American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 1539-1543, (2002)
© 2002 American Thoracic Society
Worsening of V'maxFRC in Infants with Chronic Lung Disease in the First Year of Life
A More Favorable Outcome after High-Frequency Oscillation Ventilation
Ward Hofhuis,
Marianne W. A. Huysman,
Els C. van der Wiel,
Wim P. J. Holland,
Wim C. J. Hop,
Govert Brinkhorst,
Johan C. de Jongste and
Peter J. F. M. Merkus
Department of Pediatrics, Divisions of Respiratory Medicine and Neonatology; Department for Experimental Medical Instrumentation; and Department of Biostatistics, Erasmus University Medical Center/Sophia Children's Hospital, Rotterdam; and Department of Pediatrics, Medical Center Alkmaar, Alkmaar, The Netherlands
Correspondence and requests for reprints should be addressed to Peter J. F. M. Merkus, M.D., Ph.D., Erasmus University Medical Center, Sophia Children's Hospital, Department of Pediatrics, Division of Respiratory Medicine, Room Sp-2469, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands. E-mail: merkus{at}alkg.azr.nl
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ABSTRACT
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Little is known about the development of maximal flow at functional residual capacity, a measure of airway patency, in infants with chronic lung disease (CLD). In a follow-up study, we evaluated V'maxFRC in very low birth weight infants with CLD, treated with high-frequency oscillation ventilation (HFOV) or conventional mechanical ventilation. In 36 infants with CLD, V'maxFRC was evaluated at 6 and/or 12 months corrected age, and the relationship between perinatal factors and lung function was studied. Mean (SD) birth weight and gestational age were 837 (152) g and 26.8 (1.7) weeks, respectively. At 6 and 12 months, mean V'maxFRC was significantly below normal. Between 6 and 12 months, there was a mean (95% confidence interval) reduction in V'maxFRC (Z score) of 0.5 (0.2–0.7) (p < 0.001). At 12 months, the mean V'maxFRC (Z score) was higher for children initially treated with HFOV (n = 15), as compared with children treated with conventional mechanical ventilation (n = 16): mean (95% confidence interval) difference was 0.6 (0.2–1.0) (p = 0.008). We conclude that very low birth weight infants with CLD have decreased V'maxFRC that worsen during the first year of life. Initial treatment with HFOV was associated with a more favorable outcome of V'maxFRC at 12 months corrected age.
Key Words: neonatal chronic lung disease • prematurity • pulmonary function test • high-frequency oscillation ventilation
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INTRODUCTION
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Chronic lung disease (CLD) is a common sequel of mechanical ventilation and oxygen therapy in prematurely born infants (1). Despite advances in prenatal and neonatal care, including antenatal and postnatal steroids, surfactant treatment, and high-frequency oscillation ventilation (HFOV), CLD is still one of the major complications in mechanically ventilated premature infants (2). The overall incidence of CLD has remained high as a result of the increased survival of extremely premature infants, who are most likely to develop CLD (2). Long-term studies show that survivors of CLD have abnormal pulmonary function tests at school age (3, 4), whereas infants who received initial HFOV showed normal lung function at school age (5). Only a few studies evaluated lung function during the first years of life in children with CLD. In young children with CLD, lung function parameters, such as functional residual capacity (FRCp), compliance, resistance, and conductance, show a gradual improvement toward the normal range during the first 3 years of life (6–8). Nevertheless, maximal flow at FRC (V'maxFRC), used as a measure of airway patency, is known to be decreased during the first 2 years of life (6, 8, 9). Due to advances in prenatal and neonatal care, results obtained in the past may not be valid for infants who develop CLD nowadays. There are no recent studies that evaluated V'maxFRC during the first year of life in very low birth weight (VLBW) infants with CLD, in the era of surfactant therapy and HFOV.
Therefore, we aimed at evaluating V'maxFRC at 6 and 12 months corrected age, in a group of VLBW infants with CLD. Furthermore, we studied the relationship between lung function and perinatal patient characteristics.
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METHODS
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Subjects
A follow-up study was conducted in neonates who developed CLD, born between January 1998 and September 1999. All infants were born in or transferred immediately after birth to the Neonatal Intensive Care Unit of the Sophia Children's Hospital. The inclusion criteria were (1) VLBW: birth weight of 1,250 g or less, (2) need for mechanical ventilation from Day 1 for at least 7 days, (3) need for continuous supplemental oxygen at 28 days and/or at 36 weeks gestational age, and (4) chest radiogram at 1 month of age typical for CLD. The exclusion criteria were major congenital anomalies, meconium aspiration, or suspected hypoplasia of the lungs. Artificial ventilation in the Neonatal Intensive Care Unit was administered by conventional mechanical ventilation (CMV) or HFOV. Initial ventilation strategy was not randomized in our study. Preferably, initial HFOV was started in the youngest and smallest infants. This was not always feasible due to the limited availability of HFOV equipment, and hence, initial ventilation strategy was partly determined by chance. When infants developed hyaline membrane disease, surfactant (Survanta, 100 mg/kg/dose) was administered. Neonates with severe hyaline membrane disease received additional doses. When infants developed a persistent need for artificial ventilation, treatment also included fluid restriction and diuretics. To wean them off the ventilator, most infants were treated with dexamethasone, administered in a 3-week course starting with a dose of 0.5 mg/kg/day that was gradually tapered. All infants were age-corrected to a gestational age of 40 weeks. The study was approved by the medical ethical committee of the Erasmus University Medical Center. All parents gave informed consent.
