The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 85, Issue 1

Scientific Article | January 01, 2003

Sustained Spinal Cord Compression : Part II: Effect of Methylprednisolone on Regional Blood Flow and Recovery of Somatosensory Evoked Potentials

Gregory D. Carlson, MD; Carey D. Gorden, MA; Shigenobu Nakazawa, MD; Eiji Wada, MD; Jeremy S. Smith; Joseph C. LaManna, PhD

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Investigation performed at Case Western Reserve University, Cleveland, Ohio

Gregory D. Carlson, MD
Orthopaedic Specialty Institute, 280 South Main Street, Suite 200, Orange, CA 92868. E-mail address: gcarlson@ocspine.com

Carey D. Gorden, MA
Department of Orthopaedic Surgery and University Hospitals Spine Institute, Case Western Reserve University, Cleveland, OH 44106

Shigenobu Nakazawa, MD
Otonemati 2-84-16, Maebaehishi, Gumma 371-0825, Japan. E-mail address: s-naka@dj8.so-net.ne.jp

Eiji Wada, MD
Department of Orthopaedic Surgery, Hoshigaoka Koseinenkin Hospital, 4-8-1 Hoshigaoka, Hirakata 573-8511, Japan. E-mail address: hjp42535@mopera.ne.jp

Jeremy S. Smith
Department of Orthopedic Surgery and Reeve-Irvine Research Center, University of California, Irvine, CA 92697

Joseph C. LaManna, PhD
Department of Anatomy and Neurology, Case Western Reserve University, Cleveland, OH 44106. E-mail address: jcl4@po.cwru.edu

In support of their research or preparation of this manuscript, one or more of the authors received an Orthopaedic Research and Education Foundation grant and a Veterans Administration Merit Review Research grant. None of the authors 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, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

J Bone Joint Surg Am, 2003 Jan 01;85(1):95-101

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Abstract

Background: The efficacy of methylprednisolone in the treatment of traumatic spinal cord injury is controversial. We examined the effect of methylprednisolone on regional spinal cord blood flow and attempted to determine whether recovery of electrophysiological function is dependent on reperfusion, either during sustained spinal cord compression or after decompression.

Methods: The effects of methylprednisolone therapy on recovery of somatosensory evoked potentials and on spinal cord blood flow were examined in a canine model of dynamic spinal cord compression. Methylprednisolone (30 mg/kg intravenous loading dose followed by 5.4 mg/kg/hr intravenous infusion) or saline solution was administered to thirty-six beagles (eighteen in each group) five minutes after cessation of dynamic spinal cord compression and loss of all somatosensory evoked potentials. After ninety minutes of sustained compression, the spinal cords were decompressed. Somatosensory evoked potentials and spinal cord blood flow were evaluated throughout the period of sustained compression and for three hours after decompression.

Results: Seven dogs treated with methylprednisolone and none treated with saline solution recovered measurable somatosensory evoked potentials during sustained compression. After decompression, three more dogs treated with methylprednisolone and seven dogs treated with saline solution recovered somatosensory evoked potentials. Four dogs treated with methylprednisolone lost their previously measurable somatosensory evoked potentials. In the methylprednisolone group, spinal cord blood flow was significantly higher (p < 0.05) in the dogs that had recovered somatosensory evoked potentials than it was in the dogs that had not. Reperfusion blood flow was significantly higher (p < 0.05) in the saline-solution group than it was in the methylprednisolone group. Spinal cord blood flow in the saline-solution group returned to baseline levels within five minutes after decompression. It did not return to baseline levels in the dogs treated with methylprednisolone.

Conclusions: The methylprednisolone administered in this study did not provide a large or significant lasting benefit with regard to neurological preservation or restoration. Methylprednisolone may reduce regional spinal cord blood flow through mechanisms affecting normal autoregulatory blood-flow function.

Clinical Relevance: This study suggests that a major drawback of methylprednisolone therapy may be the reduction in regional spinal cord blood flow after decompression.

