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Bronchopulmonary dysplasia in premature infants is associated with prolonged hospitalization, as well as abnormal pulmonary and neurodevelopmental outcome. In animal models, inhaled nitric oxide improves both gas exchange and lung structural development, but the use of this therapy in infants at risk for bronchopulmonary dysplasia is controversial.We conducted a randomized, stratified, double-blind, placebo-controlled trial of inhaled nitric oxide at 21 centers involving infants with a birth weight of 1250 g or less who required ventilatory support between 7 and 21 days of age. Treated infants received decreasing concentrations of nitric oxide, beginning at 20 ppm, for a minimum of 24 days. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age.Among 294 infants receiving nitric oxide and 288 receiving placebo birth weight (766 g and 759 g, respectively), gestational age (26 weeks in both groups), and other characteristics were similar. The rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was 43.9 percent in the group receiving nitric oxide and 36.8 percent in the placebo group (P=0.042). The infants who received inhaled nitric oxide were discharged sooner (P=0.04) and received supplemental oxygen therapy for a shorter time (P=0.006). There were no short-term safety concerns.Inhaled nitric oxide therapy improves the pulmonary outcome for premature infants who are at risk for bronchopulmonary dysplasia when it is started between 7 and 21 days of age and has no apparent short-term adverse effects. (ClinicalTrials.gov number, NCT00000548 [ClinicalTrials.gov] .).

OBJECTIVE: To estimate the relationship between case-mix adjusted cesarean delivery rates and neonatal morbidity and mortality in infants born to low-risk mothers. METHODS: This retrospective cohort study used vital and administrative data for 748,604 California singletons born without congenital abnormalities in 1998-2000. A total of 282 institutions was classified as average-, low-, or high-cesarean delivery hospitals based on their cesarean delivery rate for mothers without a previous cesarean delivery, in labor at term, with no evidence of maternal, fetal, or placental complications. Neonatal mortality, diagnoses, and therapeutic interventions determined by International Classification of Diseases, 9th Revision, Clinical Modification codes, and neonatal length of stay were compared across these hospital groupings. RESULTS: Compared with average-cesarean delivery-rate hospitals, infants born to low-risk mothers at low-cesarean delivery hospitals had increased fetal hemorrhage, birth asphyxia, meconium aspiration syndrome, feeding problems, and electrolyte abnormalities (P

When neonatology was emerging as a clinical discipline in the late 1950s and early 1960s, it had the advantage of a strong foundation of basic research in fetal and neonatal physiology. In particular, the new clinical enterprise (it was not yet a subspecialty) focused on cardiorespiratory pathophysiology. This foundation came from a few distinguished research laboratories studying fetal and neonatal physiology and the processes of the transition from fetal to neonatal life. The preeminent laboratory in the field was the Nuffield Institute for Medical Research at Oxford, directed by Geoffrey S. Dawes. Geoffrey Dawes became the director of the Institute in 1948. He received his medical degree in 1943, and in the following 5 years, he gained recognition as a prominent investigator in pharmacology and physiology. The very short interval between receiving his degree and being named director of an important research institute indicates how quickly the academic leadership recognized his exceptional qualities. As the new director, Dawes set the primary focus of research for the Nuffield Institute as developmental physiology. In this role, the Nuffield became the successor to the path of research started by Sir Joseph Barcroft at Cambridge early in the twentieth century. Dawes and his coinvestigators concentrated particularly on the preparations for and mechanisms of adaptation to extrauterine life. A central focus of the research was the adaptive mechanisms in the circulatory and respiratory systems, including placental function, establishment of lung function, and changes in the pulmonary and systemic circulations. Although most of the work examined cardiorespiratory physiology and its neurohumoral regulation, researchers also studied fetal growth and metabolism, and their studies included the responses to stresses such as hypoxia and hemorrhage. One of the hallmarks of the research of this highly productive group was the elegance of their experimental designs. The clinical implications of this …

Thyroid hormones are important for both perinatal adaptation and long-term psychomotor development; however, there is limited information on the effects of extreme prematurity and antenatal TSH-releasing hormone (TRH) treatment on pituitary-thyroid function. In this study we assayed plasma triiodothyronine (T3) and TSH in infants who were part of a collaborative trial of antenatal maternal TRH therapy. Within the control population (n = 166), infants of 24-28-wk and 28-32-wk gestational age had comparable levels of T3 (0.94 and 1.06 nmol/L, respectively) and TSH (5.7 and 7.2 mU/L) at birth, but the increases at 2 h and subsequent T3 levels were less in the 24-28 wk versus 28-32-wk gestation infants. In the TRH-treated group (n = 131), T3 was lower in the first day for infants delivered 7-72 h after antenatal TRH compared with control infants. TSH at birth was approximately 3.5-fold greater for infants delivered at 0-6 h after the last TRH dose compared with the control group and was suppressed in infants delivering at 7-36 h. T3 and TSH levels were not different between control and TRH-treated groups at 3-28 d of age. In TRH stimulation tests on d 28, control and TRH-treated groups had similar peak levels of TSH and incidence of exaggerated response (TSH > or = 35 mU/L). We conclude that extremely premature infants have a reduced postnatal surge in TSH and T3 and maintain lower T3 concentrations, probably reflecting tertiary hypothyroidism. The stimulatory and suppressive effects of antenatal TRH treatment observed at birth are transient and do not affect pituitary-thyroid responsiveness at 28 d of age.

