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SUMMARY A longitudinal study of the EEG'S of 15 clinically normal infants of short gestation was done to test the hypothesis that maturation of the electrical activity of the central nervous system is post-conceptionally age-specific. The infants' gestational ages at birth ranged from 29 to 37 weeks. Post-prandial recordings were taken at weekly intervals for as long as the infants remained in the nursery. A total of 52 tracings were taken. Using the criteria of amplitude, frequency and ‘spatial’ organization, it was possible to distinguish 3 EEG ‘patterns' in the following age ranges: (1) 29–32 weeks: high amplitude (100–200 μv), slow waves (1–2 cps)with occipital predominance; (2) 33–36 weeks: moderate amplitude (50–100 μv), faster waves (2–3 cps) with no localization; and (3) 37–39 weeks: low amplitude (5–20 μv) waves with a frequency of either 3–4 cps or indeterminant and no spatial predominance. Similai patterns were recorded fiom infants of the same post-conception age and independent of their post-partum age. Except in infants whose post-conception age approaches 40 weeks, the findings support the hypothesis that electrical maturation of the brain proceeds chronologically. RESUME Maturation electroencephalographique chez le premature Une etude longitudinale electro-encephalogiaphique de quinze prematures cliniquement normaux, a ete conduite pour tester l'hypothese que la maturation de l'activiteelectrique du systeme nerveux central est caracteristique de l'âge post-conceptionnel. Les âges de gestation des enfants a la naissance variaient de 29 a 37 semaines. Des enregistrements apres le repas ont ete effectues toutes les semaines aussi longtemps que les enfants sont restes au centre d'elevage. 52 traces furent pratiques. A partir des criteres d'amplitude, de frequence et de distribution spatiale, il a ete possible de distinguer trois types d'enregistrements en fonction de l'âge: 1 29–32 semaines: forte amplitude (100–200 μv.), ondes lentes (1 ou 2 cps) a predominance occipitale. 2 33–35 semaines: amplitude moderee (50–100 μv.), ondes plus rapides (2 ou 3 cps), sans localisation. 3 37–39 semaines: faible amplitude (5–20 jiv.) avec une frequence de 3 a 4 cps ou distribuee irregulieiement et absence de predominance localisee. Des enregistrements de disposition semblable ont pu etre obtenus a partir d'enfants de meme âge conceptionnel et independamment de la duree de la gestation. Excepte pour les enfants dont l'âge conceptionnel approche 40 semaines cette etude renforce l'hypothese que la maturation electrique du cerveau s'etablit en fonction du temps. ZUSAMMENFASSUNG Reifegrad des Elektroencephalogramms von fruhgeborenen Kindern Bei 15 klinisch gesunden fruhgeborenen Kindern wurde eine Verlaufskontrolle der EEG'S durchgefuhrt, urn die Hypothese zu prufen, das der Reifegrad der elektrischen Aktivitat des Zentralen Nervensystems postconceptionell altersspezifisch ist. Das Geburts-alter der Kinder betrug von 29 bis 37 Wochen. Postprandiale Aufzeichnungen wurden in wochentlichen Abstanden so lange geschrieben, wie die Kinder auf der Sauglingsstation blieben. Insgesamt wurden 52 Ableitungen geschrieben. Es wurden die Kriterien der Amplitude, der Frequenz und der ‘raumlichen’ Anordnung eingesetzt, und so war es moglich, 3 EEG ‘Muster’ in den folgenden Altersgruppen zu unterscheiden: (1) 29–32 Wochen: hohe Amplitude (100–200μv), langsame Wellen (1–2 cps) mit starkerer Auspragung occipital; (2) 33–36 Wochen: masige Amplitude (50–100 μv), schnellere Wellen (2–3 cps) ohne feste Anoidnung; und (3) 37–39 Wochen: geringe Amplitude (5–20 μv) mit einer Frequenz von entweder 3–4 cps odei unregelmasig und ohne raumlichen Vorrang. Von Kindern des gleichen postconceptionellen Alters wurden, unabhangig vom Alter post partum, Ableitungen mit ahnlichem Muster geschrieben. Mit Ausnahme derjenigen Kinder, deren postconceptionelles Alter sich 40 Wochen nahert, unterstutzen diese Befunde die Hypothese, das der elektrische Reifegrad des Gehirns chronologisch fortschreitet. RESUMEN La maduracion del electroencefalograma en ninos con gestacion corta Se efectuo un estudio longitudinal de los EEG de 15 lactantes nacidos despues de una gestacion corta, cuyos cuadros clinicos eran normales, para probar la hipotesis de que la maduracion de la actividad electrica del sistema nervioso central depende de la edad post-concepcional. Las edades gestacionales de los ninos al nacer eian de 29 a 37 semanas. Se hizo una exploracion electroencefalografica postprandial una vez a la semana mientras que los ninos se quedaban en el hospital. Se obtuvieron 52 trazados. Utilizando los criterios de amplitud, banda de frequencia y organization ‘espacial’, se podian distinguir 3EEG tipo en las escalas de edad siguientes: (1)29-32semanas: emplitud alta (100–200 μv), ondas lentas (1–2 cps) con predominio occipital; (2) 33–36 semanas: amplitud moderada (50–100 μv), ondas mas rapidas (2–3 cps) con ninguna localizacion, y (3) 37–39 semanas, ondas de amplitud baja (5–20 μv) con una frecuencia de 3–4 cps o indeterminantes y sin predominio espacial. Se registraron tipos semejantes en lactantes de la misma edad post-concepcional, independientes de su edad post partum. A exception de lactantes cuya edad post partum se acerca a 40 semanas, los hallazgos apoyan la hipotesis de que la maduracion electrica del cerebro procede cronologicamente.

