Off-label use of Gd
Gd contrast agents are only approved for IV administration, but don't people inject them into joints and the CSF? Is this safe? Is this legal?
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None of the eight commercially available gadolinium-based contrast agents have been approved for intra-articular or intrathecal administration in the United States or in most other countries. Nevertheless, regulatory government agencies in most countries permit the discretionary use of approved drugs for non-approved purposes. This is known as "off-label use" of a pharmaceutical agent.
In the United States, for example, the Food and Drug Administration (FDA) approves drugs shown to be safe and effective for certain clinical conditions, but does not control or limit how those drugs are prescribed once available on the market. As such a US physician may administer an approved MR contrast agent at a different dose or by different route (intra-articular or intrathecal) in particular clinical situations where a benefit to the patient may accrue.
Intra-articular injection of gadolinium-based contrast agents is widely and commonly performed at most larger MR centers around the world. Known as gadolinium-enhanced MR arthrography, this technique has been proved valuable in demonstrating small tears in cartilage and ligaments not visible on routine MRI.
Intra-articular injection of Gd-DTPA into the wrist
The contrast must be highly diluted with saline prior to injection, with levels of approximately 2 mmol/L recommended for most joints. (By comparison, the concentration of most undiluted Gd contrast agents is 0.5M = 500 mmol/L. In a number of European countries, an option is to use Artirem®, a version of gadoterate prediluted 100-fold and marketed by Guerbet for intra-articular use). Depending on the size of the joint, between 10 and 40 mL are typically injected. A small amount of iodinated contrast is frequently mixed in so that the injection can be followed under x-ray fluoroscopy. If the gadolinium contrast is not diluted, a signal drop-out will occur due to T2-shortening effects.
Animal studies have confirmed that the gadolinium contrast is rapidly reabsorbed after injection with no acute or long-term injury to the synovial structures. Although Gd does not appear to cause any direct toxicity or inflammation, about 2/3 of patients will experience significant joint pain developing within the first 2 days after injection. The nature of this discomfort is unclear, but probably not due to the gadolinium. It may be caused by joint distention by the injected saline or the iodine agent (the latter known to cause synovitis and pain in CT arthrography).
Animal studies have confirmed that the gadolinium contrast is rapidly reabsorbed after injection with no acute or long-term injury to the synovial structures. Although Gd does not appear to cause any direct toxicity or inflammation, about 2/3 of patients will experience significant joint pain developing within the first 2 days after injection. The nature of this discomfort is unclear, but probably not due to the gadolinium. It may be caused by joint distention by the injected saline or the iodine agent (the latter known to cause synovitis and pain in CT arthrography).
Intrathecal injection of gadolinium has been advocated for the evaluation of patients with suspected cerebrospinal fluid (CSF) leaks, and appears to be more sensitive than CT myelography for this purpose. Typically about 0.3-0.5 mL of a 0.5M gadolinium contrast (e.g., Gd-DTPA) is injected into the subarachnoid space via lumbar puncture. Higher doses will more likely result in very severe headaches and nausea. To insure even distribution, this may be diluted in 4-5 cc of saline, an iodine myelographic contrast agent like iohexol, or the patient's own cerebrospinal fluid prior to injection. Fat suppressed T1-weighted images of the spine or skull base are then obtained after a 15 minute delay.
Intrathecal gadolinium in these low doses seems well-tolerated in the limited clinical series reported to date except for headaches. However, in doses higher than 0.1 mmol, seizures, transient hemiparesis, encephalopathy, and death have been reported. The absolute safety of intrathecal gadolinium is less well established than intra-articular gadolinium, so at present I believe should be only considered in selected patients believed symptomatic from occult CSF leakage.
