Survival of infants with persistent pulmonary hypertension without extracorporeal membrane oxygenation.

A retrospective evaluation was performed of the survival after conservative therapy of infants with persistent pulmonary hypertension who met the published criteria of Bartlett et al (Pediatrics. 1985;76:479-487) or Short et al (Clinics in Perinatology. 1987;14:737-748) for extracorporeal membrane oxygenation (ECMO) therapy. An 80% to 90% mortality rate can be predicted with these criteria, which are based on historical data, if ECMO is not used. The records of infants with the diagnosis of persistent pulmonary hypertension, weighing greater than 2 kg at birth and who were treated during two time periods, January 1980 to December 1981 [23 patients] and January 1986 to December 1988 [17 patients], were reviewed. During the earlier period, hyperventilation was the mainstay of our therapy, whereas during the later period, a more conservative approach (avoidance of hyperventilation) was adopted. In 1980 to 1981, 1 of the 6 patients (17%) who were eligible for ECMO by criteria of Bartlett et al survived, which is consistent with the published data. However, in 1986 to 1988, 9 of 10 ECMO-eligible patients (90%) survived (P less than .02). The corresponding survival figures using the alveolar-arterial oxygen difference criteria of Short et al were 0 of 5 survivors (0%) in 1980 to 1981 and 8 of 9 (89%) in 1986 to 1988 (P less than .006). These data indicate that approximately 90% of patients who are candidates for ECMO now survive in our institution without the use of that therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Function and composition of pulmonary surfactant and surfactant-derived fatty acid profiles are altered in young adults with cystic fibrosis.

STUDY OBJECTIVES: To determine whether chronic lung inflammation in young adult patients with cystic fibrosis (CF) alters the composition and function of surfactant and surfactant components in bronchoalveolar secretions. DESIGN: A prospective, descriptive study. SETTING: An adult CF center in a tertiary health-care center. PARTICIPANTS: Thirteen normal volunteer (NV) subjects recruited via local advertising and 15 CF patients recruited from the CF center. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We performed BAL and measured surfactant-associated protein A (SP-A) via enzyme-linked immunosorbent assay in BAL fluid (BALF), and quantitated total phospholipid, phospholipid subclass, and fatty acid subclass content of extracted BALF. We also determined the protein and phospholipid content, SP-A content, and functional characteristics of surfactant isolated from BALF via high-speed centrifugation. The phospholipid-to-protein ratio (milligram/milligram) of surfactant isolated by centrifugation (mean +/- SEM) was 1.01 +/- 0.07 for NV subjects and 2.62 +/- 0.42 for CF patients (p = 0.0001). Minimal surface tension was < 1 dyne.s.cm(-5) in all samples from NV subjects, but 21.9 +/- 0.73 dyne.s.cm(-5) for surfactant from CF patients. Immunoblotting of isolated surfactant revealed a marked decrease in SP-A for CF patients, compared to NV subjects. However, mean concentrations of SP-A in BALF that had not been subjected to high-speed centrifugation to isolate surfactant were not significantly different for CF patients (4.7 +/- 0.8 microgram/mL) vs NV subjects (4.6 +/- 0.2 microgram/mL). Additionally, phospholipid-to-protein ratios (0.32 +/- 0.04 for NV subjects vs 0.10 +/- 0.02 for CF patients; p < 0.0001) in extracted uncentrifuged BALF, and SP-A-to-protein ratios (microgram/milligram) in BALF were significantly depressed (74 +/- 8 for NV subjects vs 16 +/- 3 for CF patients; p < 0.0001). The phospholipid and fatty acid subclass profiles of extracted CF BALF vs NV BALF revealed a decreased mean phosphatidylcholine-to-sphingomyelin ratio (20.7 +/- 10.0 vs 55.2 +/- 8.7; p = 0.002), increased oleic acid content (12.1 +/- 2.3 nmol/mL vs 3.2 +/- 0.9 nmol/mL; p < 0.01), and increased arachidonic acid content (2.2 +/- 0.5 nmol/mL vs 0.6 +/- 0.3 nmol/mL; p < 0.05) for CF patients. CONCLUSIONS: Altered phospholipid-to-protein ratios and phospholipid subclasses, altered surfactant-derived fatty acid profiles, high minimal surface tension, and decreased association of SP-A with lipid components of isolated surfactant indicate that surfactant components are considerably altered and dysfunctional in lower respiratory tract secretions of CF patients. Surfactant composition and function are altered in CF, and the pattern of phospholipid and surfactant-derived fatty acid subclass alterations in CF are characteristic of ongoing lung injury and may depress surfactant function.

