Adjunctive use of magnesium sulfate with ritodrine for preterm labor tocolysis

The purpose of the study was to determine if the adjunctive administration of magnesium sulfate with ritodrine would result in decreased dosage requirements of ritodrine, and, therefore, decrease the incidence of ritodrine-associated side effects. Candidates for tocolysis were prospectively randomized so that some received a uniform tocolytic dose of magnesium sulfate in a blinded protocol. All patients received a ritodrine infusion which was titrated in the standard manner to achieve cessation of labor. Evaluations included interval cumulative ritodrine dose, maximal ritodrine infusion rate, fluid balance, and blood chemistry studies. Contrary to our hypothesis, there were significantly more cardiovascular effects in the group that received ritodrine plus magnesium sulfate (11/24) than in the group that received ritodrine alone (1/17) (p less than or equal to 0.02). The predominant side effect was chest pain, frequently associated with electrocardiogram changes indicative of myocardial ischemia. These results are consistent with the current understanding of the regulatory mechanisms of these tocolytic agents. We conclude from the results of our prospective, randomized, blinded study that the adjunctive use of magnesium sulfate with ritodrine is associated with an unacceptable increase in serious side effects and probably does not improve efficacy.     

Potassium supplementation in ritodrine-induced hypokalemia

Acute hypokalemia occurs during infusion of beta 2 agonists for tocolysis. This study examines the efficacy of supplemental potassium in treating this hypokalemia. Four groups of dogs were anesthetized and given lactated Ringer's solution (group I), potassium chloride (group II), ritodrine hydrochloride (group III), and ritodrine plus potassium (group IV). Arterial blood gases, pH, and serum and urinary electrolytes were measured. Results were analyzed by an analysis of variance. Serum potassium fell in groups I and III, rose in group II, and remained stable in group IV. Urinary potassium levels in groups that received ritodrine (III and IV) were not different from control levels. Potassium given with ritodrine will prevent hypokalemia. However, the risks of hyperkalemia exist if vigorous replacement is undertaken. There were no dysrhythmias and no adverse effects in any of the hypokalemic animals. Therefore, the routine administration of potassium is not advocated even in obstetric patients who undergo general anesthesia.     

Effects of ritodrine and isoxsuprine with and without dexamethasone during late pregnancy.

beta-Adrenergic agents are used to inhibit preterm labor and glucocorticoids to accelerate fetal pulmonary maturation. A study was designed to investigate the metabolic effects of intravenous infusion of ritodrine (150 to 100 microgram/min) or isoxsuprine (200 to 150 microgram/min) in a series of 28 patients with gestations of 28 to 40 weeks, with and without concomitant dexamethasone therapy. Ritodrine was more potent than isoxsuprine in increasing the circulating levels of cyclic AMP, glucose, insulin, and triglycerides. The diabetogenic effect of both ritodrine and isoxsuprine was so slight that it did not have any clinical significance in women with normal glucose tolerance. The results were similar when these beta-adrenergic tocolytics were given to women concomitantly with intramuscular dexamethasone therapy, although dexamethasone appeared to minimally impair carbohydrate metabolism. Both ritodrine and isoxsuprine caused a significant fall in serum iron and potassium, and this effect was unaltered by dexamethasone. Serial serum potassium levels should be obtained during long-term infusion of beta-mimetics.     

Evaluation of maternal fluid dynamics during tocolytic therapy with ritodrine hydrochloride and magnesium sulfate.

