Acute Paraparesis due to Terbutaline Sulfate.

ABSTRACT: A woman who was 30 weeks pregnant was given terbutaline sulfate to prevent premature labor contractions. Within several days, she had an acute paraparesis with myalgias and was unable to walk. Full neurologic investigation failed to show any obvious cause. Terbutaline therapy was discontinued, and in 48 hours she became asymptomatic. Terbutaline sulfate (Brethine) is a [beta]-adrenergic agonist that works on smooth muscle. Various theories about its effect on skeletal muscle have been published. The importance of this case report is to male physicians aware of the rare muscular side effects of terbutaline, and careful observation may obviate extensive and invasive testing.

Terbutaline Sulfate, used to prevent premature labor contractions, can on rare occasions produce acute muscular weakness. We report a case of acute paraparesis in a woman treated with terbutaline sulfate at 30 weeks' gestation

CASE REPORT

A 26-year-old white woman began having premature labor contractions in the 30th week of pregnancy. She was given an injection of terbutaline sulfate (Brethine), 2.5 mg, followed by 2.5 mg orally every 6 hours. Several hours after the injection, she noticed an achy sensation in her thighs, as though her muscles were sore from exercise. Over the ensuing 72 hours, the achiness in her thighs increased and spread to her calves as a constant deep ache. She then had vague paresthesias in her hands and feet. On the fourth day, approximately 1 hour after taking an oral dose of 2.5 mg, she was getting out of the car and fell to the ground because of weakness of her legs. She was unable to stand and was taken to the hospital because of inability to walk.

Weakness was confined to the proximal muscles in the lower extremities and the pelvic girdle muscles. The patient reported no weakness in the upper extremities, no facial or neck muscle weakness, and no sphincter problems. There was no history of recent trauma, fever, skin rash, insect bite, viral illnesses, vaccinations, or food poisoning. She was not taking any medications and had been in excellent health. There was no associated headache, chest pain, stiff neck, or discoloration of the urine. Neurologic examination revealed a well-developed, wellnourished woman in no acute distress. Her mental status and cranial nerves were intact. Her neck was supple. Motor examination revealed grade 4/5 weakness in the iliopsoas and quadriceps muscles bilaterally. There was tenderness to palpation of the thigh muscles. The reflexes were 3+ and symmetrical with no pathologic reflexes, and results of sensory examination were normal. She was unable to stand unsupportetd because of proximal leg weakness. No skin rashes were present.

Lyme titers, complete blood cell count, and erythrocyte sedimentation rate were normal, as were serum electrolyte, calcium, magnesium, creatine kinase, and myoglobin valties. Results of thyroid studies, urinalysis, and pulmonary function studies were also normal.

Treatment with terbutaline sulfate was discontinued, and the patient was observed. Over 48 hours, the symptoms gradually abated, and neurologic findings were normal. At follow-up 1 month later, the patient remained normal.

DISCUSSION

This young woman was given terbutaline sulfate (Brethine) for premature labor and soon thereafter had myalgias progressing to paraparesis, which completely reversed when the medication was discontinued. Brethine is a medication commonly used for prevention and reversal of bronchospasm, but in obstetrics it helps to prevent premature labor. This patient's history and clinical course clearly indicate an adverse reaction to Brethine. The Physicians' Desk Reference does not list any muscular side effects associated with oral Brethine, but with the injectable, one of the systemic effects listed is "weakness, which can occur in 1% of patients."

The active ingredient of terbutaline sulfate is a [beta]-adrenergic agonist. It also exerts a preferential effect on [beta]-adrenergic receptors. These receptors are believed to be present in cardiac muscle in a concentration of 10% to 50% and frequently can cause tachycardia and arrhythmias. The drug also has a significant bronchodilatory effect on bronchial smooth muscle and is used in obstetrics to control premature labor contractions.

The literature contains several reports of muscular side effects from Brethine. Jartti et al (1) reported heaviness in the calves as a side effect. Stewart et al (2) reported minor muscle aches in a patient receiving terbutaline for asthma. Ditzian-Kadanoff et al (3) described a pregnant woman who had polymyositis with myoglobinuria after being on Brethine (0.5 mg) four times a day. On the fifth day of treatment, she had soreness and weakness of her muscles. She responded dramatically to prednisone. It is unclear why Brethine has an effect on skeletal muscle, since it is a [beta]-adrenergic agonist that acts primarily on smooth muscle.

