Safety and efficacy of high-frequency jet ventilation in neonatal transport.

OBJECTIVE: To evaluate the safety and efficacy of high-frequency jet ventilation for transporting critically ill hypoxic neonates to an extracorporeal membrane oxygenation (ECMO) center. STUDY DESIGN: We conducted a retrospective cohort study of 38 transported neonates. Safety was assessed by the comparison of cardiopulmonary variables before and after transport from referring hospital to our ECMO unit. Efficacy was assessed as the effect on ventilation and efficiency of pulmonary gas exchange after conversion from a conventional mechanical ventilator or a high-frequency oscillator to a high-frequency jet ventilator+/-inhaled nitric oxide. RESULT: The pre- and post transport vital signs remained stable, regardless of the type of ventilator used. Pre-transport pneumothorax was the main problem, but no transport-related deaths occurred. We found significant improvement in the ventilation of the neonates transported with a high frequency jet ventilation+/-inhaled nitric oxide that were deficient in those transported with conventional mechanical ventilation+inhaled nitric oxide (P<0.05). The improvement started before transport upon changing the mode of ventilation to a high-frequency jet ventilator. CONCLUSION: Independent of the use of inhaled nitric oxide, high frequency jet ventilation appears to provide better ventilation than conventional mechanical ventilation and is safe to transport pre-ECMO neonates.

Comparison of Infasurf (calf lung surfactant extract) to Survanta (Beractant) in the treatment and prevention of respiratory distress syndrome.

OBJECTIVE: To compare the relative safety and efficacy of Infasurf (calf lung surfactant extract; ONY, Inc, Amherst, NY, IND #27169) versus Survanta (Beractant, Ross Laboratories, Columbus, OH) in reducing the acute severity of respiratory distress syndrome (RDS) when given at birth and to infants with established RDS. DESIGN: A prospective, randomized, double-blind, multicenter clinical trial. SETTING: Thirteen neonatal intensive care units participated in the treatment arm: seven of these concurrently participated in the prevention arm. PATIENTS: The treatment arm enrolled infants of

A selective aggressive approach to the neonate exposed to meconium-stained amniotic fluid.

OBJECTIVE: We attempted to determine the effect on meconium aspiration syndrome from a selective approach of neonatal endotracheal intubation in meconium-exposed fetuses. STUDY DESIGN: All pregnancies delivered at the Medical College of Virginia in 1990 were included. Meconium was noted at membrane rupture and qualified as thick, moderate, or thin. Neonates underwent suctioning with a DeLee device at delivery. They were observed without endotracheal intubation if they fulfilled the following criteria: vaginal delivery, gestational age > 37 weeks, birth weight > 2500 gm, and anticipated Apgar score > or = 8 at 1 minute. RESULTS: Of 4289 deliveries, 659 were exposed to meconium and 48% of infants were intubated. Birth weights, gestational ages at delivery, and umbilical arterial pH were similar between intubated and nonintubated neonates. Neonatal intensive care unit admissions were significantly higher in intubated neonates. All 9 neonates diagnosed with meconium aspiration syndrome were intubated at birth. CONCLUSIONS: Utilization of this protocol resulted in reduction of neonatal intubation. Meconium aspiration syndrome did not occur in the nonintubated group.

Decreased carbon dioxide sensitivity in infants of substance-abusing mothers.

OBJECTIVE: To determine whether there is a demonstrable abnormality in control of breathing in infants of substance-abusing mothers during the first few days of life. METHODS: We enrolled 12 drug-free control infants and 12 infants of substance abusing mothers (ISAMs). These infants experienced otherwise uncomplicated term pregnancies and deliveries. The infants were assigned to a group based on the results of maternal histories and maternal and infant urine toxicology screens. Studies were performed during quiet sleep during the first few days of life. We measured heart rate, oxygen saturations via a pulse oximeter, end-tidal carbon dioxide (ET-CO2) level, respiratory rate, tidal volume, and airflow. The chemoreceptor response was assessed by measuring minute ventilation and the ET-CO2 level after 5 minutes of breathing either room air or 4% carbon dioxide. RESULTS: The gestational ages by obstetrical dating and examination of the infants were not different, although birth weights and birth lengths were lower in the group of ISAMs. Other demographic data were not different, and there were no differences in the infants' median ages at the time of study or in maternal use of tobacco and alcohol. The two groups had comparable baseline (room air) ET-CO2 levels, respiratory rates, tidal volumes, and minute ventilation. When compared with the group of ISAMs, the drug-free group had markedly increased tidal volume and minute ventilation on exposure to 4% carbon dioxide. These increases accounted for the difference in sensitivity to carbon dioxide, calculated as the change in minute ventilation per unit change in ET-CO2 (milliliters per kg/min per mm Hg). The sensitivity to carbon dioxide of control infants was 48.66 +/- 7.14 (mean +/- SE), whereas that of ISAMs was 16.28 +/- 3.14. CONCLUSIONS: These data suggest that ISAMs are relatively insensitive to challenge by carbon dioxide during the first few days of life. We speculate that this reflects an impairment of the chemoreceptor response.

