© 2002 American Thoracic Society
Phasic Vagal Influence on the Rate and Timing of Reflex SwallowingDepartment of Anesthesiology, Graduate School of Medicine, Chiba University, Chiba, Japan Correspondence and requests for reprints should be addressed to Dr. T. Nishino, M.D., Department of Anesthesiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohanacho, Chiba 260-8760, Japan. E-mail: nisino{at}med.m.chiba-u.ac.jp
We investigated the effects of sudden changes in ventilation induced by voluntary hyperpnea and breath-holding on repetitive reflex swallowing elicited by continuous infusion of distilled water into the pharynx in 13 healthy subjects. Ventilation was monitored using a pneumotachograph, and swallowing was identified by submental electromyography with interruption of airflow. We found that voluntary hyperpnea decreased the swallowing frequency whether end-tidal CO2 tension was maintained at normocapnia or allowed to be hypocapnic. Also, the frequency of swallowing immediately increased with the start of breath-holding, but there was a sudden decrease in swallowing frequency during the hyperpnea observed immediately after the resumption of ventilation (post–breath-holding hyperpnea). The preponderant coupling of swallows with the expiratory phase was lost during voluntary hyperpnea but was maintained during post–breath-holding hyperpnea. These observations may suggest that vagally mediated reflexes are operative in normal physiologic situations and play an important role in the control of swallowing rate as well as in the timing of swallowing in reference to the respiratory cycle.
Key Words: swallowing reflex • breath-holding • vagally mediated reflexes • voluntary hyperpnea
The swallowing reflex is probably the most complex "all or none" reflex that involves the coordinated contraction of several muscles in the mouth, upper airway, and esophagus. Respiration and swallowing cannot coexist because both behaviors use a common passageway, and therefore, the two activities must be coordinated so that mutual compromise does not occur. A high degree of coordination between respiration and swallowing is essential for the maintenance of adequate ventilation without causing pulmonary aspiration, particularly during repeated swallows. Although changes in swallowing pattern may change respiratory patterns and vice versa, much attention has been paid to the effects of swallowing on respiration in previous studies (1–6) and less information is available as to the effects of respiration on swallowing. In a previous study (7) we showed that lung inflation has an inhibitory influence on the swallowing reflex and modulates the timing of swallowing. Assuming that lung inflation stimulates vagal receptors in the airways, it is possible that vagally mediated reflexes play an important role in the control of reflex swallowing. If these reflexes are operative in normal physiologic situations, a sudden change in ventilation would promptly alter the frequency and timing of reflex swallowing. In the present study, we examined the effect of sudden changes in ventilation induced by voluntary hyperpnea and breath-holding on repetitive reflex swallowing elicited by continuous infusion of distilled water into the pharynx. In these experimental settings, we reasoned that voluntary hyperpnea would augment the effect of vagally mediated reflexes, whereas breath-holding would attenuate the reflex effect.
Thirteen healthy male volunteers aged 26–45 years were studied. None had histories of dysphagia, neuromuscular, cardiovascular, or pulmonary disease. Each subject provided informed consent, and the study protocol was approved by the Institutional Ethics Committee. All subjects were told about the various procedures that would be followed, but none was familiar with the hypothesis being tested. Each subject was seated during the experiment and breathed through a tightly fitting face mask connected to a pneumotachograph and a T-piece system. Details of the experimental setup are given elsewhere (8, 9). In brief, we continuously measured the following parameters: ventilatory airflow, tidal volume, end-tidal CO2 tension (PETCO2), and mask pressure. Swallowing was determined by a burst of submental electromyogram activity with interruption of airflow. Reflex swallows were induced by continuous infusion of water into the pharynx (2 ml/minute) through a thin nasopharyngeal catheter placed without the use of topical anesthesia. During the experiment, hyperoxia was maintained by passing 100% oxygen with a total flow of 10 L/minute through the T-piece. Each subject breathed through the face mask, and a period of 5–7 minutes was allowed for the establishment of a stable breathing pattern. Subsequently, continuous infusion of distilled water into the pharynx was started to induce the repetitive swallowing reflex. The subject then had two trials of voluntary hyperpnea and