Early dexamethasone-attempting to prevent chronic lung disease.

BACKGROUND: We previously demonstrated improved survival and early outcomes in a pilot trial of 2 doses of intravenous dexamethasone for infants with surfactant-treated respiratory distress syndrome. (1) A multicenter, randomized, double-blind trial was undertaken to confirm these results. METHODS: Infants <30 weeks' gestation were eligible if they had respiratory distress syndrome, required mechanical ventilation at 12 to 18 hours of age, and had received at least 1 dose of exogenous surfactant. Infants were excluded if sepsis or pneumonia was suspected or if congenital heart disease or chromosomal abnormalities were present. A total of 384 infants were enrolled-189 randomized to dexamethasone (.5mg/kg birth weight at 12-18 hours of age and a second dose 12 hours later) and 195 to an equal volume of saline placebo. RESULTS: No differences were found in the dexamethasone versus placebo groups, respectively, regarding the primary outcomes of survival (79% vs 83%), survival without oxygen at 36 weeks' corrected gestational age (CGA; both 59%), and survival without oxygen at 36 weeks' CGA and without late glucocorticoid therapy (46% vs 44%). No significant differences between the groups in estimates from Kaplan-Meier survival analyses were found for median days on oxygen (50 vs 56 days), ventilation (20 vs 27 days), days to regain birth weight (15.5 vs 14 days), or length of stay (LOS; 88 vs 89 days). Infants given early dexamethasone were less likely to receive later glucocorticoid therapy for bronchopulmonary dysplasia during their hospitalization (27% vs 35%). No clinically significant side effects were noted in the dexamethasone group, although there were transient elevations in blood glucose and blood pressure followed by a return to baseline by study day 10. Among infants who died (40 vs 33), there were no differences in the median days on oxygen, ventilation, nor LOS. However, in survivors (149 vs 162), the following were observed: median days on oxygen 37 versus 45 days, ventilation 14 versus 19 days, and LOS 79 versus 81 days, for the dexamethasone versus placebo groups, respectively. CONCLUSIONS: This dose of early intravenous dexamethasone did not reduce the requirement for oxygen at 36 weeks' CGA and survival was not improved. However, early dexamethasone reduced the use of later prolonged dexamethasone therapy, and among survivors, reduced the median days on oxygen and ventilation. We conclude that this course of early dexamethasone probably represents a near minimum dose for instituting a prophylactic regimen against bronchopulmonary dysplasia.

The effect of a neonatal telecardiology system on respiratory therapy in very low birthweight infants.

Factors in the U.S. healthcare system have shifted the site of care of many newborns to hospitals where subspecialty services are unavailable. This study examines whether a more rapid turn-around of echocardiogram interpretations and availability of interactive video during neonatal consultations reduces the morbidity of very low birthweight (VLBW) infants. The two groups (n = 21 and n = 28) were similar on the basis of known risk factors. A composite index of respiratory therapy intensivity and duration was used to measure the utilization of respiratory therapies. The index was similar in both groups, 89.6 +/- 12.6 before versus 89.5 +/- 13.0 with telemedicine. These results show little evidence of a reduction in RT utilization.

Accuracy and reliability of weight change determinations in a model infant weighing less than 750 grams.

We designed a study to address the accuracy and reliability of the weighing process for tiny infants ( < 750 gm). A model was made with intravenous bags and stockinette and the following equipment was added: umbilical artery and venous catheters, endotracheal tube, pulse oximeter probe, electrodes, and orgastric tube. The models weight was changed in intervals of 2 to 43 gm and it was then weighed on two different types of scales. The measured weight on each scale was compared with the predicted weight (calculated as initial + added mass), and the mean absolute difference (MAD) was determined. All measurements were obtained by the same two nurses. For the bedside scale the MAD was 5 gm (range - 23 to + 10; n = 30). Similar results were obtained with a sling scale; the MAD was 3 gm (range - 13 to + 6 n = 30). The range of differences noted suggests that discrepancies between measurements may lead to a difference between weights that is in the range of 4% to 7% body weight. Interobserver variability was noted to affect the reliability of the weight determinations. When five experienced neonatal intensive care units nurses weighed the model the MAD was 9 gm (-33 to + 22; n = 15) and 6 gm (range - 11 to + 28; n = 15) for the bedside and sling scales, respectively. For the predicted weight, these discrepancies represent potential errors of 7.4% and 5.2%, respectively. These values are likely to underestimate the potential errors seen clinically inasmuch as we could not duplicate infant movement or anxiety of the person weighing the infant. These results should be considered when protocols are developed for weighing extremely small preterm infants.

