INTRODUCTION

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On the basis of the anatomic role of the pharynx as a common pathway for both respiration and digestion, the precise coordination of swallowing and breathing is considered an important mechanism in minimizing the risk of pulmonary aspiration and in maintaining adequate ventilation (1). Alteration of breathing patterns and ventilation may influence the coordination of swallowing and respiration. This problem is particularly vital in patients with chronic lung disease, since a high degree of coordination of swallowing and respiration is essential for the maintenance of adequate ventilation in these patients with an already limited ventilatory capacity.

Shaker and colleagues (2) reported that coordination of swallowing and the phases of respiration is altered in patients with chronic obstructive pulmonary disease (COPD). Although the incidence of pulmonary aspiration and the ability to maintain adequate ventilation were not documented in their report, addition of mechanical and chemical loads to the respiratory system may compromise the coordination of swallowing and respiration and thereby increase the likelihood of pulmonary aspiration.

Although studies of responses to experimental loads added to the respiratory system suggest that the respiratory system has a marked ability to compensate for increased respiratory loads, breathing patterns differ markedly according to the type of respiratory loading. For example, breathing patterns during flow-resistive loading are characterized by slow, deep breathing, whereas those during elastic loading are characterized by rapid shallow breathing (3). This difference in breathing patterns with different types of loading may have different effects on coordination of swallowing and the phases of respiration. However, no study has been done to differentiate the effects of different types of added respiratory loading on this coordination. Examination of influences of resistive and elastic loads on the swallowing reflex may provide significant information about the pathogenesis of acute exacerbations of respiratory distress in patients with COPD or restrictive lung diseases. We hypothesized that there may be a difference in the coordination of swallowing and respiration with flow-resistive loading and with elastic loading. In order to test this hypothesis, we examined the coordination of respiration and reflex swallowing elicited by continuous infusion of water into the pharynx during resistive and elastic loads in awake volunteers.

	METHODS

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Fourteen healthy volunteer subjects aged 23 to 38 yr (nine men and five women) 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 Ethics Committee of Chiba University School of Medicine.

Preparation of Subjects

Experiments were performed while each subject was seated on a comfortable chair. A thin polyethylene catheter with a diameter of 1.35 mm was inserted through the naris so that the tip of the catheter lay in the epipharynx. Accurate positioning of the catheter tip was confirmed by direct observation through laryngeal scope. To prevent movement of the tip, the catheter was fixed in this position with adhesive tape on the subject's upper lip. Subjects wore a tightly fitting face ask connected to a pneumotachograph (CP-100; Allied Health Care Products, Inc., St. Louis, MO). The total instrumental dead space was about 150 ml, and the resistance was 5.5 cm H₂O/L/s at a flow rate of 0.5 L/s. Ventilatory airflow was measured with the pneumotachograph, and tidal volume (VT) was obtained by electrical integration of the inspired flow signal. Mask pressure (Pmask) was measured with a pressure transducer (Transpac IV; Abbott Critical Care Systems, Chicago, IL). End-tidal PCO₂ (PET_CO2) was continuously monitored with an infrared CO₂ analyzer (Aika MEL RAS-41; Aika Tokyo, Japan) through a port in the face mask. A pair of surface electrodes was placed in the subject's submandibular region to record a submental electromyogram (EMG) (bioelectric amplifier AB-621G; Nihon Koden, Tokyo, Japan). Airflow, VT, Pmask, PET_CO2, and the submental EMG were recorded with a thermal array recorder (Omniace RT3424; NEC, Tokyo, Japan).

Induction of Swallowing Reflexes and Added Respiratory Loads

Swallowing reflexes were induced by continuous infusion of distilled water through the nasal catheter at the rate of 3 ml/min. A swallowing act was identified by a burst of submental activity in the EMG with a transient interruption of airflow (deglutition apnea), and was also identified by visual observation of laryngeal upward movement.

To apply resistive loading, we placed a plastic tube of 3 mm I.D. and 16.5 cm length between the pneumotachograph and the face mask. The total resistance of the experimental apparatus with the resistor in place was 180 cm H₂O/L/s at a flow rate of 0.5 L/s.

Elastic loading was produced with a 16-L solid container. Use of a solenoid valve triggered by the airflow signal allowed subjects to breathe through the elastic load, which had a magnitude of 70 cm H₂O/L only during inspiration. A suitable magnitude for the load was chosen from the results of preliminary trials, as the elastic loading that produced a similar degree of respiratory discomfort to that obtained during resistive loading with the resistor described earlier.