Lung Function
Lung function measurements were performed at 6 and 12 months corrected age, when the infants were free from acute respiratory symptoms. To prevent the infants from waking up during the measurements, they were sedated with choral hydrate (50–75 mg/kg). FRCp was measured by means of a modified whole body plethysmograph (Jaeger, Würzburg, Germany). Equipment and procedures were in accordance with recently published guidelines, in which the FRCp measurement is described in detail (10). The mean FRCp of three to five technically acceptable measurements was expressed as Z score (10). V'maxFRC was assessed using the end-tidal rapid thoracoabdominal compression technique (RTC) (Custom-made equipment; Department for Experimental Medical Instrumentation, Erasmus University Medical Center, Rotterdam, The Netherlands). Equipment and procedures were in accordance with recently published guidelines, in which the rapid thoracoabdominal compression technique is described in detail (11). The mean V'maxFRC of three to five technically acceptable measurements was expressed as Z score according to Sly and coworkers (11) and Tepper and Reister (12).
Analysis
Lung function at the first and second measurements was compared using mixed-model analysis of variance (SAS, PROC MIXED). Between the groups initially treated with HFOV or CMV, lung function and anthropometric data were compared using independent-samples t tests. Comparison of percentages was done using Fisher's exact test. Where applicable, the difference in lung function was evaluated using paired Student's t test. The influence of various perinatal variables on the level of lung function was evaluated by multiple regression analyses. The significance level was set at a p value of less than 0.05.
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RESULTS
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A cohort of 36 white infants was enrolled. Lung function was measured in 28 infants at 6 months and in 31 infants at 12 months. In 23 infants, lung function was measured both at 6 and 12 months corrected age. Reasons for not completing both measurements were failure to sleep during the procedure (n = 6), airway infections (n = 5), and loss to follow-up (n = 2). Anthropometric data of the total cohort of 36 infants and of the subgroups of 28 infants measured at 6 months and 31 infants measured at 12 months are shown in Table 1
. The first and second lung function measurements were performed at mean (SD) corrected ages of 6.2 (0.9) months and 12.6 (1.1) months, respectively. The results of the FRCp and the V'maxFRC measurements are shown in Table 2
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Mean (SEM) FRCp values in Z score at the first and second measurements were -1.2 (0.3) and -0.6 (0.2), respectively. Mean (SEM) V'maxFRC in Z score was significantly below zero (normal value) at the first and second measurements: -1.7 (0.1) and -2.2 (0.1), respectively (Table 2, Figure 1)
. Between the two measurements, there was a mean (95% confidence interval) change of V'maxFRC in Z score of -0.5 (-0.7 to -0.2) (p < 0.001). When V'maxFRC in Z score was calculated using normative data by Tepper and Reister (12), similar results were seen: the mean (SEM) V'maxFRC (Z score) values at the first and second measurements were -1.6 (0.1) and -2.0 (0.1), respectively (mean [95% confidence interval] change of V'maxFRC in Z score of -0.4 [-0.7 to -0.1], p = 0.006).
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Figure 1. Lung function data of 36 infants with CLD. Mean V'maxFRC is expressed in Z score according to Sly and coworkers (11). The first (n = 28) and second (n = 31) measurements were done at mean (SD) corrected ages of 6.2 (0.9) months and 12.6 (1.1) months, respectively. Twenty-three infants completed both measurements (connected data points).
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At 12 months, the mean (SEM) V'maxFRC in Z score was better in the group that received initial HFOV (n = 15) as compared with the group that initially received CMV (n = 16): -1.9 (0.2) and -2.5 (0.1), respectively (mean [95% confidence interval] difference: 0.6 [0.2-1.0], p = 0.008) (Table 3)
. The distributions of perinatal factors did not differ between these two groups, except for birth weight (in grams) and requirement of surfactant therapy (Table 4)
. After allowing for the potential confounders (days on ventilation, gestational age, and birth weight) using multiple regression analyses, this difference remained significant (p = 0.038). However, when both ventilation groups were compared with adjustment for number of surfactant dosages, the difference in mean V'maxFRC (Z score) at 12 months lost significance (p = 0.085).