OBJECTIVE: The purpose of the study was to observe and compare the effects of ritodrine hydrochloride and magnesium sulfate on maternal fluid dynamics. STUDY DESIGN: Fourteen women in preterm labor were prospectively studied during tocolytic therapy with either ritodrine hydrochloride or magnesium sulfate. The cardiovascular and renal effects of a pretreatment crystalloid infusion were compared with those observed during tocolytic therapy. Profile analysis and repeated measures of variance were used to analyze the data. RESULTS: Ritodrine hydrochloride was associated with decreased colloid osmotic pressure, hematocrit, and serum proteins and increased maternal and fetal heart rates. Arginine vasopressin levels increased during the first 2 hours of therapy, then returned to baseline. Sodium excretion was reduced and there was marked fluid retention. Intravenous magnesium sulfate also resulted in a reduction of colloid osmotic pressure, but hematocrit, serum protein concentration, arginine vasopressin, maternal and fetal heart rates, and mean arterial pressure were minimally affected. Sodium excretion increased to a maximum at 6 to 8 hours of treatment, then returned to baseline. A positive fluid balance was also noted in magnesium sulfate-treated patients but to a lesser degree than with ritodrine. CONCLUSIONS: Sodium retention appears to be the primary cause of plasma volume expansion in ritodrine-treated patients, whereas volume expansion during magnesium sulfate therapy is probably related to intravenous overhydration. In the absence of risk factors for pulmonary capillary membrane injury, available evidence supports volume overload as the principal mechanism for pulmonary edema during tocolytic therapy.     

Evaluation of the pharmacodynamics and pharmacokinetics of ritodrine when administered as a loading dose. On establishing a potentially useful drug administration regimen in cases of fetal distress

Inhibition of labor during the intrapartum period has been suggested as a method of managing acute fetal distress. In such cases, rapid tocolysis is desirable but, in high doses, beta-adrenergic-receptor agonists, such as ritodrine, may cause severe maternal hypotension that could aggravate the existing fetal distress. We undertook the present study to establish a safe infusion protocol for ritodrine that achieves high plasma concentration rapidly. Twelve nonpregnant female volunteers received, on separate days, three infusions of ritodrine, that is, 1, 2, and 3 mg, during a 2-minute period. The peak plasma concentration measured by high-performance liquid chromatography with electrochemical detection averaged 37, 74, and 100 ng/ml after the 1, 2, and 3 mg doses, respectively. Ritodrine concentrations decreased rapidly and with the 3 mg dose the ritodrine concentration was only 14 ng/ml after 15 minutes. The elimination phase half-life of ritodrine averaged 6.11 hours. None of the doses significantly affected systolic blood pressure but ritodrine increased heart rate and the plasma glucose level and decreased diastolic blood pressure and the plasma potassium concentration. Even at the highest infusion rate, the maximal changes in cardiovascular and metabolic variables were short-lived and clinically modest; heart rate increased 29 bpm, diastolic blood pressure decreased 8 mm Hg, glucose level increased 26 mg/dl, and potassium concentration decreased 0.6 mEq/L. These data indicate that high plasma concentrations of ritodrine can be achieved rapidly without serious side effects.     

Beta 1-, beta 2-effects of ritrodine and terbutaline in the treatment of preterm labor (author's transl)

beta 2-Stimulants are at present the most effective tocolytic agents. The aim of the study was to evaluate the beta 1- . beta 2-effects of terbutaline and ritodrine in the treatment of preterm labor. 1) Terbutaline, administered intravenously at a rate of 0.4-1.2 microgram/min, and ritodrine also at a rate of 50-300 microgram/min, effectively inhibited uterine activity during 180 minutes. Among the patients there was no difference in responses between those who received terbutaline and ritodrine. 2) The levels of c-AMP and c-GMP in the blood after administration of terbutaline or ritodrine increased and showed dose-response. The levels of c-AMP during a 180-minute infusion increased from 15 to 27 pmol/ml. 3) The action of c-AMP related substances on the circulatory systems was manifested as the dose-response of beta 1 action to the maternal blood pressure, maternal and fetal heart rate. Both beta 2-stimulants produced a tolerable changes in maternal heart rate and blood pressure, no significant changes during the infusion.     

