Recent data demonstrate that patients affected with hypokalemic salt-losing tubulopathies are prone to acute cardiac arrhythmias and rhabdomyolysis. The tendency to these potentially fatal complications is especially high if chronic hypokalemia is severe, in patients with diarrhea, vomiting or a prolonged QT interval on standard electrocardiography, in patients on drug management with compounds prolonging the electrocardiographic QT interval (including antiarrhythmic agents, some antihistamines, macrolides, antifungals, psychotropics, ß2-adrenergic agonists or cisapride), following acute alcohol abuse and during exercise. Cardiac arrhythmias and rhabdomyolysis occur with sufficient frequency in hypokalemic salt-losing tubulopathies to merit wider awareness of their presence and the preparation of specific prevention and management recommendation

Bettinelli, Alberto

Bianchetti, Mario

Caiata-Zufferey, Maria

Cortesi, Cinzia

Giannini, Olivier

Lava, Sebastiano

Tammaro, Fabiana

RERO DOC Digital Library

EDITORIAL COMMENTARYCardiac arrhythmias and rhabdomyolysisin Bartter–Gitelman patientsCinzia Cortesi & Sebastiano A. G. Lava & Alberto Bettinelli & Fabiana Tammaro &Olivier Giannini & Maria Caiata-Zufferey & Mario G. BianchettiReceived: 8 April 2010 /Revised: 11 May 2010 /Accepted: 17 May 2010 /Published online: 13 June 2010# IPNA 2010Abstract Recent data demonstrate that patients affectedwith hypokalemic salt-losing tubulopathies are prone toacute cardiac arrhythmias and rhabdomyolysis. Thetendency to these potentially fatal complications isespecially high if chronic hypokalemia is severe, inpatients with diarrhea, vomiting or a prolonged QTinterval on standard electrocardiography, in patients ondrug management with compounds prolonging the elec-trocardiographic QT interval (including antiarrhythmicagents, some antihistamines, macrolides, antifungals,psychotropics, ß2-adrenergic agonists or cisapride), fol-lowing acute alcohol abuse and during exercise. Cardiacarrhythmias and rhabdomyolysis occur with sufficientfrequency in hypokalemic salt-losing tubulopathies to meritwider awareness of their presence and the preparation ofspecific prevention and management recommendations.Keywords Bartter syndrome . Cardiac arrhythmia .Gitelman syndrome . Hypokalemia . Hypomagnesemia .Rhabdomyolysis . Sudden cardiac deathHypokalemic salt-losing tubulopathies, such as Bartterand Gitelman syndromes, are a group of closely relatedtubular disorders, first described in 1962, which aretransmitted as autosomal recessive traits. All Bartter–Gitelman patients share several characteristics, includinghypokalemia (with or without concurrent hypomagnese-mia), metabolic alkalosis, normal or low blood pressure,and activated renin–angiotensin–aldosterone andprostaglandin–kinin systems [1–3].Thirteen years ago, a boy with unclassified Bartter–Gitelman syndrome in our care died suddenly [4]. Sincepotassium depletion, with or without concurrent magne-sium depletion, imparts an increased risk for developingcardiac arrhythmias culminating in syncope or even suddendeath (this link is very well documented for patientsmanaged with thiazide diuretics), we attributed the deathto hypokalemia [5–9].A prolonged QT interval on standard electrocardiography[10, 11] imparts an increased risk for developing aventricular arrhythmia culminating in syncope or suddendeath (Fig. 1). In agreement with this finding, we haveobserved during years of clinical practice that the QT-intervalis often prolonged in patients with Gitelman syndrome,which is the most frequent variant of these syndromes,leading us to speculate that these patients are of an increasedrisk of developing dangerous cardiac arrhythmias [12].However, continuous ambulatory electrocardiography andC. Cortesi : S. A. G. Lava :M. G. BianchettiDepartment of Pediatrics, Mendrisio and Bellinzona Hospitals,University of Bern,Bern, SwitzerlandA. Bettinelli : F. TammaroDepartment of Pediatrics, San Leopoldo Mandic Hospital,Merate, ItalyO. GianniniNephrology and Internal Medicine Services,Ospedale Regionale Beata Vergine,Mendrisio, SwitzerlandM. Caiata-ZuffereyInstitute of Communication