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SummaryObjective To measure mean airway pressure (MAP) delivered through the RAM Cannula® when used with a ventilator in CPAP mode as a function of percent nares occlusion in a simulated nasal interface/test lung model and to compare the results to MAPs using a nasal continuous positive airway pressure (NCPAP) interface with nares fully occluded. Study Design An artificial airway model was connected to a spontaneous breathing lung model in which MAP was measured at set NCPAP levels between 4 and 8 cmH2O provided by a Drager Evita XL® ventilator and delivered through three sizes of RAM cannulae. Measurements were performed with varying leakage at the nasal interface by decreasing occlusion from 100% to 29%, half-way prong insertion, and simulated mouth leakage. Comparison measurements were made using the Drager BabyFlow® NCPAP interface with a full nasal seal. Results With simulated mouth closed, the Drager interface delivered MAPs within 0.5 cmH2O of set CPAP levels. For the RAM cannula, with 60–80% nares occlusion, overall delivered MAPs were 60 ± 17% less than set CPAP levels (P

Increased use of non-invasive forms of respiratory support such as CPAP and HFNC in premature infants has generated a need for further investigation of the pulmonary effects of such therapies. In a series of in vitro tests, we measured delivered proximal airway pressures from a HFNC system while varying both the cannula flow and the ratio of nasal prong to simulated nares diameters. Neonatal and infant sized nasal prongs (3.0 and 3.7 mm O.D.) were inserted into seven sizes of simulated nares (range: 3-7 mm I.D. from anatomical measurements in 1-3 kg infants) for nasal prong-to-nares ratios ranging from 0.43 to 1.06. The nares were connected to an active test lung set at: TV 10 ml, 60 breaths/min, Ti 0.35 sec, compliance 1.6 ml/cm H₂O and airway resistance 70 cm H₂O/(L/sec), simulating a 1-3 kg infant with moderately affected lungs. A Fisher & Paykel Healthcare HFNC system with integrated pressure relief valve was set to flow rates of 1-6 L/min while cannula and airway pressures and cannula and mouth leak flows were measured during simulated mouth open, partially closed and fully closed conditions. Airway pressure progressively increased with both increasing HFNC flow rate and nasal prong-to-nares ratio. At 6 L/min HFNC flow with mouth open, airway pressures remained 0.9 and 50% mouth leak, airway pressures rapidly increased to 18 cm H₂O at 2 L/min HFNC flow followed by a pressure relief valve limited increase to 24 cm H₂O at 6 L/min. Safe and effective use of HFNC requires careful selection of an appropriate nasal prong-to-nares ratio even with an integrated pressure relief valve.

Background: Neonatal cholestasis is associated with increased mortality and other adverse outcomes. There are no tools for prediction of infants at risk for cholestasis. Objective: To determine if cholestasis in very-low-birth-weight (VLBW) infants is associated with alterations in cytokines or C-reactive protein (CRP) and, if so, whether inflammatory markers predict which infants will develop cholestasis. Methods: VLBW infants expected to be on parenteral nutrition for >7 days were enrolled in this prospective cohort study. Infants with direct bilirubin ≥1.0 mg/dl were considered to have a high risk for cholestasis and were compared to infants who never developed direct bilirubin ≥1.0 mg/dl. Standard descriptive statistics were used to compare biomarkers over time. Multivariable models were used to estimate associations between early inflammatory markers and cholestasis. Results: Of 63 infants enrolled, 29 were at risk for cholestasis. CRP was highly correlated with direct bilirubin. Infants in the high-risk group had significantly higher IL-1β, IL-6, IL-8, and IL-10 at 2, 4, and 6 weeks and CRP at 2 and 6 weeks. In logistic models, CRP (OR = 4.97, p = 0.02) or IL-1β (OR = 1.11, p = 0.008) at 2 weeks of age was predictive of cholestasis. In linear mixed-effects models, CRP (p < 0.001) or IL-6 (p = 0.02) and IL-8 (p < 0.001) were predictive of cholestasis. Conclusion: Elevated CRP and cytokines are associated with cholestasis in VLBW infants. These inflammatory markers are candidates for further research into the pathogenesis, prediction, and prevention of cholestasis.

We sought to determine if antenatal corticosteroid treatment administered prior to 24 weeks' gestation influences neonatal morbidity and mortality in extremely low-birth-weight infants. A retrospective review was performed of all singleton pregnancies treated with one complete course of antenatal corticosteroids prior to 24 weeks' gestation and delivered between 23 0 / 7 and 25 6 / 7 weeks. These infants were compared with similar gestational-age controls. There were no differences in gender, race, birth weight, and gestational age between the groups. Infants exposed to antenatal corticosteroids had lower mortality (29.3% versus 62.9%, P = 0.001) and grade 3 or 4 intraventricular hemorrhage (IVH; 16.7% versus 36%, P < 0.05; relative risk [RR]: 2.16). Grade 3 and 4 IVH was associated with significantly lower survival probability as compared with no IVH or grade 1 and 2 IVH ( P < 0.001, RR: 10.6, 95% confidence interval [CI]: 4.4 to 25.6). Antenatal steroid exposure was associated with a 62% decrease in the hazard rate compare with those who did not receive antenatal steroids after adjusting for IVH grade (Cox proportional hazard model, hazard ratio 0.38, 95% CI: 0.152 to 0.957, P = 0.04). The rates of premature rupture of membranes and chorioamnionitis were higher for infants exposed to antenatal corticosteroids. Exposure to a single course of antenatal corticosteroids prior to 24 weeks' gestation was associated with reduction of the risk of severe IVH and neonatal mortality for extremely low-birth-weight infants.

