Long QT syndrome caused by N-acetyl procainamide in a patient on hemodialysis

Abstract

A 65-year-old male on hemodialysis three times a week due to end-stage renal failure underwent cardiac surgery one year previously, and complained of breathlessness on exertion after surgery. Echocardiograms evidenced a significant obstruction in the left ventricular outflow with intraventricular pressure gradient of 62 mmHg, and the patient was started on beta-blocker. After a maximal dose of carvedilol was given, a class 1A antiarrhythmic drug of Na channel blocker, procainamide, was added because of insufficient relief of symptoms. Electrocardiogram (ECG) showed prolonged QT intervals (523 ms) on a regular visit one month after the administration of procainamide, and the dose of procainamide was decreased. On the next day, he was brought to our hospital due to cardiac pulmonary arrest. Initial rhythm was ventricular fibrillation and the corrected QT intervals (QTc) were prolonged (531 ms). Blood examination revealed that N-acetyl procainamide (NAPA), metabolite of procainamide, was significantly higher than the recommended threshold. NAPA was identified as the cause of prolonged QTc and procainamide was stopped. NAPA decreased under the recommended threshold on the seventh day and the QT intervals were normalized. This case report outlines the first case of long QT syndrome caused by NAPA in a hemodialysis patient.

<Learning objective: Administration of procainamide could be dangerous even in patients undergoing hemodialysis whose serum procainamide level is within normal limits. We should pay careful attention to it and must not forget to measure the concentrations of procainamide and NAPA. The measurement of QT intervals could help to avoid a fatal side effect.>

Introduction

We sometimes encounter patients with hypertrophic obstructive cardiomyopathy (HOCM) who need administration of Na channel blockers in addition to beta-blockers. They may be administered safely in many patients, but some Na channel blockers and their metabolites have K channel blockade profiles, which could provoke QT interval prolongation in a small number of patients. We encountered a patient on hemodialysis in whom the QT intervals were prolonged by procainamide metabolite, N-acetyl procainamide (NAPA). While it is well known that NAPA is more likely to accumulate in the body than procainamide, this is the first report of long QT syndrome caused by this drug in a hemodialysis patient. We are presenting this case with literature reviews.

Case report

A 65-year-old man, who was on dialysis three times a weeks due to end-stage renal failure, received surgical repair of abdominal aortic aneurysm and mitral valve plasty one year prior to this hospitalization. He had been taking 75 mg of cinacalcet, 15 mg of lansoprazole, and 100 mg of aspirin once a day.

The patient had increasingly complained of breathlessness on exertion after surgery. While there was lack of evidence of hypertrophic cardiomyopathy before surgery, echocardiography showed intraventricular septum thickness of 18 mm and posterior wall thickness of 10 mm, indicating asymmetrical septal hypertrophy. There was an intracavitary pressure gradient of 62 mmHg, and left ventricular ejection fraction was 71%. Administration of beta-blocker with carvedilol was started. Its dose was titrated up gradually and maximal dose was achieved eventually (10 mg twice daily). He continued to experience general fatigue and breathlessness on exertion; therefore, class 1A Na channel blocker (procainamide 750 mg/day) was added. After that, shortness of breath was almost resolved and intraventricular pressure gradient decreased from 62 mmHg to 45 mmHg. Electrocardiogram (ECG) at a regular clinical visit one month later showed QT prolongation and QTc intervals were 523 ms even though they were within normal limits before the administration of procainamide. The dosage of procainamide was decreased from 750 to 500 mg daily. On the next day, his wife found him unconscious in his bedroom and emergency medical service (EMS) was called. When EMS arrived on the scene, all his vital signs were absent, indicating cardiac pulmonary arrest (CPA). Automatic external defibrillator was attached and the first analysis showed shockable rhythm. After DC shock, 14 min of cardiac pulmonary resuscitation resuscitated him. Later, the rhythm was revealed as ventricular fibrillation. When he was brought to our hospital, his blood pressure was 172/65 mmHg, heart rate was 50 bpm, ECG monitor displayed regular sinus rhythms, body temperature was 36.5 °C, and level of consciousness was semi coma (Japan Coma Scale: III-100 and Glasgow Coma Scale: E2V4M6). An arteriovenous shunt, which was located in his left arm, sounded good. No additional cardiac sounds were detected but wheezing was prominent in both lateral areas of the lungs. Venous blood gas analysis revealed mild respiratory acidosis, which was considered as the main reason for persistent conscious disturbance. Blood chemistry test revealed slightly elevated serum K level of 5.7 mEq/L, which was unlikely regarded as the cause of CPA. ECG showed normal axis. PR intervals (188 ms) and QRS durations (110 ms) were within normal limits, but QTc intervals were prolonged to 531 ms (Fig. 1). Echocardiograms showed no remarkable changes compared to the images recorded one month before. Coronary angiography showed normal vessels.

Fig. 1.

Electrocardiogram comparing baseline (before administration of procainamide), the first day of hospitalization (Day 1), and the seventh day of hospitalization (Day 7). Before administration, corrected QT intervals (QTc) were within normal limits (453 ms); however, QTc were prolonged at Day 1 (531 ms). After consecutive renal replacement therapy, QTc were resolved within normal limits at Day 7 (451 ms).

