Abnormal developmental patterns of suck and swallow rhythms during feeding in preterm infants with bronchopulmonary dysplasia.

Infants with bronchopulmonary dysplasia (BFD) often have difficulty achieving coordinated suckle feeding. To analyze rhythmic differences during feeding in infants with BPD we performed weekly studies of 14 infants with BPD (eight male, six female; postmenstrual age [PMA] 32.1 to 39.7 weeks); and a PMA-matched control group without BPD (n=20), from initiation of bottle feeding until discharge, with simultaneous digital recordings of pharyngeal and nipple (teat) pressure. Unlike the control group, there was no significant correlation between PMA and stability of suckle rhythm, aggregation of suckles or swallows into runs, or length of suckle runs. Comparing those infants >35 weeks' PMA, the group with BPD had significantly decreased stability of suckle rhythm (increased coefficient of variation of suckle-suckle intervals: 0.34, SE 0.02 vs 0.254, SE 0.014; p=0.003), decreased aggregation into suckle runs (71.1, SE 3.4% vs 85.4, SE 2%;p=0.001), and decreased length of suckle runs (7.2, SE 0.9 vs 13.1, SE 1.9 suckles/run; p=0.003). Percentage of swallows in runs was also decreased in the cohort with BPD (58, SE 3.8% vs 77.2, SE 3.5%; p<0.001), as was length of swallow run (5.3, SE 0.5 vs 10.7, SE 1.1;p<0.001). Thus, in infants with BPD, anticipated maturational patterns of suckle and swallow rhythms did not occur. Delay in attainment of stable suckle and swallow rhythms in preterm infants, especially after 35 weeks' PMA, may predict subsequent feeding and neurological problems.

Developmental patterns of rhythmic suck and swallow in preterm infants.

Twenty healthy preterm infants (gestational age 26 to 33 weeks, postmenstrual age [PMA] 32.1 to 39.6 weeks, postnatal age [PNA] 2.0 to 11.6 weeks) were studied weekly from initiation of bottle feeding until discharge, with simultaneous digital recordings of pharyngeal and nipple (teat) pressure and nasal thermistor and thoracic strain gauge readings. The percentage of sucks aggregated into 'runs' (defined as > or = 3 sucks with < or = 2 seconds between suck peaks) increased over time and correlated significantly with PMA (r=0.601, p<0.001). The length of the sucking-runs also correlated significantly with PMA (r=0.613, p<0.001). The stability of sucking rhythm, defined as a function of the mean/SD of the suck interval, was also directly correlated with increasing PMA (r=0.503, p=0.002), as was increasing suck rate (r=0.379, p<0.03). None of these measures was correlated with PNA. Similarly, increasing PMA, but not PNA, correlated with a higher percentage of swallows in runs (r=0.364, p<0.03). Stability of swallow rhythm did not change significantly from 32 to 40 weeks' PMA. In low-risk preterm infants, increasing PMA is correlated with a faster and more stable sucking rhythm and with increasing organization into longer suck and swallow runs. Stable swallow rhythm appears to be established earlier than suck rhythm. The fact that PMA is a better predictor than PNA of these patterns lends support to the concept that these patterns are innate rather than learned behaviors. Quantitative assessment of the stability of suck and swallow rhythms in preterm infants may allow prediction of subsequent feeding dysfunction as well as more general underlying neurological impairment. Knowledge of the normal ontogeny of the rhythms of suck and swallow may also enable us to differentiate immature (but normal) feeding patterns in preterm infants from dysmature (abnormal) patterns, allowing more appropriate intervention measures.

Stool microflora in extremely low birthweight infants.

