INTRODUCTION

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In utero, all of the conducting airways are present prior to alveolarization of the lung, which begins during the third trimester of gestation and proceeds rapidly through the first few years of life. Airway caliber and lung volume (VL) increase many fold between infancy and adulthood; however, these two components of the lung may not increase proportionately during lung growth and development. Although infants have absolutely smaller airways than older children and adults, several studies have suggested that infants compared with older subjects have large airways relative to their VL. Specific conductance has been reported to decline during the first year of life (1). Forced expiratory flow measured at functional residual capacity (FRC) and expressed as FRC/s also declines during this period of time (2, 3). In addition, Bryan and Wohl (4) calculated that the rate constant for lung emptying during forced flows near FRC was greater in newborns than older children and adults. However, measurements of flows at FRC may be confounded by the high variability of FRC very early in life, the potential for active elevation of FRC in this age group, and the uncertainty whether flow limitation is achieved during partial maneuvers in infants.

Forced expiratory maneuvers in infants have recently been modified so that respiratory effort is inhibited and forced maneuvers start from a VL near total lung capacity and proceed to residual volume (5). In addition, flow limitation is achieved during forced expiration with this technique. The relative size of airways to VL can be assessed from the rate of emptying of the lung. The rate of emptying can be quantified as a rate constant (RC;1/s), the slope of the forced expiratory flow-volume curve, or the fraction of the forced vital capacity (FVC) expired in a specific time. We hypothesized that if VL increased more rapidly than airway caliber then the RC would decrease with increasing age during infancy.

	METHODS

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Subjects

Seventeen normal healthy infants, nine males and eight females, were evaluated at two different ages. Subjects were full term at the time of birth and had no history of prior lower respiratory illness. In addition, they had no upper respiratory symptoms for at least 3 wk before testing. The mean age (range) at the time of the first and the second evaluations were 30 (5 to 76) and 58 (28 to 98) wk, respectively. The institutional review board of Indiana University approved the study and informed consent was obtained from the parents.

Forced Expiratory Maneuvers

Forced expiratory maneuvers from elevated VL were performed using the rapid thoracic compression technique as previously described (5). Forced expiratory flows were initiated from a VL at which the airway pressure was 30 cm H₂O (V₃₀) and proceeded to residual volume. Delivering several sequential inflations to V₃₀ before the forced expiratory maneuver inhibited respiratory effort during forced expiration.

The inspiratory circuit contained an adjustable continuous flow of air and a pressure relief valve set at 30 cm H₂O, which limited inflation of the respiratory system, when the expiratory valve was occluded. Forced expiration was initiated at this elevated VL by rapidly inflating the jacket, which was wrapped around the infant's chest and abdomen. An electronic solenoid valve between the jacket and the pressure reservoir controlled jacket inflation, and jacket pressure was monitored with a differential pressure transducer (MP-45-871; Validyne, Northridge, CA) referenced to atmospheric pressure. A pneumotachometer (model 3700; Hans Rudolph, Kansas City, MO) and differential pressure transducer (MP-45-871; Validyne, Northridge, CA) were used to measure the inspiratory and expiratory flow. The analog signals of flow and pressure were amplified and filtered above 50 Hz (Validyne CD 19-A) and digitized at 100 samples per second (D/A board Data Translation, DT 3001). Volume was obtained by digital integration of the flow signal, and the signals were displayed on the computer monitor in real time and stored for subsequent analysis. Forced expiratory maneuvers were repeated with increasing jacket compression pressures until the curve with the highest expired volume and flow was obtained.

Analysis

From the two to three technically acceptable maximal flow-volume curves obtained for each subject, FVC was calculated as the expired volume between V₃₀ and residual volume. At 50% and 75% of FVC (FVC₅₀, FVC₇₅), the forced expiratory flows were measured (FEF₅₀, FEF₇₅). A rate constant between 50% and 75% FVC for forced expiration was calculated as follows:

Another assessment of the rate of emptying during forced expiration was calculated from the ratio of volume expired in 0.5 s (FEV_0.5) to FVC (FEV_0.5/FVC). The best flow-volume curve was selected as the curve with the highest product of FVC and FEF_25-75 and each individual's best curve was used for cross-sectional and longitudinal analysis.

	RESULTS

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The number of forced expiratory maneuvers obtained in these infants ranged from five to 15. From the two or three technically acceptable maneuvers obtained at the compression pressure that achieved the best flow-volume maneuver, the group mean coefficients of variation for FVC, FEV_0.5/FVC, and rate constant between 50% and 75% FVC (RC_50-75) were 1.9%, 2.3%, and 13.2%, respectively.

The values for the RC_50-75 versus age (weeks) at the initial evaluation are illustrated in Figure 1. The data are best described with a power function. In these subjects, the cross-sectional data demonstrate that RC was greater for the younger than the older infants. The longitudinal values of RC_50-75 versus age are illustrated for these subjects in Figure 2. For the whole group, there was a significant decrease in RC between the first and the second measurements, when assessed by paired t test (Table 1). It can be seen from Figure 2 that longitudinal values decreased more markedly for the younger infants. The analysis was repeated with the infants divided into younger (< 40 wk; n = 11) and older (> 40 wk; n = 6) age groups based upon age at the initial evaluation. For the younger group there was a highly significant decrease in RC_50-75 between the first and the second evaluations. There was a tendency for RC_50-75 to increase between both tests for the older infants; however, the change did not reach statistical significance and the older infants at the second test still had a significantly lower RC_50-75 than the younger infants at the first test (Table 1).