Effects of dexamethasone and triiodothyronine on oligohydramnios-induced pulmonary hypoplasia.

We observed for differential effects of maternal treatment with dexamethasone, triiodothyronine (T3), or both in late gestation on the growth of fetal rat lungs during oligohydramnios-induced pulmonary hypoplasia (PH). Timed-pregnant mothers were randomly selected into four treatment groups: controls (no hormone treatment); dexamethasone only; T3 only; and both dexamethasone and T3. Each underwent amniocentesis of one uterine horn on day 15 of gestation. Untouched littermate on the opposite horn served as internal control. On days 19 and 20, treated mothers were given dexamethasone (0.2 mg/kg) or T3 (7 mg/kg intramuscularly), or both and were delivered on day 21 (term) by hysterotomy. Amniocentesis resulted in PH, defined as decreased wet lung weight to body weight ratio and lung DNA contents, 83% and 90% of control, respectively (P < 0.05). Body weight and lung weight decreased with hormone treatment for both with and without amniocentesis. Although hormone treatment resulted in smaller lungs, there was no significant difference in lung weight to body weight ratio for either group with or without amniocentesis. This suggests that hormone treatment resulted in proportionate growth retardation. All hormone treatments decreased the total lung DNA content during amniocentesis (P < 0.05). Growth suppression of fetal lung associated with maternal hormone treatment is superimposed on the pulmonary hypoplasia induced by oligohydramnios.

Orogastric tube insertion length in very low birth weight infants.

We determined the minimal insertion lengths for appropriate placement of orogastric tubes in very low birth weight infants (< 1500 gm). Feeding tubes marked in centimeter increments were placed orogastrically by using standard neonatal intensive care unit protocol. When radiographs were taken, the centimeter marking at the lip was recorded, and an investigator blinded to the recorded measurement scored the orogastric tube position on radiograph as high (too short), low (too far), or adequate. Data were collected until measurements were available for at least five separate infants for each 250 gm interval of birth weight < 1500 gm. A total of 188 radiographs in 31 consecutive, appropriately grown, very low birth weight infants were reviewed. Seventeen (9%) could not be interpreted because of radiographic technique or because the tip of the orogastric tube was not visible. Of the 171 radiographs suitable for review, the orogastric tube position was low in 8 (5%), high in 57 (33%), and in adequate position in 106 (62%). When data were stratified according to weight groups, minimum insertion lengths were identified, and provided clear and statistically significant separation for orogastric tubes positioned adequately versus those positioned high. The number of orogastric tubes positioned low was too small to provide meaningful information. This information was then used prospectively to assist in orogastric tube(s) position, with a subsequent increase in the percentage of orogastric tubes positioned adequately to 86%. This study confirms that there are minimum orogastric tube insertion lengths required for adequate intragastric positioning. Paying attention to this information can decrease the number of orogastric tubes that are positioned in the esophagus.

Comprehensive computerized neonatal intensive care unit data system including real-time, computer-generated daily progress notes.

A neonatal intensive care unit patient data system, NeoData, which was developed using microcomputers connected by a local area network, is described. The system allows for real-time generation of daily progress notes, as well as admission and discharge summaries. It includes two databases: one for daily patient data and one for admission/discharge summary data. Both sets of data are easily accessible for later analysis and report generation. The daily patient data are entered directly into a computer by the neonatal intensive care unit medical and nurse practitioner staff; a progress note is printed immediately thereafter for inclusion in the patient's chart. Data from the previous day are selectively carried forward into the current day's note, minimizing data entry. Several benefits are derived from this progress note system, including legibility, tracking of laboratory and other data, tracking of management plans and procedures due at a later date, and significant time savings. The system has proved to be easy to learn, and the neonatal intensive care unit staff have found it to contribute to the efficient delivery of patient care.

