Functional and antigenic concentrations of alpha-1-proteinase inhibitor after administration for the prevention of chronic lung disease of prematurity.

OBJECTIVE AND METHODS: Alpha-1-proteinase inhibitor (A1PI) supplementation has been used in adults with inherited alpha-1-antitrypsin (A1AT) deficiency to impede the development of emphysema. A1PI supplementation may also be useful for protecting premature neonates who receive mechanical ventilation from the development of chronic lung disease (CLD). However, the pharmacokinetics of exogenous A1PI in this population are unknown. We attempted to determine the disposition of A1PI in premature infants with birth weight 600-1,250 g who received 60 mg/kg on days 0, 4, 7 and 14 in a randomized, placebo-controlled, double-blind trial. Functional and antigenic plasma concentrations of A1PI were measured at specified time points. RESULTS: On both functional and antigenic assays, concentrations began in the normal adult range and rose from day 0 to 10 then fell slightly, but remained above initial values. The concentrations were not significantly different between the treatment and placebo groups. CONCLUSIONS: The results of this study indicate that neonatal pharmacokinetics of A1PI differ markedly from those of the adult. Total plasma clearance of exogenous A1PI seems high in the ventilated premature neonate. Higher or more frequent doses may be necessary to maintain A1PI plasma concentrations above baseline.

A comparison of underwater bubble continuous positive airway pressure with ventilator-derived continuous positive airway pressure in premature neonates ready for extubation.

OBJECTIVE AND METHODS: As the result of vigorous bubbling, infants receiving continuous positive airway pressure (CPAP) by an underwater seal (bubble CPAP) were observed to have vibrations of their chests at frequencies similar to high-frequency ventilation (HFV). We performed a randomized crossover study in 10 premature infants ready for extubation to test whether bubble CPAP contributes to gas exchange compared to conventional ventilator-derived CPAP. Measurements of tidal volume and minute volume were made using the Bear Cub neonatal volume monitor, and gas exchange was measured using an oxygen saturation monitor and a transcutaneous carbon dioxide (tcpCO2) monitor. RESULTS: There was a 39% reduction in minute volume (p < 0.001) and a 7% reduction in respiratory rate (p = 0.004) with no change in tcpCO2 or O2 saturation for infants supported with bubble versus ventilator-derived CPAP. CONCLUSIONS: The lack of difference in blood gas parameters associated with a decrease in the infant's minute volume and respiratory rate with bubble CPAP compared with ventilator-derived CPAP suggests that the chest vibrations produced with bubble CPAP may have contributed to gas exchange. Bubble CPAP may offer an effective and inexpensive option for providing respiratory support to premature infants.

alpha1-Proteinase inhibitor therapy for the prevention of chronic lung disease of prematurity: a randomized, controlled trial.

BACKGROUND: An imbalance between increased neutrophil elastase and a decreased antiprotease shield has been suggested as a factor contributing to the development of chronic lung disease (CLD). We hypothesized that administration of alpha1-proteinase inhibitor (A1PI), also known as alpha1-antitrypsin, to premature neonates would prevent CLD. DESIGN: A randomized, placebo-controlled, prospective study of A1PI supplementation was performed. Neonates <24 hours of age with birth weights 600-1000 g on respiratory support, and 1001-1250 g with respiratory distress syndrome (RDS) were eligible. Intravenous A1PI (60 mg/kg) or placebo was infused on days 0, 4, 7, and 14. Primary outcome was CLD in survivors, defined as the need for supplemental oxygen on day 28. RESULTS: A total of 106 patients were recruited. There were no significant differences between groups in birth weight or incidence of RDS. The incidence of CLD in survivors was lower in the treated group, but the difference did not reach statistical significance (relative risk [RR], 0.79; confidence interval [CI], 0.60-1.02). This beneficial trend persisted at 36 weeks corrected gestational age (RR, 0.48; CI, 0.23-1.00). The incidence of pulmonary hemorrhage was lower in the treated group (RR, 0.22; CI, 0.05-0.98). Other complications were not significantly different between groups. CONCLUSIONS: In this, the first trial of a protease inhibitor for the prevention of CLD in premature infants, the infusions were well-tolerated. A1PI therapy may impede the development of CLD and appears to reduce the incidence of pulmonary hemorrhage in some neonates born prematurely.

