THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 2, Number 4, 2012 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2012.0019

The Use of Modest Systemic Hypothermia After Iatrogenic Spinal Cord Injury During Surgery Karthik Madhavan, M.D.,1 David M Benglis, M.D.,1 Michael Y Wang, M.D.,1 Steve Vanni, M.D.,1 Nathan Lebwohl, M.D.,2 Barth A. Green, M.D.,1 and Allan D. Levi, M.D., Ph.D.1

Iatrogenic spinal cord injury (SCI) is an uncommon (0%–3%), yet devastating, complication of spine surgery. Recent evidence based on small clinical studies indicates that modest hypothermia is a feasible treatment option for severe SCI. We extended this treatment modality to patients with devastating iatrogenic SCI. We conducted a retrospective case series of five male patients (cervical trauma—1, cervical degenerative—2, thoracic trauma—1, and thoracic scoliosis—1) with an age range of 16–51 years (average age of 46 years) with intraoperative motorevoked potential/somatosensory-evoked potential loss secondary to catastrophic events during the spinal operation associated with new SCI. Modest hypothermia was instituted immediately postsurgery for 24 hours. Four patients also received methylprednisolone. Preoperative American Spinal Injury Association (ASIA) scores were D (n = 3) and E (n = 2), while immediate postoperative scores were A (n = 1), B (n = 1), C (n = 2), and D (n = 1). Immediate postoperative MRI revealed new cord signal change in three patients. Two patients required subsequent surgery. ASIA scores at last follow-up were C (n = 1), D (n = 3), and E (n = 1) with an improvement of 1–2 grades per patient. Adverse events such as pulmonary embolism, deep venous thrombosis, coagulopathy, or infection were not observed. Hypothermia is a feasible treatment option for patients with iatrogenic SCI. While hypothermia has not been proven to improve outcomes in these situations, aggressive medical management, including cooling, resulted in better-than-expected outcomes in this small cohort. Introduction

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atrogenic spinal cord injury (SCI) is an uncommon, yet devastating, complication of spine surgery. The incidence ranges 0%–3% and depends upon the surgical approach, type of pathology, and the level of the spine involvement (Ahn and Fehlings, 2008). Current management includes steroid administration via a methylprednisolone protocol infusion (Busto et al., 1987; Bracken et al., 1990, 1992, 1997, 1998) and/or optimal spinal cord perfusion maintenance (Vale et al., 1997) with elevation of mean arterial pressures. Although no single therapy has been implemented as standard of care, recent small clinical studies indicate that modest hypothermia may also be a safe and feasible treatment option for severe SCI (Levi et al., 2009, 2010). We extended this treatment modality to patients with devastating iatrogenic SCI. To our knowledge, this is the first report of hypothermia usage after iatrogenic SCI. Materials and Methods We conducted a retrospective chart review of 7000 spine cases during February 2007–January 2011 from both the

Orthopedic and Neurosurgery spine services. Five patients in this search were found who underwent aggressive multimodality neuroprotection after intraoperative iatrogenic SCI (Table 1). All the patients were males and underwent surgery for different reasons. Two were trauma patients (n = 1 cervical; n = 1 thoracic), and three patients underwent elective surgeries (n = 2 cervical spondylotic myelopathy and n = 1 thoracic scoliosis). The age range was 16–69 years (insert mean age). After the insult in surgery, all patients had loss of intraoperative motor-evoked potential (MEP) and/or somatosensoryevoked potential (SSEP). After the procedure, the patients were also awakened and examined. Clinical examinations during preoperative, immediate postoperative, and at the time of discharge and follow-up were calculated based on the American Spinal Injury Association (ASIA) AIS grading system (ASIA, 1984). Immediate postoperative MR scans were performed on all patients. The hypothermia administration and rewarming protocol was based upon the University of Miami’s IRB-approved protocol (20071018) published by Levi et al. (2009). The Alsius Cool-Guard Catheter is a device used for inducing and maintaining hypothermia. The catheter is inserted through the femoral vein, and patients are cooled to 33C. Hypothermia is then

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The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida. Department of Orthopedics, University of Miami Miller School of Medicine, Miami, Florida.

