INTRODUCTION

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Measurements of the static properties of the respiratory system in healthy, spontaneously breathing infants have used the airway occlusion technique to evoke the Hering-Breuer reflex and a brief apnea with relaxation of the respiratory muscles (1). Both single-occlusion and multiple-occlusion techniques have been developed for such measurements, but both methods have been limited to the tidal range of breathing. The expiratory volume-clamping technique was proposed as a method to increase lung volume above the tidal breathing range while still evoking the Hering-Breuer reflex, in order to obtain a pressure-volume (PV) curve over a greater range of lung volume (2). This technique, which measures the inspiratory and not the expiratory PV curve, has had limited use since its initial description.

In studies done to obtain forced expiratory maneuvers initiated from a lung volume near TLC, we have previously used and have described a method for transiently inhibiting respiratory activity by using positive pressure at the airway opening to quickly inflate the respiratory system several times to near TLC (3). In the present report we describe how this same maneuver can be applied to induce a respiratory pause that enables deflation PV curves to be obtained from near TLC to passive FRC. We applied this methodology to measure the compliance of the respiratory system (Crs) of healthy infants.

	METHODS

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Healthy infants were recruited from general pediatric clinics in Indianapolis and from advertisements. Infants were excluded from the study if they were premature at birth (< 36 wk gestation), had congenital malformations, or had recurrent lower respiratory illnesses. Subjects were also without upper respiratory symptoms for at least 3 wk before evaluation. Histories for exposure to tobacco smoking during pregnancy and postnatal environmental tobacco smoke exposure by parents or caregivers, as well as an immediate family history of asthma, were obtained at the time of testing. The institutional review board of the Indiana University Medical Center approved the study.

Infants enrolled in the study were weighed and their length was measured with a stadiometer while they were awake. They then received 50 to 75 mg/kg of chloral hydrate orally, and measurements were obtained while each infant was sleeping in the supine position. The infant breathed through a face mask (Vital Signs, Inc., Totowa, NJ) attached to a circuit that contained a three-way valve (Model CR1163; Hans Rudolph, Kansas City, MO) with a transducer to measure mouth pressure (MP-45-871; Validyne, Northridge, CA), a pneumotachometer (Model 3700; Hans Rudolph) with a differential pressure transducer (MP-45-871; Validyne) to measure inspiratory and expiratory flow, a pressure-relief valve (Model IV-100B; Sechrist, Anaheim, CA) set at 30 cm H₂O, and a three-way valve (Model CR1163; Hans Rudolph) at the distal end of the expiratory circuit with a bias flow of 15 to 20 L/min (Figure 1). Occlusion of the distal valve resulted in inflation of the respiratory system to an airway pressure of 30 cm H₂O. Zero flow was used as the criterion for end-inflation, and subsequent release of the occlusion allowed expiration to proceed. The face mask was kept manually against the face to prevent air leaks during lung inflation and to control the position of the upper airway. The analog signals of flow and pressure were amplified and filtered above 50 Hz, digitized at 100 samples per second (Model DT 3001; Data Translation, Marlboro, MA), displayed on a computer monitor in real time, and stored for subsequent analysis. Volume was obtained by digital integration of the flow signal, with the computer controlling the breathing-circuit valves.

View larger version (16K): [in this window] [in a new window]   Figure 1.   System used for generating static deflation PV curves for infants. The infant breathes through the face mask connected to the circuit with Valve A closed and Valves B, C, and D open while flow (V') and pressure (P) are measured. There is a bias flow of air at 15 L/min through Valves C and D. Closing Valve D results in inflation of the respiratory system to 30 cm H2O airway pressure, with regulation by the pressure-relief valve (E). Reopening Valve D allows deflation. After the last inflation, Valve D is opened; however, Valve B is rapidly opened and closed many times while the respiratory system passively deflates to FRC.

After several inflations of the respiratory system to a volume at an airway pressure of 30 cm H₂O (V₃₀), passive expiration was followed by a brief respiratory pause at the passive FRC. The expired volume from V₃₀ to FRC was defined as V_30E. On the next inflation to V₃₀, the proximal valve between the airway opening and the pneumotachometer was repeatedly occluded for 500 ms and then released approximately 10 to 15 times as the lung passively deflated to FRC or the infant began spontaneous respirations (Figure 2).