Safety of lidocaine-prilocaine cream in the treatment of preterm neonates.

The safety of lidocaine-prilocaine cream (EMLA) was evaluated in an open trial in 30 preterm neonates (mean gestational age, 32.8 weeks; birth weight, 1911 gm); 0.5 gm was applied to the heel for 1 hour. Mean baseline and follow-up (4, 8, or 12 hours after EMLA application) methemoglobin levels were not different, ranging from 1.15% to 1.45%, and from 1.13% to 1.49%, respectively.

Extreme immaturity: outcome of 568 pregnancies of 23-26 weeks' gestation.

OBJECTIVE: To provide guidelines to the perinatologist regarding extremely premature infants based on the experience of the University of Toronto Newborn Service (two high-risk perinatal units and one outborn neonatal intensive care unit), with a catchment area of 60,000 deliveries annually. METHODS: The study included all births or admissions in the Newborn Service from January 1, 1982 to June 30, 1987 with gestational age determined by the best obstetric estimate of gestational age, ranging from 23-26 completed weeks. The obstetric records were reviewed and the surviving infants followed prospectively for a minimum of 2 years after delivery. RESULTS: Analysis of the neonatal and 2-year follow-up data on 568 infants born between 23-26 weeks' gestation revealed a 39% mortality rate, which increased with decreasing gestation. The highest mortality rates occurred following complicated pregnancies, including fetal growth restriction. Intact survival increased with increasing gestational age, from 11% at 23 weeks to 50% at 26 weeks. There was a marked improvement in both mortality and morbidity by 25 completed weeks. CONCLUSIONS: The results suggest that an aggressive approach before 24 completed weeks' gestation is not warranted. From a total of 60,000 live births per year, only one child born at 23 weeks' gestation and three at 24 weeks were free of major handicap at 2 years.

Randomized controlled trial of dexamethasone treatment in very-low-birth-weight infants with ventilator-dependent chronic lung disease.

This randomized controlled trial was designed to answer the question: does administration of dexamethasone to neonates with bronchopulmonary dysplasia decrease the need for assisted ventilation? Twenty-five infants with a birth weight < 1501 g, requiring mechanical ventilation and FiO2 of > or = 0.30 at 21-35 days of age, were randomized to treatment with iv dexamethasone or to sham injections for 12 days. The primary outcome criterion was extubation within seven days after study entry. Treatment (n = 12) and control (n = 13) groups were well matched at entry. Dexamethasone facilitated weaning from assisted ventilation (p = 0.0154). There was no increased incidence of infection. Dexamethasone treatment resulted in a significant increase in glucosuria (p = 0.0002) and in systolic blood pressure (p = 0.0034). There was a significant decrease in heart rate (p = 0.0001) and a significant weight loss (p = 0.0002) following dexamethasone treatment. Dexamethasone treatment facilitated weaning from assisted ventilation but several systemic effects were noted that deserve further evaluation before dexamethasone becomes routine treatment.

Bovine surfactant replacement therapy in neonates of less than 30 weeks' gestation: a randomized controlled trial of prophylaxis versus treatment.

