Kathleen A. Kennedy

Vitamin A supplementation for extremely-low-birth-weight infants

BACKGROUNDnVitamin A supplementation may reduce the risk of chronic lung disease and sepsis in extremely-low-birth-weight infants. The results of our pilot study suggested that a dose of 5000 IU administered intramuscularly three times per week for four weeks was more effective than the lower doses given in past trials.nnnMETHODSnWe performed a multicenter, blinded, randomized trial to assess the effectiveness and safety of this regimen as compared with sham treatment in 807 infants in need of respiratory support 24 hours after birth. The mean birth weight was 770 g in the vitamin A group and 769 g in the control group, and the respective gestational ages were 26.8 and 26.7 weeks.nnnRESULTSnBy 36 weeks postmenstrual age, 59 of the 405 infants (15 percent) in the vitamin A group and 55 of the 402 infants (14 percent) in the control group had died. The primary outcome - death or chronic lung disease at 36 weeks postmenstrual age - occurred in significantly fewer infants in the vitamin A group than in the control group (55 percent vs. 62 percent; relative risk, 0.89; 95 percent confidence interval, 0.80 to 0.99). Overall, 1 additional infant survived without chronic lung disease for every 14 to 15 infants who received vitamin A supplements. The proportions of infants in the vitamin A group and the control group who had signs of potential vitamin A toxicity were similar. The proportion of infants with serum retinol values below 20 microg per deciliter (0.70 micromol per liter) was lower in the vitamin A group than in the control group (25 percent vs. 54 percent, P<0.001).nnnCONCLUSIONSnIntramuscular administration of 5000 IU of vitamin A three times per week for four weeks reduced biochemical evidence of vitamin A deficiency and slightly decreased the risk of chronic lung disease in extremely-low-birth-weight infants.

Lack of Efficacy of Light Reduction in Preventing Retinopathy of Prematurity

BACKGROUNDnHospital-nursery lighting has been suggested as a factor in causing retinopathy of prematurity. Despite ongoing debate, a causal relation has not been established.nnnMETHODSnWe conducted a prospective, randomized, multicenter study of the effects of light reduction on 409 premature infants with birth weights of less than 1251 g and gestational ages of less than 31 weeks. Two hundred five infants were exposed to reduced light, and 204 to typical nursery lighting. The amount of light reaching the infants eyes was reduced within 24 hours after birth by placing goggles on the infants that reduced visible-light exposure by 97 percent and ultraviolet-light exposure by 100 percent. The babies wore the goggles until 31 weeks postconceptional age or 4 weeks after birth, whichever was longer. Once the goggles were removed, ophthalmologists masked to the treatment assignments assessed the infants for retinopathy of prematurity at least biweekly for up to 13 weeks.nnnRESULTSnThere were 188 infants in the group that wore goggles and 173 in the control group who survived and were available for follow-up. The mean birth weights were 906 g in the goggles group and 914 g in the control group; the mean gestational ages were 27.4 weeks and 27.2 weeks, respectively. The mean ambient-light level adjacent to the infants faces was 399 lux for the goggles group and 447 lux for the control group. Retinopathy of prematurity was diagnosed in 102 infants (54 percent) in the goggles group and 100 (58 percent) in the control group (relative risk, 0.9; 95 percent confidence interval, 0.8 to 1.1; P=0.50).nnnCONCLUSIONSnA reduction in ambient-light exposure does not alter the incidence of retinopathy of prematurity.

Conventional consent with opting in versus simplified consent with opting out: An exploratory trial for studies that do not increase patient risk

OBJECTIVEnThe objective of this study was to assess a modified consent procedure allowed under federal regulations and developed for studies, particularly clinical trials, that are judged by the Institutional Review Board to reduce or have no effect on patient risk.nnnSTUDY DESIGNnThis was a randomized trial of a conventional consent procedure that required parental signature to give consent (opting in) after a comprehensive disclosure of the rights of participants in research versus a modified consent procedure that required parental signature to refuse consent (opting out) after specific disclosures appropriate when risk is not increased. Consent was sought for a trial of primary follow-up care for disadvantaged infants at high risk, a trial judged by our Institutional Review Board to increase access to care for both groups. A blinded assessor interviewed mothers within 24 hours of the consent decision.nnnRESULTSnAmong the 44 mothers interviewed, the modified consent group scored higher than the conventional consent group in recall and understanding of study purpose and methods (47% vs 30%; p < 0.02). Other comparisons provided no evidence that the modified consent procedure was less desirable. Virtually all mothers reported satisfaction.nnnCONCLUSIONSnThe modified approach may improve communication and facilitate studies judged by the Institutional Review Board to be risk-neutral or risk-reducing. Further evaluation of a modified consent procedure for such studies is warranted.