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ASIA D Posterior cervical Severe transitional level decompression stenosis at C3-4 with with cord signal change, instrumentation myelomalacic change posterior to C5 and C7

Cervical myelopathy

GC 51/M

Loss of MEPs

Cord signal change behind the C 3/4 level

ASIA C

ASIA B Post op CT/MRI Loss of MEPs ASIA E Posterior long shows no cord and SSEPs in segment fixation signal changes and LE bilaterally and correction wrong path taken by the pedicle screw probe towards spinal cord

Idiopathic scoliosis

Idiopathic severe thoracic scoliosis

DL 16/M

ASIA D T3/4 reduction and segmental instrumentation from T1 to T6

T3-T4 fracture dislocation and perched facets without cord signal change

ASIA B At the T3/4 disc space (disc versus hematoma) with mild cord compression with no intrinsic cord signal change on T2 weighted images

ASIA E

Hypothermia and solumedrol

ASIA D

ASIA E Intra-operative hypothermia and methylpredisone

Hypothermia

7 months

12 months

1 month, 2 weeks

2 months, 2 weeks

Methylprednisone ASIA B and hypothermia and C7 laminectomy ASIA A

Severe dorsal cord Loss of MEPs compression and SSEPs in from the C7 LE bilaterally lamina

ASIA E C6-7 ACDF

Increased signal on T2 Right-sided weighted image at unilateral the left C6/7 facet jumped facet at C6/7 due to trauma

MA 38/M T3-T4 fracture dislocation

RI 69/M

loss of intra-op SSEP

10 months

Average follow up

Methylprednisone ASIA D and hypothermia

ASIA score at discharge

ASIA B

Treatment

New intrinsic cord change

Post-op MRI

Immediate post-op ASIA score

Loss of MEPs

Type of surgery

Intra-op monitoring

ASIA C C6-7 ACDF

Pre-op MRI

Pre-op exam

Central disc fragment (non-calcified) at the C6/7 with stenosis

Pre–op diagnosis

PM 56/M Cervical myelopathy

Patient/ age/sex

Table 1. Hospital Data

MODEST SYSTEMIC HYPOTHERMIA AFTER IATROGENIC SCI maintained for a period of 24 hours postoperatively. The rewarming is initiated at a rate of 0.1C per hour. Four patients in this cohort also received adjuvant methylprednisolone. One patient underwent immediate reoperation after MR. Results All the patients encountering iatrogenic SCI were males of ages ranging between 16 and 69 years (average of 46 years). The preoperative AIS scores were D (n = 3) and E (n = 2), while immediate postoperative scores were A (n = 1), B (n = 2), C (n = 1), and D (n = 1) (Table 1). Immediate postoperative MR revealed new cord signal change in four patients. One patient required immediate reoperation. ASIA scores at last follow-

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up were C (n = 1), D (n = 2), and E (n = 2) with an improvement of 1–2 grades per patient. Adverse events such as pulmonary embolism, deep venous thrombosis, coagulopathy, or infection were not observed in any of the patients during the stay in the hospital when hypothermia was administered. The follow-up ranged between 1½ months and 12 months. Case 1 History and physical exam A 56-year-old man with a history of progressive myelopathy and severe cervical stenosis C6/7 presented with weakness in his left upper extremity. His left deltoid, bicep, and tricep were 3/5, while his wrist extensors and hand

FIG. 1. Case 1: MRI of the cervical spine showing an extruded central disc fragment (noncalcified) at the C6/7 level resulting in severe stenosis (A, B). Immediate postoperative MR imaging revealing an area of high T2 signal abnormality at the C6/7 disc space (C, D). Six-month MRI on the follow-up showing that there are still residual cord signal changes (E, F).

186 intrinsics were 2/5, and his left leg was 3/5 in all compartments (ASIA D). Operation An anterior cervical discectomy and fusion (ACDF) was performed at the C6/7 level. During placement of the interbody graft, MEPs were lost transiently in the lower extremities bilaterally. The graft was then repositioned, and the MEPs then returned on right. Postoperative course Immediate postoperative exam revealed left side grossly 1/ 5 and his right side grossly 3/5 (ASIA B). The patient received

FIG. 2. Case 2: MRI of the cervical spine demonstrates revealed increased signal on T2 weighted image at the left C6/7 facet, but normal spinal cord (A, B). Immediate postoperative MRI demonstrating severe dorsal cord compression from the C7 lamina (C, D). Postoperative MRI after revision surgery showing mild cord signal change with good canal decompression (E, F).

