Encephalopathy after high-dose Ifosfamide: a retrospective cohort study and review of the literature

Drug Saf. 2008;31(11):989-96. doi: 10.2165/00002018-200831110-00003.


Background: Encephalopathy occurs in 10-40% of patients treated with high-dose ifosfamide. Proposed risk factors for encephalopathy include hepatic or renal dysfunction, brain metastases, electrolyte imbalances and drug-drug interactions.

Objective: The purpose of this retrospective cohort study and literature review was to estimate the prevalence of encephalopathy, identify characteristics associated with encephalopathy and evaluate the effectiveness of methylthioninium chloride (methylene blue) in its prevention.

Study design and methods: A total of 19 patients received high-dose ifosfamide for soft tissue sarcoma during a 4-year period at our medical centre. Eight patients developed encephalopathy based on adverse drug event (ADE) reports submitted by a clinical pharmacist. These reports incorporate the Naranjo probability scale, which is used to assess the likelihood that a change in clinical status is the result of an ADE rather than the result of other factors, such as progression of disease. The demographics, concurrent medication therapy, co-existing illnesses and laboratory parameters were documented from the medical records. We also conducted a review of the literature by searching MEDLINE (1996-October 2007).

Main outcome and results: A total of 19 patients received high-dose ifosfamide; eight patients experienced encephalopathy (group I, 42%) and 11 patients did not experience encephalopathy (group II, 58%). More women than men developed encephalopathy (group I, 87.5% vs group II, 27.3%). Serum albumin (group I, 3.1 +/- 0.3 vs group II, 3.6 +/- 0.3 g/dL), haemoglobin (10.5 +/- 1.5 vs 12.4 +/- 1.7 g/dL) and total bilirubin (0.5 +/- 0.2 vs 0.8 +/- 0.3 mg/dL) levels were substantially lower in patients with encephalopathy, whereas the ratio of actual bodyweight to the ideal bodyweight (1.4 +/- 0.3 vs 1.1 +/- 0.2) was substantially higher in these patients. Five (62.5%) patients received a subsequent cycle of high-dose ifosfamide; all of these patients received methylthioninium chloride to minimize the risk of encephalopathy. All of these patients developed encephalopathy. Other reports have found that hypoalbuminaemia is associated with encephalopathy and that methylthioninium chloride does not prevent ifosfamide-induced encephalopathy.

Conclusions: In summary, female sex, low total bilirubin, albumin and haemoglobin levels, and obesity appear to be associated with ifosfamide-induced encephalopathy. Methylthioninium chloride did not appear to prevent encephalopathy with subsequent doses of high-dose ifosfamide.

Publication types

  • Meta-Analysis
  • Review

MeSH terms

  • Adult
  • Albumins / metabolism
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / adverse effects*
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Bilirubin / blood
  • Brain Diseases / chemically induced*
  • Brain Diseases / drug therapy
  • Brain Diseases / epidemiology
  • Cohort Studies
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Hemoglobins / metabolism
  • Humans
  • Ifosfamide / administration & dosage
  • Ifosfamide / adverse effects*
  • Ifosfamide / therapeutic use
  • Male
  • Methylene Blue / therapeutic use
  • Middle Aged
  • Nervous System Diseases / chemically induced
  • Nervous System Diseases / epidemiology
  • Obesity / complications
  • Obesity / epidemiology
  • Retrospective Studies
  • Risk Factors
  • Sarcoma / complications
  • Sarcoma / drug therapy
  • Sarcoma / pathology
  • Sex Factors


  • Albumins
  • Antineoplastic Agents, Alkylating
  • Enzyme Inhibitors
  • Hemoglobins
  • Bilirubin
  • Methylene Blue
  • Ifosfamide