Metabolic and cardiovascular changes during prolonged ritodrine infusion in fetal lambs

Prophylaxis of threatened premature labor with ritodrine may lead to prolonged fetal exposure to the drug. To investigate the direct consequences of this, 11 fetal lambs were given ritodrine hydrochloride for periods of 2-4 days by continuous intravenous infusion at 5 or 10 micrograms/minute (1-3 micrograms/minute/kg estimated fetal weight). These dosages had no measurable effects on the ewes. In the fetus, measurements confirmed and extended the results of earlier short-term experiments, but differences from the effects of long-term maternal ritodrine infusion imply little placental transfer of the drug in sheep. Ritodrine had little or no effect on mean arterial pressure, blood pH, pCO2, plasma alpha-amino acid nitrogen, or growth hormone, but resulted in marked hypoxemia, tachycardia, hyperlactacidemia, hyperglycemia, and hyperinsulinemia during the first 24-48 hours of infusion. Despite continued ritodrine infusion, heart rate and the metabolic parameters returned toward normal within 72 hours. Hypoxemia persisted longer, but tended to lessen after 2 days of infusion. The results indicate that tachyphylaxis to ritodrine develops in the fetal lamb during prolonged administration, but that when fetal well-being is already compromised, ritodrine's effects on oxygenation and lactacidemia could jeopardize fetal survival.     

The acute effects of ritodrine infusion on maternal metabolism: measurements of levels of glucose, insulin, glucagon, triglycerides, cholesterol, placental lactogen and chorionic gonadotropin.

Twenty-nine women in premature labor were randomly assigned to a ritodrine (N = 14) or placebo (N = 15) treatment group. Thirteen serial blood samples were drawn during the first 12 hours of therapy by intravenous drug infusion and they were analyzed for a variety of metabolic substances. There was a significant increase in the blood glucose level in the ritodrine group after one hour and this persisted for the 12 hours of intravenous drug treatment. Plasma insulin levels similarly did not increase in the placebo but significantly rose in the ritodrine group by 30 minutes, peaked at 2 1/2 hours, and remained elevated throughout the infusion. There were no significant differences between levels of plasma glucagon, cholesterol triglyceride, human placental lactogen, or human chorionic gonadotropin in the two treatment groups. Ritodrine caused significant maternal and fetal tachycardia. Its use in women with carbohydrate abnormalities should be monitored carefully. The increased glucose levels may lead to an increased fetal weight.     

Placental transfer of ritodrine hydrochloride in sheep

The purpose of this study was to examine the placental passage of ritodrine hydrochloride in relation to the drug's effects on the fetal circulation. Studies were carried out on nine nulliparous pregnant (120-140 days) ewes with chronically implanted cannulae for measurements of maternal and fetal arterial pressures and for blood sampling. One group of animals received sequential infusions of doses ranging from 0.1 to 30 micrograms/kg per min for 30 min (group 1). A second group was given a constant infusion of the drug at a dose of 3.0 micrograms/kg per min for 4 h (group 2). The peak concentrations of ritodrine in maternal and fetal blood were determined by radioimmunoassay. In group 1 they were 313.4 +/- 24.1 ng/ml (mean +/- S.E.) and 12.6 +/- 3.7 ng/ml at the finish of 30.0 micrograms/kg per min infusion for maternal and fetal blood, respectively. In group 2, maternal drug levels were 81.3 +/- 20.4 ng/ml after 30 min and 95.9 +/- 17.1 ng/ml after 4 h of the infusion. Fetal plasma concentrations increased slowly from trace levels at 30 min to 3.3 +/- 0.7 ng/ml at 4 h. Fetal blood pressure and heart rate did not show any significant changes during and after the infusion of ritodrine in both treatment groups. Our findings demonstrate the maternal administration of ritodrine produces no significant effects on the circulatory system of the fetal lamb because of the low transplacental passage of this drug.     

