September-October 2017
Spine

Deleterious Effects of Intra-arterial Administration of Particulate Steroids on Microvascular Perfusion in a Mouse Model

Laredo Pic

Jean-Denis Laredo

Ninety severe and sometimes fatal neurologic events occurring immediately after epidural injection of suspensions of particular glucocorticoids were reported to the FDA between 1997 and 2014, most being foraminal injections.1 Our team reported 5 cases of paraplegia complicating selective injections of particulate steroids in the lumbar spine.2

The almost immediate onset of neurologic deficit, as well as the MR findings performed in patients who experienced this complication, are suggestive of spinal cord ischemia following the interruption of arterial blood supply.3–6 The occlusion of distal intramedullary arteries by steroid particles via an unexpected intra-arterial injection has been incriminated as the mechanism leading to cord infarction.7

We used intravital microscopy of mouse cremaster muscles to investigate the in vivo effects of an intra-arterial injection of 4 different particulate steroids—namely methylprednisolone acetate, triamcinolone acetonide, prednisolone acetate, and cortivazol—and 1 corticosteroid solution—namely dexamethasone sodium phosphate—on microvascular perfusion.8 Intra-arterial administration of 20 microliters of a pure prednisolone acetate or triamcinolone acetonide suspension completely stopped blood flow in all arterioles and venules, while methylprednisolone acetate sharply decreased perfusion as well, although some blood flow was maintained in a few areas of the arteriolar and venular network. In contrast, intra-arterial administration of a cortivazol suspension or dexamethasone sodium phosphate solution did not change microvascular blood flow.8 The formation of macroaggregates of particulate steroids, which has been suggested to lead to vascular obliteration,9 was not observed in our animal experiments. Conversely, we found that an unexpected aggregation of red blood cells, occurring immediately after injection of the particulate steroids into the blood stream, was responsible for the obstruction of arterioles.8 The particulate steroids could directly interact with red blood cells without mediation by white blood cells or plasma proteins. Scanning electron microscopy showed that, with the administration of prednisolone acetate, triamcinolone acetonide, or methylprednisolone acetate, more than 28% of the red blood cells changed in shape and were deformed into spiculated cells.8 The same direct effect of the steroids on human red blood cells was also demonstrated in vitro.8

In 2014, the FDA issued a requirement that all injectable glucocorticoid product labels carry a warning concerning the serious neurologic events after epidural injection of corticosteroids.10 However, the warning did not distinguish any difference in the risks associated with the various injection approaches (eg, interlaminar, transforaminal, and caudal) or glucocorticoid formulations (solutions and suspensions). From our results, we suggest that the particulate steroids responsible for blood flow arrest in our experiments should no longer be used for foraminal injections, both at the cervical and at the lumbar level, and as a precaution, for epidural injections as well.

In clinical practice, we presently recommend the use of dexamethasone sodium phosphate solution for epidural injection, despite its short-acting time, since it is the only available alternative to corticosteroid suspensions. Several works that compared pain reduction with transforaminal injection of either dexamethasone sodium phosphate or steroid suspensions have found no evidence that dexamethasone is less effective than particulate steroids.11 However, there is no direct evidence that nonparticulate steroids are superior to sham injections, and studies that show no difference between particulate and nonparticulate steroids are underpowered.12 Therefore, further studies are needed to confirm the effectiveness of dexamethasone sodium phosphate with this method of administration.

References

  1. Racoosin JA, Seymour SM, Cascio L, et al. Serious neurologic events after epidural glucocorticoid injection—the FDA's risk assessment. N Engl J Med 2015;373:2299–301, 10.1056/NEJMp1511754.
  2. Wybier M, Gaudart S, Petrover D, et al. Paraplegia complicating selective steroid injections of the lumbar spine. report of five cases and review of the literature. Eur Radiol 2010;20:181–89, 10.1007/s00330-009-1539-7.
  3. Houten JK, Errico TJ. Paraplegia after lumbosacral nerve root block: report of three cases. Spine J 2002;2:70–5, 10.1016/S1529-9430(01)00159-034.
  4. Huntoon MA, Martin DP. Paralysis after transforaminal epidural injection and previous spinal surgery. Reg Anesth Pain Med 2004;29:494–95, 10.1016/S1529-9430(01)00159-0.
  5. Somayaji HS, Saifuddin A, Casey ATH, et al. Spinal cord infarction following therapeutic computed tomography-guided left L2 nerve root injection. Spine 2005;30:E106–08, 10.1097/01.brs.0000153400.67526.07.
  6. Yuh WT, Marsh EE, Wang AK, et al. MR imaging of spinal cord and vertebral body infarction. AJNR Am J Neuroradiol 1992;13:145–54.
  7. Tiso RL, Cutler T, Catania JA, et al. Adverse central nervous system sequelae after selective transforaminal block: the role of corticosteroids. Spine J 2004;4:468–74, 10.1016/j.spinee.2003.10.007.
  8. Laemmel E, Segal N, Mirshahi M, et al. Deleterious effects of intra-arterial administration of particulate steroids on microvascular perfusion in a mouse model. Radiology 2016;279:731–40, 10.1148/radiol.2015142746.
  9. Derby R, Lee S-H, Date ES, et al. Size and aggregation of corticosteroids used for epidural injections. Pain Medicine 2008;9:227–34, 10.1111/j.1526-4637.2007.00341.x.
  10. Food and Drug Administration. FDA drug safety communication: FDA requires label changes to warn of rare but serious neurologic problems after epidural corticosteroid injections for pain. Published April 23, 2014. Updated January 15, 2016.
  11. El-Yahchouchi C, Geske JR, Carter RE, et al. The noninferiority of the nonparticulate steroid dexamethasone vs the particulate steroids betamethasone and triamcinolone in lumbar transforaminal epidural steroid injections. Pain Medicine 2013;14:1650–57, 10.1111/pme.12214.
  12. Rathmell JP, Benzon HT, Dreyfuss P, et al. Safeguards to prevent neurologic complications after epidural steroid injections: consensus opinions from a multidisciplinary working group and national organizations. Anesthesiology 2015;122:974–84, 10.1097/ALN.0000000000000614.

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