How much is cyclophosphamide sequestered by an ECLS/ECMO circuit?

How much is cyclophosphamide sequestered by an ECLS (extracorporeal life support/ECMO) circuit?

Comment by InpharmD Researcher

There is a paucity of kinetic data on the amount of cyclophosphamide sequestered by an extracorporeal life support (ECLS) circuit; however, available literature suggests cyclophosphamide is likely to be unaffected due to its low protein binding (~20%) and water-soluble nature. Case reports (Tables 1-4) describe concomitant ECMO use with cyclophosphamide, suggesting no serious complications associated with its use.

Background

Studies have shown two properties that affect drug sequestration in ECMO: lipophilicity and protein binding. Drugs with higher protein binding were found to have higher losses despite similar lipophilicity. Lipophilic drugs have consistently shown a greater propensity for drug sequestration compared to hydrophilic drugs, partly due to higher solubility in organic components of the circuit. Other properties, such as molecular size and ionization, are also theorized to play a role, but insufficient data are available to characterize their potential effects. Approximately 20% of cyclophosphamide is protein-bound, with no dose-dependent changes. Cyclophosphamide is also soluble in water and alcohol. [1], [2]

A review of pharmacokinetic (PK) alterations in extracorporeal membrane oxygenation (ECMO) acknowledges limited published data on the PK of drugs in adults during ECMO and makes preliminary recommendations on a possible dosing approach: integrating pre-clinical findings (e.g., ex vivo and animal ECMO models) with data from the patient, and using physicochemical properties of drugs, predict PK changes to guide effective dosing. The introduction of ECMO potentially leads to PK changes in drugs in three ways: drug sequestration by the circuit, increased volume of distribution (Vd), and/or altered drug clearance (CL). [3]

Relevant Prescribing Information

Pharmacokinetics
Distribution
Approximately 20% of cyclophosphamide is protein bound, with no dose dependent changes.

USE IN SPECIFIC POPULATIONS
Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between cyclophosphamide administration and dialysis should be considered.

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

How much is cyclophosphamide sequestered by an ECLS (extracorporeal life support/ECMO) circuit?

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-4 for your response.

Extracorporeal membrane oxygenation for the management of respiratory failure caused by diffuse alveolar hemorrhage
Design	Case report
Case Presentation	Extracorporeal membrane oxygenation (ECMO) was used for severe respiratory failure in a 51-year-old Chinese woman with severe hemoptysis caused by diffuse alveolar hemorrhage (DAH). On the first day of admission, the patient was treated with 500 mg methylprednisolone and 200 mg cyclophosphamide intravenously. To minimize exposure to cyclophosphamide, 200 mg was intravenously administered every other day originally and reduced to 200 mg twice a week on day 30 until her extubation at 60 days. The patient also received immunoglobulin and albumin therapy. The patient underwent plasmapheresis three times a day on days 5, 7, and 16 and underwent continuous renal replacement therapy (CRRT) on days 5-8 and 17-20. The patient was discharged home on hospital day 85 with normal pulmonary and renal function.
Study Author Conclusions	Immunosuppressive therapy with glucocorticoids and cyclophosphamide has dramatically improved the survival rate, and early initiation of ECMO and meticulous care during treatment should be considered an effective treatment for patients with respiratory failure caused by DAH when conventional therapy fails.

References:
[1] Guo Z, Li X, Jiang LY, Xu LF. Extracorporeal membrane oxygenation for the management of respiratory failure caused by diffuse alveolar hemorrhage. J Extra Corpor Technol. 2009;41(1):37–40.

Successful application of extracorporeal membrane oxygenation due to pulmonary hemorrhage secondary to granulomatosis with polyangiitis
Design	Case report
Case Presentation	A 65-year-old female with acute renal and respiratory failure after repeated episodes of hemoptysis was treated with extracorporeal membrane oxygenation (ECMO) and prednisolone 500 mg IV daily supported by plasmapheresis due to antineutrophil cytoplasmic autoantibody (ANCA)-antibodies. As cyclophosphamide is removed by hemofiltration pulse, it was delayed until day 2, following the second plasmapheresis and the second hemofiltration. The hemoptysis progressively decreased and stopped 6 days after ECMO initiation. Clinical, radiological, bronchoscopic, and laboratory findings showed progressive improvement that allowed ECMO weaning and discontinuation after 10 days of support, and extubation on the following day, after 11 days of mechanical ventilation. The patient recovered, maintained good respiratory function, and was discharged home after 46 days of hospitalization and chronic dialysis. Pulse cyclophosphamide was administered for a total of 3 months, up to a total dose of 4.73 gm, followed by azathioprine (100 mg orally, daily) and prednisolone (tapered to 5 mg orally daily). At 17 month follow-up, she had no relapses and maintained respiratory function.
Study Author Conclusions	Despite its risk of severe pulmonary bleeding, successful adult ECMO cases are increasing, thus raising the confidence level of its application in acute respiratory failure associated with pulmonary bleeding. In this patient, ECMO sustained life and allowed disease control together with plasmapheresis, cyclophosphamide, corticoids, and renal replacement therapy.