Continuous negative pressure ventilation utilizes subatmospheric pressure around the thorax to improve oxygenation. It has not been routinely used since the mid-1970s. We treated 37 infants with the combination of continuous negative pressure (CNP) and intermittent mandatory ventilation (IMV), after failing to attain a Pa of ≥50 torr on IMV alone. Lung diseases included pulmonary interstitial emphysema (PIE), respiratory distress syndrome (RDS), and pulmonary artery hypertension (PAH) due either to meconium aspiration syndrome (MAS) or other causes (non-MAS). All infants had evidence of severe parenchymal pulmonary disease, or pulmonary artery hypertension resulting in persistent hypoxemia and hypotension. In the PIE group, CNP was started later in the course of the disease, and both positive pressure and oxygen were maintained for a longer period. The group of infants with non-MAS PAH required CNP and positive pressure ventilation for the shortest period of time. The infants with PIE also had a greater incidence of bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH). In addition, three patients with PIE died. In the non-MAS patients with PAH, no complications and no deaths occurred. The response to CNP was a rapid improvement in oxygenation in all groups with the greatest increase of Pa in the non-MAS PAH infants: from 30 torr prior to the initiation of CNP to 140 torr within 30 minutes. No significant changes in pH or Pa occurred in any group. Significant decreases in ventilator rate, mean airway pressure (Paw) and FI in peak inspiratory pressure were possible by 12 hours of CNP. CNP and Paw were decreased from −5 cm H2O and 12.8 cm H2O prior to initiation of CNP to −1 cm H2O and 5.0 cm H2O at 72 hours of treatment. FI at 72 hours was decreased to a mean of 0.57. Combined CNP and IMV ventilator therapy improved oxygenation with lessened Paw in infants with refractory hypoxemia due to MAS and PAH and in larger infants with RDS. While we cannot advocate the routine use of CNP, it would appear to have a role in the management of infants who have failed conventional ventilator therapy. Pediatr Pulmonol 1990; 8:245-253.

In his preface to Principles of Perinatal-Neonatal Metabolism, the editor, Dr Richard M. Cowett, establishes that there are enough data on fetal and neonatal metabolism to warrant a comprehensive and critical text. He does not warn us, however, how comprehensive this text will be. An incredible amount of information is packed into 774 pages, even more impressive when one considers the small type.True to his word, Dr Cowett has an all-star array of authors, many of whom are academic household names. He has organized the text into four sections that progress logically.The first, "General Principles," is fundamental for the reader and invaluable in elaborating on many of the major modern techniques used for the study of metabolism, including kinetic techniques (eg, mass spectrometry) and animal models.The middle sections, "Maternal Metabolism During Pregnancy" and "Fetal-Placental Metabolism," are outstandingly in-depth, with superb reviews of maternal-fetal glucose metabolism and fetal-placental

The cardiovascular effects of dopamine were evaluated in 14 severely asphyxiated neonates. After a period of stabilization, either dopamine 2.5 micrograms/kg/minute or placebo was infused in a randomized double-blind protocol. In seven dopamine-treated infants, echocardiographically determined shortening fraction and mean velocity of circumferential fiber shortening increased when compared to preinfusion values (P less than 0.05). There was no significant change in these echo indices of cardiac function in the placebo-treated group. Systolic blood pressure rose in the dopamine group when compared to predopamine infusion values and to the postinfusion values of the placebo group (P less than 0.001 and 0.025, respectively). Diastolic blood pressure increased to a small degree in the dopamine group. There was no significant change in heart rate or echocardiographically measured systolic time intervals. Low doses of dopamine increase cardiac performance and raise systolic blood pressure in the severely asphyxiated neonate.

Plasma and serum hypoxanthine (Hyp) concentrations were measured by both high-pressure liquid chromatography and an oxygen consumption (pO2) technique, and the results were compared. The pO2 technique is based on the principle that oxygen is consumed when Hyp and xanthine are metabolized to uric acid by xanthine oxidase. Over the concentration range of 0–187 μ m the slope of the correlation line was 0.94 with a correlation coefficient of 0.99. Over the concentration range 0–40 μ m , the slope of the correlation line was reduced to 0.87, consistent with the fact that the pO2 technique is also influenced by the xanthine concentration. However, even when corrected for the xanthine concentration, which averaged 28% of the Hyp concentration, the pO2 technique underestimated the Hyp concentration measured by high-pressure liquid chromatography by 5%. The pO2 technique has the advantage that it is rapid and simple, however, it has the disadvantage compared to high-pressure liquid chromatography that it does not distinguish between Hyp and xanthine, and it has a lower prescision, particularly at the low Hyp concentrations normally present in human plasma.

Prior to conception, female rabbits were made hyperglycemic by streptozotocin administration. Fetal hyperglycemia and hyperinsulinemia were documented. Although plasma myoinositol concentrations were higher in the fetuses of diabetic mothers, the ratio of lung to plasma myoinositol concentrations in 29-day fetal rabbits were lower than control values. CDP-diglyceride:inositol phosphatidyltransferase was reduced by 70% in the diabetic fetuses and their lung tissue phosphatidylinositol content was decreased.

Problems emerging as more community hospitals develop neonatal intensive care are discussed, with an analysis of their possible origins and significance. A description of one solution to the problem is offered, exemplified by an outreach program from the University of California, San Diego, and University Hospital, San Diego, with the community of Las Vegas, Nevada.

