Refractory Anaphylactic Shock Associated with ...

Refractory Anaphylactic Shock Associated with Ketoconazole Treatment Ping-Yen Liu, Cheng-Han Lee, Li-Jen Lin, and Jyh-Hong Chen

OBJECTIVE:

To report a rare but severe reaction of refractory anaphylactic shock with ketoconazole treatment–associated hypotensive episodes in an elderly patient. CASE SUMMARY: A 72-year-old woman received antifungal therapy for her almost completely occluded cornea infected with Candida

albicans. She was initially prescribed oral ketoconazole 200 mg twice daily. She developed hypotension over the first 2 days of therapy (BP 136/82 mm Hg at baseline; 90/50 mm Hg on day 2). Severe hypotension (BP 90/49 mm Hg) unresponsive to fluid therapy or high-dose dopamine developed on day 4 of therapy. An invasive Swan–Ganz catheterization study showed a very low level of peripheral vascular resistance with high cardiac output index without clinical signs of infection. When laboratory tests showed a high level of plasma tryptase, anaphylactic redistribution shock was diagnosed. Her vital signs became more stable after treatment with hydrocortisone and epinephrine infusion. She was discharged in good condition after 24 hours of observation. DISCUSSION:

As of December 2004, refractory anaphylactic shock resulting from ketoconazole use had not been reported. The events of hypotension were strongly associated with the intake of ketoconazole. The hemodynamic results obtained with Swan–Ganz catheterization were compatible with anaphylactic shock. The Naranjo probability scale showed a probable association of the adverse event with ketoconazole.

CONCLUSIONS: Ketoconazole may cause severe anaphylactic shock even when taken orally. Invasive catheterization and elevated tryptase levels can provide important information in the management of anaphylactic shock. KEY WORDS: anaphylactic shock, ketoconazole, tryptase.

Ann Pharmacother 2005;39:547-50. Published Online, 8 Feb 2005, www.theannals.com, DOI 10.1345/aph.1E465

etoconazole is an effective and widely prescribed oral K antimycotic medication. We report a severe but delayed reaction of refractory anaphylactic shock with drugassociated vital sign changes in an elderly patient who was successfully treated with invasive hemodynamic monitoring and critical care. Case Report A 72-year-old woman with a chronic corneal ulcer in her left eye has regularly received ophthalmic medications, including gentamicin, amikacin, and amphotericin B, for the past 20 years. Her body mass index is 27 kg/m2. She has had a history of hypertension for 20 years and receives amlodipine 5 mg/day for control. No other CYP450 isoenzyme inhibitor medications and no other imidazole antifungals (including cimetidine and metronidazole) were recorded in her medical records, and no anaphylaxis or drug intolerance reaction had been observed before. Author information provided at the end of the text.

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The woman’s baseline liver and renal profiles were normal during this admission. Due to the progressive deterioration of her visual accuracy, she was admitted for an antifungal treatment course of her nearly occluded cornea, which was infected with Candida albicans. She was initially prescribed oral ketoconazole 200 mg twice daily. Detailed sequential vital signs are shown in Figure 1. The woman’s blood pressure was checked on the first morning at 0900 and was 136/82 mm Hg, with a heart rate of 66 beats/min. She took the first tablet of ketoconazole at 0930. No edema, pruritus, nausea, or vomiting was reported immediately after taking this medication. During the first 2 days, blood pressure readings obtained 2 hours after the patient took ketoconazole were only 90/50 mm Hg, without reflex tachycardia (HR 60 –70 beats/min). Nevertheless, because the patient was asymptomatic, she did not receive further treatment for the hypotension. On the third day of admission, she took only one tablet of ketoconazole in the morning. Her blood pressure became more stable during the medication-free period from the evening to the following early morning (~130/88 mm Hg). She resumed the twice-daily regimen on the following day. On the fourth day of admission, the woman developed an even more serious reaction, with severe hypotension unresponsive to rapid infusion of fluid (2 L of NaCl 0.9% followed by 100 mL/h) and high-dose inotropic dopamine (30 µg/kg/min) infusion started at 2000 in the after-

