[Relationship between serum estradiol levels in the early postnatal period and the occurrence of hyaline membrane disease and bronchopulmonary dysplasia in neonates].

OBJECTIVE: This study examined the changes of serum levels of estradiol during the early postnatal period in neonates in order to investigate the possible relationship between the serum estradiol levels and the occurrence of pulmonary hyaline membrane disease (HMD) and bronchopulmonary dysplasia (BPD). METHODS: Fifty-nine premature infants with the gestational age between 26 and 32 weeks and 61 full-term infants with the gestational ages between 37 and 42 weeks were enrolled. Serum levels of estradiol were measured on postnatal days 1, 3 and 7. RESULTS: Serum levels of estradiol decreased rapidly after birth in both premature and term infants and there were significant differences among different postnatal ages groups. However, there were no significant differences in the serum estradiol levels between the premature and term groups on postnatal days 1, 3 and 7. Serum estradiol levels measured in premature infants with HMD were not statistically different from those in premature infants without HMD on all time points. Serum estradiol levels in premature infants with BPD were higher than those in premature infants without BPD on postnatal day 3, but there were no noticeable differences on postnatal days 1 and 7. CONCLUSIONS: Serum estradiol levels decline rapidly within 7 days after birth in both premature and term infants. Serum estradiol levels in the early postnatal period are not associated with the occurrence of HMD and BPD, suggesting that serum estradiol in the early postnatal period can not be used as a marker for predicting the development of HMD and BPD.

Estudio controlado del tratamiento de la enfermedad de membrana hialina del recién nacido pretérmino con surfactante pulmonar exógeno (porcino vs. bovino) / Treatment of hyaline membrane disease in the preterm newborn with exogenous lung surfanctant. A controlled study

Introducción: La enfermedad de membrana hialina (EMH) por deficiencia de surfactante pulmonar en el neonato prematuro es una causa importante de morbimortalidad. El surfactante pulmonar exógeno ha revolucionado el tratamiento de esta entidad en países desarrollados, aunque este beneficio ha sido menor en países en vías de desarrollo. El surfactante porcino de manufactura cubana es económico, y su uso comparado con otros surfactantes es desconocido. Material y métodos: Se llevó a cabo un estudio prospectivo, controlado, aleatorizado, abierto, en 44 recién nacidos prematuros con EMH. Un grupo recibió surfactante bovino (SB) (Survanta), y el otro surfactante porcino (SP) de fabricación cubana (Surfacen). Se evaluó la respuesta en variables de oxigenación y ventilación, días de oxígeno suplementario, ventilación mecánica, incidencia de complicaciones, tiempo de hospitalización y mortalidad. Resultados: 23 pacientes recibieron el surfactante bovino, y 21 el porcino. Los dos grupos fueron similares clínicamente y en sus patrones de respuesta de oxigenación y ventilación, con una tendencia a mayor incremento inicial en la oxigenación en el grupo tratado con SP. La incidencia de complicaciones fue similar en los dos grupos. Fallecieron 10 pacientes (47.6%) en el grupo SP, y 12 (52.2%) en el grupo SB (p>0.05). Conclusiones: El surfactante porcino tuvo efectos clínicos similares al bovino en las variables de oxigenación y ventilación estudiadas; no hubo diferencia significativa en complicaciones y mortalidad. El surfactante porcino es una alternativa efectiva y de menor costo que el surfactante bovino para el tratamiento de la EMH.

Background: Hyaline membrane disease (HMD) due to lung surfactant deficiency in the preterm newborn is an important cause of neonatal morbidity and mortality. Exogenous lung surfactant has transformed HMD therapy in developed countries, but an equivalent benefit has not been accomplished in developing countries due to a variety of factors. Porcine surfactant developed in Cuba is an inexpensive alternative to other surfactants, and its use has not been studied in our settings. Methods: A randomized, open, prospective and controlled trial was undertaken in 44 preterm newborns with HMD diagnosis. One group received bovine surfactant (BS) (Survanta) and the other Cuban porcine surfactant (PS) (Surfacen). The following clinical response variables were evaluated: oxygenation and ventilation indexes, days with supple mentary oxygen, days with mechanical ventilation, incidence of compli cations, time of hospitalization, and mortality. Results: 23 Patients received bovine surfactant and 21 the porcine type. The two groups were clinically similar, with patterns of oxygenation and ventilation response that were the same between groups, with a tendency to higher initial oxygenation increase in the PS group. The incidence of complications was similar between groups. Ten Patients (47.6%) died in the PS group, versus 12 (52.2%) in the BS group (p>0.05) Conclusions: Porcine surfactant had similar clinical effects than bovine surfactant in the oxygenation and ventilation variables, with no significant differences in complications or mortality. Porcine surfactant is an effective and lower cost alternative to bovine surfactant in the treatment of HMD.

