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Perils of Intravascular Methylprednisolone Injection into the Vertebral ArteryAn Animal Study
Gbolahan O. Okubadejo, MD1; Michael R. Talcott, DVM2; Robert E. Schmidt, MD, PhD2; Aseem Sharma, MD2; Alpesh A. Patel, MD3; R. Brian Mackey, MD2; Anthony H. Guarino, MD2; Christopher J. Moran, MD2; K. Daniel Riew, MD2
1 Department of Orthopaedic Surgery, University of Pittsburgh, 3471 Fifth Avenue, Pittsburgh, PA 15213. E-mail address: gokubadejo@hotmail.com
2 Division of Comparative Medicine (M.R.T.) and Departments of Pathology (R.E.S.), Radiology (A.S. and C.J.M.), Orthopaedic Surgery (R.B.M. and K.D.R.), and Anesthesiology (A.H.G.), Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address for K.D. Riew: riewd@wudosis.wustl.edu
3 Department of Orthopaedic Surgery, University of Utah School of Medicine, 590 Wakara Way, Salt Lake City, UT 84108
View Disclosures and Other Information
Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants of less than $10,000 from the Barnes-Jewish-Christian Foundation. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
Investigation performed at the Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri

The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2008 Sep 01;90(9):1932-1938. doi: 10.2106/JBJS.G.01182
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Abstract

Background: Intravascular injection of particulate steroids during cervical nerve root blocks has been postulated to be a source of catastrophic neurologic complications that might be avoided with the use of non-particulate steroids. The objective of this study was to compare the effects of direct intravascular injection of particulate and non-particulate steroids on the spinal cord and central nervous system.

Methods: Eleven adult pigs underwent direct injection, under fluoroscopic guidance, into the vertebral artery while under general anesthesia. A particulate steroid (methylprednisolone) was injected into four animals (Group 1), whereas seven animals received a non-particulate steroid (dexamethasone in four animals [Group 2] and prednisolone in three [Group 3]). Following injection, the animals were assessed by direct observation of physical activity and with magnetic resonance imaging. After the animals were killed, brain and spinal cord material was retrieved, fixed in paraformaldehyde for one week, and then subjected to histopathologic analysis.

Results: All four animals in Group 1 failed to regain consciousness after the injection and required ventilatory support. The animals in Groups 2 and 3 recovered fully and demonstrated no evidence of neurologic injury. Magnetic resonance imaging revealed upper cervical cord and brain stem edema in Group 1, but not in Groups 2 and 3. Histologic analysis showed early evidence of hypoxic and ischemic damage—specifically, early eosinophilic neuronal necrosis, nuclear condensation, white-matter pallor, and extracellular edema—in Group 1 but not in Groups 2 and 3.

Conclusions: These data suggest that one etiology of neurologic complications following cervical nerve blocks may be inadvertent intravascular injection of particulate steroids, as all animals injected with methylprednisolone had neurologic deficits while none of the controls injected with non-particulate steroids were affected. To our knowledge, this study is the first to demonstrate that particulate steroids cause neurologic deficits and to suggest that use of non-particulate steroids might prevent such complications.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Gbolahan Okubadejo, MD
    Posted on January 06, 2009
    Drs. Okubadejo and Riew respond to Drs. Rathmell and Wainger
    University of Pittsburgh

    We thank Drs. Rathmell and Wainger for their comments regarding our paper, “Perils of Intravascular Methylprednisolone Injection into the Vertebral Artery” (1). This study found a 100% correlation between injection of the particulate steroid in the vertebral artery, and eventual mortality of the animal model used in this study - the pig. Nonparticulate steroids did not demonstrate such morbid outcomes.

    Drs. Rathmell and Wainger raise the question of whether the findings of this study can be extrapolated to make long-term prognoses. Our animals were kept on ventilator support for only 4 - 6 hours after the insult to the brain with none of the four animals in the Methylprednisolone group able to maintain appropriate oxygenation without ventilator support. No formal neurologic exam could be performed on these obtunded animals. They were sacrificed following the 4 – 6 hour recovery period which was deemed as appropriate for postoperative recovery. In marked contrast, all animals in the nonparticulate group were able to ambulate and appeared completely normal.

    As Drs. Rathmell and Wainger point out, it is certainly possible that, had we kept the animals alive for a longer period, they might have recovered. We agree that our results with pigs should not be used to prognosticate the long-term outcome of humans who suffer an immediate complication following particulate steroid injections; human beings are capable of overcoming and recovering from serious neurologic injuries, given enough time and proper rehabilitation. Nevertheless, there are several troubling case reports of catastrophic clinical outcomes following inadvertent injection of particulate steroids into the vertebral artery (2,3,4). In almost all instances, the patients sustained serious neurological deficits or ultimately expired. These reports suggest,unfortunately, that human correlates of our study do exist.