The influence of the timing of surfactant replacement therapy for the treatment of neonatal respiratory distress syndrome was evaluated in a study of 182 neonates of less than 30 weeks' gestation who were randomly assigned prior to delivery to one of three study groups: control (dummy instillation of air given at birth), early surfactant (surfactant given at birth), or late surfactant (surfactant given at less than 6 hours of age). Subjects in the late surfactant group could avoid treatment if they had a clear chest roentgenogram and required no supplemental oxygen at a mean airway pressure of less than 7 cm of water. All treated neonates were eligible to receive up to three additional doses during the first 5 days of life. The three groups were comparable with respect to birth weight, gestational age, and other perinatal parameters with the exception of a lower cord arterial pH and 1-minute Apgar score in the early surfactant group. Of the 60 neonates randomly assigned to late treatment, 29 (48%) were deemed surfactant sufficient and thereby avoided treatment; the other 31 received their first dose at a mean age of 2.9 hours. There was a significant improvement in gas exchange during the first week of life in both surfactant groups compared with the control group, reflected by differences in fraction of inspired oxygen, arterial/alveolar PO2, and ventilation index (peak pressure x rate on the ventilator) (P less than .001). Surfactant therapy also resulted in a lower incidence of pulmonary air leak and severe chronic lung disease (defined as requirement for respiratory support beyond 36 weeks post-conceptional age). There were no differences between early and late surfactant groups in any of these parameters. The only statistically significant difference between the surfactant groups was that the early group had a higher incidence of mild chronic lung disease (respiratory support beyond 28 days of age) than the late treatment group (P less than .005). Neonates in the late treatment group were extubated earlier and had a shorter neonatal intensive care unit stay than control neonates (P less than .05), whereas those in the early group were not significantly different from control neonates in these parameters. It is concluded that replacement therapy with bovine lung surfactant extract in neonates of less than 30 weeks' gestation results in decreased oxygen and ventilatory requirements during the first week of life and a lower incidence of pulmonary air leak and severe chronic lung disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Cerebral-blood-flow-velocity measurements in neonates: technique and interobserver reliability.

The interobserver reliability for absolute cerebral-blood-flow-velocity measurements by colour and duplex Doppler sonography was tested in 32 neonates with a mean birth weight of 1489 (SD 644) g, and a gestational age of 29.9 (SD 3.5) weeks. Using standardized technique, two observers recorded on videotape, the Doppler spectrum of the anterior cerebral artery, the intracranial internal carotid artery and the middle cerebral artery. Peak systolic flow, end diastolic flow, mean flow velocity, resistive index and pulsatility index were computed from 3 consecutive waveforms by each observer. The estimates of interobserver reliability using the intraclass correlation coefficient of the examiners varied from 0.95 to 1.00. Therefore, cerebral blood flow velocity can be reliably measured in premature infants.

Single- versus multiple-dose surfactant replacement therapy in neonates of 30 to 36 weeks' gestation with respiratory distress syndrome.

To assess the efficacy of a multiple-dose protocol of surfactant replacement therapy in neonates of 30 to 36 weeks' gestation, 75 neonates were randomly assigned to control, single-dose surfactant, or multiple-dose surfactant groups. Neonates at less than 6 hours of age with a diagnosis of respiratory distress syndrome were eligible. Subjects were randomly assigned to receive either 100 mg/kg of bovine surfactant or air placebo. Neonates in the multiple-dose group were eligible to receive up to three additional doses as indicated. Neonates in both surfactant groups showed a positive response to treatment, with marked improvement in oxygenation by 10 minutes postinstillation (P less than .0001). Both surfactant groups had better oxygenation than control subjects at lower ventilatory parameters over the first 24 hours. A deterioration in oxygenation and ventilatory requirements was seen in both treatment groups starting 6 to 12 hours after the first dose. The deterioration in oxygenation could be minimized by the use of multiple doses; however, extra doses had no effect on diminishing ventilatory requirements or time to extubation. It is concluded that surfactant therapy at less than 6 hours of age is effective in acutely reducing oxygen and ventilatory requirements in neonates of 30 to 36 weeks' gestation with respiratory distress syndrome. It appears that multiple doses of surfactant have a greater effect on sustaining improvements in oxygenation than on ventilatory requirements. Further study is required to determine optimal dosage and retreatment strategy.