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noon. She became lethargic, complained of general weakness and dizziness, and finally collapsed with a blood pressure of only 60/40 mm Hg. The patient, however, did not lose consciousness. There were no clinical signs or symptoms of infection and no growth of bacteria or fungus in her blood cultures. Her extremities were warm (body temperature 37 ˚C). No signs of pruritus or urticaria were found on her entire body. The jugular veins were not engorged, and central venous pressure, which was measured later by catheterization, was normal at 12 mm Hg. The lung fields were bilaterally clear, and no cardiac murmur was detected. A screen echocardiogram showed a well-contracted left ventricle without valvular disorder or pericardial tamponade. An invasive Swan–Ganz catheterization study was performed; data showed a very low level of peripheral vascular resistance with high cardiac output index, which might indicate anaphylactic redistribution shock (Table 1). Thyroid and adrenal function were normal. No skin prick test was done and no serum immunoglobulin (Ig) E antibody tests were performed. However, the plasma tryptase level tested by ELISA drawn one hour after the onset of symptoms was high at 35 ng/L (normal 20 ng/L) might indicate a reaction clinically classified as anaphylaxis. A clinical trial was conducted on the diagnosis of anaphylaxis after a 64-sting challenge.9 The investigators found that serial changes of tryptase lev-

Figure 1. The sequential responses and changes of vital signs.The upper and lower lines indicate the systolic and diastolic blood pressures, respectively, with vital signs checked 4 times per day.

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Refractory Anaphylactic Shock Associated with Ketoconazole

els between baseline and peak levels could increase the sensitivity and specificity of diagnosis made by peak tryptase level alone. Positive serum-specific IgE antibodies indicate anaphylactic shock, manifesting as an immunemediated nature of the reactions. Anaphylactic shock may clinically mimic septic shock with low peripheral vascular resistance and high cardiac output. Initially, our patient was treated with ketoconazole for a corneal infection with C. albicans. Sepsis should be taken into consideration during the first differential diagnosis. However, no growth of bacteria or fungus was found in her blood cultures. In addition, the higher serum tryptase level during the event with a lower level during follow-up in this case helps us in the differential diagnosis of possible shock etiologies.1,9 Azole antifungals have been reported to substantially inhibit the metabolism of calcium-channel blockers.10,11 Although amlodipine has never been specifically implicated in these reports, amlodipine is a substrate of CYP3A4, of which ketoconazole is a potent inhibitor. An interaction was possible between these 2 drugs and potentially prolonged the duration of hypotension. This concomitant use of amlodipine reduced the possibility of an anaphylactic reaction due only to ketoconazole in this case report. Adrenal insufficiency is well known as one of the adverse effects of high-dose ketoconazole, but it has also been reported to occur within 2 days with doses as low as 200 mg twice daily.12 Our patient’s plasma cortisol level was normal during the event, which may indicate an insufficient response to the shock status. However, the normal data after follow-up supported that adrenal crisis was less likely in this event.

Conclusions The findings presented here suggest that ketoconazole may cause a severe anaphylactic shock reaction even when taken orally. Invasive catheterization and plasma-elevated tryptase can add additional and important information in the management of anaphylactic shock. Since anaphylaxis can be a serious reaction occurring even in the delayed period of usage, healthcare professionals should be aware of this possibility when prescribing these agents. Ping-Yen Liu MD, Clinical Assistant Professor of Medicine, Division of Cardiology, Department of Internal Medicine, National ChengKung University Medical Center; Institute of Clinical Medicine, National Cheng-Kung University, Tainan, Taiwan Cheng-Han Lee MD, Senior Fellow of Cardiovascular Medicine, Division of Cardiology, Department of Internal Medicine, National Cheng-Kung University Medical Center Li-Jen Lin MD, Chief of Cardiovascular Medicine, Associate Professor of Medicine, Division of Cardiology, Department of Internal Medicine, National Cheng-Kung University Medical Center Jyh-Hong Chen MD PhD FACC, Dean of National Cheng-Kung University Hospital; Professor of Medicine, Division of Cardiology, Department of Internal Medicine, National Cheng-Kung University Medical Center Reprints: Dr. Liu, National Cheng-Kung University Medical Center and Institute of Clinical Medicine, National Cheng-Kung University, No.138 Sheng-Li Rd., Tainan 704, Taiwan, fax 886-6-2753834, [email protected]

