M. G. Ervin

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.

Antenatal Glucocorticoids Alter Postnatal Preterm Lamb Renal and Cardiovascular Responses to Intravascular Volume Expansion

We assessed renal and cardiovascular function in preterm newborn lambs after antenatal glucocorticoid exposure. Pregnant ewes were randomly assigned to receive betamethasone or saline via either direct fetal or maternal injection at 122 d gestation. Lambs were delivered 15 h later, and cardiovascular and renal function was assessed. Two hours after delivery, baseline urine flow, urinary sodium excretion, and urinary osmolar clearance were similar in all groups. Volume expansion (saline, 2.5% of body weight, for 10 min) increased values for urine flow (0.23 ± 0.04 to 0.58 ± 0.09 mL·min−1·kg−1), urinary sodium excretion (29.7 ± 5.8 to 76.2 ± 12.3 μEq·min−1·kg−1), and osmolar clearance (12.2 ± 1.2 to 24.3 ± 1.6 mL/100 mL GFR) in the fetal group. Increases in urine values were also observed in the maternal group, but control values did not change significantly. Mean arterial pressure was increased in both betamethasone-treated groups relative to controls. Short-term antenatal betamethasone exposure 1) augments preterm newborn kidney adaptive responses to acute volume expansion, and 2) increases postnatal blood pressure in preterm newborn lambs.

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.

Fetal Atrial Natriuretic Factor and Arginine Vasopressin Responses to Hyperosmolality and Hypervolemia

ABSTRACT: Atrial natriuretic factor (ANF) is a class of diuretic and natriuretic peptides secreted by mammalian cardiac atria. Although basal plasma ANF levels in the ovine fetus are elevated relative to the adult, fetal secretion of ANF increases in response to intravascular isotonic saline infusion. Recent in vitro and in vivo studies indicate that ANF secretion also may be stimulated by increased plasma osmolality and/or sodium concentration. The present studies were conducted to determine if volume expansion associated with increased plasma osmolality would further augment ANF secretion in the ovine fetus. In response to successive 30-min intravenous infusions of 3% saline at 0.5 and 1.0 ml/kg/min fetal plasma ANF significantly increased from a basal level of 98 ± 31 pg/ml to a peak of 439 ± 42 pg/ml (p < 0.05). During a 30-min postinfusion recovery period, fetal plasma ANF significantly decreased from peak values to 224 ± 10 pg/ml (p < 0.05), although remaining above basal levels. Fetal plasma osmolality significantly increased from 300 ± 2 mosmol to 325 ± 3 mosmol (p < 0.05) whereas fetal plasma arginine vasopressin increased from 1.9 ± 0.4 to 10.9 ± 7.0 pg/ml (p < 0.05) at the conclusion of the 3% saline infusion. During the saline infusion a significant increase in fetal heart rate and decrease in fetal hematocrit were noted. Fetal blood pressure and maternal plasma ANF and arginine vasopressin concentrations remained unchanged. Despite the potential stimulatory effects of hyperosmolality, increased plasma arginine vasopressin, and intravascular volume expansion, the increase in fetal plasma ANF in the present study did not exceed that induced by isotonic saline alone. These results suggest that plasma osmolality does not act additively with intravascular volume loading for stimulation of ANF secretion in the ovine fetus.

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