The safety and efficacy of early, low-dose, prolonged therapy with inhaled nitric oxide in premature newborns with respiratory failure are uncertain.We performed a multicenter, randomized trial involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation. Newborns were randomly assigned to receive either inhaled nitric oxide (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1000 to 1250 g). The primary efficacy outcome was a composite of death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age. Secondary safety outcomes included severe intracranial hemorrhage, periventricular leukomalacia, and ventriculomegaly.Overall, there was no significant difference in the incidence of death or bronchopulmonary dysplasia between patients receiving inhaled nitric oxide and those receiving placebo (71.6 percent vs. 75.3 percent, P=0.24). However, for infants with a birth weight between 1000 and 1250 g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent); for the cohort overall, such treatment reduced the combined end point of intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly (17.5 percent vs. 23.9 percent, P=0.03) and of periventricular leukomalacia alone (5.2 percent vs. 9.0 percent, P=0.048). Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events.Among premature newborns with respiratory failure, low-dose inhaled nitric oxide did not reduce the overall incidence of bronchopulmonary dysplasia, except among infants with a birth weight of at least 1000 g, but it did reduce the overall risk of brain injury. (ClinicalTrials.gov number, NCT00006401 [ClinicalTrials.gov].).

OBJECTIVE To compare calfactant (CA) and poractant alfa (PA) administration traits, short-term clinical responses, and resource use in the neonatal respiratory distress syndrome (RDS) setting. METHODS An open label series of 277 (213 PA and 64 CA) infants was evaluated for 445 administrations. Registered respiratory therapists collected patient, surfactant administration, and postadministration clinical data. Economic analysis involved labor costs of surfactant administration and usage, wastage, and product average wholesale price. Analysis utilized the Mann-Whitney rank sum test for differences in administration time and either the chi-square or Fisher's exact test for categorical variables. RESULTS PA had a statistically lower bedside administration time than CA (3.8 minutes vs. 5.3 minutes; P = .006) and a higher percentage of doses administered in less than five minutes (58.9% vs. 4.3%; P < .001). Doses administered per patient were similar (1.67 vs. 1.72). PA and CA were similar in time to recovery (81.4% vs. 74.3%), percent desaturation (24.8% vs. 26.7%), and bradycardia (3.8% vs. 8.5%). Reflux was significantly higher (13.2% vs. 3.5%; P < .001) with CA. Economic analyses found total administration costs per dose were $2.21 for PA and $3.08 for CA. Mean wastage costs were $141.21 for PA and $337.34 for CA (P < .001). CONCLUSIONS PA appeared to utilize fewer neonatal intensive care unit resources than CA due to reduced administration time and less wastage of drug product. Future studies should more closely evaluate time, resource, wastage, and post-administrative clinical effects to fully assess the impact of surfactant products in this setting.

Various cosyntropin doses are used to test adrenal function in premature infants, without consensus on appropriate dose or adequate response.The objective of this study was to test the cortisol response of extremely low birth weight infants to different cosyntropin doses and evaluate whether these doses differentiate between groups of infants with clinical conditions previously associated with differential response to cosyntropin.The design was a prospective, nested study conducted within a randomized clinical trial of low-dose hydrocortisone from November 1, 2001, to April 30, 2003.The setting was nine newborn intensive care units.The patients included infants with 500-999 g birth weight.The drug used was cosyntropin, at 1.0 or 0.1 microg/kg, given between 18 and 28 d of birth.We measured the cortisol response to cosyntropin.Two hundred seventy-six infants were tested. Previous hydrocortisone treatment did not suppress basal or stimulated cortisol values. Cosyntropin, at 1.0 vs. 0.1 microg/kg, yielded higher cortisol values (P0.001) and fewer negative responses (2 vs. 21%). The higher dose, but not the lower dose, showed different responses for girls vs. boys (P = 0.02), infants receiving enteral nutrition vs. not (P0.001), infants exposed to chorioamnionitis vs. not (P = 0.04), and those receiving mechanical ventilation vs. not (P = 0.02), as well as a positive correlation with fetal growth (P = 0.03). A response curve for the 1.0-microg/kg dose for infants receiving enteral nutrition (proxy for clinically well infants) showed a 10th percentile of 16.96 microg/dl. Infants with responses less than the 10th percentile had more bronchopulmonary dysplasia and longer length of stay.A cosyntropin dose of 0.1 microg/kg did not differentiate between groups of infants with clinical conditions that affect response. We recommend 1.0 microg/kg cosyntropin to test adrenal function in these infants.