Effect of diet-induced sodium deficiency on normal and compensatory growth of the lung in young rats.

Sodium deficiency is associated with decreased muscle growth and protein synthesis. We investigated the influence of diet-induced sodium deficiency on the rate and extent of compensatory growth of the right lung after left pneumonectomy in young rats of 83 +/- 1 g body weight. Starting 1 wk before surgery, all rats were fed a diet deficient only in sodium (2-9 mumol Na+/g of food) ad libitum. Sodium-deficient rats were supplied with distilled water, whereas sodium-replete controls were supplied water containing 37 mM NaCl. After 7 d on the experimental diets, both groups were divided and subjected either to sham thoracotomy (Sham) or to left pneumonectomy (PNX). Somatic growth and both normal and compensatory growth of the lungs were assessed 3, 4, and 7 d later. Sodium-deficient animals grew more slowly than control animals. In control PNX rats, right lung weight to body weight ratio (LW/BW) increased to equal that of the combined LW/BW in control Shams by postoperative d 4, and remained at the Sham combined LW/BW value on postoperative d 7. Compensatory lung growth was less rapid in sodium-deficient PNX animals. At postoperative d 4, right LW/BW was low relative to combined LW/BW of sodium-deficient Shams. This ratio approached but did not reach the sodium-deficient Sham combined LW/BW value by d 7. Sodium deficiency thus reduced the rate of compensatory growth of the right lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Gamma-carboxyglutamic acid excretion into rat amniotic fluid during late gestation.

The amino acid gamma-carboxyglutamate is the product of post-translational vitamin K-dependent carboxylation of peptide bound glutamic acid residues. Activity of the microsomal vitamin K-dependent carboxylase which catalyzes gamma-carboxyglutamate formation has been studied in numerous tissues, including liver and lung. Catabolism of gamma-carboxyglutamate containing proteins leads to gamma-carboxyglutamate excretion into the urine, thus quantitation of urinary gamma-carboxyglutamate can be used to assess vitamin K status, as well as the turnover of gamma-carboxyglutamate containing proteins. Since fetal urine is a major component of amniotic fluid, samples were obtained during late gestation in the rat (days 18-20) and analyzed for gamma-carboxyglutamate by reversed phase liquid chromatography to better define gestational changes in fetal vitamin K-dependent carboxylation. Relative to gestational age 18 days, amniotic fluid gamma-carboxyglutamate concentrations increased by 25% at 19 days (P less than 0.02) and by 105% at 20 days (P less than 0.001). When expressed per unit creatinine to correct for change in body mass and/or amniotic fluid volume, these differences are 15% (NS) at 19 days and 70% (P less than 0.02) at 20 days. These increases are prevented by maternal treatment with sodium warfarin. Amniotic fluid gamma-carboxyglutamate concentrations are 7-12 times greater than those in adult rat urine. During the same developmental interval (18-20 days), both lung and liver carboxylase activities increase by more than two-fold. These studies suggest that gestational age associated increases in carboxylase activity measured in vitro are associated with increased turnover of gamma-carboxyglutamate containing proteins in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Bladder distention as a cause of inferior vena caval obstruction in the newborn: demonstration with ultrasonography.

We report an unusual case of inferior vena caval (IVC) obstruction secondary to a tensely distended urinary bladder in an asphyxiated newborn. The use of portable real-time ultrasonography gave a reliable diagnosis of the correct etiology and ruled out more ominous possibilities, such as IVC thrombosis. This case presentation provides an interesting addition to the differential diagnosis of IVC obstruction, and once again emphasizes the valuable role of bedside ultrasonography in the neonatal intensive care unit.

Vitamin K-dependent carboxylase activity in fetal rat lung: developmental effects of dexamethasone and triiodothyronine.