Amniotic fluid arborization: effect of blood, meconium, and pH alterations.

The effects of blood and meconium at various dilutions and pH alterations on the fern test were evaluated in an in vitro study. Thirty-six specimens of amniotic fluid across gestational ages (16 to 42 weeks) were tested. The fern test was unaffected by meconium at any concentration and by blood at dilutions of 1:10 or greater. When blood and amniotic fluid were mixed in equal amounts, ferning was not present. Arborization of amniotic fluid was unaffected by pH alterations. These findings support the clinical usefulness of the fern test for the determination of ruptured membranes, even in the presence of blood or meconium contamination, and of pH alterations.

Erythropoietin in human fetuses with immune hemolytic anemia and hydrops fetalis.

OBJECTIVE: To determine whether plasma erythropoietin is increased in fetuses with anemia due to Rh isoimmunization. METHODS: Hemoglobin and erythropoietin were measured in samples obtained by funipuncture from 15 fetuses with Rh isoimmunization (gestational age 26.2 +/- 5.0 weeks, mean +/- standard deviation) and from 13 control fetuses (23.1 +/- 6.7 weeks). Hemoglobin and erythropoietin also were determined in umbilical cord blood collected at birth from 20 term fetuses delivered by elective cesarean. RESULTS: Fetuses with Rh isoimmunization had lower hemoglobin and higher plasma erythropoietin measurements than mid-gestation controls (6.1 +/- 3.9 versus 10.7 +/- 1.5 g/dL and 105.5 +/- 168.1 versus 12.5 +/- 3.1 mU/mL, P < .05, respectively). Hemoglobin and plasma erythropoietin increased with gestational age in control fetuses. There was an inverse association between hemoglobin and plasma erythropoietin in control and Rh-isoimmunized fetuses (r = -0.56, P < .005). Using multiple linear regression, hemoglobin and gestational age were associated independently with plasma erythropoietin (overall F2,25 = 12.3, multiple r2 = 0.49, P < .001). Despite marked decreases in hemoglobin, fetuses below 24 weeks' gestation had minimal increases in plasma erythropoietin compared to fetuses above that gestational age. Mildly anemic Rh-isoimmunized fetuses (hemoglobin 11.6 +/- 2.0 g/dL) delivered vaginally had significantly higher erythropoietin levels in umbilical cord plasma than Rh-isoimmunized fetuses with comparable hemoglobin (10.9 +/- 3.5 g/dL) delivered by elective cesarean without labor (1246 +/- 856 versus 106 +/- 66 mU/mL, respectively, P < .05). CONCLUSION: Fetuses with anemia at mid to late gestation respond with increases in plasma erythropoietin, but these changes are substantially attenuated before 24 weeks' gestation.

Is there a role for antenatal TRH therapy for the prevention of neonatal lung disease?