The purpose of this study was to determine whether the interval between antenatal steroid exposure and delivery influences neonatal outcome in very low birth weight infants.A retrospective review was performed of all live-born singleton infants who weighed between 500 and 1500 g and who were exposed to a partial course (1 dose) or a complete course (2 12-mg doses of betamethasone given 24 hours apart) of antenatal corticosteroids. Infants were divided into 4 groups, depending on the interval between the first dose of antenatal corticosteroids and delivery (24 hours, between 24 and 48 hours, between 48 hours and 7 days, and7 days). Logistic regression was used to control for differences between the 4 groups.Three hundred twenty-five singleton deliveries were reviewed. Gestational age at delivery and birth weight were similar for all 4 groups. The babies in the last group were treated with antenatal corticosteroids at a slightly earlier gestational age. There was no statistical difference between the groups with respect to respiratory distress syndrome treated with surfactant, intraventricular hemorrhage, necrotizing enterocolitis, and deaths.In infants who weighed 500 to 1500 g, the time interval between exposure to antenatal corticosteroids and delivery does not appear to affect neonatal outcome. Further studies should evaluate the effects of antenatal corticosteroids and the effects of the interval from exposure to delivery in very low birth weight infants.

Perinatally acquired bacterial neonatal sepsis is a low-incidence,high-risk disease. Although incidence of the most common etiology,group B Streptococcus, has been reduced by prophylactic strategies,neonatal sepsis has not been eradicated, and vigilance must remain high. Accurate diagnosis is difficult: signs and symptoms are hard to distinguish from other causes of neonatal distress, and definitive diagnostic tests are not available. The clinician must make a judgment call, considering the perinatal history, the constellation of signs and symptoms, and the results of existing diagnostic tests,before neonatal sepsis can diagnosed or excluded. With diagnosis,knowledge of the specific disease states and clinical algorithms for management aid in formulating a plan of treatment with antimicrobial agents and supportive care.

Objective This study was undertaken to determine the clinical outcome for neonates who were exposed to indomethacin during gestation. Study design We identified 124 infants with in utero exposure to indomethacin and matched them to 124 infants whose mothers did not receive indomethacin. The two groups were matched for gestational age at birth, sex, and exposure to antenatal betamethasone. Sixty-two of the indomethacin-exposed infants were born within 48 hours of last exposure. These infants were also compared with their matched controls. Results There were no significant differences between the indomethacin-exposed infants and control infants in birth weight, Apgar scores, frequency of cesarean section deliveries, and multiple gestation. The incidence of respiratory distress syndrome, need for surfactant treatment, patent ductus arteriosus, necrotizing enterocolitis, and intraventricular hemorrhage was similar between the indomethacin-exposed group and the control group. Indomethacin-exposed infants who were born within 48 hours of last exposure had similar incidence of respiratory distress syndrome but greater need for surfactant treatment ( P =.02) compared with controls. All other complication rates were similar. Conclusion Indomethacin exposure in our study was not associated with increased neonatal complications for infants delivered within or beyond 48 hours of last exposure.

To measure mean airway pressure (MAP) delivered through the RAM Cannula® when used with a ventilator in CPAP mode as a function of percent nares occlusion in a simulated nasal interface/test lung model and to compare the results to MAPs using a nasal continuous positive airway pressure (NCPAP) interface with nares fully occluded.An artificial airway model was connected to a spontaneous breathing lung model in which MAP was measured at set NCPAP levels between 4 and 8 cmH2 O provided by a Dräger Evita XL® ventilator and delivered through three sizes of RAM cannulae. Measurements were performed with varying leakage at the nasal interface by decreasing occlusion from 100% to 29%, half-way prong insertion, and simulated mouth leakage. Comparison measurements were made using the Dräger BabyFlow® NCPAP interface with a full nasal seal.With simulated mouth closed, the Dräger interface delivered MAPs within 0.5 cmH2 O of set CPAP levels. For the RAM cannula, with 60-80% nares occlusion, overall delivered MAPs were 60 ± 17% less than set CPAP levels (P 0.001). Further, MAP decreased progressively with decreasing percent nares occlusion. The simulated open mouth condition resulted in significantly lower MAPs to1.7 cmH2 O. The one-half prong insertion depth condition, with closed mouth, yielded MAPs approximately 35 ± 9% less than full insertion pressures (P 0.001).In our bench tests, the RAM interface connected to a ventilator in NCPAP mode failed to deliver set CPAP levels when applied using the manufacturer recommended 60-80% nares occlusion, even with closed mouth and full nasal prong insertion conditions.