Improved oxygenation with exogenous surfactant administration in experimental meconium aspiration syndrome.

Fifteen adult New Zealand white rabbits were used to determine if exogenous surfactant immediately improves oxygenation in experimental meconium aspiration syndrome (MAS). They were ventilated with 100% O2 before insufflating 3 mL/kg of 40% filtered meconium. Arterial blood gases, dynamic lung compliance (CLdyn) and resistance (RL) were monitored for 2 hours before and 1 hour after the intratracheal administration of calf lung surfactant extract or air placebo. The arterial/alveolar O2 tension ratio [P (a/A)O2] increased 133% within 1 hour of surfactant therapy but CLdyn did not change. The increase of RL was comparable in the surfactant and control groups after meconium instillation. A further increase of 44% in RL occurred after surfactant administration with no change in the controls. Qualitative histologic analysis confirmed the presence of alveolar meconium as well as inflammation and atelectasis. Persistently elevated RL suggested airway obstruction in both groups throughout the study. Most likely no increase in CLdyn occurred with surfactant administration or it could not be detected because it was measured only with ventilator-induced breaths and ventilator settings were held constant. In the face of airway obstruction CLdyn is an inadequate reflection of pulmonary elasticity. We conclude that exogenous surfactant therapy improves oxygenation in this model of MAS. Further studies are needed to understand the mechanism of this improvement.

Intravenous infusion of lipid for the prevention of essential fatty acid deficiency in premature infants.

This study was designed to determine the amount of linoleic acid required to prevent essential fatty acid deficiency in premature infants. This was achieved by infusing 1 g intravenous lipid.kg-1.d-1 over 18-20 h beginning on day 2 and increasing by 0.5 g.kg-1.d-1 to a maximum of 3 g.kg-1.d-1. The actual mean amounts of linoleic acid administered (mg/kg) were 613 on day 2, 767 on days 3 and 4, 862 on day 5, and 1062 on day 6. None of the neonates managed in this fashion showed a high triene-tetraene ratio on days 3 or 7 (in contrast to control subjects, 80% whom were abnormal). Plasma triglycerides and nonesterified fatty acids (NEFAs) increased during the infusions but not to concentrations indicative of fat intolerance. The rise in NEFAs was associated with evidence of bilirubin displacement from circulating albumin but this occurred to only a modest degree.

Evaluation of a system for the delivery of inhaled beclomethasone dipropionate to intubated neonates.

Since systemic dexamethasone therapy for bronchopulmonary dysplasia is associated with numerous side effects, a simple system to deliver aerosolized beclomethasone dipropionate (BDP) directly to the lungs of intubated neonates was developed and evaluated in vitro. The system consists of a self-inflating bag, metered dose inhaler (MDI) adapter, Tygon spacer and endotracheal tube (ETT). A dose is delivered by discharging the MDI into the system and giving 3 'breaths' with the bag. Different sizes of ETT do not affect the drug output (1.17 +/- 0.29 vs. 1.32 +/- 0.34 micrograms of BDP per dose using a 3.0-mm or 3.5-mm ETT, respectively; means +/- SD). However, a shorter system spacer substantially reduces the drug output. The majority (54.0%) of the particles exiting the ETT and available to the patient are in the respirable range (0.5-5.5 microns). Based on adult doses and delivery of BDP and the relative sizes of the adult and neonatal lung, it is estimated that a neonate will require 1-6 doses/day. Replacing dexamethasone in the treatment of bronchopulmonary dysplasia with aerosol topical steroids delivered by this system may improve both the safety and efficacy.

Essential fatty acid deficiency in premature infants.

To better characterize essential fatty acid (EFA) deficiency in neonates, we assessed 63 premature infants by serial determinations of plasma fatty acids for the level of linoleic acid, the presence of an abnormal trienoic acid (5,8,11-eicosatrienoic acid [20:3 omega 9]), and the ratio of this compound to arachidonic acid, ie, the triene-tetraene ratio. The data indicated that at age 7 d, 67% of these infants had low plasma linoleic acid levels, 62% showed readily detectable 20:3 omega 9, and 44% had a high triene-tetraene ratio. Infants fed by age 2 d had a normal mean linoleate level at 7 d and none showed detectable 20:3 omega 9 by 10 d. In contrast, infants who were not fed until 7 d showed a very high incidence of abnormal fatty acid status. By maintaining a daily record of linoleate intake, we calculated from regression models that the average amount required to achieve normal fatty acid nutrition was 1.19 g.kg-1.d-1.

Zinc supplementation and plasma concentration of vitamin A in preterm infants.

