Soluble interleukin-2 receptor levels in infants with bronchopulmonary dysplasia.

Soluble interleukin-2 receptors (sIL2R) in plasma have been identified as a marker of lymphocyte activation. Lymphocyte activation as a manifestation of inflammation may be important in the pathogenesis of bronchopulmonary dysplasia (BPD). To test the hypothesis that infants with BPD have higher sIL2R levels, 12 infants with or at risk of developing BPD (GA +/- SD, 27 +/- 5 weeks; BW +/- SD 1,053 +/- 733 g) had plasma sIL2R levels determined and were compared to 20 infants being ventilated for respiratory distress syndrome (RDS) (GA +/- SD, 28 +/- 3.5 weeks; BW +/- SD, 1,133 +/- 390 g: P = NS for both GA and BW, t test). Tracheal aspirates in both groups were also analyzed for sIL2R levels. To control for the effects of postnatal age (PNA) and study weight (SW) on the sIL2R levels, another group of 16 nonventilated babies (NVB) had plasma analyzed for sIL2R (PNA +/- SD: 39 +/- 40 days NVB vs. 48 +/- 36 days BPD; P = NS); (SW +/- SD: 1391 +/- 250 g NVB vs. 1212 +/- 700 g BPD; P = NS). The following data were obtained for the plasma sIL2R levels (mean +/- SEM U/mL): RDS controls, 1,231 +/- 80; BPD infants, 1,790 +/- 120; NVB controls, 1,319 +/- 76; P = 0.0005 RDS vs. BPD and P = 0.002 BPD vs. NVB. There was no significant difference in the sIL2R levels for the infants at risk of developing BPD vs. the infants with established BPD. Also, when analyzed separately, infants at risk of BPD and the infants with established BPD had higher sIL2R levels than the RDS and NVB controls. No differences were noted in the tracheal sIL2R levels in the BPD vs. RDS groups. These data indicate that infants with BPD had significantly higher sIL2R levels in plasma than either RDS or NVB controls. Therefore, lymphocyte activation may play a role in the pathogenesis of BPD.     

Urinary leukotriene E(4) excretion during the first month of life and subsequent bronchopulmonary dysplasia in premature infants

BACKGROUND: Inflammation plays an important role in the pathogenesis of bronchopulmonary dysplasia (BPD), but the exact nature of this inflammatory process is incompletely understood. Older infants with established BPD have higher levels of urinary leukotriene E(4) (LTE(4)) compared to healthy infants of the same age. This suggests that cysteinyl leukotrienes may play a role in the abnormalities seen in BPD. OBJECTIVES: To measure urinary LTE(4) levels during the first month of life in premature infants, and to determine whether there are significant differences in premature infants who develop BPD, as compared to those who do not develop BPD. DESIGN: Prospective, blinded, controlled study. SETTING: Neonatal ICUs of a tertiary-care university hospital. METHODS: Thirty-seven premature infants (< 33 weeks of gestational age) were enrolled prospectively at birth. Urinary LTE(4) levels were measured blinded, using a standard radioimmunoassay technique at 2 days, 7 days, and 28 days of life. At 1 month of age, infants were classified as with or without BPD, based on need for supplemental oxygen, and characteristic chest radiographs. Clinical features and urinary LTE(4) were compared between the two groups. RESULTS: Mean +/- SD gestational age was 29 +/- 2.6 weeks. None of the infants had a family history of asthma. Thirteen of 37 infants were classified as having BPD at 28 days after birth. Mean gestational age in infants who developed BPD was 27 +/- 2.4 weeks, compared to 30 +/- 2 weeks in infants who did not develop BPD (p < 0.05). In infants with BPD, mean urinary LTE(4) levels of urinary creatinine were 1,762 +/- 2,003 pg/mg, 1,236 +/- 992 pg/mg, and 5,541 +/- 5,146 pg/mg at days 2, 7, and 28, respectively, compared to 1,304 +/- 1,195 pg/mg, 1,158 +/- 1,133 pg/mg, and 2,800 +/- 2,080 pg/mg in infants without BPD. LTE(4) levels at 2 days, 7 days, and 28 days did not correlate with the subsequent development of BPD. LTE(4) levels at day 28 were significantly higher than LTE(4) levels at day 2 and day 7 in both groups, even after correcting for gestational age or birth weight (p < 0.05). There was significant inverse correlation between LTE(4) levels at day 2 with gestational age and birth weight (p < 0.05). All 13 infants with BPD received steroid pulses, compared to 3 of 26 infants without BPD. Gestational age and use of postnatal steroid pulses, diuretics, and theophylline (for apnea of prematurity) were significantly associated with each other and with the subsequent development of BPD. CONCLUSION: Urinary LTE(4) levels measured on the second day of life in very-low-birth-weight infants inversely correlate with gestational age and birth weight. Urinary LTE(4) levels may reflect lung injury and/or inflammation in premature infants, not necessarily related to BPD as it is presently defined.     