Pulmonary surfactant-associated protein A levels in cadaveric sera with reference to the cause of death.

Pulmonary surfactant-associated protein A (SP-A) is an exclusively lung specific protein, and is considered to leak into the blood stream in alveolar septal damage. In this study we examined the serum SP-A level in forensic autopsy materials using an enzyme immunoassay with monoclonal antibodies to assess the postmortem level in relation to the cause and mode of death. Although a gradual postmortem degradation should be taken into consideration, topological relationship of serum level seemed to be fairly stable (arterial> or =venous blood in most cases), indicating no evident influence of postmortem diffusion. Significant elevation of serum SP-A (76.7-250 ng/ml in left heart blood) was observed in hyaline membrane diseases from various causes independent of the postmortem intervals (<30 h). However, mean SP-A levels in postmortem heart blood were usually low in asphyxia including hanging, strangulation and choking (left, 25.5 ng/ml; right, 22.3 ng/ml), polytrauma (left, 13.1 ng/ml; right, 9.0 ng/ml) and stab wound to the neck (left, 34.1 ng/ml; right, 29.4 ng/ml). Prominent elevation was noted in a case of fatal strangulation with complication of idiopathic interstitial pneumonia, and also in some deaths due to drowning, burns in fires, blunt and gunshot chest injuries. These findings indicated that postmortem elevation of serum SP-A levels was associated with alveolar septal damage due to inflammation, mechanical and physical stresses, which caused leakage of SP-A into the bloodstream.

Surfactant therapy prior to the interhospital transport of preterm infants.

The risk-to-benefit ratio of surfactant treatment of outborn preterm infants prior, as opposed to after, transportation to a perinatal center is not known. The objective of this study was to document current practice and to examine clinical outcomes in North America. In phase I (December, 1991 to January, 1992) questionnaires were distributed to 114 perinatal centers in the United States and Canada. The centers returned 98 surveys. Over half (50.5%) of the centers report giving surfactant rescue prior to infant transport, but only a minority (9.5%) of the centers report doing so for prophylaxis. In phase II (January, 1992 to December, 1992), clinical outcomes of surfactant-eligible babies requiring interhospital transport at a university hospital were evaluated to determine which infants ultimately received surfactant and when. The infants were compared between groups and did not differ significantly in gestational age, birthweight, sex type, number of multiple births, five-minute Apgar scores, or whether antenatal steroids were used. In phase II, the 66 consecutive, ventilator-dependent, outborn infants with average, and median, gestational age of 28 weeks were compared. The infants receiving surfactant prior to transport, when compared to the infants that got it after transport (9 hours later), did not do any better. There was 6% more survival without bronchopulmonary dysplasia in the group receiving surfactant after transport (65.2% versus 59.3%, p = 0.665). The infants receiving surfactant after transport were off the ventilator sooner (95% C.I. 6.0-28.7 versus 11.8-25.9 days) and discharged from the perinatal center earlier (95% C.I. 37.8-70.8 versus 47.9-69.0 days). Furthermore, arterial blood gases before and after transport reveals that there were no short-term advantages in administering surfactant prior to transport when compared to waiting for reevaluation at the perinatal center. These findings suggest that surfactant can be used safely prior to the interhospital transport of preterm infants, but this treatment does not seem to confer benefit over waiting for reevaluation, and possible surfactant treatment, at the tertiary perinatal center.

Plasma cysteine concentrations in infants with respiratory distress.

Because factors that predispose infants to persistent pulmonary hypertension of the newborn (PPHN) may cause oxidant stress, which in turn may increase demands for cysteine and glutathione, we investigated the availability of cysteine and its precursors in PPHN and related disorders. Plasma concentrations of four sulfur-containing and two non-sulfur-containing amino acids were measured by gas chromatography-mass spectrometry in blood from infants with PPHN, both those managed conventionally (PPHN group) and those treated with extracorporeal membrane oxygenation, as well as from infants with hyaline membrane disease. Concentrations also were measured in umbilical venous cord blood samples from a healthy control population, in venous plasma from infants receiving only intravenously administered glucose-containing solutions because they had noncardiopulmonary illnesses ("fasted" group), and from otherwise healthy, orally fed infants ("fed" group). The plasma total cyst(e)ine concentration was markedly lower in the three groups (PPHN, PPHN and extracorpeal membrane oxygenation, and hyaline membrane disease) receiving an elevated inspired oxygen concentration (0.6 to 1.0) than in fasted or fed control infants. In contrast, levels of plasma methionine, the other major sulfur amino acid, were low in the three groups receiving an elevated inspired oxygen concentration, as well as in fasted infants. Glycine and serine, two non-sulfur-containing amino acids, had a pattern similar to that of plasma methionine. Thus infants with PPHN and hyaline membrane disease have low plasma total cyst(e)ine levels, an effect that does not appear to result primarily from nutritional deprivation. We speculate that the role of cysteine in bioactivation of nitric oxide and as a precursor of glutathione may be relevant to the pathogenesis and evolution of PPHN and respiratory distress syndrome. Further studies are needed to determine whether increased demands for cysteine exist in these disorders.