one trial of breath-holding. The order of these three trials was randomized with an interval of 3 minutes between trials. In each of the trials, when the swallowing response to continuous infusion of water was stable, breathing and swallowing were recorded for 3 minutes (baseline period). Then, we asked the subject to change the breathing pattern suddenly by performing either voluntary hyperpnea or breath-holding (test period). The voluntary hyperpnea was started by the experimenter's signal and continued for 90 seconds. The degree of hyperpnea was left to the subject, but the subject was instructed to maintain forced breathing until the signal for its cessation. During the voluntary hyperpnea, PETCO2 was allowed to decrease (hypocapnic hyperpnea) or was maintained at a normocapnic concentration by addition of external dead space (normocapnic hyperpnea). Breath-holding was started at end-expiration and continued as long as possible. After the cessation of voluntary hyperpnea and breath-holding, the subject was asked to relax and to breathe freely for 5 minutes (recovery period). The changes in respiration and swallowing were analyzed using the data from the last 1 minute of the baseline period, the last 60 seconds of a 90-second period of voluntary hyperpnea, the first 30 seconds of breath-holding, and the first 1 minute of a 5-minute recovery period following voluntary hyperpnea or breath-holding. For quantitative analysis of the effects of sudden changes in ventilation on the swallowing reflex, changes in the respiratory variables and swallowing rate during the baseline, test, and recovery periods were analyzed. In addition, the timing of the swallows in relation to the phase of the respiratory cycle was determined as described previously (8, 9). Statistical analysis was performed by using repeated measures analysis of variance or Friedman repeated measures analysis of variance on ranks followed by Tukey's test and a paired t test, when appropriate. A p value less than 0.05 was considered significant.
None of the 13 subjects showed signs of laryngeal irritation such as apnea and coughing in response to continuous infusion of water into the pharynx during the periods of resting breathing and post–breath-holding hyperpnea. Although some coughing was observed occasionally in some subjects during voluntary hyperventilation, the coughing subsided within a short period of time and all 13 subjects were able to complete the experimental protocol. The short period of coughing did not interfere with analysis of the data. A total of 1,180 swallows was analyzed.
Changes in Respiratory Variables
Frequency of Swallowing Figure 1 shows experimental records illustrating the effects of voluntary hyperpnea on reflex swallowing obtained in a single subject. Immediately after the start of voluntary hyperpnea, the frequency of swallowing decreased whether PETCO2 was allowed to decrease (Figure 1A) or was maintained at a normocapnic concentration (Figure 1B). After the cessation of voluntary hyperpnea, the decreased swallowing frequency gradually returned to the prehyperpneic concentration. Similar results were obtained from all subjects. The values of swallowing frequency in the hypocapnic hyperpnea trial during baseline, test, and recovery periods were 11.5 ± 4.9, 6.7 ± 3.4, and 10.0 ± 4.3 swallows/minute, respectively. Similarly, the values of swallowing frequency in the normocapnic hyperpnea trial during baseline, test, and recovery periods were 11.3 ± 4.8, 8.0 ± 3.4, and 10.1 ± 4.3 swallows/minute, respectively. In both trials, the values during the test period were significantly smaller (p < 0.01) than those during the baseline and recovery periods.
In contrast to the changes observed during hyperpnea, the frequency of swallowing increased during breath-holding (Figure 2) . However, the swallowing frequency decreased immediately with the resumption of breathing. The values of swallowing frequency obtained from all subjects before, during, and after breath-holding were 10.6 ± 4.0, 15.5 ± 5.1, and 7.6 ± 3.7 swallows/minute, respectively. The values during breath-holding were significantly higher than those before breath-holding (p < 0.01), and the values after breath-holding were significantly smaller than those before breath-holding (p < 0.01).
Timing of Swallows The distribution of the timing of swallows in reference to the phase of the respiratory cycle for each experimental condition is illustrated in Figure 3 . The distribution of the timing of swallows was changed during voluntary hyperpnea. Thus, expiratory swallows most commonly observed during the baseline period significantly decreased, whereas swallows at the expiratory–inspiratory transition phase significantly increased during hypocapnic and normocapnic hyperpnea. On the other hand, the preferential occurrence of expiratory swallows persisted during post–breath-holding hyperpnea (Figure 4) .