Serial changes in levels of IL-6 and IL-1beta in premature infants at risk for bronchopulmonary dysplasia

The aim of this study was to define the inflammatory changes occurring in the lungs of infants at risk for bronchopulmonary dysplasia (BPD) over the first 28 days of life, and to define an optimal strategy for steroids therapy in the prevention of BPD. We measured levels of interleukin-6 (IL-6) and interleukin-1 beta (IL-1beta) in tracheal aspirate (TA) samples and blood of premature infants with severe respiratory distress syndrome RDS (n = 45) on the first day of life prior to initiation of surfactant therapy and on days 5-7, 12-14, 19-21, and 26-28. Levels of IL-6 and IL-1beta were determined with a commercially available enzyme-linked immunoassay. Logistic regression analyses were performed in order to examine differences in trends in levels of IL-6 and IL-1beta between groups of infants. Infants were divided into group I (n = 30, FiO(2) < or = 0.35 at 28 days) and group II (n = 15, FiO(2) > 0.35 based on their likelihood of developing BPD at 36 weeks postconceptional age (PCA). The infants were comparable with respect to mean ( +/- SEM) birth weight (895 +/- 33 g vs. 900 +/- 40 g), gestational age (27 +/- 0.38 weeks vs. 27 +/- 0.54 weeks), and severity of respiratory illness at entry into the study (mean airway pressure: 12 +/- 1 cmH(2)O vs. 12 +/- 1 cmH(2)O, and oxygen index: 15 +/- 2 vs. 19 +/- 4) (group I vs. group II, respectively). Logistic regression analyses failed to reveal any significant differences in linear trends of levels of IL-6 and IL-1beta in TA samples between both groups of infants. No particular pattern of change in levels of IL-6 or IL-1beta could be identified among groups of infants. Levels of IL-6 and IL-1beta in TA samples on the first day of life failed to predict the need for FiO(2) > 0.35 at 28 days of age. We could not identify an increasing trend or a specific pattern of changes in postnatal levels of IL-6 or IL-1beta in TA samples of infants who were at greater risk of developing BPD at 36 weeks PCA compared to infants who were not.     

Interleukin-10 -1082 G/A polymorphism and risk of death or bronchopulmonary dysplasia in ventilated very low birth weight infants

IL-10 is an anti-inflammatory cytokine that may have a protective role in acute lung injury. IL-10 expression is affected by a single-nucleotide polymorphism (SNP) located at position -1082 (G to A). The A allele is associated with lower IL-10 production. Low IL-10 production has been linked to the development of BPD. Thus, the IL-10 -1082 SNP may be a genetic risk factor for the development of BPD in the premature newborn. The IL-10 -1082 SNP was determined in 294 (235 African American, 56 Caucasian, and 3 Hispanic) mechanically ventilated very low birth weight (VLBW) infants and compared to outcome (death and/or development of BPD). Differences in groups were analyzed using ANOVA (continuous variables) or chi square (proportions). The frequency of the A allele in our population was 0.62. Thirty-nine (13.3%) infants were homozygous GG, 146 (49.7%) were heterozygous GA, and 109 (37.0%) were homozygous AA. There were no significant differences between genotype groups with respect to ethnic origin, gender, need for surfactant replacement therapy, and isolation of Ureaplasma urealyticum or Mycoplasma hominis from tracheal aspirates at birth. However, AA infants were slightly more mature and of greater birth weight than GA infants (26.9 +/- 0.2 weeks vs. 26.3 +/- 0.2 weeks, P < 0.05, and 940 +/- 22 g vs. 882 +/- 18 g, P < 0.05, respectively). There was no significant effect of the IL-10 -1082 SNP on mortality or the development of BPD (O2 on 28 days or 36 weeks postconceptional age). However, when considered together, the IL-10 -1082 AA/GA genotypes (lower IL-10 production) were associated with a trend toward reduction in risk for the combined outcome of BPD or death (18/39 vs. 80/255, respectively; P = 0.068). The incidence of other complications of prematurity (retinopathy of prematurity, intraventricular hemorrhage, or periventricular leukomalacia) was not different between groups. In conclusion, the IL-10 -1082 G/A SNP does not have a major influence on mortality or the development of BPD in ventilated VLBW infants.     