Radioactive palmitic acid, choline, and phosphate were given to rabbits 28 and 30 days pregnant, and the labeling of phosphatidylcholine in the fetal lung and alveolar wash was studied. Labeled phosphatidylcholine was detected initially in the alveolar wash three hours after isotope administration. The three-hour delay was independent of precursor studied or gestational age, and the radioactive phosphatidylcholine continued to accumulate in the wash fluid for at least 18 hours. Each labeled precursor of phosphatidylcholine sequentially labeled the phosphatidylcholine from microsomal, lamellar body and alveolar wash lung fractions of the 30 day fetal animals.

Lamellar bodies and alveolar lavage from adult mammalian lung contain unusually high concentrations of phosphatidylglycerol that could serve as a sensitive indi- cator of surfactant. Phosphatidylglycerol was absent and phosphatidylinositol was correspondingly prominent in sur- factant from the preterm rabbit fetus. Phosphatidylglycerol rapidly appeared and phosphatidylinositol decreased fol- lowing the delivery. Surfactant isolated from the pre- maturely born rabbit or from humans with respiratory distress syndrome never contained phosphatidylglycerol. Comparison between lamellar bodies from fetal and post- natal rabbits revealed remarkably similar composition ex- cept for the acidic phospholipids; however, the physico- chemical properties were different. The compressibility of the surface film (i.e. the ratio of the fractional decrease in surface area and the corresponding decrease in surface tension) at low surface tensions was higher with fetal than with postnatal surfactant, whereas the difference in minimum surface tensions was small. These data suggest that phosphatidylglycerol is not an essential component required for the formation of the complex, but it im- proves the properties of surfactant in stabilizing the alveoli.

The lung profile run by two-dimensional thin-layer chromatography is described, including the LIS ratio and the percentages of disaturated acetone precipitated lecithin, PI, and PG. Results show that the accuracy of this profile increases that of the mature L/S ratio value even further, while decreasing the missed predictions with low LIS ratios to only about 7%.

Hypoxanthine, the end product of purine metabolism, is usually very elevated in body fluids during severe hypoxia. We measured hypoxanthine in the cerebrospinal fluid of hydrocephalic preterm infants (12 with posthemorrhagic, one with congenital hydrocephalus) to determine whether hydrocephalus is associated with anaerobic metabolism of brain tissue. Cerebrospinal fluid hypoxanthine was undetectable in normal infants. In hydrocephalic infants, the concentration of hypoxanthine ranged from 7.5 mumol/L to 28 mumol (means = 14.3 mumol/L). The hypoxanthine concentrations fell from a mean of 12.8 mumol/L to a mean of 2.0 mumol/L (P less than 0.05) with successful treatment of the ventriculomegaly by lumbar puncture or by ventriculoperitoneal shunt. Patients with acute posthemorrhagic hydrocephalus had similar concentrations of hypoxanthine (means = 14.5 mumol/L) as patients with late or with congenital hydrocephalus (means = 13.8 mumol/L), indicating that brain hypoxia is probably a consequence of the ventriculomegaly and not of the hemorrhagic insult.

The lung profile in amniotic fluid was studied in relation to the various classes of diabetes, to prolonged rupture of membranes, and to hypertension in pregnancy. Pregnancy-induced (Class A, gestational) diabetes mellitus showed a statistically significant delay in appearance of PG, thus a delay in maturation not related to lecithin; also PI levels in Class A diabetes remained elevated longer than normal. Other classes of diabetes were no different from normal except for accelerated maturation in F and R diabetes, where PG appeared before L/S ratios were mature (>2.0), but the small numbers of studies from patients with F and R diabetes were obscured when combined with the much larger number from D diabetes, which statisticaUy were no different from normal. Prolonged rupture of membranes by regression analysis showed clear statistically significant acceleration of maturation affecting both the L/S ratio and PG, which appeared early. HypertensiOn in pregnancy included mostly patients with mild terminal pre-eclampsia who were no different from normal; the relatively small number of samples from patients with severe pregnancy-induced hypertension, “chronic” toxemia, showed accelerated maturation (sometimes with L/S ratios >2.0 and early PG) which was obscured by the large number of mild problems. The appearance of PG signals the late (“final”) maturation of surfactant. Diabetic pregnancy of any class can safely be delivered free of ADS after PG appears.

We have compared the actual contribution of surfactant deficiency in respiratory distress syndrome to left-to-right shunting across a patent ductus arteriosus in premature infants with severe RDS by performing serial phospholipid analysis of tracheal aspirates and echocardiograms, and we have correlated these findings with the infants' clinical courses and management of ventilation. This analysis was combined with surgical or pharmacologic closure of PDA if a significant shunt existed. Qualitative surfactant abnormalities at birth and the subsequent maturation of phospholipids after birth were similar in all three groups of infants (Group 1, RDS alone; Group 2, RDS+PDA in infants weighing >1.2 kg; Group 3, RDS+PDA in infants ≤ 1.2 kg). The largest infants had isolated RDS (Group 1) and, after a brief period of stabilization after birth, had declining ventilatory and oxygen requirements. Infants in Group 2 had a gradual decrease in ventilatory and oxygen requirements which was accelerated markedly by cessation of PDA shunting. Infants in Group 3 had increasing ventilatory and oxygen requirements despite a maturing tracheal aspirate phospholipid pattern; their course, especially if they were asphyxiated, was characterized by early development of a significant left-to-right shunt and worsening clinical condition which improved following ablation of the shunt. The data suggest that severe RDS presents as a developmental spectrum and provides the justification for a controlled trial of very early closure of the PDA in the very low-birth-weight infant with severe RDS.