MADHAVAN ET AL. methylprednisolone and hypothermia at 33.5C for 24 hours as described previously by Levi et al. (2009). Postoperative MRI revealed an area of high T2 signal abnormality at the C6/7 disc space. Throughout the course of his 2-week hospital stay, the patient had gradually improved motor function to the equivalent of his preoperative status (ASIA D). Case 2 History and physical exam A 69-year-old man was involved in a motor vehicle accident resulting in a right-sided unilateral jumped facet at the C6/7 level. On exam, the patient was neurologically intact, and the symptom of radiculopathy was noted in the right C7

MODEST SYSTEMIC HYPOTHERMIA AFTER IATROGENIC SCI nerve root distribution. MR imaging revealed increased signal on T2-weighed image at the left C6/7 facet, but normal spinal cord. Operation An ACDF was performed at C6/7. Intraoperatively, severe interruption of the disk space was noted with the C6 vertebrae fish-mouthed in relation to C7. During graft placement and reduction, MEPs and SSEPs were lost from the lower extremities bilaterally. The graft was removed, and the inspection of the disc space did not show any residual disc. The graft was replaced, and the fusion was completed. Postoperative course On awakening, the patient had no movement in his lower extremities bilaterally (ASIA A). An emergent MR revealed severe dorsal cord compression from the C7 lamina. The patient underwent emergent posterior decompression. The patient was started on hypothermia with a target of 33.5C and

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methylprednisolone intravenous drip. The patient received both for a period of 24 hours. The patient was taken back to the surgery, and a complete C7 laminectomy and partial C6/ T1 laminectomies were performed. At the time of discharge, the motor function of his upper extremities was normal, and he had not recovered any lower-extremity motor function. He also had bowel and bladder dysfunction, but retained sensory function of his lower extremities bilaterally (ASIA B). Case 3 History and physical exam A 38-year-old obese man was involved in a motorcycle accident and sustained a pulmonary contusion and T3–T4 fracture dislocation with evidence of distraction at the disc space and perched facets without cord signal change on MRI. On physical exam, the patient had retained some motor and sensory function of his lower extremities. Patient motor exam was consistent with an ASIA D with half of the muscles below the level of injury >3.

FIG. 3. Case 3: CT scan of the thoracic spine demonstrating T3–T4 fracture dislocation with evidence of distraction at the disc space and perched facets (A, B) without cord signal change on MRI (not shown). Immediate postoperative MRI demonstrating mild obliteration of the cerebro spinal fluid (CSF) space ventrally eccentric to the right at the T3/4 disc space (disc versus hematoma) with mild cord compression with no intrinsic cord signal change on T2-weighed images (C, D).

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Operation

Case 4

A T3 laminectomy with T3/4 reduction and segmental instrumentation from T1 to T6 was performed. Before positioning the patient prone, we were able to obtain SSEPs, but no MEPs. A wakeup test after prone positioning revealed that the patient had retained preop-motor function in his lower extremities bilaterally. During the final tightening of the rods, the SSEPs on both lower extremities were lost. Of note, the patient did have an extended period of intraoperative hypotension with mean systolic blood pressures in the 70’s.

History and physical exam

Postoperative course Immediate postoperative MRI revealed mild obliteration of the cerebro spinal fluid (CSF) space ventrally eccentric to the right at the T3/4 disc space with mild cord compression with no intrinsic cord signal changes. Examination revealed no motor function in the lower extremities bilaterally, retained sensation, and diminished rectal tone (ASIA B). Hypothermia was instituted the next morning for 24 hours. Over his hospital stay, he regained some motor function of his lower extremities to antigravity strength in all muscle groups. At 3month follow-up in the clinic, the patient was doing well with full strength returned to his lower extremities and ambulating with assistance of a walker. He continues to have bowel, bladder, and sexual dysfunction (ASIA D).