The outcome of triplet, quadruplet, and quintuplet pregnancies managed in a perinatal unit: obstetric, neonatal, and follow-up data.

Multifetal gestation is associated with increased frequency of maternal complications and higher perinatal morbidity and mortality. The need for contemporary data on the outcome of multifetal gestations is further underscored when selective reduction is considered. The present study details the obstetric management, neonatal outcome, and follow-up data of 24 triplet, five quadruplet, and one quintuplet pregnancies delivered in a perinatal center. The early neonatal mortality rate was 31.6, the late neonatal mortality rate was 21, and the perinatal mortality rate was 51.5. Survival to discharge was 93%. The incidence of respiratory distress syndrome was 43%, bronchopulmonary dysplasia 6%, retinopathy of prematurity 3%, intraventricular hemorrhage 4%, and cerebral palsy 2%. Follow-up from 1 to 10 years shows that only one child is moderately handicapped, whereas 99% have no significant medical problem. Early diagnosis by ultrasonography, meticulous antenatal care, early hospitalization, delivery by cesarean section, and on-site availability of a neonatologist for each baby at the time of delivery are the probable major determinants of improved outcome.

Two-year follow-up of infants enrolled in a randomized trial of surfactant replacement therapy for prevention of neonatal respiratory distress syndrome.

A randomized clinical trial of the use of bovine surfactant for the prevention of neonatal respiratory distress syndrome was completed at our Institution in 1984 (Pediatrics 1985;76:145-153). All infants entering the trial were enrolled in our follow-up clinic and seen at regular intervals for assessment of growth and development, neurologic and sensory status, and incidence of respiratory disease and allergic conditions. Infants have now been followed-up for at least 2 years. Of those infants for whom follow-up is complete, two of 32 (6.3%) surfactant-treated infants died, five (15.6%) had major neuro-developmental handicaps, and five had minor neurodevelopmental handicaps. In the control group, eight of 33 (24%) infants died, whereas only two (6.1%) survived with major neurodevelopmental handicaps, and four (12.1%) were left with minor handicaps. Except for an increased neonatal death rate in the control group, other differences were not statistically significant. The groups were also comparable in terms of the incidence of late respiratory or allergic disease as assessed by history. Treatment with bovine surfactant at birth of premature infants at high risk for respiratory distress syndrome appears to be safe and of short-term benefit, although no decrease in neurodevelopmental handicap at 2 years' follow-up can be demonstrated.

Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period.

The follow-up records of 605 infants with birth weights of less than 1,500 g, with data available for 2 years after birth, were examined for evidence of abnormal pulmonary signs or symptoms. A total of 119 infants were identified and the neonatal oxygen requirements of these infants were compared with those of 486 infants who had normal pulmonary function. A requirement for oxygen at 28 days of life had a positive predictive value for abnormal pulmonary findings at the time of follow-up of only 38%, whereas 31% of those with normal pulmonary findings at the time of follow-up were still receiving oxygen at this age. The need for oxygen at 28 days was a good predictor of abnormal findings in infants of greater than or equal to 30 weeks' gestational age at birth but became increasingly less useful as gestational age decreased. It was found that, irrespective of gestational age at birth, the requirement for additional oxygen at 36 weeks' corrected postnatal gestational age was a better predictor of abnormal outcome, increasing the positive predictive value to 63%. The prediction of a normal outcome remained 90% for infants not receiving oxygen at this corrected gestational age.

Serial measurements of cerebral blood flow velocity in preterm infants during the first 72 hours of life.