To examine the cost effects of a single dose (5 ml/kg) of a protein-free synthetic surfactant (Exosurf) as therapy for neonatal respiratory distress syndrome, for both rescue and prophylactic therapy.Nonblinded, randomized clinical trials of both rescue and prophylactic therapy. Regression analyses were used to control for the independent effects of sex, multiple birth, delivery method, birth weight, and surfactant therapy.The prophylactic trial was conducted at a university medical center only; the rescue trial also included a tertiary community hospital.Prophylaxis was administered immediately after birth to 36 infants (38 control subjects) with birth weights between 700 and 1350 gm. Rescue therapy was administered at 4 to 24 hours of age to 53 infants (51 control subjects) with established respiratory distress syndrome and birth weightsor = 650 gm (no upper limit). Infants in the prophylactic trial were not eligible for the rescue trial.For the rescue trial, there was a $16,600 reduction in average hospital costs (p = 0.18), which was larger than the cost of the surfactant ($450 to $900), yielding a probable net savings. For the prophylactic trial, hospital costs were larger for treated infants versus control subjects who weighed less than about 1100 gm at birth and lower for treated infants versus control subjects who weighed more than 1100 gm at birth (p0.05). For the prophylactic sample, the result was an average cost per life saved of $71,500.Single-dose rescue surfactant therapy is probably a cost-effective therapy because it produced a lower mortality rate for the same (and probably lower) expenditure. Single-dose prophylactic therapy for smaller infants (or = 1350 gm) appeared to yield a reduction in mortality rate for a small additional cost. The use of multiple-dose therapy in infants who do not respond to initial therapy may alter the effects described above to either increase or decrease the observed cost-effectiveness of surfactant therapy. Regardless, surfactant therapy will remain a cost-effective method of reducing mortality rates, relative to other commonly used health care interventions.

We randomly assigned eight concurrently symptom-free premature infants (birth weight less than or equal to 1250 gm) at high risk of requiring erythrocyte transfusions for anemia of prematurity to 6 weeks of intensive treatment with either subcutaneous recombinant human erythropoietin (r-HuEPO group) or a placebo (control group). Treatment with r-HuEPO was initiated at a dose of 100 units/kg per day 5 days a week, and was increased to 200 units/kg per day after 2 or 3 weeks if target reticulocyte counts were not achieved. All patients were given supplemental oral iron therapy at a dose of 6 mg/kg per day, as tolerated. Mean reticulocyte counts in r-HuEPO-treated and control infants were 64,600 versus 67,500 cells/mm3 at entry; were 245,600 versus 78,000 cells/mm3 after 1 week; and averaged 262,600 versus 136,400 cells/mm3 during the study. Mean reticulocyte counts in r-HuEPO-treated infants were 251,200 cells/mm3 during the week when r-HuEPO, 100 units/kg per day, was given, and were 269,500 cells/mm3 after the dose was increased to 200 units/kg per day. Mean hematocrit values at entry were 33.4% in babies who received r-HuEPO versus 33.6% in the control subjects, and were 31.4% in r-HuEPO-treated and 25.2% in the control subjects at the end of treatment. One r-HuEPO-treated and three control babies received transfusions during the study; the total volume of blood given was 17 ml in the r-HuEPO group and 101 ml in the control subjects. The percentage of hemoglobin F increased in infants not given transfusions. We conclude that r-HuEPO stimulates endogenous erythropoiesis in small premature babies who are receiving supplemental oral iron therapy. A controlled multicenter trial has been undertaken to confirm these promising preliminary observations.

Experimental and clinical data implicate inadequate erythropoietin production as an important reason that infants acquire this anemia and suggest that recombinant human erythropoietin (r-HuEPO) might be used to treat or prevent it. We therefore randomly assigned 20 small premature infants (birth weight less than or equal to 1250 gm) who were highly likely to require erythrocyte transfusions for anemia of prematurity to receive 6 weeks of treatment with either intravenously administered r-HuEPO (at a dose of 100 units/kg twice each week) or a placebo. Hematologic measurements, transfusion requirements, and growth were followed during therapy and for 6 months thereafter. Treated (EPO) and control babies did not differ with respect to weight, hematocrit, overall mean absolute reticulocyte count, calculated erythrocyte mass, or rate of growth. However, reticulocyte counts increased earlier in patients given r-HuEPO. Six of ten babies in the EPO group, and 8 of 10 assigned to the control group, received at least one erythrocyte transfusion during treatment. For all infants the amount of blood sampled for laboratory tests was strongly predictive of the volume of packed erythrocytes transfused (r = 0.890; p = 0.0001). Of nine infants who had less than 20 ml packed erythrocytes removed for laboratory tests, none of four given r-HuEPO received a transfusion, whereas three of five infants assigned to the placebo group received one. No toxic effects were attributable to r-HuEPO, and no significant changes in leukocyte or platelet counts occurred during treatment. Reticulocyte counts were correlated with simultaneous platelet counts and were inversely related to absolute neutrophil counts in both study groups. We conclude that r-HuEPO administration is safe and feasible at the dose studied. Additional controlled trials utilizing higher doses of r-HuEPO and larger numbers of patients are justified.

