Two hundred eight neurons were respiratory modulated, and 24 were nonrespiratory; 104 of the respiratory and 6 of the nonrespiratory-modulated neurons had altered peak firing rates during the FER. Increased firing rates of bulbospinal neurons and expiratory laryngeal premotor and motoneurons during the expiratory burst of FER were accompanied by changes in the firing patterns of putative propriobulbar neurons proposed to participate in the eupneic respiratory network. The results support the hypothesis that elements of the rostral and caudal ventral respiratory groups participate in generating and shaping the motor output of the FER. A model is proposed for the participation of the respiratory network in the expiration reflex.

Afferent modulation of neonatal rat respiratory rhythm in vitro: cellular and synaptic mechanisms.

In mammals, expiration is lengthened by mid-expiratory lung inflation (Breuer-Hering Expiratory reflex; BHE). The central pathway mediating the BHE is paucisynaptic, converging on neurones in the rostral ventrolateral medulla. An in vitro neonatal rat brainstem-lung preparation in which mid-expiratory inflation lengthens expiration was used to study afferent modulation of respiratory neurone activity. Recordings were made from respiratory neurones in or near the pre-Bötzinger Complex (preBötC). Respiratory neurone membrane properties and BHE-induced changes in activity were characterized. Our findings suggest the following mechanisms for the BHE: (i) lung afferent signals strongly excite biphasic neurones that convey these signals to respiratory neurones in ventrolateral medulla; (ii) expiratory lengthening is mediated by inhibition of rhythmogenic and (pre)motoneuronal networks; and (iii) pre-inspiratory (Pre-I) neurones, some of which project to abdominal expiratory motoneurones, are excited during the BHE. These findings are qualitatively similar to studies of the BHE in vivo. Where there are differences, they can largely be accounted for by developmental changes and experimental conditions.

Cough, expiration and aspiration reflexes following kainic acid lesions to the pontine respiratory group in anaesthetized cats.

The importance of neurons in the pontine respiratory group for the generation of cough, expiration, and aspiration reflexes was studied on non-decerebrate spontaneously breathing cats under pentobarbitone anesthesia. The dysfunction of neurons in the pontine respiratory group produced by bilateral microinjection of kainic acid (neurotoxin) regularly abolished the cough reflexes evoked by mechanical stimulation of both the tracheobronchial and the laryngopharyngeal mucous membranes and the expiration reflex mechanically induced from the glottis. The aspiration reflex elicited by similar stimulation of the nasopharyngeal region persisted in 73% of tests, however, with a reduced intensity compared to the pre-lesion conditions. The pontine respiratory group seems to be an important source of the facilitatory inputs to the brainstem circuitries that mediate cough, expiration, and aspiration reflexes. Our results indicate the significant role of pons in the multilevel organization of brainstem networks in central integration of the aforementioned reflexes.

Hiccup reflex is mediated by pharyngeal branch of glossopharyngeal nerve in cats

Hiccup reflex is a coordinated motor activity that causes a brief strong inspiratory movement accompanied by glottic adduction. Our previous study has demonstrated that mechanical stimulation of the dorsal epipharynx elicits hiccup-like response. To identify the afferent pathway of the hiccup-like response, the pharyngeal branch of the glossopharyngeal nerve (PB-GPN) which distributed to the dorsal epipharyngeal area was electrically stimulated in anesthetized, spontaneously breathing cats. To access the epipharynx and to directly observe a glottic movement, we made a submental opening at the region rostral to the epiglottis. An activity from the lateral cricoarytenoid (LCA) muscle of the larynx was recorded as an index of glottic adduction, and intrapleural pressure (Ppl) as an index of an inspiratory movement. Electrical stimulation of PB-GPN evoked a fixed motor pattern of hiccup-like response representing a spiky strong negative change in Ppl accompanied by an initial brief burst of LCA electromyogram (EMG). LCA excitation occurred prior to the spiky inspiratory movement. An initial and transient glottic adduction during the response was confirmed by direct observation. Electrical stimulation of the main trunk of the glossopharyngeal nerve evoked expiratory reflex, but not inspiratory (hiccup-like) response. These results indicated that PB-GPN is responsible for hiccup reflex.

