Author: Krupa Desai, MD – Children’s Hospital of Philadelphia; Chinwe Unegbu, MD – Children’s National Hospital
A 3 year-old-child with hypoplastic left heart syndrome (HLHS) status post hybrid palliation and subsequent comprehensive stage II repair presents for cardiac magnetic resonance imaging (MRI). The imaging cardiologist plans to utilize ferumoxytol instead of gadolinium contrast. Which of the following is the MOST LIKELY indication for ferumoxytol contrast versus gadolinium contrast?
Correct!
Wrong!
Question of the Week 327
Ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, MA) is an intravenous formulation of enteral iron classically used to treat severe iron deficiency anemia in adult patients with chronic kidney disease. Ferumoxytol has been shown to be an effective and safe magnetic resonance imaging (MRI) contrast agent. Ferumoxytol allows for contrast enhanced imaging in patients with contraindications to gadolinium-based contrast agents (GBCA), such as renal failure. Ferumoxytol has recently been used with increasing frequency in smaller and more medically fragile children.
Due to the long half-life, ferumoxytol does not have to be administered during the cardiac MRI exam itself. Rather, it can be administered hours prior to the cardiac MRI. This is particularly beneficial in tenuous cardiac patients in order to decrease the time spent outside of the intensive care unit (ICU) by administration of ferumoxytol at bedside prior to transport. Ferumoxytol is impermeable to vascular capillaries and is not filtered by the kidneys. Thus, it remains in the intravascular compartment until it is ingested by macrophages and then excreted by the liver. Due to its large molecular size and dextran coat, ferumoxytol has a long intravascular half-life of approximately 14–15 hours, which provides a long and stable time window for vascular enhancement and imaging. As the uptake and metabolism of ferumoxytol is by the reticuloendothelial system, the risk of nephrogenic systemic fibrosis and central nervous system deposition is nil compared to GBCA.
In pediatric patients, the additional benefits of ferumoxytol are quite noteworthy. Ferumoxytol allows for patients with renal dysfunction to have contrast-enhanced MRI imaging when needed due to a lack of renal metabolism and excretion. Administration of ferumoxytol is quite beneficial in patients with cardiac lesions whose residual disease burden can be best addressed by contrast enhanced imaging. This includes patients with Fontan physiology, anomalous coronaries, and those with aortopulmonary collaterals. Use of ferumoxytol negates the need for suspended respirations during cardiac MRI studies due to prolonged vascular enhancement. Suspended respirations are typically requested to obtain better-quality imaging with GBCA and to minimize motion artifact related to respiratory efforts. As a result, patients undergoing cardiac MRI with GBCA are more likely to be intubated and receive neuromuscular blocking agents to facilitate suspended respirations during MRI gating. Imaging parameters are enhanced with the use of ferumoxytol negating the need for respiratory pauses. Ultimately, this results in a reduced time needed for the cardiac MRI imaging and general anesthesia when compared to imaging obtained with GBCA.
Ferumoxytol has an excellent safety profile with a long history of use. Due to its long half-life, however, anaphylactic reactions (0.03% aggregate rate in post-market surveillance of > 8000 administrations) can be serious and difficult to treat. The majority of anaphylactic reactions are recognizable within 5 minutes of starting the infusion. Thirty percent of individuals who develop anaphylatic reactions have had at least one prior allergic reaction to a medication. Due to the long half-life of ferumoxytol, some consider a history of anaphylaxis to any other medication a “soft” contraindication to ferumoxytol. Hypersensitivity reactions resulting in hypotension and death have been reported with the use of ferumoxytol for the treatment of anemia in adults. The reports of hypersensitivity to ferumoxytol in adults led to a black box warning in 2015 by the Food and Drug Administration (FDA). Monitoring for signs of anaphylaxis (hypotension, erythema, rash, bronchospasm, etc.) is prudent. Blood pressure measurements should be performed routinely up until 30 min after completion of the infusion. Early treatment with diphenhydramine and epinephrine has successfully treated anaphylaxis.