Premature infants have higher cortisol precursor concentrations than term infants; however, many sick preterm infants have surprisingly low cortisol concentrations. Those who develop chronic lung disease (CLD) have lower cortisol values than those who recover. We hypothesized that some infants have a decreased ability to synthesize cortisol, leading to physiologic disruptions including amplified inflammatory responses, thereby resulting in CLD. We measured cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, 17-hydroxypregnenolone, dehydroepiandrosterone sulfate, and ACTH in 40 extremely low birth weight infants enrolled in a study of low-dose hydrocortisone therapy to prevent CLD. Thirty-four infants survived and 15 developed CLD. Hydrocortisone therapy did not suppress ACTH or any measured steroid value. Before study (48 h of life), 17-OH progesterone was higher in CLD infants, as was the ratio of 17-OH progesterone to 11-deoxycortisol. On d 15-19 (or =72 h after end of therapy), basal and stimulated cortisol concentrations were lower in CLD infants. In contrast, the basal ratio of 11-deoxycortisol to cortisol was higher in CLD infants, as were stimulated values of 17-OH progesterone and stimulated ratios of 17-OH progesterone to 11-deoxycortisol and 11-deoxycortisol to cortisol. Thus, infants who developed CLD had lower basal and stimulated cortisol values, but elevated cortisol precursors and precursor to product ratios, compared with infants who recovered. These data support the hypothesis that these immature infants have a decreased capacity to synthesize cortisol, which may lead to a relative adrenal insufficiency in the face of significant illness.

✓ Serotonin (5-HT) produces constriction of peripheral collateral blood vessels. Using an animal model, the authors tested the hypothesis that 5-HT constricts collateral vessels in the cerebrum. A branch of the middle cerebral artery (MCA) was occluded proximally and cannulated distally in anesthetized dogs. Blood flow to the area at risk for infarction was detected by perfusing the cannulated MCA branch with microsphere-free blood during systemic injection of radioactive microspheres (shadow flow technique). Blood flow to collateral-dependent and normal cerebrum was measured during intravenous infusion of 5-HT (10 and 40 mg/kg/minute). Serotonin produced a dose-related reduction of blood flow to collateral-dependent cerebrum, increased collateral vessel resistance in large cerebral arteries and collateral vessels, and decreased cerebral artery perfusion pressure. In contrast, blood flow to normal cerebrum was not altered because a decrease in small vessel resistance effectively compensated for a decrease in MCA perfusion pressure. These findings indicate that 5-HT produces constriction of collateral vessels in the cerebrum. This response is clearly different from normal small cerebral vessels, which dilate during 5-HT infusion.

C-peptide concentrations in the cord blood of 29 macrosomic neonates born of nondiabetic mothers were higher than in 23 control infants whose birth weight was appropriate for gestational age, and there was a significant direct correlation between birth weight and C-peptide concentration. Six of the macrosomic infants studied (20%) had hypoglycemia in the first 24 hours of life, compared with none of the infants born with appropriate weight. We conclude that chronic fetal hyperinsulinemia may be one of the causes of macrosomia and neonatal hypoglycemia in infants of nondiabetic mothers.

At 33 hospitals in the United States, a double-blind, randomized clinical trial was performed to compare one versus three prophylactic doses of synthetic surfactant in 700 to 1100 gm inborn infants. All 826 infants received an initial prophylactic dose of surfactant within 30 minutes of birth. Subsequently 410 infants received two doses of placebo (air) 12 and 24 hours later, and 416 infants received two additional doses of surfactant. By the age of 28 days, 70 infants who received one dose of surfactant and 40 infants who received three doses were dead, a 43% relative reduction in the mortality rate (30 fewer deaths; p = 0.002). By the age of 1 year after term, 87 infants who received one dose and 62 infants who received three doses were dead: a 29% relative reduction in the mortality rate (25 fewer deaths; p = 0.027). Infants who received three doses of surfactant required significantly less oxygen and less mean airway pressure for the first week of life. Necrotizing enterocolitis (9 vs 25 infants; p = 0.005), and use of high-frequency ventilation (13 vs 26 infants; p = 0.037); pancuronium (43 vs 62 infants; p = 0.045); and leukocyte transfusions (0 vs 4 infants; p = 0.042) were less frequent in the three-dose group, but air leak, bronchopulmonary dysplasia, intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and infections were not different. These results indicate that physiologic findings, mortality rates, and probably morbidity rates are improved by two additional prophylactic doses of synthetic surfactant. (J PEDIATR 1995;126:969-78)