AIM: To serially characterise aerobic and anaerobic stool microflora in extremely low birthweight infants and to correlate colonisation patterns with clinical risk factors. METHODS: Stool specimens from 29 infants of birthweight <1000 g were collected on days 10, 20, and 30 after birth. Quantitative aerobic and anaerobic cultures were performed. RESULTS: By day 30, predominant species were Enterococcus faecalis, Escherichia coli, Staphylococcus epidermidis, Enterbacter cloacae, Klebsiella pneumoniae, and Staphylococcus haemolyticus. Lactobacillus and Bifidobacteria spp were identified in only one infant. In breast milk fed (but not in formula fed) infants, the total number of bacterial species/stool specimen increased significantly with time (2.50 (SE 0.34) on day 10; 3.13 (0.38) on day 20; 4.27 (0.45) on day 30) as did quantitative bacterial counts; Gram negative species accounted for most of the increase. On day 30, significant inverse correlations were found between days of previous antibiotic treatment and number of bacterial species (r=0.491) and total organisms/g of stool (r=0.482). Gestational age, birthweight, maternal antibiotic or steroid treatment, prolonged rupture of the membranes, and mode of delivery did not seem to affect colonisation patterns. CONCLUSIONS: The gut of extremely low birthweight infants is colonised by a paucity of bacterial species. Breast milking and reduction of antibiotic exposure are critical to increasing fecal microbial diversity.

Ureaplasma urealyticum respiratory tract colonization is associated with an increase in interleukin 1-beta and tumor necrosis factor alpha relative to interleukin 6 in tracheal aspirates of preterm infants.

OBJECTIVE: To determine whether Ureaplasma urealyticum respiratory tract colonization in very low birth weight infants during the first week of life is associated with changes in tracheal aspirate concentrations of the cytokines interleukin 1-beta (IL-1-beta), tumor necrosis factor alpha (TNF-alpha) and IL-6. METHODS: Infants with birth weights < or =1250 g were prospectively enrolled. Samples were obtained from the endotracheal tube or nasopharynx on Day 1 and again between Days 7 and 10 for U. urealyticum culture. The concentrations of IL-1-beta, TNF-alpha and IL-6 were measured in tracheal aspirate samples by enzyme-linked immunosorbent assay. RESULTS: There were 18 positive cultures for U. urealyticum from 15 of 96 infants (15.6%). IL-1-beta in tracheal aspirates expressed as concentration per volume or as a ratio of IL-1-beta to IL-6 were 7- and 14.9-fold higher, respectively, in Ureaplasma-positive infants than in Ureaplasma-negative infants (P < 0.05). The TNF-alpha/IL-6 ratio was 18.9 and 15.5 times higher in the Ureaplasma-positive aspirates than in the Ure aplasma-negative aspirates on Day 1 and Days 7 to 10 (P < 0.05). Concentrations of IL-1-beta and TNF-alpha were significantly correlated on Day 1 and Days 7 to 10. Although there was no clinical association demonstrated between U. urealyticum colonization and the development of bronchopulmonary dysplasia (BPD) in this study, infants who developed BPD had significantly higher IL-1-beta concentrations and ratios of IL-1-beta to IL-6 in Day 1 aspirates than infants who did not develop BPD. Conclusions. Isolation of U. urealyticum from the respiratory tract is associated with increased IL-1-beta concentrations and IL-1-beta-IL-6 ratios on Day 1 and increased TNF-alpha-IL-6 ratios on Days 1 and 7 to 10 in tracheal aspirates of colonized infants. Infants who developed BPD had higher IL-1-beta concentrations and IL-1-beta-IL-6 ratios, suggesting that these may be early markers of lung inflammation.

Cromolyn sodium prophylaxis inhibits pulmonary proinflammatory cytokines in infants at high risk for bronchopulmonary dysplasia.

An imbalance of proinflammatory cytokines such as TNF-alpha, IL-1 beta, and the neutrophil chemotactic factor IL-8 and inhibitors (e.g., soluble TNF receptors and IL-1ra) in the lung during the first week of life may contribute to prolonged pulmonary inflammation and fibrosis in bronchopulmonary dysplasia (BPD). Disodium cromoglycate (DSCG) has anti-inflammatory effects in asthma, a disease with many similarities with BPD. In a prospective, randomized, blinded study, we examined whether early DSCG therapy inhibits proinflammatory cytokines in infants at risk for BPD. Twenty-six infants who were identified as high risk (> or = 75% probability) for oxygen-dependency at 28 d by a 12-h predictive score and survived 48 h were randomized to nebulized DSCG 20 mg (n = 13) or 2 cc NS (control, n = 13) every 6 h from Day 3 to Day 28. Lung lavage was collected on Day 3 (pre-study) and Day 7 and analyzed for cell count and differential and TNF-alpha, sTNFR1, sTNFR2, IL-1 beta, IL-1ra, and IL-8 concentrations. The groups' pre-study lavage cytokine concentrations were similar, but TNF-alpha and IL-8 concentrations were 3.6- and 4.9-fold lower in the DSCG group on Day 7 compared with levels in the control group. Soluble TNF receptors were unaffected by DSCG. There was a trend towards lower IL-1 beta levels in DSCG-treated infants on Day 7, but IL-1ra levels were unaffected by DSCG therapy. Three control subjects, but no DSCG-treated infants, died during the study period (p = 0.07). There were no significant differences between survivors of the two groups for oxygen-dependency at 28 d (100% control subjects; 85% DSCG). These results suggest that nebulized DSCG may exert an anti-inflammatory effect in the lungs of infants < or = 1,000 g at risk for BPD.