Electrophysiologic latency to the external obliques of the laryngeal cough expiration reflex in humans.

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. 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. The mean (standard deviation) latency to the external abdominal oblique muscle was 17.6 +/- 10.6 msec. No adverse events to inhalation were reported. SIn 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.

Cough reflex induced by microinjection of citric acid into the larynx of guinea pigs: new coughing model.

We developed a new coughing model that evoked coughs by microinjection of citric acid into the larynx in unanesthetized unrestrained guinea pigs; additionally, we recorded synchronous sounds and waveforms of coughing utilizing built-in microphones and a whole body plethysmograph. The coughing model was able to distinguish a coughing response from other expiratory responses, such as an expiratory reflex or a sigh, by examining the waveform of the expiratory response and the existence of sound. It was not necessary to distinguish a cough from a sneeze, since the administration site was restricted to the larynx. Microinjection of 0.4 M citric acid, total of 20 microl (10 times, 2 microl at 30-s intervals), induced coughs (27.03 +/- 4.03 coughs in 10-min observation) that were stable and independent of the inhalation volume. In the inhalation studies, animals were exposed to citric acid only once, because the number of coughs remarkably decreased with repeated administration at intervals of 24 h (tachyphylaxis). However our coughing model was able to repeatedly challenge the microinjection of citric acid at an interval of 24 h. These results indicated that this coughing model was highly sensitive and correctly assessed the cough response.

Activity of the laryngeal abductor and adductor muscles during cough, expiration and aspiration reflexes in cats

We studied the temporal relationships and the patterns of electromyographic activities of the posterior cricoarytenoid and thyreoarytenoid muscles (laryngeal abductor and adductor), the diaphragm and abdominal muscles in anesthetized cats during mechanically induced tracheobronchial and laryngopharyngeal coughs, expiration and aspiration reflexes. The posterior cricoarytenoid muscle activity reached the maxima just before the peak of diaphragmatic activity in both types of cough and aspiration reflexes and slightly before the top of abdominal muscle activity in coughs and the expiration reflex. Thus, this muscle contributes to the inspiratory phase of coughs and aspiration reflex and also to the expulsive phase of coughs and the expiration reflex. The thyreoarytenoid muscle presented strong discharges in the compressive phase of coughs and expiration reflex (during the rising part of the abdominal muscle activity) and in the subsequent laryngoconstriction (following the diaphragmal and/or abdominal muscle activity) in all four reflexes. This muscle was also slightly activated at the beginning of the aspiration reflex. The existence of four phases of the cough reflex is also discussed.

Reflexes from airway rapidly adapting receptors

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 expiration reflex from the vocal folds.

The authors present their 30 years' experience with expiration reflex. The reflex can be elicited from vocal folds by mechanical, chemical or electrical stimulation of the superior laryngeal nerve of man and laboratory animals, except mice and rats. It manifests itself by a short, forcible expiratory effort without a preceding inspiration which is indispensable for cough effort. The role of expiration reflex is to prevent penetration of foreign bodies into airways, expelling phlegm and detritus from subglottal area. The initial inspiration before expiration is undesired and could lead to inspiration pneumonia. The reflex is well known to laryngologists as '"laryngeal cough." Its receptors are small in number, localised mainly in medial margin of vocal folds deep in mucosa which can explain their stability in pathological conditions of the larygx. Afferentiation of the reflex is via laryngeal nerve similarly to sneezing and cough. Expiration reflex is not co-ordinated by a single "centre" but rather by a network system in the brain stem. Its motor pattern is supposedly produced by "multifunctional" population of medullar neurones in Botzinger complex and the rostral ventral respiratory group involved also in the genesis of breathing and cough. However, in cats also other neurones may play a vital role in production, shaping and mediation of the motor pattern of respiratory reflex, localised in rostral pons, lateral tegmental field or in the raphe medullar midline.