Figures in this Article

Introduction

Traumatic spinal cord injury is caused by acute compression or laceration of the spinal cord, which results from malalignment of the spinal column, migration of bone fragments, or dislocation of soft tissue and/or bone. The mechanical injury rarely transects the cord completely, even when the injury is considered complete, as defined by a loss of voluntary motor or sensory function below the level of the lesion ¹ . The primary injury initially causes cord compression, which is followed by delayed or sustained cord displacement ^2,3 . A vast amount of damage occurs after the initial traumatic event and is caused by secondary mechanisms of injury. Secondary damage may be the consequence of vascular changes, electrolyte changes, biochemical changes, mediators of the inflammatory response, edema, and apoptosis ^1,2 .

The use of methylprednisolone as a pharmacological agent to attenuate the secondary effects of traumatic spinal cord injury has been studied extensively. It is the only neuroprotective drug currently in widespread use for the treatment of spinal cord injury. Investigators who have conducted multicenter clinical trials have reported that methylprednisolone administered within eight hours after spinal cord injury improves neurological function in humans ^3-5 . A delay in treatment with methylprednisolone was associated with decreased neurological recovery ⁴ . This finding is not surprising since numerous clinical and experimental studies have shown that secondary effects of sustained cord compression are time-dependent ^2,6-14 . Also, uptake of methylprednisolone by injured spinal tissue rapidly declines over time ⁶ . Among other variables, a progressive decrease in blood flow to the injury site potentiates the secondary injury. High-dose methylprednisolone has been shown to improve posttraumatic spinal cord blood flow and to promote recovery of spinal cord function ^7-9 . However, several experiments have failed to demonstrate methylprednisolone-induced improvement in spinal cord blood flow or recovery of evoked potentials, an indicator of spinal cord function ^10-12 . These conflicting experimental reports ^10,11,13-15 combined with relatively small neurological improvements in humans ^16,17 have prompted some researchers and physicians, including the Alberta Medical Association, to question the efficacy of methylprednisolone therapy for the treatment of posttraumatic spinal cord injury ^17-20 . Further investigation of the ability of methylprednisolone to reduce secondary damage in the spinal cord is required. To this end, we studied the effects of methylprednisolone on spinal cord blood flow and the recovery of somatosensory evoked potentials to test the hypothesis that recovery of electrophysiological function is dependent on reperfusion blood flow, either during sustained spinal cord compression or after decompression.

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Fig. 1:: Mean percentages of recovery (and standard error of the mean) of somatosensory evoked potential amplitudes (normalized lower extremity-to-upper extremity ratio [see text]) of dogs treated with methylprednisolone or saline solution. The values were recorded five minutes after commencement of dynamic spinal cord compression (DyC) (t -30 to t0), during compression (t0 to t90), and after decompression (t90 to t270). Only dogs that recovered potentials during the 270-minute observation period are represented.

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Fig. 2:: Mean spinal cord blood flow (and standard error of the mean) in dogs treated with methylprednisolone or saline solution and subjected to dynamic spinal cord compression and decompression. t0 = end of dynamic compression; d - 5 = five minutes before decompression, d + 5 = five minutes after decompression, and d + 180 = 180 minutes after decompression. *p < 0.05.

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Fig. 3:: Mean reperfusion spinal cord blood flow (and standard error of the mean) in dogs treated with methylprednisolone or saline solution. Reperfusion is measured as the interval change between the end of dynamic spinal cord compression and five minutes after decompression. *p < 0.05.

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Fig. 4:: Mean spinal cord blood flow (and standard error of the mean) in dogs treated with methylprednisolone that did or did not recover somatosensory evoked potentials. t0 = end of dynamic compression, d - 5 = five minutes before decompression, d + 5 = five minutes after decompression, and d + 180 = 180 minutes after decompression. *p < 0.05.

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Fig. 5:: Mean percentages of recovery (and standard error of the mean) of somatosensory evoked potential amplitudes (normalized lower extremity-to-upper extremity ratio [see text]) of dogs treated with methylprednisolone or saline solution. The values were recorded five minutes after commencement of dynamic spinal cord compression (DyC) (t -30 to t0), during compression (t0 to t90), and after decompression (t90 to t270). Only dogs that recovered potentials during the 270-minute observation period are represented.

