Comprehensive management of methotrexate poisoning: A case study and review

A. Prahathes1, Niveanthini2

1Final year Emergency medicine resident, Kauvery hospital, Alwarpet, Chennai

2Consultant, Department of Emergency medicine, Kauvery hospital, Alwarpet, Chennai

Abstract

Methotrexate (MTX) is a folate antagonist commonly used in the treatment of malignancies, autoimmune diseases, and ectopic pregnancies. Despite its efficacy, MTX toxicity can occur due to dosing errors, drug interactions, or renal impairment. This article reviews methotrexate poisoning through a detailed case study, laboratory findings, and management strategies, supported by recent literature.

Introduction

Methotrexate, a cornerstone in chemotherapeutic regimens and immunosuppressive therapy, inhibits dihydrofolate reductase, impairing DNA synthesis, repair, and cellular replication. While therapeutic doses are generally well-tolerated, toxicity can arise, necessitating prompt recognition and intervention to prevent severe complications.

Case presentation

A 75 years aged female patient presented with a chief complaints of fresh blood in stools while defecation for 2 days.

Diagnosis : Lichenoid psoriasis, hypertension, T2DM

Medication: Weekly methotrexate (5 mg), glyciphage sr, chlorthalidone

Presentation:  patient presented to ER with alleged H/O accidental ingestion of tab. Methotrexate 1 tab (5mg) daily for the past 10 days (instead of actual prescribed dosage of 1tab/week for 10 weeks) and started having diffuse abdomen, pain crampy type, continuous for 2 days.

No H/O fever, neck pain/stiffness, blurring of vision/diplopia, vomiting, loss of consciousness, seizures, abdomen distension, dysuria, haematuria, chest pain, palpitation, shortness of breath, cough, cold, sore throat. Patient was not on any blood thinners.

Physical examination

Initial 10 seconds

Conscious, oriented, afebrile

Primary survey

  • Airway – patent and self-maintained
  • Breathing – RR-20/min, bilateral air entry equal, normal vesicular breath sounds. SpO2- 98% in room air.
  • Circulation – BP- 100/70mmhg, PR-82bpm, CRT- <2 seconds.
  • Disability – GCS -15/15. Bilateral pupils equally reacting to light , 2mm in size, CBG- 233mg/dl.

Secondary survey

HEENT – oral ulcers +, ear, nose- normal

CVS – S1,S2 – heard, no murmur.

RS – BAE+, no added sounds

P/A – soft, non tender, BS+, no organomegaly.

P/R– no haemorrhoids / anal fissure, normal soft stools.

CNS – GCS- E4,V5,M6, moves all 4 limbs.

Local examination: Hyperpigmented rashes + over hand, wrist, foot and legs.

Management at ER:

  • Propped up position, IV access secured, to maintain Sp02>94%.
  • ECG- rate- 75bpm, normal sinus rhythm, and axis- horizontal, very low amplitude RRS from V4 to V6, t wave flattening with u waves in V3-V6.
  • POC- chem-8, Na- 128, K- 2.9, cl-89, glu- 193, bun- 5, crea-0.4, hb-10.2.
  • Inj Kcl 40 meq in 100 ml NS IV over 5 hr.
  • Inj Folinic acid 15 mg IV every 6 hr.
  • Tab Allegra 180 mg HS.
  • Methotrexate was stopped.
InvestigationsResults
CBC
WBC2,000/µL (neutrophils 40%)
Hb9 g/dL
Platelets70,000/µL
Renal Function
BUN10 mg/dL
Creatinine0.4mg/dL
Liver Function
AST120 U/L
ALT110 U/L

Secondary Management

  • Patient was admitted in ICU for further management. Patient was hemodynamically stable throughout. Patient was treated appropriately. Serial monitoring of labs was found to be within normal limits. Patient was then shifted to ward.
  • Folinic acid discontinued after 3 days.
  • Patient was discharged after 5 days of observation in hemodynamically stable condition.

Pathophysiology

Methotrexate exerts its toxic effects primarily through the inhibition of folate metabolism, leading to impaired DNA synthesis and repair. Rapidly dividing cells, such as those in the bone marrow, gastrointestinal tract, and mucosa, are particularly vulnerable. Renal dysfunction exacerbates toxicity by reducing methotrexate clearance.

Diagnosis

Methotrexate toxicity is diagnosed based on clinical presentation and confirmed by elevated serum methotrexate levels. Differential diagnosis includes other causes of pancytopenia and mucositis, such as infections, other drug toxicities, and hematological disorders.

