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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%.

Description of procedures for determining the leci-thin/sphingomyelin ratio, and its interpretation as an estimation of fetal lung maturity.

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.

The significance of the lecithin/sphingomyelin (L/S) ratio is well established. However, numerous variations in techniques are appearing, and certain issues about techniques have emerged; among these, acetone precipitation, phosphorus determination rather than densitometry or area measurement, measurement of total phospholipids rather than the L/S ratio, and determination of lecithin concentration rather than the L/S ratio are discussed. Acetone precipitation allows examination of the physiologic (surface-active) fraction of lecithin; this fraction also helps to evaluate the rapidly maturing lung and possibly prevent false predictions. Maturational acceleration of the L/S ratio may be secondary to chronic stress or to acute stress such as acute placental infarction or ruptured membranes. Further evidence is presented that there is continuity between the fetal lungs and amniotic fluid. General principles are presented as a guide in clinical interpretation of the L/S ratio.

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.

Phosphatidyl glycerol is present in lamellar bodies and in the material obtained by alveolar wash representing 12.3 and 11.5%, respectively, of the total phospholipid phosphorus. Lung microsomes catalyze the formation of phosphatidyl glycerol from the known precursors, L-glycerol 3-phosphate and CDP-diglyceride. The rate of [14C]L-glycerol 3-phosphate incorporation into phosphatidyl glycerol was 30% higher in microsomes as compared to mitochondria. The addition of mercuric chloride inhibited the synthesis of phosphatidyl glycerol, and stimulated the incorporation into another as yet incompletely identified lipid. After pulse labeling of microsomal phosphatidyl glycerol in vitro , further incubation of microsomes with lamellar bodies or alveolar wash resulted in nearly quantitative appearance of label in surfactant.

In seven years the nation's first newborn special care unit has succeeded in reducing its infant mortality rate to less than half the national average. The first step was to reject the isolation and fragmentation that conventional concepts of infection control impose on the treatment of problem newborns.

Studies on 302 amniocenteses show that changes in phospholipids in amniotic fluid (PLAF) reflect those in the lung of the developing fetus. A sudden increase in lecithin concentration after 35 weeks heralds maturity of the pulmonary alveolar lining when respiratory distress syndrome will not occur should the fetus then be born. Clinical interpretation is made on a thin-layer chromatogram by inspection; a lecithin spot clearly larger than that of sphingomyelin marked pulmonary maturity in the fetus.

The paucity of data regarding phagocytosis in the newborn is reviewed. A method of evaluating phagocytosis in the human is presented, in which the proportion of "effective phagocytes" (cells containing 10 or more carbon particles) is scored, rather than the total number of cells engulfing particles. Employing the criteria described, we have found significant differences in phagocytic ability between the blood of premature infants and that of adults or full-term infants. Differences observed between full-term infants and adults in respect to phagocytic capacity of leukocytes were not clearly significant. In general, increasing phagocytosis was observed, approaching adult levels with increase in birth weight. Addition of fresh, normal adult serum to invitro preparations of premature infants' blood significantly enhanced phagocytosis. The substances in serum which stimulated phagocytosis were identified by electrophoresis to be in the fractions generally known as α1-, α2-, and β-globulin. A possible therapeutic use for adult serum in the premature is postulated and is being studied.

Extract: The surface-active complex lining alveoli in normal lung lowers surface tension on expiration, thus preventing alveolar collapse. Surface activity follows a developmental timetable. Infants with idiopathic respiratory distress syndrome (RDS) almost exclusively are prematurely born, and their lungs lack adequate surface activity and are deficient in the principal surface-active component, lecithin. This deficiency implies that RDS is a “disease of development,” with fetal and neonatal timetables for lecithin synthesis. The biosynthesis of lung lecithin in the living human infant was studied by examining phospholipids in lung effluent (pharyngeal aspirates, mucus), which have identical phospholipids to those in lung lavage (alveolar wash). The fatty acid esters of isolated lecithin and phosphatidyl dimethylethanolamine (PDME) were examined. The β-carbon fatty acids are indicators of the primary pathways of synthesis of lecithin: (1) a preponderance of palmitic acid signifying cytidine diphosphate choline (CDP-choline) + D-α,β-diglyceride → lecithin (choline incorporation pathway) and (2) a preponderance of myristic acid signifying phosphatidyl ethanolamine (PE) + 2 CH3 → PDME + CH3 → lecithin (methylation pathway). Fetal lung of 18 and 20 weeks showed slight incorporation by CDP-choline pathway, absence of PDME, and almost no methylation. Salivary lecithin had totally different fatty acids from lecithin in aspirates. Phosphatidyl dimethylethanolamine (PDME) (therefore methylation) was identified in aspirates as early as 22–24 week-gestation. Lecithin fatty acid esters in aspirates from premature infants after birth or those with no RDS closely resembled PDME fatty acids. With RDS, PDME disappears and β-carbon palmitic acid (therefore dipalmitoyl lecithin) increases. With recovery, PDME reappears, as does the premature infant's major lecithin, palmitoylmyristoyl. Full term infants are born with more β-carbon palmitic acid (20–40%) and by 12–18 hr have equal palmitic and myristic acids, indicating function of both lecithin synthesis pathways. Stress (hypoxia acidosis, hypothermia) cause disappearance of PDME and loss of β-carbon myristic acid. Similar changes in full term infants who do not get RDS are due to adequate lecithin synthesis by the GDP-choline pathway. The capacity to synthesize lecithin in the lung by methylation in the human fetus and newborn allows the human to be born prematurely; rabbits and sheep lack this capacity and cannot be prematures, but die from respiratory insufficiency if born too soon. Speculation: The diagnosis of RDS can be made objectively by looking for PDME in aspirates (lung effluent). Prognosis also can be established by lack or presence of PDME. The effects of various therapies also can be assessed this way. The techniques and consideration described herein can be employed to study biochemically the effects of other stresses to lung, including oxygen toxicity and anesthesia.