Materials and Methods

Experimental Design

The effect of methylprednisolone was studied in a canine experimental model of dynamic compression of the spinal cord under conditions described in detail in Part I of this paper ²¹ . Briefly, dynamic cord compression was initiated with a loading device precalibrated to indent the spinal cord at a constant 0.17 mm/min ^5,10 . Somatosensory evoked potentials were continuously monitored. When the amplitudes of the evoked potentials in the lower extremity were reduced by approximately 50% of baseline, piston movement was halted, thereby stopping dynamic compression. At this functional end point, sustained cord compression was maintained for ninety minutes. The ninety-minute duration was chosen on the basis of previous data that demonstrated that 50% of dogs subjected to compression for that time-interval recovered somatosensory evoked potentials after decompression ²² . After the ninety minutes, the spinal cord was decompressed by removing the piston, and the somatosensory evoked potentials were regularly monitored over a 180-minute recovery period (t90 to t270). Regional spinal cord blood flow was measured at baseline (t - 30), at the end of dynamic compression (t0), five minutes before decompression (d - 5), five minutes after decompression (d + 5), and 180 minutes after decompression (d + 180).

To test the effect of early steroid treatment on spinal cord blood flow and recovery of somatosensory evoked potentials after spinal cord compression, methylprednisolone (30 mg/kg intravenous loading dose followed by 5.4 mg/kg/hr intravenous infusion; Pharmacia-Upjohn, Simi Valley, California) was administered to eighteen beagles five minutes after cessation of dynamic cord compression (t5) and loss of all somatosensory evoked potential conduction. The methylprednisolone-treatment group was compared with a control group of eighteen beagles that received a similar volume of normal saline solution intravenously at the same testing point.

Surgical Preparation and Technique

The experimental design and procedures for this study were approved by the Institutional Animal Care and Use Committee. Thirty-six beagle dogs weighing 12 to 14 kg were anesthetized with thiopental solution (15 to 20 mg/kg intravenous induction dose), a mixture of 50% nitrous oxide and 50% oxygen, and halothane (0.5% to 0.7%) and maintained under anesthesia as described in Part I of this paper ²¹ . The right and left femoral arteries were catheterized, and a 7-Fr Cordis femoral internal mammary catheter (Baxter Healthcare, Deerfield, Illinois) was introduced through the right femoral artery into the left ventricle for pressure recording and microsphere injection. Arterial blood gases were sampled periodically.

A laminectomy was performed at the thirteenth thoracic segment (T13). A hydraulic piston-loading device (specially constructed by the Engineering Department of Case Western Reserve University) was suspended over the dura and rigidly attached with 2.0-mm bone screws to the transverse processes of T13 ²² . The diameter of the piston was 7 mm, which approximated the diameter of the spinal canal. A subminiature pressure transducer (Kyowa Electronic Instruments, Kyowa, Japan), attached to the spinal cord contact end of the loading piston, relayed real-time spinal cord interface pressures to an amplifier and computerized data-acquisition system with custom-written software ²³ .

Monitoring of Somatosensory Evoked Potentials

Somatosensory evoked potentials were obtained by stimulating the median and tibial nerves and recording cortical evoked potentials on a Viking IV Evoked Potential System (Nicolet Biomedical Instruments, Madison, Wisconsin), as described in Part I ²¹ . The normalized lower extremity-to-upper extremity ratio (LE/UE) ²¹ was calculated by dividing the mean posterior tibial cortical evoked amplitude by the mean median nerve amplitude. Functional recovery was determined by the return of lower-extremity somatosensory evoked potentials.

Regional Spinal Cord Blood Flow

Microspheres and injection technique: Regional spinal cord blood flow was quantitated with use of a fluorescent microsphere technique (E-Z TRAC; Interactive Medical Technology, Irvine, California). Five million fluorescent 15-µm cross-linked polystyrene-divinylbenzene microspheres (NuFLOW; Interactive Medical Technology) were injected into the left ventricle with a saline-solution bolus. The microspheres lodged into the tissue microvasculature in direct proportion to the cardiac output of that tissue. Blood for the arterial reference sample was withdrawn from the left femoral artery with a Harvard withdrawal pump (Bioscience; Harvard Apparatus, Holliston, Massachusetts) at a constant rate of 3.22 mL/min for a period of 150 seconds ⁵ .