To assess the effect of zinc supplementation on plasma retinol levels, 24 preterm infants were randomly assigned to receive 400 micrograms.kg-1.d-1 of intravenous Zn or no Zn supplementation. Intakes of protein, energy, and vitamin A were similar for both groups as were day 0 plasma concentrations of retinol, retinol-binding protein (RBP), and Zn. Zn concentrations were not significantly different between groups at any time during the 3-wk study; however, retinol values in wk 1 increased more in the supplemented group (delta = 10.0 vs 0.9 micrograms/dL, or 0.35 vs 0.031 mumol/L; p less than 0.005). RBP appeared to increase more in the supplemented group but did not reach statistical significance. We hypothesize that the increase in plasma retinol levels noted in the preterm infants receiving Zn supplementation may be mediated by an increased production of RBP in the liver that in turn enhances the hepatic release of retinol.

Tissue levels of vitamin E (alpha-tocopherol) in response to continuous intravenous multivitamin infusion.

Weanling rats were made vitamin E deficient over a 10-week course. Vitamin E was then provided at 4 IU/kg/day as a continuous infusion of the alpha-tocopherol in Berocca PN. Tissue samples of heart, lung, liver, and perinephric fat and plasma were analyzed for vitamin E levels at 24 and 72 hr. Compared to experimental controls that received a rat chow containing 372 IU/g mixed tocopherol, normal levels were achieved in the test group within 24 hr in plasma and liver. Lung and heart muscle levels were within the normal range by 24-72 hr, although significantly below the control level; fat levels did not normalize. Continuous infusion of vitamin E as tocopherol in a multivitamin preparation results in normal tissue levels in lung and liver in a fashion similar to that achieved by previously described methods of single bolus intravenous infusion or repeated subcutaneous injection.

Changes in erythrocyte and plasma carnitine concentrations in preterm neonates.

Erythrocyte and plasma total, free, and acyl carnitine concentrations in 13 low birthweight, preterm infants were determined between birth and 21 days of age. Although erythrocytes contributed 73.6 +/- 4% (mean +/- SD) of total blood carnitine at birth, the contribution by day 14 declined to 42.2 +/- 14.1. Linear regression analysis showed no significant correlation between plasma and erythrocyte concentrations. At 3 wk erythrocyte total carnitine concentrations were similar to adult values, but erythrocyte acyl carnitine concentrations were markedly lower. Although a significant (p less than 0.05) positive correlation between plasma carnitine concentrations and mean daily intake from birth was found at 7, 14, and 21 days of age (r = 0.66, 0.87, and 0.88, respectively), no significant relationships between erythrocyte carnitine concentrations and carnitine intake could be demonstrated by linear regression analysis. It appears that the carnitine present in plasma and erythrocytes represents two separate pools which are influenced by different factors in preterm infants.

Early intravenous correction of vitamin E deficiency in premature infants.

We undertook to determine the efficacy of intravenous alpha-tocopheryl acetate in rapidly correcting the vitamin E deficiency of the premature infant. Twenty-nine infants were assigned to either a control or treatment group. The latter group received a median intravenous dose of 3 IU/kg/day alpha-tocopheryl acetate as MVI-12 (USV Pharmaceuticals, Inc.). On days 1, 2, 3, 7, 14, and 21, plasma tocopherol isomers and peroxide-induced hemolysis were analyzed. While all but one control infant with initial tocopherol deficiency were still deficient on day 3, all but two of the treatment infants were normal. Rapid, safe correction is possible with an intravenous multivitamin preparation.

Transcutaneous bilirubinometry: a comparison of old and new methods.

Two devices for hyperbilirubinemia screening were compared: the Minolta jaundice meter and the 30-year-old Ingram icterometer. Serum bilirubin values were obtained from a population of 106 healthy newborns with jaundice. A linear correlation existed between serum bilirubin values and the readings on the jaundice meter (y = 0.91x + 9.25, r = .74, standard error of the estimate (sy X x) = 2.02). The device classified hyperbilirubinemia with a sensitivity of 94% and specificity of 77.5%. A linear correlation existed between serum bilirubin values and the readings on the icterometer (y = 0.17x + 1.74, r = .63, sy X x = 0.38). The device classified hyperbilirubinemia with a sensitivity of 82% and specificity of 74%. The population studied was preselected for the presence of jaundice and each data point obtained was from a different patient. As a result, the correlation coefficient obtained from the jaundice meter is lower than others reported, but is more representative of the value that should be obtained under routine nursery situations. Both devices perform well as screening devices; at optimal cutpoints, no statistically significant difference in their efficacy can be demonstrated. Despite the availability of more complex and expensive devices, the icterometer continues to serve as a cost-effective screening device for hyperbilirubinemia.

An evaluation of vitamin E status in premature infants.

