Antenatal and early postnatal dexamethasone treatment decreases cortisol secretion in preterm infants

Glucocorticoids are used antenatally to accelerate the maturation of fetal respiratory and cardiovascular systems when a threat of preterm delivery exists. Postnatally, they are used to prevent and treat respiratory distress syndrome. This study investigates the effects of antenatal (ACT) and early postnatal corticosteroid treatment (PCT) on serum cortisol and plasma catecholamine and adenosine 3',5'-cyclic monophosphate (cAMP) concentrations in preterm neonates. The infants in the ACT group had a significantly lower cortisol concentration than the infants in the non-ACT group on the first day of life. After birth, the infants were further divided into non-PCT and PCT groups. PCT suppressed cortisol levels significantly after 2 days, and the cortisol levels were still lower 2 days after discontinuation of PCT. No effect of PCT on plasma cAMP or catecholamine concentrations was observed. The results indicate that both ACT and a short PCT can significantly suppress basal cortisol levels in preterm infants.     

Effects of CO2 rebreathing on pulmonary mechanics in premature infants

The effects of hypercapnia produced by CO2 rebreathing on total pulmonary, supraglottic, and lower airway (larynx and lungs) resistance were determined in eight premature infants [gestational age at birth 32 +/- 3 (SE) wk, weight at study 1,950 +/- 150 g]. Nasal airflow was measured with a mask pneumotachograph, and pressures in the esophagus and oropharynx were measured with a fluid-filled or 5-Fr Millar pressure catheter. Trials of hyperoxic (40% inspired O2 fraction) CO2 rebreathing were performed during quiet sleep. Total pulmonary resistance decreased progressively as end-tidal PCO2 (PETCO2) increased from 63 +/- 23 to 23 +/- 15 cmH2O.l-1.s in inspiration and from 115 +/- 82 to 42 +/- 27 cmH2O.l-1.s in expiration between room air (PETCO2 37 Torr) and PETCO2 of 55 Torr (P less than 0.05). Lower airway resistance (larynx and lungs) also decreased from 52 +/- 22 to 18 +/- 14 cmH2O.l-1.s in inspiration and from 88 +/- 45 to 30 +/- 22 cmH2O.l-1.s in expiration between PETCO2 of 37 and 55 Torr, respectively (P less than 0.05). Resistance of the supraglottic airway also decreased during inspiration from 7.2 +/- 2.5 to 3.6 +/- 2.5 cmH2O.l-1.s and in expiration from 7.6 +/- 3.3 to 5.3 +/- 4.7 cmH2O.l-1.s at PETCO2 of 37 and 55 Torr (P less than 0.05). The decrease in resistance that occurs within the airway in response to inhaled CO2 may permit greater airflow at any level of respiratory drive, thereby improving the infant's response to CO2.     

Effects of antenatal glucocorticoid therapy on hippocampal histology of preterm infants

Objective

To investigate if antenatal glucocorticoid treatment has an effect on hippocampal histology of the human preterm newborn.

Patients and Methods

Included were consecutive neonates with a gestational age between 24 and 32 weeks, who were born between 1991 to 2009, who had died within 4 days after delivery and underwent brain autopsy. Excluded were neonates with congenital malformations and neonates treated postnatally with glucocorticoids.The brains were routinely fixed, samples of the hippocampus were stained with haematoxylin and eosin and sections were examined for presence or absence of large and small neurons in regions of the hippocampus. Additional staining with GFAP, neurofilament and vimentin was performed to evaluate gliosis and myelination. The proliferation marker Ki67 was used to evaluate neuronal proliferation. Staining with acid fuchsin-thionin was performed to evaluate ischemic damage.

Results

The hippocampi of ten neonates who had been treated with antenatal glucocorticoids showed a lower density of large neurons (p = 0.01) and neurons irrespective of size (p = 0.02) as compared to eleven neonates who had not been treated with glucocorticoids. No difference was found in density of small neurons, in myelination, gliosis, proliferation or ischemic damage.

Conclusion

We found a significantly lower density of neurons in the hippocampus of neonates after antenatal glucocorticoid treatment. Although the pathophysiological and clinical interpretations of these findings are not clear, they are consistent with those from experiments in mice and rhesus monkeys.     

