Prevention
Methods for prevention of ifosfamide-induced encephalopathy include:rrr
- regular assessment
- early recognition of symptoms and prompt action
- avoiding the concurrent use of opioids, benzodiazepines, sedatives, CYP2B6 and CYP3A4 inhibitors
- prolonging the infusion or fractionating the dose
- alkalinisation to facilitate the elimination of chloroacetaldehyde
- methylene blue (methylthioninium chloride) prophylaxis, particularly for patients with previous grade 3 or 4 reactions.r
Treatmentrr
In the event of a change in neurological status:
- stop the ifosfamide infusion immediately
- continue mesna infusion as per protocol
- notify the medical officer to perform an immediate assessment of the patient
- ensure a safe environment for the patient (e.g. lower the bed, remove any equipment from patient's reach etc)
- ensure adequate IV hydration with glucose 5%
- if ordered, administer methylene blue or thiamine (particularly if toxicity ≥ grade 2)
- hourly neurological observations.
Methylene blue
Whilst the exact mechanism of action is unclear, methylene blue is thought to act on some of the metabolic pathways involved in ifosfamide-induced encephalopathy including:rr
- acting as an alternative electron acceptor to prevent the accumulation of chloroethylamine
- inhibiting plasma & extra-hepatic monoamine oxidases to reduce the accumulation of chloroacetaldehyde.
The use of methylene blue for ifosfamide-induced encephalopathy is off-label as it is currently not licenced by the Therapeutic Goods Administration Australia for this indication. However, there is literature supporting its use and clinician discretion is recommended.
Methylene blue dose and administrationrr
Treatment dose: 50 mg IV/PO as a single dose or every 4 to 8 hours until symptoms resolve.
Prophylaxis dose: 50 mg IV/PO every 6 to 8 hours for the duration of the ifosfamide infusion.
Methylene blue 0.5% or 1% injection can be given intravenously or orally.
Intravenous: Administer undiluted as a slow IV bolus over 3 - 5 minutes (to prevent local high concentrations with toxic effects) or dilute in 50 mL glucose 5% and infuse over 10 to 15 minutes. rr
Oral: IV formulation may be given orally (if patient is able to swallow). Dilute dose in 100 to 200mL of water to minimise dysuria and gastrointestinal side effects.
Onset of response may vary from hours to days.
Contraindications: do not administer methylene blue if the patient has:
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
- Known hypersensitivity to methylene blue or to any other thiazide dyes.
- Severe kidney dysfunction.
- Methaemoglobinaemia: due to chlorate poisoning or during treatment of cyanide poisoning.
Intrathecal and subcutaneous injections of methylene blue are also contraindicated, as they can result in neural damage (intrathecal administration) and necrotic abscess (subcutaneous administration).
Precautions when administering methylene blue
- Methylene blue may cause falsely low pulse oximetry readings.
- Ensure all patients receiving methylene blue have daily monitoring of haemoglobin (Hb).
- Due to the potential risk of cardiac arrhythmia and hypotension, electrocardiograph (ECG) and blood pressure monitoring is recommended. r
- Large doses of methylene blue may cause headaches, dizziness, mental confusion, agitation, profuse diaphoresis, hypertension, hypotension, arrhythmias, chest pain, dyspnoea, hypoxia, dysuria, abdominal pain, nausea and vomiting, thrombophlebitis (if not adequately diluted) and necrosis (if extravasation occurs).
- Blue-green discolouration of urine, stool and saliva and a blue discolouration of the skin (may hinder a diagnosis of cyanosis).
- Methylene blue is a potent monoamine oxidase inhibitor (MAOI) and can cause serotonin toxicity if given concomitantly with other serotonergic drugs.
The rare but more serious side effects of methylene blue include anaphylaxis, cardiac arrhythmias, coronary vasoconstriction, haemolytic anaemia, paraesthesia, and syncope.rr
Thiamine
The neurological side effects of ifosfamide are similar to Wernicke’s encephalopathy, which is caused by severe thiamine deficiency.rThiamine is a coenzyme in carbohydrate metabolism and has a function in nerve conduction, leading to improved neuronal function.r
Thiamine dose and administrationrr
Treatment dose: 100 mg IV every 4 hours.
Administration:
- IV infusion: dilute in 100 mL sodium chloride 0.9% and infuse over 10 to 30 minutes.
- Continue until symptoms have resolved or significantly improved.
- Thiamine can also be administered via other methods, consult the available product information and follow local institutional policies.
Other
Albumin administration to provide binding sites that are unable to cross the blood-brain barrier and haemodialysis, have also been found to be effective in the management of ifosfamide-induced encephalopathy.r