Barbara S. Stonestreet

Hemodynamic Effects of Delayed Cord Clamping in Premature Infants

BACKGROUND AND OBJECTIVE: Delayed cord clamping (DCC) has been advocated during preterm delivery to improve hemodynamic stability during the early neonatal period. The hemodynamic effects of DCC in premature infants after birth have not been previously examined. Our objective was to compare the hemodynamic differences between premature infants randomized to either DCC or immediate cord clamping (ICC). METHODS: This prospective study was conducted on a subset of infants who were enrolled in a randomized controlled trial to evaluate the effects of DCC versus ICC. Entry criteria included gestational ages of 240 to 316 weeks. Twins and infants of mothers with substance abuse were excluded. Serial Doppler studies were performed at 6 ± 2, 24 ± 4, 48 ± 6, and 108 ± 12 hours of life. Measurements included superior vena cava blood flow, right ventricle output, middle cerebral artery blood flow velocity (BFV), superior mesenteric artery BFV, left ventricle shortening fraction, and presence of a persistent ductus arteriosus. RESULTS: Twenty-five infants were enrolled in the DCC group and 26 in the ICC group. Gestational age, birth weight, and male gender were similar. Admission laboratory and clinical events were also similar. DCC resulted in significantly higher superior vena cava blood flow over the study period, as well as greater right ventricle output and right ventricular stroke volumes at 48 hours. No differences were noted in middle cerebral artery BFV, mean superior mesenteric artery BFV, shortening fraction, or the incidence of a persistent ductus arteriosus. CONCLUSIONS: DCC in premature infants is associated with potentially beneficial hemodynamic changes over the first days of life.

The effects of variations in PaCO2 on brain blood flow and cardiac output in the newborn piglet.

ABSTRACT. The acute effects of normoxemic hypocarbia and hypercarbia were examined in six newborn piglets. Brain blood flow was maintained during hypocarbia until extremely low Paco2 (<15 mm Hg) levels were achieved at which time total brain and cerebral blood flow decreased significantly from baseline values. Blood flow to the thalamus, cerebellum and brain stem was unchanged from baseline conditions during hypocarbia. This suggests that the newborn brain is relatively insensitive to moderate degrees of hypocarbia. Extreme hypocarbia (Paco2 <15 mm Hg) was associated with a significant increase in heart rate, accompanied by a significant decrease in mean arterial blood pressure; however, cardiac output was not significantly different from baseline determinations. Hypercarbia with normoxemia was associated with significant increases in total brain blood flow, with greater blood flow to the brain stem, cerebellum, and thalamus than to the cerebrum. The percentage of cardiac output received by the brain was also significantly increased, although total cardiac output was unchanged. This demonstrates that the newborn cerebral vasculature is sensitive to hypercarbia and that regional differences in sensitivity may account for the greater increments in blood flow to the caudal portions of the brain than that to the cerebrum.

Clostridia colonization and clostridial toxin in neonatal necrotizing enterocolitis

produce clinical copper deficiency (except for a lower hematocrit at six months) in premature infants fed much lower copper intakes. This study suggests the age at which infants of different gestations can be expected to have an increase in serum copper and ceruloplasmin concentrations. Infants past that age (after 3 months in most very premature infants) who have very low serum copper concentrations may be copper deficient, especially if clinically compatible, and may benefit from additional copper supplies. Prior to that time, serum copper and ceruloplasmin values are probably inadequate indicators of total body copper status, and the benefit to risk ratio of copper supplementation is not established. In the great majority of infants, serum copper concentrations will rise spontaneously as either the liver, gastrointestinal tract, or both, mature.

Comparison of three dosing procedures for administration of bovine surfactant to neonates with respiratory distress syndrome

A multicenter, randomized, double-blind, controlled trial compared three beractant (Survanta) administration procedures in the treatment of neonatal respiratory distress syndrome. Infants weighing > or = 600 gm with respiratory distress syndrome who required assisted ventilation were treated within 8 hours of birth with beractant administered intratracheally. Procedure A required administration in two fractional doses after removal of the infant from the ventilator. Procedure B required administration in two fractional doses through a neonatal suction valve and did not require removal of the infant from the ventilator, and procedure C required administration in four fractional doses during removal from the ventilator. Procedure C is the method used in all previous beractant studies. Of the 299 infants enrolled, 103 were randomly assigned to procedure A, 100 to procedure B, and 96 to procedure C. The results indicate no significant differences among the treatment groups in the clinical outcome measures of fractional inspired oxygen, mean airway pressure, and arterial-alveolar ratio of partial pressure of oxygen at 72 hours of life, or in the incidences of air leaks, pulmonary interstitial emphysema, or death through 72 hours of life. There were no significant differences in the lowest heart rates recorded during administration of doses, but there was less oxygen desaturation during administration of dose 1 with procedure B than with procedure A (p = 0.001), and more reflux of beractant after procedure B than after procedure C (p = 0.007). We conclude that the three procedures are equally effective and can be used to administer beractant safely and effectively. Procedure B has the advantage of allowing administration without interrupting mechanical ventilation.