Inhibition of premature labor: A multicenter comparison of ritodrine and ethanol

A randomized controlled study was carried out at three medical centers to compare the efficacy and side effects of ethanol and ritodrine in the treatment of threatened premature labor. One hundred and thirty-five patients judged to be between the twentieth and thirty-sixth week of gestation and presenting with clinical symptoms of premature labor were included. Sixty-seven patients were treated with intravenous infusion of 10 per cent ethanol. Sixty-eight patients were treated with intravenous infusion of ritodrine for 12 hours followed by oral ritodrine. If labor recurred prematurely, up to two additional courses of ethanol or ritodrine were given. Delivery was postponed for more than 72 hours in 49 of 67 patients (73 per cent) with ethanol and in 61 of 68 patients (90 per cent) with ritodrine; this difference was significant. Patients in the ethanol group gained a mean of 27.6 days while patients in the ritodrine group gained a mean of 44.0 days. Fifty-four per cent of the ethanol group and 72 per cent of the ritodrine group carried their infants to 36 weeks of gestation. Five infants in the ethanol group and one infant in the ritodrine group died from respiratory distress syndrome. The most frequent side effects of ethanol were nausea and vomiting. The most frequent side effects of ritodrine were tachycardia and blood pressure changes which were easily controlled by lowering the infusion rate. Ethanol and ritodrine were both found to be effective inhibitors of premature labor with ritodrine giving the most favorable results.     

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.     

Cardiovascular alterations in severe pregnancy-induced hypertension: acute effects of intravenous magnesium sulfate

The central hemodynamic effects of intravenous magnesium sulfate were studied in five patients with severe pregnancy-induced hypertension. All five patients had a Swan-Ganz and a radial artery catheter placed prior to initiation of magnesium sulfate therapy. Four grams of magnesium sulfate was given over 15 minutes followed by a continuous infusion of 1.5 gm per hour. There was a 12.5% increase in cardiac index immediately after the infusion but cardiac index returned to pretherapy values by 15 minutes after infusion. The mean arterial pressure was significantly (p less than 0.01) decreased 30 minutes after the 4 gm loading dose but had returned to baseline values by 1 hour. There were no other significant changes in any of the hemodynamic or oxygen-related variables measured. Our data confirm previous hemodynamic studies in patients with severe pregnancy-induced hypertension indicating a hyperdynamic state with large fluctuations in systemic and pulmonary vascular resistances. In addition, magnesium sulfate has been shown to have a transient hypotensive effect on mean arterial pressure, related to bolus infusion, that is not present with continuous infusion.     

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.     

Myometrial desensitization to continuous but not to intermittent beta-adrenergic agonist infusion in the sheep

Infusion of the long-acting beta-adrenergic agonist ritodrine (3 micrograms/kg/min) caused by rapid inhibition of uterine activity in the ovariectomized, nonpregnant sheep. This inhibition could only be maintained for 6.4 +/- 0.8 hours, with high-frequency activity returning by 11.4 +/- 2.6 hours despite continuous infusion of ritodrine. Intermittent administration of ritodrine did not prolong uterine relaxation, probably as a consequence of its long half-life. Continuous infusion of the short-acting beta-agonist isoproterenol (0.16 micrograms/kg/min) initially inhibited uterine contractions but high-frequency activity returned by 50 minutes. In contrast, intermittent infusion of isoproterenol (30 minutes on and 30 minutes off) significantly inhibited the frequency of contractions during each of the infusion periods for the duration of the study (13 hours). Our data demonstrate that either continuous administration of beta-agonists or intermittent administration of the long-acting beta-agonist ritodrine resulted in myometrial desensitization in the sheep. In contrast, intermittent administration of the short-acting beta-adrenergic agonist isoproterenol prevented the onset of myometrial desensitization.     

Effects of acid and base infusion on umbilical hemodynamics

The effects of infusion of sodium bicarbonate (0.6M) and hydrochloric acid (0.3M) solutions on umbilicoplacental hemodynamics and on blood pH and respiratory gases were investigated in near-term fetal lambs. Despite marke changes in blood pH, no significant alterations occurred in umbilical blood flow, pressures, and resistances during either acidosis or alkalosis. On the basis of this and previously reported data, it can be stated that: (1) change in blood pH persse does not significantly affect systemic, pulmonary, and umbilical circulation, and (2) the hemodynamic alterations produced by base infusion are related to the tonicity of the solution rather than to acid-base changes. Acidosis was associated with an increase and alkalosis with a decrease in blood Po₂; these changes are related largely to the Bohr effect.     