References:
[1] Hohenforst-Schmidt W, Petermann A, Visouli A, et al. Successful application of extracorporeal membrane oxygenation due to pulmonary hemorrhage secondary to granulomatosis with polyangiitis. Drug Des Devel Ther. 2013;7:627–633.

Extracorporeal membrane oxygenation in diffuse alveolar hemorrhage secondary to systemic lupus erythematosus
Design	Case series
Case 1	A 33-year-old Haitian female previously diagnosed with systemic lupus erythematosus (SLE) manifested by serositis, vasculitis, proteinuria, and positive antinuclear antibody (ANA), and anti-double-stranded DNA titers presented to the emgergency department with progressive dyspnea, hemoptysis, and diffuse abdominal pain. Bronchoscopy was performed and confirmed alveolar hemorrhage. Blood cultures were positive for Klebsiella pneumonaie, and broad-spectrum antibiotic coverage was initiated. She was admitted to the ICU for sepsis and her clinical condition continued to deteriorate. Veno-venous extracorporeal membrane oxygenation (ECMO) was started. For the first 24 hours, a trillium-coated Affinity NT filter (Medtronic^®) was used before changing it to a heparin-coated Quadrox D filter (Maquet^®) for the sake of effectiveness and long-term use. Pulse corticosteroids and IV cyclophosphamide were also initiated. The patient then progressed into multi-organ failure with acute renal failure. Continuous veno-venous hemodialysis (CVVH) was required. Her alveolar hemorrhage progressed dramatically and eventually died profound hemodynamic collapse secondary to diffuse severe bleeding and septic shock 48 h later.
Case 2	A 36-year-old male, also of Haitian origin, was hospitalized for dyspnea, fatigue, and SLE after a positive ANA titer and alveolar infiltrates. He was given steroids and discharged with oral cyclophosphamide. After two days, the patient was readmitted for severe cellulitis and panniculitis of the leg. Antibiotics and IV steroids were started. After surgical exploration, the patient was admitted to the ICU for severe sepsis and then developed hypoxemic respiratory failure. Bronchoscopy revealed diffuse bleeding in both main stem bronchi. The patient remained hypoxemic despite volume-controlled ventilation. Veno-venous ECMO was started with the same filter strategy as for the first patient. Pulse intravenous corticosteroids were administered for 72 hours, as was intravenous cyclophosphamide, in light of significant clinical deterioration secondary to SLE flare-up. ECMO continued for a total of 6 days. The patient recovered and was weaned off mechanical ventilation after 10 days. He was discharged from hospital on oral prednisone (60 mg daily) and intravenous cyclophosphamide. He was stable and free of neurologic sequelae at his last follow-up appointment 1 year later.
Study Author Conclusions	Both cases of acute respiratory failure did not respond to conventional support methods and installation of veno-venous ECMO provided adequate gaseous exchanges and respiratory support while immunosuppressive agents (including concomitant cyclophosphamide) became effective. Little is known about the bioavailability of the cyclophosphamide or other immunosuppressive agents in the setting of ECMO and whether dose adjustment is necessary.

References:
[1] Pacheco Claudio C, Charbonney E, Durand M, Kolan C, Laskine M. Extracorporeal membrane oxygenation in diffuse alveolar hemorrhage secondary to systemic lupus erythematosus. J Clin Med Res. 2014;6(2):145–148.

Successful use of artificial lung (ECMO) and kidney in the treatment of a 20-year-old female with Wegener's syndrome
Design	Case Report
Case Presentation	A 20-year-old female with renal and pulmonary anti-neutrophil cytoplasmic autoantibody (ANCA)- positive vasculitis had ECMO temporarily applied. Immunomodulating therapy consisted of cyclophosphamide 0.5 g, cortisone, methylprednisolone, and plasma exchanges during ECMO. She was weaned off ECMO after a couple of days, and with immunosuppressive therapy, her condition improved. She was disconnected from the respirator on day 59, at which time also regular dialysis was withdrawn. Gradually, the lung infiltrates cleared completely and the patient was discharged on day 91.
Authors conclusion	The patient was considered at risk of death if ECMO treatment had not been applied. The dose of cyclophosphamide was considered adequate.

References:
[1] Hartmann A, Nordal KP, Svennevig J, et al. Successful use of artificial lung (ECMO) and kidney in the treatment of a 20-year-old female with Wegener's syndrome. Nephrol Dial Transplant. 1994;9(3):316-9.