Ifosfamide - Induced Encephalopathy in Children and Young People ( IEE ) - Guideline for the Management of

Publication: 20/02/2015  
Next review: 04/12/2023  
Clinical Guideline
ID: 4112 
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2020  


This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Guideline for the Management of Ifosfamide - Induced Encephalopathy in Children and Young People (IEE)


This guideline covers the management, including secondary prevention, of Ifosfamide-Induced Encephalopathy IIE in children and young people.

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Ifosfamide is an alkylating agent commonly used in a wide range of paediatric solid tumours. It is thought that 10-30% of patients treated with ifosfamide will develop some degree of encephalopathy known as ifosfamide induced encephalopathy or IIE (1). The symptoms, which can occur within hours or days of treatment, may range from mild somnolence to deep coma and an occasional fatal outcome has been reported. Mild cases often resolve spontaneously after a few days but more serious cases need appropriate intervention with methylene blue +/- other supportive interventions.

It is thought the encephalopathy results from a toxic metabolite of ifosfamide, chloracetaldehyde (CAA) (2). This disrupts the mitochondrial respiratory chain and leads to an accumulation of nicotinamide adenine dinucleotide (reduced), (NADH). Methylene blue acts as an alternative electron acceptor and also prevents the formation of the toxic metabolite CAA.

Methylene blue has been shown to shorten the duration of IIE and also prevent or reduce severity of IIE occurring in subsequent treatment courses.

Risk factors for developing encephalopathy include:    

  • Short infusion time of ifosfamide
  • Reduced creatinine clearance
  • Hypoalbuminaemia
  • Previous cisplatin treatment
  • Advanced/bulky pelvic disease (2)

During ifosfamide treatment, patients should be monitored closely for any change in neurological condition and any concerns should be discussed with a senior member of medical staff. (The scope of this guideline does not cover the neurological examination of the patient and diagnosis of encephalopathy).

This guideline covers the management, including secondary prevention, of IIE in children and young people.

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This diagnosis of IIE should be made in a patient with altered neurological status, after exclusion of other causes (see below).

The degree of encephalopathy should then be graded according to the Common Toxicity Criteria (CTC) toxicity guidelines (3) as follows:

- Grade 1      mild somnolence or agitation
- Grade 2      moderate somnolence or agitation
- Grade 3      severe somnolence, agitation, confusion, disorientation or hallucination             
- Grade 4     coma, seizures, toxic psychosis

Once the diagnosis of grade 2 or above ifosfamide induced encephalopathy has been confirmed, treatment should be initiated with methylene blue. Methylene blue treatment should NOT be initiated if grade 1 toxicity is observed as these cases are mild and resolve spontaneously. If there is any uncertainty as to if Grade I or Grade 2 is experienced, it is better to discuss.

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The investigation of IIE is directed towards excluding other possible causes of neurological deterioration. The following should be considered:

  • FBC and coagulation
  • U+E’s
  • LFT’s including albumin
  • Calcium and magnesium
  • Glucose
  • MRI scan. Focal neurological deficits, seizures or severe encephalopathy should be investigated with a MRI or CT scan to exclude raised intracranial pressure. Subdural haematomas and intracranial haemorrhages need to be excluded if the patient has a coagulopathy or profound thrombocytopenia.

This list is not comprehensive and other investigations may be necessary depending on the individual.

Glucose-6 phosphate dehydrogenase (G6PD) deficiency status should always be confirmed prior to the administration of methylene blue. If the patient is G6PD deficient, they should not receive methylene blue. (This test should be carried out before starting the first course of chemotherapy for any patient likely to receive ifosfamide and should be annotated on the chemotherapy flow sheet in the patient’s notes.)

If the patient does not improve once the ifosfamide has been stopped or the methylene blue has been initiated, then other causes of the encephalopathy must be considered, for example viral encephalitis.

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Treatment / Management

Treatment (4) (5)

Patients must experience neurotoxicity of Grade II or above and the case discussed with the consultant haematologist/oncologist before specific treatment with methylene blue is commenced. If there is any uncertainty as to if Grade I or Grade II is experienced, it is better to discuss.

