Ritodrine Infusion Research Articles

Type I Second-Degree AV Block (Mobitz Type I, Wenckebach AV Block) During Ritrodrine Therapy for Preterm Labor

A patient, while on intravenous ritodrine therapy for preterm labor, experienced an episode of acute chest pain. The electrocardiogram (ECG), which was read as normal prior to ritodrine infusion, demonstrated a type I second-degree AV block which disappeared upon discontinuation of ritodrine therapy. This case illustrates the need for close ECG monitoring during ritodrine treatment when clinical symptoms arise.

Effects of ritodrine infusion on hemodynamics and lung lymph in awake sheep

The effect of the β-agonist, ritodrine HCl, was studied on cardiac output (CO) and pulmonary lymph flow (Q L) in sheep. Increased CO is associated with an increase in pulmonary Q L in sheep during exercise. Isoproterenol increases CO but has not been shown to increase pulmonary Q L. Ritodrine HCl was chosen because of its association with pulmonary edema when used to halt premature labor in pregnant women. Unanesthetized sheep received an intravenous infusion of ritodrine in increasing doses over 4 h up to a maximum of 6.3 μg/kg/min. Pulmonary pressure increased 2 mmHg after 1 h and returned to baseline by hours 3 and 4 with no change in left atrial pressure or lymph to plasma protein ratio. Pulmonary Q L increased by 61% and CO by 80% at hour 3 of infusion (ritodrine dose 5.4 μg/kg/min) and remained at this level. Pulmonary Q L and CO (normalized to baseline) correlated, r = 0.72, p< 0.001, but there was no correlation between pulmonary Q L and calculated microvascular pressure. Although an increase in pulmonary microvascular endothelium permeability with concurrent pulmonary vasodilation can not be completely ruled out, it appears from this study that β-agonist theray with ritodrine increases pulmonary Q L by a CO related recruitment of microvessels.

473 Changes in ovine uterine venous PGFM following intravenous infusion of ritodrine

473 Changes in ovine uterine venous PGFM following intravenous infusion of ritodrine

171 A comparison of side effects with two ritodrine infusion regimens

171 A comparison of side effects with two ritodrine infusion regimens

Desensitization of β-Receptor Mediated Responses to Epinephrine in Fetal Lambs by Prolonged Ritodrine Administration

During prolonged administration of beta-agonists such as ritodrine directly to chronically cannulated fetal lambs, the cardiovascular, metabolic, and endocrine changes observed during the 1st day of administration, lessen and return to normal within 3-4 d despite continuing drug administration. In our investigation, heart rate, plasma FFA, lactate, glucose, and insulin concentrations all increased significantly during the 1st day of ritodrine infusion (10 micrograms/min), whereas blood PO2 and base excess were significantly decreased. After 3 d, despite continued drug infusion, all these changes had ameliorated. To examine the hypothesis that this tachyphylaxis to ritodrine also results in decreased sensitivity to endogenous catecholamines, epinephrine (1 microgram/min i.v. for 60 min, then 2 micrograms/min i.v. for a further 60 min) was infused into fetal lambs (124-130 d gestation) 1 d before, then 5 +/- 1 d after, and again 10 +/- 1 d after beginning ritodrine infusion. Before ritodrine administration, epinephrine significantly increased plasma FFA, lactate, glucose, and glucagon concentrations and decreased insulin. However, after ritodrine treatment for either 5 +/- 1 or 10 +/- 1 d, epinephrine resulted in no significant increases in FFA or glucagon, and those in lactate and glucose were significantly reduced. Decreases in insulin during epinephrine administration were unchanged by ritodrine. Initial responses of mean arterial pressure and heart rate to epinephrine were significantly greater during prolonged ritodrine treatment. Fetal responses to epinephrine mediated through beta-adrenergic receptor mechanisms were clearly decreased when administration of beta-agonists was prolonged beyond 24 h.

Activation of the renin-angiotensin system during ritodrine treatment in preterm labor

Plasma renin activity, active renin concentrations, and total renin concentrations were measured serially in 15 women in preterm labor treated with ritodrine. All three parameters showed rapid increases during treatment that depended on ritodrine doses and paralleled changes in maternal pulse rate. The slope of the correlation between plasma renin activity and active renin concentrations suggested an increase in both active renin and renin substrate during ritodrine treatment. In contrast, levels of inactive renin remained unchanged for several hours during ritodrine infusion, showing only a late and much smaller response than that of either total or active renin concentrations. Thus ritodrine treatment results in further activation of an already activated renin-angiotensin system in pregnancy. This activation relates to an increase in both renin enzyme and its substrate. It may be responsible for the disturbance in water balance and the risk of pulmonary edema associated with beta-sympathomimetic drug treatment in preterm labor.