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TABLE 3. Lung function at 12 months corrected age, after initial high-frequency oscillation ventilation or conventional mechanical ventilation
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TABLE 4. Anthropometric data of 31 infants measured at 12 months corrected age, subgrouped by initial ventilation treatment
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Similar results were seen within the subgroup of 23 infants who completed both measurements. To study the difference between 6 and 12 months precisely, individual mean V'maxFRC values were inter- or extrapolated linearly to values at exactly 6 and 12 months corrected age. At 6 and 12 months, the mean (SEM) of these adjusted V'maxFRC (Z score) values were -1.7 (0.1) and -2.1 (0.1), respectively (mean [95% confidence interval] change: -0.4 [-0.7 to -0.1], p = 0.006). At 12 months, the mean (SEM) of the adjusted V'maxFRC in Z score was better in the group that received initial HFOV (n = 12) as compared with the group that received CMV (n = 11): -1.9 (0.2) and -2.4 (0.1), respectively (mean [95% confidence interval] difference: 0.6 [0.1–1.0], p = 0.014) (Figure 2)
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Figure 2. Effect of first intention HFOV on V'maxFRC. Mean V'maxFRC in Z score (11) in the subgroup of 23 infants who completed both lung function measurements at 6 and 12 months. Individual mean V'maxFRC values were inter- or extrapolated to values at exactly 6 and 12 months corrected age. Infants treated with first intention HFOV (open symbols, n = 12) are compared with infants treated with CMV (closed symbols, n = 11). Error bars represent SEM.
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DISCUSSION
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In a follow-up study, we evaluated lung function in a cohort of 36 VLBW infants with CLD, during the first year of life. Furthermore, we studied the relationship between lung function and perinatal patient characteristics. During the first year of life, mean V'maxFRC was below reference values and showed a significant worsening between 6 and 12 months corrected age. At 12 months, mean V'maxFRC was significantly better in the initial HFOV-treated group, as compared with the group treated with CMV.
To our knowledge, this is the first study on growth of airway function during the first year of life in VLBW infants with CLD, which also addresses a possible relationship with HFOV. Tepper and coworkers (6) and Iles and Edmunds (9) also found decreased V'maxFRC during the first year of life. However, due to the survival of younger and smaller infants and differences in treatment modalities, our study population cannot be compared with the population studied by Tepper and coworkers (6). Iles and Edmunds (9) studied a population more comparable to our population, but no information about treatment modalities was provided. The decreasing V'maxFRC may reflect abnormal functional or anatomic development of the airways (6), which is consistent with pathologic findings (13). This could explain the abnormal pulmonary function tests in preterm-born children with CLD at school age (3, 4). Alternatively, worsening of airway patency may be due to airway damage and dysfunction of peripheral airways (14), and central airway damage and collapse during dynamic compression (15). Factors such as thickened airway walls, increased smooth muscle layer, disturbed development of airway size and/or airway compliance (16), or altered alveolar architecture may also play a role here (17). Furthermore, the relative decline of V'maxFRC during the first year of life was irrespective of the reference equation used (11, 12). The FRCp was within the normal range at 6 months and demonstrated a trend to normalization at 12 months of age. This is consistent with previous reports (6–8, 18). With no apparent decline of the mean FRCp between 6 and 12 months, the change in FRCp cannot explain the reduction in V'maxFRC (19).
First intention HFOV is associated with a shorter time of ventilator dependency and oxygen dependency in VLBW infants with respiratory distress syndrome (20). Furthermore, it is speculated that early HFOV used with a lung recruitment strategy in combination with surfactant therapy ameliorates acute neonatal lung injury that predisposes some preterm infants to develop CLD (5). The HIFI study group (21) found that the use of HFOV, in comparison with CMV, did not improve V'maxFRC at 9 months corrected age. In our study, the V'maxFRC at 12 months was significantly better in the group initially treated with HFOV, compared with the group initially managed with CMV. This discrepancy could be explained by the difference in timing of measurement or by the fact that in our study, HFOV was used as initial therapy. Our data suggest that, in VLBW infants, initial treatment with HFOV is associated with a more favorable development of V'maxFRC at 12 months corrected age. This finding provides further suggestive evidence that initial HFOV combined with surfactant therapy reduces acute neonatal lung injury (5). Initial ventilation treatment was not intentionally randomized in our study, and therefore this association cannot be considered causal. Nevertheless, the HFOV and CMV groups were not different by any perinatal patient characteristic, except for a small difference in birth weight in grams, but not in Z score, and number of surfactant doses. The difference in birth weight does not explain our finding, as the lower birth weight of the HFOV group would unfavorably affect lung function, whereas we found better results after HFOV. Fewer doses of surfactant were given to the infants who were initially ventilated with HFOV, as compared with CMV. This may reflect reduced respiratory distress after HFOV. We regard the number of surfactant doses not as a confounder but as a possible first positive outcome of HFOV.
In summary, VLBW infants with CLD, born in the era of surfactant therapy and HFOV, show a worsening of decreased V'maxFRC during the first year of life. Initial treatment with HFOV was associated with a more favorable development of V'maxFRC at 12 months corrected age. This finding supports the hypothesis that initial treatment with HFOV in premature neonates prone to develop CLD leads to less airway damage and better medium-term outcome.
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FOOTNOTES
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Supported by an unrestricted grant from GlaxoSmithKline, The Netherlands.
Received in original form February 19, 2002;
accepted in final form August 8, 2002
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Copyright © 2002 American Thoracic Society
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ABSTRACT
INTRODUCTION