Physiological and pathophysiological implications of upper airway reflexes in humans.

The upper airway is a vital part of the respiratory tract. Although the upper airway serves several functions, protection of the airway and preservation of airway patency are the most essential functions subserved by upper airway reflexes. Various types of nerve endings have been identified in and under the epithelium of the upper airway, and afferent nerve endings are the natural starting of all reflex activity. The upper airway reflexes consist of many different types of reflex responses such as sneezing, apnea, swallowing, laryngeal closure, coughing, expiration reflex, and negative pressure reflex. Although the activation of upper airway reflexes does not necessarily occur at one particular site of the respiratory tract, individual reflex response is usually considered to be highly specific for the particular respiratory site which has been affected. The upper airway reflexes are modified by many factors such as sleep, anesthesia, and background chemical ventilatory drive. Both depression and exaggeration of upper airway reflexes cause clinical problems. Depression of upper airway reflexes enhances the chance of pulmonary aspiration and compromises the maintenance of the airway, whereas exaggeration of airway reflexes such as laryngospasm and prolonged paroxysm of cough can be harmful and dangerous. In this review, various aspects of upper airway reflexes are discussed focusing on the functions of upper airway reflexes in humans and some pathophysiological problems related to clinical medicine.

Inspiratory and expiratory patterns of the pectoralis major muscle during pulmonary defensive reflexes.

Experiments were conducted to determine the discharge pattern of the pectoralis major muscle during pulmonary defensive reflexes in anesthetized cats (n = 15). Coughs and expiration reflexes were elicited by mechanical stimulation of the intrathoracic trachea or larynx. Augmented breaths occurred spontaneously or were evoked by the same mechanical stimuli. Electromyograms (EMGs) were recorded from the diaphragm, rectus abdominis, and pectoralis major muscles. During augmented breaths, the pectoralis major had inspiratory EMG activity similar to that of the diaphragm, but during expiration reflexes the pectoralis major also had purely expiratory EMG activity similar to the rectus abdominis. During tracheobronchial cough, the pectoralis major had an inspiratory pattern similar to that of the diaphragm in 10 animals, an expiratory pattern similar to that of the rectus abdominis in 3 animals, and a biphasic pattern in 2 animals. The pectoralis major was active during both the inspiratory and expiratory phases during laryngeal cough. We conclude that, in contrast to the diaphragm or rectus abdominis muscles, the pectoralis major is active during both inspiratory and expiratory pulmonary defensive reflexes.

Upper Airway Reflexes during a Combination of Propofol and Fentanyl Anesthesia

The effects of intravenous anesthetics on airway protective reflexes have not been fully explored. The purpose of the present study was to characterize respiratory and laryngeal responses to laryngeal irritation during increasing doses of fentanyl under propofol anesthesia. Twenty-two female patients anesthetized with propofol and breathing through the laryngeal mask airway were randomly allocated to three groups: (1) eight patients who received cumulative total doses of 200 microg fentanyl given in the form of two doses of 50 microg and one dose of 100 microg spaced 6 min under mechanical controlled ventilation while end-tidal carbon dioxide tension (PCO2) was maintained at 38 mmHg (fentanyl-controlled ventilation group), (2) eight patients who received cumulative total doses of 200 microg fentanyl while breathing spontaneously while end-tidal PCO2 was allowed to increase spontaneously (fentanyl-spontaneous ventilation group), and (3) six spontaneously breathing patients who were anesthetized with propofol alone (propofol group). The laryngeal mucosa of each patient was stimulated by spraying the cord with distilled water, and the evoked responses were assessed by analyzing the respiratory variables and endoscopic images. Before administration of fentanyl, laryngeal stimulation caused vigorous reflex responses, such as expiration reflex spasmodic panting, cough reflex, and apnea with laryngospasm. Increasing doses of fentanyl reduced the incidences of all these responses, except for apnea with laryngospasm, in a dose-related manner in both the fentanyl-controlled ventilation and the fentanyl-spontaneous ventilation groups. Detailed analysis of endoscopic images revealed several characteristics of laryngeal behavior during the airway reflex responses. Incremental doses of fentanyl depress airway reflex responses in a dose-related manner, except for apnea with laryngospasm.