BACKGROUND There has been a large increase in both the number of neonatal intensive care units (NICUs) in community hospitals and the complexity of the cases treated in these units. We examined differences in neonatal mortality among infants with very low birth weight (below 1500 g) among NICUs with various levels of care and different volumes of very-low-birth-weight infants. METHODS We linked birth certificates, hospital discharge abstracts (including interhospital transfers), and fetal and infant death certificates to assess neonatal mortality rates among 48,237 very-low-birth-weight infants who were born in California hospitals between 1991 and 2000. RESULTS Mortality rates among very-low-birth-weight infants varied according to both the volume of patients and the level of care at the delivery hospital. The effect of volume also varied according to the level of care. As compared with a high level of care and a high volume of very-low-birth-weight infants (more than 100 per year), lower levels of care and lower volumes (except for those of two small groups of hospitals) were associated with significantly higher odds ratios for death, ranging from 1.19 (95% confidence interval [CI], 1.04 to 1.37) to 2.72 (95% CI, 2.37 to 3.12). Less than one quarter of very-low-birth-weight deliveries occurred in facilities with NICUs that offered a high level of care and had a high volume, but 92% of very-low-birth-weight deliveries occurred in urban areas with more than 100 such deliveries. CONCLUSIONS Mortality among very-low-birth-weight infants was lowest for deliveries that occurred in hospitals with NICUs that had both a high level of care and a high volume of such patients. Our results suggest that increased use of such facilities might reduce mortality among very-low-birth-weight infants.

In the United States there are about 4 million births annually,1 of which about 10% are premature. The percentage of premature births has increased over the last decade2 and every year there are >20 000 infants whose birth weight is 1250 g or under who survive beyond 28 days of life.3 An additional 32 000 surviving infants weigh between 1251 and 1500 g at birth. Both birth weight strata contain, by all that we know about the disease, infants at the highest risk for the development of retinopathy of prematurity (ROP). If infants of these birth weights are to be examined by ophthalmologists competent to perform indirect ophthalmoscopy on these tiny prematures, an average of 6 times during the period of highest susceptibility for the development of threshold ROP4 disease—32 to 40 weeks postconceptional age5,6—then we are talking about ±300 000 such examinations per year in the neonatal intensive care units across this country.

Background. Medical care for very low birth weight (VLBW) infants and their mothers has changed dramatically during the 1990s, yet it is unclear how these changes have affected mortality and morbidity.Objective. We used the Vermont Oxford Network Database to identify trends in clinical practice and patient outcomes for VLBW infants born from 1991 to 1999.Methods. Logistic regression was used to evaluate temporal trends in practices and outcomes while adjusting for patient characteristics and accounting for clustering of cases within hospitals.Results. There were 118 448 infants 501 to 1500 g from 362 neonatal intensive care units enrolled in the Network Database from 1991 to 1999. Prenatal care, cesarean section, multiple births, antenatal steroids, and 1-minute Apgar scores increased during this period, as did the use of nasal continuous positive airway pressure, high-frequency ventilation, surfactant, and postnatal steroids. The proportion of white infants decreased; the proportions of Hispanic infants and those of other races increased. The crude and adjusted rates of mortality, pneumothorax, intraventricular hemorrhage (IVH), and severe IVH declined from 1991 to 1995, whereas from 1995 to 1999, the rates of mortality, IVH, and severe IVH did not change significantly, and pneumothorax increased.Conclusions. There have been major changes in both obstetric and neonatal care during the 1990s. These changes were associated with decreases in mortality and morbidity for VLBW infants during the first half of the decade. However, since 1995, no additional improvements in mortality or morbidity have been seen, ending a decades-long trend of improving outcomes for these infants.

Objective. In 1976, the Committee on Perinatal Health recommended that hospitals with no neonatal intensive care unit (NICU) or intermediate NICUs transfer high-risk mothers and infants that weigh Methods. Birth certificates of 16 732 singleton infants who had a BW of Results. Compared with birth in a hospital with a regional NICU, risk-adjusted mortality of infants with BW of Conclusions. These results support the recommendation that hospitals with no NICU or intermediate NICUs transfer high-risk mothers with estimated fetal weight of

OBJECTIVE: To compare the neurodevelopmental outcome of premature infants treated with recombinant human erythropoietin with that of control infants. STUDY DESIGN: A total of 20 treated infants and 20 control infants who had completed randomized, double-blind, placebo-controlled studies of recombinant human erythropoietin as treatment for anemia of prematurity were followed for growth and developmental outcome in an intensive care nursery follow-up program. Infants were assessed by standard developmental tests. RESULTS: No differences were found between groups for neurologic outcome, cognitive outcome, or growth patterns. All infants treated with recombinant human erythropoietin were neurologically normal. The rate of cognitive deficits was similar in the two groups. CONCLUSION: In this small sample we did not see differences in neurodevelopmental outcome between infants treated with recombinant human erythropoietin and control infants.