and Health,Università della Svizzera Italiana,Lugano, SwitzerlandM. G. Bianchetti (*)San Giovanni Hospital,6500 Bellinzona, Switzerlande-mail: mario.bianchetti@pediatrician.chPediatr Nephrol (2010) 25:2005–2008DOI 10.1007/s00467-010-1580-4exercise testing failed to detect significant abnormalities ofcardiac rhythm in our Gitelman patients [13]. Nonetheless,since both hypokalemia and hypomagnesemia were rathermild in these patients, we presumed [14] that dangerouscardiac arrhythmias may occur in patients with severehypokalemia (and hypomagnesemia), as indicated by thecase of a newborn with profound hypokalemia in the contextof the antenatal form of Bartter syndrome, who developedsevere cardiac arrhythmias and cardiac arrest [15].Considering the persisting uncertainty related to thepossible occurrence of cardiac arrhythmias culminating insyncope or sudden death in the context of Bartter–Gitelmansyndromes, we conducted a survey/inquiry among physi-cians caring for Bartter–Gitelman children, which disclosedfour patients with lethal and three with severe non-lethalcardiac arrhythmias [16]. Six recent case reports support theassumption that hypokalemia may cause dangerous cardiacarrhythmias in Bartter–Gitelman patients [17–21].In addition to its potential to cause cardiac arrhyth-mias, severe hypokalemia may effect dissolution of theperipheral striated muscle fibers with leakage of theintracellular constituents, a distinctive condition knownas rhabdomyolysis [22, 23]. The immediate consequencesof rhabdomyolysis include hyperkalemia (and hyperphos-phatemia) resulting from the release of potassium andphosphorous from damaged muscle, which in turn maycause cardiac arrhythmias, and acute kidney injury. In fact,two recent reports indicate that Bartter–Gitelman patientsoccasionally do develop rhabdomyolysis [24, 25].Based on the afore-mentioned data, we offer some take-home messages relevant to the prevention of hazardouscardiac arrhythmias and rhabdomyolysis in patients affectedwith hypokalemic salt-losing tubulopathies. The value ofour advice should be confirmed in long-term observationalstudies.1) Severe chronic hypokalemia (≤2.5 mmol/L) is hazard-ous [5–7]. Consequently, in addition to potassium saltsand cyclooxygenase inhibitors [1, 2], potassium-sparing diuretics and blockers of the renin–angioten-sin–aldosterone system deserve consideration in patientswith refractory hypokalemia or with gastrointestinal sideeffects secondary to potassium supplementation ormedication with nonselective anti-inflammatory drugs.However, very limited clinical experience has beenreported to date with blockers of the renin–angiotensin–aldosterone system in these patients [26, 27].2) In Bartter–Gitelman patients, acute diarrhea orvomiting [16], even if mild, may cause very severehypokalemia (≤2.0 mmol/L). In this setting, earlyreferral and prompt electrolyte and fluid repair are ofparamount importance, since the repair of hypokale-mia with oral potassium supplementation, potassium-sparing diuretics, cyclooxygenase inhibitors, andblockers of the renin–angiotensin–aldosterone systemoften meets with limited success. In fact, hypokalemiais largely secondary to extracellular fluid volumedepletion, a potent stimulus for the renin–angioten-sin–aldosterone system [28], suggesting that address-ing directly extracellular fluid volume depletion mightV2V2bV2V3V3V3V4V4V4PlasmaPotassium1.4 mmol/LPlasmaPotassium1.8 mmol/LPlasmaPotassium2.0 mmol/LabcFig. 1 Electrocardiographic changes induced by hypokalemia are aflat or even inverted T wave (a), a depressed ST segment (b), and thepresence of a U wave (c). Other findings, especially in the presence ofcoexistent hypomagnesemia, include a prolonged QT interval,ventricular extrasystoles, ventricular tachycardia, torsades de pointes,and ventricular fibrillation. The figure depicts the electrocardiographicsignals in a female patient with the presumed diagnosis of Barttersyndrome admitted with a potassium level of 1.4 mmol/L. The figureillustrates electrocardiography at presentation and following an initialcorrection of hypokalemia2006 Pediatr Nephrol (2010) 25:2005–2008be a