INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Configuration and function of the upper airway change markedly during the first year of life, as is true of the other vital organs in humans (1). These developmental changes may significantly influence mechanisms and efficacy of upper airway maintenance for breathing, which is fundamental and crucial for survival. No study has evaluated changes in pharyngeal collapsibility during infancy.

Current concepts of upper airway maintenance suggest that neural regulation of the upper airway dilating muscle activities (neural mechanism) and structural properties of the upper airway (anatomic mechanism) are major determinants of upper airway size (2). The contribution of each mechanism to upper airway maintenance during development, however, has not been systematically elucidated because of methodological difficulty in separating these mechanisms. As reported previously, we succeeded in developing a method for evaluation of anatomic properties of the pharynx independently of the neural mechanism (5, 6). The neural mechanism is completely eliminated by producing total muscle paralysis under general anesthesia. Under such circumstances, the anatomic properties of the atonic pharynx can be assessed by measuring cross sectional area of the pharynx at various pharyngeal luminal pressures under conditions of no respiratory airflow. The static mechanics of the passive pharynx is graphically expressed by a pressure-area relationship plot, which exhibits the maximal area, the pressure at which the area is zero (closing pressure), and the passive compliance. Anatomic differences are demonstrated as differences of the static pressure-area relationship.

This approach allowed us to test the hypothesis that anatomic properties of the pharynx change during development in normal infants. We therefore measured the static pressure- area relationships of the passive pharynx of anesthetized and paralyzed normal infants age 2 to 12 mo, and asked whether there was significant correlation between age and the mechanical variables obtained by the pressure-area relationships.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Subjects

Parents of nine infants who were scheduled to have minor surgeries such as repair of inguinal hernia at Chiba University Hospital were invited to include their child in the study. Premature infants were not included in the study. We excluded infants whose height or weight was beyond ± 2 SD from mean values for their age according to cross-sectional growth charts published by the Ministry of Health and Welfare of Japan in March 1992. None of the subjects had a history of cardiac or pulmonary diseases. In addition, according to their parents' observations, the subjects neither snored nor had apneic events during sleep. Age, sex, and body size for each infant are presented in Table 1. We selected the infants so that the age distributed normally and ranged from 2 to 12 mo. Height, ranging from 0.57 m to 0.75 m, and weight, ranging from 5.0 kg to 8.8 kg, also distributed normally in this group of subjects.

After explaining the importance of this study for understanding the pathogenesis of upper airway obstruction, we explained our experimental procedure and duration of the experiment to each of the parents. Because development of hypoxemia during the apneic test was considered to be a major potential risk in this study protocol, we explained to the parents the safeguards of the study, including risk management and the monitoring system. Informed consent was obtained from each after the explanation. Nine of 13 parents whom we contacted agreed to participate in this study. The hospital ethics committee approved the investigation. The study was designed to have minimal interference with the routine anesthetic and surgical procedures.

Pharyngeal Endoscopy under General Anesthesia

Preparation of the subjects. Endoscopic evaluation of the pharynx was performed with the subject placed in the supine position on the operating table, with neck in the neutral position (the face straight up position). The subject wore a modified anesthetic nasal mask. The possibility of air leaks between the mask and the face was indicated by inadequate increases in airway pressure, and actively investigated by feeling around the mask and corrected. General anesthesia was induced by inhalation of gas mixture of nitrous oxide (33%) and sevoflurane (2 to 5%). After intravenous injection of atropine (0.1 mg), a muscle relaxant (vecuronium 0.15 mg/kg, intravenously) produced complete paralysis throughout the experiment. Anesthesia was maintained by inhalation of 1 to 2% sevoflurane in 100% oxygen while the subject was ventilated with positive pressure using an anesthetic machine. A slim endoscope (3 mm outer diameter, FB 10X; Pentax Inc., Tokyo, Japan) was inserted through the nasal mask and naris to visualize the cross-section of the pharynx. A closed-circuit camera (ETV8; Nisco, Saitama, Japan) was connected to the endoscope, and pharyngeal images were recorded on videotape. An endotracheal tube or a laryngeal mask airway was placed after the experiment, and the surgery was performed.