To the Editor .— Fanaroff et al1 reported that treatment for hypotension in extremely low birth weight infants is associated with adverse outcomes including longer hospital stays and increased rates of death, severe intraventricular hemorrhage, impaired motor development, and hearing loss. These findings are of interest to those who provide care to such infants, but the details of the study raise some concerns: 1. The authors describe the results as being associated with “treated hypotension,” …

Anemia of prematurity (AOP) results from several interacting processes, including phlebotomy losses, a temporary failure to release erythropoietin in response to anemia, a short life span of erythrocytes, and rapid growth of body mass and, hence, blood volume after the first few weeks of life. Infants with AOP have erythroid progenitors that respond to erythropoietin in vitro, suggesting that treatment with recombinant erythropoietin might reduce the need for transfusions for AOP. Many pilot studies were needed to define the dose of recombinant erythropoietin (500 to 750 U/kg/wk) that stimulated the early onset of erythropoiesis in infants with AOP. Three large controlled trials have demonstrated that recombinant erythropoietin therapy reduces transfusions in AOP and is apparently safe. Unresolved issues include the ideal dose, the optimal nutrition needed during therapy, the target population, and timing of the start of treatment.

It has been well established that erythropoietin (EPO) in the dosage range of 500 units/kilo/week and perhaps slightly lower doses will produce a brisk reticulocyte response in infants with anemia of prematurity. Controlled clinical trials to demonstrate that this therapy can result in significant reductions in transfusion in these babies face several complex issues of experimental design. 1. Should the study population be relatively bigger, healthier babies (< 1500 grams birth weight, not on ventilatory support) who have lower transfusion requirements, or smaller sicker infants (< 1250 grams birth weight and on ventilators) who have higher transfusion requirements? These infants will need adequate nutrition and liberal supplementation with iron if they are to respond adequately, but the sicker smaller infants will take longer to meet these nutritional goals. 2. Timing is important because spontaneous recovery occurs at about 35 to 36 weeks of corrected gestational age, so to be effective, therapy must start before 33 weeks of gestational age and preferably earlier than that. 3. Since the end point is transfusion, the criteria used for transfusions become a critical issue. If liberal transfusion criteria are used, the study will be doubly biased in favor of EPO efficacy. There will be an increased number of transfusion events in the control population and spontaneous recovery from the anemia of prematurity will be overly suppressed in the control population. It's likely that the current transfusion criteria are too liberal thus introducing these biases to experimental design.(ABSTRACT TRUNCATED AT 250 WORDS)

There is a high level of erythropoiesis in the growing fetus. In utero relative hypoxia results in a relatively high haematocrit and predominant synthesis of haemoglobin F, with erythropoietin (EPO) produced in the liver regulating erythropoiesis. At birth after full-term pregnancy, fetal EPO concentrations are high, but decline progressively thereafter. In pre-term infants the expected postnatal decline in haemoglobin is more prolonged than in full-term infants and the premature infants may become anaemic. It has been shown in a randomized, double-blinded, placebo-controlled trial that recombinant human erythropoietin (r-HuEPO) at a dose of 100 U/kg given intravenously twice weekly for 6 weeks to infants with anaemia of prematurity produced an earlier increase in reticulocyte counts compared with placebo; however, the difference between treatments was not significant. r-HuEPO therapy did not suppress subsequent release of endogenous EPO. It is concluded that a higher dose of r-HuEPO may be required to treat anaemic premature infants.

In Reply.— Dr Kattwinkel suggests in his letter that there has been no serious effort by investigators in neonatology and pulmonary biology to identify the best possible surfactant for use for replacement therapy in hyaline membrane disease. Furthermore, he implies that there has been a national or perhaps international conspiracy to ignore natural human surfactant in the large clinical trials done to date. In reaching these opinions, Dr Kattwinkel seems to have ignored several facts of which he should be aware.

Background Pulmonary disease is common in preterm infants, despite antenatal glucocorticoid therapy. The addition of antenatal thyrotropin-releasing hormone therapy has been reported to decrease pulmonary morbidity in these infants. Methods We enrolled 996 women at 13 North American centers who were in preterm labor at

Plasma Thyroid Hormone Concentrations in Premature Infants and Effect of Thyrotropin Releasing Hormone (TRH) † 954

The Clinical Risk Index for Babies (CRIB) Predicts Chronic Lung Disease (CLD) in Very Low Birth Weight (VLBW) Infants † 983