Turnover and clearance of lung surfactant phospholipids were studied with particular reference to myoinositol-induced perturbation in the acidic phospholipids. Administration of myoinositol decreased [(3)H]palmitate and [(32)P]phosphate incorporation into phosphatidylglycerol by 80-90% in whole lung, and by 94-99% in lamellar bodies and in alveolar lavage. The increased incorporation of radioactive isotopes into phosphatidylinositol following myoinositol, was inverse to the decrease in phosphatidyl-glycerol incorporation. Myoinositol treatment affected neither content nor labeling of phosphatidylcholine or disaturated phosphatidylcholine as studied within 50 h of administration. Phosphatidylglycerol was pulse labeled by intravenous [(32)P]phosphate and [(3)H]palmitate, followed by myoinositol. The biological half-lives of phosphatidylglycerol in the microsomal fraction, lamellar bodies, and alveolar lavage were 1.6, 4.6, 5.4 h (with (3)H), and 2.8, 6.5, 7.0 h (with (32)P), respectively.(32)P-labeled lung surfactant tracer was applied to the airways in saline suspension and the clearance of phospholipid radioactivity was measured in alveolar lavage, alveolar macrophages, lamellar bodies and lung homogenates. The clearance rates of phosphatidylcholine, disaturated phosphatidylcholine, phosphatidylglycerol, and phosphatidylinositol as studied in whole lung over 6 h were 3.4-5.8% h. Only a small amount of phospholipid radioactivity was recovered in the alveolar macrophage fraction (including bis-[monoacylglycerol]phosphate). Phospholipid radioactivity in alveolar lavage fell to 40-70% of the maximum during the 1st h, and to 5-18% over the next 6 h. During 2 h after the application of phospholipids, the radioactivity in the lamellar body fraction increased, and the specific radioactivities approached those in alveolar lavage. The association of phosphatidylglycerol with lamellar bodies was unaffected by myoinositol. Phosphatidylinositol entered more slowly than did phosphatidylglycerol from microsomes to the alveolar lavage fraction, and from alveolar lavage to lamellar bodies. These differences may be of importance regarding the poor performance of phosphatidylinositol-containing surfactant at birth. Further investigations are needed to clarify the possible role for the postulated bidirectional surfactant flux between the lamellar body and alveolar lavage fractions in maintaining the activity of surfactant.

This report summarizes a consecutive experience with 59 preterm infants with clinical, radiographic, and echocardiographic findings of a large patent ductus arteriosus. Thirty-five infants who met defined criteria received indomethacin, and 24 infants underwent PDA ligation. Analysis of the clinical course of these infants revealed no selective indomethacin morbidity and suggests that infants undergoing ligation require more prolonged ventilator therapy with increased exposure to FiO2 greater than or equal to 0.3. Mortality rates between ligated and pharmacologically treated groups were similar. This study documents that inhibition of prostaglandin synthesis to constrict and close the PDA in the premature infant is an effective alternative to operative closure.

The course and complications of fifty-two infants with patent ductus arteriosus requiring closure were assessed prospectively. Twenty-six infants with a PDA received indomethacin for pharmacologic closure of the PDA, and 26 underwent ligation. The current study analyzes and compares the longitudinal follow-up with respect to somatic growth, neurologic function, psychomotor and mental development, and renal, ophthalmologic, and audiologic function in 21 infants in each group who entered the follow-up. No selective morbidity was attributable to PDA closure with indomethacin when compared to surgically treated infants.

The minor phospholipids in amniotic fluid from normal pregnancies were correlated with the well-established index of lung maturity, the lecithin/sphingomyelin (L/S) ratio. When the L/S ratio was less than 1.0, the acidic phospholipids phosphatidylglycerol (PG) and phosphatidylinositol (PI) were absent or low in concentration (0.0 to 2.5 per cent of lipid phosphorus). Parallel to the increase in the L/S ratio to 2.0, the content of PI increased to 6.0 to 8.5 per cent of lipid phosphorus. PG, the unique phospholipid of lung surfactant, first appeared and PI concomitantly decreased when the L/S ratio exceeded 2.0, indicating the secretion of mature lung surfactant. Analysis of PI and PG in amniotic fluid as markers of surfactant seems to be of value as an additional index of prenatal evaluation of lung maturity and may be particularly useful when the specimen is contaminated with blood.

The turnover and pool size of surfactant has been studied in animals, but there is little similar information in humans. In the present investigation lung effluent phospholipids were studied in 29 small preterm infants with severe RDS. Thirteen were treated with mechanical ventilation, and 16 additionally received natural human surfactant. The first dose (60 mg surfactant/kg body wt) was given between 2 and 10 h of age, and the surfactant was given again if there was an insufficient response. Together 260 aspirates, recovered during routine suctioning of the airways, were analyzed for phospholipids. Phosphatidylglycerol, present only in exogenous surfactant, was used as a specific marker to estimate the apparent pool size and the half-life of surfactant phospholipid. In addition, the saturated phosphatidylcholine/sphingomyelin ratios were correlated with the ventilatory index (mean airway pressure x fractional inspiratory oxygen/arterial oxygen tension). There was a linear correlation between the ventilatory index and the saturated phosphatidylcholine/ sphingomyelin (r ~ -0.70) but no consistent correlation between the ventilatory index and the amount of phospholipids in the aspirate. The saturated phosphatidylcholine/ sphingomyelin ratio increased during the surfactant-induced remission of respiratory failure, decreased during the relapse of respiratory failure (present among 50% of the surfactant-treated infants), and increased again during the recovery. The control infants tended to have lower saturated phosphatidylcholine/sphingomyelin ratios during the first week than the surfactant-treated infants. The recipients of surfactant had slightly more severe lung disease than the controls, when the results were adjusted by covariance to remove the differences in the saturated phosphatidylcholine/ sphingomyelin ratio. Exogenous surfactant increased the apparent endogenous pool size at least fivefold. The apparent half-life of phosphatidylglycerol was 30 h (20–36 h). The half-life was independent of the amount of exogenous surfactant (60 versus 120 mg/kg). Therefore, the apparent turnover rate after 120 was higher than after 60 mg/kg surfactant (p

