Prolongation of Ventricular Depolarization

Prolongation of Ventricular Depolarization* ECG Manifestation of Mexiletine Toxicity Matthew Q Nora, M.D.; Krishnaswamy ChandrO$ekaran, M.D.; Stephen C. Hammill. M.D.; and Guy 5. Reeder. M.D.

FIGURE 1. Chest ,,-ray film showing bilateral infiltrates.

ical ventilatory support, volume replacement, and dopamine infusion were initiated. A pulmonary arterial catheter was inserted, showing high pulmonary arterial (45/23 mm Hg) and normal capillary (11 mm Hg) pressures. An abdominal ultrasonogram showed gallstones, and the findings from an e"ploratory laparatomy were normal e"cept for ascites and hepatomegaly. Cultures of blood , sputum, and urine were obtained, and ceftazidime and tobramycin were administered. The patient developed disseminated intravascular coagulation and acute renal failure. All cultures were negative, and on the tenth day a physical e"amination disclosed a black scar under the hair on the head. Blood was collected for serologic studies, therapy with antibiotics was suspended, and treatment with tetracyclines was initiated. During the ne"t 12 days the patient became afebrile and was successfully weaned from mechanical ventilation, and a positive Weil-Felh reaction and complement filCation antibodies for Rickettsia canoni were found. The patient was discharged on the 22nd day of hospitalization.

DISCUSSION A meticulous physical examination in the search for the

tache noire gave the clue to the diagnosis in our patient.

This finding was found in 87 percent of patients with boutonneuse fever in a recent study.' The incidence of acute respiratory failure and noncardiogenic pulmonary edema in boutonneuse fever remains to be determined, but it seems to be an extraordinary event.

REFERENCES Montenegro MR, Mansueto S, Hegarty BC, Walker DH. The histology of "taches noires" of boutonneuse fever and demonstration of Rickettsia conorii in them by immunolluorescence. Virchows Arch (Pathol Anat) 1983; 400:309-17 2 Walker DH, Gear JH5. Correlation of the distribution of Rickettsia conorii, microscopic lesions, and clinical features in South African tick-bite fever. Am J Trop Med Hyg 1985; 34:361-71 3 Walker DH, Herrero-Herrero JI, Ruiz-Beltran R, Bullon-Sopelana A, Ramos-Hidalgo A. The pathology of fatal Mediterranean spotted fever. Am J Clin Patholl987; 87:669-72 4 Garcia Miguel MJ, Garcia-Ali" Perez A, de Jose Gomez MI, et al. Fiebre botonosa en el nino. An Esp Pediatr 1985; 22:353-58

Mexiletine is a type 18 antiarrhythmic drug similar to lidocaine. Prolongation of ventricular depolarization has not been previously reported with the usual oral dosage of mexiletine. We describe a patient with renal failure and heart failure on low-dose oral therapy who developed mexiletine toxicity, which was manifested by ECG prolongation of ventricular depolarization. This was confirmed by elevated plasma concentration of mexiletine. This case illustrates that contrary to the usual belief, mexiletine pharmacokinetics are altered by renal failure. It is important to monitor mexiletine therapy by plasma levels in patients with impaired renal function to avoid mexiletine (Chest 1989; 95:925-28) toxicity.

M

exiletine is a type IB antiarrhythmic drug used as an anticonvulsant in the late 1960s. Since the early 1970s, it has been used as an antiarrhythmic in Europe. Its efficacy and pharmacokinetics are well established,'-12 and side effects include hypotension and disturbances in rhythm. 13·" The renal clearance of mexiletine and the effect of urine pH on its excretion have been well elucidated. I._I~ Mexiletine is generally considered to be relatively safe for treating ventricular dysrhythmia in patients with renal insufficiency because of its primarily hepatic elimination. " We describe a case demonstrating prolongation of ventricular depolarization (QRS duration) as a manifestation of mexiletine toxicity, resulting from low-dose (200 mg every 8 h) oral therapy, in a patient with chronic renal failure and non-Q wave myocardial infarction. CASE REPORT A 65-yeaJ'oold white woman with significant coronary artery disease and chronic renal failure was hospitalized for the management of unstable angina. Clinical evaluation demonstrated class 3 heart failure with moderate mitral regurgitation, aortic regurgitation, and frequent ventricular e"trasystoles. Laboratory tests revealed the following values: blood urea, 148 mwdL; creatinine, 4.3 mgldL; and creatine kinase, 91 UIL with an MB fraction of 7 percent-indicating renal failure and myocardial necrosis. A chest ,,-ray film revealed cardiomegaly and pulmonary congestion. Electrocardiogram revealed sinus tachycardia, left ventricular hypertrophy with strain pattern, and frequent ventricular premature beats (Fig 1). During the hospital course, a coronary angiogram revealed diffuse significant coronary artery disease involving all three major vessels. An echocardiogram revealed moderate mitral and aortic valvular regurgitation with poor left ventricular systolic function (ejection fraction, 15 percent). On the fifth hospital day, the blood urea value was 218 mgldL, and serum creatinine was 4.7 mgldL. On the same day, because offrequent comple" ventricular premature -From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN.