Objective. —To examine the effects of neonatal intensive care unit (NICU) patient volume and the level of NICU care available at the hospital of birth on neonatal mortality. Design. —Birth certificate data linked to infant death certificates and to infant discharge abstracts were used in a logistic regression model to control for differences in each patient's clinical and demographic risks. Hospitals were classified by the level of NICU care available (no NICU: level I; intermediate NICU: level II; expanded intermediate NICU: level II+: tertiary NICU: level III) and by the average patient census in the NICU. Setting. —All nonfederal hospitals in California with maternity services. Patients. —All births in nonfederal hospitals in California in 1990 (N=594 104), 473 209 (singletons only) of which were successfully linked with discharge abstracts. Of these infants, 53 229 were classified as likely NICU admissions. Main Outcome Measures. —Death within the first 28 days of life, or within the first year of life, if continuously hospitalized. Results. —Patient volume and level of NICU care at the hospital of birth both had significant effects on mortality. Compared with hospitals without an NICU, infants born in a hospital with a level III NICU with an average NICU census of at least 15 patients per day had significantly lower risk-adjusted neonatal mortality (odds ratio, 0.62; 95% confidence interval, 0.47-0.82; P =.002). Risk-adjusted neonatal mortality for infants born in smaller level III NICUs, and in level II+ and level II NICUs, regardless of size, was not significantly different from hospitals without an NICU, and was significantly higher than hospitals with large level III NICUs. Conclusions. —Risk-adjusted neonatal mortality was significantly lower for births that occurred in hospitals with large (average census, >15 patients per day) level III NICUs. Despite the differences in outcomes, costs for the birth of infants born at hospitals with large level III NICUs were not more than those for infants born at other hospitals with NICUs. Concentration of high-risk deliveries in urban areas in a smaller number of hospitals that could provide level III NICU care has the potential to decrease neonatal mortality without increasing costs.

Recent reports suggest that antenatal steroids (ANS) reduce the need for treatment of hypotension in preterm infants. We analyzed data from a randomized, controlled trial of Exosurf® (Pediatrics 88:1, 1991) to determine the effect of ANS on mean arterial blood pressure (MABP) and on the need for treatment of hypotension during the first 24 h of life in small preterm infants. MABP was measured continuously and directly via an arterial catheter and all babies were managed with a consistent protocol for treatment of hypotension. We included all inborn infants with gestational age (GA)≤31 weeks and birthweight (BW) ≤1250 g except if they died in the first 48 h, were small for GA, had major congenital anomalies or incomplete courses of steroids. Babies who received at least 2 doses of steroids, with the first given between 24 h and 7 d before delivery, were considered to have received a complete course of steroids (CS); the no steroids (NS) group included infants who received no dose for at least 7 d before delivery. There were 57 babies, 38 received CS and 19 had NS. MABP in the first 24h of life showed significant positive correlation with BW and GA.

There was a rapid increase in the number of neonatal intensive care units(NICUs) in California in the 1980s. Most of this expansion occurred among intermediate, or level II NICUs and Community NICUs (a California classification for expanded level Ils that can provide prolonged assisted ventilation). Most of these new units and many of the existing level II units were quite small. We used the 1990 California birth/infant death cohort file(N=594,104), linked to the hospital discharge abstracts for mothers and infants. Logistic regression was used to examine the effects of patient volume and level of NICU care at the hospital of birth on neonatal mortality, controlling for sex and race of the infant, type of insurance coverage, birth weight, and maternal and neonatal diagnoses associated with increased neonatal mortality. The results indicate that level of care and patient volume both have strong effects on risk-adjusted mortality. Compared to level I hospitals, infants born in regional centers with an average patient census >15 had much lower risk-adjusted mortality (Odds Ratio=0.70, p=0.002). Smaller level Ills and both types of level Ils, regardless of patient volume, had mortality rates that were not significantly different from those at level I units. Infants insured by HMOs had mortality rates that were 30% (p=0.01) higher than those of other private insurers. Medicaid mortality was 32% (p=0.003) higher than those with private insurance. When costs or length of stay are used as the dependent variable, the larger level III units are in the middle of the range across the different types of NICUs, controlling for the other factors in the model. Further, 80% of the births in level Ils or community NICUs occur in hospitals located within 25 miles of a level III. These findings suggest that the recent competitive trends in California have had a significant adverse effect on neonatal mortality without achieving any cost savings.

Regionalization and improvement in transport systems have had a major impact on the care of LBW infants. However, as birth weight increases, the need for intensive care decreases. To identify subgroups of LBW infants likely to benefit from maternal referral, the 594, 104 infants included in the 1990 California birth/infant death cohort file were analyzed according to the level of neonatal care (1993 survey of the California Association of Neonatologists) at the place of birth: level 1 (well baby nursery), level 2 (mechanical ventilation,MV, available only prior to transport), level 2 plus (availability of MV on a long term basis), and level 3 (long term MV and surgical capabilities). A logistic regression analysis using birth weight and discharge diagnoses was done in the 53,229 ill infants to create a model that best predicted mortality. This model was applied to LBW infants born at three different levels of care and the ratios of risk-adjusted observed versus expected mortality (O/E ratio) were calculated by birth weight(table). Overall, there was an effect of both level of care and birth weight on O/E ratio (p

This article presents several cases and certain key clinical-ethical questions associated with the provision of neonatal intensive care. Summaries of five papers on major considerations affecting these issues are included. The authors propose a moral policy stating areas of responsibility and ethical guidelines for decisions about care of newborn infants.