Pharmacokinetics of ritodrine administered intravenously: Recommendations for changes in the current regimen

We define the pharmacokinetics of ritodrine in 13 pregnant women who received the drug intravenously. With constant infusion of 50 micrograms/minute, steady state ritodrine concentrations reached 28 +/- 11 ng/ml (SD) with a range of 15 to 45 ng/ml. This wide variation is a result of differences in plasma clearance, which ranged from 1.0 to 3.3 L/min, mean 1.94 +/- 0.71 L/min. The apparent volume of distribution was 6.95 +/- 3.54 L/kg, indicating that ritodrine is extensively bound to extravascular tissue. When an infusion of ritodrine is stopped, plasma concentrations fall rapidly initially with a distribution half-life of 5.9 +/- 6.0 minutes. After the initial rapid fall, plasma concentrations decrease more slowly with a mean disposition half-life of 156 +/- 51 minutes. On the basis of the pharmacokinetic parameters defined, we recommend that the current infusion regimen for ritodrine be changed. The infusion rate of ritodrine should start at 50 micrograms/minute rather than 100 micrograms/minute. The maximal infusion rate of 350 micrograms/minute should be increased and once labor is inhibited, the infusion rate should be reduced.

Peripartum Cardiomyopathy A Rare Cause of Pulmonary Oedema in Late Pregnancy

A 23-year-old primigravida was admitted to hospital at 36 weeks' gestation because of marked peripheral edema and proteinuria. She was anemic but initially not hypertensive. Membranes ruptured spontaneously and she was transferred to the regional center with an infusion of ritodrine as a tocolytic agent. On arrival, her BP was 140/95 mmHg, proteinuria 2+, and moderate preclampsia was diagnosed. A lumbar pidural catheter was inserted and 0.25% bupivacaine 8 ml injected. She also received approximately 1500 ml of crystalloid IV. One hour later she complained of shortness of breath and chest pain, BP was 160/110 mmHg, HR 140 beats/min. Bilateral basal crepitations and chest X-ray confirmed pulmonary edema. She was given furosemide. CVP via an antecubital vein gave a reading of zero. Emergency cesarean section was performed under general anesthesia without complications. On recovery, BP was 150/110 mmHg, HR 110 beats/min and CVP 4 cm H2O. Diuresis was good in response to furosemide. However, during the night, she suffered an exacerbation of the pulmonary edema with a HR of 175 beats/min. She responded to further furosemide and diamorphine, but still remained in pulmonary edema. An ECG 2 days postpartum showed widespread T-wave inversion in the anterior leads. A balloon tipped flow-directed pulmonary artery catheter was inserted and showed a wedge pressure of 30 and pulmonary artery pressure of 44/35 mmHg. Echocardiography showed a dilated left ventricle and a low ejection fraction. She was treated with isosorbide infusion, digoxin and diuretics and improved gradually. Echocardiography again revealed a dilated left ventricle with poor contraction and also demonstrated mitral regurgitation and paradoxical movement of the septum. A diagnosis of peripartum cardiomyopathy was considered. The woman continued to improve and was discharged 18 days postpartum after complete radiologie resolution of pulmonary edema and cardiomegaly.

The Effects Of Ritodrine Infusion On Fetal Myocardial Function And Fetal Hemodynamics

The effects of ritodrine infusion on fetal myocardial function and fetal hemodynamics were studied in 18 singleton, healthy, pregnant women with premature uterine contractions. Ritodrine was given intravenously for 2 1/2 h. In 10 cases both M-mode echocardiographs of the fetal heart and measurements of the blood flow in the fetal descending thoracic aorta were made before and after the infusion. No changes took place in the functional parameters or ventricular size of the fetal heart during the infusion. Fetal heart rate increased significantly. In the aorta both the volumetric flow and time-averaged systolic peak, mean and end-diastolic velocities increased significantly, while there were no changes in wave-form indices. In 8 other cases, blood velocity waveform indices were measured by color Doppler flow mapping from the fetal middle cerebral, renal and umbilical arteries. During the infusion the waveform indices decreased significantly in the middle cerebral and renal arteries. There was no change in the indices of the umbilical artery. Ritodrine did not cause any unfavorable changes in the fetal myocardial function or blood flow in the aorta and umbilical artery. The decreased waveform indices in fetal middle cerebral and renal arteries might indicate decreased vascular resistance in these vessels.

Cardiac isoenzymes and electrocardiographic changes during ritodrine tocolysis

To investigate the potential myocardial ischemic effects of ritodrine, we studied 36 singleton and four twin preterm pregnancies during ritodrine therapy. We serially determined serum creatinine phosphokinase (CPK-MB fraction) and lactic dehydrogenase isoenzymes and performed electrocardiography before and during ritodrine infusion and again within the first 24 hours of oral drug therapy. We observed that serum CPK-MB and lactic dehydrogenase isoenzymes remained within the normal range during therapy periods. The incidence of sinus tachycardia and non-specific T wave changes were 100% and 25%, respectively. In three of four twin pregnancies, ST-T segment depression in leads I, V 4, V 5, and V 6 of the electrocardiogram was noted. Our study suggests that (1) the recommended ritodrine regimen does not produce direct myocardial damage, and (2) ritodrine may cause cardiac ischemia as determined by electrocardiography, which theoretically would progress to myocardial damage if not treated properly.