Experimental procedure. After inspection of the entire pharynx, the scope tip was positioned to visualize the velopharyngeal airway (VP; airway behind the soft palate). To determine the pressure-area relationship of the pharynx, the breathing circuit was switched from the anesthetic machine to a pressure controller system capable of accurately producing a constant, preselected airway pressure (Paw) ranging from 20 cm H₂O to +20 cm H₂O in steps of 1 cm H₂O. A blower produced positive and negative Paw, and the level of the Paw was set manually by changing the current to the blower while measuring the Paw using a water manometer. Apnea followed the cessation of mechanical ventilation owing to complete muscle paralysis. Paw was immediately increased and maintained at 20 cm H₂O. While the subject remained apneic, Paw was slowly reduced from 20 cm H₂O to velopharyngeal closing pressure, i.e., the pressure at which the velopharynx was seen to close completely. This procedure of experimentally induced apnea allowed construction of the pressure-area relationship of the visualized pharyngeal segment. Distance between the tip of the endoscope and narrowing site was measured by a wire passed through the aspiration channel of the endoscope.

Safeguards of the Study

A board-certified anesthesiologist had responsibility for subjects' safety, secured by continuous monitoring of Sa_O2, electrocardiogram, and blood pressure throughout the experiment. The experiment was performed only after confirming the capability of maintaining airway patency and mask ventilation while advancing the mandible under paralysis. To avoid hypoxemia, the subject was mechanically ventilated with 100% oxygen before the apneic test. Mean apnea time was 59 ± 6 s. Sa_O2 remained greater than 90% during this apneic test in all subjects. Although we did not measure Pa_CO2, we considered that the Pa_CO2 would not increase above 50 mm Hg at the end of the apneic test because Pa_CO2 was reported to increase by 3 to 6 mm Hg during an apnea for 1 min (7). Accordingly, we considered that such mild increase in Pa_CO2 did not significant affect infant safety.

Data Analysis

To convert the monitor image to an absolute value of cross sectional area of the pharynx, magnification of the imaging system was estimated at 1.0-mm interval distances between the endoscopic tip and the object in the range of 5 to 30 mm. At a defined value of Paw, the image of the pharyngeal lumen was traced and counted pixels included in the area (SigmaScan version 2.0; Jandel Scientific Software, San Rafael, CA). The pixel number was converted to pharyngeal cross-sectional area according to the distance-magnification relationship. Using tubes of known diameter, we tested the accuracy of our cross-sectional area measurements. For a constant distance, the measured areas systematically deviated from actual areas. The largest known area tested (0.95 cm²) was underestimated by 11% because of image deformation at the outer image area, and the smallest known area tested (0.03 cm²) was overestimated by 13% because of reduction of the image resolution.

The measured luminal cross-sectional area was plotted as a function of Paw. We defined closing pressure (P_close) as the pressure corresponding to the zero area. At high values of Paw, relatively constant cross-sectional areas were revealed; therefore, maximal area (A_max) was determined as the mean value of the three highest Paw (18, 19, and 20 cm H₂O). As reported previously (5, 6), the pressure-area relationship of each pharyngeal segment was fitted by an exponential function, A = A_max  B*exp(K*Paw), where B and K are constants. A nonlinear least-square technique was used for the curve fitting, and the quality of the fitting was provided by coefficient R² (SigmaPlot version 2.0; Jandel Scientific Software, San Rafael, CA). A regressional estimate of closing pressure (P'_close), which corresponds to an intercept of the curve on the Paw axis, was calculated from the following equation for each pharyngeal segment: P'_close = ln(B/A_max)K¹. The shape of the pressure-area relationship was described by the value of K. When the pressure-area relationship is curvilinear, compliance of the pharynx defined as a slope of the curve varies with changes in Paw. Therefore, a single value of compliance calculated for a given Paw does not represent collapsibility of the pharynx for entire ranges of Paw. By contrast, K value represents a rate of changes in the slope of the curve. When K value is high, a small reduction of Paw results in a significant increase in compliance leading to a remarkable reduction in cross sectional area. Accordingly, collapsibility of the pharynx increases with increasing K value. We suggest that both P'_close and K values represent collapsibility of the pharynx, whereby the former determines the position of the exponential curve, and the latter characterizes the shape of the curve.