The Biochemical Development of Surface Activity in Mammalian Lung: II. The Biosynthesis of Phospholipids in the Lung of the Developing Rabbit Fetus and Newborn

IN the last twenty years, the staphylococcus has replaced the streptococcus as the chief cause of infection in maternity units. Sporadic and epidemic staphylococcal infection among newborn infants now ranks as one of the most serious hazards in the modern nursery (as summarized by Williams et al.1). Previous reports2 3 4 indicate that hexachlorophene-containing compounds applied to newborn infants reduce staphylococcal infections in nurseries and incidentally decrease nasal carriage of staphylococci. The opening of the new Palo Alto—Stanford Hospital Center in the summer of 1959 afforded an opportunity to institute a program centered around the prevention of staphylococcal colonization of the . . .

With elucidation of the biochemistry of pulmonary surfactant (the substance that normally prevents collapse of the alveoli with each breath) and of the timetable of its maturation in fetal life, th...

Determination of the lecithin/sphingomyelin ratio in amniotic fluid and the newborn infant’s own tracheal fluid has proved of significant value in identifying the premature infant whose lungs have not yet matured to the point at which surface-active pulmonary lecithin will be synthesized rapidly enough after birth, and who are thus at risk for respiratory distress, with its high mortality and high percentage of associated neurologic and intellectual deficits.

Examination of the brains of 69 infants revealed spongiform changes restricted to myelinated tracts of the brainstem in seven of them. This type of myelinopathy consistently develops in experimental animals after hexachlorophene intoxication. Common factors in affected infants were multiple exposures to hexachlorophene, prematurity with low birth weight, and the presence of dermal rashes or wounds.

Extract: A simple technique, precipitation with acetone, was described to separate the surface-active lecithin fraction from the nonsurface-active fraction. Surface activity in lung phospholipids was found in the acetone-precipitated fractions of lecithin, sphingomyelin, phosphatidyl dimethylethanolamine and phosphatidyl inositol. Normal surface activity of saline extract of pooled fetal rabbit lung was observed from 28 days of gestation. It was possible to isolate surface-active lecithin from lung parenchyma long before the 29th day of gestation when surface-active lecithin first is found in the alveolar wash. During the nonbreathing fetal state, even at term, only 11% of lecithin from alveolar wash is surface-active increasing after one hour's breathing to approximately 50% of the total lecithin. The rabbits delivered prematurely after 28 full days of gestation clinically had respiratory distress and their percentage of surface-active lecithin in alveolar wash increased at a slow rate compared to full-term animals. Good temporal correlation was seen between intracellular storage of surface-active lecithin during the fetal state and the findings with electron microscopy of increasing numbers of osmiophilic inclusion bodies as gestation progresses. Speculation: Surface activity is shared by several phospholipids in lung but is related principally to lecithin. During fetal development there is production of intracellular surface-active lecithin with storage possibly in osmiophilic lamellar inclusion bodies until near term when some (11%) begins to appear in alveolar wash. After breathing, a great release of surface-active lecithin into alveolar wash occurs, with 50% of alveolar lecithin being surface active throughout the life of the animal. Prematurely delivered rabbits take much longer to increase their surface-active alveolar lecithin.

RECENT studies at the Yale–New Haven Medical Center1 , 2 have demonstrated that properly performed antiseptic skin and umbilical-cord care brings about a striking decrease in colonization of newborn infants by pathogenic staphylococci.§ Gluck and Wood2 suggested that this effect may be due to the interruption of a major epidemiologic route operative in nurseries — namely, staphylococci from all sources first colonize the skin or cord, or both, and are then carried into the nose. They found a 51 per cent overall colonization of nose and cord in a control group of 500 infants on "dry" skin care and a prompt drop . . .