Regional spinal cord blood flow was measured after the laminectomy (baseline), immediately after cessation of the dynamic cord loading (t0), five minutes before decompression (d - 5), five minutes after decompression (d + 5), and 180 minutes after decompression (d + 180). Animals were killed with an overdose of pentobarbital, and spinal cord tissue samples were harvested from the compressed T13 region.

Extraction of microspheres and analysis: Blood and tissue samples were placed in preweighed polypropylene centrifuge tubes and sent to Interactive Medical Technology E-Z TRAC. The number of microspheres in the tissue and the reference blood samples were analyzed with use of an extraction protocol that recovers fluorescent microspheres for flow cytometric analysis. Spinal cord blood flow values were calculated according to the equation QSC = (CSC × QR)/CR, where QSC is the spinal cord blood flow per gram (mL/min/g), CSC is the microsphere count per gram of tissue, QR is the withdrawal rate of the reference blood sample (mL/min), and CR is the microsphere count in the reference blood sample.

Statistical Methods

Statistical analyses were performed with SigmaStat software (Jandel, San Rafael, California). Differences in mean values between treatment groups were evaluated with analysis of variance. Significance between repeated events in time with normal variance were analyzed with repeated-measures analysis of variance or two-way repeated-measures analysis of variance. Multiple-comparison procedures were performed with a Tukey post-hoc test. Data without normal parametric distribution were analyzed with the Friedman repeated-measures analysis of variance on ranks, analysis of variance on ranks, or Mann-Whitney rank-sum test. Differences between mean values were considered significant at p < 0.05. Data are reported as the mean and standard error of the mean.

Results

Recovery of Somatosensory Evoked Potentials

The spinal cord was compressed at a constant velocity until the amplitudes of the somatosensory evoked potential decreased by approximately 50%. Thus, at t0, the LE/UE was 34.5 ± 7.8 in the methylprednisolone group and 33.6 ± 5.9 in the saline-solution group, which represented decreases of approximately 66% from baseline values.

All dogs had a complete loss of somatosensory evoked potentials five minutes after cessation of the piston loading (t5) ( Fig. 1 ). Seven of the eighteen dogs treated with methylprednisolone recovered measurable somatosensory evoked potentials during the sustained spinal cord compression (t0 to t90). Of those seven dogs, five recovered measurable somatosensory evoked potentials thirty minutes after maximum compression and two had such recovery sixty minutes after maximum compression. None of the dogs treated with saline solution recovered somatosensory evoked potentials during compression (t0 to t90) ( Fig. 1 ).

Three methylprednisolone-treated dogs that had not regained electrical signals during the sustained spinal cord compression recovered them after decompression (t90 to t270). Thus, a total of ten of the eighteen dogs treated with methylprednisolone recovered somatosensory evoked potentials and eight did not. Six of the ten dogs that recovered somatosensory evoked potentials sustained the recovery throughout the entire decompression period. Of the four dogs that did not sustain the recovery, one lost evoked potential signals prior to the decompression and three did so thirty, ninety, or 120 minutes after the decompression. In the saline-solution group, seven of the eighteen dogs recovered somatosensory evoked potentials after decompression, and the potentials remained stable throughout the post-decompression period ( Fig. 1 ).

Somatosensory evoked potentials in the upper extremity remained stable throughout the experiment in both the methylprednisolone group and the saline-solution group.

Spinal Cord Blood Flow

The baseline spinal cord blood flow in the T13 region did not differ significantly between groups (methylprednisolone group, 18.3 ± 1.8 mL/100 g/min; saline-solution group, 21.8 ± 1.9 mL/100 g/min) ( Fig. 2 ). At the end of dynamic compression (t0), the mean spinal cord blood flow decreased by 86% in the methylprednisolone group and by 82% in the saline-solution group. Spinal cord blood flow in the methylprednisolone group measured five minutes before decompression (d - 5) rebounded by 71%, reaching 50% of the baseline spinal cord blood flow. Spinal cord blood flow in the saline-solution group rebounded by 48%, reaching 35% of the baseline spinal cord blood flow. There was no significant difference in spinal cord blood flow between the methylprednisolone and saline-solution groups at d - 5 ( Fig. 2 ).