Several theories have been discussed regarding the physiologic and chemical effects of Brethine. Ha et al (4) studied the effects of terbutaline on force and intracellular calcium in slow twitch skeletal muscle fiber in the rat. They concluded that it primarily modulated force by alternating the amplitude and decay rate of the calcium transients, the phosphorylation of the ryanodine receptor and the SR pump regulatory protein phospholamban. The high variability of responses of slow twitch muscles to the [[beta].sub.2]-agonist reflects individual differences in basal phosphorylation levels of phospholamban relative to that of the ryanodine receptor. Djurhuus et al (5) reported a case of hypokalemic paralysis treated successfully with terbutaline. Because terbutaline is a sodium-potassium-ATPase-stimulating drug, they believe it acts at the cellular membrane, effecting sodium and potassium flux. Niisato et al (6) reported that terbutaline affected the intracellular and extra-cellular calcium flux. Braden et al (7) found that terbutaline induced profound hypokalemia by stimulating cellular potassium uptake, causing significant renal sodium and fluid retention and cardiac arrhythmias. Kovarik et al (8) suggested an interaction of reversible inhibition of cholinesterase by terbutaline.

In summary, skeletal muscle weakness is a rare complication of terbutaline sulfate therapy. Some authors have theorized that the action on skeletal muscle is at a cellular ionic level involving the sodium-potassium and calcium flux or that the actin microfilament is involved. Terbutaline sulfate is an important medication for use as a bronchodilator and also in obstetrics to prevent premature labor contractions. This case report calls attention to a rare adverse reaction that may be misleading and cause unnecessary diagnostic investigation and testing, when simple discontinuance of terbutaline therapy and observation may be all that is necessary.

From the Baptist Hospital, Miami, Fla.

Reprint requests to Allan Herskowitz, MD, 8820 SW 105 St, Miami, FL 33176.

References

(1.) Jartti TT, Kuusela TA, Kaila TJ, et al: The dose response effects of terbutaline on the variability, approximate entropy and fractal dimension of heart rate and blood pressure. BrJ Clin Pharmacol 1998; 45:277-285

(2.) Stewart IC, Rhind GB, Power JT, et al: Effect of sustained release terbutaline on symptoms and sleep quality in patients with nocturnal asthma. Thorax 1997; 42:797-800

(3.) Ditzian-Kadanoff R, Reinhard JD, Thomas C, et al: Polymyositis with myoglobinuria in pregnancy: a report and review of the literature. J Rheumatol 1998; 15:513-514

(4.) Ha TN, Posterino GS, Fryer MW: Effects of terbutaline on force and intracellular calcium in slow twitch muscle fibers in the rat, Br J Clin Pharmacol 1999; 126:1717-1 724

(5.) Djurhuus MS, Klitgaard NA, Jensen BM, et al: Multiple anomalies. hypokalemic paralysis and partial symptomatic relief with terbutaline. Acta Pediatr 1998; 87:475-477

(6.) Niisato N, Nakahari T, Tanswell AK, et al: Beta-2 agonist regulation of cell volume in fetal distal lung epithelium. Can J Physiol Pharmacol 1997; 8:1030-1033

(7.) Braden GL, von Oeyen PT, Germain MJ, et al: Ritodrine and terbutaline induced hypokalemia in preterm labor. mechanism and consequences. Kidney Int 1997; 51:1867-1875

(8.) Kovarik Z, Radic Z, Grgas B, et al: Amino acid residues involved in interaction of acetyicholinesterase and butyryl-cholinesterase with carbamates. Biochin Biophys Acta 1999; 1:261-271

* Terbutaline sulfate used to prevent premature labor contractions can on rare occasion produce acute muscular weakness.

RELATED ARTICLES: KEY POINTS

* This case reports a rare side effect of terbutaline sulfate, which can cause profound muscle weakness.

* Recognition of this potential adverse symptom and withdrawal of the medication will rapidly restore normal strength. This will obviate an unnecessary workup.