Agranulocytosis associated with intravenous ritodrine hydrochloride therapy: two case reports by different mechanisms

Ritodrine hydrochloride has been widely used for tocolysis, although serious side-effects have been reported. We report two cases of agranulocytosis induced by ritodrine hydrochloride, which probably occurred by different mechanisms. Two patients were hospitalized because of preterm labor and were given intravenous ritodrine hydrochloride. The nadir of neutrocytes was 199/mm(3) and 13/mm(3) in the two cases, respectively. The total dose of ritodrine hydrochloride was calculated to be 7800 mg for 26 days and 2500 mg for 22 days, respectively. The total doses were heavier and administration duration was longer in Case 1, which suggested a toxic mechanism of agranulocytosis, while in Case 2, they were smaller and shorter, suggesting an immunological mechanism. For patients receiving ritodrine hydrochloride, the white blood cell count should be checked frequently regardless of the duration of therapy and a drug lymphocyte stimulation test should be performed.     

ST segment depression in paired electrocardiograms and serum electrolytes in pregnant women receiving intravenous ritodrine

Forty-three women admitted for preterm labor had electrocardiograms and serum potassium and glucose levels determined before and two and four hours after the initiation of intravenous ritodrine tocolysis. The ST segment depression found at two and four hours was significant but not dependent upon a fall in potassium or increase in the heart rate or glucose level. Such symptoms as chest pain and dyspnea were also not dependent upon potassium, glucose or heart rate changes. These findings support the concept of an intrinsic drug effect.     

Tako-Tsubo cardiomyopathy caused immediately following cesarean section delivery of triplets: a case report

The name 'tako-tsubo' cardiomyopathy was initially used to describe a unique 'short-neck round-flask'-shaped form of left ventricular apical ballooning, resembling a Japanese tako-tsubo, a jar (tsubo) used for capturing octopus (tako). Tako-tsubo cardiomyopathy exhibits acute onset, transient left ventricular apical wall motion abnormalities with chest symptoms and minimal myocardial enzymatic release, mimicking acute myocardial infarction in patients without angiographic stenosis on coronary angiography. There have been few case reports on tako-tsubo cardiomyopathy, and this disorder is especially rare in pregnant women. A 30-year-old woman who was pregnant with triplets, and had been treated with ritodrine hydrochloride for 12 weeks for threatened premature delivery, underwent cesarean section with spinal anesthesia at 30 weeks' gestation. Three hours later, she complained of acute chest pain, dyspnea and episodes of unconsciousness. She was transferred to the intensive care unit and intubated for ventilatory support. We diagnosed heart failure due to tako-tsubo cardiomyopathy based on heart ultrasonography, blood tests, chest X-ray, electrocardiogram and myocardial scintigraphy. She was extubated from the ventilator after 3 days of catecholamine, furosemide and carperitide administration. She was discharged from the hospital on day 53 without symptoms.     

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.     

Type I second-degree AV block (Mobitz type I, Wenckebach AV block) during ritodrine 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.     

Ritodrine Hydrochloride in the Control of Premature Labor Implications for Use

Ritodrine hydrochloride is the only pharmacologic agent approved by the FDA for use in control and prevention of premature labor. The physiologic effects of ritodrine hydrochloride are reviewed and some practical guidelines for its administration are discussed.     

Effect of ritodrine on uterine activity, heart rate, and blood pressure in the pregnant sheep: combined use of alpha or beta blockade.

Ritodrine hydrochloride was administered parenterally to pregnant ewes during spontaneous or oxytocin-induced uterine activity. The effects of ritodrine on the uterus and cardiovasculature were assessed both with and without simultaneous administration of either alpha or beta blockade. Ritodrine was found to be an effective inhibitor of both spontaneous and induced uterine activity. Ritodrine did cause maternal tachycardia but no significant hypotension. Alpha-adrenergic blockade did not influence the effects of ritodrine. Beta blockade with propranolol reversed the uterine and cardiovascular effects of ritodrine, whereas beta blockade with practolol reversed the cardiovascular effects without interfering with the inhibition of uterine activity produced by ritodrine.     