View larger version (36K): [in this window] [in a new window]   Figure 2.   Tracing of volume and airway pressure with time. The respiratory system is inflated three times to a volume at an airway pressure of 30 cm H2O, with each inflation followed by passive expiration. The expired volume from V30 to FRC on the last uninterrupted passive deflation was defined as V30E. On the next inflation to V30, the proximal valve between the airway opening and the pneumotachometer was repeatedly occluded for 500 ms, and was then released approximately 10 to 15 times as the lung passively deflated to FRC.

Data Analysis

Volume drift was measured for 10 s immediately after the completion of each maneuver. Using this calculated rate of volume drift, which was small, we digitally corrected the digital signal during the compliance maneuver. We defined the occurrence of a pressure plateau during an airway occlusion as a change in mouth pressure of less than 0.5 cm H₂O for more than 200 ms. PV curve was constructed by plotting the mouth pressure plateau during each occlusion against the volume expired from V₃₀ (Figure 3). Crs was calculated from a linear regression of data points between 5 and 15 cm H₂O. This midrange of the PV curve was linear, although at lower and higher pressures, the PV curves were nonlinear.

View larger version (51K): [in this window] [in a new window]   Figure 3.   Volume expired versus plateau in mouth pressure at each airway occlusion during passive expiration from V30 to FRC. Crs was calculated from the linear regression of data points between 5 and 15 cm H2O. This midrange of the PV curve was linear, although at lower and higher pressures the PV curves were nonlinear.

The relationships between Crs and the independent variables of body length, V_30E, sex, and respiratory history were assessed through multiple linear regression analysis.

	RESULTS

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Forty-nine healthy infants (26 males and 23 females) with a mean age of 47 wk (range: 1 to 104 wk) were evaluated. Eleven of the 49 infants had a history of maternal smoking during pregnancy, and 12 of the 49 infants had a history of asthma in an immediate family member (parent or sibling). For each infant, from 3 to 14 paired pressure- and volume-data points were included in the linear regression equation used to calculate Crs, and all regression equations had a correlation coefficient of 0.99.

Crs increased with increasing body length (p < 0.001), and after adjusting for body length, we found that Crs was greater in male than in female infants (p = 0.006) (Table 1). V_30E also increased with increasing body length (p < 0.001), and after accounting for the variance related to body length, we found that infants exposed to maternal smoking during pregnancy had lower V_30E values than infants whose mothers did not smoke during pregnancy (p < 0.04) (Table 1, Figure 4). In addition, females had lower values of V_30E than did males (p < 0.05) (Figure 5). Crs correlated significantly better with V_30E than with body length, and after accounting for the variance related to V_30E we found only a tendency for male infants to have greater values for Crs than female infants (p = 0.09). Neither Crs nor V_30E were related to family history of asthma. When specific compliance was calculated as Crs/V_30E, there was a small but significant decline in specific compliance with increasing age or body length (Table 1, Figure 6), and no significant differences related to sex or maternal smoking. Each subject had from two to four technically acceptable PV curves recorded. The means (ranges) for the coefficients of variation for Crs and V_30E for the group were 6% (1 to 18%) and 4% (1 to 13%), respectively.

View larger version (14K): [in this window] [in a new window]   Figure 4.   V30E versus body length. Infants exposed to maternal smoking during pregnancy (x) had lower values of V30E than did infants with mothers who did not smoke during pregnancy (open squares) (p < 0.05).

View larger version (11K): [in this window] [in a new window]   View larger version (14K): [in this window] [in a new window]   Figure 5.   (A) V30E versus body length. Male infants (plus signs) had larger values of V30E than did female infants (diamonds) (p < 0.04); (B) Crs versus body length. Male infants (plus signs) had larger values of Crs than did female infants (diamond ) (p < 0.04).

View larger version (13K): [in this window] [in a new window]   Figure 6.   Specific compliance of the respiratory system (Crs/V30E) declined with increasing body length (cm) (p < 0.01). The differences between male (plus signs) and female (diamonds) infants were not statistically significant.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Our study measured in healthy infants the static deflation PV curve of the respiratory system between lung volumes near TLC and FRC. Most prior studies of the static properties of the respiratory system of healthy infants have either been limited to the lung volume range of tidal breathing or have made their measurements in anesthetized and/or intubated subjects (1). Our results suggest a greater compliance in male infants than in female infants, related to a larger lung volume in the former, and also suggest that maternal smoking during pregnancy may result in a hypoplastic lung. In addition, we found that Crs normalized to volume declined with increasing age during infancy.