To determine the maturation of pulmonary surfactant at birth, phospholipid patterns in tracheal or pharyngeal aspirates of 54 newborn infants were analyzed by two-dimensional thin-layer chromatography. The compositions of phospholipids and their surface tension-lowering abilities were assessed after gestations with various complications. Preterm infants with respiratory distress syndrome (RDS) lacked phosphatidylglycerol and had lower lecithin/sphingomyelin ratios than infants without RDS. An acceleration of both phosphatidylcholine (lecithin) and phosphatidylglycerol concentrations was observed in 21 preterm infants born after prolonged rupture of the membranes and treatment with isoxuprine. In these infants, the phospholipid pattern of lung effluent was similar to that of term infants even at gestational ages less than or equal to 30 weeks. Biochemical lung maturation was delayed in aneccephalic infants, infants of diabetic mothers, and one infant of a mother with hypothyroidism.

Phosphatidylglycerol (PG) was absent from lung effluent in 41 infants with respiratory distress syndrome of the newborn (RDS), whereas effluent from healthy control subjects of similar gestational age contained this phospholipid (4.9 +/- 2.4% of lipidphosphorus (P), n = 32). Control infants of 28 weeks of gestation or less with various respiratory disturbances other than RDS also had low PG (0.2 +/- 0.2% of lipid-P, n = 5). In RDS surfactant complex often could be isolated from the airways using differential and density gradient centrifugation. The material thus obtained had prominent phosphatidylinositol (PI) (13.6 +/- 2.8% of lipid-P, n = 6), but no PG. Of those 18 infants who had such surfactant even in the early stages of RDS, 13 were 35 weeks of gestation or more, 3 were offspring of diabetic mothers, and 2 had severe perinatal asphyxia. In healthy control subjects PG sometimes appeared first within an hour of birth, but in RDS PG did not appear until recovery from RDS. In RDS type II (transient tachypnea of the newborn) PG in lung effluent also was abnormally low (1.3 +/- 0.6% of lipid-P, n = 5) and PI was correspondingly prominent (9.7 +/- 3.6% of lipid-P, n = 5), indicating immaturity of surfactant similar to RDS. Surfactant with PG and PI has superior surface-active properties compared to that containing PI, but no PG. Surfactant without PG does not seem to stabilize the alveoli of the newborn as well as does surfactant with PG. The failure of PG appearance following birth therefore may precipitate RDS, especially beyond 35 weeks of gestation.

Rapid diagnosis on the basis of simple clinical signs and immediate, aggressive therapy are required in handling such newborn problems as persistence of fetal circulatory patterns, respiratory distress syndrome, and acute necrotizing enterocolitis.

Autopsy findings suggest that lung surfactant is damaged in the adult respiratory distress syndrome. In the present study 225 bronchoalveolar lavage specimens (78 from 36 patients, 1-78 yr old with respiratory failure, 135 from another 128 patients with other respiratory disease, and 12 from healthy controls) were assayed for the lung profile [lecithin/sphingomyelin (L/S) ratio, saturated lecithin, phosphatidylinositol, and phosphatidylglycerol]. Bronchoalveolar lavage fluid was further analyzed for phospholipids and for phosphatidic acid phosphohydrolase, phospholipase A2, and phosphatidylinositol phosphodiesterase activities. A lipid-protein complex was isolated and analyzed for surface activity, and plasma was measured for myoinositol. There were only small differences seen in the recovery of total phospholipid between respiratory failure patients and normal controls. However, in respiratory failure, phospholipids in bronchoalveolar lavage were qualitatively different from those recovered either from normal controls or from patients with other lung disease: the LO/S ratio, phosphatidylglycerol, and disaturated lecithin were low, whereas sphingomyelin and phosphatidylserine were prominent. These abnormalities were present early in respiratory failure and tended to normalize during recovery. Low L/S ratio (less than 2), and low phosphatidylglycerol (1% or less of glycerophospholipids) in bronchoalveolar lavage was always associated with respiratory failure. Abnormal lavage phospholipids were not due to plasma contamination. The phospholipase studies revealed little evidence of increased catabolism of phospholipids. In respiratory failure, the lipid-protein complexes from lung lavage were not surface active, whereas that from healthy controls had surface properties similar to lung surfactant. Phospholipids from patients with respiratory failure were similar to those from respiratory distress syndrome in the newborn. However, the latter condition is characterized by fast recovery of surfactant deficiency and by high plasma myoinositol that suppresses the synthesis of surfactant phosphatidylglycerol and increases phosphatidylinositol (Pediatr. Res. 1981. 15: 720). On the other hand, in adult respiratory distress syndrome, the abnormality in surfactant phospholipids may last for weeks and in most cases is associated with low phosphatidylinositol, low phosphatidylglycerol, and low plasma myoinositol.

This article reviews the many methods commonly proposed to assess the maturity of the fetus and discusses a method that directly measures the developmental composition of surfactant phospholipids in amniotic fluid.

