Ernest N. Kraybill

Risk factors for chronic lung disease in infants with birth weights of 751 to 1000 grams

We performed a multicenter, historical-cohort analysis to identify factors associated with chronic lung disease (CLD) in extremely low birth weight infants. The 235 infants who were born in 1984 with birth weights of 751 to 1000 gm and admitted to any of 10 participating neonatal intensive care units comprised the study population. We analyzed demographic characteristics, status at birth, severity of acute atelectasis, and early respiratory treatment in relation to CLD, which we defined as having received oxygen at age 30 days. By univariate analysis, CLD was associated with lower gestational age (p less than 0.001), male sex (p = 0.004), more severe acute atelectasis as indicated by a higher roentgenographic score (p less than 0.001), a higher ventilation rate at 96 hours (p = 0.012), and lower PaCO2 at 48 hours (p = 0.04). Infants receiving mechanical ventilation whose highest PaCO2 levels at 48 or 96 hour were less than 40 mm Hg were 1.45 times as likely to develop CLD as those whose highest PaCO2 levels were greater than 50 mm Hg (95% confidence interval 1.04 to 2.01). CLD rates by center were inversely related to mean PaCO2 levels in infants receiving mechanical ventilation at 48 and 96 hours (Spearman rank correlations 0.60 and 0.55; p less than 0.001). A logistic risk model that included sex, PaCO2 at 48 hours, roentgenographic score, gestational age, and race showed only male sex (p = 0.009) and lower PaCO2 at 48 hours (p = 0.04) to be independent predictors of CLD. We conclude that mechanical ventilation that results in PaCO2 levels above the physiologic range may decrease the risk of CLD in extremely low birth weight infants.

Neurodevelopmental, health, and growth status at age 6 years of children with birth weights less than 1001 grams

The neurodevelopmental, health, and growth outcomes for 28 six-year-old extremely low birth weight (ELBW) (birth weight less than 1001 gm) children were compared with those of 26 control children born at term. The two groups did not differ in mean weight or height, but the ELBW group had smaller head circumferences (p = 0.015). Kaufman mental processing scores correlated with head circumference (p = 0.0003). Significantly more of the ELBW children (61%) had mild or moderate to severe neurologic problems compared with control children (23%) (p = 0.003). Three ELBW children had mild spastic diplegia; one was blind. Eighteen (64%) of the ELBW children had required rehospitalization versus five (20%) of the comparison group. The mean Kaufman Mental Processing Composite was lower for the ELBW group, but when the data were analyzed by maternal education, only those children whose mothers had a twelfth-grade education had significantly lower scores (p = 0.0001). A similar pattern of group differences was seen for scores on visual-motor function (p = 0.0045), visual-perceptual abilities (p = 0.003), and attention span (p = 0.0001). No group differences were seen regarding hyperactivity or parental stress. Overall functional disability among the ELBW children was considered absent in 46%, mild in 36%, and moderate to severe in 18%. There was a significant association (p = 0.029) between classification of handicap at 12 to 34 months and classification at 6 years. No neonatal factors correlated with 6-year outcome. A significant proportion of ELBW children had no severe disabilities, but many had dysfunctions likely to affect learning and behavior in school.

Very-Low-Birthweight Infants at Seven Years An Assessment of the Health and Neurodevelopmental Risk Conveyed by Chronic Lung Disease

To determine whether history of chronic lung disease (CLD) in children born at very low birthweight (VLBW) confers additional risk for impaired health, growth, and neurodevelopment, 17 VLBW children born in 1984 who had CLD (requiring supplemental oxygen more than 30 days after birth) in infancy and 28 VLBW children who did not have CLD were assessed at age 7 years. Assessments included a medical history, standard physical and neurological examinations, pulmonary-function tests, and tests of neuropsychological and psychoeducational functioning. Health status did not differ between the groups. In contrast, children with CLD did not perform as well in neuropsychological and psychoeducational assessments. Although CLD confers little added risk to health, it seems to add significantly to risks for poor school performance that are known to be associated with very low birthweight.

Transplacental ampicillin: Inhibitory concentrations in neonatal serum

Concentrations of ampicillin were measured in maternal serum at delivery, in cord serum, and in neonatal serum sampled at 1, 4, and 8 hours after ampicillin had been administered prophylactically to 22 mothers who were undergoing cesarean section. The concentrations of ampicillin in maternal serum at delivery ranged from 4.6 to 50 micrograms per milliliter and were inversely related to the time between administration of the drug and delivery. Concentrations in cord serum ranged from 4.4 to 23 micrograms/ml and were lower than those in corresponding maternal samples in all but two cases. The ratios of cord/maternal concentrations of ampicillin ranged from 0.16 to 1.3 and were directly related to the time which had elapsed between administration of ampicillin and delivery. The mean concentration of ampicillin in cord and neonatal serum declined exponentially in the 8 hours after infusion; it exceeded the minimal inhibitory concentration against Escherichia coli for 4 hours and against Listeria monocytogenes and group B streptococcus for at least 8 hours.

