Irreversible Coma, Ergotamine, and Ritonavir
- 1Intensive Care Unit, Clinica Puerta de Hierro, Madrid, Spain
- 2Department of Internal Medicine, Clinica Puerta de Hierro, Madrid, Spain
- 3Department of Radiology, Clinica Puerta de Hierro, Madrid, Spain
- Dr. Candido Pardo Rey, Intensive Care Unit, Clinica Puerta de Hierro, San Martin de Porres, 4, 28035 Madrid, Spain (candypar{at}eresmas.com).
Abstract
We report the first case in the medical literature (to our knowledge) of a patient with human immunodeficiency virus infection who was being treated with ritonavir and developed signs of severe vascular involvement and irreversible coma after the administration of 3 mg of ergotamine tartrate.
Ergotism is a serious complication of the acute or chronic ingestion of ergot derivatives. It usually produces vascular insufficiency of peripheral limbs and, more rarely, of vital organs [1–4]. Ritonavir, a competitive inhibitor of cytochrome P450 3A4 (CYP3A4), increases the ergotamine concentration by inhibiting its metabolism, an effect that can produce symptoms of ergotism at low ergotamine doses [5, 6]. We report the first case in the medical literature (to our knowledge) of a patient with HIV infection who was being treated with ritonavir and developed signs of severe vascular involvement and irreversible coma after the administration of 3 mg of ergotamine tartrate.
Case report. The patient was a 34-year-old woman who smoked 40 cigarettes/day. She had been receiving ritonavir (600 mg every 12 h), lamivudine (150 mg every 12 h) and stavudine (40 mg every 12 h) for the past 3 years to treat HIV infection. She presented to the emergency service at our institution with complaints of dizziness, loss of vision, headache, vomiting, diarrhea, and a feeling of cold in her left foot. Physical examination revealed an arterial blood pressure of 160/60 mm Hg, a heart rate of 80 beats/min, the absence of peripheral pulses in all 4 extremities, and acral cyanosis.
The patient's vision recovered spontaneously during the first hour of her stay in the emergency service. During the next hour, she showed signs of a decreased level of consciousness; no other changes were found on examination. At that time, she underwent cranial CT and MRI, which revealed nothing abnormal. She was admitted to the intensive care unit for observation and monitoring. During the next 12 h, she recovered a normal level of consciousness, although with some confusion and disorientation. Hemoglobin concentration, hematocrit, platelet count, and leukocyte count were normal, as were renal function, liver function, coagulation, 12-s erythrocyte sedimentation rate, and urinary sediment and the findings of chest radiography and electrocardiographic examination. HIV load was 859 copies/mL, and CD4 cell count was 400 cells/μL.
Twenty-four hours after admission to the intensive care unit, the patient again had a decrease in level of consciousness, as well as arterial hypotension, and orotracheal intubation was necessary. Systemic arteriography revealed signs of stenosis and vasospasm in medium and large vessels that diffusely affected the mesenteric, renal, femoral, humeral, and internal carotid arteries, with cerebral hypoperfusion. There was no response to intra-arterial infusion of nimodipine. Because vasculitis was suspected, treatment with a perfusate containing dobutamine, corticosteroids, and heparin was begun, but there was no response to treatment.
The serum electrophoresis banding pattern and levels of complement components C3 and C4 were normal. The patient tested negative for rheumatoid factor, for anti-nuclear, anti-cardiolipin and anti-neutrophil cytoplasmic antibodies, and for cryoglobulins. There was no serological evidence of Borrelia, and results of Venereal Disease Research Laboratory (VDRL) testing was negative. Analysis of CSF, cell counts, and glucose and protein levels yielded normal findings, and the results of culture, Ziehl-Neelsen stain, adenosine deaminase, and VDRL and cryptococcal latex agglutination tests were negative. Examination of biopsy specimens of the temporal artery and muscle revealed nothing abnormal. Cerebral biopsy was considered unnecessary, on the basis of angiography findings and the case report.
Because the clinical characteristics and laboratory findings were not sufficient for diagnosis, the patient's family was interviewed. They reported that she had taken three 1-mg tablets of ergotamine tartrate during the 4 days preceding the onset of signs and symptoms. Ergotism secondary to the association between ritonavir and ergotamine was suspected; therefore, ritonavir therapy was discontinued, and alprostadil was added to the perfusate regimen for 7 days, after which alprostadil therapy was discontinued because of a lack of improvement.
Despite receiving treatment, the patient's neurological condition deteriorated, and she remained in coma vigil. A cranial CT scan performed at this time revealed the existence of multiple subcortical infarcts. However, arteriography carried out 1 month after the onset of the symptoms demonstrated that vasospasm had disappeared from all the previously involved arteries. There was no change in the patient's neurological state (coma vigil) in 2003, 2 years after the diagnosis was made.
Discussion. Poisoning with ergot derivatives can produce (1) acute poisoning due to hypersensitivity mechanisms, (2) acute poisoning due to the ingestion of high doses, or (3) chronic poisoning due to prolonged intake at therapeutic doses. The most common signs include gastrointestinal symptoms (nausea, vomiting, and abdominal pain), neurological symptoms (headache, dizziness, and decreased level of consciousness), and vascular symptoms produced by vasospasm and, more rarely, thrombosis. The most frequently affected arteries are those of the extremities; involvement of visceral arteries, such as the aorta and renal, mesenteric, coronary, retinal, and carotid arteries, is less common [1–4].
Drugs that inhibit CYP3A4, among them ritonavir and other protease inhibitors, can raise the ergotamine concentration to toxic levels, even when ergotamine is administered at low doses [5, 6]. The cases of ergotism associated with concomitant ingestion of protease inhibitors that have been described in the literature predominantly involve women with headaches who took ritonavir and low-dose ergotamine; most of the patients presented with limb ischemia, and their symptoms improved after use of the implicated drugs was discontinued and a number of other treatments were introduced. The diagnosis of vasospasm was based on findings of Doppler ultrasonography, arteriography, or MRI in every case [7–13]. The patient we describe developed the signs and symptoms of severe ergotism with generalized vasospasm and involvement of cerebral vessels, which led to irreversible coma, after the ingestion of only 3 mg of ergotamine tartrate. The ergotamine concentration probably increased to toxic levels because of the concomitant use of ritonavir.
Physicians who treat HIV-infected individuals must be aware of the fact that the interaction between ritonavir and ergot derivatives can produce serious clinical pictures, such as that reported here. The concomitant use of ergot derivatives should be avoided when antiretroviral therapy is begun, as is recommended in the information provided in the reference guide for ritonavir [14].
- Received January 27, 2003.
- Accepted April 25, 2003.
- © 2003 by the Infectious Diseases Society of America
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