In the present study, we have shown that very low birth weight (VLBW) infants (birth weight < 1,500 g) with BPD exhibit reduced somatic growth (in terms of body weight and length) and impairment of some lung function parameters, compared to VLBW infants without BPD, when assessed at the same PMA. With the exception of the tidal breathing parameters VT
, we found no evidence for catch-up during the first 15 months of life. This is in agreement with the data obtained from sequential lung function measurements performed at 6, 12, and 24 months after birth on 44 infants with moderate-to-severe BPD, which showed that lung function abnormalities persisted [29
]. A study by Baraldi et al. [13
] of 24 VLBW infants with BPD showed that pulmonary mechanics improved during the first years of life but substantial airway functional impairment remained, as revealed by a low V'maxFRC
The extent to which lung function in BPD survivors improves with age remains controversial [24
]. Blayney et al. [30
] investigated 32 former BPD infants at mean ages of 7 and 10 years. Those with normal lung function at age 7 years demonstrated normal lung growth whereas those with evidence of impaired lung function at 7 years of age exhibited continued lung growth or repair, or both, during later school years. In another study, Koumbourlis et al. [31
] performed repeated lung functional testing of 17 former BPD subjects between the ages of 8 and 15 years and found that although airflow obstruction may persist, this does not deteriorate later in life; an improvement in air trapping over time was evident. A more recent study by Doyle et al. [24
] on 147 former VLBW infants, of whom 33 formerly had BPD, showed that, at a mean age of 19 years, those with former BPD had poorer lung function than those without former BPD.
In the present study, the most significant lung function differences between the two patient groups were in the tidal breathing parameters (VT
), lung compliance and end-expiratory lung volume. Whereas FRCpleth
did not differ between former BPD and non-BPD infants, FRCSF6
(which measures the lung volume in actual communication with the airways) was significantly lower in former BPD compared to non-BPD infants. However, all differences in tidal breathing, lung compliance and FRC values disappeared after normalization of such parameters to actual body weight. This is attributable to the significant somatic growth retardation evident in former BPD infants. Normalization in terms of weight is usually performed after LFT of infants to reduce the extent of (the otherwise high) inter-subject variability. However, in infants experiencing growth retardation, such normalization may lead to overestimation of lung function. Hence, the results should be interpreted with caution. The reasons for the poor growth of preterm infants with former BPD remain unknown, but likely include dysfunction of various organ systems, decreased nutrient intake, and increased energy requirements [31
Immaturity and BPD independently impair postnatal lung function. Hoo et al. [32
] were the first to show that the V'maxFRC
was reduced in preterm infants in the absence of any neonatal disease or therapy. The reduction was attributable to the arrest of lung and airway development. A preliminary study by Gappa et al. [33
], measuring V'maxFRC
in premature infants with and without BPD, suggested that prematurity per se
may be a more important contributor to the observed impairment in lung function than is BPD. This may explain why we did not find any statistically significant difference in V'maxFRC
values between preterm infants with and without former BPD.
Although the measurement of V'maxFRC
is currently the most frequently used lung function test in infants who are unable to cooperate, the effect of the BPD on lung function can not only reduced on the assessment of the small airways. Hjalmarson and Sandberg [10
] found in preterm infants with severe BPD a reduced FRC and increased inhomogeneity indices indicating an impaired alveolar gas mixing. Furthermore they found a reduced lung compliance and changes in the breathing pattern; the tidal volume was decreased and the respiratory rate increased. The differences between healthy preterm infants and those with mild-to-moderate BPD were distinctly lower.
Several studies [12
] using tracer gas techniques have shown that the FRC is reduced in former BPD infants, in good agreement with the findings of the present study. This reduction in FRCSF6
may not necessarily reflect a defect in lung development (the FRCpleth
values were identical in either group) but rather a reduction in the proportion of the lung volume that participates in pulmonary gas exchange, in turn attributable to structural changes in the lung caused by BPD and the use of mechanical ventilation. All of our BPD infants required invasive mechanical ventilation.