Metabolic and respiratory effects of flow-resistive loading in preterm infants

Oxygen consumption (VO2) was measured during hypoventilation induced by moderate-sized flow-resistive loading in 12 preterm infants, and the results were compared with those obtained under basal conditions immediately before and after the loaded run, each of which lasted for 7-10 min. Loading was performed with a continuous flow-resistive load (inspiratory and expiratory), which was approximately threefold greater in magnitude than the intrinsic resistance of preterm infants. VO2, minute ventilation (VE), transcutaneous oxygen tension (PtCO2), and transcutaneous carbon dioxide tension (PtcCO2) were continuously monitored. Results revealed that VE decreased significantly with loading, from 336 +/- 103 to 231 +/- 58 (SD) ml.min-1.kg-1 (P less than 0.001), while returning to basal levels of 342 +/- 59 ml.min-1.kg-1 after discontinuation of the load. VO2 decreased from 7.2 +/- 1.2 to 5.9 +/- 0.9 ml.min-1.kg-1 with loading (P less than 0.001) and returned to 7.2 +/- 1.2 ml.min-1.kg-1 at the second basal measurement. PtcCO2 remained unchanged with loading, and PtcCO2 only increased from 39 +/- 8 to 41 +/- 9 Torr (P less than 0.05) with loading, while returning to 40 +/- 9 Torr at the second basal measurement. Results indicate a decrease in the metabolic rate and ventilation with loading, with relatively little increase in PtcCO2. These data can explain prior observations that minimal disturbances in oxygen and carbon dioxide tensions occur with hypoventilation during flow-resistive loading in neonates, although the precise mechanism for this reduction remains to be determined.     

Ontogeny of respiratory control and pulmonary mechanics in newborn rabbits

Maturation of the respiratory pattern and the active and passive mechanical properties of the respiratory system were assessed in 19 tracheotomized rabbits (postnatal age range: 1-26 days) placed in a body plethysmograph. With maturation both minute ventilation and tidal volume significantly increased, whereas respiratory frequency decreased. When normalized for body weight (kg) both the passive (Rrs X kg) and active (R'rs X kg) resistances of the respiratory system significantly increased with age, whereas the corresponding passive (Crs X kg-1) and active (C'rs X kg-1) compliances significantly decreased. At any given age R'rs X kg only slightly exceeded Rrs X kg, whereas C'rs X kg-1 was significantly lower than Crs X kg-1. Moreover, the maturational increases in Rrs X kg and R'rs X kg exceeded the corresponding decreases in Crs X kg-1 and C'rs X kg-1, resulting in significant age-related increases in both the passive (tau rs) and active (tau'rs) time constants of the respiratory system. Due to the age-related increases in tau'rs, producing a delayed volume response to any given inspiratory driving pressure, the relative volume loss obtained at any time during inspiration was greater in the maturing rabbit. On the other hand, because of concomitant compensatory changes in respiratory pattern, evidenced by increases in inspiratory duration with age, the end-inspiratory tidal volume loss in the maturing animal was maintained generally less than 10% at all postnatal ages. Thus maturational changes in respiratory pattern appear coupled to changes in the active mechanical properties of the respiratory system. The latter coupling serves to optimize the transduction of inspiratory pressure into volume change in a manner consistent with establishing the minimum inspiratory work of breathing during postnatal development.     

Development of stability of the respiratory system in preterm infants

Chest wall distortion leads to increased minute volume displacement of the diaphragm (MVDD) and diaphragmatic work (DW) in preterm infants. Lung mechanics, MVDD, and DW were measured at weekly intervals in six preterm infants between 29 and 36 wk postconceptional age. Over the period of study, MVDD and DW decreased significantly, whereas dynamic lung compliance consistently increased. There was no consistent change in the pulmonary ventilation, total pulmonary resistance, the work performed on the lungs, or the change in intraesophageal pressure with tidal breathing. The improvement in the stability of the chest wall, as indicated by the change in these dynamic measurements of diaphragmatic function, parallels the decrease in static chest wall compliance and the clinical course of the resolution of apnea of prematurity.     

Effects of fibrogenic mediators on the development of pancreatic fibrosis in a TGF-beta1 transgenic mouse model

The pancreas morphology of transgenic mice that overexpress transforming growth factor-beta1 (TGF-beta1) in the pancreas resembles partially morphological features of chronic pancreatitis, such as progressive accumulation of extracellular matrix (ECM). Using this transgenic mouse model, we characterized the composition of pancreatic fibrosis and involved fibrogenic mediators. On day 14 after birth, fibrotic tissue was mainly composed of collagen type I and III. At this time, mRNA levels of TGF-beta1 were increased. On day 70, the ECM composition was expanded by increased deposition of fibronectin, whereas connective tissue growth factor, fibroblast growth factor (FGF)-1, and FGF-2 mRNA expression levels were elevated in addition to TGF-beta1. In parallel, the number of pancreatic stellate cells (PSC) increased over time. In vitro, TGF-beta1 stimulated collagen type I expression but not fibronectin expression in PSC, in contrast to FGF-2, which stimulated both. This confirms that TGF-beta1 mediates pancreatic fibrosis through activation of PSC and deposition of collagen type I and III at early time points. Furthermore, this points to an indirect mechanism in which TGF-beta regulates pancreatic ECM assembly by induction of additional growth factors.     