Does the Intravenous Infusion of Ritodrine or Magnesium Sulfate Alter the Hemodynamic Response to Hemorrhage in Gravid Ewes?

Departments of Anesthesia and Obstetrics and Gynecology, University of Iowa College of Medicine, Iowa City, Iowa

Effects of ritodrine and fetal oxygenation after in utero fetal surgery in sheep.

Surgical procedures which involve the pregnant uterus are associated with preterm labor contractions in the postoperative period. Because uterine contractions decrease fetal oxygen tension, we investigated the effect of maternal ritodrine infusion on fetal oxygen consumption in catheterized fetal sheep 5 h postoperatively. During ritodrine infusion, uterine activity promptly abated, but the oxygen tension in the umbilical vein and descending aorta decreased. The arterial-venous oxygen content difference, the umbilical blood flow, and consequently, fetal oxygen consumption did not change significantly. We conclude that fetal oxygenation is not improved by eliminating uterine activity with maternal ritodrine infusion in the postoperative period.

Dexamethasone effects on ritodrine-induced changes in myometrial contractility and β-adrenergic receptor function

We have previously demonstrated in pregnant sheep that ritodrine infusion for 24 hours reduces myometrial β-adrenergic receptor density and isoproterenol-stimulated adenylate cyclase activity. These receptor-associated changes were accompanied by an increasing inability of ritodrine to inhibit uterine contractility induced by a bolus of oxytocin. In the present study, we evaluated whether these ritodrine-induced effects could be altered by dexamethasone. Ten pregnant sheep at gestational ages of 92 to 130 days received ritodrine 2 μg/kg/min for 24 hours. Five animals also received dexamethasone 10 mg intravascularly twice during the ritodrine infusion. Before and at 4 and 24 hours of ritodrine infusion, the animals were given an identical dose of oxytocin as a bolus, and the area under the uterine pressure-time curve was quantified. Myometrial biopsy specimens were obtained before and after ritodrine infusion. Dexamethasone treatment prevented ritodrine-induced reductions in (3-adrenergic receptor density and isoproterenol-stimulated adenylate cyclase activity. Despite these receptor-associated effects, dexamethasone did not prevent the loss of tocolytic efficacy associated with prolonged ritodrine infusion.

Does the intravenous infusion of ritodrine or magnesium sulfate alter the hemodynamic response to hemorrhage in gravid ewes?

The purpose of this study was to determine whether the intravenous infusion of ritodrine or magnesium sulfate alters the hemodynamic response to maternal hemorrhage in gravid ewes. Twenty-seven experiments were performed in 12 chronically instrumented animals at 0.8 of timed gestation. Each animal was subjected to hemorrhage (20 ml/kg over 60 minutes) during infusion of ritodrine (0.004 mg/kg/min), magnesium sulfate (4 gm/hour), or saline solution control. Infusion of magnesium sulfate increased the mean (±SEM) maternal serum magnesium concentration to 4.8 ± 0.2 mg/dl before hemorrhage and 5.3 ± 0.3 mg/dl after hemorrhage. At the end of hemorrhage maternal mean arterial pressures were 63% ± 4%, 82% ± 2%, and 79% ± 6% of baseline in the magnesium sulfate, ritodrine, and control groups, respectively. The maternal mean arterial pressure response in the magnesium sulfate group differed significantly from the maternal mean arterial pressure responses in the ritodrine and control groups (p < 0.01). Fetal pH was decreased significantly only in the magnesium sulfate group (p = 0.0001). Fetal Po2 was decreased significantly in the magnesium sulfate and ritodrine groups (p < 0.001) but not in the control group. We conclude that magnesium sulfate but not ritodrine, worsened the maternal hypotensive response to hemorrhage in gravid ewes.

A pharmacologic approach to the infusion of ritodrine

The recommended regimen for the infusion of ritodrine leads to unnecessarily high plasma concentrations. A review of basic pharmacologic principles provides a basis for changing the infusion regimen. A regimen is proposed that results in lower average and peak concentrations and reduces the total amount of drug given. These changes may decrease the risk of developing side effects without adversely affecting the ability to inhibit preterm labor.