The major findings in this study are as follows: (1) voluntary hyperpnea decreased the swallowing frequency whether PETCO2 was maintained at normocapnia or allowed to be hypocapnic, (2) the frequency of swallowing increased during breath-holding, but a sudden decrease in swallowing frequency was observed immediately after the resumption of ventilation, and (3) the preponderant coupling of swallows with the expiratory phase was lost during voluntary hyperpnea but was maintained during post–breath-holding hyperpnea. There are a number of possible mechanisms that might be considered to explain the decrease in frequency of swallows during voluntary hyperpnea and post–breath-holding hyperpnea. First, it is possible that the effort necessary to achieve hyperpnea is strong enough to suppress intentionally the swallowing reflex, and thus the decrease in frequency of swallows might be due to conscious intervention. However, this possibility is unlikely because both voluntary hyperpnea and involuntary hyperpnea following breath-holding caused a similar decrease in the frequency of swallowing. In addition, the swallowing reflex is an "all or none" type of reflex, and volitional control of the swallowing reflex is very difficult, if not impossible. Second, the act of hyperpnea may cause mechanical deformation of the upper airway innervated by the vagus nerve, which in turn might set up a reflex that modifies the swallowing reflex. In support of this, it has been shown previously that specific information from the upper airway receptors is facilitative to the elicitation of the swallow and that peripheral feedback is critical for the repetition of reflex swallowing (10, 11). Thus, it is likely that the act of hyperpnea may reflexively exert an inhibitory influence on the peripheral sensory feedback, causing a decrease in the frequency of swallows. Third, it is also possible that hyperpnea may cause inhibition of the swallowing reflex through a vagally mediated lung inflation reflex. Our previous studies (7, 12) showed that nasal continuous positive airway pressure or negative extrathoracic pressure applied in normal human adults can decrease the frequency of reflex swallowing during continuous infusion of water into the pharynx. A similar decrease in the frequency of swallows has been observed during hyperpnea due to hypercapnia (8). These results together with the results of the present study suggest that the lung-volume–related lung reflex may play an important role in the inhibition of the swallowing reflex. The finding that the frequency of swallows increased suddenly with the start of breath-holding is compatible with the inhibitory influence of this lung-volume–related reflex on the swallowing reflex because withdrawal of phasic lung inflation during breath-holding may cause disinhibition of the lung-volume–related reflex effect. Finally, it has been suggested that CO2 may directly exert an inhibitory influence on the central nervous mechanisms regulating the frequency of swallows (8). However, we found in this study that the frequency of swallows decreases immediately after the start of hyperpnea whether it is voluntary or involuntary and regardless of the concentrations of PETCO2. This suggests that the decrease in the frequency of swallows is associated with the effect of vagally mediated reflexes rather than with the direct effect of CO2 on the central nervous mechanisms regulating the frequency of swallows. In this study, we found that the preponderant coupling of swallows with the expiratory phase is lost during voluntary hyperpnea regardless of the concentrations of PETCO2. A similar change in the timing of swallows has been observed during increased ventilation due to hypercapnia (8) both with the addition of respiratory elastic loading (9) and during the lung inflation due to negative extrathoracic pressure (7). By contrast, the preponderant coupling of swallows with the expiratory phase was maintained during the period of post–breath-holding hyperpnea. It is unclear why the effect of voluntary hyperpnea on the timing of swallowing differs from that of post–breath-holding hyperpnea. However, there was a marked difference in magnitude of ventilation between voluntary hyperpnea and post–breath-holding hyperpnea, and it may be possible that the greater the magnitude of ventilation, the later the occurrence of swallowing in the respiratory cycle. In this context, the presence of an active mechanism that controls the coupling of swallowing with the phases of respiration has been proposed (7–9). Such a mechanism may play an important role in maintaining adequate ventilation with minimum disturbance of airflow during repetitive swallowing in response to respiratory loading. In conclusion, we have shown that both voluntary hyperpnea and post–breath-holding hyperpnea decrease the frequency of repetitive swallows induced by continuous infusion of water into the pharynx, whereas breath-holding increases the frequency of repetitive swallows. These observations are in agreement with the hypothesis that vagally mediated reflexes are operative in normal physiologic situations and play an important role in the control of reflex swallowing.
The authors are grateful to Dr. Eileen Mulligan for constructive criticism of the manuscript. Supported in part by a grant-in-aid for Scientific Research (B) (2) (11470316) from the Ministry of Education, Science, and Culture of Japan. Received in original form August 17, 2001; accepted in final form March 10, 2002
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