Respiratory compliance of healthy newborn infants measured by endinspiratory airway occlusion technique in the first hours of life

The compliance of the respiratory system (Crs) has been measured by an airway occlusion technique in 78 healthy newborn infants [gestational age (GA) 36.2 +/- 2.9 weeks, range 28-41 weeks; birth weight (BW) 2.418 +/- 0.879 kg, range 0.830-4.350 kg; body height (BH) 45.2 +/- 4.4 cm, range 33-52 cm in the first 8 h after birth (206.2 +/- 100.8 min, range 45-480 min). The prediction equations were (Crs, ml/cm H2O): Crs = 0.087.GA -1.173 (r = 0.49, p less than 0.0001), Crs = 0.372.BW +1.067 (r = 0.62, p less than 0.0001), Crs = 0.076.BH -1.493 (r = 0.61, p less than 0.0001). The Crs values were very similar to the values measured in curarized newborn infants and quoted in the literature. There was only one newborn infant with a Crs of less than 1 ml/cm H2O (GA = 34 weeks, BW = 0.830 kg, BH = 33 cm, Crs = 0.909 ml/cm H2O).     

Long-term pulmonary functional outcome of bronchopulmonary dysplasia and premature birth

Pulmonary function and exercise tolerance were evaluated in late childhood in two groups of prematurely born children: one group with bronchopulmonary dysplasia (BPD) [n] = 15; gestational age at birth (GA): 29.6 ± 2.8 weeks; birth weight (BW): 1,367 ± 548 g; age at test: 7.9 ± 0.6 years, and a second group without significant neonatal lung disease [pre-term (PT)] (n = 9; GA: 30.3 ± 1.7 weeks; BW: 1,440 ± 376 g; age at test: 7.8 ± 0.22 years). The results were compared with a control group of children of similar ages and heights, born at term [term born (TB)]. We observed that total lung resistance (R_L) was significantly higher in BPD (11 ± 3 cmH₂O/L/s), and in PT (9 ± 2) than in TB [5 ± 1; (P < 0.001 and P < 0.05, respectively)]. In BPD R_L was higher than in PT (P < 0.05). Dynamic lung compliance (C_LdY) was decreased in BPD (43 ± 11 mL/cmH₂O) and in PT (56 ± 17) compared with TB (76 ± 20) (P < 0.001 and P < 0.05), and also in BPD compared with PT (P < 0.05). Forced expiratory volume in 1 second (FEV₁) and FEV₁/forced vital capacity (FVC) were lower in BPD (1.07 ± 0.15 L and 72 ± 7%) than in PT (1.29 ± 0.23 L, and 80 ± 7%) (P < 0.05). Exercise tests were performed in six boys with BPD. The ratio between minute ventilation at maximal workload (V_Emax ) and the predicted value of maximal voluntary ventilation (MVV) was elevated in the six BPD boys tested, compared with five boys of Group 2 and five TB boys (87 ± 15% vs. 62 ± 14% and 65 ± 13%) (P < 0.05). We conclude that: (1) prematurity and BPD is followed by long-term airway obstruction and a mild degree of exercise intolerance and; (2) premature birth without BPD may be followed by a milder degree of airway obstruction in childhood than in infants who developed BPD during the neonatal period. Pediatr Pulmonol. 1995; 20:289–296 . © 1995 Wiley-Liss, Inc.     

Pulmonary function in bronchopulmonary dysplasia

The purpose of this study was to examine lung function and bronchodilator responsiveness in infants with a history of prematurity and bronchopulmonary dysplasia (BPD), using the raised volume rapid thoracoabdominal compression technique as well as with whole-body plethysmography. Spirometric measurements were obtained in 28 infants with a history of BPD, defined as preterm birth with O2 requirement at 36 weeks postmenstrual age (gestational age at birth, 26.4 +/- 2.1 weeks, mean +/- SD; birthweight, 898 +/- 353 g; age at study, 68.0 +/- 35.6 weeks). Fractional lung volumes were measured in 27 subjects. Values were expressed as percentage of predicted normal values. Compared to normal infants, those with a history of BPD exhibited decreases in forced expiratory flows including forced expiratory volume in 0.5 sec (76.3 +/- 19.6%), forced expiratory flow at 75% of expired forced vital capacity (FEF75; 59.5 +/- 30.7%), and FEF(25-75) (74.0 +/- 26.8%; P<0.01 for all). Functional residual capacity (107.9 +/- 25.3%), residual volume (RV, 124.5 +/- 42.7%), and RV/total lung capacity (RV/TLC, 128.2 +/- 35.3%) were increased in infants with a history of BPD (P<0.05 for each). There was no difference in TLC between groups. Seventeen infants were studied both pre- and postalbuterol, and 6 (35%) demonstrated significant bronchodilator responsiveness. Infants with recurrent wheezing showed greater expiratory flow limitation, hyperinflation, and airways responsiveness, whereas those without wheezing showed only modest airway dysfunction. We conclude that infants with a history of BPD have pulmonary function abnormalities characterized by mild to moderate airflow obstruction and air trapping.     