Dexamethasone (Dex) and triiodothyronine (T3) were administered to pregnant rats during late gestation to evaluate potential developmental effects on fetal lung vitamin K-dependent carboxylation. Maternal rats were injected on the 2 d before study with Dex (0.2 mg/kg intraperitoneally), with T3 (0.7, 3.5, or 7 mg/kg intramuscularly), or with a combination of both hormones. Fetal lung microsomes were prepared at 18, 19, and 20 d of gestation, and carboxylase activity was assessed by measuring the incorporation of 14CO2 into a synthetic pentapeptide substrate. Dex alone resulted in a small but consistent increase in activity in all three gestational ages. T3 alone increased activity approximately 85% at 20 d of gestation. Treatment with a combination of Dex and T3 caused a 60% increase in vitamin K-dependent carboxylation at each gestational age. Decreased lung growth was noted with combination hormone treatment in all rats studied at 19 and 20 d of gestation. Lung growth expressed as lung wt/body wt was more sensitive to the effects of Dex plus T3 than was carboxylase activity. Decreased lung wt/body wt (decreased 25%) was noted with Dex plus T3 (0.7 mg/kg); however, no induction of carboxylase enzyme activity was evident at this dose. This study demonstrates that vitamin K-dependent carboxylase activity in fetal rat lung can be induced by the exogenous administration of Dex and T3 to pregnant rats. Fetal lung microsomes contain multiple endogenous substrates for the vitamin K-dependent carboxylase enzyme. These hormones play a significant developmental role not only in protein biosynthesis, but in posttranslational processing as well.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin K-dependent carboxylation of pulmonary surfactant-associated proteins.

Rat type II pneumocytes expressed vitamin K-dependent carboxylase activity that incorporated 14CO2 into microsomal protein precursors of molecular weights similar to those of surfactant-associated proteins (SAP). Compared to carboxylated precursor proteins present in the liver, these molecules appeared to be unique to the lung. Antibodies raised against purified rat surfactant reacted with SAP resolved by NaDodSO4/PAGE and with surfactant-containing lamellar bodies in type II pneumocyte cytoplasm. NaDodSO4/PAGE of microsomal proteins, after carboxylase-catalyzed incorporation of 14CO2, demonstrated radiolabeled, immunoreactive products identical to SAP. The presence of gamma-carboxyglutamic acid in these proteins was confirmed by HPLC analysis of SAP hydrolysates. Furthermore, lung carboxylase activity and SAP matured over similar time courses during fetal lung development. These results show that SAP are carboxylated by type II cells via a vitamin K-dependent pathway analogous to that for hepatic carboxylation of clotting factors. Further analogy to the clotting system suggests that gamma-carboxyglutamic acid residues in SAP polypeptides play a role in Ca2+ binding and thus in the known requirements for both the cation and SAP in the physiological function of pulmonary surfactant.

Risk factors for microwave scald injuries in infants.

An infant sustained second- and third-degree scald burns of the oropharynx from drinking formula heated in a microwave oven. The circumstances leading to the scald injuries were recreated. Factors contributing to the injury included the volume of formula, the initial temperature of the formula, and the temperature gradient between the liquid core and the bottle surface after microwave heating. These studies indicate that infant formula should be warmed only with extreme care in microwave ovens and should be tested for suitability of temperature prior to feeding.

Tolazoline pharmacokinetics in lambs.

Tolazoline has often been administered experimentally to lambs without consideration of its pharmacokinetics. We have used a chemically specific assay to determine tolazoline pharmacokinetic parameters in lambs after pulse and infusion doses: alpha = 0.184 +/- 0.046 (min-1), beta = 0.010 (pulse) and 0.0098 (infusion) +/- 0.0010 (min-1), Vdarea = 2534 +/- 688 ml/kg (pulse), and Vdss = 2890 +/- 342 ml/kg (infusion). The following doses can be used to reach steady-state plasma tolazoline concentrations: loading dose (microgram/kg) = 2890 X desired concentration (microgram/ml); infusion rate (microgram/kg X min) = 2890 (.010) X desired concentration (microgram/ml). These doses were used to produce 68 steady-state concentrations from 0.25 to 10.0 micrograms/ml. Clearances at steady state averaged 166 ml/min or 27.1 ml/min X kg at 2-17 days but increased markedly by 4 weeks of age. Using these doses, tolazoline-receptor interactions can be studied at constant plasma concentrations that approximate constant receptor concentrations.