A technique to diagnose subependymal hemorrhage (SEH), intraventricular hemorrhage (IVH), intracerebral hemorrhage, and posthemorrhage hydrocephalus in tiny infants, using real time ultrasound studies of the brain ventricular system, is described. This is a bedside technique that visualizes the brain through the fontanelles and the sutures, in three planes: coronal, sagittal, and horizontal. Excellent visualization of the ventricular system, caudate nuclei, the thalamus, the choroid plexus, the corpus callosum, and the foramen of Monro is obtained. This method has good definition using high frequency transducers since there is no bone interference. The ultrasound diagnosis correlated well with computed tomography (CT) and with direct pathologic studies. This technique was more sensitive in diagnosing small IVH/SEH and organized clots than were CT studies. IVH/SEH were found in 90% of 113 infants less than or equal to 34 weeks of gestation; 49% of the hemorrhages were large and 41% were small. Most hemorrhages were found in the first scan, usually shortly after birth. Twenty-one premature infants who never had perinatal asphyxia or respiratory distress syndrome had IVH/SEH. The hemorrhages were followed until disappearance, usually in one to three months in cases of large hemorrhages.

Basic principles are offered to support the suggestion that use of special care space must be made with a mind toward prevention of obsolescence. Certain conventional design features should be examined critically and decisions made as to their applicability to the needs of a particular program.

• We report the preschool growth and development of preterm infants with problematic patent ductus arteriosus requiring either surgical ligation or indomethacin treatment in the neonatal period. Of 60 who completed longitudinal growth assessments, no differences in growth to 3 years could be demonstrated except at 18 months, when male infants who underwent surgical ligation were lighter than those treated with indomethacin. There were no significant differences in vision or hearing abnormalities except for four cases of regressed retinopathy of prematurity among the ligated infants. Developmental tests (Bayley Scales of Infant Development and the Peabody Picture Vocabulary Test) showed no group differences at preschool ages. Although psychomotor performance on the Bayley Scales in the first 1½ years was significantly lower among the surgically treated infants, later analysis showed that a similar number in both treatment groups scored within the normal range. No selective short- or long-term adverse effects of indomethacin treatment could be demonstrated. ( Am J Dis Child 1982;136:507-512)

By means of an alveolar cell carcinoma (A549) model, the effect of prolactin on pulmonary surfactant phospholipid biosynthesis was investigated. Preliminary results suggest that phosphatidylcholine synthesis via the phosphatidic acid phosphohydrolase pathway in addition to phosphatidylglycerol may be stimulated by the presence of prolactin.

Pregnant rabbits were given continuous intravenous insulin between days 26.7 and 28.7 after conception. The treatment decreased fetal serum glucose, insulin, and myoinositol. Furthermore, maternal insulin decreased fetal growth slightly, and improved the survival of the prematurely delivered fetuses. Analysis of phospholipids recovered by alveolar lavage revealed that the lung surfactant was quantitatively and qualitatively superior to the surfactant from the fetuses of the saline-glucose control animals. This effect on the lung was more striking than that of glucocorticoid. Another group of pregnant rabbits received continuous intravenous glucose between days 27.0 and 29.0 after conception. The hyperinsulinemic fetuses of the glucose-infused does weighed more and had higher serum glucose and myoinositol than did those of the control animals. There was no detectable difference in alveolar lavage phospholipids between hyperinsulinemic and normoinsulinemic fetuses of glucose-infused does. The possible importance of these findings in understanding the mechanism of acceleration of lung maturation is discussed.

The surfactant phospholipids in the tracheal effluent of eight pairs of preterm twins were followed, serially. In four pairs only one of the twins had RDS; in the other four pairs both twins had RDS. Twins with and without RDS had markedly different surfactant phospholipids. Phosphatidylglycerol was absent in all twins with RDS. L/S ratios in tracheal effluent increased after birth in infants with and without RDS. With recovery from RDS, phosphatidylinositol increased. The study helps confirm previous studies of the necessity of the acidic phospholipids, PI and PG, in stabilizing lecithin, as well as that surfactant composition can be independent of gestational age.

Lamellar inclusion bodies, apparent precursors for alveolar surfactant lining, have remarkably similar phospholipid composition to surfactant from alveolar lavage, but distinctly different from other fractions studied: mitochondria, microsomal fraction containing endoplasmic reticulum membranes, plasma membranes and nuclei. Surfactant contained (as % of total phospholipid phosphate): 75.5-77.0% lecithin, 11.0-11.2% phosphatidylglycerol, 4.2-4.6% phosphatidylethanolamine, 3.0-3.2% phosphatidylinositol, 1.5-1.7% bis-(monoacylglycerol) phosphate, 1.2-1.9% phosphatidylserine, and 0.7-1.5% sphingomyelin. Fatty acids of phosphatidylglycerol from lamellar bodies were similar to those from microsomes but different from those in mitochondria. Lung homogenate in continuous sucrose density gradient displayed two major activity peaks of phosphatidylglycerol synthesis: the heavier from mitochondria; the lighter from endoplasmic reticulum. Studies on mechanism of phosphatidylglycerol synthesis in vitro revealed (in these two fractions) CDP-diglyceride and sn-glycerol phosphate precursors to phosphatidylglycerol phosphate, that hydrolysed to phosphatidylglycerol. In microsomes disaturated CDP-diglycerides were 1.6-1.9 times more active substrates than in mitochondria, whereas CDP-diglycerides from egg lecithin were almost equally active. In contrast to lung mitochondria no cardiolipin synthesis was detected in microsomes. The highest specific activities for phosphatidate cytidyltransferase, CDP-diglyceride-inositol phosphatidyltransferase, choline phosphotransferase, and phosphatidylethanolamine methyltransferase were all found in microsomes. The present in vitro studies and additional evidence (M. Hallman and L. Gluck, (1975) Fed. Proc. 34, 274) support the hypothesis that de novo synthesis of surfactant lecithin phosphatidylinositol and phosphatidylglycerol takes place in the endoplasmic reticulum of alveolar cells.

