Lynne M. Berry

Postnatal Cardiovascular and Metabolic Responses to a Single Intramuscular Dose of Betamethasone in Fetal Sheep Born Prematurely by Cesarean Section

ABSTRACT: Although the benefits of antenatal hormone treatment are well accepted, most studies have reported only pulmonary effects. There is evidence of beneficial cardiovascular and metabolic effects in studies using chronically catheterized animals; however because of the route of administration, the results are not directly applicable to clinical strategies. We previously demonstrated significant pulmonary effects in animals treated antenatally with a single, direct fetal, intramuscular injection of glucocorticoids. This study was performed to determine the effects of a single fetal injection of betamethasone (BETA) alone or in combination with thyroxine (T4) on cardiovascular and metabolic responses after preterm birth. Hemodynamic and metabolic responses at birth were determined in fetuses (126-d gestation; term = 150 d) treated with ultrasound-guided intramuscular injections of 0.5 mg/kg BETA (n = 7), BETA plus 60 g/kg T4 (n = 7), or saline (SAL, n = 9). After 48 h, lambs were delivered by cesarean section and studied for 3 h. BETA treatment increased mean arterial blood pressure [56 ± 6 (SEM) versus 42 ± 3 mm Hg], heart rate (152 ± 5 versus 123 ± 4 beats/min), and cardiac output (467 ± 17 versus 349 ± 36 mL/min/kg) versus SAL. Responses of BETA + T4-treated animals were not different from animals treated with BETA alone. Glucose and FFA were similar among all groups. The increase in catecholamine levels normally seen at birth was significantly attenuated in both the BETA and BETA + T4-treated animals. A single, intramuscular injection of glucocorticoids 48 h before delivery improves cardiovascular responses to preterm birth. This effect is not augmented by concomitant administration of T4.

Single Dose Fetal Betamethasone Administration Stabilizes Postnatal Glomerular Filtration Rate and Alters Endocrine Function in Premature Lambs

These studies determined the effects of fetal treatment with betamethasone alone, or in combination with thyroid hormone (thyroxine; T4), on postnatal renal and endocrine adaptations in preterm newborn lambs. Ovine fetuses (126 d of gestation; term = 150 d) received single, ultrasound-guided intramuscular injections of saline, 0.5 mg/kg betamethasone (Celestone Soluspan®, or 0.5 mg/kg betamethasone plus 60 μg/kg T4. After 48 h, lambs were delivered, treated with surfactant (Survanta®, 100 mg/kg), and ventilated for 3 h. Due to maintained urine flow in the betamethasone-treated animals and a significant decrease in the saline group, betamethasone versus saline urine flow values (0.11 ± 0.03versus 0.03 ± 0.004 mL·min-1·kg-1) were significantly elevated by the end of studies. GFR (1.5 ± 0.3 versus 0.8 ± 0.2 mL·min-1·kg-1) and mean blood pressure (61± 4 versus 42 ± 3 mm Hg) values also were higher in the betamethasone-treated animals. Although renal blood flow, renal plasma flow, and fractional sodium excretion rates did not differ, betamethasoneversus saline values for the filtration fraction (11.9 ± 1.5versus 7.4 ± 1.5%) and total sodium reabsorption (196± 38 versus 81 ± 16μEq·min-1·kg-1) were increased. Betamethasoneversus saline treatment also was associated with significant reductions in plasma angiotensin II (125 ± 23 versus 550± 140 pg/mL) and AVP (116 ± 19 versus 230 ± 77 pg/mL) levels. Overall, the effects of combined betamethasone + T4 treatment were similar to the effects of betamethasone alone. Conclusions: 1) fetal betamethasone injection 48 h before delivery stabilizes GFR and significantly alters endocrine function in preterm newborn lambs, and 2) the addition of T4 does not augment betamethasone-induced renal and endocrine responses.

Repetitive Antenatal Glucocorticoid Exposure Matures Preterm Newborn Lamb Renal Responses to Phenylephrine-induced Increases in Blood Pressure 250

Fluid and electrolyte homeostasis in preterm newborns is compromised due to immature renal function. A single antenatal glucocorticoid treatment augments preterm newborn kidney adaptive responses. To assess the effect of multiple betamethasone (BETA) exposures on kidney adaptation (glomerular autoregulation), pregnant ewes were randomized to receive 1 dose of 0.5 mg/kg BETA at 104d gestation (ONE), 3 doses of BETA at 104, 111, and 118 d gestation(MULT) or saline (control; CON). Lambs were delivered at 125 d (Preterm) or 145 d (Term). Two hours following delivery, Preterm mean arterial pressure(MAP), urine flow (Uflow) and glomerular filtration rate (GFR) did not differ among the groups. Phenylephrine infusion (0.4-26μg/kg/min; over 14 min) increased [mean±SEM (p<0.05)] Preterm MAP (41±3 to 53±4mmHg), GFR (0.59±0.12 to 1.59±0.13 ml/min/kg) and Uflow (0.05±0.03 to 0.16±0.04 ml/min/kg) in the MULT group. While MAP also increased in the ONE and CON groups, GFR and Uflow did not change. Term CON, ONE and MULT responses to phenylephrine infusion were similar to the Preterm MULT increases. Conclusions: 1) Kidney immaturity in preterm newborns includes the absence of renal vascular responses to increases in MAP 2) Preterm newborns exposed to repetitive doses of BETA respond to increased MAP mimicing the term newborn response and 3) Renal maturation at term is not affected by early BETA exposure.

Short-term Antenatal Glucocorticoid Exposure Alters Preterm Newborn Lamb Renal Responses to Intravascular Volume Expansion. • 823

Short-term Antenatal Glucocorticoid Exposure Alters Preterm Newborn Lamb Renal Responses to Intravascular Volume Expansion. • 823

RENAL AND CARDIOVASCULAR FUNCTION IN PRETERM NEWBORN LAMBS FOLLOWING ANTENATAL FETAL OR MATERNAL BETAMETHASONE ADMINISTRATION. † 1159

RENAL AND CARDIOVASCULAR FUNCTION IN PRETERM NEWBORN LAMBS FOLLOWING ANTENATAL FETAL OR MATERNAL BETAMETHASONE ADMINISTRATION. † 1159

BETAMETHASONE CLEARANCE IN FETAL LAMBS FOLLOWING FETAL OR MATERNAL INTRAMUSCULAR ADMINISTRATION. |[dagger]| 1160

Antenatal betamethasone (BETA) administration is recommended in most instances of threatened premature delivery. To provide fetal BETA pharmacokinetic data, we assessed plasma BETA levels in chronically catheterized fetal lambs following maternal or direct fetal BETA treatments as follows (mg/kg): Ewe 0.2 (n=4), Ewe 0.5 (n=3), Fetal 0.2 (n=3) and Fetal 0.5(n=3). Plasma BETA levels were determined by HPLC and are presented graphically. Conclusions: 1) Maternal betamethasone administration increases fetal plasma levels within 90 minutes, and 2) Despite large differences in initial plasma BETA levels, fetal plasma levels are similar by 4 hrs regardless of route of administration. Figure