Palivizumab efficacy in preterm infants with gestational age < or = 30 weeks without bronchopulmonary dysplasia

The present study was designed to determine the efficacy of administration of palivizumab to preterm infants with gestational age (GA) < or = 30 weeks without bronchopulmonary dysplasia (BPD). All patients born with GA < or = 30 weeks without BPD on Day 28 and hospitalized for RSV bronchiolitis in Burgundy (12 hospitals) from December 1 to April 30 of the next year were included in this prospective observational study during five successive RSV seasons (1999-2000, 2000-2001, 2001-2002, 2002-2003, and 2003-2004). Palivizumab was given to premature infants with a gestational age < or = 30 weeks without BPD in the 2002-2003 and 2003-2004 periods only. In the cohort of premature infants with GA < or = 30 weeks without BPD, the respiratory syncytial virus (RSV) bronchiolitis hospitalization rate was reduced significantly (P < 0.01) in the two seasons with palivizumab prophylaxis (2002-2003: 0% and 2003-2004: 2%) versus the three previous RSV seasons (1999-2000: 14.3%; 2000-2001: 16.7%; 2001-2002: 10.2%). The number needed to treat to prevent one hospitalization for RSV bronchiolitis was 6 (95%CI: 4-11). Such favorable results have not been always found in the few available postmarketing epidemiological studies on hospitalization rate after palivizumab prophylaxis. Differences in health care organization could explain those discrepancies.     

Vascular endothelial growth factor in preterm infants with respiratory distress syndrome

Respiratory distress syndrome (RDS) secondary to surfactant deficiency is a common cause of morbidity and mortality in premature infants. Increasing evidence suggests that vascular endothelial growth factor (VEGF) may contribute to surfactant secretion and pulmonary maturation. However, differences in cord blood VEGF concentrations in infants with and without respiratory distress syndrome have not been reported. We hypothesized that premature infants with higher VEGF levels in cord blood had a lower risk of developing RDS. Cord blood samples were obtained from preterm infants born at 32 weeks of gestation or earlier. Infants were excluded if there was evidence of prenatal maternal infection or any infection within the first 3 days of life. Cord blood VEGF levels were measured using an enzyme-linked immunosorbent assay (ELISA). We found that neonates with clinically diagnosed RDS had a lower gestational age (GA), lower birth weight (BW), higher incidence of mechanical ventilation requirements, longer duration of mechanical ventilation, and lower Apgar scores at 1 and 5 min. Infants with RDS had significantly lower cord blood VEGF levels. GA, BW, premature rupture of membranes (PROM), and antenatal steroid treatment were not associated with changes in cord blood VEGF levels. The specificity of cord blood VEGF above 34 pg/ml for predicting the absence of RDS was 86%, the sensitivity was 53%, the positive predictive value was 84%, and the negative predictive value was 56%. Our data demonstrated that cord blood VEGF elevation was significantly correlated with an absence of RDS.     

Low birth weight and later development of insulin resistance and biochemical/clinical features of polycystic ovary syndrome

Reduced insulin sensitivity in adult life has been reported in subjects born at term small for gestational age (SGA) and in those born prematurely with very low birth weight (LBW) (<1,500 g). We assessed whether LBW (<2,500 g) young women, irrespective of whether they were born SGA or adequate for gestational age (premature AGA), exhibited a reduction in insulin sensitivity through a prospective historical design. The risk of developing biochemical and clinical features of polycystic ovary syndrome was also investigated. The study population included 35 LBW women (19 SGA [BW range, 1,000-2,400 g] and 16 premature AGA [BW range, 1,700-2,440 g]) aged 21.8 +/- 1.8 years and 35 term AGA controls, of similar age, recruited from a neonatal registry. All women underwent clinical, ultrasonographic, hormonal, and metabolic evaluations, including the composite insulin sensitivity index. Women under hormonal contraception (21.4%) were excluded from hormonal and metabolic analyses. Composite insulin sensitivity index was significantly lower in LBW women even when the 2 LBW subgroups, SGA and premature AGA, were analyzed separately (4.4 +/- 2.2 and 4.0 +/- 1.7, respectively) than in controls (6.9 +/- 4.4). The LBW women showed a significantly higher incidence proportion of irregular menses (14/35 [40%] vs 2/35 [5.7%]) and a significantly higher free androgen index (5.8 +/- 3.5 vs 3.9 +/- 3.2). They also showed a nonsignificantly higher proportion of hirsutism, acne, and polycystic ovaries. In conclusion, LBW (<2,500 g) young women, irrespective of whether they were SGA and premature AGA, exhibited a reduction in insulin sensitivity as compared with born at term AGA women. Furthermore, they exhibited an increased risk of developing clinical and biochemical features of polycystic ovary syndrome.     