Elevated immunoreactive endothelin-1 levels in newborn infants with persistent pulmonary hypertension.

To study the potential role of endothelin-1, a potent endothelium-derived vasoconstrictor peptide, in the pathophysiology of persistent pulmonary hypertension of the newborn (PPHN), we measured arterial concentrations of immunoreactive endothelin-1 (irET-1) in 24 neonates with PPHN. Secondary diagnoses included meconium aspiration syndrome (13 patients), sepsis (2), congenital diaphragmatic hernia (1), asphyxia (1), pulmonary hemorrhage (1), aspiration of blood (1), and respiratory distress syndrome (1). Compared with irET-1 levels in umbilical cord blood in normal infants (15.1 +/- 4.1 pg/ml; mean +/- SEM) and in newborn infants with hyaline membrane disease who were supported by mechanical ventilation (11.8 +/- 1.2 pg/ml), infants with PPHN had markedly elevated circulating irET-1 levels (27.6 +/- 3.6 pg/ml; p < 0.01 vs cord blood, hyaline membrane disease). Infants with severe PPHN requiring extracorporeal membrane oxygenation (ECMO) therapy had higher irET-1 levels than infants with milder disease (31.0 +/- 4.7 for ECMO-treated infants vs 21.2 +/- 2.0 for non-ECMO-treated infants; p < 0.05). In patients treated without ECMO, irET-1 progressively decreased during the following 3 to 5 days, paralleling clinical improvement. In contrast, irET-1 concentrations remained elevated in infants with severe PPHN during ECMO therapy. We conclude that circulating irET-1 levels are elevated in newborn infants with PPHN, are positively correlated with disease severity, and decline with resolution of disease in patients who do not require ECMO therapy. Whether endothelin-1 contributes directly to the pathophysiology of PPHN or is simply a marker of disease activity remains speculative.

Metabolic and endocrine consequences of depriving preterm infants of enteral nutrition.

Plasma enteroglucagon, pancreatic polypeptide, gastrin, motilin, neurotensin, gastric inhibitory polypeptide, secretin, vasoactive intestinal peptide and blood glucose, alanine, ketone bodies, lactate and pyruvate were measured on the sixth postnatal day in (a) a group of 10 preterm infants who on account of hyaline membrane disease had not received enteral feeding since birth and (b) before and at 55, 90, and 120 minutes after feeding in a group of healthy preterm infants fed three-hourly on human milk. Gut hormones were also measured in umbilical venous cord blood. The infants receiving regular boluses of milk from birth demonstrated postnatal surges in preprandial concentrations of gut hormones together with cyclical hormonal responses to feeding. None of these changes were seen in infants receiving intravenous fluids. The latter infants also had lower concentrations of blood alanine, glycerol and hydroxybutyrate and lacked the phasic changes in intermediary metabolites seen in the infants receiving enteral boluses of milk. Thus deprivation of enteral feeding results in a profound alteration of the metabolic and endocrine milieu which may have important effect on the process of adaptation to postnatal life.

Prolactin, estradiol, and thyroid hormones in umbilical cord blood of neonates with and without hyaline membrane disease: a study of 405 neonates from midpregnancy to term.

Concentrations of prolactin (PRL), estradiol (E2), thyroxine (T4), triiodothyronine (T3), and reverse T3 in umbilical cord blood were measured by radioimmunoassay in neonates with (n = 60) and in a control group without (n = 345) hyaline membrane disease. Mean levels of all hormones assayed were not significantly different between the two groups at various stages of gestation. In the control group, gestational age correlated positively with PRL and inversely with reverse T3, whereas birth weight correlated positively with PRL, T4, and T3, but inversely with reverse T3 levels. Thus, larger, more mature neonates tended to have higher cord levels of PRL, T4, T3 and lower concentrations of reverse T3. The data also suggest that, in the premature neonate, various obstetric complications and exposure in utero to beta-mimetic drugs and glucocorticoids may be important determinants of the concentrations of E2 and thyroid hormone in cord blood.

Frequency of transient hypothyroxinaemia in low birthweight infants. Potential pitfall for neonatal screening programmes.