View larger version (12K): [in this window] [in a new window]   Figure 1.   Individual values (closed circles) of RC (1/s) versus age (weeks) for 17 healthy infants at the first test. Regression equation (solid line) for power function fit to values.

View larger version (17K): [in this window] [in a new window]   Figure 2.   Longitudinal values of RC (1/s) versus age (weeks) for 17 healthy infants.

The values for FEV_0.5/FVC versus age (weeks) at the initial evaluation are illustrated in Figure 3. These data are best described with a power function. The cross-sectional data demonstrate that FEV_0.5/FVC was greater in the younger than the older infants. The longitudinal values of FEV_0.5/FVC versus age are illustrated in Figure 4. For the whole group, there was not a significant change in FEV_0.5/FVC between the first and the second measurements, when assessed by paired t test (Table 2). It can be seen from Figure 4 that longitudinal values of FEV_0.5/FVC decreased for the younger infants but not for the older infants. For the younger group (< 40 wk) there was a significant decrease in FEV_0.5/FVC between the first and the second evaluations; however, there was no significant change in FEV_0.5/FVC for the older infants. When the entire analysis was repeated using mean values from each individual's multiple flow-volume maneuvers, the results were the same as those obtained using the parameters obtained from the individual's best flow-volume curve.

View larger version (12K): [in this window] [in a new window]   Figure 3.   Individual values (closed circles) of FEV0.5/FVC (1/s) versus age (weeks) for 17 healthy infants at the first test. Regression equation (solid line) for power function fit to values.

View larger version (16K): [in this window] [in a new window]   Figure 4.   Longitudinal values of FEV0.5/FVC (1/s) versus age (weeks) for 17 healthy infants.

	DISCUSSION

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We found that the rate of emptying during forced expiration was greatest in the youngest infants and decreased during infancy in both cross-sectional and longitudinal analysis. The rate of emptying was assessed using two different measurements from the flow volume curve, the RC between 50% and 75% FVC and the fraction of the FVC expired in 0.5 s. Our findings are consistent with the concept that younger infants have large airways relative to their VL and that VL increases more rapidly than airway caliber early in life.

Our assessment of the rate of lung emptying was obtained from forced expiratory maneuvers. For one index of the rate of lung emptying, we measured the RC between 50% and 75% expired volume, which is in the VL range of tidal breathing. The RC that we found in our youngest infants was similar to the value reported in newborns assessed with partial forced expiratory maneuvers (4). In contrast to previous studies that measured maximal flows at FRC with a potentially variable and actively controlled end-expiratory level, the parameters we measured from full flow-volume maneuvers are not referenced to VL at FRC. Therefore, these parameters are independent of the variability associated with transient changes in the end-expiratory level. In addition, we measured FEV_0.5/ FVC, which included the higher portion of the flow-volume curve. Both of the parameters that we measured (RC_50-75 and FEV_0.5/FVC) gave results consistent with each other; emptying was more rapid in the youngest age group.

Forced expiratory flows are an indirect measure of airway caliber as maximal flows depend upon cross-sectional area of the airway, airway wall compliance, and lung recoil pressure (6). Although there are limited measurements of airway wall compliance, published data in humans and animals suggest that the airway walls stiffen with maturation (7, 8). Therefore, more compliant airways in the less mature subject should not contribute to proportionately higher flows in the younger infant. Similarly, limited data on lung elastic recoil pressure in infants suggest lower values in younger infants (9). This would also suggest that the faster rate of emptying in the younger infant should be related to relatively larger airways for the VL that is to be emptied. In our analysis, we used the ratio FEV_0.5/FVC as an index of the rate of lung emptying. In older children and adults, flows are normalized to volume using FEV₁ in contrast to our use of FEV_0.5. We were unable to use FEV₁ for the infants because the forced maneuver was complete before 1 s in most of the infants. This again is an indication of the more rapid emptying of the infant lung relative to VL.

Our findings would be consistent with cross-sectional data for changes in VL, compliance, and resistance during the first few years of life. Both VL and compliance increase approximately threefold, whereas airway and pulmonary resistance halves (1, 14). The product of resistance and compliance also expresses a time constant for the respiratory system, which would increase secondary to the greater increase in compliance or volume compared with the decrease in resistance. This is consistent with the increase in the time constant (inverse of RC) of passive tidal expiration between infancy and early childhood (22).

In conclusion, we have demonstrated that the rate of emptying during forced expiration decreases during lung growth early in life. The rate of emptying decreases whether measured as RC_50-75 or the fraction of FVC expired in 0.5 s. This finding is consistent with the concept that infants have large airways relative to their VL, and that VL increases more rapidly than airway caliber early in life.