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Internist, Intensivist, Department of Intensive Care, Twenteborg Hospital Almelo, Almelo, Netherlands
General Surgeon, Intensivist, Departments of Intensive Care and Surgery, University Hospital Maastricht, Maastricht, Netherlands
Clinical Pharmacist, Department of Clinical Pharmacology, University Hospital Maastricht
Internist, Intensivist, Department of Intensive Care, University Hospital Maastricht
Reprints: Dr. van Mook, University Hospital Maastricht, P Debyelaan 25, 6202 AZ Maastricht, Netherlands, fax 31 (0)43 3874330, Wvm{at}sint.azm.nl
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Abstract |
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CASE SUMMARY: A 33-year-old woman with a 5 year history of systemic lupus erythematosus was admitted to the intensive care unit because of respiratory insufficiency due to Candida albicans pneumonia. Therapy with intravenous fluconazole 200 mg/day, with dose later adjusted according to her renal function, was started. Prolongation of the QTc interval and torsade de pointes occurred. Initially, domperidone, which had been initiated the day before fluconazole, was suspected as the possible cause and was discontinued; ultimately, both drugs were discontinued. However, torsade de pointes recurred several weeks later when the patient was treated with fluconazole for a second time and disappeared again on withdrawal of the drug. According to the Naranjo probability scale, this adverse reaction was highly probable.
DISCUSSION: The risk of torsade de pointes does not correlate in a linear fashion with prolongation of the QTc interval, but an interval beyond 500 msec is considered a significant risk factor. Given that both fluconazole and domperidone are metabolized by the cytochrome P450 system, they may intensify each other's proarrhythmic effects, particularly in patients with concurrent renal dysfunction. These risks are of particular concern in patients whose baseline QTc interval is prolonged for any reason.
CONCLUSIONS: From the case history, as well as use of the Naranjo scale, we concluded that fluconazole was the highly probable cause of the development of torsade de pointes in our patient.
Key Words: Candida pneumonia, domperidone, fluconazole, QTc interval, systemic lupus erythematosus, torsade de pointes
Published Online, July 18, 2006. www.theannals.com, DOI 10.1345/aph.1G741
QT prolongation has been described in patients using combinations of drugs, including fluconazole,5-7 as well as in patients with baseline cardiac abnormalities who are receiving fluconazole.8 To our knowledge, prolongation of the QTc interval and development of torsade de pointes when fluconazole was administered as monotherapy has been previously reported only twice.9,10 We report a patient who initially received fluconazole and domperidone combination therapy, and later fluconazole alone, and developed prolongation of QTc interval and torsade de pointes during both episodes.
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Laboratory investigations showed an elevated C-reactive protein serum concentration (28.9 mg/dL) and normal renal function (serum creatinine 1.03 mg/dL, urea 23.0 mg/dL). Lumbar puncture was negative for microorganisms. Blood cultures and cultures of cerebrospinal fluid revealed no growth of microorganisms. No valvular vegetation or pericardial effusion was visualized on transesophageal echocardiography. Left ventricular function was normal. Since cerebral viral herpes infection could not be ruled out completely, the patient was empirically treated with acyclovir.
The woman was intubated and mechanically ventilated. Chest X-ray was suggestive for infiltrates in the right lower lobe. Bronchoalveolar lavage (BAL) was performed. No Pneumocystis jirovecii (ie, Pneumocystis carinii) was identified, but Candida albicans was found intracellularly in leukocytes in the May-Grünwald stain, which strongly suggested Candida pneumonia. Culture results showed C. albicans in the sputum. Treatment with fluconazole was started (200 mg/day intravenously, adjusted according to her renal function). In addition, amoxicillin/clavulanate and gentamicin were initially prescribed for treatment of pneumosepsis. Vancomycin was added later based on the definitive culture results from the BAL fluid, which also yielded coagulase-negative Staphylococcus. As exacerbation of SLE could not be ruled out, the woman was also treated intravenously with immunoglobulins prednisone. The initial prednisone dose, used on admission to the ICU, was 20 mg daily; it was increased to 60 mg/day 2 weeks later. Serum antinuclear factor concentration was 800 U/L and anti-dsDNA was positive.
An electrocardiogram (ECG), routinely performed on admission, showed sinus tachycardia with a QTc interval of 476 msec, which is prolonged. There were no arrhythmias during the first days of the patient's stay in the ICU.
Because of deterioration of renal function (serum creatinine increased to 5.83 mg/dL, urea increased to 204 mg/dL), continuous veno-venous hemofiltration (CVVH) was started. Approximately 2 weeks after admission to the ICU, the patient developed episodes of self-limiting torsade de pointes, alternating with bradycardia (50 beats/min). The QTc interval was 675 msec and the T waves were changed (Figure 1). At that time, the patient was not receiving any drugs suspected of causing prolongation of QTc interval except fluconazole and domperidone, which was used as a prokinetic agent to promote gastric emptying (Table 1). There were no electrolyte disturbances (serum calcium 4.24 mEq/L, serum albumin 0.96 g/dL, serum sodium 137 mEq/L, serum potassium 4.0 mEq/L, serum magnesium 1.52 mEq/L). Our patient was treated with infusion of magnesium and isoproterenol, which shortened the QTc interval rapidly to values of 443 msec. Domperidone was discontinued.