Our methodology for obtaining static deflation PV curves in healthy infants used a combination of mild hyperventilation and recruitment of the Herring-Breuer inflation reflex to induce a respiratory pause. We have previously used this same technique to inhibit respiratory activity during forced expiratory maneuvers in infants of the same age group as in the present study (3). In this study we used the criterion of a pressure plateau of 200 ms. to define the presence of relaxation with a static recoil pressure. Other investigators have also used this length of time, although most infants in our study had plateaus that were closer to 400 ms. (1). The static deflation PV curves that we obtained in these healthy infants appear similar to those obtained from older children and adults, who actively cooperate to relax their respiratory muscles. In contrast to older children and adults, who perform the static deflation PV maneuver in the upright position, either sitting or standing, our infants were evaluated in the supine position. For many of our infants, the PV curve was nonlinear at low pressures, which may reflect airway closure at low lung volumes in the supine body position. A similar curvilinearity of the PV curve at low airway pressures has been observed with the volume clamping technique in sedated infants, as well as in infants under general anesthesia (2, 4).

Using the volume clamping technique in sedated healthy infants, Grunstein and colleagues reported an average Crs/kg of 1.6 ml/cm H₂O/kg (2), which is similar to the value of 1.8 ml/cm H₂O/kg for our infants. The smaller value in the volume clamping technique may reflect the calculation of Crs as a chord slope between 0 and 20 cm H₂O with the volume clamping technique, as well as the recording of values on the inspiratory portion of the PV curve. The study with measurements most comparable to ours was that done by Sharp and coworkers (4), who calculated Crs in the linear, midrange portion of the PV curve obtained during deflation from TLC to FRC; however, their measurements were obtained with anesthetized and intubated infants and children. For a subject with a body length of 80 cm, the values of Crs predicted from our study and theirs were 20.3 versus 19.5 ml/cm H₂O, respectively. The good agreement of our values with those obtained from anesthetized infants suggests that our methodology produced good relaxation of the respiratory system. Reported values for Crs measured in the tidal lung volume range with the single- or multiple-occlusion technique are lower than those obtained either by Sharp and coworkers or in our current study, and this probably reflects the curvilinear shape of the PV curve at lower lung volumes, as well as the greater difficulty in obtaining respiratory relaxation at lower lung volumes (1). This would be in agreement with the results of Fletcher and colleagues, who reported that increasing the tidal volume resulted in an increase in Crs measured in anesthetized infants and young children (5).

The effect of tobacco smoke exposure on Crs remains unclear. In the Boston epidemiologic study, tobacco smoke exposure was associated with greater values of Crs very early in life; however, there was a slower increase in Crs and FRC with increasing age among infants exposed to maternal smoking during pregnancy (6). Previous measurements of lung volume in infants have been limited to FRC and FVC, and an effect of tobacco smoke exposure has not been found (7). This may relate to the high variability of FRC in infants, and the latter may therefore not be a sufficiently sensitive measure for assessing lung hypoplasia. In rats, exposure to tobacco smoke during pregnancy produces lung hypoplasia with fewer but larger alveoli and saccules, as well as fewer elastin fibers (14). Among our infants, V_30E was smaller in those exposed to tobacco smoke during pregnancy, which would be consistent with lung hypoplasia, although we cannot exclude the possibility of an increased FRC. We did not find evidence for alteration in the elastic properties of the respiratory system of infants with tobacco smoke exposure in utero.

We found that specific compliance of the respiratory system, when measured in the mid-lung-volume range, declined with increasing age and increasing body length. Our finding is consistent with that of Papastamelos and colleagues, who measured chest wall compliance (Cw) in infants. These investigators reported that Cw/kg decreased with increasing age during infancy (15). The decline that we observed in Crs with age may well be a result of stiffening of the chest wall early in life.

In conclusion, we describe a technique to measure static deflation PV curves in healthy sedated infants. With this technique, we found that Crs increases with body length and lung volume, with male infants having greater values of Crs and V_30E than do female infants. In addition, our data suggest that maternal smoking during pregnancy may produce lung hypoplasia.