Reprint requests: Dr. Reeder; 200 First Street, Sw. Rochester. MN 55905 CHEST I 95 I 4 I APRIL. 1989

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FIGl"RE 1. Electrocardiogram on admission. beats. mexiletine therapy was started, 200 mg every 8 h. Ventricular dysrhythmias responded well to mexiletine, and cardiac monitoring was discontinued after day 6. She was observed to be lethargic and disoriented on day ;. Blood urea and serum creatinine values were 184 mwdL and 4.; mWdL. respectively. Blood was drawn for determination of the plasma mexiletine level. On the ninth day, the patient was drowsy, lethargic. disoriented. and complained of nausea. Clinical examination revealed a pericarof-:--

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dial friction rub but no evidence of decompensated congestive failure. The serum creatinine value was 5.2 mwdL; urea. 175 mgldL; and mexiletine level drawn 36 to 48 h before was 5.3 ....glml (normal. <2.0 ....glml). Electrocardiogram demonstrated a sinus rhythm with first degree AV block and LBBB configuration (Fig 2). Mexiletine therapy was stopped. Subsequently the patient's mental changes improved. On the 12th day. the urea value was 146 mgldL; creatinine. 4.6 mgldL; and the electrocardiogram was similar to

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FIGl'RE 2. Electrocardiogram illustrates mexiletine toxicity. Interventricular conduction delay is present.

926

Prolongation of Ventricular Depolarization (Nora at 8/)

FIGl:RE 3. Resolution of the electrocardiographic changes (interventricular conduction delay) after reducing the mexiletine dosage. the initial tracing (Fig 3). The plasma mexiletine level was 1.3, well within normal limits. Mexiletine therapy was resumed at a very low dose (100 mg twice a day) with adequate control of ectopic activity, and she was discharged to home on day 13. DISCUSSION

Mexiletine is an orally active antiarrhythmic drug, structurally similar to lidocaine. Mexiletine acts on the fast sodium current to reduce the maximal rate ofdepolarization, phase 0 of the action potential. It elevates the threshold of ventricular excitability and reduces ventricular automaticity.,u8 It has no effect on normal sinus node function and very little effect on atrial-His or His-Purkinje conduction."" However, underlying conduction disturbances within the His-Purkinje system or sinus node dysfunction may accentuate the drugs depressant effects on conduction.··' 2 Mexiletine is well absorbed with a high bioavailability and reaches peak plasma level in two to four hours.'2 Ninety percent is metabolized in the liver through oxidative and reductive processes. The half-life is about 10 to 17 h." The therapeutic blood level is in the range of 0.75 to 2.00 .... Wml.·· Higher values are seen in patients with liver disease but not usually in those with renal failure.'1tl Approximately 2 to 10 percent of mexiletine is excreted in the urine as the unchanged drug.'u"" Excretion of mexiletine is pH-dependent: at acidic urine pH, renal clearance increases and elimination half-life decreases. Conversely, elimination half-life increases with alkaline urine.9-" Mexiletine usually is given 200 to 300 mg every 8 h to produce a plasma concentration in the range of 0.75 to 2.00 ....Wml. It has a very narrow therapeutic to toxic margin." The frequency of side effects ranges between 20 and 50 percent in most studies, and approximately 10 to 20 percent