Unfortunately, surfactant therapy is not routinely available to infants in some parts of the world because of its cost. It is the hypothesis of this article that in situations where surfactant is not available, there may be a role for antenatal thyrotropin-releasing hormone (TRH) plus glucocorticoid therapy. Data from randomized clinical trials, which compared therapy with antenatal glucocorticoid plus TRH to that with glucocorticoid alone were extracted and subjected to meta-analysis. The trials that incorporated surfactant therapy were analyzed separately from those in which surfactant was not used. In addition, because surfactant therapy was only available to some patients in the Australian ACTOBAT trial, each group analysis was performed with and without the ACTOBAT data. A characteristic of the earlier presurfactant trials is that few were designed for "intention to treat" analysis. In most of these studies, it was decided a priori to include babies who delivered within a specified time period after hormone therapy. The addition of TRH did not decrease respiratory distress syndrome in those trials in which surfactant therapy was used. In the presurfactant trials, respiratory distress syndrome was significantly decreased when "intention to treat" data were examined, as well as in those infants who delivered between 1 and 10 days after maternal therapy. There was also a significant decrease in oxygen dependency at 28 days after birth, and in oxygen dependency or death at this time, in those infants who delivered 1 to 10 days after treatment. Antenatal TRH had no significant effect of on neonatal complications such as air leak, intraventricular hemmorhage, patent ductus arteriosus, retinopathy of prematurity, or necrotizing enterocolitis. However, TRH did produce transient suppression of the pituitary thyroid axis. There were also a variety of transient complications in the mothers, including nausea, vomiting or flushing, light-headed feeling, and increased blood pressure. The authors conclude that the implementation of appropriate antenatal glucocorticoid treatment is the first priority. Once this has been established, the data presented here suggest that addition of antenatal TRH should be considered in those situations where surfactant is not available.

Combined hormonal therapy for the prevention of respiratory distress syndrome and its consequences.

In performing this meta-analysis, we have attempted to use comparable data, but there are limitations to the information that is available at present. Some studies reported results for all patients entered, whereas others reported only optimally treated patients (Table 2). Many of the trials have not yet been published in final form and subjected to peer review. In addition, all the studies reported here were conducted before the widespread use of surfactant therapy. It is unclear whether the benefit of antenatal TRH and steroid therapy on end points such as death or BPD would persist if surfactant was also used. (Surfactant has, however, little impact on the percentage of survivors with BPD, perhaps because sicker infants survive with this treatment and go on to develop BPD.) Studies comparing antenatal TRH plus steroid plus postnatal surfactant to antenatal steroid plus postnatal surfactant are clearly required, and are in progress in a number of centers around the world. Because of these limitations, the routine use of antenatal TRH plus steroid cannot be currently recommended. However, the apparent benefits of this therapy in terms of RDS, death, and CLD that have been reported here do suggest that it might be used in selected situations. An example is threatened delivery of a very premature infant with an immature amniotic fluid pulmonary maturation profile. These infants are at risk for RDS and CLD, even if antenatal steroid and postnatal surfactant therapy is used.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of respiratory distress syndrome.

RDS continues to be a major problem for premature infants despite a better understanding of its pathophysiology and of ways to try to prevent it. To date, prenatal administration of glucocorticoids has been the most widely used method of accelerating fetal lung development. However, several limitations of this therapy have prompted the search for alternative approaches. Most efforts have focused on the potential use of combined hormonal therapy with glucocorticoids and either thyroid hormones or TRH. The easy transplacental passage of the latter tends to favor its use. The use of hormonal therapy prenatally and surfactant administration at birth appears currently to be the best approach to prevent RDS. The greatest benefit would clearly come from the prevention of prematurity (Fig 1), but this has not proved to be an easy task.

Effect of betamethasone on maternal, fetal and neonatal rat cellular immunity.

OBJECTIVE: We evaluated the effect of maternal administration of betamethasone (0.2 mg/kg per day) on mitogen-induced lymphocyte proliferation and interleukin-2 (IL-2) production by maternal, fetal, and neonatal rat splenic lymphocytes. STUDY DESIGN: Betamethasone was injected intramuscularly on days 19 and 20 of gestation to timed-pregnant rats (Sprague-Dawley). Fetuses were delivered on day 21 of gestation, or allowed to deliver spontaneously at term (22 days), followed by sacrifice at various intervals after birth. Lymphocyte proliferation was determined by 3H-thymidine incorporation with and without phytohemagglutinin (PHA), and IL-2 by proliferation of IL-2 dependent CTLL-2 cells. RESULTS: Maternal lymphocytes had higher spontaneous proliferation than lymphocytes from nonpregnant female rats. Betamethasone use resulted in a decrease in PHA-induced lymphocyte proliferation and IL-2 production by maternal lymphocytes. These effects were observed until 4 days after delivery. Significant decreases in these parameters were also seen in 21-day fetuses of betamethasone-treated mothers. These effects were still present 6 days after birth but not at 12 days of age. CONCLUSION: These findings suggest that, in the rat, exposure to betamethasone during late pregnancy results in marked, but transient decreases in PHA-induced lymphocyte proliferation and IL-2 production in both the mothers and their offspring.