We measured hematocrit and serum albumin concentration at birth and red blood cell and plasma volume soon after birth in prematurely born infants with erythroblastosis fetalis of varying severity and examined the realtionships between these variables and the presence and severity of hydrops fetalis. Blood volumes in most of these infants were similar to the established normals for newborn infants without erythroblastosis. There was no simple association between blood volume and the presence of hydrops. Nonhydropic and severely hydropic infants had, on the average, similar and normal blood volumes, while mildly hydropic infants had low blood volumes. Anemia correlated fairly well with severity of hydrops but almost a quarter of the infants with severe hydrops were only mildly anemic. Red blood cell volume decreased and plasma volume increased proportionally with the degree of anemia at birth. Thus, hydropic infants with severe anemia had large plasma volumes while those with milder anemia did not. On the other hand, hypoalbuminemia was common and correlated closely with severity of hydrops. We suggest that hydrops results at least in part from low plasma colloid osmotic pressure due to hypoalbuminemia.

We measured the in vivo oxygen saturation of hemoglobin in the arterial blood of 34 sick newborn infants with a new, rapidly responding, continuously recording, catheter oximeter. The oxygen saturation, SaO2, was found to fluctuate between 85 and 95% in infants with pulmonary disease who are in a stable condition and breathing spontaneously. Severe disaturation occurred during apnea and after procedures such as chest percussion and suctioning of the endotrachael tube. The effects of changes in respiratory therapy were quickly manifested by changes in SaO2. This was particularly useful in guiding resuscitation of newborn infants who were asphyxiated at birth. Blood sampling for measurement of PaO2 can be done less frequently, reducing the need for blood transfusions in small infants.

Summary Nineteen newborn lambs, spontaneously breathing room air, were hemorrhaged of 50% of their measured blood volume over a 30-min period. They were then observed for the following 90 min. No fluid or blood was reinfused during the study. Eight of the 19 lambs survived beyond the study period, the other 11 died at the end of the hemorrhage or during the recovery period. All lambs became hypotensive and bradycardic during the hemorrhage. All became tachycardic after the hemorrhage. Blood pressure of the survivors returned towards baseline levels whereas it continued to fall in the non-survivors. All animals became anemic, acidotic, and hypocarbic but remained normoxemic. Myocardial blood flow fell to approximately 50% of baseline levels in both survivors and non-survivors during, and at the end of the hemorrhage. It returned to near baseline levels in the survivors by 90 min posthemorrhage. Cerebral blood flow remained at baseline levels during the hemorrhage in the survivors but cerebral oxygen delivery decreased. Flow rose 10% above baseline levels 90 min after hemorrhage but oxygen delivery remained low. In the non-survivors, cerebral blood flow fell to 60% of baseline and cerebral oxygen delivery was 50% of baseline by the end of the hemorrhage. A group of five lambs was hemorrhaged and studied in the same fashion as the 19, except that they breathed 4.5% CO2 beginning 15 min before the hemorrhage, during the hemorrhage and 90 min recovery period. Four of these five survived the study period. They remained normocarbic and became more acidotic than the animals that breathed room air. Blood pressure and heart rate fell during hemorrhage but these decreases were less than in either group of room air breathing animals. During recovery they became tachy­ cardic and blood pressure returned to baseline levels. Myocardial blood flow increased 20% above baseline by the end of hemorrhage and 40% above baseline by 90 min posthemorrhage. Cerebral blood flow increased 40% above baseline during the hemorrhage and remained at that level at the end of hemorrhage and 90 min afterwards. The increase in brain blood flow was sufficient to maintain oxygen delivery to the brain at baseline levels throughout the experiment.

Management of perinatal asphyxia is one of those rare opportunities in clinical medicine when death or life-long disability can be prevented with several minutes of skillful and judicious action. Fetal and neonatal asphyxia is approached most successfully as a joint obstetric, pediatric, and anesthetic effort. This article reflects the team approach to perinatal asphyxia.

Erythropoietin, hemoglobin, hematocrit, oxygen affinity (P50), and reticulocyte counts were measured weekly starting at 1 week of age in 10 very-low-birth-weight infants and on a single occasion in 15 healthy men. In the adults, "available oxygen" (derived from oxygen carrying capacity and P50) averaged 13.1 ml/dl blood and the mean erythropoietin level was 15.2 mU/ml. Erythropoietin levels in the infants were inversely related to concentration of hemoglobin, P50, and available oxygen. However, despite the much lower mean "available oxygen" of 9.3 ml/dl in the infants compared with that in adults (P less than 0.001), the mean erythropoietin value of 8.2 mU/ml in the infants was less than in adults (P less than 0.001). Furthermore, the erythropoietin response to decreased "available oxygen" was lowest in the least mature infants. VLBW infants often develop clinical evidence of hypoxia during the anemia of prematurity. The relatively low erythropoietin levels in relation to "available oxygen" are compatible with a decreased erythropoietin response to hypoxia compared with that in adults. Such a difference in response could be a contributing factor to the anemia of prematurity.