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During the next few days, torsade de pointes recurred frequently, and the patient required cardioversion on one occasion. Attempts to decrease the dose and subsequently stop isoproterenol administration resulted in an increase of the QTc interval; it was then restarted. After discontinuation of fluconazole, the frequency of torsade de pointes decreased, the QTc interval decreased to the preexistent values over several days (Figure 2), and isoproterenol could be successfully withdrawn. Torsade de pointes did not recur during this time. In the following week, the patient's renal function improved; the creatinine concentration decreased to 1.61 mg/dL, allowing discontinuation of CVVH.
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Fluconazole was immediately withdrawn and magnesium and isoproterenol were administered. Torsade de pointes disappeared gradually and did not recur during the rest of the patient's stay in the ICU. The QTc interval returned to preexistent values 3 days after the last dose of fluconazole (Figure 2). The woman's further stay in the ICU was complicated by difficulties in weaning from the ventilator and polyneuropathy associated with critical illness. Eventually she was transferred to the general internal medicine department. Six weeks after that, she was discharged to a rehabilitation clinic, where she recovered without major neurologic deficits.
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As several cases of ventricular arrhythmia due to domperidone have been reported, this was initially considered the most likely cause of torsade de pointes in our patient.15-20 Drugs with similar molecular structures can prolong the QTc interval. Combining drugs with different molecular structures, which are also QTc interval-prolonging drugs, can increase the risk for torsade de pointes.21,22 At the time of the initial prolongation of the QTc interval, fluconazole and domperidone were the only agents in our patient's treatment regimen known to prolong the QTc interval. Given that both of these medications are metabolized by the cytochrome P450 system, they might have intensified each other's effect on prolonging the QTc interval. When used in combination with other drugs that inhibit the function of cytochrome P450 isoenzymes, especially in a patient with impaired renal function, the concentration of fluconazole can rise above therapeutic level.
Since torsade de pointes resolved 14 days after discontinuation of both domperidone and fluconazole, fluconazole was initially not recognized as the major cause of the QTc interval prolongation and torsade de pointes. Torsade de pointes, however, recurred after fluconazole treatment—but not domperidone—was reinitiated several weeks later. The result of this rechallenge strongly suggests a causal relationship between fluconazole, prolongation of the QTc interval, and development of torsade de pointes. Scoring according to the Naranjo probability scale revealed a highly probable relationship between the drug and these reactions.23 Several factors may have contributed to the occurrence of QTc prolongation in our patient. It has been reported that hemodialysis and hemodiafiltration reduce plasma fluconazole concentration (suggesting that patients treated with fluconazole during CVVH should receive standard maintenance dosages, ie, neither supplementation nor dosage adjustment is required).24
Recently, it was shown that fungicidal fluconazole concentrations can be reached in critically ill patients on CVVH in an ICU setting using doses of 800 mg/day. In previous studies, effective fluconazole concentrations during CVVH were not attained with dosages of 200-600 mg daily.25 Although possible, it is unlikely that, during the first episode of torsade de pointes, while our patient was undergoing CVVH, the concentration of fluconazole was too high. During this episode, the combination of domperidone and fluconazole contributed to the pronounced QTc prolongation and torsade de pointes. However, in the second episode of torsade de pointes, while our patient was not on CVVH, the concentration of fluconazole, despite dose adjustment according to her impaired renal function, may have been high enough to cause QTc prolongation and torsade de pointes. Serum concentration of fluconazole to support this hypothesis was not determined.
Several other risk factors for the development of torsade de pointes26,27 can be identified in our patient: female gender, T wave instability, and T wave morphologic changes during drug treatment. Females, who have longer QTc intervals than males,12 are more prone to develop torsade de pointes when using drugs that can cause further prolongation of the QTc intervals.28
Neurologic causes such as cerebral infarction, transient ischemic attack, and intracerebral hemorrhage can prolong the QT interval.29 In acute stroke, QTc prolongation seems to be related to the size of the lesion.30 Both CT and MRI scanning revealed a small, hypodense lesion on the right side in the pons in our patient. Whether this small cerebral infarction played a contributory role in the prolongation of the QTc interval remains speculative.
Neither pericardial effusion nor pericardial thickening were identified on transesophageal echocardiography, and no changes in PR or ST segments were shown on the ECG. Thus, pericarditis as a cause of prolonged QTc interval was not probable. Myocarditis is also a known cause of QT interval prolongation, but was considered unlikely because of the patient's normal left ventricular function, also determined by transesophageal echocardiography.
Previous ECGs had shown normal QTc intervals, and the patient's family history was negative for cardiac abnormalities and syncope, thereby making a preexisting (but unknown) long QT syndrome less likely. Furthermore, after cessation of all known QT-prolonging drugs, the QTc interval decreased to 409 msec, which is normal.
The patient's history of SLE raised the question as to whether this could be a risk factor for long QT syndrome and torsade de pointes. Although there is a relationship between connective tissue disease and long QT syndrome (58% of pts. with anti-Ro/SSA antibodies have QTc intervals >440 msec),31 we could not find any reports on SLE and long QT syndrome. Therefore, we are unable to answer the question as to why this patient's QTc interval was prolonged before administration of the drugs reported here.
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Monitoring of the heart rhythm and associated QTc interval is advisable, and determination of fluconazole serum concentration may be a useful adjunct in preventing this potentially lethal complication in patients with several risk factors for prolongation of QTc interval and torsade de pointes. This strategy should be further evaluated.
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This article has been cited by other articles:
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  J. H. McMahon and M. L. Grayson Torsades de pointes in a patient receiving fluconazole for cerebral cryptococcosis Am. J. Health Syst. Pharm., April 1, 2008; 65(7): 619 - 623. [Abstract] [Full Text] [PDF]
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