    We also agree that, in theory,that it may be possible for artifacts related to tissue processing to produce histological findings similar to what we found. However, as the data in this study were so consistent and reproducible, and had correlates with MRI and clinical findings, we believe that it is reasonable to conclude that the radiographic and histologic changes that were observed are indeed representative of true pathology as opposed to being artifact.

    In conclusion, we agree with Drs. Rathmell and Wainger that with our short-term animal study, we cannot judge the permanency of the neural injury following injection of particulate steroids. We believe that our study should serve as a cautionary note when utilizing particulate steroids for injections. Finally, we agree that there needs to be further study regarding the safety and effectiveness of non-particulate steroids before recommending its use.

    References

    1. Perils of intravascular methylprednisolone injection into the vertebral artery. An Animal Study. Okubadejo GO, Talcott MR, Schmidt RE et al. JBJS Am 2008; 90:1932-1938

    2. Derby R, Lee SH, Kim BJ et al. Complications following cervical epidural injections by expert interventionalists in 2003. Pain Physicians 2004; 7:445-449.

    3. McMillan MR, Crumpton C. Cortical blindness and neurologic injury complicating cervical transforaminal injection for cervical radiculopathy. Anesthesiology 2003; 99: 509 – 511.

    4. Rozin L, Rozin R, Koehler SA et al. Death during transforaminal epidural steroid nerve root block (C7) due to perforation of the left vertebral artery. Am J Forensic Med Path 2003; 24:315 – 355.

    James P. Rathmell, MD
    Posted on December 15, 2008
    Clarifying mechanism of neurologic injury following intra-arterial injection of particulate steroid
    Department of Anesthesia & Critical Care, Massachusetts General Hospital, Boston, Massachusetts

    To The Editor:

    We commend Dr. Okubadejo and colleagues for the article “Perils of Intravascular Methylprednisolone Injection into the Vertebral Artery. An Animal Study” (1). They show a convincing association between intra- arterial injection of particulate steroid and catastrophic neurologic injury. This study should help to eliminate remaining questions about the mechanism of injury. We offer a caution about judging permanency of neural injury and issue a call for further study of the safety and effectiveness of non-particulate steroids, particularly dexamethasone.

    In practice, patients are given days or longer to recover from neurological insult before concluding that the likelihood of improvement is minimal. Indeed, ventilated patients often require tracheostomy to progress to unassisted respiratory function. Caution in delivering a poor prognosis is paramount, especially in cases with inconclusive or absent imaging as is the case for two of the four animals that received particulate steroid. The dramatic changes on diffusion-weighted MR imaging studies that appear early following acute stroke are not predictive of the final size of the lesion and do not represent irreversibly infarcted tissue (2). To better understand the magnitude of the insult suffered by these animals, we would like to know more. How long were the animals given in order to wean from the ventilator? Did they show signs of spontaneous breathing? Did examination after recovery from any anesthetics document diffuse injury to the brainstem, corticospinal, sensory, and arousal systems? The pathology demonstrates dramatic degeneration, but correlation with the clinical exam is essential; albeit unlikely, artifacts related to tissue processing could have produced similar findings.

    Cases of stroke and spinal cord infarction have been reported following presumed intra-arterial injection of particulate steroid; most have been associated with transforaminal injections (3). The exact mechanism of injury is unknown, but intra-arterial injection of particulate steroid acting as emboli has been postulated. The current study establishes a clear link between the intra-arterial injection of particulate steroid and devastating neurological injury. No complications have been reported with the non-particulate steroid dexamethasone, and this report provides encouraging data regarding the safety of this agent. Nonethless, we have limited clinical evidence that this agent is safe or effective (4). Practitioners are likely to move to routine use of dexamethasone for transforaminal injection. We must send a strong call for further study to document the safety and treatment benefits of non- particulate alternatives. For those who are injured following steroid injection, this study should not be used as evidence in determining long- term prognosis.

    The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

    References

    1. Okubadejo GO, Talcott MR, Schmidt RE, Sharma A, Patel AA, Mackey RB, Guarino AH, Moran CJ, Riew KD. Perils of intravascular methylprednisolone injection into the vertebral artery. An animal study. J Bone Joint Surg Am 2008;90:1932-1938.

    2. Mezzapesa DM, Petruzzellis M, Lucivero V, Prontera M, Tinelli A, Sancilio M, Carella A, Federico F. Multimodal MR examination in acute ischemic stroke. Neuroradiology 2006;48:238-46.

    3. Rathmell JP, Aprill C, Bogduk N. Cervical transforaminal injection of steroids. Anesthesiology 2004;100:1595-600.

    4. Dreyfuss P, Baker R, Bogduk N. Comparative effectiveness of cervical transforaminal injections with particulate and nonparticulate corticosteroid preparations for cervical radicular pain. Pain Med 2006;7:237-42.

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