References

1. Di Giampaolo L, Toto E, Travaglini P, Russi M, Huang SH, Boscolo P, et al. [Serum tryptase: marker of occupational anaphylaxis] Italian. G Ital Med Lav Ergon 2003;25(suppl):144-5. 2. Gonzalez-Delgado P, Florido-Lopez F, Saenz de San Pedro B, CuevasAgusti M, Marin-Pozo JF. Hypersensitivity to ketoconazole. Ann Allergy 1994;73:326-8. 3. Valsecchi R, Pansera B, di Landro A, Cainelli T. Contact dermatitis from ketoconazole (letter). Contact Dermatitis 1993;29:162. Table 1. Swan–Ganz Catheterization Profiles Before and After 4. van Dijke CP, Veerman FR, Haverkamp HC. Anaphylactic reactions to ketoconazole (letter). Br Med J (Clin Res Treatment with Epinephrine and Hydrocortisone Ed) 1983;287:1673. Before Treatment After Treatment Reference 5. Cauwenbergh G. Safety aspects of ketoconazole, the Parameter (day 4, 2200) (day 5, 0800) Range most commonly used systemic antifungal. Mycoses 1989;32(suppl):59-63. RA pressure (mm Hg) 12 13 0–6 6. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, RV pressure (mm Hg) 26/11 24/13 17–30/0–6 Roberts EA, et al. A method for estimating the probabiliPA pressure (mm Hg) 27/13 25/15 15–30/5–13 ty of adverse drug reactions. Clin Pharmacol Ther PCW pressure (mm Hg) 12 14 2–12 1981;30:239-45. 7. Tang AW. A practical guide to anaphylaxis. Am Fam Cardiac output (L/min) 6.2 5.6 3–7 Physician 2003;68:1325-32. Cardiac index (L/min/m2) 4.0 3.6 2.5–4.5 8. Dybendal T, Guttormsen AB, Elsayed S, Askeland B, SVR (dynes•sec/cm5) 672 1082 900–1400 Harboe T, Florvaag E. Screening for mast cell tryptase SVRI (dynes•sec•m2/cm5) 1048 1656 1640–2580 and serum IgE antibodies in 18 patients with anaphylactic shock during general anaesthesia. Acta Anaesthesiol PVR (dynes•sec/cm5) 39 29 37–97 Scand 2003;47:1211-8. PVRI (dynes•sec•m2/cm5) 60 44 70–180 DOI 10.1046/j.1399-6576.2003.00237.x Heart rate (beats/min) 64 60 9. Brown SG, Blackman KE, Heddle RJ. Can serum mast BP (mm Hg) cell tryptase help diagnose anaphylaxis? Emerg Med systolic 90 126 Australas 2004;16:120-4. diastolic 49 80 10. Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazole mean 63 95 greatly increases plasma concentrations and effects of felodipine. Clin Pharmacol Ther 1997;61:410-5. PA = pulmonary artery; PCW = pulmonary capillary wedge; PVR = pulmonary vas11. Heinig R, Adelmann HG, Ahr G. The effect of ketoconacular resistance; PVRI = pulmonary vascular resistance index; RA = right atrium; zole on the pharmacokinetics, pharmacodynamics, and RV = right ventricle; SVR = systemic vascular resistance; SVRI = systemic vascusafety of nisoldipine. Eur J Clin Pharmacol 1999;55:57-60. lar resistance index. 12. Best TR, Jenkins JK, Murphy FY, Nicks SA, Bussell

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P-Y Liu et al. KL, Vesely DL. Persistent adrenal insufficiency secondary to low-dose ketoconazole therapy. Am J Med 1987;82:676-80.

