Open Collections

The effects of the beta-adrenergic agonist, ritodrine, in the fetal lamb

University of British Columbia

Ritodrine is a beta-adrenergic agonist commonly used to inhibit premature labor contractions in women. The primary goal of ritodrine tocolysis is to prolong gestation, however, other indications may include fetal distress. The purpose of the current study was to examine the metabolic and behavioral effects of ritodrine in the fetus, using the chronically instrumented pregnant sheep as an experimental model. Ritodrine was infused continuously into 11 fetal lambs at a rate of 2.6 ug/minute for a period of 8, 12 or 24 hours. Samples were taken simultaneously at predetermined time periods from a fetal femoral artery, umbilical vein, maternal femoral artery and uterine vein for the analysis of fetal and maternal arterial and umbilical and uterine venous blood gases, acid-base status, hematocrit, ritodrine concentration, uterine and umbilical blood flow, and glucose, lactate and oxygen concentrations and fluxes. Cardiovascular and behavioral variables were monitored continuously. The average concentration of ritodrine in fetal arterial plasma was 20.0 ± 2.7 ng/ml (range 9.5 to 3 4.7 ng/ml) at the end of the infusion. This concentration is within the range of cord levels obtained in ritodrine exposed human fetuses at birth (7 to 79 ng/mL) . Fetal arterial plasma ritodrine levels at 8 hours post-infusion were still sufficiently elevated to exert considerable fetal effects. The apparent tolerance of the fetus to given plasma levels of drug varied considerably among animals. The infusion of ritodrine resulted in many typical beta-adrenergic receptor mediated responses in the fetus. Fetal arterial glucose levels rose to 79% above the control by the end of the infusion. This was associated with an increase in fetal glucose delivery (70% above the control), a decrease in the umbilical veno-arterial glucose concentration difference and a tendency for fetal glucose uptake to decline. Fetal arterial plasma lactate concentrations rose more than fivefold during the infusion of ritodrine. This was associated with a rise in fetal lactate delivery (540% above the control), a slight increase in the umbilical veno-arterial plasma lactate concentration difference and a tendency for fetal lactate uptake to rise. Fetal oxygen consumption rose progressively and significantly throughout the infusion of ritodrine and during the first 8 hours of post-infusion, reaching a maximum of 22% above the control by 8 hours post-infusion. Umbilical blood flow remained unchanged, therefore umbilical oxygen delivery was not increased to meet the additional oxygen demands of the fetus. The rise in fetal oxygen consumption was hence accomplished through an increase in fetal fractional oxygen extraction (from a control value of 32.0±1.1% to a maximum of 51.6±1.8% by 1.5 hours of infusion). The rise in fetal oxygen extraction resulted in concurrent declines in fetal arterial Po₂ (78% of the control) and O₂ content (55% of the control) and a widening of the veno-arterial oxygen content difference. By the end of the infusion, umbilical venous Po₂ and O₂ content values had also fallen significantly to 78% and 75% of the control respectively. These latter changes resulted in a concurrent 25% decline in fetal oxygen delivery which in turn contributed to the rise in fetal oxygen extraction. Fetal arterial and umbilical venous pH declined rapidly and significantly from control values of 7.370±0.004 and 7.401±0.005 to 7.274±0.025 and 7.306±0.023 respectively by the end of the infusion. The acidemia was reflected by significant declines in base excess values and appeared to be entirely metabolic in nature, resulting from elevated blood lactate levels. The acidemia likely contributed to the progressive fall in fetal blood O₂ content through a rightward shift of the oxyhemoglobin dissociation curve (Bohr effect). The rise in fetal oxygen consumption was reflected by a similar (although nonsignificant) increase in uterine oxygen consumption. Uteroplacental oxygen consumption appeared to remain unaltered. The rise in uterine oxygen consumption was not accompanied by a corresponding increase in uterine oxygen delivery, hence uterine oxygen extraction rose to 23.8±1.9% (from a control value of 19.5±1.6%) by 1.5 hours post-infusion. The rise in uterine oxygen extraction resulted in significant declines in uterine venous Po₂ and CO₂ values which likely contributed to the fall in fetal oxygen delivery. Fetal heart rate increased significantly to 21% (34 beats per minute, bpm) above the control (162±7 bpm) during the first 1.5 hours of ritodrine infusion. It remained elevated by an average of 16% (26 bpm) throughout the remainder of the infusion and the first 8 hours of post-infusion, returning to the control by the end of the post-infusion period. Fetal arterial pressure remained unchanged from the control (46.2±1.5 mm Hg). The incidence of fetal breathing activity fell significantly from an overall average control value of 43.2±2.6% to an average of 28.1±6.8% during the ritodrine infusion period. In most animals, breathing was most depressed near the end of the infusion. The incidence of low voltage electrocortical (ECoG) activity also fell significantly by an average of 7.5% while that of high voltage ECoG rose by 7.3%. Alterations in intermediate voltage activity were not observed. The incidence of fetal rapid eye movement also tended to fall by an average of 8.2% during the infusion of ritodrine. These behavioral changes may have resulted from the development of fetal hypoxemia, rather than as a direct effect of ritodrine. In conclusion, these data have demonstrated that ritodrine infusion to fetal lambs results in significant physiological and behavioral changes in the fetus. These effects may put the fetus at risk, particularly in situations where fetal oxygen delivery is already reduced, as in various states of compromised pregnancy.

Text

2010-12-16

For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.

http://hdl.handle.net/2429/30417

Reproductive and Developmental Sciences

University of British Columbia

Graduate