Consistent with the findings of the present study, Hjalmarson and Sandberg [10
] found no significant difference in respiratory resistance between former BPD and non-BPD infants. Further, the variation in lung compliance did not persist after normalization to actual body weight. In contrast to studies from the presurfactant era, which predominantly investigated infants born at term [37
], no difference in the elastic performance of the respiratory system was evident between former BPD and non-BPD preterm infants. This may be explained by the fact that respiratory compliance after birth, in both groups, was very low, as a result of immaturity (as reflected by the low birth weights). Rapid catch-up growth during the first 15 months of life was evident; normal values of approximately 14 mL/kPa/kg [39
] were eventually attained. Former BPD infants attained such values somewhat more slowly than did non-BPD infants (Figure , top). Baraldi et al. [13
] also found that the respiratory compliance of VLBW infants with former BPD became normal at 2 years of age.
Catch-up growth in terms of lung compliance during the first year of life was reported in a study of BPD infants performed by Gerhardt et al. [40
] in the presurfactant era 25 years ago).
The cited authors speculated that, in former BPD infants, the increase in compliance evident upon aging was associated with lung growth, and more specifically to the formation of new alveoli. Specific compliance increased with age, as was also the case in our present work (Figure , bottom), supporting the interpretation of Gerhardt et al. [40
As the lung grew, maturation of the breathing pattern was observed in both groups, as shown by an increase in tidal volume and a fall in the respiratory rate. However, a distinct delay in maturation was apparent in former BPD infants. Only a few studies have measured tidal breathing parameters in preterm BPD infants. Previously [41
], we found that BPD infants showed an increased respiratory rate and elevated minute ventilation, but no change in tidal volume, compared with healthy controls delivered at term. Similar results were obtained by Latzin et al. [12
], who compared preterm former BPD infants with preterm healthy newborns at 44 weeks PMA. Hjalmarson and Sandberg [10
] described a similar pattern in preterm infants with mild-to-moderate former BPD. Tidal volume (normalized to body weight) was significantly reduced in infants with severe BPD, compared to healthy preterm controls. Although the data did not attain statistical significance, we also noted increases in both respiratory rate and minute ventilation, normalized to body weight at term, in the present study. This breathing pattern is characteristic of stiff lungs and is energetically optimal [43
]. However, with increasing age, a decrease in minute ventilation (normalized to body weight) was evident in former BPD infants. This was caused by a decrease in tidal volume. In non-BPD infants, minute ventilation per kilogram of body weight was near-constant. It remains unclear whether the decrease in minute ventilation in former BPD infants is attributable to impairment of respiratory mechanics resulting in a lower FRC, to the existence of a lower respiratory drive, or to a defect in respiration control.
The present study had several strengths and limitations. The strengths are the depth at which LFT was performed; we measured tidal breathing, respiratory mechanical parameters, lung volume, maximal respiratory flow, and blood gas levels. Also, all patients were examined by the same investigator, using the same equipment and protocol. Apart from the known intersubject variability of several of the parameters that we measured, LFT remains highly device- and protocol-dependent. This poses major problems in multicenter studies [17
]. The limitations of our study are the retrospective nature of our analysis, the small sample sizes of both groups (limiting our power to detect differences between former BPD and non-BPD infants with statistical significance), and the lack of a control group of healthy infants [44
]. It is virtually impossible to recruit such a control group, for both practical and ethical reasons. Because our study was observational in nature, no causal relationships can be deduced from our findings.
In conclusion, the extent of somatic growth, and the evolution of some lung function parameters, of very preterm infants with former BPD lag behind those characteristic of preterm infants without BPD for the first 15 months of life. The differences between the groups in most lung function parameters disappear after the somatic growth retardation of former BPD infants is taken into account. Longitudinal LFT of preterm infants after discharge from hospital may help to identify those at risk of incomplete recovery of respiratory function, which can lead to development of respiratory problems in childhood and adolescence.