ODD of gentamicin at 4 mg/kg in neonates >/=34 weeks' gestation is the preferable treatment strategy based on: 1) significantly improved SGC performance compared with TDD; 2) elimination of the need for routine SGC collection in infants on short courses of therapy; and 3) significant antibiotic-associated hospital cost savings when compared with conventional therapy of TDD and SGC analysis.
Fetal sheep appear less responsive to infused angiotensin II (ANG II) than pregnant ewes. This may reflect a greater fetal metabolic clearance rate (MCRANGII) and thus lower plasma ANG II levels. We therefore determined fetal MCRANGII, half-life (T1/2), and placental removal of ANG II. Fetal sheep (n = 13; 113-139 days of gestation) received 0.573-5.73 micrograms ANG II/min iv for 30 min while arterial pressure and heart rate were monitored. Serial blood samples were obtained before and during a 30-min infusion to measure ANG II and calculate MCRANGII and after stopping the infusion to determine T1/2. MCRANGII was similar across gestation and at doses < or = 2.29 micrograms/min (683 +/- 49 vs. 74 +/- 5 ml.min-1.kg-1 for adults) but was 30-40% lower with 5.73 micrograms ANG II/min (494 +/- 57 ml.min-1.kg-1, P < 0.05). T1/2 was 15-21 s. Fetal placental ANG II removal averaged 87 +/- 3 vs. 20 +/- 6% for uteroplacental removal; this was unaffected by dose and was linear with plasma ANG II levels, and saturation was not evident. Plasma ANG II levels rose proportionally with infusion rate and did not change significantly over time; thus fetal plasma ANG II concentrations can be predicted from MCRANGII. Measured and predicted ANG II levels at each infusion rate and time point were similar: r = 0.87, slope = 0.87 (P < 0.001). At equivalent predicted plasma ANG II levels fetal and maternal pressor responses were similar (P > 0.1); however, increases in umbilical vascular resistance exceeded those in uteroplacental vascular resistance (P < 0.03). Fetal MCRANGII is approximately 10-fold greater than maternal, partially reflecting the extensive capacity of ANG II removal by the placental circulation. Contrary to previous conclusions, fetal-maternal pressor sensitivity to ANG II does not differ, whereas the placental vasculature is more sensitive to ANG II than the uteroplacental circulation.
To determine separate and joint effects of increases (delta) in fetal plasma concentrations of arginine (Af) and glucose (Gf) on fetal insulin (If) secretion (delta If), 15 late-gestation fetal sheep were given 5-min arginine bolus infusions (40, 86, 144, 201, and 402 mumol/kg estimated fetal wt) at 90 min of 120 min steady-state glucose clamps (basal Gf, basal + 0.6 mM Gf, and basal + 1.1 mM Gr), producing absolute and percent increases above basal Af of 25.8 +/- 1.3 microM (+33%), 50.9 +/- 6.3 microM (+66%), 83.8 +/- 7.1 microM (+108%), 122.1 +/- 9.4 microM (+156%), and 302.2 +/- 28.2 microM (+386%), respectively. Acute hyperglycemia alone produced an increase above basal If of 9 +/- I microU/ml (+80%) and 19 +/- 2 microU/ml (+170%) after basal + 0.6 mM Gf and basal + 1.1 mM Gf, respectively. Increasing values of delta Af showed separate but lesser effects on delta If, which were significant only at very high values of Af (> 100% above mean normal Af) unless marked hyperglycemia (1.5- to 2-fold normal) was also present, demonstrating joint effects of delta Af and delta Gf on delta If according to a best-fit inverse polynomial response surface. We conclude that physiological increases in Af at normal glucose concentrations are not a potent-stimulus to insulin secretion in fetal sheep.
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