Statistical Analysis

Correlation between the variables was assessed by Pearson correlation coefficients. All values are expressed as means ± SD. A value of p < 0.05 was considered to be significant.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Endoscopic evaluation of the passive pharynx during anesthesia was successfully performed and the pressure-area relationships of the velopharynx were obtained in all nine infants. The exponential function satisfactorily fitted the relationships (R² = 0.95 ± 0.02; range: 0.93 to 0.97). Results of the curve-fitting analysis for each infant are presented in Table 2.

Figure 1 presents the static pressure-area relationships of the passive pharynx for all infants. The pressure-area curves of the younger infants are located below those of older infants with smaller maximal areas and greater closing pressures.

View larger version (28K): [in this window] [in a new window]   Figure 1.   Static pressure-area relationships of passive pharynx are exhibited for all infants. Closed circles represent measured pressure-area data points. Curves represent results of curve-fitting analysis by an exponential function. AVP = velopharyngeal cross-sectional area. See Table 1 for anthropometric characteristics of each subject.

As clearly shown in Figure 2A, we found significant correlation between age and A_max (r = 0.840, p = 0.005). A_max progressively increased during development. In addition, A_max was significantly correlated with body weight (r = 0.930, p = 0.0003) and height (r = 0.825, p = 0.006).

View larger version (13K): [in this window] [in a new window]   Figure 2.   Correlation between age and static mechanical variables. (A) Maximal velopharyngeal area (Amax). (B) Estimated closing pressure (P'close). (C ) K values.

As shown in Figures 2B and 2C, both K value (r = 0.855, p = 0.003) and P'_close (r = 0.809, p = 0.008) significantly decreased with increase in age. It should be noted that P'_close approaches atmospheric pressure in younger infants although all P'_close were below atmospheric pressure.

All three mechanical variables, A_max, P'_close, and K value, were significantly correlated with each other (A_max versus P'_close: r = 0.696, p = 0.04; A_max versus K value: r = 0.787, p = 0.001; K value versus P'_close: r = 0.887, p = 0.001).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

We successfully evaluated developmental changes in static pressure-area relationships of the passive pharynx in paralyzed and anesthetized normal infants. We found that maximal pharyngeal area increased and pharyngeal collapsibility assessed by closing pressure and airway stiffness decreased during development. The results strongly indicate that anatomic properties of the pharynx gain stability in favor of maintaining patent airway during development in normal infants.

Study Design

Passive pharyngeal mechanics was evaluated by manipulating airway pressure during apnea in paralyzed infants in our study. The study design allowed evaluation of anatomic characteristics of the pharynx without influence of neuromuscular regulation of the upper airway muscles as we previously reported (5, 6). In addition, gradual reduction of airway pressure during the apneic test has an advantage of minimizing influence of surface adhesive force, which was reported to play a significant role in maintenance of infant upper airway (8). Paralyzed condition further provided an opportunity to maintain neutral neck position throughout the measurement. A possible shortcoming of our method, however, is uncontrolled lung volume during the procedure because lung volume is known to influence pharyngeal collapsibility (9, 10). Lung volume systematically varied with changing airway pressure in our study, possibly resulting in alteration of the static pressure-area relationship.