Intramuscular versus intravenous ritodrine hydrochloride for preterm labor management

A prospective, interinstitutional comparative trial was undertaken to examine the efficacy, safety, and pharmacodynamics of different administration routes of ritodrine hydrochloride for the management of preterm labor. Forty-five subjects between 20 and 36 weeks' gestation received either intravenous (n = 24) or intramuscular (n = 21) therapy. Successful tocolysis occurred in 14 of 21 (67%) patients in the group treated intramuscularly and in 16 of 24 (67%) patients in the group treated intravenously. A greater mean dose (8.6 versus 3.3 mg/hour) and a higher mean serum concentration (38.9 versus 24.7 micrograms/ml) were needed to achieve successful tocolysis in the intravenous group as compared with the intramuscular group. Patients who did not respond to tocolytic therapy in both groups had levels of ritodrine in the blood either equivalent to or greater than those of subjects who were successfully treated. Analysis of ritodrine levels in the successfully treated intramuscular group demonstrated significant differences in blood levels depending on muscle group used. These differences can be at least partially attributed to higher mean doses administered to patients receiving vastus lateralis injections as compared with those receiving gluteal muscle injections. The results suggest that intramuscular administration of ritodrine is an efficacious and safe route of drug delivery. Additional studies are needed to better define dose-response curves for the intramuscular administration of ritodrine hydrochloride.     

Effect of Intravenous Tocolytics on Uteroplacental and Fetoplacental Doppler Flow Velocity Waveforms

The vasodilatory effects of ritodrine hydrochloride and magnesium sulfate (MgSO₄) were investigated by analyzing fetoplacental and uteroplacental Doppler flow velocity waveforms (FVWs) obtained from pregnant women about to undergo external version for abnormal fetal lie. These healthy women were chosen for study because they were known to have uncomplicated pregnancies at 37-38 weeks gestation by a reliable last menstrual period and confirming ultrasound. Twenty patients were studied with continuous wave Doppler ultrasound immediately prior to and at least 30 min after intravenous infusion of 100 μ.g/min of ritodrine, and 20 patients were studied before and after the administration of a 6 g intravenous bolus of MgSO₄. No statistically significant alterations of maternal or fetal FVW systolic to diastolic (S/D) ratios were detected after administration of either ritodrine or MgSO₄. We conclude that the intravenous infusion of 100 μ.g/min of ritodrine hydrochloride or 6 g of MgSO₄ in normal healthy women at term has no effect on impedance to placental perfusion as measured by Doppler ultrasound.     

Rhabdomyolysis during prolonged intravenous tocolytic therapy

A patient with twin gestation was hospitalized because of preterm labor and treated with intravenous ritodrine hydrochloride and magnesium sulfate. After more than 5 weeks of therapy, the patient developed muscle pain, which was diagnosed as rhabdomyolysis.     

Cardiac and uterine hemodynamic responses to ritodrine hydrochloride administration in pregnant sheep.

The changes in the maternal circulation following administration of ritodrine hydrochloride were investigated in chronically prepared pregnant sheep. Low infusion rates of ritodrine (see text) elevated the maternal heart rate and cardiac output and decreased peripheral vascular resistance. Stroke work fell while minute work increased. The distribution of uterine blood flow did not change, as measured with microspheres. Simultaneously measured fetal cardiac output and umbilical blood flow were not altered. When ritodrine infusion rates (see text) were increased there was a slight but significant decrease in uterine perfusion pressure, and an increase in uterine vascular resistance with uterine blood flow decreasing. These changes were observed when the ewes were not in labor, and similar changes were again recovered with ewes in labor despite the simultaneous inhibition of uterine contractions. Selective beta blockade with practolol during ritodrine administration decreased the maternal tachycardia without affecting cardiac output, peripheral vascular resistance, or uterine vascular resistance.     

Rhabdomyolysis caused by tocolysis with oral ritodrine hydrochloride in a pregnant patient with myotonic dystrophy

Drug-induced rhabdomyolysis during pregnancy is extremely rare. We report here a rare case of ritodrine-hydrochloride-induced rhabdomyolysis in a pregnant patient with myotonic dystrophy. A 32-year-old primigravida was admitted because of premature labor at 31 weeks of gestation. She had been diagnosed as having myotonic dystrophy by electromyographic investigations and abnormal serum creatinine phosphokinase (CPK) levels. Tocolysis was initiated with oral ritodrine hydrochloride (15 mg/day) alone. There was a prompt response to the ritodrine hydrochloride. Three days after administration began, serum CPK levels had become markedly elevated to 10,897 mg/dl and myoglobinuria was detected (1,800 ng/dl), suggesting the presence of rhabdomyolysis. There was no evidence of worsening of the myotonic symptoms. Tocolysis was stopped immediately, and the laboratory data improved gradually. At 37 weeks of gestation, she spontaneously delivered a healthy male baby. Rhabdomyolysis has been recognized as a complication of tocolytic therapy with ritodrine hydrochloride. Therefore, beta-adrenergic agents should be used with great care, especially for patients with myotonic dystrophy, because of these agents' tendency to aggravate or precipitate myotonia and to induce rhabdomyolysis.     