Hyperoxia was maintained throughout the experiment by introducing 100% oxygen into the breathing circuit at a rate of 10 L/min.

Experimental Protocol

All subjects were accustomed to breathing against added loads and to continuous infusion of water into the pharynx before the study measurements were made. Measurements were made with and without continuous infusion of water while the subject breathed under three different respiratory load conditions (a control condition without the external respiratory load, with the resistive load, and with the elastic load). The measurements under the various conditions were made in a random manner.

Data Analysis

We analyzed the last 2 min of recorded data during a 5 min period of stable respiration without continuous infusion of water. Patterns of respiration and swallowing were determined during the last 2 min of a 5-min period of continuous infusion of water. Respiratory rate (RR), swallowing rate, and VT were obtained by averaging values for 2 min. Minute ventilation (E) was calculated as the product of VT and RR. In addition, both the timing of swallows in relation to the phase of the respiratory cycle and the duration of deglutition apnea were determined. The onset of swallowing was defined as the onset of deglutition apnea, which was determined from the airflow tracing. Swallows preceded by and followed by inspiratory flow were marked as inspiratory swallows, whereas swallows preceded by and followed by expiratory flow were designated as expiratory swallows. Swallows occurring at the transition between inspiration and expiration were designated inspiratory-expiratory (I-E) transition swallows, and swallows occurring at the transition between expiration and the inspiratory phase of the next breath were designated expiratory-inspiratory (E-I) transition swallows. Incidents of laryngeal irritation were defined by a single cough or a series of coughs, which were identified from the airflow recording.

Statistical significance of respiratory and other variables among the respiratory loads was determined by Kruskal-Wallis one-way analysis of variance (ANOVA) on ranks, and Dunnett's method was used for comparison of the control condition and other conditions. Effects of water infusion in each condition were evaluated with the Mann-Whitney U test. Fisher's exact test was used to analyze significant increases in the incidence of laryngeal irritation among the different respiratory loads.

	RESULTS

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Thirteen subjects completed the experimental protocol. Because one subject could not tolerate the 5 min of continuous water infusion with elastic loading, the 2-min data before termination of the measurement were used for analysis. A total of 922 swallows in 14 subjects were analyzed.

Figure 1 shows representative recordings in a subject with and without continuous water infusion for each respiratory loading. A reduction of RR with an increase in VT was observed during resistive loading, whereas elastic loading increased RR and decreased VT. Continuous infusion of water without the addition of an external load (control) condition induced swallows with minimally altered E. The frequency of swallows elicited by water infusion did not change remarkably during resistive loading, but increased remarkably during elastic loading. No sign of laryngeal irritation was observed in the subject on whom these findings were made during either resistive or elastic loading. However, it is noteworthy that the timing of swallows was apparently modified according to the type of respiratory load. Thus, swallows occurred mainly during the I-E transition phase of the respiratory cycle during resistive loading, and swallows occurred regularly during the E-I transition phase of the respiratory cycle during elastic loading, whereas swallows were observed only during expiration under the control condition.

View larger version (22K): [in this window] [in a new window]   Figure 1.   Experimental records illustrating the respiratory pattern and reflex swallowing elicited by continuous infusion of distilled water into the pharynx under the control condition and with resistive loading and elastic loading (VT = tidal volume; Pmask = mask pressure; PETCO2 = end-tidal PCO2; EMG = submental electromyogram).

Load Compensation During Swallowing

Table 1 summarizes changes in respiratory frequency, minute ventilation, and PET_CO2 during addition of external loads.

As compared with the control condition, RR was significantly higher during elastic loading and was significantly lower during resistive loading. However, water infusion had no additive influence on the RR. Although addition of an elastic load caused a significant increase in E with a concomitant decrease in PET_CO2, neither E nor PET_CO2 during water infusion was significantly different from the respective control value. In contrast, addition of a resistive load caused a significant decrease in E with a concomitant increase in PET_CO2. However, no additive influence of repetitive swallows induced by water infusion on either E or PET_CO2 was observed during resistive loading.

