Serious Neurological Events Complicating Epidural Injections Of

RMD Open: first published as 10.1136/rmdopen-2016-000320 on 22 September 2016. Downloaded from Editorial Serious neurological events complicating epidural injections of glucocorticoid suspensions: evidence for a direct effect of some particulate steroids on red blood cells Jean-Denis Laredo,1 Elisabeth Laemmel,2 Eric Vicaut2 To cite: Laredo J-D, The Food and Drug Administration (FDA) into the vertebral artery has also been Laemmel E, Vicaut E. Serious has not approved any injectable glucocortic- demonstrated in an animal study.7 Occlusion neurological events complicating epidural oid product for epidural administration, but of distal intramedullary arteries by steroid injections of glucocorticoid epidural injection of glucocorticoids is com- particles via an unexpected intra-arterial suspensions: evidence for a monly used to manage radicular neck and injection has been incriminated as the mech- direct effect of some back pain.1 Severe and sometimes fatal anism leading to cord infarction in severe particulate steroids on red neurological events have occurred immedi- neurological deficit occurring after foraminal blood cells. RMD Open 8 2016;2:e000320. doi:10.1136/ ately after epidural injection of glucocorti- steroid injections at the cervical spine. It has rmdopen-2016-000320 coids. Indeed, 90 events were reported to the been suggested that the tendency of steroid FDA Adverse Event Reporting System particles to coalesce and the size of their 2 fi ▸ Prepublication history and (FAERS) between 1997 and 2014. nal aggregates, which differ among the dif- additional material for this In the December 10, 2015 issue of the New ferent types of particulate steroids, may influ- 2 paper is available online. To England Journal of Medicine, Racoosin et al, ence the risk of arterial embolisation.9 view these files please visit from the FDA, found that all the catastrophic To explore the mechanisms by which ster- the journal online neurological events (brain and spinal cord oids provoke the cord infarction, we used (http://dx.doi.org/10.1136/ rmdopen-2016-000320). infarctions resulting in permanent disability intravital microscopy of mouse cremaster or death) reported to the FAERS were asso- muscles to investigate the in vivo effects of an http://rmdopen.bmj.com/ Received 19 June 2016 ciated with injection of a glucocorticoid sus- intra-arterial injection of four different par- Accepted 26 July 2016 pension, with only a few cases, involving ticulate steroids, namely methylprednisolone temporary symptoms, reported with gluco- acetate, triamcinolone acetonide, prednisol- corticoid solutions. However, the authors one acetate and cortivazol and one cortico- found that suspension formulations still steroid solution, namely dexamethasone accounted for more than 80% of the com- sodium phosphate, on microvascular perfu- mercially available corticosteroid products sion10. Intra-arterial administration of 20 µL used for epidural injections in 2013, accord- of pure prednisolone acetate or triamcino- on September 24, 2021 by guest. Protected copyright. ing to Medicare and IMS health data, despite lone acetonide suspension completely the increasing use of solutions. stopped blood flow in all arterioles and Potential causes of neurological complica- venules, which decreased the functional tions after spinal injections of a suspension capillary density to zero (see online supple- 1From the service de of particulate steroids include intrathecal mentary material). Methylprednisolone Radiologie ostéo-articulaire, injection, epidural hematoma, direct spinal acetate sharply decreased perfusion as well, Hôpital Lariboisière-Fernand cord injury and cord infarction due to an although some blood flow was maintained in Widal, APHP et Université arterial spasm or vascular obliteration after a few areas of the arteriolar and venular Paris-Diderot-Sorbonne, inadvertent intra-arterial injection.2 However, Paris-cité, France network. In contrast, intra-arterial administra- 2Laboratoire Etude de la the almost immediate onset of neurological tion of the cortivazol suspension or dexa- Microcirculation, Université deficit, as well as the MR findings performed methasone sodium phosphate solution Paris-Diderot-Sorbonne, in patients who underwent this complication, did not change microvascular blood flow.10 Paris-cité, France are very suggestive of spinal cord ischaemia The formation of macroaggregates of par- following interruption of arterial blood Correspondence to ticulate steroids, which has been suggested to 3–6 9 Professor Jean-Denis Laredo; supply. Brain or spinal cord ischaemia lead to vascular obliteration, was not [email protected] resulting from particulate steroid injection observed in our animal experiments. An