Treatment with methylene blue must be discussed with the consultant on-call.

  • Stop ifosfamide infusion,
  • BUT continue mesna hydration schedule as prescribed.
  • Prescribe methylthionium chloride (methylene blue) at a dose of 1mg/kg (max 50mg) every FOUR hours in 50ml glucose 5% infused over 10-30 minutes. (It can also be given NEAT over a minimum of FIVE minutes but this must be via a central line, if volume limitations are severe.)
  • Continue until all symptoms have resolved.
  • Commence half hourly neurological observations.
  • Continue any other supportive measures required.

Other supportive measures may be required, for example for the management of seizures or electrolyte disturbances. The role of these supportive agents is not discussed within this guideline.

Secondary prophylaxis of Ifosfamide Induced Encephalopathy

IIE does not necessarily occur with further exposure to ifosfamide, and encephalopathy does not usually preclude further treatment with ifosfamide.
The inclusion of ifosfamide in the next course should be discussed with the appropriate consultant.

Methods to reduce the risk of further episodes of encephalopathy include:

  • Ensure patient not hypoalbuminaemic
  • Prescribe methylene blue prophylaxis at a dose of 1mg/kg (max 50mg) QDS oral or IV.
  • Start prophylaxis four hours prior to ifosfamide and continue until 72 hours post administration.
  • Consider prolonging the infusion time of short 1 hour infusions up to 3 hours, or if a 3 hour infusion has been given, consider increasing to 24 hours.
  • If symptoms of encephalopathy do occur then increase the frequency of the methylene blue to four hourly (intravenously) and discuss with the consultant on call.

Future management

If the ifosfamide infusions do continue to be problematic then the following measures can be considered:

  • Prolong infusion time further if possible (up to 24 hours)
  • Reduce the ifosfamide dosage
  • Substitute cyclophosphamide for the ifosfamide


  • Methylene blue is contraindicated in patients with G6PD deficiency( they will not respond and there is also a risk of haemolytic anaemia)
  • Methylene blue should be used in caution in patients with severe renal impairment.
  • It should not be given by the subcutaneous route as it causes necrotic abscesses.

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Record: 4112

To provide an up to date treatment strategy for the management of ifosfamide induced encephalopathy for paediatric, teenage and young adult oncology patients.

- To identify the risk factors for the development of ifosfamide induced encephalopathy
- To provide guidance to allow accurate grading of encephalopathy
- To provide clear guidance for the treatment of ifosfamide induced encephalopathy with methylene blue
- To provide clear guidance for the secondary prophylaxis of ifosfamide induced encephalopathy with methylene blue.
- To identify ways to minimise further episodes of ifosfamide induced encephalopathy.

Clinical condition:

Paediatric, teenage and young adult haematology and oncology patients

Target patient group: Patients who develop ifosfamide induced encephalopathy after receiving ifosfamide.
Target professional group(s): Pharmacists
Secondary Care Doctors
Adapted from:

Evidence base

  1. Lee at al. Overview of neurologic complications of non-platinum cancer chemotherapy. Up To Date. [Online] October 2014. [Cited: 5th Nov 2014.] http://www.uptodate.com/contents/overview-of-neurologic-complications-of-non-platinum-cancer-chemotherapy?source=search_result&search=ifosfamide+encephalopathy&selectedTitle=1%7E150#H34.
  2. Prediction of ifosfamide/mesna associated encephalopathy. Meanwell et al. 1986, European Journal Cancer Clinical Oncology, p. 815.
  3. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTC) version 4. EORTC. [Online] 2009. [Cited: 5th November 2014.] http://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.
  4. Ifosfamide Encephalopathy. Ajithkumar et al. 2007, Clinical Oncology, pp. 108-114.
  5. Methylene Blue Drugdex evaluation. Micromedex. [Online] [Cited: 5th November 2014.] http://www.micromedexsolutions.com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/DAACEA/ND_AppProduct/evidencexpert/

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Approved By

Trust Clinical Guidelines Group

Document history

LHP version 1.0

Related information

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