Surfactant protein A, phosphatidylcholine, and surfactant inhibitors in epithelial lining fluid. Correlation with surface activity, severity of respiratory distress syndrome, and outcome in small premature infants.

Although surfactant deficiency at birth is the major cause of respiratory distress syndrome (RDS), there is insufficient data on surfactant and surfactant inhibitors after birth. In the present study, a total of 345 airway specimens (AS) from 61 neonates of gestational age of 24 to 29 wk (54 with RDS) were analyzed for concentrations of phosphatidylcholine (PC), saturated PC (SPC), surfactant protein A (SP-A), nonsedimentable protein, and free amino acids in epithelial lining fluid (ELF). The relationship between surfactant indices, surface activity, and severity of RDS was studied. Treatment with human surfactant containing SP-A increased [PC]ELF and [SPC]ELF to levels found in infants without RDS. In placebo-treated infants similar concentrations were first reached between Days 4 and 7. Surfactant treatment increased the low SP-A/SPC ratio, although this ratio remained lower than that in exogenous surfactant. In RDS, the concentrations of free amino acids in ELF were 6 to 31 times higher than in infants without RDS. The nonsedimentable proteins of AS and cationic amino acids increased the minimum surface tension of SP-A-deficient surfactant from AS. Addition of SP-A improved the surface activity. According to multiple regression analysis, In [PC]ELF (p less than 0.0001), SPC/PC ratio (p less than 0.0001), In SP-A/SPC ratio (p less than 0.0002), and [protein]ELF (p less than 0.01) correlated with alveolar-arterial oxygen pressure gradient. Of the infants weighing less than 1,000 g, those who were going to die or develop bronchopulmonary dysplasia had a strikingly lower SP-A/SPC ratio during the first week (less than 25 ng/nmol) than those surviving without BPD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of early furosemide administration in neonates with respiratory distress syndrome

The effect of early furosemide-induced diuresis was prospectively evaluated in 39 neonates less than 24 hr of age with clinical respiratory distress syndrome (RDS) who received either four doses of furosemide (1 mg/kg) or no diuretic. Measurements of FiO2 alveolar-arterial oxygen gradient (P[A-a]O2), peak inspiratory pressure (PIP), and urine output as a fraction of intake (O/I) were averaged for every 8 hr. The furosemide group overall showed a significant decrease (P less than 0.01) in FiO2, P[A-a]O2, and PIP with an earlier (32 hr vs 52 hr) and more pronounced diuresis (35% greater O/I) when compared to the controls. This effect was accentuated in the subgroup with 1,000-1,500 g birth weight (significantly lower FiO2 and P(A-a)O2 from 16 to 48 hours), while no increase in urine output was observed for the infants weighing less than 1,000 g. A significant reduction in supplemental oxygen and need for ventilatory support at 96 hr of age was observed in the furosemide-treated, less than 1,500-g infants. The incidence of patent ductus arteriosus was not increased following furosemide therapy, and no significant difference in echocardiographic parameters was observed in 21 infants from both groups, who were followed daily during the first week of life. This study suggests that early furosemide-induced diuresis, particularly in infants weighing 1,000-1,500 g at birth, promotes improvement in pulmonary functions in RDS and leads to faster reduction in oxygen and ventilatory support.     