The Effect of Vasopressor Agents Upon Uterine Artery Blood Flow Velocity in the Gravid Guinea Pig Subjected to Ritodrine Infusion

The beta-sympathomimetic agent ritodrine exerts its tocolytic effects via its beta-2 receptor effects on uterine smooth muscle. However, it also produces maternal cardiovascular effects by means of its beta-1 receptor stimulating effects. Since ritodrine has a half-life of 32±21 minutes its effects may persist when anesthesia is required in pregnant women after failure of tocolysis. The current study was designed to assess the effects of various vasopressors on uterine artery blood flow velocity (UBFV) after ritodrine infusion.

Effects of β-2 Agonist on Hepatic Glycogen Metabolism in the Fetal Lamb

To determine the effects of fetal beta-2 agonist exposure on fetal hepatic glycogen metabolism, we infused ritodrine at a rate of 1.3 +/- 0.4 microgram/kg/min (mean +/- SD) for 24 h into six chronically catheterized twin fetal lambs starting between 128 and 134 days gestation. The control twins received 0.9% saline at 1.2 +/- 0.12 ml/kg/h. In addition, 15 uncatheterized fetuses were killed between 115 and 148 days gestation as unoperated controls. Ritodrine infusion produced a 1.7-fold elevation in fetal serum glucose level, from 23 +/- 5 to 42 +/- 15 mg/dl, and a 2-fold elevation in serum insulin level, from 16 +/- 5 to 34 +/- 8 mg/ml, p less than 0.01. Hepatic glycogen content increased 7-fold in the uncatheterized controls between 115 and 148 days gestation (r = 0.9, p less than 0.001). Ritodrine infusion reduced hepatic glycogen content by 50% from 179 +/- 19 micrograms/mg in twin controls to 90 +/- 25 micrograms/mg in the ritodrine-infused twins, p less than 0.001. Hepatic glycogen phosphorylase kinase activity was elevated 1.3-fold from 0.149 +/- 0.100 mU/mg protein in control twins to 0.186 +/- 0.007 mU/mg protein in the ritodrine infused twins, p less than 0.001. Glycogen phosphorylase a activity was also increased 1.4-fold from 8.60 +/- 0.76 nM NADPH/min/mg protein in control twins to 11.85 +/- 0.68 nM NADPH/min/mg protein in the ritodrine infused twins, p less than 0.001.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term hypotensive effect of beta-agonist in conscious dogs.

The purpose of this study was to investigate the arterial pressure response to long-term administration of beta-agonists in the chronically instrumented conscious animal model. Chronically instrumented dogs were given intravenous infusions of ritodrine (2 micrograms.kg-1.min-1) for a period of 2 wk. Several cardiovascular and renal parameters were monitored before, during, and after the ritodrine infusion, and renal function curves were constructed. After the 1st wk of infusion, a new steady state was reestablished, and this was characterized by hypotension, reduced plasma protein concentration, elevated cardiac output, expanded extracellular fluid space, and near normal levels of activity of renin-angiotensin-aldosterone systems. The renal function curve during ritodrine infusion shifted to the left with no change in slope. We propose the following: 1) the persistence of hypotension is most probably related to the resetting of the arterial pressure-kidney blood volume servocontrol mechanisms, and 2) the persistent elevation of cardiac output and reduction in peripheral resistance are most probably related to increased oxygen and nutrient demand during beta-agonist infusions.

The Effect of Vasopressor Agents upon Uterine Artery Blood Flow Velocity in the Gravid Guinea Pig Subjected to Ritodrine Infusion

The Effect of Vasopressor Agents upon Uterine Artery Blood Flow Velocity in the Gravid Guinea Pig Subjected to Ritodrine Infusion

The Anesthetic Contribution of Magnesium Sulfate and Ritodrine Hydrochloride in Rats

The anesthetic effects of the tocolytic agents, magnesium sulfate and ritodrine hydrochloride, were investigated by determining their effect on the minimal alveolar anesthetic concentration (MAC) of halothane in male and in pregnant and nonpregnant female rats. Magnesium and ritodrine were administered by continuous intravenous infusion to mechanically ventilated rats anesthetized with halothane. The tail-clamp technique was used to establish the MAC of halothane before and then again during the infusion of either magnesium or ritodrine. Ritodrine produced no change in halothane MAC. Increasing magnesium dosages and magnesium plasma levels were associated with nonlinear reductions in halothane MAC that were unrelated to sex or pregnancy. The alveolar halothane MAC concentration in pregnant rats (0.85 +/- 0.02) was not significantly different from the halothane MAC in nonpregnant female or male rats. At the highest plasma magnesium concentrations (15.8 +/- 1.57 mg/dl) achieved in the pregnant rats, the alveolar halothane MAC was 0.36 +/- 0.13, a 61.6% reduction in MAC. The anesthetic effects of magnesium were not attributable to cardiovascular, respiratory, or neuromuscular depression. Major decreases in blood pressure occurred only in the pregnant rats with the highest magnesium concentrations.