Comparison of intravenous and endotracheal epinephrine during cardiopulmonary resuscitation in newborn piglets.

OBJECTIVE To compare the efficacy of intravenous and endotracheal epinephrine administration, and intravenous administration above and below the diaphragm, during cardiopulmonary resuscitation in newborn piglets. DESIGN Prospective, randomized, experimental laboratory protocol. SETTING Perinatal cardiovascular research laboratory at a university school of medicine. SUBJECTS Forty newborn piglets (Sus domesticus). INTERVENTIONS After cardiac arrest by ventricular fibrillation, cardiopulmonary resuscitation was begun. Radiolabeled epinephrine or placebo (0.9% sodium chloride) was administered into the right atrium, femoral vein, or endotracheal tube. Chest compressions and ventilation were continued for 10 mins. MEASUREMENTS AND MAIN RESULTS After epinephrine or placebo administration, samples were obtained from the systemic arterial circulation for measurement of radioisotope activity and plasma epinephrine concentrations. Mean carotid arterial blood pressure, right atrial, and inferior vena caval pressures were measured continuously. Epinephrine administration via the right atrium and femoral vein resulted in significant increases in plasma epinephrine concentration, percent of radioisotope recovery, and mean carotid arterial blood pressure, whereas endotracheal epinephrine administration did not. Placebo administered into the femoral vein resulted in a significant increase in percent radioisotope recovery, but not in plasma epinephrine concentration or carotid arterial blood pressure. Endotracheal administration of placebo did not result in significant increases in plasma epinephrine concentration, percent radioisotope recovery, or carotid arterial blood pressure. There were no significant differences between right atrial or inferior vena caval pressures among the groups. CONCLUSIONS During cardiopulmonary resuscitation in newborn piglets, intravenous administration of epinephrine is more efficacious than endotracheal administration. Furthermore, efficacy is similar between femoral venous and right atrial administration.

Glucocorticoid accelerates renal functional maturation in fetal lambs

Renal function was measured in seven premature lambs delivered spontaneously after a fetal injection of betamethasone, four near term lambs delivered via cesarean section after a fetal injection of a placebo and in ten spontaneously delivered full term lambs. Glomerular filtration rates were significantly higher in the premature betamethasone treated than in the near term placebo treated and the full term lambs. Fractional sodium excretions were significantly lower in the betamethasone treated preterm than the placebo treated near term lambs. This suggests that glucocorticoid accelerates renal glomerular and possibly tubular maturation. As in the lung, fetal administration of glucocorticoid stimulates functional maturation of the kidney.

The effects of different rates of plasmanate infusions upon brain blood flow after asphyxia and hypotension in newborn piglets

Brain blood flow was determined in 21 spontaneously breathing, awake, newborn piglets during control, asphyxia, superimposed hypotension, and subsequent volume expansion (15 ml/kg of plasmanate). The piglets were divided into three groups based upon the rate of volume expansion: rapid infusion group-piglets received plasmanate in three minutes; slow infusion group-piglets received plasmanate in 30 minutes: the noninfused group-piglets did not receive plasmanate. The results showed comparable increases in brain blood flow among each group during asphyxia, and similar reduction to preasphyxia values during superimposed hypotension. Although pressure-passive changes occurred, the rate of volume expansion did not influence the magnitude of change in brain blood flow. Significantly lower arterial blood pressure and brain blood flow were observed in those piglets who did not have a plasmanate infusion. Intracranial hemorrhages were not observed at autopsy in any of the study subjects. These data indicate that rapid or slow infusion of plasmanate for volume restoration did not influence the pattern of brain blood flow and that in these relatively mature brains, intracranial bleeding was not observed. Both plasmanate infused groups had higher brain blood flows at study completion (when compared to controls), reflecting compensation for anemia to maintain adequate oxygen delivery. Furthermore, regional differences in blood flow were found during asphyxia and superimposed hypotension (brain-stem greater than cerebellum greater than cerebrum), probably reflecting compensatory protection of vital portions of the central nervous system.

Autoregulation of brain blood flow in the newborn piglet: Regional differences in flow reduction during hypotension

The potential use of a piglet as a model for investigation of brain blood flow was evaluated by assessing the presence of autoregulation in 11 spontaneously breathing newborn piglets. Blood pressure was altered by phlebotomy. When the mean arterial blood pressure was greater than 50 mm Hg, no significant change in brain blood flow (microsphere technique) occurred (r = 0.04), indicating the presence of autoregulation. When the animals became hypotensive a pressure passive relationship exists between brain blood flow and mean arterial blood pressure. However, since the piglets breathed spontaneously and hyperventilated during hypotension, both the mean arterial blood pressure and PaCO2 fell and both correlated with brain blood flow. Thus, it cannot be determined which factor is responsible for the reduction in flow. The blood flow to the specific regions of the brain (cerebrum, cerebellum, brainstem) and mean arterial blood pressure also showed no correlation when the latter was greater than 50 mm Hg. During hypotension, each region demonstrates pressure passive relationships, but the reduction in blood flow is most pronounced in the cerebrum, less in the cerebellum, and least in the brainstem (mean +/- S.E., 64 +/- 8%, 41 +/- 13%, 32 +/- 13% reductions from control respectively, P less than 0.05). The study indicates that a newborn piglet may serve as an appropriate model for the study of brain hemodynamics particularly with regard to autoregulation. Furthermore, during hypotension, preferential protection of vital regions of the brain (cerebellum and brainstem) occur which may have important implications in interpreting the effect of hypotension on the newborn central nervous system.