Postmortem lung weight/body weight standards for term and preterm infants

Assessment of lung development is a crucial component of the perinatal autopsy, especially in preterm infants. In current pathology practice, the diagnosis of lung hypoplasia in very premature infants (<28 weeks of gestation) is based on a lung weight/body weight ratio (LW/BW) of 1.5% or less. While useful to confirm the presence of marked pulmonary hypoplasia, the 1.5% threshold may be too stringent to detect more subtle degrees of pulmonary hypoplasia, as seen in association with rupture of membranes. The aim of this study was to establish reference values for postmortem LW/BW in preterm and term infants. To this end, we performed a retrospective analysis of fetuses and newborns (16-41 weeks of gestation) without known risk factors for pulmonary hypoplasia. Mean LW/BW ranged between 2.98-3.15% between 16-27 weeks, and decreased to 2.55% by 28-36 weeks and 1.79% at term. The 10th percentile for LW/BW was significantly higher in preterm infants (2.24% between 20-23 weeks, and 2.59% between 24-27 weeks) than in term infants (1.24% at >or=37 weeks, P < 0.01). We then correlated LW/BW of infants with risk factors for pulmonary hypoplasia with the newly established reference values. As expected, mean LW/BW of infants with congenital diaphragmatic hernia or severe renal anomalies was <1.5% (0.98% and 1.40%, respectively). Mean LW/BW of infants with prolonged (> 1 week) rupture of membranes (PROM) was 2.08%. Three of 12 (25%) preterm infants with PROM had pulmonary hypoplasia according to the traditional criteria (LW/BW <1.5%). However, an additional 4/12 (33%) infants with PROM had a LW/BW between 1.5% and the 10th percentile for age (2.2%), indicative of more subtle but potentially relevant pulmonary underdevelopment. In conclusion, we determined LW/BW reference values for preterm and term infants. Correlation of LW/BW with age-matched reference values at postmortem examination represents an invaluable additional tool to evaluate lung growth, particularly in preterm infants.     

Risk factors associated with the need for a tracheostomy in extremely low birth weight infants

In an attempt to determine the risk factors associated with the need for a tracheostomy in extremely low birth weight (ELBW) infants, a retrospective, case control study was conducted (each infant with a tracheostomy [case] was matched to two controls). Medical records were reviewed for patients' characteristics, risk factors for tracheostomy and outcome. During the study period (June 1996 to Dec 2010), 934 ELBW infants were admitted to our institution and nine infants had a tracheostomy and were matched to 18 controls. There were no differences in birth weight (BW) and gestation age (GA) between cases and controls (828.1 ± 136.2 g vs. 822.0 ± 140.9 g [P = 0.91] and 26.6 ± 1.8 weeks vs. 26.5 ± 1.6 weeks [P = 0.88], respectively). In comparison to their controls, infants with a tracheostomy had a higher rate of intubation (median 13 [11–15] vs. 3 [2–5], P ≤ 0.001), a higher rate of total intubation attempts (median 18 [13–21] vs. 5.5 [3–7], P = 0.001), and more days of mechanical ventilation prior to their tracheostomy (mean 100.7 ± 27.7 vs. 29.2 ± 19.8 days [P < 0.001]). Also infants with a tracheostomy had a higher rate of non‐congenital upper airway obstruction (55% [5/9] vs. 0% [0/18]; P = 0.001), a higher rate of chronic lung disease (100% [9/9] vs. 5% [1/18]; P < 0.001) and a higher mortality (44% [4/9] vs. 0% [0/18]; P = 0.007) than their controls. In conclusion, chronic lung disease, multiple intubations and intubation attempts, duration of mechanical ventilation, and non‐congenital upper airway obstruction are risk factors associated with tracheostomies in ELBW infants. Pediatr Pulmonol. 2013; 48:146–150. © 2012 Wiley Periodicals, Inc.     

Acute effects of PEEP on tidal volume and respiratory center output during synchronized ventilation in preterm infants

BACKGROUND: Positive end expiratory pressure (PEEP) is routinely used in mechanically ventilated preterm infants to maintain lung volume. An acute increase in PEEP can affect lung mechanics and tidal volume, but it is unknown if these effects elicit compensatory changes in respiratory center output. OBJECTIVES: To investigate the acute effects of changes in PEEP on tidal volume (V(T)), lung compliance (C(L)), and respiratory center output (RCO) during synchronized intermittent mandatory ventilation (SIMV) in preterm infants at different levels of basal respiratory drive. METHODS: Preterm infants were studied during SIMV at three levels of PEEP (2, 4, and 6 cm H(2)O for 2-3 min each) and at two levels of inspired CO(2). Peak inspiratory pressure (PIP) was adjusted to maintain the same delta pressure at the airway. RCO was assessed by measuring total diaphragmatic electrical activity. The level of inspired CO(2) was adjusted by modifying the instrumental dead space. RESULTS: Sixteen preterm infants GA: 25 +/- 2 weeks, BW: 786 +/- 242 g, age: 18 +/- 15 days, SIMV: rate 14 +/- 3 b/min, Ti: 0.35 +/- 0.01 s, PIP: 16 +/- 1 cm H(2)O, and FiO(2): 0.31 +/- 0.06 were studied. At both levels of inspired CO(2), C(L), V(T), and V'(E) from spontaneous and mechanical breaths decreased significantly with higher PEEP. RCO did not change, but at lower respiratory drive, there was a trend towards an increase in RCO with higher PEEP. CONCLUSION: Higher PEEP levels can have acute negative effects on lung mechanics and ventilation in preterm infants without a sufficient compensatory increase in RCO.     