Prematurely born, low birth weight infants are abnormal by their very existence ex utero. Thus, the well-documented finding in such infants of low plasma vitamin E concentrations when compared to the adult poses philosophical and pragmatic difficulties as to whether or not a true deficiency state exists: do these low levels represent age-adjusted reference values or do they in fact represent a deficiency state, warranting treatment? We examined multiple measures of vitamin E status in 62 prematurely born, low birth weight infants in order to address this issue. Mathematical and statistical modeling of these measures during the first 21 days of life lead us to conclude that the ex utero antioxidant protective role of vitamin E is best achieved at plasma concentrations of tocopherol very close to those observed in the adult; specifically, when total tocopherol is greater than 0.64 mg/dl and alpha-tocopherol is greater than 0.50 mg/dl. Thus, at birth, a true deficiency in vitamin E exists for most preterm, low birth weight infants and early treatment is warranted.

Relationship of vitamin A (retinol) status to lung disease in the preterm infant.

Plasma concentrations of retinol and retinol-binding protein were measured at birth in 91 preterm infants. In 64% of these babies retinol values were less than 20 micrograms/dl, suggestive of vitamin A deficiency. Forty-seven of these infants were observed with sequential measurements of retinol and retinol binding protein through 21 days of age. In babies with respiratory distress syndrome retinol values were similar to those in babies without respiratory distress syndrome. The retinol binding protein levels were lower on the third day of life in babies with respiratory distress syndrome. Babies who developed bronchopulmonary dysplasia had lower concentrations of retinol at birth (P less than 0.05) and on day 21 (P less than 0.05) than did babies who did not develop bronchopulmonary dysplasia, despite receiving recommended intakes of vitamin A. Many preterm infants are deficient in vitamin A at birth, and failure to correct this deficiency may contribute to the development of chronic lung disease.

Vitamin A losses to plastic intravenous infusion devices and an improved method of delivery.

This study was designed to reevaluate the kinetics of vitamin A losses in the plastic intravenous infusion system used clinically in premature infants and to attempt to establish an improved method of delivery that would avoid significant and unpredictable losses. The losses of retinol, retinyl acetate, and retinyl palmitate were assessed in the presence of various concentrations of the emulsifier Tween 20. For a period of more than 24 h and at a concentration of 0.0085% Tween 20, retinol and retinyl acetate were delivered at 17.4 and 33.9% of the originally intended dose, respectively, while retinyl palmitate was at 100%. At 1% Tween 20, retinyl acetate was completely delivered but even at 2% Tween 20 only 51% of the retinol was delivered. The data suggest that predictable infusions of vitamin A may be attained by using retinyl palmitate rather than retinol in multivitamin preparations.

Tocopherol isomers in intravenous lipid emulsions and resultant plasma concentrations.

Conflicting reports exist regarding the relative tocopherol isomer content of Intralipid ranging from 99% as alpha-tocopherol to as much as 90% as gamma-tocopherol. Our direct assay of Intralipid as well as plasma levels measured in premature infants receiving Intralipid confirm the existence of a low alpha, high gamma-tocopherol content and imply the need for alpha-tocopherol supplementation in patients receiving Intralipid, particularly the relatively tocopherol-deficient premature infant. Furthermore, the observation of abnormal erythrocyte hemolysis test values despite "normal" total tocopherol plasma concentrations may be explained by high plasma levels of non-alpha, biologically less active isomers. The quantitation of tocopherol isomers helps explain this discrepancy and suggests the need for future studies of vitamin E status to employ measurements of tocopherol isomers in reporting results.

Enteral administration of agar as an effective adjunct to phototherapy of neonatal hyperbilirubinemia.

Phototherapy increases the biliary excretion of unconjugated bilirubin. In this form, bilirubin would be subject to enterohepatic circulation, and the true efficacy of phototherapy would be blunted. We tested the hypothesis that sequestration of lumenal unconjugated bilirubin by enteral agar administration would enhance the efficacy of phototherapy in jaundiced infants. Fifty-two infants were studied, 21 control and 31 agar-supplemented. The birth weights, sex distribution, and postnatal age at onset of phototherapy did not differ between the two groups of infants; pre- and post-phototherapy bilirubin concentrations also did not differ between the groups. The bile acid concentrations and bilirubin saturation indices were also similar. The rate of declination of the plasma bilirubin concentrations after 24 h of phototherapy was greater and significantly more uniform in the agar-supplemented infants (-1.59 +/- 2.3 versus -2.51 +/- 1.44). Stool frequencies were greater in control infants (5.5 versus 4.3 per 24 h) whereas fecal bilirubin excretions were greater in agar-supplemented infants during the second day of phototherapy (1.32 versus 3.29 mg . kg-1 . 24 h-1). Agar supplementation reduced the duration of phototherapy by 23% (37.6 +/- 3.2 versus 48.1 +/- 5.0 h).