Vitamin A to prevent bronchopulmonary dysplasia in very-low-birth-weight infants: has the dose been too low?

OBJECTIVEnInconsistent effects of vitamin A supplementation on prevention of bronchopulmonary dysplasia have been reported. Meta-analysis of these reports resulted in a relative risk of 0.69-1.02 for death or bronchopulmonary dysplasia associated with vitamin A supplementation. Effective dosage regimens or serum retinol concentrations have not been determined in previous reports. The purpose of this pilot study was to define a vitamin A regimen that produces serum retinol concentrations of 25-55 micrograms/dl.nnnSTUDY DESIGNnIn this three-phase study, 91 infants (mean birth weight 799-864 g) were enrolled. Vitamin A was administered three times/week for 4 weeks at an average daily dose of 986-2143 IU/day. Physical examinations were performed and serum retinol specimens were collected weekly to assess clinical signs of toxicity.nnnRESULTSnThe majority of serum retinol concentrations remained < 25 micrograms/dl until an intramuscular vitamin A dose of 5000 IU/dose three times/week was used. No clinical signs of toxicity were associated with the higher dosage and higher serum concentrations of vitamin A.nnnCONCLUSIONnA large clinical trial of vitamin A supplementation with 5000 IU/dose three times/week (25-114% more than the dose used in the three published clinical trials) is needed to assess whether vitamin A supplementation safely reduces the risk of bronchopulmonary dysplasia in very-low-birth-weight infants.

Training pediatric house staff in evidence-based ethics: An exploratory controlled trial

OBJECTIVE: To evaluate an educational intervention in evidence-based ethics (emphasizing clinical knowledge, epidemiologic skills, and recognition of ethical issues) administered to house staff before rotating through our neonatal intensive care unit.STUDY DESIGN: A controlled trial of 64 pediatric house staff assigned to alternating control and intervention rotations. Questionnaires were administered at the end of the rotation.RESULTS: Some benefits of the intervention were observed. However, a large percentage of intervention and control house staff substantially overestimated (>1.25 correct value) predischarge mortality (23% vs. 55% of house staff; p<0.02), mortality or major morbidity (74% vs. 46% of house staff; p=0.04), and cerebral palsy rates (70% vs. 87%; p=0.12). Neither group cited many methodological criteria for evaluating follow-up studies (3.3 vs. 2.4 criteria; p=0.05) or ethical issues considered in treatment recommendations for extremely premature infants (3.1 vs. 2.8 issues; p=0.35).CONCLUSION: Improved house staff training in evidence-based ethics is needed.

Effect of in Vivo Hyperoxia on the Glutathione System in Neonatal Rat Lung

Relative resistance to oxygen toxicity in newborn animals of some species has been associated with a rapid increase in antioxidants in lung tissue homogenate. This study investigated the effect of hyperoxia on the glutathione system antioxidants in lung tissue of neonatal rats exposed to hyperoxia for 15 days. Neonatal rats were exposed to either 100% oxygen or air for 0, 3, 6, 9, 12, and 15 days prior to sacrifice for determination of glutathione and the glutathione system antioxidant enzymes in whole lung homogenate. There were significantly higher levels of total glutathione at 3, 6, and 9 days and of reduced glutathione at 3 and 6 days in oxygen-exposed animals compared to air-exposed controls. These differences were no longer present after 12 or 15 days of exposure to hyperoxia. Glutathione peroxidase and glucose-6-phosphate dehydrogenase remained higher in lung tissue from oxygen-exposed animals from 6 through 12 days of hyperoxia. The failure to maintain sustained high levels of total glutathione during hyperoxia might suggest that glutathione depletion is a factor in the timing of death from oxygen toxicity in these animals. The absence of a sustained increase in oxidized glutathione disulfide is more consistent with other explanations for this transient increase in total glutathione.

