Roberta A. Ballard

Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial

BACKGROUND Cerebral hypothermia can improve outcome of experimental perinatal hypoxia-ischaemia. We did a multicentre randomised controlled trial to find out if delayed head cooling can improve neurodevelopmental outcome in babies with neonatal encephalopathy. METHODS 234 term infants with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography (aEEG) were randomly assigned to either head cooling for 72 h, within 6 h of birth, with rectal temperature maintained at 34-35 degrees C (n=116), or conventional care (n=118). Primary outcome was death or severe disability at 18 months. Analysis was by intention to treat. We examined in two predefined subgroup analyses the effect of hypothermia in babies with the most severe aEEG changes before randomisation--ie, severe loss of background amplitude, and seizures--and those with less severe changes. FINDINGS In 16 babies, follow-up data were not available. Thus in 218 infants (93%), 73/110 (66%) allocated conventional care and 59/108 (55%) assigned head cooling died or had severe disability at 18 months (odds ratio 0.61; 95% CI 0.34-1.09, p=0.1). After adjustment for the severity of aEEG changes with a logistic regression model, the odds ratio for hypothermia treatment was 0.57 (0.32-1.01, p=0.05). No difference was noted in the frequency of clinically important complications. Predefined subgroup analysis suggested that head cooling had no effect in infants with the most severe aEEG changes (n=46, 1.8; 0.49-6.4, p=0.51), but was beneficial in infants with less severe aEEG changes (n=172, 0.42; 0.22-0.80, p=0.009). INTERPRETATION These data suggest that although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes.

Scientific basis and therapeutic regimens for use of antenatal glucocorticoids

Abstract The scientific basis for use of prenatal steroid therapy in preparing the human fetus for premature delivery is extensive and convincing. Studies in numerous animal species have documented precocious maturation of lung and other tissues after administration of glucocorticoids to the fetus, and ablation experiments indicate delayed organ maturation with a deficiency of endogenous corticosteroid. The timing of lung differentiation correlates well with the developmental increase in circulating corticosteroid, supporting the concepts that endogenous corticosteroids, interacting with other hormones, are important physiologic modulators of tissue maturation and that prenatal steroid therapy mimics the effect of endogenous glucocorticoids. In fetal lung the response to glucocorticoid involves induction of a limited number of proteins, including all the components of surfactant, as well as key lipogenic enzymes. These effects are mediated by glucocorticoid receptors, occur with physiologic concentrations of hormone, are primarily exerted at the level of gene activation, and are reversible on removal of hormone from cultured tissue. These various observations predict that a relatively brief exposure of the human fetus to glucocorticoid accelerates the normal developmental process in lung and other tissues and reduces disease resulting from developmental immaturity. Prenatal treatment with either betamethasone or dexamethasone at the recommended doses provides similar physiologic stress levels of glucocorticoid activity in fetal plasma sufficient to provide a near-maximal occupancy of receptors and induction of target proteins. Elevated glucocorticoid levels are maintained during the course of treatment and values return to normal by 2 days after the last dose. Treatment causes a transient suppression of maternal and fetal adrenal function; however, treated infants respond to newborn stress with a near-normal cortisol surge. However, there is little information, and reason for concern, regarding the safety of higher or repeated dose of prenatal steroid, and accordingly, routine retreatment of women who are not in active labor is not advised. The recommendation of the consensus panel that corticosteroid therapy is indicated for women at risk of premature delivery with few exceptions is thus well supported by evidence relating to glucocorticoid effects, mechanisms, and pharmacokinetics.