This is a 16-year-old patient with idiopathic severe thoracic scoliosis and no associated intrinsic spinal cord anomaly. Posterior long-segment fixation and correction were deemed the appropriate treatment. Operation The procedure was uneventful with pedicle visualization. The screw placement was unremarkable till the apex of the curve. A temporary pedicle marker was placed in the anterior/posterior (A/P) plane under fluoroscopic guidance. At this point, the MEPs and SSEPs were lost in both lower extremities. The blood pressure was chemically elevated, and a slight return of SSEPs on the right was noted. The patient was also started on ice-cold saline through peripheral intravenous catheters. The procedure was aborted. Upon awakening, the patient was found to have a loss of motor function in his left lower extremity and to have retained function in his right. The patient’s temperature at the time of awakening was 34.5C. An Alsius CoolGard catheter was placed in the left femoral vein, and cooling was initiated to 33.5C for a period of 24 hours as well as the methylprednisolone trauma protocol.

FIG. 4. Case 4: A 16 y/o African American male with neglected severe dextroscoliosis of the thoracic spine preoperative X-rays, denoting the severe dextroscoliosis of the thoracic spine; postoperative sagittal and axial CT with axial MRI spine demonstrates the entry point of the pedicle screw marker over the cord (A). Loss of EMG activity in bilateral lower extremities after the screw placement (B).

MODEST SYSTEMIC HYPOTHERMIA AFTER IATROGENIC SCI

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FIG. 4. (Continued). Postoperative course The postoperative MRI showed no signal changes in the cord, and it was noted that the path used by the probe for the pedicle screw placement was directly into the cord. The patient remained in the ICU for 5 days. His motor function at the time of discharge was improving in his left lower extremity, with his iliopsoas 3/5, quadriceps 4/5, and extensor hallucis longus 4/5. The patient was once again operated on in December of 2009 when he underwent T4 to L2 fusion with no intraoperative complications. The patient did, however, have deep vein thrombosis during the second hospital stay. At the time of discharge, the patient had left lower extremity hyper-

reflexic knee jerk, but was otherwise neurologically normal. At 12-month follow-up, the patient was noted to have had some numbness in the lateral aspect of the left thigh, but otherwise there was no other sensory or motor deficit. Case 5 History and physical exam A 51-year-old man with cervical myelopathy and preoperative weakness in hands bilaterally with gait disturbance. MRI revealed a severe stenosis at C3–4 with signs of previous myelomalacia posterior to C5 and C7, although this level was well decompressed (image not shown).

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FIG. 5. Case 5: Preoperative imaging revealed a severe transitional level stenosis at C3–4 with cord signal change, prior myelomalacic change posterior to C5 and C7, but this level was well decompressed and had CSF signal in front and behind the cord (not shown). Immediate postoperative MRI demonstrating MRI of the cervical region revealed cord signal change behind the C3/4 level (A, B). MRI of the cervical spine at a 2-month follow-up showing residual signal changes at the C3/4 level (C, D).

Operation The patient underwent posterior cervical decompression and fusion. Intraoperatively, the patient lost MEPs in the lower extremities bilaterally. Postoperative course Immediate postoperative MRI of the cervical region revealed cord signal change behind the C3/4 level. Examination revealed no motor function in the arms or legs, except for 2/5 in the right foot (ASIA C). The patient received hypothermia and methylprednisolone. MRI of the cervical spine at 2-month follow-up showed residual signal changes at the C3/4 level. His exam revealed 4/5 strength in his right leg and 2/5 strength in the left. Sensory examination intact to deep sensation and pin prick (ASIA D). Discussion Iatrogenic SCI, although uncommon, is a known, devastating complication of spine surgery with an incidence of 0%–3% (Ahn and Fehlings, 2008). Common factors influencing outcomes are the surgical approach, type of pathology, and level of the spine surgery (Fielding, 1992; Faciszewski et al., 1995). Several precautionary measures are careful padding and positioning, fiber optic intubation to prevent overextension of the neck, and multimodal neuromonitoring devices such as SSEPs and MEPs to allow for real time feed-