Effects of ritodrine hydrochloride on uterine activity and the cardiovascular system in toxemic patients.

The effects of ritodrine hydrochloride were evaluated in 25 toxemic patients in active labor utilizing continuous electronic monitoring of fetal and maternal cardiovascular systems and uterine activity. Fetal scalp blood and free flowing maternal antecubital venous blood was obtained for pH, Po2, Pco2, base deficit and blood glucose determinations prior to and immediately following the study period. The initial ritodrine dose was 50 mug/min for 15 minutes. The dose was increased by 50 mug/min each 15 minutes until there was a clinically apparent reduction in uterine activity. Once this was accomplished, the infusion was maintained for 30 minutes. There was a consistent increase in the maternal heart rate (MHR) and a significant rise in fetal heart rate (FHR) late in the infusion and in the postinfusion period. There was a widening of the maternal pulse pressure mainly due to a reduction in diastolic pressure with little change in the mean blood pressure. Maternal and fetal pH decreased and base deficit increased during the study although the PO2 and PCO2 remained unchanged. Maternal and fetal blood glucose rose significantly following ritodrine infusion.     

Effect of purified beta glucuronidase infusion in normal dogs and dogs with acidosis.

The effects of systemic infusion of purified beta glucuronidase, lactic acid and a combination of these were studied in normal dogs from the viewpoints of hemodynamics and blood coagulation. In none of the groups was an obvious deterioration in arterial blood pressure, pulse rate, central venous pressure, portal venous pressure and electrocardiogram observed after the infusions. On the other hand, beta glucuronidase infusion with preceding acidosis caused substantial thrombocytopenia accompanied by a decrease in fibrinogen levels and abnormal thromboelastogram. A similar trend was found by the infusion of beta glucuronidase only. An intermediate abnormality was found by the infusion of lactic acid alone. Histologically, fibrin clots in the pulmonary arteries were often observed in the dogs of all groups, but the quantitative difference among the groups was difficult to evaluate. In the present investigation, shock could not be produced, but other data seemed to indicate that increased levels of acid hydrolases in the blood are concerned with deterioration and irreversibility of shock, especially in an acidotic condition.     

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

We have previously demonstrated in pregnant sheep that ritodrine infusion for 24 hours reduces myometrial beta-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 micrograms/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 beta-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.     

Pulmonary edema after ritodrine therapy during pregnancy and subsequent cesarean section with epidural anesthesia

Ritodrine, a beta-sympathicomimetic drug that is frequently used for the prevention of preterm birth. Preterm delivery is an important cause of low birth weight. One of the most important side-effects of ritodrine is pulmonary edema. In patients developing pulmonary edema after ritodrine therapy, aggressive fluid resuscitation during the operation period should be avoided. Successful epidural anesthesia can be achieved with a slow-onset epidural block after moderate fluid infusion. We report the management of a pregnant patient developing pulmonary edema after ritodrine therapy and undergoing cesarean section with epidural anesthesia.     

Dose-dependent effects of prostaglandin D2 on hemodynamics, renal function, and blood gas analyses

Dose-response effects of prostaglandin D2 (0.125, 0.25, 0.5, and 0.75 micrograms/kg/min) infused intravenously in pentobarbital-anesthetized dogs were studied with particular reference to renal, pulmonary, and systemic effects. Another group receiving the vehicle alone served as controls. Prostaglandin D2 administration resulted in a significant dose-dependent increase in renal artery flow, urine output, creatinine clearance, plasma renin activity, sodium excretion, potassium excretion, and pulmonary artery pressure. A significant decrease occurred in renal resistance and arterial PO2. There were no appreciable changes in mean arterial pressure, heart rate, hematocrit, platelet count, arterial pH, and PCO2. In the vehicle control group, all other parameters remained relatively stable, except for some increase in the mean arterial pressure, plasma renin activity, and potassium excretion. The results of this study suggest that prostaglandin D2 administered intravenously at levels lower than those required to produce adverse pulmonary and systemic effects will improve the renal blood flow and function.