Thyroid function was studied in 54 low birthweight infants during a 3-week period. Each infant was placed in one of three groups. Group 1 (n = 21), infants who were well and appropriately grown fro gestational age; group 2 (n = 23), infants who were appropriately grown but who had hyaline membrane disease; group 3 (n = 10), infants who were small-for-gestational-age. In group 1, 5 (24%) infants had at least one serum thyroxine value less than 3.0 micrograms/100 ml (39 nmol/l). There were 8 (35%) infants in group 2 who had similarly low serum thyroxine values as did 5 (50%) of the 10 infants in group 3. Serum thyrotropin levels and serum binding of the thyroid hormones, as measured by a T3-charcoal uptake test, were normal in all infants. In all instances but 2, serum thyroxine values were at least 4.0 micrograms/100 ml (51 nmol/l) by the end of the 3-week period. There is thus a high incidence of transient 'hypothyroxinaemia' in low birthweight infants, particularly if such infants have hyaline membrane disease or are small-for-gestational-age. These findings must be considered when interpreting results of screening programmes for congenital hypothyroidism and they lend further support to the use of a combination of serum thyroxine and thyrotropin determinations for optimum screening of such infants.

Hyaline membrane disease. A controlled study of inspiratory to expiratory ratio in its management by ventilator.

Sixty-nine neonates with severe hyaline membrane disease (HMD) were mechanically ventilated using either a 1:2 or a 2:1 inspiratory to expiratory (I/E) ratio. Survivors in the 2:1 group required a lower fraction of oxygen in the inspired air (FiO2) and lower end-expiratory pressure to achieve satisfactory oxygenation. During the first week of life, time of exposure to FiO2 greater than 0.60 while being mechanically ventilated was 29.7 +/- 7.5 hours for the 1:2 group and 6.6 +/- 2,7 hours for the 2:1 group, while time of exposure to end-expiratory pressure greater than 3 cm H2O was 49.4 +/- 7.9 hours for the 1:2 group and 13.4 +/- 7.4 hours for the 2:1 group. Mortality and the incidence of air leak, patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, and pulmonary hemorrhage were not different for the two groups. Using an increased I/E ratio during the acute phase of HMD improved oxygenation but did not alter morbidity or mortality.

Abnormal lung surfactant related to essential fatty acid deficiency in a neonate.

A low-birth-weight infant, suffering from chronic bronchopulmonary dysplasia following hyaline membrane disease and recurrent episodes of necrotizing enterocolitis, developed biochemical evidence of essential fatty acid (EFA) deficiency in the plasma. Fatty acid composition of phosphatidylcholine and phosphatidylglycerol in the lung lavage fluid was abnormal. Plasma changes included a decrease in the level of linoleic acid and an increased level of palmitic, palmitoleic, oleic, and 5,8,11-eicosatrienoic acid to arachidonic acid being greater than 0.4:1. A lower than normal level of palmitic acid and an increased level of palmitoleic and oleic acids were seen in pulmonary sufactant phospholipid components. Upon treatment and recovery from EFA deficiency, the fatty acid pattern both in plasma and surfactant phospholipids returned to normal along with clinical improvement. An association between EFA deficiency and altered fatty acid composition of pulmonary surfactant phospholipids is suggested.

Postnatal changes in blood S-adenosylmethionine concentration. Some observations in hyaline membrane disease.

The blood concentration of S-adenosylmethionine in 18 premature neonates affected by hyaline membrane disease did not differ from that found in a control group of healthy premature newborns. However, these values are higher than those found in full-term infants: this fact suggests that the methionine cycle is active in both the fetus and premature neonate with consequent conservation of homocysteine sulfur. These data provide ancillary evidence in support of the hypothesis that in premature babies cyst(e)ine is an essential amino acid. The concentration of S-adenosylmethionine reaches its lowest level 30 days after birth and then stabilizes at the age of 2--5 months with blood levels similar to those of the normal adult.

Umbilical cord plasma estradiol levels in relation to complications of pregnancy and newborn and to cortisol levels.

The average estradiol concentrations in umbilical cord plasma from newborns which developed respiratory distress with or without hyaline membrane disease (RDS) were lower by 25% than in controls. Complication of pregnancy by maternal diabetes or pruritus has been associated with abnormalities in estrogen concentrations in the mother, but cord plasma estradiol levels in these cases were essentially normal. Because of reports that treatment of the mother before delivery with estrogens or glucocorticoids results in a decreased incidence of RDS in newborns the relationship between endogenous estradiol and cortisol levels in cord plasm was investigated. There was no significant correlation between the concentrations of these steroids in 65 specimens; the cortisol levels associated with two cases of severe RDS were low.