Cough and Other Reflexes on Irritation of Airway Mucosa in Man

Both human and animal studies show that irritation of airway mucosa elicits a variety of reflex responses such as coughing, apnoea, and laryngeal closure. Most of the information concerning these reflex responses were obtained in anesthetized conditions with little applicability to awake conditions. Various aspects of cough and other reflexes on irritation of the airway mucosa are discussed. Studies on awake humans showed that stimulation of the laryngeal mucosa with a small amount of distilled water during wakefulness causes elicitation of the expiration reflex, cough reflex, and swallowing reflex while other types of responses are scarcely observed. In addition, the duration of these responses is remarkably short. In contrast, the same stimulation causes more variant, prolonged, and exaggerated responses during a light depth of anesthesia. An increase in depth of anesthesia abolishes expiratory efforts such as coughing and the expiration reflex whereas the apnoeic reflex and laryngeal closure reflex are resistant to the depressant effect of anesthesia. Also, the respiratory reflex responses to airway irritation varied, depending on the site of stimulation: both laryngeal and tracheal stimulation cause vigorous respiratory responses whereas bronchial stimulation causes little or no respiratory responses. These results indicate not only that the types and magnitude of reflex responses is greatly modified by the central nervous state but also that the site of stimulation is crucial for determining the pattern of respiratory responses elicited by airway stimulation in humans.

Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters

Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters

Involvement of bulbar respiratory and non-respiratory neurons in onset of expiration reflex

It was shown that excitation of high- and low-threshold superior laryngeal afferents triggers reflexes of varying complexity in a considerable proportion of non-respiratory neurons during experiments on cats anesthetized by Nembutal involving stimulation-induced expiration reflex. Systemic alterations in background firing activity were noted during this reflex in "respiratory" neurons; reflex reaction setting in as a result of low-threshold laryngeal afferent activation was also recorded in 22.4% of this group. Oligo- and polysynaptic excitatory connections were found between low-threshold laryngeal afferents and inspiratory beta neurons, P-cells, and laryngeal muscle motoneurons as opposed to inhibitory connections with inspiratory gammaneurons. This article discusses involvement of the neurons investigated in mechanisms of inspiratory inhibition, closure of the vocal chords, and adaptive decline in breathing rate occurring during expiration reflex.

Responses of bulbospinal neurons during expiration reflex in cats

The responses of 129 bulbospinal (BS) neurons were investigated an anesthetized cats during the expiration reflex evoked by mechanical stimulation of the vocal folds or electrostimulation of the superior laryngeal nerve. It was found that in addition to expiratory and inspiratory neurons, a large number of nonrespiratory BS cells localized bilaterially, primarily in the giant-cell tegmental fields, are activated. It is shown that expulsive expiration during this reflex is to a considerable extent provided by activation of non-respiratory BS neurons participating also in the transmission of descending influences from high-threshold afferents of other modalities.

Laryngeal and Respiratory Responses to Tracheal Irritation at Different Depths of Enflurane Anesthesia in Humans