Serial measurements of cerebral blood flow velocity (CBFV) were made in 29 preterm infants, using continuous wave Doppler ultrasound. CBFV was measured in both anterior cerebral arteries and quantitative measurements of CBFV were determined using the area under the velocity curve. In all ventilated infants, CBFV increased significantly during the first 6 hours of life and continued to increase until 16 hours of age. Thereafter, CBFV remained relatively constant. This increase in CBFV was primarily the result of increased diastolic flow. Three infants who had evidence of intraventricular haemorrhage on cranial ultrasound, had similar CBFV compared with the infants with no evidence of haemorrhage. Two infants died and both demonstrated areas of periventricular leukomalacia at autopsy. These infants had a prolonged period of low CBFV. These measurements provide normal data for ventilated, preterm infants. As previously suggested in term infants, the initial rise in CBFV may be secondary to closure of the ductus although a generalized decrease in peripheral vascular resistance could also be a contributing factor. Fluctuations in CBFV rather than individual readings are probably more important in the genesis of IVH. An episode of significantly reduced CBFV is a poor prognostic sign.

Review of causes of perinatal mortality in a regional perinatal center, 1980 to 1984.

During 1980 to 1984, 279 deaths occurred among 15,306 births in a regional perinatal unit. Survival to discharge corrected for lethal malformations was 81% or better in infants with a birth weight above 749 gm. Congenital malformations (23.2%), infections (21.3%), asphyxia (19.8%), and hyaline membrane disease (11%) caused most perinatal deaths.

Fetal heart rate monitoring and neonatal mortality in the very preterm infant.

A retrospective study was performed to determine the usefulness of intrapartum fetal heart rate patterns in managing infants of 26 to 30 weeks' gestational age by a comparison of intrapartum tracings with neonatal outcome. Fetal heart rate patterns of 26 infants who died were matched for gestational age with those of infants who did not die or demonstrate developmental abnormalities after a 1-year follow-up were analyzed. A normal fetal heart rate pattern was associated with a good outcome (p less than 0.05), the only deaths (three) being secondary to unrelated factors. An abnormal fetal heart rate tracing predicted 90% of deaths; however, an abnormal fetal heart rate tracing was also found in 15 of 31 infants with no mortality or morbidity. Evidence would thus suggest that the very preterm infant can tolerate the stress associated with normal labor and that a normal fetal heart rate pattern predicts good fetal outcome in the absence of unrelated perinatal abnormality. With significantly abnormal patterns, however, further parameters must be evaluated before the diagnosis of fetal distress associated with subsequent mortality can be made with certainty.

Perinatal factors associated with death or handicap in very preterm infants.

That death or major developmental handicap is associated with prematurity and low birth weight is well recognized. The importance of other perinatal factors related to presentation and management, however, is far from certain. In an attempt to elucidate the importance of some of these factors, data from 383 live-born infants delivered at 26 to 30 weeks' gestation were analyzed. All infants were born in a tertiary perinatal unit and long-term follow-up had been carried out on the survivors for at least 1 year. A group of 39 infants who died in the neonatal period and 34 infants with long-term handicap were compared with matched normal control infants. Perinatal factors related to outcome were analyzed and it was found that, while initial poor condition at birth was correlated with death, there were few predictors of subsequent handicap. More refined methods of both prenatal and neonatal assessment are required to define these factors.

Management of the extremely low birthweight infant.

Current perinatal management of the infant less than 1000 grams is outlined with a review of the common problems encountered by this group of infants. The problem of drug dosage with currently available pharmacological preparations is outlined.

Perinatal intensive care: where and how to draw the line.

With the rapid advances in perinatal intensive care and resultant changes in neonatal prognosis, it is often difficult for the medical personnel involved to know where application of such care is justified, whether major intervention for fetal reasons is warranted, or what information to give parents as to probable outcome. To aid in developing guidelines for these areas of concerns, 730 consecutive live births that occurred in a perinatal unit between 23 and 32 weeks' gestation were analyzed for mortality and long-term morbidity by gestational age at birth. Probability of a normal outcome varies considerably according to which method of analyzing outcome is used. With a greater than 50% probability of intact survival from 25 weeks' gestation and above, intervention for fetal reasons seems to be justified if indicated on purely medical grounds, although prolonged use of restricted resources at or below 25 weeks remains a concern.