Laredo J-D, et al. RMD Open 2016;2:e000320. doi:10.1136/rmdopen-2016-000320 1 RMD Open: first published as 10.1136/rmdopen-2016-000320 on 22 September 2016. Downloaded from RMD Open arterial spasm was not observed as well. Our results dis- that ‘serious neurological events, some resulting in death, closed another mechanism for microvascular occlusion. have been reported with epidural injection of corticoster- We found that an unexpected aggregation of red blood oids’ and that the ‘safety and effectiveness of epidural cells (RBCs), occurring immediately after injection of administration of corticosteroids have not been estab- the particulate steroids into the blood stream, was lished and corticosteroids are not approved for this use’.1 responsible for the obstruction of arterioles.10 As well, However, the warning did not distinguish any difference the particulate steroids could directly interact with RBCs in the risk associated with the various injection without mediation by white cells or plasma proteins. approaches (interlaminar, transforaminal and caudal), Scanning electron microscopy provided some insight locations of spinal injections (cervical, thoracic, lumbar into the mechanism of RBC agglutination, showing and sacral) or glucocorticoid formulations (solutions and RBCs with a deformed shape and their transformation suspensions), because ‘the data suggested that each into spiculated cells with prednisolone acetate, triamci- approach, location, and formulation was associated with nolone acetonide and methylprednisolone acetate some risk of neurological injury’.2 An advisory committee administration (figure 1). More than 28% of the RBCs meeting of the FDA, held in November 2014, decided changed into spiculated cells with these three cortico- not to modify the warning.2 This decision was taken steroid suspensions.10 despite all catastrophic events reported to the FAERS We were not able to determine the exact mechanisms occurred after injection of a glucocorticoid suspension.2 by which the particulate steroids induced an altered RBC In a recent review, MacMahon et al11 concluded that, in shape. The role of drug concentration, osmolarity and cervical, thoracic and high lumbar transforaminal epidural viscosity remains to be studied. In addition, why some steroid injections, a growing consensus of the literature particulate steroids induce the altered RBC shape and supports the exclusive use of non-particulate glucocortic- finally vascular occlusion while cortivazol, another par- oid to reduce the risk of embolic injury to the brain and ticulate steroid, does not, remains to be explained. Our spinal cord, but that both particulate and non-particulate results were obtained in an animal model of microvascu- glucocorticoid are acceptable choices in lower lumbosacral larisation. However, the same direct effect of the steroids transforaminal epidural spine injection since serious on human RBCs was also demonstrated in vitro.10 neurological events are exceedingly rare at this level. Other potential causes of vascular occlusion such as However, we believe that cord infarction is rarer at the vascular obliteration due to particulate steroids aggre- lower lumbar level compared to upper levels just gates or a vascular spasm were not specifically addressed because the anatomical disposition of a metameric in our work. Therefore, up to now, it is not possible to artery contributing to the cord vascularisation is only discriminate if there is only one or several mechanisms present in very few persons.12 responsible for the neurological deficits in humans. From our results, we suggest that the particulate ster- In 2014, the FDA issued a requirement that all inject- oids responsible for blood-flow arrest in our experiments, http://rmdopen.bmj.com/ able glucocorticoid product labels carry a warning stating namely methylprednisolone acetate, triamcinolone Figure 1 Scanning electron microscopy images of a mixture of human blood mixed with saline showing normal red blood cells (A) and human blood mixed with prednisolone acetate at different on September 24, 2021 by guest. Protected copyright. magnifications (B–D) showing spiculated red blood cells tending to interdigitate. (Images courtesy Massoud Mirshahi MD, PhD, UMR 965, Université Paris-Diderot, Paris, France). 2 Laredo J-D, et al. RMD Open 2016;2:e000320. doi:10.1136/rmdopen-2016-000320 RMD Open: first published as 10.1136/rmdopen-2016-000320 on 22 September 2016. Downloaded from Editorial acetonide and prednisolone acetate, should no longer be non-commercially, and license their derivative works on different terms, used for foraminal injections at the cervical as well at the provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ lumbar level and

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