The effect of three different depths of enflurane anesthesia (1.0, 1.4, and 1.8 MAC) upon laryngeal and respiratory responses to tracheal instillation of distilled water in nine female patients in whom a double-cuffed endotracheal tube had been inserted was investigated. The laryngeal responses were monitored by measuring the pressure in the saline-filled cuff positioned within the larynx, and the respiratory responses were monitored by measuring ventilatory flow and tracheal airway pressure. Increases in laryngeal cuff pressure in response to tracheal irritation were 19.7 +/- 4.5 cmH2O (mean +/- SD) at 1.0 MAC, 13.9 +/- 3.6 cmH2O at 1.4 MAC, and 7.6 +/- 1.8 cmH2O at 1.8 MAC, respectively (P less than 0.01 for anesthetic dose). At 1.0 MAC of enflurane anesthesia, tracheal instillation of saline caused immediate laryngeal constriction and all components of the tracheal response, such as apnea, expiration reflex, cough reflex, and spasmodic panting. At 1.4 and 1.8 MAC, the same stimulation caused only apnea and constriction of the larynx in the majority of patients. These results indicate that changes in depth of anesthesia can modify the laryngeal and respiratory responses to tracheal irritation. The close association of laryngeal and respiratory responses may be an integral part of the defensive reflex synergism.

EFFECTS OF I.V. LIGNOCAINE ON AIRWAY REFLEXES ELICITED BY IRRITATION OF THE TRACHEAL MUCOSA IN HUMANS ANAESTHETIZED WITH ENFLURANE

We have investigated the effects of bolus administration of lignocaine 1.5 mg kg-1 i.v. on respiratory responses to airway irritation induced by instillation of distilled water into the trachea in 10 patients anaesthetized with enflurane (1.5% end-tidal). Before administration of lignocaine, airway irritation elicited not only the cough reflex, but also other respiratory reflexes such as expiration, apnoea and spasmodic panting. Immediately after administration of i.v. lignocaine, when plasma concentrations of lignocaine exceeded 4.7 micrograms ml-1, tracheal irritation elicited only brief apnoea. Other reflex responses were suppressed completely; they recovered gradually with progressive decrease in plasma concentration of lignocaine. The apnoeic reflex was not eliminated at plasma lignocaine concentrations greater than 7.0 micrograms ml-1, whereas the expiration reflex, cough reflex and spasmodic panting were eliminated effectively by plasma concentrations of lignocaine greater than 3.5, 2.8 and 2.2 micrograms ml-1, respectively.

Influence of CPAP on reflex responses to tracheal irritation in anesthetized humans.

We investigated the effects of lung inflation during continuous positive airway pressure breathing (CPAP) on airway defensive reflexes in 10 enflurane-anesthetized spontaneously breathing humans. The airway defensive reflexes were induced by instillation into the trachea of 0.5 ml of distilled water at two different levels of end-expiratory pressure (0 and 10 cmH2O CPAP). The tracheal irritation at an end-expiratory pressure of 0 cmH2O caused a variety of reflex responses including apnea, spasmodic panting, expiration reflex, cough reflex, an increase in heart rate, and an increase in blood pressure. Lung inflation during CPAP of 10 cmH2O did not exert any influence on these reflex responses in terms of the types, latencies, and durations of reflex responses although the intensity of the expiration reflex and cough reflex was augmented by lung inflation. Our results suggest that the pulmonary stretch receptors do not play an important role in the mechanisms of airway defensive reflexes in humans.

Respiratory Reflex Responses to Stimulation of Tracheal Mucosa in Enflurane-Anesthetized Humans

We investigated respiratory reflex responses to tracheal mucosa stimulation induced by injection of distilled water in 13 female patients under three different depths of enflurane anesthesia (0.7, 1.0, and 1.3 minimum alveolar concentration). Detailed analysis of the types of reflex responses revealed that there are at least six different responses: 1) the apneic reflex, 2) the expiration reflex, 3) spasmodic, panting breathing, 4) the cough reflex, 5) slowing of breathing, and 6) rapid, shallow breathing. Among these reflex responses, the cough reflex was the most sensitive and the apneic reflex followed by slowing of breathing was the most resistant to deepening anesthesia, whereas the sensitivity of other types of reflex responses was in between. Our results indicate that the types of respiratory reflex responses to tracheal mucosa stimulation are associated with depths of anesthesia and that the differences in sensitivity to anesthesia may be a valuable sign in clinical assessment of depth of anesthesia.