›Leucovorin must continue after glucarpidase
›Indication
›High-dose methotrexate with acute kidney injury and a level above 1 micromol/l with delayed clearance
›Most effective when given within 48 to 60 hours of the start of the infusion
›Dose
›Glucarpidase 50 units/kg IV as a single dose over 5 minutes
›A second dose is rarely required and only for a persistently toxic rebound level measured by chromatographic assay
›Interaction with leucovorin dosing
›Separate leucovorin and glucarpidase by at least 2 hours in each direction because leucovorin is also a substrate
›For 48 hours after glucarpidase, keep dosing leucovorin from the pre-glucarpidase methotrexate level
›Do not reduce leucovorin based on the low post-glucarpidase immunoassay result
›Assay caveat
›DAMPA cross-reacts with immunoassays for about 48 hours and produces falsely elevated readings
›Follow the true level with a chromatographic method such as HPLC or LC-MS/MS
›Adverse effects
›Flushing, paraesthesia, hypotension and hypersensitivity are uncommon, and anti-drug antibodies can form
Hydration and urinary alkalinisation
›Intravenous fluid to establish a forced euvolaemic diuresis
›Isotonic crystalloid to achieve urine output of approximately 100 to 150 ml/m2 per hour, roughly 2 to 3 ml/kg per hour
›Begin before and continue throughout high-dose methotrexate, and in any significant systemic exposure
›Watch for iatrogenic pulmonary oedema in pneumonitis, oliguric acute kidney injury, third-spacing and cardiac disease
›Urinary alkalinisation with sodium bicarbonate
›Sodium bicarbonate 150 mmol in 1 litre of 5 percent dextrose, infused at 125 to 250 ml per hour
›Optional initial bolus sodium bicarbonate 1 to 2 mmol/kg IV
›Titrate to a urine pH of 7.0 or higher, ideally 7.5, checked every 1 to 2 hours
›Reduce the infusion rate if serum pH exceeds 7.55 or serum bicarbonate rises excessively
›Hold the infusion for a serum bicarbonate producing serum pH above 7.55
›Methotrexate and 7-hydroxymethotrexate are far more soluble at urine pH 7 than at pH 5, which prevents tubular precipitation
›Potassium and magnesium during alkalinisation
›Alkalinisation and diuresis drive hypokalaemia, and urine will not stay alkaline while the patient is hypokalaemic
›Add potassium chloride 20 to 40 mmol/l to the infusion once urine output is confirmed and serum potassium is not high
›Replace magnesium to support potassium correction
›Acetazolamide 250 to 500 mg IV is a second-line adjunct to alkalinise urine but worsens systemic acidosis and is usually avoided
›Continue fluids and alkalinisation until the methotrexate level is below 0.05 micromol/l
Extracorporeal removal and gastrointestinal decontamination
›High-flux intermittent haemodialysis
›Removes roughly 50 to 70 percent of circulating methotrexate per 4-hour session
›Expect a rebound rise of 10 to 30 percent as methotrexate redistributes from tissue, so plan serial sessions
›Reserved for severe acute kidney injury with a dangerously high level when glucarpidase is unavailable
›It does not replace leucovorin
›Continuous renal replacement therapy
›Lower clearance per hour but less rebound and better tolerated in haemodynamic instability
›Charcoal haemoperfusion is largely of historical interest and is not first-line
›Enteral decontamination and interruption of enterohepatic recycling
›Activated charcoal 1 g/kg orally, maximum 50 g, for an ingestion within 1 to 2 hours with a protected airway
›Multi-dose activated charcoal 0.25 to 0.5 g/kg every 2 to 4 hours if tolerated
›Cholestyramine 4 g orally every 6 to 8 hours is a weak-evidence adjunct to bind methotrexate in the gut
›Withhold all enteral binders in ileus, vomiting, or severe mucositis
Haematologic support and neutropenic fever
›Filgrastim for neutropenia
›Filgrastim 5 micrograms/kg subcutaneously once daily until the absolute neutrophil count recovers above 1.0 x10^9/l
›Indicated for profound or prolonged neutropenia and for neutropenic fever
›Platelet transfusion thresholds
›Platelet count below 10 x10^9/l without bleeding
›Below 20 x10^9/l with fever or mucosal bleeding
›Below 50 x10^9/l with active bleeding or before an invasive procedure
›One adult apheresis unit raises the count by roughly 30 x10^9/l
›Red cell transfusion
›Haemoglobin below 70 g/l, or below 80 g/l with cardiac disease or active bleeding
›Neutropenic fever antibiotics
›Blood cultures then an antipseudomonal beta-lactam within 60 minutes: cefepime 2 g IV every 8 hours or meropenem 1 g IV every 8 hours
›Prefer cefepime or meropenem over piperacillin-tazobactam 4.5 g IV every 6 hours because penicillins reduce methotrexate tubular secretion, though a single course is usually acceptable
›Add vancomycin 15 to 20 mg/kg IV every 8 to 12 hours for catheter or skin infection, instability, or known MRSA colonisation
›Add empirical antifungal cover if fever persists beyond 4 to 7 days
›Paediatric cefepime 50 mg/kg IV every 8 hours, with age-appropriate dosing under 1 month of age