Ritodrine hydrochloride infusion in pregnant baboons. II. Sodium and water compartment alterations

To evaluate the effects of intravenously administered ritodrine hydrochloride on sodium and water metabolism, a pregnant baboon model was studied. Animals given ritodrine retained significantly more sodium (p less than 0.001) and administered fluids (p less than 0.002) compared with control animals. Although plasma volume did not change significantly within or between the two groups, extracellular volume increased by a mean of 1,480 ml in those given ritodrine compared with 790 ml in the control animals. There was no significant difference between animals given ritodrine and their controls regarding serial hematocrits, serum sodium, or colloid oncotic pressures. From this we conclude that the retained sodium and water was in the interstitial space. Since plasma volume was unaltered by ritodrine administration it seems unlikely that pure volume overload can explain the pulmonary edema induced by beta-mimetics. Combined with the prior observation that direct pulmonary capillary membrane toxicity does not occur, the likely pathophysiology of beta-agonist-induced pulmonary edema involves left ventricular failure.     

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.     

Ritodrine-induced neutropenia

Ritodrine hydrochloride, a beta-sympathomimetic treatment for premature labor, has been associated with the development of pulmonary edema, various metabolic derangements, myocardial ischemia, and infarction. We present the first reported case of absolute neutropenia after prolonged intravenous administration of ritodrine with rapid, spontaneous reversal once the medication was discontinued.     

Effects of KUR-1246, a selective uterine relaxant, on transplacental passage and transmigration to milk

AIM: To evaluate the safety of KUR-1246 as a tocolytic agent, we determined the effects of its constant infusion on efficacy, transplacental passage, and transmigration to milk in pregnant or puerperal animals and compared them to the effects of ritodrine hydrochloride. METHODS: A balloon method was used to evaluate the inhibitory effects of KUR-1246 constant infusion on spontaneous uterine motility in pregnant rats. We also measured transplacental passage and transmigration to milk of KUR-1246 in pregnant and/or puerperal animals. KUR-1246 and ritodrine hydrochloride concentrations were quantified using a liquid chromatography-tandem mass spectrometry method. RESULTS: Constant infusion of KUR-1246 and ritodrine hydrochloride clearly inhibited spontaneous uterine motility in vivo. The ED50 value for KUR-1246 was 1.1 mg/kg/min, a potency which was approximately 40-fold greater than that of ritodrine hydrochloride. Transplacental passage (proportions of fetal plasma/maternal plasma) of KUR-1246 in pregnant rats and/or guinea pigs were approximately one-half to one-third of that of ritodrine hydrochloride. Transmigration of KUR-1246 to milk in puerperal rats disappeared by 48 h after injection. CONCLUSIONS: KUR-1246 is a promising drug for the treatment of preterm labor in obstetric practice because it is as efficacious as currently used agents yet less likely to produce direct effects on the fetus.     

Nifedipine versus ritodrine for suppressing preterm labor

Fifty-eight women in preterm labor were selected randomly to receive either oral nifedipine or intravenous ritodrine hydrochloride. In comparison to ritodrine, nifedipine had similar tocolytic efficacy with fewer adverse maternal and fetal side effects. On Doppler studies nifedipine had an insignificant effect on umbilical blood flow. Preliminary data suggest that nifedipine is a safe, effective and well-tolerated tocolytic agent. It may prove to be a suitable alternative to ritodrine hydrochloride, especially for women in whom beta-sympathomimetics are contraindicated.     

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.     

Magnesium sulfate and ritodrine hydrochloride: a randomized comparison

The efficacy of magnesium sulfate was analyzed in relation to ritodrine hydrochloride. Patients presenting in preterm labor between 20 and 35 weeks' gestation were prospectively randomized. Tocolysis was achieved for more than 72 hours in 35 of 40 cases (88%) where magnesium sulfate was administered and 31 of 39 cases (79%) in which ritodrine hydrochloride was infused. Delay of greater than or equal to 7 days was achieved in 75% and 72% of cases, respectively. The mean dosage to achieve tocolysis was 4.5 gm/hr, in the magnesium sulfate group and 210.0 micrograms/hr in ritodrine hydrochloride-treated patients. The mean magnesium level to achieve tocolysis was 6.60 mg/dl. Side effects in the two groups were similar in number but less alarming in the magnesium sulfate group. Magnesium sulfate was found to be easy to administer and clinically efficacious. Its tocolytic action was found to be dose dependent and drug concentrations are easily determined. On the basis of this work and data from other investigators, magnesium sulfate should be used as the first line of tocolytic therapy with ritodrine hydrochloride as its pharmacologic backup.     

Double blind trial of ritodrine and placebo in twin pregnancy.

In a double blind trial, 25 patients with twin pregnancy were given 40 mg of ritodrine hydrochloride by mouth daily and 24 similar patients received a placebo. The ritodrine group had no significant prolongation of pregnancy nor increase in birth weight, and a high incidence of side effects occurred.