Hypotension alone (nonimmunologic) has also been associated with ferumoxytol and is thought to be related to the release of free iron. Other intravenous iron formulations have similar effects on blood pressure (hypotension). As a result, the FDA has recommended dilution and slow administration of ferumoxytol over approximately 15 minutes.
Ferumoxytol is contraindicated in patients with a history of allergic reactions to ferumoxytol or other intravenous iron products and those with iron overload such as hemochromatosis, severe chronic hemolysis, frequent blood transfusion, and prolonged hemodialysis. Additionally, use is cautioned in patients with severe hepatic disease.
All MRI images may be altered by ferumoxytol for days to months. This complicates subsequent MRI imaging of other areas of the body such as the brain. As a result, close coordination and communication is needed with respect to the sequence of imaging in patients requiring MRI scans of other regions of the body in addition to the cardiac MRI.
References
1. Ruangwattanapaisarn N, Hsiao A, Vasanawala SS. Ferumoxytol as an off-label contrast agent in body 3T MR angiography: a pilot study in children. Pediatr Radiol. 2015; 45(6): 831-839. doi:10.1007/s00247-014-3226-3.2.
2. Corot C, Robert P, Idee J, Port M. Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev. 2006; 58(14): 1471-1504. doi:10.1016/j.addr.2006.09.013
3. Nguyen KL, Yoshida T, Han F, et al. MRI with ferumoxytol: A single center experience of safety across the age spectrum. J Magn Reson Imaging. 2017; 45(3): 804-812. doi:10.1002/jmri.25412.
4. Van Wyck DB. Labile iron: manifestations and clinical implications. J Am Soc Nephrol 2004; 15: S107–S111.
5. Wise-Faberowski L, Velasquez N, Chan F, Vasanawala S, McElhinney DB, Ramamoorthy C. Safety of ferumoxytol in children undergoing cardiac MRI under general anaesthesia. Cardiol Young. 2018; 28(7): 916-921. doi:10.1017/S1047951118000306
6. Li W, Tutton S, Vu AT, et al. First-pass contrast-enhanced magnetic resonance angiography in humans using ferumoxytol, a novel ultrasmall superparamagnetic iron. (USPIO)-based blood pool agent. J Magn Reson Imaging. 2005; 21: 46–52.
7. Rampton D, Folkersen J, Fishbane S, et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014; 99: 1671–1676.
Due to the long half-life, ferumoxytol does not have to be administered during the cardiac MRI exam itself. Rather, it can be administered hours prior to the cardiac MRI. This is particularly beneficial in tenuous cardiac patients in order to decrease the time spent outside of the intensive care unit (ICU) by administration of ferumoxytol at bedside prior to transport. Ferumoxytol is impermeable to vascular capillaries and is not filtered by the kidneys. Thus, it remains in the intravascular compartment until it is ingested by macrophages and then excreted by the liver. Due to its large molecular size and dextran coat, ferumoxytol has a long intravascular half-life of approximately 14–15 hours, which provides a long and stable time window for vascular enhancement and imaging. As the uptake and metabolism of ferumoxytol is by the reticuloendothelial system, the risk of nephrogenic systemic fibrosis and central nervous system deposition is nil compared to GBCA.
In pediatric patients, the additional benefits of ferumoxytol are quite noteworthy. Ferumoxytol allows for patients with renal dysfunction to have contrast-enhanced MRI imaging when needed due to a lack of renal metabolism and excretion. Administration of ferumoxytol is quite beneficial in patients with cardiac lesions whose residual disease burden can be best addressed by contrast enhanced imaging. This includes patients with Fontan physiology, anomalous coronaries, and those with aortopulmonary collaterals. Use of ferumoxytol negates the need for suspended respirations during cardiac MRI studies due to prolonged vascular enhancement. Suspended respirations are typically requested to obtain better-quality imaging with GBCA and to minimize motion artifact related to respiratory efforts. As a result, patients undergoing cardiac MRI with GBCA are more likely to be intubated and receive neuromuscular blocking agents to facilitate suspended respirations during MRI gating. Imaging parameters are enhanced with the use of ferumoxytol negating the need for respiratory pauses. Ultimately, this results in a reduced time needed for the cardiac MRI imaging and general anesthesia when compared to imaging obtained with GBCA.