Effect of dexamethasone on rat plasma platelet activating factor acetylhydrolase during the perinatal period.

It has been previously reported that the administration of dexamethasone (DEX) to adult rats increases the activity of plasma platelet-activating factor acetylhydrolase (PAF-AH) and prevents the development of intestinal necrosis caused by platelet activating factor (PAF) injection. In this report, we examined the effect of DEX administration on plasma PAF-AH activity during the perinatal period. Timed-pregnant rats received DEX (0.2-1.0 mg/kg/d) or normal saline (controls) on days 16-18 (early group) or days 18-20 (late group) of gestation. Maternal plasma PAF-AH activity was lower in late gestation than in postpartum period (P < 0.001). Fetal and neonatal plasma PAF-AH activity was higher than maternal values (P < 0.05). No changes of PAF-AH activity were seen in maternal, fetal or neonatal plasma after prenatal DEX administration at the aforementioned doses. A higher dose of DEX (1.3 mg/kg/d x 4d) or cortisone (200 mg/kg/d) produced an elevation of maternal plasma PAF-AH activity (DEX 79.2+/-3.0, cortisone 70.5+/-1.9 vs. controls 49.4+/-2.3 nmol/min/ml, P < 0.01), but resulted in a high fetal mortality. Treatment of newborn rats with DEX (0.5 mg/kg/d) on days 1-3 after birth, increased plasma PAF-AH activity on day 4 (DEX 292+/-5 versus controls 140+/-9 nmol/min/ml, P < 0.001) and day 6 (DEX 302+/-12 versus controls 136+/-6 nmol/min/ml, P < 0.001). Postnatal administration of DEX increases the plasma PAF-AH activity in the rat. Only high doses of prenatal corticosteroids that cause fetal death can elevate maternal plasma PAF-AH activity.

Amniotic fluid Clara cell protein concentration in normal pregnancy, a marker of fetal airway growth or fetal lung maturation?

OBJECTIVE: To evaluate the relationship of Clara cell protein (CCP) in amniotic fluid (AF) with the lecithin/sphingomyelin (L/S) ratio, and the concentrations of saturated phosphatidylcholine (Sat PC) and surfactant protein A (SP-A). STUDY DESIGN: AF samples were obtained by amniocentesis from 98 pregnancies without conditions known to influence fetal lung maturation between 25 and 41 weeks of gestation. These samples were used for determinations of CCP, L/S ratio, Sat PC, and SP-A. Simple and multiple linear regressions were used to analyze the data. RESULTS: CCP in AF increased logarithmically with gestational age (R(2)=0.51, p=0.006). The L/S ratio (R(2)=0.41, p<0.001), and the concentrations of Sat PC (R(2)=0.26, p<0.001) and SP-A (R(2)=0.52, p<0.001) also increased with advancing gestation. Weak correlations of CCP with the L/S ratio (R(2)=0.22, p=0.009) and Sat PC (R(2)=0.12, p=0.004), but not with SP-A (R(2)=0.07, p=0.10), were found. Using multiple linear regressions, gestational age was the only predictor of CCP (F=10.9, R(2)=0.13, p=0.015). Conversely, gestational age, Sat PC, and SP-A accounted for most of the variation of the L/S ratio (F=34.7, R(2)=0.61, p=0.0001). CONCLUSION: CCP correlated very poorly with known and widely accepted indices of fetal lung maturation. The increasing concentration of CCP in AF throughout gestation probably reflects growth and development of the fetal airways.

Severe fetomaternal hemorrhage. A report of four cases.

Four cases of severe fetomaternal hemorrhage (FMH) presented with severe anemia and signs of circulatory failure. One of the patients developed the syndrome of persistent fetal circulation. The diagnosis of FMH was confirmed in all using Kleihauer-Betke tests, which demonstrated abundant fetal erythrocytes in the maternal circulation. Three infants survived after prompt volume replacement and correction of anemia. The only fatality was related to an underlying chromosomal disorder. The majority of reported neonatal deaths due to FMH have occurred when shock was the presenting manifestation.