Management

Initial Assessment and Stabilization

1. Immediate discontinuation of Methotrexate

Stop the administration of methotrexate immediately to prevent further toxicity.

2. Assessment of vital signs and clinical status:

Monitor blood pressure, heart rate, temperature, respiratory rate, and oxygen saturation.

Perform a thorough physical examination focusing on signs of mucositis, hematological abnormalities, and renal function.

Laboratory investigations

  • Complete Blood Count (CBC): Evaluate the extent of pancytopenia, which is common in methotrexate toxicity due to bone marrow suppression.
  • Renal Function Tests: Assess blood urea nitrogen (BUN) and serum creatinine levels to evaluate renal function
  • Liver Function Tests: Check AST and ALT levels to detect hepatic involvement.
  • Serum Methotrexate Levels: Measure serum methotrexate concentration to confirm toxicity and guide further treatment.

Specific management

1. Leucovorin (Folinic Acid) Rescue

  • Mechanism: Leucovorin bypasses the blockade of dihydrofolate reductase caused by methotrexate, replenishing folate stores necessary for DNA synthesis and cell survival.
  • Administration: Initiate with a dose of 10-100 mg/m² intravenously every 6 hours. The dose and frequency are adjusted based on serum methotrexate levels and patient response. Continue until methotrexate levels fall below 0.1 µM and there is clinical improvement.

2. Glucarpidase

  • Mechanism: Glucarpidase is an enzyme that rapidly hydrolyzes methotrexate into inactive metabolites.
  • Indications: Use in cases of severe methotrexate toxicity, particularly when there is delayed methotrexate clearance due to renal dysfunction.
  • Administration: Typically, a single intravenous dose of 50 units/kg. This should be given alongside leucovorin but separated by at least two hours to avoid reducing leucovorin’s effectiveness.

3. Hydration and Alkalinization

  • Hydration: Administer intravenous fluids aggressively (3-5 liters/m²/day) to enhance renal elimination of methotrexate.
  • Alkalinization: Use sodium bicarbonate to maintain urine pH above 7.0, which increases methotrexate solubility and prevents precipitation in renal tubules. Monitor urine pH regularly.

4. Monitoring and supportive care

  • Frequent Monitoring: Check serum methotrexate levels every 12-24 hours, along with renal and liver function tests, electrolytes, and CBC.
  • Blood Products: Administer blood transfusions or platelet transfusions if necessary to manage anemia and thrombocytopenia.
  • Infection Prophylaxis: Given the immunosuppression associated with pancytopenia, prophylactic antibiotics or antifungals may be warranted.

5. Adjunctive measures

  • Pain management: Address pain from mucositis with appropriate analgesics, such as oral lidocaine or systemic pain relievers, while avoiding nephrotoxic drugs.
  • Nutritional support: Provide nutritional support, potentially including parenteral nutrition if mucositis severely limits oral intake.
  • Psychological support: Offer psychological support to the patient and family, addressing anxiety and emotional distress related to the toxicity and treatment process.

6. Long-term follow-up

  • Monitor for delayed toxicities: Be vigilant for delayed effects of methotrexate, such as liver fibrosis or interstitial lung disease.
  • Renal function recovery: Regular follow-up to assess and support recovery of renal function.
  • Adjustment of Methotrexate therapy: Reevaluate the methotrexate dosing regimen for underlying conditions, considering alternative therapies or dose adjustments to prevent recurrence.

Conclusion

The management of methotrexate poisoning is complex and requires a multidisciplinary approach involving immediate cessation of the drug, administration of antidotes like leucovorin and glucarpidase, supportive care, and:  continuous monitoring. The detailed management of this patient highlights the importance of early intervention, aggressive supportive measures, and tailored antidotal therapy to mitigate the severe consequences of methotrexate toxicity.

References

  • Howard, S. C., McCormick, J., Pui, C. H., Buddington, R. K., & Harvey, R. D. (2016). Preventing and managing toxicities of high-dose methotrexate. The Oncologist, 21(12), 1471-1482.
  • Widemann, B. C., & Adamson, P. C. (2006). Understanding and managing methotrexate nephrotoxicity. The Oncologist, 11(6), 694-703.
  • Pinedo, H. M., & Chabner, B. A. (2002). Role of folate and folate antimetabolites in cancer chemotherapy. Cancer Research, 62(5), 1255-1258.
  • Rask, C., Albertsson, M., & Liljegren, G. (2003). Treatment of high-dose methotrexate intoxication with continuous venovenous hemodiafiltration and carboxypeptidase-G2: Case report and discussion of treatment options. Pediatric Hematology and Oncology, 20(3), 231-238.

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