References
Albayram S, Kilic F, Ozer H, et al. Gadolinium-enhanced MR cisternography to evaluate dural leaks in intracranial hypotension syndrome. AJNR Am J Neuroradiol 2008; 29:116-121. [DOI Link]
Chazen JL, Talbott JF, Lantos JE, Dillon WP. MR myelography for identification of spinal CSF leak in spontaneous intracranial hypotension. AJNR Am J Neuroradiol 2014; 35:2007-12. [DOI Link]
Dillon WP. Intrathecal gadolinium: its time has come? AJNR Am J Neuroradiol 2008; 29:3-4. [DOI Link]
Edeklev CS, Halvorsen M, Løvland G, et al. Intrathecal use of gadobutrol for glymphatic MR imaging: prospective safety study of 100 patients. AJNR Am J Neuroradiol 2019; 40:1257-64. [DOI LINK]
Giaconi JC, Link TM, Vail TP et al. Morbidity of direct MR arthrography. AJR Am J Roentgenol 2011; 196:868-874. [DOI Link]
Hajek PC, Sartoris DJ, Gylys-Morin V, et al. The effect of intra-articular gadolinium-DTPA on synovial membrane and cartilage. Invest Radiol 1990; 25:179-183. (no joint damage detected in rabbit model) [DOI Link]
Lenk C, Duttge G. Ethical and legal framework and regulation for off-label use: European perspective. Therap Clin Risk Management 2014; 10:537-546. [DOI Link]
Patel M, Atyani A, Salameh J-P, et al. Safety of intrathecal administration of gadolinium-based contrast agents: a systematic review and meta-analysis. Radiology 2020; (in press) [DOI Link]
Schulte-Altedorneburg G, Gebhard M, Wohlgemuth W, et al. MR arthrography: pharmacology, efficacy and safety in clinical trials. Skel Radiol 2003; 32:1-12. [DOI Link]
Wittich CM, Burkle CM, Lanier WL. Ten Common Questions (and their answers) about off-label drug use. Mayo Clin Proc 2012; 87:982-990. [DOI Link]
Albayram S, Kilic F, Ozer H, et al. Gadolinium-enhanced MR cisternography to evaluate dural leaks in intracranial hypotension syndrome. AJNR Am J Neuroradiol 2008; 29:116-121. [DOI Link]
Chazen JL, Talbott JF, Lantos JE, Dillon WP. MR myelography for identification of spinal CSF leak in spontaneous intracranial hypotension. AJNR Am J Neuroradiol 2014; 35:2007-12. [DOI Link]
Dillon WP. Intrathecal gadolinium: its time has come? AJNR Am J Neuroradiol 2008; 29:3-4. [DOI Link]
Edeklev CS, Halvorsen M, Løvland G, et al. Intrathecal use of gadobutrol for glymphatic MR imaging: prospective safety study of 100 patients. AJNR Am J Neuroradiol 2019; 40:1257-64. [DOI LINK]
Giaconi JC, Link TM, Vail TP et al. Morbidity of direct MR arthrography. AJR Am J Roentgenol 2011; 196:868-874. [DOI Link]
Hajek PC, Sartoris DJ, Gylys-Morin V, et al. The effect of intra-articular gadolinium-DTPA on synovial membrane and cartilage. Invest Radiol 1990; 25:179-183. (no joint damage detected in rabbit model) [DOI Link]
Lenk C, Duttge G. Ethical and legal framework and regulation for off-label use: European perspective. Therap Clin Risk Management 2014; 10:537-546. [DOI Link]
Patel M, Atyani A, Salameh J-P, et al. Safety of intrathecal administration of gadolinium-based contrast agents: a systematic review and meta-analysis. Radiology 2020; (in press) [DOI Link]
Schulte-Altedorneburg G, Gebhard M, Wohlgemuth W, et al. MR arthrography: pharmacology, efficacy and safety in clinical trials. Skel Radiol 2003; 32:1-12. [DOI Link]
Wittich CM, Burkle CM, Lanier WL. Ten Common Questions (and their answers) about off-label drug use. Mayo Clin Proc 2012; 87:982-990. [DOI Link]
Related Questions
So many gadolinium contrast agents are now available. What are the differences among them?
So many gadolinium contrast agents are now available. What are the differences among them?