EXTRACTO OBJECTIVO: El ketoconazol es un fármaco antimicótico eficaz por vía oral que se prescribe ampliamente. Describimos una reacción adversa rara y grave consistente en shock anafiláctico refractario con cambios de los signos vitales asociado al uso de ketoconzal en una paciente de edad avanzada. RESUMEN DEL CASO: Una mujer de 72 años recibió tratamiento antimicótico para la córnea casi totalmente blancuzca infectada con Candida albicans. Inicialmente, se le prescribió ketoconazol oral y desarrolló hipotensión como respuesta tardía. Finalmente, la hipotensión fue grave y no respondió al tratamiento intravenoso ni a dosis altas de dopamina. Mediante un catéter de Swan–Ganz se determinó que había un nivel muy bajo de resistencia vascular periférica con un índice alto del rendimiento cardíaco, sin signos de infección. La información adicional sobre los niveles elevados de triptasa en plasma, permitió diagnosticar el cuadro de shock anafiláctico de redistribución. Los signos vitales se estabilizaron tras el tratamiento con una infusión de hidrocortisona y epinefrina. La paciente se dio de alta con buen estado al día siguiente, tras permanecer 24 horas en observación. DISCUSION: Es la primera vez que se notifica un caso de shock anafiláctico refractario debido al uso de ketoconazol. La hipotensión estuvo muy relacionada con el uso del ketoconazol. La paciente fue sometida a una cateterización de Swan–Ganz, y los resultados hemodinámicos fueron compatibles con un shock anafiláctico. Se aplicó el algoritmo de causalidad de Naranjo y la reacción adversa al medicamento se clasificó como “probable” para el uso de ketoconazol. CONCLUSIONES: El uso del ketoconazol podría causar una reacción de shock anafiláctico grave aun cuando se toma por vía oral. Una cateterización invasiva y los niveles elevados de triptasa pueden aportar información importante para el manejo del shock anafiláctico.

Rafaela Mena

SOMMAIRE DU CAS: Une femme âgée de 72 ans a reçu un traitement antifongique pour une infection invasive de la cornée à Candida albicans; elle présentait un ulcère chronique de la cornée pour lequel elle a reçu périodiquement au cours des vingt dernières années, des gouttes de gentamycine, d’amikacine, et d’amphotéricine B. De plus, elle était suivie pour de l’hypertension qui était traitée par de l’amlodipine, à raison de 5 mg par jour. Dans son historique, on n’a noté aucune réaction anaphylactique passée ni l’emploi d’autres inhibiteurs du cytochrome P450 ou d’autres antifongiques de type azoles. Au début, on lui a prescrit de la kétoconazole orale pour le traitement de l’infection cornéenne. Elle a présenté de l’hypotension retardée, soit 2 heures après la prise du médicament; cette hypotension était grave et n’a pas répondu à une thérapie liquidienne (bolus de 2 L de NaCl 0.9% suivi d’une perfusion de 100 mL/h) ainsi qu’à la dopamine à dose élevée (30 µg/min/kg). L’insertion d’un cathéter de Swan-Ganz a montré une faible résistance vasculaire périphérique et un débit cardiaque élevé sans signes de septicémie. De plus, sachant que le niveau plasmatique de tryptase était élevé, on a porté un diagnostic de choc anaphylactique avec redistribution. Les signes vitaux sont devenus plus stables 4 heures après des infusions d’hydrocortisone (100 mg iv aux 2 h pour 4 doses) et d’épinéphrine (perfusion de 15 µg/min, puis en doses décroissantes aux 30 min, cessée après 8 h). DISCUSSION: C’est la première fois qu’un cas de choc anaphylactique réfractaire est rapporté lors d’un traitement par le kétoconazole; cependant, des réactions mineures (rash ou urticaire) et des évènements hypotensifs avec étourdissements ont déjà été associés à la prise de kétoconazole. Les résultats d’un cathétérisme de Swan–Ganz dans ce cas étaient compatibles avec un choc anaphylactique. L’échelle d’imputabilité d’effets indésirables médicamenteux de Naranjo a été appliquée à ce cas et montre une probabilité que ce choc anaphylactique soit lié au kétoconazole. Dans ce cas, sachant que les antifongiques de type azoles inhibent le métabolisme des bloqueurs des canaux calciques, que l’amlodipine est un substrat du CYP3A4, duquel le kétoconazole est un puissant inhibiteur, une interaction médicamenteuse est possible et a pu prolonger la durée de la réaction hypotensive. CONCLUSIONS: L’emploi de kétoconazole peut causer un choc anaphylactique grave, même lorsqu’il est administré par la voie orale, comme c’est le cas ici. Un cathétérisme invasif et le niveau plasmatique de tryptase peuvent fournir de l’information importante pour le traitement du choc anaphylactique.

RÉSUMÉ

Le kétoconazole est un médicament antifongique oral efficace et largement prescrit. Dans cet article, les auteurs rapportent un cas rare mais grave de choc anaphylactique réfractaire avec modifications des signes vitaux et lié à un traitement par le kétoconazole chez une personne âgée.

OBJECTIF:

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Denyse Demers

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