LETAVERNIER Et Al-2006-Hemodialysis International

8/19/2019 LETAVERNIER Et Al-2006-Hemodialysis International

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Verapamil and mild hyperkalemia in

hemodialysis patients: A potentially

hazardous association

Emmanuel LETAVERNIER, Lionel COUZI, Yahsou DELMAS, Karine MOREAU,

Olivier MURCOTT, Valérie de PRÉCIGOUT

Service de néphrologie et d’hémodialyse, CHU Pellegrin, Bordeaux, France

Abstract

During the past 3 years, 3 patients undergoing intermittent hemodialysis (or about to do so) in our

hospital developed a third-degree atrioventricular block while being treated with verapamil for blood

pressure or supraventricular arrhythmia. In the 3 cases, mild hyperkalemia was concomitant. The

medical history of these patients revealed no intrinsic cause of atrioventricular conduction distur-

bance. We report herein the 3 cases and draw attention to the risks of atrioventricular block in this

particular context.

Key words: Atrioventricular conduction, hemodialysis, hyperkalemia, K(1)(ATP) channels,

verapamil

CASE 1

A 63-year-old-man underwent liver allograft 4 years be-

fore and chronic ciclosporin nephrotoxicity led to hemo-dialysis. He had a history of hypertension treated withconventional-release verapamil and a previous echocar-diography evidenced left ventricular hypertrophy. Previ-ous electrocardiograms revealed a sinusal rhythm and aright bundle-branch block. The patient received 360 mg/ day conventional-release verapamil, calcium carbonate,trimetazidine, omeprazole, ferrous sulfate, rilmenidine,intravenous erythropoietin, sodium polystyrene sulfon-ate, ciclosporin, and steroids. He was found unconsciousand a third-degree atrioventricular block was dia-gnosed. At the time of admittance, serum potassiumlevel was 6.8 mmol/L (No4.9). Serum bicarbonate level

was 13mmol/L (N423), serum calcium level was2.31 mmol/L (2.2oNo2.6), and serum protein levelwas 57g/L (N460). The concentration of verapamil in

blood was 0.6 mg/L (therapeutic level below 0.2 mg/L andtoxic level above 2mg/L). Clinical evolution was goodafter verapamil withdrawal and no pacing was required.

Despite diet inobservance and recurrent hyperkalemia,often superior to 7 mmol/L, the patient remained asymp-tomatic during the 3 following years.

CASE 2

A 57-year-old man had progressive renal failure of unde-termined etiology and underwent intermittent hemodial-ysis for 3 years. Two years before, a brief atrioventricularnodal reentrant tachycardia occurred and 240mg/day slow-release verapamil was prescribed. He received cal-

cium carbonate and intravenous erythropoietin too.Echocardiography revealed a moderate left ventricularconcentric hypertrophy. Previous electrocardiograms re-vealed that heart rhythm was sinusal with a left bundle-branch block. The patient fainted because of a third-de-gree atrioventricular block. At the time of the admittance,serum potassium level was 6.41mmol/L (No4.9). Serumcalcium level was 2.28 mmol/L (2.2oNo2.6) and serumprotein level was 57 g/L (N460). Atropin was success-

Correspondence to: E. Letavernier, Service de néphrologie etd’hémodialyse, CHU Pellegrin, 33700 Bordeaux, France.E-mail: [email protected]

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fully used and verapamil was withdrawn. Four days later,a supraventricular arrhythmia was evidenced and pacingwas indicated.

CASE 3 A 58-year-old man had end-stage renal failure due to ne-phroangiosclerosis. Hemodialysis intermittent treatmentwas planned. Inflammatory bowel disease, without evi-dence of systemic amyloidosis, also affected him. He re-ceived 240mg/day slow-release verapamil because of hypertension. Other treatments were azathioprine, ram-ipril, nicardipine, pravastatine, calcium carbonate, citrate,zopiclone, and darbepoietin alpha. Previous electro-cardiograms were normal and no previous echocardiog-raphy was realized. Eleven days after receivingverapamil, the patient fainted and was taken to the car-

diology unit. A third-degree atrioventricular block with a junctional rhythm was diagnosed. Serum potassiumlevel was 6.7 mmol/L (No4.9). Serum calcium levelwas 2.05 mmol/L (2.2oNo2.6), serum protein levelwas 59g/L (N460), and serum bicarbonate level was17 mmol/L (N423). An emergency hemodialysis wasperformed and verapamil was withdrawn. The patientrapidly recovered, electrocardiograms normalized, and nopacing was indicated. The patient remained asymptomat-ic, despite recurrent predialysis hyperkalemia during thefollowing year.