Determinants of outcomes after head cooling for neonatal encephalopathy

OBJECTIVE. The goal of this study was to evaluate the role of factors that may determine the efficacy of treatment with delayed head cooling and mild systemic hypothermia for neonatal encephalopathy. METHODS. A total of 218 term infants with moderate to severe neonatal encephalopathy plus abnormal amplitude-integrated electroencephalographic recordings, assigned randomly to head cooling for 72 hours, starting within 6 hours after birth (with the rectal temperature maintained at 34.5 ± 0.5°C), or conventional care, were studied. Death or severe disability at 18 months of age was assessed in a multicenter, randomized, controlled study (the CoolCap trial). RESULTS. Treatment, lower encephalopathy grade, lower birth weight, greater amplitude-integrated electroencephalographic amplitude, absence of seizures, and higher Apgar score, but not gender or gestational age, were associated significantly with better outcomes. In a multivariate analysis, each of the individually predictive factors except for Apgar score remained predictive. There was a significant interaction between treatment and birth weight, categorized as ≥25th or <25th percentile for term, such that larger infants showed a lower frequency of favorable outcomes in the control group but greater improvement with cooling. For larger infants, the number needed to treat was 3.8. Pyrexia (≥38°C) in control infants was associated with adverse outcomes. Although there was a small correlation with birth weight, the adverse effect of greater birth weight in control infants remained significant after adjustment for pyrexia and severity of encephalopathy. CONCLUSIONS. Outcomes after hypothermic treatment were strongly influenced by the severity of neonatal encephalopathy. The protective effect of hypothermia was greater in larger infants.

Recombinant human erythropoietin in the anemia of prematurity: Results of a placebo-controlled pilot study

Experimental and clinical data implicate inadequate erythropoietin production as an important reason that infants acquire this anemia and suggest that recombinant human erythropoietin (r-HuEPO) might be used to treat or prevent it. We therefore randomly assigned 20 small premature infants (birth weight less than or equal to 1250 gm) who were highly likely to require erythrocyte transfusions for anemia of prematurity to receive 6 weeks of treatment with either intravenously administered r-HuEPO (at a dose of 100 units/kg twice each week) or a placebo. Hematologic measurements, transfusion requirements, and growth were followed during therapy and for 6 months thereafter. Treated (EPO) and control babies did not differ with respect to weight, hematocrit, overall mean absolute reticulocyte count, calculated erythrocyte mass, or rate of growth. However, reticulocyte counts increased earlier in patients given r-HuEPO. Six of ten babies in the EPO group, and 8 of 10 assigned to the control group, received at least one erythrocyte transfusion during treatment. For all infants the amount of blood sampled for laboratory tests was strongly predictive of the volume of packed erythrocytes transfused (r = 0.890; p = 0.0001). Of nine infants who had less than 20 ml packed erythrocytes removed for laboratory tests, none of four given r-HuEPO received a transfusion, whereas three of five infants assigned to the placebo group received one. No toxic effects were attributable to r-HuEPO, and no significant changes in leukocyte or platelet counts occurred during treatment. Reticulocyte counts were correlated with simultaneous platelet counts and were inversely related to absolute neutrophil counts in both study groups. We conclude that r-HuEPO administration is safe and feasible at the dose studied. Additional controlled trials utilizing higher doses of r-HuEPO and larger numbers of patients are justified.

Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

OBJECTIVE: To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000–10 000 U/L; area under the curve = 117 000–140 000 U*h/L). METHODS: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. RESULTS: Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13 780, and 33 316 U/L, and total Epo exposure (area under the curve) was 50 306, 131 054, and 328 002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. CONCLUSIONS: Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.

Dysfunction of pulmonary surfactant in chronically ventilated premature infants

Infants of <30 wk gestation often require respiratory support for several weeks and may develop bronchopulmonary dysplasia (BPD), which is associated with long-term pulmonary disability or death in severe cases. To examine the status of surfactant in infants at high risk for BPD, this prospective study analyzed 247 tracheal aspirate samples from 68 infants of 23–30 wk gestation who remained intubated for 7–84 d. Seventy-five percent of the infants had one or more surfactant samples with abnormal function (minimum surface tension 5.1–21.7 mN/m by pulsating bubble surfactometer), which were temporally associated with episodes of infection (p = 0.01) and respiratory deterioration (p = 0.005). Comparing normal and abnormal surfactant samples, there were no differences in amount of surfactant phospholipid, normalized to total protein that was recovered from tracheal aspirate, or in relative content of phosphatidylcholine and phosphatidylglycerol. Contents of surfactant proteins (SP) A, B, and C, measured in the surfactant pellet by immunoassay, were reduced by 50%, 80%, and 72%, respectively, in samples with abnormal surface tension (p ≤ 0.001). On multivariable analysis of all samples, SP-B content (r = −0.58, p < 0.0001) and SP-C content (r = −0.32, p < 0.001) were correlated with surfactant function. We conclude that most premature infants requiring continued respiratory support after 7 d of age experience transient episodes of dysfunctional surfactant that are associated with a deficiency of SP-B and SP-C.