Potential role of interleukin-1 in the development of bronchopulmonary dysplasia.

Increased activities of inflammatory mediators unopposed by their inhibitors contribute to chronic lung injury and impaired healing in BPD. The deleterious effects of IL-1 beta, a cytokine involved in inflammation and host defense, are blocked by IL-1 receptor antagonist (IL-1Ra). We proposed that an imbalance of IL-1 beta and its inhibitors may contribute to the development of BPD. To determine the relative antigen concentrations of IL-1 beta and IL-1Ra and functional IL-1 activity in lung lavage of infants at risk for BPD, lung lavage was serially obtained from 1 to 28 days from 17 infants with evolving BPD, 13 infants with self-limited RDS, and 6 controls ventilated for nonpulmonary reasons. Overall, there was a high correlation between IL-1 beta antigen concentration and IL-1 activity (r = 0.82, p = 0.0001). There were no significant differences among the groups for lung lavage variables on day 1. However, in infants who developed BPD, IL-1 beta antigen concentration and IL-1 activity increased 16- and 61-fold, respectively, during the first week. IL-1Ra remained relatively unchanged during the first month. IL-1 beta/IL-1Ra antigen ratio was significantly higher on days 5 (median 0.024) and 7 (median 0.025) compared with day 1 (median 0.004), p < 0.05. These results suggest that a relative imbalance of IL-1 beta and IL-1Ra may contribute to prolonged inflammation in BPD.

Increased activity of interleukin-6 but not tumor necrosis factor-alpha in lung lavage of premature infants is associated with the development of bronchopulmonary dysplasia.

Although considerable evidence suggests that bronchopulmonary dysplasia (BPD) is the result of prolonged inflammation and impaired healing of the immature lung, the mediators that regulate inflammation in neonatal lung injury have not been completely elucidated. We examined whether the cytokines IL-6 and tumor necrosis factor-alpha (TNF) interact to modulate a cascade of cell-cell signaling events involved in inflammation contributing to the development of BPD. To determine the relative activities of these cytokines in neonatal lung injury, lung lavage samples were serially obtained from 1 to 28 d from 11 infants with self-limited respiratory distress syndrome (RDS), 19 infants with evolving BPD, and 10 control infants ventilated for nonpulmonary reasons. On the first day of life, there were no differences in antigenic IL-6 concentrations in lavage fluids among the BPD, RDS, and control groups, but IL-6 activity determined by the 7TD1 proliferation assay was 15-fold and 6.6-fold higher in lung lavage of infants who developed BPD compared with activities in lavage from control and RDS infants, respectively (control, 49.4 +/- 17.6; RDS, 117.3 +/- 59.6; BPD, 779.5 +/- 212.6 x 10(3) hybridoma units/L, mean +/- SEM, p = 0.02). This suggests that pathways for inactivating or inhibiting IL-6 that may be present in the lungs of RDS and control infants may be deficient in BPD infants. IL-6 activity remained elevated in lavage of BPD infants for the first 2 wk and declined to low levels by d 28.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of position on pulmonary mechanics in healthy preterm newborn infants.