Surfactant protein profile of pulmonary surfactant in premature infants

Although premature infants are known to be deficient in pulmonary surfactant, there is limited information regarding surfactant protein (SP) composition. To assess the postnatal profile of SPs, tracheal aspirate samples were collected from 35 intubated infants of 23-31 weeks of gestation between 8 and 80 days of age. In 71 large aggregate surfactant samples that had normal in vitro function (minimum surface tension of less than 1 mN/m by pulsating bubble surfactometry), mean +/- SEM contents of SP-A, SP-B, and SP-C (3.7 kD) were 7.1 +/- 1.4%, 1.8 +/- 0.2%, and 4.6 +/- 0.6%, respectively, of phospholipid. To assess SPs in the 1st week of life, we analyzed samples from additional infants receiving only synthetic replacement surfactant. On the 2nd day of life, contents of SP-A, SP-B, and SP-C were 13.4%, 8.4%, and 0.1%, respectively, of the mean levels for Day 8-80 samples. The major postnatal increases for SP-A, SP-B, and SP-C occurred during the 1st, 2nd, and 3rd weeks, respectively. We conclude that surfactant of newborn premature infants is markedly deficient in SPs, in particular SP-C. Despite continuing lung disease, some infants who are more than 1 week of age have surfactant with normal in vitro function that contains SPs at levels comparable to adult surfactant.     

Sleep apnea and hypoxemia in recently weaned premature infants with and without bronchopulmonary dysplasia

Infants with bronchopulmonary dysplasia (BPD) experience significant hypoxemia. Apnea indices and oxygen saturation levels of ten infants with BPD were compared to ten healthy premature infants who were evaluated to rule out apnea or bradycardia prior to discharge from the hospital. Infants with BPD who had been recently (less than 7 days) weaned from supplemental oxygen were evaluated on and off supplemental oxygen. Premature controls had never received oxygen nor ventilation assistance. Infants with BPD were born significantly more prematurely (28.1 +/- 1.0 vs. 33.0 +/- 3.9 weeks; P = 0.0012) while chronologic ages at the time of evaluation, adjusted for prematurity, were equal (37.1 +/- 3.1 vs. 38.0 +/- 2.7 weeks). Comparisons of apnea densities (expressed as percent of sleep time) between BPD and non-BPD prematures revealed the following: neither the average obstructive apnea (0.15 +/- 0.36 vs. 0.14 +/- 0.31) nor periodic breathing densities (6.0 +/- 8.56 vs. 10.2 +/- 5.84) were different. Infants with BPD experienced significantly more central apnea (0.62 +/- 0.34 vs. 0.16 +/- 0.11; P = 0.003) than did non-BPD prematures. Average oxygen saturation levels were significantly less among BPD vs. non-BPD prematures (90.0 +/- 10.18% vs. 95.7 +/- 4.33%; P = 0.033). When supplemented with oxygen, BPD prematures had significantly higher saturation (X = 94.5%) than when breathing room air (X = 90.0%). Both central apnea and periodic breathing densities declined significantly with this improvement in saturation (0.64 vs. 0.04% and 6.0 vs. 1.4%, respectively). These data suggest that saturation status may indicate central respiratory stability in chronic lung disease.     

Acinar arterial changes with chronic lung disease of prematurity in the surfactant era

Because echocardiographic studies on infants with chronic lung disease (CLD) suggest that pulmonary hypertension (PH) may contribute to its severity, we studied acinar arterial walls in the following surfactant-era infants: controls (n=38): 22-41 weeks of gestational age (GA), exposed briefly to oxygen and positive pressure ventilation, died within 48 hr of birth; prolonged rupture of fetal membranes (PROM) and persistent pulmonary hypertension (PPHN) (n=17); and SCORE (integrated area under curve of average daily FiO2 x average daily MAP) groups (<20, 20-69, and 70-500; mild, moderate, and severe clinical lung disease, respectively, n=35): 23-30 weeks GA, lived 7-79 days. Lungs were stained for elastic tissue and smooth muscle actin. Vessels were assessed for percent of vessel circumference with smooth muscle, extent of elastic laminae in the walls, and percent arterial wall thickness (%AWT) at three levels: terminal to respiratory bronchiole transition (TRB), alveolar duct, and saccule. At the alveolar ductal and saccular levels, percent arterial wall thickness (%AWT) in mild CLD (SCORE < 20) was less than controls (P < 0.05) and those with more severe CLD (SCORE 70-500), indicating that normal postnatal arterial wall thinning may be delayed, or there is remodeling associated with increased %AWT. Severe CLD infants also had a significantly higher percent of circumferential actin than those with milder disease (SCORE < or = 69) and controls. In moderate and severe CLD, there was an increase in extent of the elastic laminae compared to controls and mild CLD. These changes were also significantly greater in PROM and PPHN infants compared to even severe CLD. We conclude that PH is a real possibility in severe CLD infants after discharge at 36 weeks. Grading the severity of CLD at discharge, and echocardiographic studies, may guide subsequent oxygen therapy.     