Effects of nasal CPAP therapy on respiratory and spontaneous arousals in infants with OSA.

Obstructive sleep apnea (OSA) in infants has been shown to resolve frequently without a cortical arousal. It is unknown whether infants do not require arousal to terminate apneas or whether this is a consequence of the OSA. We studied the apnea and arousal patterns of eight infants with OSA before and after treatment with nasal continuous positive airway pressure (CPAP). These infants were age matched to eight untreated infants with OSA and eight normal infants. Polysomnographic studies were performed on each infant. We found that the majority of central and obstructive apneas were terminated without arousal in all OSA infants. After several weeks of nasal CPAP treatment, the proportion of apneas terminating with an arousal during rapid-eye-movement sleep increased in treated infants compared with untreated infants. Spontaneous arousals during rapid-eye-movement sleep were reduced in all OSA infants; however, during CPAP treatment, the spontaneous arousals increased to the normal control level. We conclude that OSA in infants possibly depresses the arousal response and treatment of these infants with nasal CPAP partially reverses this depression.     

Differences in CO2 threshold of respiratory muscles in preterm infants

Because neonatal apnea is frequently associated with airway obstruction, we compared relative changes in activity between various upper airway muscles and the diaphragm during hypercapnic stimulation. The technique of hyperoxic CO2 rebreathing was employed in 17 healthy, sleeping preterm infants studied at a postnatal age of 32 +/- 12 days. Surface diaphragm (DIA) electromyograms (EMGs) were recorded in all infants, and noninvasive measurements of posterior cricoarytenoid (PCA), genioglossus (GG), and alae nasi (AN) EMGs were analyzed in 11, 9, and 8 infants, respectively. During the control period, consistent phasic EMGs were recorded from the DIA in all infants and from the PCA in 8 infants, but from the GG and AN each in only one infant. During CO2 rebreathing, minute ventilation and end-tidal CO2 increased linearly as CO2 rose from 31 +/- 5 to 51 +/- 5 Torr. DIA and PCA EMGs also had proportional and comparable increases throughout rebreathing. In contrast, both GG and AN responses differed from the DIA and PCA (P less than 0.001) and exhibited minimal or absent responses at low levels of hypercapnia. Consistent GG and AN EMGs appeared at comparable levels of end-tidal CO2 (47 +/- 5 and 45 +/- 5 Torr, respectively) and subsequently increased linearly in most infants. We conclude that during CO2 rebreathing the initially delayed and subsequently linear responses of the GG and AN EMGs indicate a high CO2 threshold for these muscles.     

Effects of vagotomy on respiratory mechanics in newborn and adult pigs

We have examined breathing patterns and respiratory mechanics in anesthetized tracheostomized newborn piglets and adult pigs and the changes determined by cervical bilateral vagotomy. Piglets had a respiratory system compliance and resistance, on a per kilogram basis, respectively, higher and smaller than the adults. After vagotomy neither variable changed in the newborn, but resistance dropped in the adult. This may suggest that efferent vagal control of bronchomotor tone is more pronounced in the adult. Respiratory system time constant was longer in newborns both before and after vagotomy. The distortion of the chest wall, examined as the ratio between the volume inhaled spontaneously and the passive volume for the same abdominal motion, was more marked in newborns, reflecting their higher chest wall compliance. The work per minute, computed from the pressure and volume changes, was larger in piglets. After vagotomy the external work per minute was not different; however, the larger tidal volumes were accompanied by a larger chest distortion. This may indicate that vagal control of the breathing pattern, by limiting the depth of inspiration and hence the amount of chest distortion, has implications on the energetics of breathing.     

Postnatal thyroxine administration for idiopathic respiratory distress syndrome in preterm infants

Thirty-six preterm infants of less than 34 weeks of gestation with idiopathic respiratory distress syndrome (IRDS) were studied. Eighteen of them were treated with intravenous thyroxine (T4) and compared with 18 control prematures to evaluate the effect of postnatal T4 administration on the course of IRDS. After treatment, serum T4 levels were similar to those of healthy term infants. No statistically significant effect on mortality rate, duration of mechanical ventilation (p greater than 0.3), need of high oxygen environment (p greater than 0.05) and development of bronchopulmonary dysplasia (p greater than 0.2) was observed between the two groups. These observations show that postnatal use of T4 does not carry any benefit for preterm infants with IRDS.