Summary: The lung lecithin of term newborn rabbits was labeled by injecting the lecithin precursors palmitic acid and cholme into the pregnant doe shortly before delivery of the newborn rabbits by cesarean section. The newborn lungs were lavaged to yield an alveolar wash lecithin sample and the tissue was homogenized and fractionated into lamellar body and microsomal fractions by differential and density gradient centrifugation. Lecithin was isolated from the lung parenchyma, microsomes, lamellar bodies, and alveolar wash by two-dimensional thin layer chromatography, and the specific activity of the lecithin in each fraction was determined. Comes are presented showing the time of appearance of the radioactive lecithin in each lecithin fraction. The apparent biological half-life of lecithin in each fraction was measured. The specific activity of lecithin was high in microsomal fractions soon after palmitic acid or choline administration. The lamellar body fraction was free of radioactive lecithin for 3 hr, and maximal specific activity of lamellar body lecithin was reached only after 20 hr. The appearance of radioactive alveolar lecithin followed a curve very similar to that of the lecithin in the lamellar body fraction. The apparent half-life of lung parenchymal lecithin from newborn lung labeled with palmitic acid was 57 hr, whereas the apparent half-life of alveolar lecithin was 136 hr. The lecithin in lung and alveolar wash labeled with choline had a longer halflife than did lecithin labeled with palmitic acid. Measurements of lecithin appearance and apparent half-life are compared to similar measurements in adult rabbits. Speculation: The striking characteristics of newborn lung lecithin are the 3-hr lag before the appearance in the alveolus of de novo synthesized lecithin, the prolonged time (20 hr) before maximal specific activity of alveolar lecithin is achieved, and the very long apparent half-life of alveolar lecithin. If these measurements are applicable to other term and premature mammals, they must rely entirely on lecithin stored in anticipation of birth to maintain alveolar stability at birth. The long lag before significant lecithin synthesized de novo can reach the alveolar space precludes synthesis contributing to alveolar stability until many hours after birth. The recovery from the respiratory distress syndrome may not depend on maturation of the ability to synthesize lecithin; rather, the prolonged recovery phase may reflect the long times required for appreciable quantities of de novo synthesized lecithin to reach the alveolar space. However, once alveolar stability is achieved, short interruptions of lecithin synthesis, by reversible acidosis, for example, should not cause respiratory distress mediated by lecithin deficiency.

In normal pregnancy lecithin/sphingomyelin ratios correlate with gestational age. In complicated pregnancies biochemical maturation of fetal lung may be accelerated or delayed, depending upon maternal, fetal, or placental conditions. Surfactant contains other phospholipids besides lecithin, including phosphatidylglycerol (PG), the second major component of mature surfactant. Ninety phospholipid patterns in amniotic fluid were studied by two-dimensional thin-layer chromatography. In uncomplicated pregnancies PG was absent until 37 weeks' gestation, then increased there after. In complicated pregnancies (pre-eclampsia, diabetes Classes D, F, and R, premature rupture of membranes) PG was identified before 35 (as early as 29 weeks' gestation. These results verify accelerated lung maturation in certain complicated pregnancies. No newborn infant developed respiratory distress syndrome in the presence of PG.

The experience of the Special Care Nursery of the University of California Medical Center, San Diego, in the management of the high risk newborn with progressive ventricular enlargement is reviewed, and the physiopathological basis of progressive ventricular enlargement is analyzed. (Neurosurgery 14:612-618, 1984)

Summary: Phospholipids were measured in the lamellar bodies and alveolar lavage of perinatal rabbits. Between 28 and 31 fetal days, phosphatidylinositol (PI) increased, and phosphatidylserine decreased. Small amounts of phosphatidylglycerol (PG) appeared at term. After birth, PG markedly increased and PI concomitantly decreased. PG increased prematurely after removal from the uterus of fetuses 29 days gestation or more. Fatty acid analysis of PG and PI revealed the presence of 62 to 63%, and 58 to 59%, of saturated species, respectively. As measured in total lung homogenate, PI increased between 28 and 31 fetal days, and PG increased between term and the first neonatal day. Glycerol incorporation into PG increased at birth, according to the measurement of lung slices. myo-Inositol incorporation into PI increased in the fetus parallel to accumulation of surfactant. The development of the following enzyme activities was studied in subcellular fractions derived from lung homogenates: phosphatidate cytidyltransferase, cytidine 5′-diphosphate (CDP)-diglyceride:inositol transferase, glycerophosphate phosphatidyltransferase, and phosphatidylglycerophosphatase. As measured in the microsomal fraction, all the activities increased between 27 and 30 fetal days. Shortly after birth, phosphatidate cytidyltransferase and glycerophosphate phosphatidyltransferase increased further, whereas the two other enzyme activities decreased somewhat. Cytidine 5′-diphosphate diglyceride:inositol transferase increased after the newborn period. There were only small developmental changes in Km's. In contrast to microsomes, the mitochondrial activities mainly decreased during development. Phosphatidylglycerophosphatase was the only activity that was present in significant amounts in lamellar bodies. It is proposed that the developmental changes in the acidic surfactant phospholipids are due to changes in the biosynthesis rates in type II cell microsomes. This may be controlled both by changes in the enzyme activities (phosphatidate cytidyltransferase, cytidine 5′-diphosphate diglyceride:inositol transferase, and glycerophosphate phosphatidyltransferase) and by changes in substrate concentrations (myo-inositol and sn-glycerol-3-P). Speculation: Besides surfactant lecithin, phosphatidylglycerol is critical to alveolar stability and its absence may precipitate respiratory distress syndrome in the newborn. Surfactant phosphatidylglycerol and phosphatidylinositol serve as indices of fetal lung maturity or help to specify diagnosis of respiratory distress in the neonate. Because several hormones seem to regulate individual surfactant phospholipids, the measurement of these components (lung profile) could be a way to analyze consequences of hormonal or nutritional balance and eventually correct it if necessary.

