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


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).


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.
Sweiss
Karen I
KI
University of Illinois at Chicago College of Pharmacy and University of Illinois Medical Center at Chicago, Chicago, Illinois, USA.
Beri
Rakesh
R
Shord
Stacy S
SS
D000328:Adult; D000418:Albumins / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001663:Bilirubin / Q000097:blood; D001927:Brain Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000453:epidemiology; D015331:Cohort Studies; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008751:Methylene Blue / Q000627:therapeutic use; D008875:Middle Aged; D009422:Nervous System Diseases / Q000139:chemically induced / Q000453:epidemiology; D009765:Obesity / Q000150:complications / Q000453:epidemiology; D012189:Retrospective Studies; D012307:Risk Factors; D012509:Sarcoma / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D012737:Sex Factors
D000418:Albumins; D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D001663:Bilirubin; D008751:Methylene Blue; D007069:Ifosfamide