Pharyngeal Collapsibility during Development

Compared with the adult, the tip of the epiglottis approximates more closely to the uvula, particularly in young infants (1). This anatomic configuration prevented evaluation of static mechanical properties at the base of the tongue. Although we believe that the velopharyngeal airway is the most collapsible segment in the pharynx, the oropharynx may be more collapsible than the velopharynx. This is probably unlikely because of the observation of Mathew and coworkers that the obstruction site during apnea in preterm infants was identified to be higher level of the pharynx by measuring pharyngeal airway pressure during the apnea (11).

Closing pressures of the passive velopharynx in all normal infants were below atmospheric pressure (range: 0.7 to 9.8 cm H₂O; mean ± SD: 3.6 ± 2.7 cm H₂O). Absence of disordered breathing during sleep may be associated with the level of the closing pressure in infants as previously demonstrated in children and adults (5, 6, 12, 13). Progressive reduction of the passive pharyngeal collapsibility during development reported here is in agreement with the report of Roberts and coworkers (14). They observed that closing pressures of the pharynx in three micrognathic infants progressively decreased with growth from 4 cm H₂O to 13 cm H₂O on average. Because the upper airway muscles were actively contracting in their experimental setting, the developmental changes in the closing pressure could be attributed to either anatomic changes or functional changes of neuromuscular regulation of the upper airway muscles.

Although we do not know the mechanisms of the observed improvement of the pharyngeal collapsibility during development, we speculate three possible fundamental mechanisms based on anatomic changes of the upper airway structures during infancy. First, increased stiffness of the soft tissue surrounding the upper airway may reduce the collapsibility of the pharynx because connective tissues such as elastic fibers distribute less prominently than muscle fibers in the infantile pharynx (1). Second, downward displacement of the larynx and hyoid bone during development may decrease the compliance of the pharyngeal airway wall, possibly owing to increased longitudinal tension of the pharyngeal airway wall. This is supported by previous animal studies demonstrating that the position of the larynx and hyoid bone significantly influences collapsibility and resistance of the pharynx (15, 16). Lastly, increase in functional residual capacity during development may decrease pharyngeal collapsibility, probably because of increase in tracheal traction that possibly acts to the pharyngeal wall as longitudinal tension (15, 16).

Comparison of Static Mechanical Properties Among Generations

Using the same technique, we previously reported the static mechanical properties of the passive velopharyngeal airway in normal children and adults (5, 6). Taking into consideration these data together with the results presented here, we have an opportunity to discuss differences of mechanical properties of the pharynx among the generations (Figure 3). We consider that a human being starts his or her life with relatively collapsible pharynx with higher compliance and closing pressure. Airway stability increases within the first year of life with decrease of closing pressure and compliance, as we demonstrated in this study. This finding agrees well with the polysomnographic observation that obstructive apnea frequency decreased during infancy (17). Airway stability is further increased during childhood in terms of pharyngeal wall compliance and closing pressure of the pharynx. However, closing pressure increased during adulthood to the level of the infants whereas compliance appears to be lower than that of the infants. The differences in the mechanical properties between children and adults are also in agreement with the fact that the normal values of the number of apnea were much smaller in children than in adults (18, 19). However, the differences of the structural properties alone do not explain why adults had more apneas than infants whereas both generations had identical mean closing pressures of the pharynx. This suggests significant roles of the neuromuscular mechanisms in determining the airway patency in infants in accordance with the finding that even preterm infants were able to augment upper airway muscle activities in response to airway occlusion (20). We still lack knowledge on pharyngeal collapsibility of neonates, adolescents, and the elderly in addition to developmental changes of regulation of pharyngeal muscle activity.

View larger version (13K): [in this window] [in a new window]   Figure 3.   Differences of Amax, P'close and K value among different generations. (A) Data obtained by the present study (nine infants). (B) Data from Reference 6 (13 children), (C ) Data from Reference 5 (17 adults). All data were obtained under general anesthesia with complete paralysis. Closed circles represent mean values; bars indicate SD.