© 2005 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Treatment of Accidental Intrathecal Methotrexate Overdose
Affiliations of authors: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD (BCW, FMB); Children's Hospital of Philadelphia, Philadelphia, PA (PCA)
Correspondence to: Brigitte C. Widemann, MD, Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Bldg. 10 CRC Room 1–5750 MSC 1101, Bethesda, MD 20892 (e-mail: bw42y{at}nih.gov).
We thank Drs. Gosselin and Isbister for their letter and welcome the opportunity to provide additional information. The causes of the accidental intrathecal methotrexate overdoses in our report are similar to those previously reported (1,2). There were two main causes of the accidental intrathecal methotrexate overdoses reported in our study. Three of the patients in our study were scheduled to receive methotrexate intravenously as a bolus dose and as an intrathecal injection on the same day. Accidental intrathecal administration of the higher intravenous dose, which was prepared in a small volume, resulted in the overdose. The other four overdoses were due to preparation errors; for three overdoses, the wrong-sized vial of methotrexate (1 g instead of 20 mg) was reconstituted. For one patient no details regarding the preparation error were available.
We calculated the amount of methotrexate that was removed by lumbar drainage by multiplying the volume of cerebrospinal fluid (CSF) removed by the concentration of methotrexate measured in an aliquot of the CSF drainage. Table 1 shows the sequence of rescue interventions undertaken for each patient in our study. Six of seven patients underwent ventriculolumbar perfusion or ventricular or lumbar exchange. However, we had an aliquot from the entire volume exchanged for only one of those patients (patient 4), in whom 20% of the administered methotrexate dose was removed by lumbar exchange.
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The survey performed by Drs. Gosselin and Isbister showed a surprising lack of awareness of treatment options, such as CSF exchange and carboxypeptidase G2 (CPDG2), for accidental intrathecal metho-trexate overdoses considering the fact that recommendations on potential treatment options for such overdoses based on the pharmacokinetics of methotrexate in CSF have been previously published (3–6). Within 1 hour of lumbar injection of a radiolabeled tracer, radioactivity can be detected in the basal cisterns (7), implying that removal of an intrathecally injected drug such as methotrexate via lumbar drainage can only be successful if it occurs within a short time period after intrathecal injection. In 1981, Addiego et al. (3) developed a pharmacokinetic model that predicted the amount of methotrexate that can be removed by lumbar puncture and drainage by gravity at various time points after intrathecal methotrexate overdoses. They concluded that lumbar CSF drainage alone is unlikely to rescue patients who receive more than 10-fold the intended dose of methotrexate unless large volumes of CSF are removed within 15 minutes of the overdose, and they recommended emergency ventriculostomy placement and ventriculolumbar perfusion as a cornerstone of treatment.
The availability of CPDG2 allows us to modify these recommendations. In cases of accidental intrathecal methotrexate overdose, we recommend immediate lumbar drainage to remove CSF followed by intrathecal administration of CPDG2. Preparation for ventriculolumbar perfusion should be made in case the patient's clinical condition deteriorates. Meanwhile, systemic corticosteroids and leucovorin should be administered to minimize chemical meningitis and the risks of systemic toxicity, respectively. The rapid action of CPDG2 may improve the outcome of patients and, in some cases, might obviate the need for the more invasive and less readily available procedure of ventriculolumbar perfusion.
Although procedures to prevent the inadvertent administration of an overdose of intrathecal methotrexate are critical, institutions should have a plan to treat an intrathecal methotrexate overdose should it occur.
REFERENCES
(1) Spiegel RJ, Cooper PR, Blum RH, Speyer JL, McBride D, Mangiardi J. Treatment of massive intrathecal methotrexate overdose by ventriculolumbar perfusion. N Engl J Med 1984;311:386–8.[Web of Science][Medline]
(2) Ettinger LJ. Pharmacokinetics and biochemical effects of a fatal intrathecal methotrexate overdose. Cancer 1982;50:444–50.[CrossRef][Web of Science][Medline]
(3) Addiego JE, Ridgway D, Bleyer WA. The acute management of intrathecal methotrexate overdose: pharmacologic rationale and guidelines. J Pediatr 1981;98:825–8.[Web of Science][Medline]
(4) Balis F, Holcenberg J, Blaney S. General principles of chemotherapy. In: Pizzo P, Poplack D, editors. Principles and practice of pediatric oncology. Philadelphia (PA): Lippincott Williams & Wilkins; 2002. p. 237–308.
(5) Poplack D. Massive intrathecal overdose: "check the label twice." N Engl J Med 1984;311:400–1.[Web of Science][Medline]
(6) Thomas LL, Mertens MJ, von dem Borne AE, van Boxtel CJ, Veenhof CH, Veies EP. Clinical management of cytotoxic drug overdose. Med Toxicol Adverse Drug Exp 1988;3:253–63.[Medline]
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J Natl Cancer Inst 2005 97: 609-610.
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