Fetal-neonatal uremia in advanced maternal diabetes.

A symmetrically growth retarded premature infant was born to a mother with advanced diabetic nephropathy, chronic renal failure, and hypertension, and managed with aggressive medical therapy without the use of dialysis. The neonatal course was uncomplicated, except for cord blood creatinine and BUN concentrations of 4.7 mg/dl and 116 mg/dl, respectively, that fell to 1.1 mg/dl and 44 mg/dl by 2 days of age. Strict glucose control, careful management of the metabolic abnormalities of uremia, and periodic surveillance of fetal well-being led to a successful pregnancy.

Late closure of the ductus arteriosus using indomethacin in the preterm infant.

Several studies have shown a lack of effect of indomethacin therapy for the closure of a patent ductus arteriosus (PDA) in premature infants over 14 days of postnatal age. In this report we describe two cases in which a hemodynamically significant PDA was closed with indomethacin in preterm infants over 20 days of age. The response to indomethacin may be more related to postconceptual age than to actual postnatal age. We suggest that intravenous indomethacin therapy should be attempted before surgical ligation is performed in those premature infants under 34 weeks postconceptual age who have a hemodynamically significant patent ductus arteriosus.

Randomized trial of sterile water by gavage drip in the fluid management of extremely low birth weight infants.

OBJECTIVE: To determine whether extremely low birth weight infants who receive enteral sterile water have a reduction in treated patent ductus arteriosus or death by 28 days compared to infants with routine management. STUDY DESIGN: A total of 214 infants were enrolled and randomized by 36 h of age to receive up to 50 ml kg(-1) per day of enteral sterile water (n=109) for 7 days or routine fluid management (n=104). Patent ductus arteriosus treatment was defined as either indomethacin treatment or surgical ligation. RESULT: The proportion of infants with a treated patent ductus arteriosus or death at <28 days of age was 63% in the sterile water group vs 64% in the control group (relative risk 0.99, 95% confidence interval 0.81 to 1.22). There were no differences in the proportion of infants in the sterile water group vs control group with a treated patent ductus arteriosus (55 vs 48%), death (21 vs 28%), necrotizing enterocolitis or death (24 vs 32%), or bronchopulmonary dysplasia or death at <28 days (80 vs 77%). Daily mean glucose levels were significantly higher (P=0.04) in control infants than sterile water infants. CONCLUSION: The use of sterile water did not decrease the incidence of patent ductus arteriosus or other adverse clinical outcomes. The role of enteral sterile water in the fluid management of extremely low birth weight infants remains uncertain.

Influence of theophylline on fetal rat lung phosphatidylcholine synthesis in vivo.

In an attempt to resolve conflicting reports on the effectiveness of theophylline in stimulating fetal lung surfactant production in vivo, we examined the influence of theophylline on fetal rat lung phosphatidylcholine synthesis. Intraperitoneal administration of theophylline to the pregnant rat produced elevated serum levels in both mother and fetus. The fetal:maternal ratio was 0.85:0.90. Doses of theophylline ranging between 5 and 180 mg/kg/day resulted in no increase in the rate of incorporation of choline into phosphatidylcholine or its disaturated species. There was also no increase in the lung tissue concentration of these phospholipids. Theophylline does not appear to stimulate fetal rat lung phosphatidylcholine synthesis at nontoxic serum levels.

Effects of betamethasone and thyroid hormone on fetal rat lung maturation in vivo.

We studied the effect of maternal administration at various intervals of betamethasone, triiodothyronine (T3), or both, on fetal rat lung maturation. T3 alone did not enhance choline incorporation to phosphatidylcholine by 20-day fetal lung explants, or morphometric lung maturation. Betamethasone, and betamethasone plus T3, increased both of those parameters over control and T3 values. However, addition of T3 offered no advantage over administration of betamethasone alone. Significant enhancement of morphometric lung maturation was already present after only 24 h of exposure to beta-methasone, or to the combination of hormones. However, choline incorporation to phosphatidylcholine only increased significantly by 36 h of exposure to betamethasone with or without T3.