Preterm infants are often placed in the supine position to facilitate care and observation. Prone positioning may positively affect later neurodevelopmental outcome, but it may also affect pulmonary function. Using a computerized system, we examined the effect of positioning on pulmonary mechanics in spontaneously breathing healthy preterm infants. Eleven infants with a mean birth weight (+/- SD) of 1523 +/- 171 gm and a mean gestational age (+/- SD) of 31.7 +/- 1.5 weeks were studied during the first 2 weeks of life. Pulmonary mechanic measurements were obtained in both supine and prone positions by mask pneumotachography and esophageal balloon technique. Respiratory rate and oxygen saturation were unaffected by positioning. There was a statistically, but not clinically, significant increase in heart rate in the prone position. However, there were no significant differences in tidal volume, minute ventilation, pulmonary resistance, or dynamic compliance between positions. The contribution of intrasubject variability of serial measurements was assessed in a separate group of four infants studied three times in the same position. There was no significant difference in respiratory rate, tidal volume, dynamic compliance per kilogram, or total pulmonary resistance in the same infant when studied in the same position over time (p > or = 0.24). The maximum variability (95% confidence limit) was 25.5% for tidal volume, 21% for dynamic compliance, and 44.3% for resistance. Because prone positioning did not adversely affect pulmonary mechanics or oxygen saturation in these healthy preterm infants, we suggest that prone position be used to facilitate the developmental needs of these infants.

Disordered pathways of fibrin turnover in lung lavage of premature infants with respiratory distress syndrome.

Premature infants who have self-limited respiratory distress syndrome (RDS) rapidly improve, whereas infants with a complicated respiratory course are more likely to develop bronchopulmonary dysplasia (BPD), a chronic lung disorder that is the result of prolonged lung injury and impaired healing. The balance of competing activities of coagulation and fibrinolysis may contribute to the premature lung's response to acute injury and determine, in part, whether there is early resolution or protracted alveolar inflammation. To determine the relative activities of the coagulation and fibrinolytic pathways in neonatal lung injury, procoagulant (PC) and plasminogen activator (PA) activities were measured in undiluted cell-free lung lavage samples obtained serially over the first 28 days of life from 11 infants with self-limited RDS, 11 infants with evolving BPD, and 5 mechanically ventilated control infants without lung disease. Lung lavage from all three groups contained readily detectable procoagulant activity due mainly to the tissue factor-Factor VII complex. Plasminogen activator activity was relatively high in control lavage samples but depressed on the first day of life in the two groups of infants with lung disease: median, 0.3814 IU/ml (control); 0.0541 IU/ml (RDS); and 0.0454 IU/ml (BPD), p < 0.05 in each case compared with control. Two infants with severe lung disease had no detectable plasminogen activator activity in lung lavage on the first day of life. Depressed fibrinolytic activity correlated with severity of lung disease assessed radiographically and by pulmonary function measurements. Plasminogen activator activity was due to both tissue plasminogen activator and urokinase.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between rhythmic swallowing and breathing during suckle feeding in term neonates.

Little is known of the development of efficient coordination between suckle feeding and breathing in human infants. To establish baseline data, we recorded breathing and swallowing activity during bottle feeds in 23 infants at 14-48 h postnatal age. Most swallows (overall mean 68%) were organized into runs, with intervals starting at 0.6-0.8 s and slowing to 1-1.3 s after 30-40 s. The proportion of run swallows to total swallows increased significantly with age. Swallow intervals were regular (coefficient of variation = 18-38%) compared with breathing (coefficient of variation = 50%). Both breathing rate and tidal volume were significantly reduced by the onset of suckle feeding, and the pattern of respiratory airflow became markedly irregular. Mild transient desaturation was common, but was not accompanied by changes in heart rate. Swallows could occur in all phases of breathing. Overall, equal numbers of swallows were preceded by expiration and inspiration, but twice as many were followed by expiration compared with inspiration. Swallows were classified by the respiratory phases both preceding and following the swallow. Swallows occurred in all possible classifications in each of the infants studied. The incidence of the most frequent classification (inspiration-swallow-expiration), was 24% overall (individual range 5-50%). The phase relation between swallows and breaths changed frequently but showed occasional short periods of stability during which the breathing became regular and tidal volume increased. We conclude that at less than 48 h the normal infant has little coordination between swallowing and breathing rhythms and maintains rhythmic swallowing at the expense of eupnea.