Swallowing Pattern During Mechanical Loading

Although the added resistive load did not change the frequency of swallows elicited by water infusion, the frequency of swallows increased significantly during elastic loading (Figure 2). The distribution of the timing of swallows in reference to the phase of the respiratory cycle for each respiratory load is illustrated in Figure 3. Half of the swallows occurred at the I-E transition during resistive loading and at the E-I transition during elastic loading, whereas swallows during expiration were most commonly observed under the control condition. Notably, the peak of the distribution apparently shifted to the left with resistive loading and shifted to the right with elastic loading. The averaged values of duration of deglutition apnea during the control condition, flow-resistive loading, and elastic loading were 1.49 ± 0.29 s, 1.36 ± 0.29 s, and 1.47 ± 0.37 s, respectively. There was no statistically significant difference among the three conditions.

View larger version (34K): [in this window] [in a new window]   Figure 2.   Changes in the frequency of swallows under the control condition and with resistive loading and elastic loading (*p < 0.05, significantly different from control).

View larger version (17K): [in this window] [in a new window]   Figure 3.   Timing of swallows in relation to phase of the respiratory cycle during continuous infusion of water. Percentage of swallows coinciding with each phase of the respiratory cycle was calculated for individual subjects; the values shown are mean ± SD (*p < 0.05, compared with the values during other phases of the respiratory cycle).

Incidence of Laryngeal Irritation with Pattern of Swallowing

Figure 4 shows examples of laryngeal irritation following swallows during the E-I transition during elastic loading. Although the first three swallows shown in the figure occurred in the expiratory phase without a sign of laryngeal irritation, the swallow during the E-I transition, indicated by an arrow, was followed by an inspiration and subsequent expiration efforts that we considered to be induced by laryngeal stimulation.

View larger version (25K): [in this window] [in a new window]   Figure 4.   Experimental record showing the incidence of laryngeal irritation during continuous infusion of water. Arrow indicates E-I transition swallow, and star indicates laryngeal irritation.

The incidence of laryngeal irritation during elastic loading was significantly higher than that during the control condition or resistive loading, as illustrated in Figure 5.

View larger version (42K): [in this window] [in a new window]   Figure 5.   Occurrence of laryngeal irritation during continuous infusion of water (*p < 0.05 compared with control value).

On the basis of laryngeal responses, the total of 42 trials (trials under three different conditions in 14 subjects) could be divided into two groups as follows: 29 trials during which laryngeal irritation did not occur (negative laryngeal response group) and 13 trials during which laryngeal irritation occurred (positive laryngeal response group). Both respiratory and swallowing rates were significantly higher in the positive laryngeal response group than in the negative laryngeal response group (Figure 6).

View larger version (14K): [in this window] [in a new window]   Figure 6.   Comparison of frequency of swallows and respiratory frequency in the positive laryngeal response group (+) and the negative laryngeal response group () (**p < 0.01 compared with values obtained from the negative laryngeal response group).

When a total of 35 laryngeal irritations occurring in 10 subjects during elastic loading were analyzed, 23 incidents occurred after E-I transition swallows, nine occurred after I-E transition swallows, and three occurred after inspiratory swallows. No signs of laryngeal irritation were observed after expiratory swallows.

	DISCUSSION

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Major findings in the present study were that: (1) added respiratory loads modulate patterns of respiration and swallowing elicited by continuous infusion of water into the pharynx; (2) the dominant timing of swallows differed with different respiratory load conditions (i.e., expiratory phase in the control condition, I-E transition phase during resistive loading, and E-I transition phase during elastic loading); (3) laryngeal irritation most often occurred after E-I transition swallows during elastic loading.

Interpretation of Results

In this study, addition of external loads caused considerable changes in breathing pattern. The observation that respiratory frequency decreased during resistive loading and increased during elastic loading is compatible with the hypothesis proposed by Mead that there is an optimal respiratory frequency at which the total work of breathing is minimal (4). The finding of significant increases in both respiratory and swallowing frequencies during elastic loading may be associated with the one-to-one or one-to-two rhythmic coupling of swallowing and respiration often observed during continuous infusion of water (5). Similar coupling of swallowing and respiration has been observed in anesthetized animals during continuous stimulation of the superior laryngeal nerve, indicating that rhythmic coupling of swallowing and respiration does not require a conscious behavioral response to laryngeal nerve activity (6). Such rhythmic coupling of swallowing and respiration might not be influenced by the addition of external elastic loading, thus resulting in parallel changes in respiratory frequency and swallowing frequency.