A three-dose prophylactic regimen of synthetic surfactant replacement has been shown to improve neonatal and 1-year survival rates in infants of 700 to 1100 gm birth weight when compared with a single prophylactic dose. The purpose of this study was to evaluate the growth, development, and late morbidity at 1 year adjusted age among the survivors of the 826 patients enrolled in the protocol. Complete follow-up data were obtained for 75% of the survivors in both groups. Chronic lung disease, need for respiratory support, neurologic disease requiring medication, visual or auditory impairments, and the incidence and severity of retinopathy of prematurity were equivalent in the two groups. The frequency of neurodevelopmental impairment was also comparable in the groups that received one dose versus three doses: moderate to severe cerebral palsy was found in 9% versus 6%, mental retardation assessed by Bayley Scales of Infant Development scores less than 69 was found in 16% vs 14%, and moderate to severe impairments of any kind were found in 33% vs 24%, respectively. Furthermore, the absolute number of impaired survivors was 92 in the three-dose group versus 106 in the one-dose group, despite a higher survival rate in the three-dose group. This study demonstrates that developmental outcomes of infants weighing 700 to 1100 gm who received three prophylactic doses of synthetic surfactant are at least as good as those of infants receiving a single dose, and that improving survival rates of very premature infants with synthetic surfactant does not result in increased numbers of infants with impairments.

Infants enrolled in three clinical trials of prophylactic treatment for respiratory distress syndrome with a single dose of synthetic surfactant (Exosurf Neonatal) or air placebo were monitored through 1-year adjusted age. A total of 1046 infants with birth weights from 500 to 1350 gm were enrolled in the three trials; of the 735 infants who survived to 1 year of age, follow-up evaluations were completed for 597 (80%, air placebo group; 82%, synthetic surfactant group). Infants in the air placebo and synthetic surfactant treatment groups had no differences in general health, growth, or nerodevelopmental outcomes or impairments. These follow-up results at 1-year adjusted age for infants who received a single dose of synthetic surfactant indicate that a single dose of synthetic surfactant reduces mortality without increasing the absolute number or proportion of infants with impairments at 1 year of age.

Increased use of non-invasive forms of respiratory support such as CPAP and HFNC in premature infants has generated a need for further investigation of the pulmonary effects of such therapies. In a series of in vitro tests, we measured delivered proximal airway pressures from a HFNC system while varying both the cannula flow and the ratio of nasal prong to simulated nares diameters. Neonatal and infant sized nasal prongs (3.0 and 3.7 mm O.D.) were inserted into seven sizes of simulated nares (range: 3-7 mm I.D. from anatomical measurements in 1-3 kg infants) for nasal prong-to-nares ratios ranging from 0.43 to 1.06. The nares were connected to an active test lung set at: TV 10 ml, 60 breaths/min, Ti 0.35 sec, compliance 1.6 ml/cm H₂O and airway resistance 70 cm H₂O/(L/sec), simulating a 1-3 kg infant with moderately affected lungs. A FisherPaykel Healthcare HFNC system with integrated pressure relief valve was set to flow rates of 1-6 L/min while cannula and airway pressures and cannula and mouth leak flows were measured during simulated mouth open, partially closed and fully closed conditions. Airway pressure progressively increased with both increasing HFNC flow rate and nasal prong-to-nares ratio. At 6 L/min HFNC flow with mouth open, airway pressures remained1.7 cm H₂O for all ratios; and10 cm H₂O with mouth closed for ratios0.9. For ratios0.9 and 50% mouth leak, airway pressures rapidly increased to 18 cm H₂O at 2 L/min HFNC flow followed by a pressure relief valve limited increase to 24 cm H₂O at 6 L/min. Safe and effective use of HFNC requires careful selection of an appropriate nasal prong-to-nares ratio even with an integrated pressure relief valve.

In an across study analysis of five multicenter, placebo-controlled trials of the Synthetic surfactant, Exosurf Neonatal, involving infants with birth weights 700 gm or greater the incidence of clinical pulmonary hemorrhage was 1.9% in treated infants and 1.0% in control infants. To determine whether this apparent increase in pulmonary hemorrhage was the result of a bleeding diathesis, we retrospectively reviewed charts for 39 of 41 infants with clinical pulmonary hemorrhage. The incidence of nonpulmonary bleeding was the same in control- and surfactant-treated infants. Platelet counts, hematocrit values, and the number of transfusions with platelets or red blood cells did not differ between the two groups. There was no evidence that surfactant treatment was specifically associated with a generalized bleeding diathesis.

Perinatally acquired bacterial neonatal sepsis is a low-incidence, high-risk disease with a relatively benign treatment. Accurate diagnosis is difficult because there is no definitive diagnostic test; even blood cultures have an unacceptably low sensitivity. Therefore, the clinician must accept that a number of neonates will have treatment initiated for sepsis who do not have the disease. In order to treat rapidly all infants with sepsis and to minimize therapy for those without infection, historical, clinical, and laboratory data can be used together in a management approach to achieve optimal results.

Background. Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks’ postmenstrual age, particularly in infants exposed to histologic chorioamnionitis.Methods. Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks’ postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation ≥90%).Results. Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect.Conclusions. Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.