further, hitherto rather neglected treatment optionfor hypokalemia [3]. It is therefore tempting to advisea more liberal fluid and salt intake in order to prevent—at least in part—the tendency toward severe,chronic hypokalemia. Conversely, in patients withacute diarrhea and vomiting, parenteral rehydrationwith isotonic saline may be as important as directpotassium replacement to treat very severe hypokale-mia. One further critical therapeutic principle con-cerns the intravenous administration of potassium inglucose-free solutions, since this sugar may cause afurther decrease in potassium level, precipitatingarrhythmias and rhabdomyolysis [7].3) A prolonged QT interval on standard electrocardiographyimparts an increased risk for the development of cardiacarrhythmias, culminating in syncope or sudden death thatreflects both acquired (including potassium levels) andcongenital factors [10, 11]. Considering that a prolongedQT interval has been associated with Bartter–Gitelamansyndromes whatever the potassium levels, the QTinterval has to be systematically measured in thesepatients. In those patients with a prolonged QT interval,potassium levels have to be more closely (≥3.0 mmol/L)controlled.In Bartter patients with a prolonged QT interval (Table 1),as in patients with hypertrophic cardiomyopathy, coronaryartery anomalies, Marfan syndrome, aortic stenosis, andWolff–Parkinson–White syndrome, exercise or participationin recreational and, especially, competitive sports isassociated with some risk of sudden cardiac death [10, 11].In these patients, a history of syncope is a further powerfulpredictor of life-threatening cardiac events [10, 11]. As aconsequence, Bartter–Gitelman patients with a prolonged QTinterval should avoid getting involved in competitive sports.This recommendation is supported by the results of a studythat demonstrated an impaired capacity to adapt leftventricular function in response to exercise in Bartter–Gitelman patients [29]. Considering that the recommendationis often hard on adolescents and adults involved incompetitive sport activities, we usually seek the advice of acardiologist.Finally, in Bartter patients, further promoters of cardiacarrhythmias or rhabdomyolysis deserve consideration.1) In patients with either a congenital or acquired long QTinterval, acute alcohol abuse and a number of com-pounds (including antiarrhythmic agents, some antihist-amines, macrolides, antifungals, psychotropics, β2-adrenergic agonists or cisapride) may cause a furtherQT prolongation and, therefore, cardiac arrhythmias[10, 11].2) Conversely, alcohol abuse and both illicit (mostfrequently cocaine or ecstasy) and prescribed drugs(most frequently statins and antipsychotic drugs) arepotentially myotoxic. The spectrum of severity is broadand varies from an asymptomatic increase in bloodcreatine kinase level to acute rhabdomyolysis. Hence,we assume (but can not prove) that these factors mayenhance the tendency towards rhabdomyolysis inBartter syndrome [22, 23]. Educating Bartter patients,their family members and their family physicians onalcohol abuse and illicit or prescribed drugs that mayprolong the QT interval or cause myotoxicity is oftremendous importance.In conclusion, improving the outcome of rare diseasesis of the utmost concern. Cardiac arrhythmias andrhabdomyolysis occur, in our opinion, with sufficientfrequency in Bartter–Gitelman patients to merit a widerawareness of their presence and the preparation of specificprevention and management recommendations.References1. Bettinelli A, Vezzoli G, Colussi G, Bianchetti MG, Sereni F,Casari G (1998) Genotype-phenotype correlations in normoten-sive patients with primary renal tubular hypokalemic metabolicalkalosis. J Nephrol 11:61–692. Zelikovic I (2003) Hypokalemic salt-losing tubulopathies: anevolving story. Nephrol Dial Transplant 18:1696–17003. 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Cardiac arrhythmias and rhabdomyolysis in Bartter-Gitelman patients

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Cardiac arrhythmias and rhabdomyolysis in Bartter-Gitelman patients

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