There was meconium staining of the amniotic fluid in 8.8% of 1,000 consecutive newly born infants. At birthmeconium was present in the tracheas of 56% of those with meconium staining. From all infants who became "sick", meconium was aspirated from their airways; eight had meconium below the vocal cords, but none in the mouth or larynx. Twenty percent of those who were meconium stained had pulmonary disease which required increased ambient oxygen to maintain the Pa O 2 above 50 mm Hg andlor had a pneumothorax or pneumomediastinum during the first three days of life. All infants survived, including two who required mechanical ventilation for respiratory failure.

The purpose of this study was to determine whether an inappropriately low erythropoietin response in premature infants might be a basis for the anemia of prematurity. Erythropoietin was measured by radioimmunoassay in conjunction with hemoglobin and reticulocyte count in untransfused premature infants between birth and 60 days of age. The 27 infants had a mean gestational age of 31 weeks and a mean birth weight of 1378 gm. Between 2 and 30 days, mean erythropoietin concentration was 9.7 mU/ml, significantly and substantially lower than 15.2 mU/ml in 15 concurrently studied healthy adults (P less than 0.01). Subsequently, from 30 to 60 days, values rose gradually to a mean of 17.2 mU/ml, which did not differ significantly from the mean value in adults. Hemoglobin values fell from a mean of 12.9 gm/dl during the first month to 9.0 gm/dl between 30 and 60 days. Thus, during the second postnatal month, preterm infants had essentially the same erythropoietin values as in adults despite a mean hemoglobin concentration that averaged less than two thirds the adult value. This failure to mount a greater erythropoietin response may help to explain why hemoglobin declines to such low values at 2 months of age.

Persistent pulmonary hypertension of the newborn infant can be difficult to distinguish from other cardiopulmonary causes of cyanosis during the newborn period. Infants with PPHN have cyanosis, tachypnea, acidemia, normal pulmonary parenchymal markings on the chest radiography, and anatomically normal hearts. We have identified and treated 11 infants and have noted several signs and symptoms not previously emphasized. These are cineangiocardiographic evidence of atrioventricular valve insufficiency in association with systolic murmurs and slow ventricular emptying, apnea, hypocalcemia, only a small rise in abdominal aortic blood oxygen tension during breathing of 100% oxygen, and no response to continuous positive airway pressure. Right-to-left shunting through the patent ductus arteriosus was documented in nine infants: in all six of those in whom simultaneous temporal and abdominal aortic blood oxygen tension measurements were made; in three by means of cardiac catheterization. Ten infants survived after variable courses and treatments which makes it difficult to ascribe improvement to any one therapy. The distinct increase in blood oxygen tension with tolazoline HCl and curare in some instances is discussed.

Continuous positive airway pressure (CPAP) was used to support the ventilation of infants less than 3 months of age who had undergone thoractomy for cardiovascular surgery. The functional residual capacity, which was approximately 30 per cent of predicted at zero CPAP, increased 35 per cent in cyanotic and 33 per cent in acyanotic infants with the application of 5 mm Hg pressure. Increasing airway pressure from zero to 5 mm Hg increased PaO2 4 per cent in cyanotic and 13 per cent in acyanotic infants. There was no change in heart rate, respiratory rate, mean arterial pressure, pH or PaC02 under similar circumstances, but central venous pressure increased 1.5 mm Hg in cyanotic and 0.8 mm Hg in acyanotic infants.

We determined the incidence of pneumothorax in 295 infants (mean birthweight, 1,917 gm) with the respiratory distress syndrome (RDS) treated according to the same protocol. Fifty-five infants (mean birthweight, 1,594 gm) developed pneumothorax (incidence, 19%); incidence varied with severity of RDS and intensity of respiratory assistance. Pneumothorax occurred in 3.5% (2 of 58) of infants who received no assisted ventilation and in 11% (14 of 124) of infants who received continuous positive airway pressure (CPAP) as the only form of assisted ventilation; the difference between these two groups is not significant. Forty-nine infants initially treated with CPAP later required mechanical ventilation with positive end-expiratory pressure (PEEP). Pneumothorax occurred in 12 of the 49 (24%) and in 21 of 64 (33%) of those infants initially treated with PEEP; the incidence of pneumothorax for both these groups was significantly higher than for those treated with no assisted ventilation or CPAP only. To assess the value of frequent measurement of vital signs, blood gas tensions, and pH in the recognition of pneumothorax, we analyzed these variables by the cumulative sum statistical technique. We noted the following significant changes associated with pneumothorax: arterial blood pressure, heart rate, and respiratory rate decreased in 77% of cases; pulse pressure narrowed in 51% of cases; Po2 decreased in 17 of 20 cases in which ventilatory settings were constant for at least three hours prior to pneumothorax. However, pH and PCO2 showed no consistent changes. Frequent measurements of vital signs and Po2 aid in the early diagnosis of pneumothorax.