The Challenge of Informed Consent in Neonatal Research

The modern doctrine of informed consent dates back only about a half century to the Nuremberg Code. Its first premise ‘‘The voluntary consent of the subject is absolutely essential’’ established the bedrock principle of protection of human research subjects. In subsequent decades, some investigators ignored the Code in the belief that it was written for criminals rather than for well-meaning scientists. In 1964, its relevance for physician-investigators was articulated clearly in the World Medical Association’s Declaration of Helsinki. Still, it was not until the US National Research Act of 1974 created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research that things began to change. The Commission’s work led to the Belmont Report and the Code of Federal Regulations. The latter established Institutional Review Boards. Only after these were in place did informed consent become the norm for US investigators whose research involved human subjects. From that shaky beginning, the understanding and practice of informed consent has matured, slowly but surely. While the letter of the law can be fulfilled by a signature on a piece of paper, the spirit demands more. Informed consent is properly thought of as a process, rather than a document. To be sure, the document is a necessary record, but to be truly informed a prospective subject needs a discussion with the investigator, an opportunity to ask questions and to have them answered. Even given that process, misunderstandings abound in research that involves treatment of ill subjects. In this setting, the physician-investigator has two roles and two sets of obligations. The duties of a physician to a patient are different from the obligations of a researcher to a research subject and to science. At times these differing obligations may be in conflict. The patient-subject must also be seen in two perspectives, as patient and as research subject. If it is difficult for physician-investigators to appreciate these differences, it may be nearly impossible for patients (and parents of patients) to do so. The term ‘‘therapeutic misconception’’ describes this conflation of treatment and research. It is perhaps most prevalent in Phase I clinical trials of chemotherapeutic agents for treatment of cancer. The stated purpose of Phase I trials is to establish dose-limiting toxicity, not to provide direct benefit to the subjects. Yet, in one study, 85% of cancer patients in a Phase I trial said that they enrolled for reasons of possible therapeutic benefit. Given the tendency for subjects to misunderstand the purpose, risks and benefits of research that involves treatment of sick individuals, it is appropriate that investigators look critically at their consent process and ask ‘‘What did the patient (or parent) understand?’’ In this issue of the Journal, Ballard, et al. report on having done just that. Parents whose infants had been subjects in the NEOPAIN study were interviewed later to determine whether the parents had adequate knowledge to provide valid informed consent. Their findings, though disturbing, are similar to those of many other studies evaluating validity of consent for participation in research. Among the 64 parents interviewed, five (7.8%) had no recollection of the study. Of those who did remember the study only 68% could state the purpose. Most disturbing is that only 5% could name even one risk of the study. Using a stringent set of criteria, only 3% of parents were considered to have given valid informed consent. These are sobering findings for neonatologists who seek to enroll their patients in clinical studies. What could account for this apparent lack of understanding? First, one must ask whether the investigators provided the right information, at the right time, in the right manner, and in the right setting. Although such an assessment could only be made by a third-party observer, the measures taken by the original study team to assure adequate communication seem appropriate and were probably equal or superior to those generally employed. Second, parents’ circumstances, including the stress of having an imperiled infant, the large volume of clinical information and the uncertainty of the outcome may be unavoidable factors that overwhelm parents’ ability to comprehend information. Third, parents’ trust in their infants’ physicians may have replaced their careful attention to what they were being told. Finally, interpretation of the findings would seem to be limited by the long time intervals (3 to 28 months) between the study and the parent interviews. There was Address correspondence and reprint requests to Ernest N Kraybill, MD, Professor Emeritus of Pediatrics, The University of North Carolina at Chapel Hill, 301 Weaver Mine Trail, Chapel Hill, NC 27517-7592, USA. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Team Medicine in The NICU: Ship or Flotilla of Lifeboats?

The image of a majestic ocean liner plowing the Atlantic, a square-jawed captain firmly gripping the wheel, does not fit the Newborn Intensive Care Unit (NICU). All the NICUs in which I have worked have been small and overcrowded, not at all majestic. The lives that hang in the balance there are also small and fragile. Clearly, the physical symbolism of a ship is not appropriate. What about the organizational metaphor? Is the physician truly, captain of the NICU ship? If there is indeed a captain, who are the crew members, who the passengers, and what is their destination? Is the NICU really a ship, or a flotilla of lifeboats?