In accord with results of several previous studies (2, 5, 7), we observed that before the addition of respiratory loads, the majority of swallows interrupted respiration in the expiratory phase. However, this interruption occurred more often during the E-I transition with elastic loading, and more often during the I-E transition with resistive loading. It is possible that the changes in the timing of swallows are simply associated with the changes in respiratory frequency under the different load conditions. For example, swallows that occurred in the expiratory phase have to be distributed to the other phases during tachypnea induced by elastic loading, owing to the reduction in expiratory time. However, it has been shown that the preferential distribution of swallows to the expiratory phase is intensified and that postdeglutitive respiration is resumed preferentially with expiration during exercise-induced tachypnea (2). Similarly, the preferential occurrence of swallows during the I-E transition with resistive loading may not solely be explained by the changes in respiratory frequency. Thus, there may exist an active mechanism that controls the coupling of swallowing with phases of respiration in response to respiratory loads. Such a mechanism may play an important role in maintaining adequate ventilation with minimum disturbance of inspiratory and expiratory airflow during continuous swallowing in the face of severe respiratory loads. In this study, we observed no statistically significant difference in the duration of deglutition apnea among the three different respiratory load conditions. This finding suggests that the duration of deglutition apnea may not be influenced by either the type of respiratory loads or by the timing of swallowing relative to the respiratory cycle.

Our results also showed that the incidence of laryngeal irritation was significantly higher during elastic loading than that during the control condition or resistive loading. Although the detailed mechanisms of the occurrence of laryngeal irritation were not clarified in this study, the higher incidence of laryngeal irritation during elastic loading seems to be associated with the preferential occurrence of E-I swallows during this type of loading. It may be possible that with an E-I transition swallow, incompletely eliminated pharyngeal content is aspirated into the larynx during the subsequent inspiration. In this regard, it has been suggested that swallows coinciding with the E-I transition phase are the most liable to produce aspiration (10). A high incidence of laryngeal irritation observed after E-I transition swallows during hypercapnia (5) may also support the notion that the timing of swallows is an important factor in determining the occurrence of laryngeal aspiration.

Limitations of the Study

In the present study, the resistive load was effected throughout the entire respiratory cycle, whereas the elastic load was added only at inspiration. Such differences in the application of loads might burden the respiratory system with different mechanical and chemical loads. For example, a combined inspiratory-expiratory resistive load might cause the development of a constant positive airway pressure (CPAP). Although the effects of CPAP on the coordination of swallowing and respiration were not systematically examined in this study, it has been shown that CPAP inhibits the swallowing reflex (11).

The magnitude of respiratory loads was not precisely controlled in this study. The finding that ventilation was fully compensated during elastic loading but not fully compensated during resistive loading suggests that the magnitude of respiratory stress might not have been equivalent with the resistive and elastic loads chosen in this study. This also suggests that there may have been a difference in the central respiratory activities in response to the resistive and elastic loads chosen in this study. Such differences in central respiratory activities may potentially modify the coordination of swallowing and respiration, but this study did not provide any answer to this question.

In addition, the difference in PET_CO2 caused by the different capacities for compensation with the two different loads used in the present study may have modified the coordination of swallowing and respiration. In this context, it has been shown that the frequency of swallowing decreases with increasing PET_CO2 during continuous infusion of water into the pharynx (5, 12). Thus, a lower frequency of swallows during resistive loading may be partly associated with an increase in PET_CO2. The finding that the incidence of laryngeal irritation during resistive loading did not differ from that during unloaded breathing suggests that the incidence of laryngeal irritation may be associated with the type rather than with the magnitude of a respiratory load.

Clinical Relevance

Until recently, no study had elucidated the way in which swallowing coordinates with the phases of respiration in patients with lung diseases. However, a recent study by Shaker and colleagues (2) demonstrated that during disease exacerbations, patients with COPD swallow more often during the inspiratory phase of the respiratory cycle than in the basal state. Such a change in the timing of swallows could increase the likelihood of aspiration, and might be associated with the arterial oxygen desaturation during meals observed in some patients with severe COPD. To our knowledge, there has been no study of the coordination of swallowing and phases of respiration in patients with restrictive lung diseases characterized by increased lung elasticity. Although a simple extrapolation of the results of our study to other clinical situations may not be entirely valid, we can speculate that tachypneic patients with restrictive lung disease may have a higher incidence of deglutitive aspiration than bradypneic patients with COPD. Further studies are definitely needed to examine whether any differences exist in the incidence of deglutitive aspiration in obstructive and restrictive lung diseases.