Five minutes after decompression (d + 5), spinal cord blood flow increased to 73% of the baseline value, to a mean of 13.4 mL/100 g/min, in the methylprednisolone group. However, this value was significantly lower than that in the saline-solution group, in which spinal cord blood flow rebounded (from t0) by 84% of the baseline value, increasing to a mean of 23.4 mL/100 g/min, which surpassed the baseline spinal cord blood flow ( Fig. 2 ).

Spinal cord blood flow in the methylprednisolone group remained lower than that in the saline-solution group throughout the decompression period. At the end of the decompression period (d + 180), spinal cord blood flow in the methylprednisolone group was 55% of the baseline value, which was significantly lower than that in the saline-solution group.

Reperfusion blood flow, measured as the interval change between the end of dynamic compression (t0) and five minutes after decompression (d + 5), was significantly higher (p < 0.05) in the saline-solution group ( Fig. 3 ). As a result, spinal cord blood flow in that group returned to baseline levels within the first five minutes after decompression (d + 5).

Spinal Cord Blood Flow and Recovery of Somatosensory Evoked Potentials

In the methylprednisolone group, baseline spinal cord blood flow did not differ significantly between the dogs that subsequently recovered somatosensory evoked potentials and those that did not ( Fig. 4 ). However, during sustained compression (d - 5), spinal cord blood flow was significantly higher (p < 0.05) in the dogs that recovered somatosensory evoked potentials (11.8 mL/100 g/min) than in those dogs that did not (5.7 mL/100 g/min) in the methylprednisolone group. Similarly, spinal cord blood flow during sustained compression in the saline-solution-treated group was significantly higher (p < 0.05) in the dogs that subsequently recovered somatosensory evoked potentials (11.3 ± 2.7 mL/100 g/min) than it was in those that did not (4.4 ± 0.95 mL/100 g/min).

Biomechanical Analysis of Spinal Cord Interface Pressure

Spinal cord interface loading pressures were similar for the methylprednisolone and saline-solution groups throughout the period of sustained compression ( Fig. 5 ). Maximum pressures measured at the end of dynamic compression (t0) decreased 56% within the first five minutes of sustained compression (t5). At t90, spinal cord interface pressures were decreased by 69% in the dogs treated with methylprednisolone and by 78% in the saline-solution-treated dogs. No significant difference in the loading pressures was noted between the dogs that recovered and those that did not recover evoked potentials (data not shown). Thus, loading pressure did not have a significant effect on recovery of evoked potentials with or without methylprednisolone.

Physiological Parameters

Mean systolic blood pressure did not differ significantly between the methylprednisolone and saline-solution groups. Arterial blood gases remained relatively constant throughout the experiment (see Appendix) and there were no significant differences in pH, Pco2, or Po2 between the treatment groups at any of the time-intervals. The saline-solution-treated dogs had a significant increase (p < 0.05) in Pco2 from the baseline value. There were no other significant changes in pH, Pco2, or Po2 in the saline-solution or methylprednisolone group.

No animal died or had an infection during the experiment. All data could be obtained from every animal.

Discussion

We believe that our study is the first to demonstrate the recovery of somatosensory evoked potentials with early administration of methylprednisolone during sustained spinal cord compression. Seven of eighteen dogs that received methylprednisolone recovered somatosensory evoked potentials during the period of sustained displacement. None of the dogs without methylprednisolone treatment had such recovery before decompression. However, methylprednisolone had no beneficial effect on post-decompression recovery of somatosensory evoked potentials. This was surprising because, on the basis of the recovery of somatosensory evoked potentials during sustained cord compression, we anticipated an even greater post-decompression recovery. However, three of the seven dogs that had recovered spinal cord function lost the evoked potentials after decompression, whereas a fourth dog lost evoked potentials just prior to decompression. The quantitative amplitude recovery was not significantly different between the methylprednisolone and saline-solution groups (p = 0.13) thirty minutes after the decompression. This finding indicates that methylprednisolone does not provide a large or significant lasting benefit with regard to neurological preservation or restoration. Researchers evaluating the findings in clinical trials have reached a similar conclusion ^18,19 .