Ferumoxytol has an excellent safety profile with a long history of use. Due to its long half-life, however, anaphylactic reactions (0.03% aggregate rate in post-market surveillance of > 8000 administrations) can be serious and difficult to treat. The majority of anaphylactic reactions are recognizable within 5 minutes of starting the infusion. Thirty percent of individuals who develop anaphylatic reactions have had at least one prior allergic reaction to a medication. Due to the long half-life of ferumoxytol, some consider a history of anaphylaxis to any other medication a “soft” contraindication to ferumoxytol. Hypersensitivity reactions resulting in hypotension and death have been reported with the use of ferumoxytol for the treatment of anemia in adults. The reports of hypersensitivity to ferumoxytol in adults led to a black box warning in 2015 by the Food and Drug Administration (FDA). Monitoring for signs of anaphylaxis (hypotension, erythema, rash, bronchospasm, etc.) is prudent. Blood pressure measurements should be performed routinely up until 30 min after completion of the infusion. Early treatment with diphenhydramine and epinephrine has successfully treated anaphylaxis.
Hypotension alone (nonimmunologic) has also been associated with ferumoxytol and is thought to be related to the release of free iron. Other intravenous iron formulations have similar effects on blood pressure (hypotension). As a result, the FDA has recommended dilution and slow administration of ferumoxytol over approximately 15 minutes.
Ferumoxytol is contraindicated in patients with a history of allergic reactions to ferumoxytol or other intravenous iron products and those with iron overload such as hemochromatosis, severe chronic hemolysis, frequent blood transfusion, and prolonged hemodialysis. Additionally, use is cautioned in patients with severe hepatic disease.
All MRI images may be altered by ferumoxytol for days to months. This complicates subsequent MRI imaging of other areas of the body such as the brain. As a result, close coordination and communication is needed with respect to the sequence of imaging in patients requiring MRI scans of other regions of the body in addition to the cardiac MRI.
References
1. Ruangwattanapaisarn N, Hsiao A, Vasanawala SS. Ferumoxytol as an off-label contrast agent in body 3T MR angiography: a pilot study in children. Pediatr Radiol. 2015; 45(6): 831-839. doi:10.1007/s00247-014-3226-3.2.
2. Corot C, Robert P, Idee J, Port M. Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev. 2006; 58(14): 1471-1504. doi:10.1016/j.addr.2006.09.013
3. Nguyen KL, Yoshida T, Han F, et al. MRI with ferumoxytol: A single center experience of safety across the age spectrum. J Magn Reson Imaging. 2017; 45(3): 804-812. doi:10.1002/jmri.25412.
4. Van Wyck DB. Labile iron: manifestations and clinical implications. J Am Soc Nephrol 2004; 15: S107–S111.
5. Wise-Faberowski L, Velasquez N, Chan F, Vasanawala S, McElhinney DB, Ramamoorthy C. Safety of ferumoxytol in children undergoing cardiac MRI under general anaesthesia. Cardiol Young. 2018; 28(7): 916-921. doi:10.1017/S1047951118000306
6. Li W, Tutton S, Vu AT, et al. First-pass contrast-enhanced magnetic resonance angiography in humans using ferumoxytol, a novel ultrasmall superparamagnetic iron. (USPIO)-based blood pool agent. J Magn Reson Imaging. 2005; 21: 46–52.
7. Rampton D, Folkersen J, Fishbane S, et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014; 99: 1671–1676.