DISCUSSION

Verapamil, a phenylalkylamine, is useful in the treatmentof hypertension, stable angina, and narrow QRS supra-ventricular arrhythmias. Although it is the oldest calciumchannel blocker, recent studies evidenced its effectivenessand verapamil is being rediscovered in the light of evi-dence-based trials.1,2 Moreover, a recent study suggestedthat calcium channel blockers (dihydropyridines andnondihydropyridines) use was associated with a lowerrisk of mortality among end-stage renal disease patients.3

The 3 patients received verapamil, a drug with low prev-

alence in our hemodialysis unit (o

5%), in order to con-trol blood pressure and supraventricular arrhythmia;none of them had previous conduction disturbance ex-cept bundle-branch block, which is not a contraindica-tion to verapamil prescription.

Verapamil’s use in essential hypertension seems to besafe. None of the 4247 patients (aged 17–89 years) whoreceived slow-release verapamil 240 mg in an open study developed atrioventricular block.4

No changes in dose or mode of application of verapa-mil (conventional or slow release) are recommended withany mode of renal replacement therapy. The terminalelimination rate constant, clearance, volume of distribu-tion, and bioavailability of verapamil are not significantly

different between patients undergoing maintenancehemodialysis and normal subjects.5,6 Nevertheless, thereare reports of complete atrioventricular blockade second-ary to conventional and slow-release verapamil in patientson hemodialysis.7,8

The liver function of the 3 patients was normal and theprescribed doses were similar to those recommended by the guidelines. There was no reason to suspect a drugoverdose, although the quantity of verapamil in bloodwas measured in the first case only and was above theusual therapeutic range (but markedly below the toxiclevel). Moreover, no drug with negative chronotropic ordromotropic effects was associated to the verapamil andthere was no other electrolyte abnormality with the ex-ception of acidosis and no evidence for tissue underper-fusion. Atrioventricular conduction defects amonguremic patients have also been attributed to extensivemetastatic calcifications,9 consecutive to elevated cal-cium-phosphate product. Actually, one patient (Case 1)exhibited aortic and mitral valve calcifications. No othercause of intrinsic atrioventricular conduction disturbancesuch as ischemia, infiltrative disease, collagen vasculardisease, myotonic muscular dystrophy, trauma, and fa-milial or infectious disease was found, although the sec-ond case illustrates that idiopathic degeneration cannot

be excluded. Patients who present with heart block onmedication often have recurrent heart block after themedication has been withdrawn.10 However, there wasno recurrence of atrioventricular block after verapamilwithdrawal, although predialysis hyperkalemia was fre-quent during the follow-up (Cases 1 and 3).

A mild hyperkalemia (such as 6.5 mmol/L) is a com-mon metabolic disorder among patients undergoing in-termittent hemodialysis and often reflects dietinobservance. Nevertheless, atrioventricular conductiondisturbance is fortunately less common.

Verapamil is not a pure calcium channel blocker but

also blocks the cardiac ATP-sensitive potassium channels(K(1)(ATP) channels).11 K(1)(ATP) channels are het-eromeric complexes of pore-forming inwardly rectifyingpotassium channel subunits and regulatory sulfonylureareceptor subunits that are activated during ischemia. Micelacking the gene encoding Kir6.1 (known as Kcnj8), aK(1)(ATP) channel, have a high rate of sudden deathassociated with cardiac ischemia followed by atrioven-tricular block,12 and activation of K(1)(ATP) channels by

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pinacidil restores conduction and excitability in the bor-der zones of healing infarcts.13 Moreover, aprikalim, aK(1)(ATP) channel opener, attenuates the Na1-Ca21

exchange outward current elevated by hyperkalemia,which may attenuate the intracellular calcium elevation

during hyperkalemia and improve the contractilefunction after hyperkalemia-induced cardioplegia in theventricular myocytes.14 Thus, coexistence of mild hyper-kalemia and K(1)(ATP) channels blockade by verapamilmight explain why atrioventricular blockade occurred inthis context.

In conclusion, patients treated with verapamil and whoare undergoing intermittent hemodialysis, or with end-stage renal failure, are likely to develop a third-degreeatrioventricular block when mild hyperkalemia occurs.Thus, physicians should be particulary watchful aboutthe diet of these patients and electrocardiographic follow-up should be recommended. Aortic and mitral valve cal-cifications, left ventricular hypertrophy, or bundle-branchblock should make the physicians cautious too. Finally,verapamil indication could be discussed when observ-ance of the low potassium diet is poor.

Manuscript received May 2005; revised November 2005.

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11 Kimura S, Bassett AL, Xi H, Myerburg RJ. Verapamil di-minishes action potential changes during metabolic in-hibition by blocking ATP-regulated potassium currents.Circ Res. 1992; 71:87–95.

12 Miki T, Suzuki M, Shibasaki T, et al. Mouse model of Prinzmetal angina by disruption of the inward rectifierKir6.1. Nat Med. 2002; 8:466–472.

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LETAVERNIER Et Al-2006-Hemodialysis International