Sixty-six nonhydropic fetuses received intra-uterine transfusions for severe erythroblastosis fetalis; 24 survived the neonatal period–the youngest is now more than 1 year and the oldest 5 years of age. Serial evaluations of growth and development of the survivors were compared with their course in the perinatal period. Twenty-one were normal; one suffered severe central nervous system damage associated with severe cardiorespiratory failure, prolonged acidosis, and hypoxia during the neonatal period; one has a handicap due to hearing loss and one has a speech handicap. The results support the use of intra-uterine transfusion in appropriately selected fetuses when combined with aggressive treatment of cardiorespiratory distress and hyperbilirubinemia during the neonatal period.

We applied a continuous positive airway pressure to 20 infants (birth weight 930 to 3800 g) severely ill with the idiopathic respiratory-distress syndrome. They breathed spontaneously. Pressure, up to 12 mm of mercury, was delivered through an endotracheal tube to 18 infants and via a pressure chamber around the infant's head to two. Arterial oxygen tension rose in all, permitting us to lower the inspired oxygen an average of 37.5 per cent within 12 hours. Minute ventilation decreased with increased continuous positive airway pressure, but this had little effect on arterial carbon dioxide tension, pH, arterial blood pressure and lung compliance. Sixteen infants survived, including seven of 10 weighing less than 1500 g at birth.

We wish to call attention to an apparently common misconception about the efficiency of exchange transfusions. The mechanics of the procedure are: a substance (bilirubin and/or antibody-coated red cells) is washed out of a compartment (the baby's blood volume) by the removal of a fraction of that compartment and its replacement by an equal volume of diluent (donor blood). This flushing process is repeated many times, usually until the total volume replaced is 2 to 3 times the volume of the compartment itself.

We have adapted and calibrated an accurate method for measuring residual placement blood volume (RPBV). We used this method in 33 normal vaginal deliveries and 18 cesarean section deliveries in which the umbilical cord was clamped from 5 to 118 seconds after delivery. Infants born vaginally received 10 to 20 ml. per kilogram of body weight of placental transfusion when umbilical cord was not clamped until 30 seconds or more after delivery. Equivalent delay of umbilical cord clamping in cesarean section infants produced no placental transfusion.

We measured the residual placental blood volume (RPBV) of 20 infants delivered at term by cesarean section of women not in labor. In all cases, the umbilical cord was clamped within 40 seconds of birth. RPBV decreased significantly with increasing age at cord clamping. In addition, RPBV for infants with cords clamped within 20 seconds of birth correlated inversely with maternal systolic blood pressure (mean RPBV = 54.8 ml. per kilogram at 105 torr and 28.4 ml. per kilogram at 148 torr). However, RPBV did not correlate with maternal blood pressure for the whole group of 20 infants or for those with cords clamped later than 20 seconds after birth. These data indicated that in infants delivered by cesarean section placental transfusion is time related during the first 40 seconds of life and that maternal blood pressure also influences the magnitude of placental transfusion during the first 20 seconds after birth. Analysis of data from this study combined with data from a previous study shows that after 40 seconds the net flow between placenta and infant reverses and that cord clamping delayed beyond this point is accompanied by a rise in RPBV back to the level found when the cord was clamped before 20 seconds.

Renal cortical and medullary infarction are 2 of the severe complications of perinatal asphyxia and shock. The angiographic and ultrasonographic findings in these conditions have not been described previously. They demonstrate nephromegaly, a nonhomogeneous nephrogram, and internal echoes. Similar findings may be seen in renal vein thrombosis, hydronephrosis, and polycystic kidneys.

We studied erythropoiesis in infants with the anemia of prematurity by counting the number of colonies derived from erythroid burst-forming units (BFU-E) in the blood of 11 premature infants before they received transfusions. Colony growth in blood from the infants was compared with growth in blood from adults and umbilical-cord blood from term infants, in the presence of erythropoietin, 0 to 2000 mU per milliliter. Addition of increasing concentrations of erythropoietin resulted in a stepwise increase in the number of colonies derived from BFU-E (P less than 0.0005) of all three groups of subjects. Cultures stimulated with 2000 mU of erythropoietin yielded 28.1 +/- 7.6, 88.0 +/- 19.4, and 121.0 +/- 22.5 bursts (mean +/- SE) per 10(5) cells plated in blood from adults, blood from premature infants, and cord blood, respectively. Although more BFU-E-derived colonies appeared when 200 or 2000 mU were present per milliliter in cultures of the infants' blood and cord blood, the intrinsic responsiveness of BFU-E to erythropoietin was similar in all groups. Although the mean hematocrit was 26 percent, mean serum erythropoietin concentrations (+/- SD) in the infants (20.7 +/- 10.0 mU per milliliter) were not significantly different from those in the adult controls (24.0 +/- 6.5). We conclude that progenitor cells committed to erythroid differentiation are present during the anemia of prematurity, and that the intrinsic responsiveness of the circulating BFU-E pool to erythropoietin is normal. These results implicate inadequate production of erythropoietin as the cause of the anemia of prematurity and suggest that recombinant erythropoietin might provide a therapeutic alternative to transfusion for symptomatic babies with this condition.