Objective: Treatment of pregnant mothers with a single course of antenatal corticosteroids significantly reduces neonatal mortality and morbidity. Multiple weekly courses are often given. However, the safety and efficacy of repeated courses of antenatal corticosteroids have not been adequately studied. Study Design: A retrospective study was performed for 609 mothers and their 713 infants who were treated with 1 to 12 courses of antenatal corticosteroids. Data for 369 singleton preterm infants born at ≤34 weeks' gestation, 210 multiple gestations, and 134 infants delivered at ≥35 weeks' gestation were analyzed separately. Results: The incidence of respiratory distress syndrome was 45% for single-course and 35% for multiple-course groups ( P = .005; odds ratio, 0.44; 95% confidence interval, 0.25-0.79). The multiple-course group also had significantly less patent ductus arteriosus (20% vs 13%; P = .016). Incidence of death before discharge and other neonatal morbidities were similar. The multiple-course group had a reduction of 0.46 ± 0.19 cm in head circumference at birth ( P = .013) when adjusted for gestational age and preeclampsia. The 2 groups had similar birth weights. Infants born at ≥35 weeks' gestation, multiple-gestation infants, and infants who were born >7 days after the last corticosteroid dose had similar outcomes, regardless of the number of courses they received. Mothers treated with multiple courses compared with a single course had a significantly higher incidence of postpartum endometritis ( P = .013), even though they had a lower incidence of prolonged rupture of membranes (24% vs 33%, P = .06) and similar cesarean delivery rates. Conclusion: Exposure to multiple courses of antenatal corticosteroids compared with a single course resulted in a significant reduction in the incidence of respiratory distress syndrome in singleton preterm infants delivered within a week of the last corticosteroid dose. This was associated with a reduction in birth head circumference and an increased incidence of maternal endometritis. Whether the potential benefits of repeated therapy clearly outweigh the risks will ultimately be determined in randomized prospective controlled trials. (Am J Obstet Gynecol 2000;182:1243-9.)

Perinatally acquired bacterial neonatal sepsis is a low incidence, high risk disease with a relatively benign treatment. Accurate diagnosis is difficult because there is no definitive diagnostic test; even blood cultures have an unacceptably low sensitivity. Therefore, the clinician must accept that a number of neonates who do not have the disease will have treatment initiated for sepsis. In order to treat rapidly all infants with sepsis and to minimize therapy for those without infection, historical, clinical, and laboratory data can be used together in a management approach to achieve optimal results. A systemized approach using history, examination, sepsis screen laboratory tests, and cultures is presented to guide clinical management.

To study the effect of spironolactone on dietary electrolyte supplementation, pulmonary function, and electrolyte balance in premature infants with chronic lung disease.A double-blind, randomized, and placebo-controlled trial was designed to study two groups of low birth weight infants with chronic lung disease at Pennsylvania Hospital. The placebo group received chlorothiazide and a placebo, and the spironolactone group received chlorothiazide and spironolactone during the 2-week study period. A two-tailed t-test was used to determine equivalence between the two groups.Pulmonary compliance, resistance and tidal volume, serum sodium and potassium, and FIO2, were not statistically different between the two groups. The need for sodium and/or potassium chloride did not differ between the two groups, nor did the quantity of each salt.The addition of spironolactone did not reduce the requirement for supplemental electrolytes, nor did it improve pulmonary mechanics or electrolyte balance.

Background. Many extremely low birth weight infants ( Methods. We conducted a randomized, double-masked, placebo-controlled pilot study to test whether early treatment with low-dose hydrocortisone for 12 days (1 mg/kg/day for 9 days followed by .5 mg/kg/day for 3 days), begun before 48 hours of life, would increase the likelihood of survival without CLD. Results. Forty patients were enrolled at two centers. Birth weight and gestation were similar for treatment and placebo groups: 732 ± 135 g versus 770 ± 135 g and 25.2 ± 1.3 weeks versus 25.4 ± 1.5 weeks. More infants treated with hydrocortisone achieved study success, defined as survival without supplemental oxygen at 36 weeks' postconception (12/20 [60%] vs 7/20 [35%]). Lower birth weight, histologic chorioamnionitis, and preeclampsia were significant risk factors, whereas study center, prenatal steroids, sex, and ethnicity were not significant. Hydrocortisone treatment decreased days on >40% oxygen, days on >25% oxygen, days on ventilator, and oxygen at discharge. Among infants exposed to chorioamnionitis, hydrocortisone treatment also was associated with increased enteral intake during the first month of life and with increased weight at 36 weeks' postconception. Five treated infants and 6 placebo infants developed sepsis; 3 in each group died. Conclusions. First, early treatment with low-dose hydrocortisone in this population of extremely low birth weight infants increased the likelihood of survival without CLD. Second, the benefit was particularly apparent in infants with chorioamnionitis. Third, a larger multicenter trial is needed to verify the primary outcome and to better evaluate risks and benefits.