To the Editor.— We wish to answer the negative and often inappropriate responses generated by our commentary.1 As stated clearly, we do not oppose the transcutaneous Doppler technique; we intended only to discuss the technical problems inherent in continuous wave Doppler transducers and the interpretations made from indirect "measurements of cerebral blood flow" (CBF) and patterns of pulsatile blood flow. Most of the technical problems described in our commentary probably can be avoided by using two-dimensional, range-gated, pulsed Doppler ultrasonography.

Lung injury was induced in young rats by a continuous infusion of hypoxanthine intravenously and breathing 100% oxygen for 48 h (group 1). Control animals were rats infused glucose and breathing 100% oxygen (group 2), rats infused hypoxanthine in room air (group 3), and untreated rats (group 4). In group 1 rats interstitial and alveolar edema was found with a tendency toward marked margination of polymorphonuclear neutrophils in small vessels (P less than 0.025 compared with group 2). The main elastase inhibitor alpha 1-antitrypsin (alpha-1-PI) was significantly elevated in group 1; 2-, 3- and 5-fold, respectively, when compared with groups 2, 3, and 4. The surfactant phospholipids from alveolar lavage were normal in all groups. The protein-rich fraction of the lavage fluid from group 1 rats inactivated, however, the surface properties of lung surfactant. Minimum surface tension in group 1 rats was 14.5 dyn/cm compared with 7.0 dyn/cm in group 2, 2.9 dyn/cm in group 3 and 3.5 dyn/cm in group 4 (P less than 0.05, group 1 and 2 versus 4). We conclude that the combination of hypoxanthine and high levels of oxygen causes lung injury, possibly via free oxygen radicals. We discuss the possibility that these findings demonstrate a basic pathogenetic mechanism for the hypoxic-hyperoxic insult and can contribute to the understanding of pathogenesis of a variety of diseases both in pediatrics and adult medicine.

Liggins 1.2 first observed during studies on sheep that corticosteroid administration not only induced early parturition (117 to 123 days vs normal 150-day gestation), but that some of the lambs had partially expanded lungs, an unexpected finding as compared to control lamb fetuses of the same gestational age. Other investigators 3-9 have verified and extended these observations in several species (rabbits, sheep, monkeys). Corticosteroids administered to fetuses promote normalization of the pressure-volume characteristics of premature fetal lungs, which is general evidence of acceleration of maturation of the surfactant-producing systems in lung. Elevated concentrations of lecithin in lungs of premature fetuses also have been reported following corticosteroid administration. 10 There is evidence that corticosteroids enhance the activity of the choline incorporation pathway, the major route in the lung for the biosynthesis of lecithin. 11 Surfactant plays a crucial role in stabilization of alveoli by lowering the surface tension at the alveolar

Summary: Lung phosphatidylcholine metabolism was studied in vivo in premature rabbits delivered by cesarean section as early in gestation as compatible with prolonged viability (28.9 days). The newborn rabbits initially required supplemental oxygen and had respiratory distress. The amount of phosphatidylcholine isolated from the lung parenchyma changed little over the first 3 days of life, while phosphatidylcholine in the alveolar wash increased in 3 days from 0.05–3.1 μmol/50 g animal. The phosphatidylcholine of the lungs of the premature rabbits was pulse labeled with isotopically labeled palmitic acid, choline, and phosphate given to the pregnant does 10 min before delivery of the newborns. After the initial incorporation period, the total amount of radioactive precursor (palmitic acid, choline, or 32P) incorporated into lung phosphatidylcholine did not change for a period of 4 days. Labeled phosphatidylcholine was detected initially in alveolar wash 3 hr after administration of the three precursors and continued to accumulate for many hours. The biological half-life values for lung and alveolar phosphatidylcholine indicated that phosphatidylcholine was turning over very slowly. However, if the effect of dilution on the measured specific activity caused by phosphatidylcholine accumulation was considered, virtually no labeled alveolar or lung phosphatidylcholine disappeared during the 3–4 days of these observations. These results with premature newborn rabbits were similar to those for term newborn rabbits, but different from similar measurements made in the adult rabbit. Speculation: Premature newborn rabbits are unable to deliver newly synthesized phosphatidylcholine rapidly to the alveolar space in the hours immediately after birth. These newborn animals seem to depend on stored phosphatidylcholine to maintain alveolar stability at birth. Continuous de novo synthesis then produces a slow accumulation of phosphatidylcholine in the alveolar space. If these results can be generalized to the premature human with respiratory distress syndrome, phosphatidylcholine synthesized shortly before or after birth would not be expected to mitigate alveolar collapse. A considerable period of respiratory support would be anticipated before large amounts of newly synthesized alveolar phosphatidylcholine would become available for the maintenance of alveolar stability. However, any phosphatidylcholine present may have a very long biological half-life as increasing amounts of alveolar phosphatidylcholine accumulate during the recovery period.