of patients must discontinue therapy because of these side effects.9-" The most frequent side effects include anorexia, nausea, and vomiting, and may be reduced by administering the drug with meals.·· w Central nervous system side effects include tremors, dizziness, blurred vision, ataxia, drowsiness, confusion, nystagmus, diplopia, and dysarthria.·· w ,,, Psychosis and seizures also have been noted to occur.' The severity ofCNS side effects correlated with dose and plasma concentrations; levels above 2 .... Wml are associated with a greater frequency of severe side effects." Cardiovascular side effects include hypotension, sinus bradycardia, worsening of ventricular arrhythmia, complete heart block, and a low probability of precipitating torsade de pointes.... "··u3 Our patient demonstrated, in addition to the major gastrointestinal and CNS side effects, electrocardiographic changes associated with mexiletine toxicity resulting from low-dose oral therapy. Electrocardiographic changes following a single oral dose of 300 mg of mexiletine in patients with renal failure were studied by Wang and associates. ,. There were no changes in the ECG three hours after the oral dose. Cocco et al,23 in a report of a case of torsade de pointes resulting from oral dose of mexiletine (100 mg every 6 h), found no change in the ECG before or after the abrupt onset of torsade. Unfortunately, plasma concentration of mexiletine was not obtained in these studies for correlation. Campbell et aI," described widening of QRS complexes in two patients. In his study these two patients received rapid intravenous infusions of 200 mg of mexiletine. Furthermore, both these patients had acute myocardial infarction. Mexiletine has been shown to exaggerate the underlying conduction disturbance within the His-Purkinje system or in sinus node dysfunction....,. Elimination half-life is prolonged in patients CHEST I 95 I 4 I APRIL, 1989

927

with acute myocardial infarction as demonstrated by shortterm intravenous therap~11 This is probably related to changes in protein binding or hepatic congestion due to clinical or subclinical heart failure. Our patient had a small non-Q wave myocardial infarction, suggested by a creatine kinase MB fraction of7 percent, and \WS in compensated congestive heart failure. Although her liver function test results were normal, congestion still could very well have affected the metabolism resulting in increased elimination half-life. This effect was compounded by preexisting renal failure in our patient, resulting in clinical symptoms of mexiletine toxicit~ The electrocardiographic changes are due to mexiletine toxicity, as indicated by an elevated plasma mexiletine concentration of 5.2 JLWmL that reverted to normal once the drug was discontinued. The plasma level was 1.1 JLWml when the electrocardiographic changes normalized. This case illustrates that, contrary to the general belief, 19.20 mexiletine toxicity can occur in patients with renal failure, as suggested by EI Allaf et al. 24 Transient hepatic congestion without liver function abnormality may be sufficient to prolong the elimination half-life, resulting in clinical toxicity, especially in patients in whom renal clearance of mexiletine is decreased because of renal failure. The usual oral dose of 200 to 300 mg of mexiletine every 8 h required to obtain optimum therapeutic levels (ie, 0.75 to 2.00 JLWml) may, in fact, be too much in patients with renal failure and associated heart failure. Checking the plasma concentration of mexiletine may be helpful in distinguishing gastrointestinal and CNS symptoms of mexiletine toxicity from those of uremia and also in patients with congestive heart failure. This case also illustrates that oral mexiletine can cause prolongation of ventricular depolarization, observed previously by Campbell et aI, II with rapid intravenous infusion of mexiletine in patients with acute myocardial infarction. To our knowledge, this has not been previously observed with the normally recommended oral mexiletine dosage. REFERENCES 1 Talbot RG, Clark RA, Nimmo J, Neilson JMM, Julian DG, Prescott LF. Treatment of ventricular arrhythmias with mexiletine (Ko 1173). Lancet 1973; 2:399-404 2 Waleffe A, Kulbertus HE. The efficacy of intravenous mexiletine on ventricular ectopic activi~ Acta Cardio11977; 32:269-82 3 Kuhn ~ Klicpera M, Kroiss A, Zilcher H, Kaindl F. Antiarrhythmic and haemodynamic effects of mexiletine. Postgrad Med J 1977; 53(suppll):81-83 4 Campbell NPS, Kelly JG, Shanks RG, Adgey AAJ. Long term oral antiarrhythmic therapy with mexiletine. Postgrad Med J 1977; 53(suppll):I43 5 Prescott LF, Pottage A, Clements JA. Absorption, distribution and elimination of mexiletine. Postgrad Med J 1977; 53(suppl 1):50-55