›Reverse-barrier nursing, mouth care, and avoidance of rectal instrumentation while neutropenic
›Leucovorin rescue continues throughout; folic acid supplementation resumes only after recovery
Organ-specific toxicity: pneumonitis and neurotoxicity
›Methotrexate pneumonitis
›Stop methotrexate permanently and exclude infection with cultures, a respiratory viral panel and often bronchoalveolar lavage
›Supplemental oxygen to the target range for the patient's chronic lung status
›Prednisolone 0.5 to 1 mg/kg per day orally, or methylprednisolone 1 mg/kg per day IV if severe, with a taper over weeks
›Continue empirical antimicrobial cover, including for pneumocystis, until infection is excluded
›Escalate to non-invasive or invasive ventilation with lung-protective settings for refractory hypoxaemia
›Subacute methotrexate neurotoxicity and stroke-like syndrome
›Aminophylline 2.5 mg/kg IV over 30 to 60 minutes as an adenosine-receptor antagonist for the stroke-like syndrome
›Dextromethorphan 1 to 2 mg/kg per day orally in divided doses is an anecdotal NMDA-antagonist option
›Intravenous leucovorin and supportive care; most episodes resolve over days
›This syndrome is not thromboembolic, so thrombolysis is neither indicated nor safe
›Intrathecal methotrexate overdose
›Immediate neurosurgical CSF drainage and ventriculolumbar perfusion with warmed isotonic saline for large overdoses
›Systemic leucovorin, dexamethasone 4 mg IV every 6 hours, and specialist-directed intrathecal glucarpidase
›Never attempt to neutralise intrathecal methotrexate with intrathecal leucovorin
›Chemical arachnoiditis
›Self-limited headache, fever and meningism within 24 hours of an intrathecal dose
›Analgesia, antipyretics and reassurance, after excluding bacterial meningitis if neutropenic
Mucositis care, analgesia and antiemesis
›Mucositis supportive care
›Saline or sodium bicarbonate mouth rinses every 2 to 4 hours and meticulous oral hygiene
›Viscous lidocaine 2 percent, 5 ml swish and spit every 3 hours, maximum 8 doses per day, not swallowed because denuded mucosa absorbs systemically
›Nystatin oral suspension 100000 units per ml, 5 ml four times daily for candidiasis; aciclovir 400 mg orally five times daily if herpes simplex is suspected
›Early parenteral nutrition if oral intake is impossible for more than a few days
›Analgesia
›Paracetamol 1 g orally or IV every 6 hours, maximum 4 g per day, reduced to a maximum of 3 g per day with significant transaminitis
›Morphine 2 to 4 mg IV every 2 to 4 hours titrated, or patient-controlled analgesia, for severe mucositis pain
›Use hydromorphone 0.2 to 0.4 mg IV or reduce the morphine dose in renal impairment because active metabolites accumulate
›Do not use NSAIDs or aspirin at any dose: ibuprofen 400 mg or naproxen 500 mg reduce renal methotrexate clearance and add bleeding risk on thrombocytopenia
›Antiemesis
›Ondansetron 4 to 8 mg IV every 8 hours, with ECG and electrolyte monitoring because of additive QT prolongation
›Metoclopramide 10 mg IV every 8 hours as an alternative if the QT is prolonged
›Stress ulcer prophylaxis
›Use famotidine 20 mg IV every 12 hours rather than a proton pump inhibitor, which impairs methotrexate elimination
›Stop methotrexate itself and remove it from the medication administration record
›In low-dose toxicity do not restart until toxicology and the prescriber agree, and re-educate on weekly dosing
›Antifolate and clearance-reducing drugs to hold
›Trimethoprim-sulfamethoxazole: substitute atovaquone 1500 mg orally daily or pentamidine 4 mg/kg IV daily for pneumocystis cover
›NSAIDs and aspirin, including low-dose aspirin 75 to 100 mg daily: replace with paracetamol and opioids
›Proton pump inhibitors: replace with famotidine 20 mg IV every 12 hours
›Probenecid, penicillins and ciprofloxacin where an alternative exists
›Nephrotoxins to avoid
›Aminoglycosides, iodinated contrast, and ACE inhibitors or ARBs during volume depletion
›Anaesthetic agents
›Avoid nitrous oxide, which inactivates methionine synthase and deepens the antifolate state
›Routine interventions that are contraindicated or need modification
›NSAIDs for analgesia: contraindicated for renal clearance and bleeding reasons
›Therapeutic anticoagulation and pharmacologic VTE prophylaxis: hold when platelets are below 50 x10^9/l or with mucosal bleeding
›Thrombolysis: contraindicated with severe thrombocytopenia, and not indicated for the methotrexate stroke-like syndrome
›Large-volume fluid loading: needed for clearance but titrated against pneumonitis and oliguria
›Intubation: expect friable bleeding mucosa, so use a smaller tube and the most experienced operator
›Intra-aortic balloon pump and other mechanical circulatory support: only if a separate cardiac indication exists, and anticoagulation is hazardous with thrombocytopenia
›Live vaccines and rectal instrumentation while neutropenic: avoid