Objective: To investigate secretory leukocyte protease inhibitor (SLPI) concentrations in tracheal lavage fluids of neonates with an endotracheal tube in place during the first month of life, and to evaluate the relationship of SLPI to neutrophil counts and elastase activity in patients in whom bronchopulmonary dysplasia (BPD) developed versus those in whom it did not. Design: A prospective, inception cohort study. Setting: University children's hospital neonatal intensive care unit. Patients: Fifty-three neonates who weighed

The pulmonary outcome for preterm infants 1 year after synthetic surfactant replacement for respiratory distress syndrome was assessed by examining their pulmonary status and the results of pulmonary function tests. A total of 47 infants were followed: 13 infants mean +/- SD: birth weight, 1960 +/- 616 gm; gestation, 32 +/- 1.1 weeks) had been assigned to the placebo group and 34 (birth weight = 1890 +/- 530 gm; gestation = 32 +/- 2.5 weeks) to surfactant treatment. The infants were examined at 3 to 6 months of age (n = 45) and at 9 to 12 months of age (n = 36). There were no significant differences between the two groups in predisposing clinical conditions that would lead to chronic lung disease. The infants had similar patterns of growth, respiratory-related illness, and need for theophylline therapy, diuretic therapy, or both. None had hypoxemia by pulse oximetry. Mean (+/- SEM) values for pulmonary mechanics and energetics in surfactant-treated infants were significantly (p0.01) lower for total pulmonary resistance in late infancy (57.7 +/- 11.7 vs 35.3 +/- 4.6 cm H2O/L per second). Lower values (mean +/- SEM) of resistive work of breathing were also measured in the surfactant-treated group (60.7 +/- 12.0 vs 38.2 +/- 3.6 gm-cm/kg per breath). The dynamic pulmonary compliance values were in the low-normal range for both groups, and the mean (+/- SEM) peak-to-peak esophageal pressure values were elevated (11.47 +/- 2.26 cm H2O in the placebo group; 9.24 +/- 0.69 cm H2O in the surfactant group). Forced expiratory flow measurements in late infancy demonstrated significant (p0.01) improvement in expiratory reserves and reduced evidence of airflow obstruction in the surfactant-treated infants (peak flow (mean +/- SEM): 287.1 +/- 69 vs 396.9 +/- 27 ml/sec; forced expiratory flow (mean +/- SEM) at functional residual capacity: 56.3 +/- 7.5 vs 83.4 +/- 19.5 ml/sec). No significant differences in pulmonary functions were noted in early infancy. These data suggest that surfactant replacement for respiratory distress syndrome may be associated with beneficial long-term effects on the resistive airflow properties of larger preterm infants.

Pulmonary mechanics and energetics were determined in 32 neonates with respiratory distress syndrome, who were randomly assigned to receive treatment with an exogenous synthetic surfactant, Exosurf Neonatal, or air placebo. Pulmonary mechanics were measured before and 2 hours after surfactant (n = 13) or air placebo (n = 19) treatment, then longitudinally at 24, 48, and 72 hours after treatment, and again at 7, 14, and 28 days of age. There were no significant differences in the values for pulmonary mechanics or energetics 2 hours after the first dose of surfactant. Improvement in pulmonary mechanics was apparent 24 hours after surfactant treatment, when dynamic compliance was 36% greater than in the placebo group (p less than 0.03). Lung compliance values were also higher in surfactant-treated infants 48 and 72 hours after treatment, with a maximal increase of 64% at 7 days of age (p less than 0.03). Surfactant treatment also caused a significant decrease in total pulmonary resistance at 48 and 72 hours after initial treatment and at 14 days of age (p less than 0.04). Similarly, a decrease in flow-resistive work of breathing was demonstrated 24, 48, and 72 hours after surfactant treatment. At 28 days of age, pulmonary mechanics were not different in the two groups. We conclude that beneficial effects of surfactant on pulmonary mechanics were not apparent 2 hours after dosing but were evident 24 hours after dosing and persisted for the first 7 to 14 days of life.

Neutrophil elastase activity and the concentration of surfactant proteins A and B (SP-A, B) were measured in tracheal aspirate fluid from preterm neonates who were treated with the synthetic surfactant Exosurf Neonatal or air placebo in randomized, placebo-controlled, clinical trials. Elastase activity was transiently reduced in surfactant-treated infants on the second day of life, but the reduction was not sustained. In placebo-treated infants with established respiratory distress syndrome, tracheal aspirate SP-A was low on the first day of life and increased with time as respiratory distress syndrome resolved. In infants with respiratory distress syndrome treated with surfactant, significantly higher levels of SP-A were observed by 2 days after treatment and were maintained through at least the sixth day of life. These data suggest that lung inflammation is not increased and that endogenous surfactant secretion may be stimulated, not suppressed, by treatment with synthetic surfactant.