Atrial natriuretic factor in hydrops fetalis caused by Rh isoimmunisation.

Plasma concentrations of atrial natriuretic factor were determined by radioimmunoassay in 16 human fetuses of between 19 and 38 weeks' gestation. Fifteen fetuses had varying degrees of anaemia as a result of Rh isoimmunisation, and one fetus was normal. Eight fetuses had ultrasonographic evidence of severe hydrops fetalis and an additional three fetuses had mild hydrops. Severely hydropic fetuses were more anaemic and immature than those with mild or no hydrops. Among fetuses from which samples were taken before in utero transfusion, concentrations of atrial natriuretic factor were higher in those with severe hydrops than in the other groups. An inverse relationship between the haemoglobin concentration and that of atrial natriuretic factor was found. In four fetuses in which severe hydrops resolved after intravascular transfusions in utero, there were significant decreases in plasma atrial natriuretic factor concentrations; in the fifth fetus the decrease was less pronounced. Raised concentrations of atrial natriuretic factor in fetuses with severe anaemia and hydrops may be the result of atrial natriuretic factor release induced by hypoxia.

Platelet-activating factor in surfactant preparations.

Surfactant administration is used for treatment of neonatal respiratory distress syndrome. We studied whether currently used surfactant preparations contain platelet-activating factor (PAF), a potent lipid mediator produced by fetal lungs. Three surfactant preparations from animal sources contained between 36 and 218 pmol of PAF per mL, whereas PAF was undetectable in an artificial surfactant. Based on current recommendations, about 144-654 pmol PAF would be administered per dose of natural surfactant, sufficient to exert possible physiological effects on the lung. The action of PAF may be exacerbated by low activity of PAF-acetylhydrolase, which inactivates PAF, in tracheal fluid from infants with respiratory distress syndrome.

Maternal administration of glucocorticoid and thyrotropin-releasing hormone enhances fetal lung maturation in undisturbed preterm lambs.

OBJECTIVE: We hypothesized that combined treatment with glucocorticoid plus thyrotropin-releasing hormone administered to pregnant ewes with preterm gestation accelerates fetal lung maturation of undisturbed lambs better than single hormonal treatment does. STUDY DESIGN: Twenty-five pregnant ewes at 123 days of gestation were randomized to receive (1) 0.9% sodium chloride (controls), (2) betamethasone (12 mg intramuscularly every 24 hours two times), (3) thyrotropin-releasing hormone (400 micrograms intravenously every 8 hours six times), or (4) thyrotropin-releasing hormone plus betamethasone. After delivery by cesarean section at 125 days fetal lamb lung compliance and alveolar lavage phospholipid content were determined. RESULTS: Betamethasone plus thyrotropin-releasing hormone significantly increased fetal lung compliance expressed as milliliters of air per gram of wet weight at 40 cm H2O and 5 cm H2O (0.82 +/- 0.13 and 0.35 +/- 0.10 ml/gm wet lung, respectively) versus betamethasone (0.37 +/- 0.02 and 0.07 +/- 0.02), thyrotropin-releasing hormone (0.38 +/- 0.02 and 0.14 +/- 0.03), and control (0.25 +/- 0.03 and 0.09 +/- 0.01) groups. Also, total phospholipids and saturated phosphatidylcholine concentrations in alveolar lavage were significantly higher in the combined betamethasone plus thyrotropin-releasing hormone group (27.3 +/- 4.9 and 16.9 +/- 4.3 micrograms/gm wet lung, respectively) versus betamethasone (10.9 +/- 3.5 and 6.7 +/- 2.1), thyrotropin-releasing hormone (15.2 +/- 5.6 and 7.3 +/- 2.0), and control (7.9 +/- 2.4 and 3.6 +/- 1.0) groups. CONCLUSION: Combined maternal administration of betamethasone plus thyrotropin-releasing hormone improves lung maturation in undisturbed fetal lambs at 125 days' gestation more than does either hormone given alone.