Monitoring Postnatal Growth in the Neonatal Intensive Care Unit

Standards for growth of premature infants have often been based on in utero growth rates even though infants born prematurely do not exhibit in utero growth patterns after birth. These growth charts do not allow for daily recording of data and are prone to error in recording data as a function of postmenstrual age. Other growth curves based on observations in preterm infants do not extend beyond 40 to 105 days of age, although these infants are often hospitalized for longer periods of time. To address these practical limitations of available growth charts, we devised a method of plotting growth parameters in the neonatal intensive care unit on the basis of previously published standards of growth and estimates of expected growth. Compared with previously published curves, the monitoring system we present offers the following advantages: (1) weight tracking based on postnatal age and head circumference and length tracking based on postmenstrual age; (2) daily recording of weight for 168 days; and (3) recor...

VALIDATION OF THE PULSED DOPPLER TECHNIQUE FOR ASSESSMENT OF CEREBRAL BLOOD FLOW VELOCITY

Non-invasive measurements of intracranial blood flow velocities can be made through the fontanel by the Doppler technique. A range gated 2 and 5 MHz instrument with a 2-4 mm long sampling volume was used in an in vitro model, simulating intracranial blood flow in newborns. The Doppler instrument measured the maximum and the cross-sectional mean frequency Doppler shifts. Calibration signals were used to transform the frequency shift to velocity. The computed time average of the mean frequency Doppler signal was the best measure of absolute flow (r=0.985, p < 0.001) in artificial blood vessels with 1.0-2.8 mm diameters, over a wide range of flows, 4-94 ml/minute. A fontanel was created surgically in newborn lambs and the blood flow velocities in the basal intracranial arteries were measured with the Doppler instrument. Simultaneous recordings of the carotid blood flow were made by electromagnetic flow cuffs. Occlusions of one or both carotid arteries induced changes in intracranial blood flow velocities, closely correlated to the carotid blood flow on the same side (r=0.89, p<0.01). The pulsatility index was not a useful indicator of changes in blood flow. The range gated Doppler instrument can measure blood flow velocities in very small arteries, at a defined depth under the fontanel. The time average of the mean frequency Doppler signal is the closest estimate of absolute blood flow, when the diameter of the blood vessel under study cannot be measured.

EFFECT OF EPIDERMAL GROWTH FACTOR ON LUNG LIQUID PRODUCTION AND CATECHOLAMINE BLOOD LEVELS IN FETAL LAMBS

Epidermal growth factor (EGF) has been shown to accelerate fetal lung maturation, and it also has an inhibitory effect on gastric HCl secretion. Fetal lung liquid (LL) production is associated with an active Cl-transport. The effect of EGF on lung liquid production(LLP) was examined in fetal lambs with the impermeable tracer (125I-albumin) technique. EGF given i.v. over a 4 hour period (½ injection, ½ infusion) in a total dose of 70 microg/kg to 6 fetal lambs at 0.6 to 0.95 of term resulted in a decreased LLP (6.1 ± 1.4 ml/hr vs 1.5 ± 1.1 ml/hr)*. During EGF, K+ concentrations decreased in LL and plasma and remained low in LL 2-4 hours after infusion when plasma levels had normalized. Na+ and Cl− concentrations in LL did not change significantly. Heart rate increased from 156 ± 3 to 212 ± 11* b.p.m. Mean plasma concentrations of epinephrine increased from 27 ± 5 to 67 ± 13 pg/ml and norepinephrine increased from 257 ± 31 to 544 ± 69 pg/ml* (5 determinations in 3 lambs). EGF infusions (20 microg/kg) during beta-adrenergic blockade with propranol (1 mg/kg + 0.2 mg/kg/hr) reduced LLP in 5 lambs from 7.5 ± 1.8 to 3.3 ± 1.2 ml/hr* without associated tachycardia. Onset of EGF effect on LLP was within 1 hour. Liquid absorption was seen on 3 occasions. It is concluded that EGF given to fetal lambs will stimulate catecholamine secretion, and that EGF exerts an inhibitory effect on fetal lung liquid production which appears to be independent of a possible indirect catecholamine effect. *p <0.05. Values are Mean ± SEM