Antenatal steroids decrease blood-brain barrier permeability in the ovine fetus

Antenatal corticosteroid therapy reduces the incidence of intraventricular hemorrhage in premature infants. Enhanced microvascular integrity might provide protection against intraventricular hemorrhage. In the adult, there is evidence to suggest that the blood-brain barrier may be under hormonal control. We hypothesized that antenatal corticosteroids decrease blood-brain barrier permeability in the preterm ovine fetus. Chronically instrumented 120-day-gestation fetuses were studied 12 h after the last of four 6-mg dexamethasone (n = 5) or placebo (n = 6) injections had been given over 48 h to the ewes. Blood-brain barrier function was quantified with the blood-to-brain transfer constant (Ki) for alpha-aminoisobutyric acid (AIB). Ki was significantly lower across brain regions in the fetuses of ewes that received antenatal dexamethasone compared with placebo (ANOVA; interaction, F = 2.54, P < 0.004). In fetuses of dexamethasone- and placebo-treated ewes, Ki (microliter . g brain wt-1. min-1, mean +/- SD) was, respectively, 2.43 +/- 0.27 vs. 3.41 +/- 0.74 in the cortex, 4.46 +/- 0.49 vs. 5.29 +/- 0.85 in the cerebellum, and 3.70 +/- 0.49 vs. 5.11 +/- 0.70 in the medulla. We conclude that antenatal treatment with corticosteroids reduces blood-brain permeability in the ovine fetus.Antenatal corticosteroid therapy reduces the incidence of intraventricular hemorrhage in premature infants. Enhanced microvascular integrity might provide protection against intraventricular hemorrhage. In the adult, there is evidence to suggest that the blood-brain barrier may be under hormonal control. We hypothesized that antenatal corticosteroids decrease blood-brain barrier permeability in the preterm ovine fetus. Chronically instrumented 120-day-gestation fetuses were studied 12 h after the last of four 6-mg dexamethasone ( n = 5) or placebo ( n = 6) injections had been given over 48 h to the ewes. Blood-brain barrier function was quantified with the blood-to-brain transfer constant ( K i) for α-aminoisobutyric acid (AIB). K i was significantly lower across brain regions in the fetuses of ewes that received antenatal dexamethasone compared with placebo (ANOVA; interaction, F = 2.54, P < 0.004). In fetuses of dexamethasone- and placebo-treated ewes, K i(μl ⋅ g brain wt-1 ⋅ min-1, mean ± SD) was, respectively, 2.43 ± 0.27 vs. 3.41 ± 0.74 in the cortex, 4.46 ± 0.49 vs. 5.29 ± 0.85 in the cerebellum, and 3.70 ± 0.49 vs. 5.11 ± 0.70 in the medulla. We conclude that antenatal treatment with corticosteroids reduces blood-brain permeability in the ovine fetus.

Antenatal dexamethasone: effect on ovine placental 11beta-hydroxysteroid dehydrogenase type 2 expression and fetal growth.

Antenatal glucocorticoids are routinely given to women at risk for preterm delivery. The fetus is protected from excessive glucocorticoids by the placental enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2), which catalyzes the conversion of cortisol to its biologically inactive metabolite, cortisone. We examined the effects of antenatal dexamethasone on the expression of placental 11β-HSD-2 in fetal sheep. Ewes were randomized to receive repeated or single courses of dexamethasone or placebo beginning at 76-78 or 104-106 d of gestation, respectively. In the single course group, the ewes received dexamethasone (6 mg, n = 7) or placebo (n = 6) as four intramuscular injections over 48 h up to 18 h before placental harvest. In the repeated course group, the ewes received the same treatment (dexamethasone, n = 10, or placebo, n = 9) once a week for 5 consecutive weeks starting at 76–78 d of gestation. Placental harvest occurred at 106–108 d of gestation in the four groups. By semi-quantitative RT-PCR, we found that placental 11β-HSD-2 expression was lower in the fetuses of ewes exposed to a single course of dexamethasone than placebo (p < 0.05). Placental 11β-HSD-2 expression did not differ significantly between fetuses of ewes treated with repeated courses of dexamethasone compared with placebo, or a single course of dexamethasone. Fetuses of dexamethasone treated ewes weighed less than those of placebo treated ewes (ANOVA, main effects for dexamethasone versus placebo treatment:F = 14.5, p = 0.007). Fetuses of ewes exposed to repeated courses of dexamethasone weighed less than those of ewes exposed to placebo or a single course of dexamethasone (p < 0.05). We conclude that maternal antenatal dexamethasone treatment reduces placental 11β-HSD-2 expression and fetal weight at mid-gestation in the ovine pregnancy.