The segregation of animals into "recovery" and "non-recovery" groups after identical conditions of compression injury allowed us to examine the hypothesis that neurological recovery is related to greater reperfusion spinal cord blood flow after decompression of the spinal cord. In the methylprednisolone group, dogs that recovered somatosensory evoked potentials had significantly higher spinal cord blood flow during sustained cord compression than did animals that did not recover early somatosensory evoked potentials (p < 0.05). Throughout the post-decompression period, regional blood flow in the methylprednisolone group remained substantially below baseline levels and somatosensory evoked potentials did not reach baseline levels. Similarly, in the saline-solution group, dogs that recovered somatosensory evoked potentials had had significantly higher spinal cord blood flow during sustained compression than did dogs that did not recover somatosensory evoked potentials (p < 0.05). This observation suggests that higher regional blood flow during and after sustained compression results in better recovery of somatosensory evoked potentials. We had similar findings in our prior study, which showed that post-decompression recovery of somatosensory evoked potentials was associated with increased blood flow during and after sustained compression ²² .

Post-decompression blood flow (d + 5) in the saline-solution group rebounded to precompression levels or to hyperemia ( Fig. 2 ). (Hyperemia has been demonstrated in previous studies ^24-26 .) Accordingly, some of the saline-solution-treated dogs recovered somatosensory evoked potentials. It was not anticipated that all dogs would recover evoked potentials because in our earlier studies half of the animals did not recover them after ninety minutes of compression ^22,25 . Reperfusion blood flow, the interval change from the beginning of sustained displacement (t0) to five minutes after decompression (d + 5), was significantly lower (p < 0.05) in the methylprednisolone group ( Fig. 3 ). This indicates that methylprednisolone may inhibit the normal microvasculature autoregulatory mechanisms associated with reperfusion blood flow during and after spinal cord compression, resulting in loss of somatosensory evoked potentials after decompression. In turn, the microvascular autoregulatory dysfunction may have counteracted the reputed benefits of methylprednisolone.

Methylprednisolone may induce a mild reduction of mean arterial blood pressure after spinal cord injury at the lower thoracic or lumbar levels ^8,9,12,27 . The hypotension may be attributable to the vasodilatory effect of methylprednisolone ⁹ . Systemic hypotension can be associated with a further decrease in spinal cord blood flow at the injury site because of loss of autoregulation in the injured cord ^1,27 . Although the present study demonstrated a decrease in regional spinal cord blood flow in association with methylprednisolone treatment, this effect was not reflected in changes in systemic hemodynamic parameters.

Our study demonstrated an early neuroprotective effect of methylprednisolone therapy, which may depend, in part, on the amount of regional blood flow. The precise mechanism by which methylprednisolone helps patients with spinal cord injury is unknown. Since secondary injury is caused by a conglomerate of factors, it is more than likely that a combination of drugs with different mechanisms of action will be the most beneficial to such patients. Alternately, our results indicate that techniques to increase reperfusion spinal cord blood flow concurrent with decompressive surgery ² may reduce neural damage and improve recovery after spinal cord injury.

The early perfusion of blood flow to the injury site following decompression may be particularly important for the recovery of electrophysiological and neurological function. This study suggests that a major drawback of methylprednisolone therapy may be the reduction in regional spinal cord blood flow after decompression. Methylprednisolone may reduce regional spinal cord blood flow through mechanisms affecting normal autoregulation of blood flow. These in vivo findings may provide some explanation of why an increasing number of studies are showing that methylprednisolone does not satisfactorily improve neurological recovery after acute spinal cord injury in humans ^17-20 .

Appendix

Tables showing systolic blood pressure and other physiologic parameters of the animals during the study are available with the electronic versions of this article, on our web site at www.jbjs.org (go to the article citation and click on "Supplementary Material") and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM).

Note: The authors thank Heather S. Oliff, PhD, for her assistance with the preparation of the manuscript.

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Topics

vascular flow ; dog, domestic ; methylprednisolone ; regional blood flow ; spinal cord compression ; decompression, external ; spinal cord ; somatosensory evoked potentials ; saline solution

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Gregory D. Carlson, Carey D. Gorden, Shigenobu Nakazawa, Eiji Wada, Jeremy S. Smith, Joseph C. LaManna; Sustained Spinal Cord Compression Part II: Effect of Methylprednisolone on Regional Blood Flow and Recovery of Somatosensory Evoked Potentials. The Journal of Bone & Joint Surgery. 2003 Jan;85(1):95-101.

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