We investigated blood concentrations of procainamide and NAPA. The concentration of procainamide was 2.6 μg/mL below the recommended threshold; however, that of NAPA was 27.7 μg/mL beyond the recommended threshold (Table 1). Procainamide administration was stopped, and consecutive renal replacement therapy was performed for 7 days. Hypothermotherapy was introduced and his consciousness was restored. The concentrations of procainamide and NAPA on the seventh day were below the recommended threshold. The QTc intervals were normalized in ECG (451 ms, Fig. 1). He was discharged from the hospital without neurological sequelae on the 43rd day.

Table 1.

Serum concentrations of procainamide, N-acetyl procainamide (NAPA).

	Day 1	Day 7
Procainamide (μg/mL) Criteria: 4–10 μg/mL	2.6	<0.1
NAPA (μg/mL) Criteria: 10–20 μg/mL	27.7	8.1

Discussion

Patients with HOCM often complain of dyspnea on exertion related to exacerbation of intraventricular pressure gradient. Beta-blockers are usually administered as first-line drugs. However, further medication is required because of insufficient benefits of beta-blockers alone in some patients. Class 1A Na channel blocker is used as an additional therapy in these patients.

Antiarrhythmic drugs have proarrhythmic profile. The most serious consequence is prolonged QTc intervals due to prolonged action potential durations, which are mainly configured between phase 0 and 3 of myocardial potential 1, 2. The phase 3 is mainly regulated by the repolarizing currents such as IKs or IKr. Procainamide and NAPA inhibit IKr as class 3 antiarrhythmic drugs [3] and work more strongly as heart rate decreases, which is known as reverse frequency dependence [1]. We had a concern that the direct influence by a class 1A drug caused micro-reentry on pathogenic myocardial muscle of HOCM. One observational study, however, revealed that there were no significant differences in cardiac events between class 1A drug arm and the other arm [4]. In our clinical practice, QT prolongation was obvious and the direct influence was not taken into account.

In our patient, procainamide at normal level was not a culprit drug for QT prolongation, but NAPA at toxic concentration was. It is estimated that 40% and 60% of procainamide are renally excreted and metabolized in the liver into NAPA by N-acetyltransferase II, respectively. In patients without renal or hepatic malfunction, procainamide can be given safely within permissible dosage, except for potential Brugada's syndrome patients [5]. The dialysis rate of procainamide and NAPA was 30% and it is not sometimes controlled strictly in hemodialysis patients compared to renally impaired patients without dialysis. However, NAPA tends to accumulate in the body more than procainamide does because of different pharmacokinetics [6]. For one thing, a rapid phenotype of N-acetyltransferase II, which exists in the majority of Japanese people, might contribute to elevation of NAPA/procainamide ratio. As a result, the concentration of NAPA, regardless of equivalent dialysis rate, remained at higher levels whereas the concentration of procainamide did not. A former report revealed the importance of measuring serum levels of both procainamide and NAPA even in hemodialysis patients [7]. A clinical trial demonstrated that NAPA could cause long QT syndrome [8] and there were also prior case reports of procainamide/NAPA-related long QT syndrome in renally impaired patients without hemodialysis 9, 10. On the other hand, the excretion of procainamide and NAPA is facilitated in patients undergoing hemodialysis. Therefore, QT prolongation should be more unlikely in patients undergoing hemodialysis than in patients without hemodialysis. However, we believe that this is the first report of a hemodialysis patient with long QT syndrome induced by procainamide and NAPA. Any lethal arrhythmias had not been reported in hemodialysis patients previously even if the concentration of NAPA was at toxic levels [9]. The presence of hypertrophic cardiomyopathy may have affected QTc intervals and triggered abnormal electrical activities in our patient.

Our patient had taken 10 mg of carvedilol twice daily and it decreased heart rate. In his situation, IKr was strongly inhibited with reverse frequency dependence, and eventually it was related to drug-induced long QT syndrome. It was difficult to avoid heart rate drop because of the necessity of beta blockade in our patient. We should have measured procainamide and NAPA concentrations and QTc intervals one week after the administration of procainamide.

After removal of procainamide, his dry weight was not set strictly at the ideal level because mild dyspnea presented due to intraventricular obstruction. In the future, if heart failure worsens or if he suffers from breathlessness, surgical septal-myectomy or percutaneous transluminal septal myocardial ablation should be considered.

Thus, we observed secondary long QT syndrome caused by NAPA in a hemodialysis patient. Although procainamide is not absolutely contraindicated and is able to be administered even in patients with renal dysfunction, it can be a harmful prescription. We should remember that antiarrhythmic drugs affect multi channels in vivo and that there is a probability that side effects can be induced even if dialyzable drugs are used in hemodialysis patients. The frequent evaluations of QT intervals with measurements of serum procainamide and NAPA levels can help to avoid a fatal side effect.

Conflict of interest

There is no conflict of interest.