Profound Sinus Bradycardia After Intravenous Nicardipine

Abstract

Nicardipine, a calcium entry-blocking drug used for treatment of hypertension, has clinical side effects, such as tachycardia. Tachycardia is generally attributed to the increased activity of the sympathetic nervous system (1). There have been no clinical reports of nicardipine-induced bradycardia, although it has been observed in some experimental studies (2,3). We report a patient who developed nicardipine-induced bradycardia after esophagectomy. Case Report A 75-yr-old man (weight, 43 kg; height, 161 cm) with esophageal carcinoma was scheduled for an esophagectomy. Twenty-two days before the operation, paroxysmal atrial fibrillation was noted. He was administered disopyramide (50 mg IV), and synchronized cardioversion was attempted by the cardiologist at 70 J one time, at 100 J two times, and twice at 150 J. Atrial fibrillation was not terminated, although he became asymptomatic. Methyl digoxin 0.1 mg/d and pilsicainide 150 mg/d were prescribed for 7 days. His electrocardiogram (ECG) still showed atrial fibrillation 14 days before the operation, and the cardiologist withdrew these medications. On the day of surgery, his ECG showed a sinus rhythm. It was unclear at which time point his atrial fibrillation terminated. One epidural catheter was inserted into the T6-7 interspace for the thoracotomy and another into the T10-11 interspace for the laparotomy in the operating room. Anesthesia was induced with thiamylal (250 mg) and vecuronium (6 mg) and maintained with inhaled anesthetics (isoflurane and nitrous oxide) and epidural anesthetics (lidocaine and morphine) under controlled ventilation. Morphine (2 mg) was administered at the beginning of the operation through the T10-11 epidural catheter, followed by continuous infusion of 1% lidocaine 8 mL/h. In the middle of the operation, as the laparotomy ended and the thoracotomy began, epidural lidocaine infusion was changed from the T10-11 to the T6-7 catheter. The infusion was stopped 30 min before the end of the operation. The vital signs of the patient during the anesthesia were stable except for bradycardia and hypothermia. His heart rate decreased to 45 bpm four times, and his heart rate increased to only 55 bpm after atropine (0.25 mg) injection. His rectal temperature gradually decreased during the operation from 36.4°C to 34.2°C by the end of surgery. The duration of the anesthesia was 372 min. On admission to the intensive care unit (ICU), he was unconscious, and mechanical ventilation was initiated. Sedative drugs were not used. A surface warmer with heated air was applied because his rectal temperature had decreased to 33.0°C. Morphine was infused at a rate of 0.15 mg/h through the T6-7 epidural catheter. Eighty minutes after his admission to the ICU, his temperature was still low, at 34.2°C, his blood pressure was >190/100 mm Hg, and his heart rate was 60 bpm. Hypertension was treated with nicardipine (1 mg) injection. His blood pressure did not decrease, but his heart rate decreased to 50 bpm. Approximately 3 min later, the same dose of nicardipine was repeated. Within 1 min, the patient’s systolic blood pressure slowly decreased to 120 mm Hg. At that time, his heart rate suddenly decreased to 10 bpm (Fig. 1), and cardiopulmonary resuscitation was started immediately. Hemodynamic variables recovered promptly after epinephrine (1 mg) was administered. The ECG did not show Osborne waves (Fig. 2), and serum electrolytes and blood gas analyses were all within normal ranges immediately after resuscitation. The remainder of his ICU stay was uneventful, and he was discharged from the ICU on the following day.Figure 1: Electrocardiograms recorded at the injection of nicardipine in the intensive care unit. Resuscitation was started immediately after the patient developed severe bradycardia.Figure 2: Electrocardiograms (ECGs) recorded after resuscitation. There was a notch like an Osborne wave in the QRS complex, but it was not a true Osborne wave, because it was also observed in his past ECG and did not disappear after rewarming.Discussion Calcium entry-blocking drugs inhibit the calcium influx into cardiac and vascular smooth muscle cells (1). They suppress the sinoatrial node directly (3). Therefore, they might cause hypotension and bradycardia. The propensity of these drugs to produce a negative inotropic response is variable. Because the selectivity of the action of nicardipine on the vascular smooth muscle is more than 10,000 times that of its action on the myocardium (4), in clinical cases, nicardipine usually causes hypotension and, not bradycardia, but tachycardia, which is attributed to an increased sympathetic activity (1). However, in a rat heart-lung preparation, nicardipine decreased the heart rate at a concentration of 200 ng/mL (2). Likewise, Satoh et al. (3) reported that bolus administration of nicardipine >30 μg/kg decreased the heart rate and inhibited the tachycardia induced by cardiac sympathetic nerve stimulation in in vivo hearts free from the neural influence of the autonomic nervous system of anesthetized dogs. These findings suggested that nicardipine could decrease the heart rate in the absence of the cardiac sympathetic tone. The conventional dose for bolus administration is 10–30 μg/kg, and two minutes after bolus administration of 30 μg/kg to adult patients, the plasma concentration is approximately 220 ng/mL. Our patient was administered 2 mg (approximately 47 μg/kg) of nicardipine over a short interval, and the plasma concentration might have been enough to decrease the heart rate in the absence of cardiac sympathetic tone based on some experimental studies (2,3). The cause of hypertension in the ICU might have been the emergence from anesthesia. Although there was a long interval from the end of the epidural lidocaine infusion to the nicardipine injections, we could assume that although the cardiac sympathetic nerve activity was only segmentally blocked, it had not recovered completely when nicardipine was injected. The last epidural lidocaine infusion was given via the T6-7 catheter and would block cardiac sympathetic nerves. Hypothermia also prolonged the effect of epidural lidocaine. A depression of the cardiac sympathetic tone induced by epidural anesthesia could have contributed to nicardipine-induced bradycardia in this patient. Hypothermia may depress the conduction system of the heart and can cause virtually any type of arrhythmia, including bradycardia (5). Moreover, if sympathetic stimulation had been prevented, the heart rate would have decreased as the temperature decreased (5). On the basis of these considerations, it seems possible that nicardipine caused bradycardia in a hypothermic patient whose cardiac sympathetic activity was blocked by epidural anesthesia. This patient’s previous paroxysmal atrial fibrillation might have been one of the factors contributing to nicardipine-induced bradycardia, because many older patients with atrial fibrillation have concomitant AV nodal disease and often have associated sick sinus syndrome (6). Unfortunately, our patient did not undergo electrophysiological examination of his cardiac conduction system. His preoperative medications, namely, methyl digoxin and pilsicainide, could not have played a role, because they had been withdrawn two weeks before the operation. Although the mechanism of occurrence of nicardipine-induced bradycardia was not clarified, three factors—namely, hypothermia, cardiac sympathetic blockade, and some kind of abnormality of his heart conduction system—might have contributed to this event in our patient. We conclude that large doses of nicardipine should be given carefully to hypothermic patients with sympathetic blockade, because severe bradycardia may occur.