Fetal sex and prenatal betamethasone therapy.

We examined the influence of fetal sex on the occurrence of respiratory distress syndrome in premature infants after maternal treatment with betamethasone. Among treated infants of 1,251 to 1,750 gm birth weight, the incidence of RDS was 40.9% in 22 males and 7.1% (P = 0.03) in 14 females. Cord serum levels of betamethasone were similar for infants of both sexes, and there was no sex difference in suppression of serum cortisol, dehydroepiandrosterone sulfate, and growth hormone after treatment. These findings suggest that prenatal corticosteroid therapy is less effective in male infants than in female infants. This effect is not due to a difference in transfer or metabolism of betamethasone, nor is it reflected in the responsiveness of the fetal hypothalamic-pituitary-adrenal axis to synthetic glucocorticoid.

Effect of medical and social risk factors on outcome of prematurity and very low birth weight

A cohort of 129 infants with birth weights less than or equal to 1250 gm was followed for more than 4 1/2 years (mean +/- SD: 60 +/- 10 months) to determine the independent effects of two medical risk factors--intracranial hemorrhage and severe chronic lung disease--and a parenting risk factor (abuse or neglect) on neurodevelopmental outcome. In infants without any intracranial hemorrhage or parenting risk factors, severe chronic lung disease was not related to neurologic or cognitive outcome. Infants with increasing grades of intracranial hemorrhage had increasing rates of neurologic and cognitive abnormalities. However, the factor associated with the highest incidence of later abnormality was the parenting risk factor. We conclude that infants with medical risk factors may have additional social risk factors, and that both of these influences must be considered in an examination of the long-term sequelae of neonatal complications.

Risk factor analysis of intraventricular hemorrhagein low-birth-weight infants

Sixty of 63 newborn infants weighing less than 1,250 gm, admitted consecutively to the Intensive CareNursery during a 15-month period, were prospectively investigated for the incidence of intraventricular hemorrhage by early computerized tomography, or by autopsy. Nineteen of the 60 infants had evidence of IVH. The incidence of IVH was correlated with the presence of possible neonatal, obstetrical, asphyxial, or therapeutic risk factors. There was a significant difference in only one of the risk factors: birth outside the perinatal center. Fifteen of 27 outborn infants (56%) developed IVH, whereas only four of 33 inborn infants (12%) developed IVH ( P P P P P

One-Year Respiratory Outcomes of Preterm Infants Enrolled in the Nitric Oxide (to Prevent) Chronic Lung Disease Trial

OBJECTIVE To identify whether inhaled nitric oxide treatment decreased indicators of long-term pulmonary morbidities after discharge from the neonatal intensive care unit. STUDY DESIGN The Nitric Oxide (to Prevent) Chronic Lung Disease trial enrolled preterm infants (<1250 g) between 7 to 21 days of age who were ventilated and at high risk for bronchopulmonary dysplasia. Follow-up occurred at 12 +/- 3 months of age adjusted for prematurity; long-term pulmonary morbidity and other outcomes were reported by parents during structured blinded interviews. RESULTS A total of 456 infants (85%) were seen at 1 year. Compared with control infants, infants randomized to inhaled nitric oxide received significantly less bronchodilators (odds ratio [OR] 0.53 [95% confidence interval 0.36-0.78]), inhaled steroids (OR 0.50 [0.32-0.77]), systemic steroids (OR 0.56 [0.32-0.97]), diuretics (OR 0.54 [0.34-0.85]), and supplemental oxygen (OR 0.65 [0.44-0.95]) after discharge from the neonatal intensive care unit. There were no significant differences between parental report of rehospitalizations (OR 0.83 [0.57-1.21]) or wheezing or whistling in the chest (OR 0.70 [0.48-1.03]). CONCLUSIONS Infants treated with inhaled nitric oxide received fewer outpatient respiratory medications than the control group. However, any decision to institute routine use of this dosing regimen should also take into account the results of the 24-month neurodevelopmental assessment.