Chronic lung injury in preterm lambs. Disordered respiratory tract development

The cause of chronic lung disease of early infancy, often called bronchopulmonary dysplasia (BPD), remains unclear, partly because large-animal models that reliably reproduce BPD have not been available. We developed a model of BPD in lambs that are delivered prematurely and ventilated for 3 to 4 wk after birth to determine whether the histopathology of chronic lung injury in premature lambs mimics that which occurs in preterm infants who die with BPD, and to compare two ventilation strategies to test the hypothesis that differences in tidal volume (VT) influence histopathologic outcome. The two ventilation strategies were slow, deep ventilation (20 breaths/min, 15 +/- 2 ml/kg body weight VT; n = 5) or rapid, shallow ventilation (60 breaths/min, 6 +/- 1 ml/kg body weight VT; n = 5). Lambs were delivered at 125 +/- 4 d gestation (term = 147 d), treated with surfactant, and mechanically ventilated with sufficient supplemental oxygen to maintain normal arterial oxygenation (60 to 90 mm Hg). Quantitative histologic analysis revealed lung structural abnormalities for both groups of experimental lambs compared with lungs of control term lambs that were < 1 d old (matched for developmental age; n = 5) or 3 to 4 wk old (matched for postnatal age; n = 5). Compared with control lambs, chronically ventilated preterm lambs had pulmonary histopathology characterized by nonuniform inflation patterns, impaired alveolar formation, abnormal abundance of elastin, increased muscularization of terminal bronchioles, and inflammation and edema. Slow, deep ventilation was associated with less atelectasis, less alveolar formation, and more elastin when compared with rapid, shallow ventilation. We conclude that prolonged mechanical ventilation of preterm lambs disrupts lung development and produces pulmonary histopathologic changes that are very similar to those that are seen in the lungs of preterm infants who die with BPD. This chronic lung disease is not prevented by surfactant replacement at birth, does not appear to require arterial hyperoxia, and is influenced by VT.     

Early changes in respiratory compliance and resistance during the development of bronchopulmonary dysplasia in the era of surfactant therapy

Despite the availability of surfactant treatment, extremely low birth weight (ELBW) infants continue to be at high risk of developing bronchopulmonray dysplasia (BPD). Evidence suggests that pathologic changes occur within the first few days of life. We hypothesized that the changes in early respiratory system compliance and resistance in ELBW infants with or without hyaline membrane disease (HMD) would correlate with BPD severity and aid in its prediction. Respiratory system compliance (Crs) and resistance (Rrs) were measured at the end of weeks 1, 2, 3, and 4 in 46 infants weighing 1,000 g or less at birth, using the single breath airway occlusion method. Twenty-four infants had HMD and 22 did not. Fifteen infants with and 10 infants without HMD developed BPD with radiological changes and oxygen needs at 28 days. Twelve BPD infants required supplemental oxygen beyond 36 weeks, defined as chronic lung disease (CLD). Irrespective of whether the infant initially had HMD, the week 1 results showed that infants who subsequently developed BPD had a significantly higher respiratory system resistance than those who did not (P = 0.0014). Though week 1 compliance was lower, it was not statistical significant. Multiple logistic models consisting of simple neonatal variables and week 1 respiratory mechanics showed that Rrs was independently associated with subsequent BPD (P = 0.026) and CLD (P = 0.016), while compliance was not. Prediction of CLD improved with the inclusion of Rrs results as compared to prediction using clinical variables alone. Throughout the 4-week study period, Rrs was significantly higher in BPD infants than in those without BPD, and resistance was particularly abnormal in those who had CLD or subsequently required corticosteroid treatment. These observations provide rationale for interventions to prevent BPD within the first week of life. Respiratory mechanics measurements could be useful in the assessment of therapeutics in the current surfactant era.