Surfactant protein-A (SP-A) was measured in bronchoalveolar lavage (BAL) samples from ventilated neonates in order to study the concentration of SP-A with regard to: 1) high-frequency oscillatory ventilation (HFOV) vs. conventional mechanical ventilation (CMV); 2) the postnatal course and ontogeny of SP-A; and 3) the correlation with measurements of pulmonary function. Patients on HFOV had markedly lower BAL SP-A concentrations on days 1 and 2 compared to those on CMV, which may indicate influence of mode of ventilation on surfactant metabolism. The SP-A concentrations increased postnatally concurrent with resolution of acute respiratory distress syndrome. Finally, there were only weak correlations between BAL SP-A concentration and dynamic lung compliance and oxygen requirement. Pediatr Pulmonal 1990; 9:166–169.

Prophylaxis against Early Adrenal Insufficiency to Prevent Chronic Lung Disease in Premature Infants

Effect of Early Inhaled Glucocorticord Therapy on Tracheobronchial Lesions in Mechanically Ventilated Preterm Infants

Implications of Hypocapnia, Normocapnia, Hypercapnia and the Variance of PaCO2 to Immediate Neonatal Outcome

Impaired Glucocorticoid Synthesis in Preterm Infants Who Develop Chronic Lung Disease (CLD)

Effect of Multiple Courses of Antenatal Steroids as Compared to Single Course on Neonatal Lung Mechanics

Effect of Single Versus Multiple Courses of Antenatal Steroids on Neonatal Outcome of Very Low Birthweight Infants

Dopamine (DA) Induces Selective Increases in Renal Blood Flow (RBF) Velocity in Preterm Neonates Independent of Its Effect on Blood Pressure (BP). † 937

Low total protein (TP) (serum TP

Color flow and pulsed Doppler ultrasonography provides non-invasive estimates of blood flow impedance and has been applied to the evaluation of hemodynamics in newborns. Specctral doppler flow profiles of middle and anterior cerebral arteries of 151 preterm neonates

Although dopamine (DA) increases blood pressure (BP) and urine output in the hypotensive and/or oliguric neonate (Seri I, J Pediatr 126:333, 1995), the regional hemodynamic effects of the drug on organ blood flows have not been studied in the neonate. We compared the vascular responses to DA in the renal(RA), superior mesenteric (SMA), and middle cerebral (MCA) artery, and in the descending aorta (DAo) in 10 non-hypotensive, preterm neonates(GA=26.9±2.8, range=23-31 weeks; BW=1005±399, range 461-1810 g) during the first 2 days of life who presented with RDS and poor peripheral perfusion. Blood flow velocity profile was measured by Acuson XP color and a duplex Doppler unit with a 5.0/7.0 MHz Sector Probe at a close to zero angle. The pulsatility index (Pl = peak systolic velocity - lowest diastolic velocity divided by the mean velocity) was used to assess the drug-induced selective alterations in the renal (RBF), mesenteric (MBF), cerebral (CBF) and DAo(DAoBF) blood flows at a DA dose (2.5-7.5 μg/kg/min) which raised BP by 15 to 20% and improved peripheral perfusion. Table

Oral diuretic therapy is often required by premature infants with chronic lung disease (CLD). Although spironolactone (SP) is frequently used in combination with chlorthiazide (CT), the effects of SP on electrolyte losses, electrolyte supplementation and pulmonary function have not been evaluated. We tested the hypothesis that the addition of SP to CT administration will not improve pulmonary mechanics or minimize the need for dietary electrolyte supplementation. 16 infants received CT + placebo, and 17 infants received CT+ SP in a randomized, double-blind study. Baseline mean measurements in the two groups: BW 859 vs 837 gm, GA 26 vs 26 wks, PCA 32.5 vs 33 wks, lung compliance (CL)(1.15 vs 1.14 ml/cmH2O/kg), total lung resistance(RL) (56.8 vs 52.5 cmH2O/1/sec), FiO2 0.25 vs 0.27 and serum electrolytes were similar (p=ns). Mean data after 14 days of treatment:Table

Elevated serum bilirubin (SB) 10.9 mg/dl was noted in a six hr old, 3969g term infant with severe BO disease (Hct 29%, Hct 40%). Intensive photoRx resulted in only a modest fall in rate of SB rise; Ex appeared inevitable. Hourly BOX feedings (60 Units/kg/d), begun at 22 hrs were associated with decrease stool bile pigments and more rapid than expected fall in SB. No Ex needed. Findings in this infant are presented in comparison to those in the seven other term infants with BO disease Rx at PA H from 1991 to 1995. All needed Ex. Their SB and age at Ex (mean ± SD), were 20.2 mg/dl ± 2.4; 28.6 hs ± 7.3 resp.(See Table).

By inducing developmentally regulated dose-dependent cardiovascular, renal, and endocrine effects, dopamine (DA) increases blood pressure (BP) and urine output in the hypotensive and/or oliguric neonate (Seri I, J Pediatr 126:333-344, 1995). In adults, the drug-induced selective renal and mesenterial vasodilation contributes to the beneficial effects of DA. However, no study has confirmed the presence of these selective vascular dopaminergic effects in neonates.