6 Campbell NPS, Kelly JG, Adgey AAJ, Shanks RG. The clinical pharmacology of mexiletine. Br J Clin Phannacoll978; 6:10308 7 Leahey EB Jr, Giardina EG~ Bigger JT Jr. Effect of ventricular failure on steady state kinetics of mexiletine. Clin Res 1980; 28:239A 8 Roos JC, Paalman ACA, Dunning AJ. Electrophysiological effects of mexiletine in man. Br Heart J 1976; 38:1262-71 9 Schrader BJ, Bauman JL. Mexiletine: a new type I antiarrhythmic agent. Drug Intell Clin Pharm 1986; 20:255-60 10 Fenster PE, Comess KA. Pharmacology and clinical use of mexiletine. Pharmacotherapy 1986; 6:1-9

928

11 Chew CYC, Collett J, Singh BN. Mexiletine: a review of its pharmacological properties and therapeutic efficacy in arrhythmias. Drugs 1979; 17:161-81 12 Singh BN, Cho ~ Kuemmerle HE Clinical pharmacology of antiarrhythmic drugs: a review and overvievv, part II. Int J Clio Phannacol Ther Toxicoll981; 19:185-99 13 Velebit ~ Podrid ~ Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 1982; 65:886-94 14 Campbell NPS, Paotridge JF, Adgey MJ. Mexiletine in the management of ventricular dysrhythmias. Eur J Cardiol 1977; 6:245-58

15 Nimmo J. The development of mexiletine in the treatment of cardiac arrhythmias. Postgrad Med J 1977; 53(suppll):I20-23 16 Kiddie MA, Kaye CM, Turner E The inHuence of urinary pH on the elimination of mexiletine. Br J Clin Pharmacol 1974; 1:229-32 17 Johnston A, Burgess CD, Warrington SJ, Wadsworth J, Hamer NAJ. The effect of spontaneous changes in urinary pH on mexiletine plasma concentrations and excretion during chronic administration to healthy volunteers. Br J Clin Phannacol 1979; 8:349-52 18 Vaughan Williams EM. A classification ofantiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol 1984; 24:129-47 19 WangT, Wuellner D, Woosley RL, Stone WJ. Pharmacokinetics and nondialyzability of mexiletine in renal failure. Clin Pbarmacol Ther 1985; 37:649-53 20 Nitsch J, Steinbeck G, Luderitz B. Increase of mexiletine plasma levels due to delayed hepatic metabolism in patients with chronic liver disease. Eur Heart J 1983; 4:810-14 21 Palileo E~ Welch ~ Hoff J, Strasberg B, Bauernfeind RA, Swiryn S, et ale Lack of effectiveness of oral mexiletine in patients with drug-refractory paroxysmal sustained ventricular tachycardia: a study utilizing programmed stimulation. Am J Cardioll982; 50:1075-81 22 Campbell RWF. Memetine. N Eng} J Med 1987; 316:29-34 23 Cocco G, Strozzi C, Chu D, Paosini R. Torsades de pointes as a manifestation of mexiletine toxicity. Am Heart J 1980; 100:87880 24 El A1laf D, Henrard L, Crochelet L, Delapierre D, Carlier J, Dresse A. Pharmacokinetics of mexiletine in renal insufficiency. Acta Cardiol 1980; 25(suppl):55-65

Breakage and Detachment of an Abrams Needle in the Pleural Cavity During Performance of a Pleural Biopsy* Enriqueta Fife, M.D.; Uu{s Force, M.D.; Francese Casarramona, M.D.; and Albert Verdaguer, M.D.

nus is the report of a case of breakage and detachment in the pleural cavity of the tip of a nearly new Abrams needle during performance of a pleural biopsy. We have not found any reference in the literature to similar accidents and do not know what later complications may be produced by the metal body in the pleural cavity. In this case, there have been no complications 12 months after the incident.

P

(Cheat 1989; 95:928-J9)

leural biopsy of transthoracic puncture is an effective means of obtaining parietal pleura samples. It is indi-

*From Hospital L'Alian~

Mataronina, Matar6, Barcelona, Spain.

Breakage and Detachment of Abrams Needle in Pleural Cavity (Fite et eJ)