back of neural pathways (Ahn and Fehlings, 2008). Despite these precautions, iatrogenic SCIs still occur. Although many neuroprotective strategies exist for treatment of SCI, no single therapy has been implemented as a standard of care. We introduce hypothermia as an alternative and potentially beneficial option. In our small case series, we demonstrate that it is a feasible option and carries low risk to the patients. Hypothermia was first documented in a specific patient population by Dr. Temple Fay in early 1930s. He used the concept of subnormal temperature for terminally ill cancer patients. He later extended his work in cancer patients to those with traumatic brain injury. Albin and White introduced local hypothermia as neuroprotective therapy through their work in canine and primate models (Albin et al., 1967). Throughout the 1980s and 1990s, there was a decline in the use of hypothermia due to its presumed morbidity and the rise of new pharmacologic therapies. These complications included cardiac arrhythmias, hypotension, coagulopathies, systemic infections, and electrolyte disturbances (Kwon et al., 2008). Busto et al. (1987) demonstrated that, however, mild hypothermia (34C) gave a protective effect in a brain ischemia rodent model without the complications encountered at cooler temperatures. These data were then translated for use in an SCI model. Moderate hypothermia affects the nervous system by enabling neurons to maintain optimum ATP (adenosine triphosphate) by slowing down cellular energy requirements,

MODEST SYSTEMIC HYPOTHERMIA AFTER IATROGENIC SCI leading to decreased enzymatic activity (Arrica and Bissonnette, 2007). This leads to the preservation of electrolyte content in cells and confers membrane stability and integrity. Hypothermia also reduces oxygen requirements by twofold to fourfold for every 10C (Erecinska et al., 2003). Other positive effects of hypothermia are the reduction of neuronal excitotoxicity by decreasing extracellular glutamate, the inhibition of enzymatic pathways that contribute to apoptotic cell death mechanisms, the accumulation and activation of healthy neutrophils and microglia, and the inhibition of harmful free-radical production (Lei et al., 1994; Globus et al., 1995; Zornow, 1995; Inamasu et al., 2000; Hachimi-Idrissi et al., 2004; Wang et al., 2004; Ohmura et al., 2005). Hypothermia has also been shown to spare dendrites and axons as well as to reduce scar formation proximal to injury zones in rat models of SCI (Westergren et al., 1999; Yu et al., 2000). Although there have been significant positive effects noted with hypothermia in animal studies, this has not been the case with human studies; there have been no prospective randomized studies evaluating systemic hypothermia after SCI. It is often difficult to differentiate the reasons for recovery after SCI. Fawcett et al. reanalyzed spontaneous recovery in spinal cordinjured patients from the Sygen trial (Fawcett et al., 2007; Lammertse et al., 2007; Steeves et al., 2007; Tuszynski et al., 2007). They utilized the AIS grading system, which ranges from A to E, where A is complete injury, and E is neurologically intact. In this analysis, it was noted that spontaneous recovery after SCI was predominantly in the first 3 months after injury with a final plateau noted up to the end of first year. About 80% of the ASIA A group remained unchanged; 10% progressed to ASIA B; and the remaining 10% progressed to ASIA C or D. In a recent small study (n = 14 patients) conducted by Levi et al. (2010) using hypothermia after SCI of grade A, it was demonstrated that 57.1% of the patients remained ASIA A, 21.4% were B, 14.3% were C, and 7.1% were D at the end of 52 weeks. We are working toward developing a prospective randomized trial in traumatic SCI, but in the interim, we are extending our experience with this neuroprotective strategy to iatrogenic SCI after spinal surgery. Conclusions Hypothermia is a feasible treatment option for patients with iatrogenic SCI and can be started immediately postoperatively as described in our small group of five patients. Hypothermia has not been objectively proven to improve outcomes after SCI in humans. Further, randomized studies to evaluate for efficacy of hypothermia are required. Disclaimer The authors were not compensated nor have a financial interest in any of the products discussed. None of the authors are consultants for any corporations involved in the manufacture or sale of any of the cooling devices mentioned in this article. Disclosure Statement The authors declare that no competing financial interests exist. References Ahn H, Fehlings MG. Prevention, identification, and treatment of perioperative spinal cord injury. Neurosurg Focus 2008;25:E15.

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Albin MS, White RJ, Locke GS, Massopust LC Jr, Kretchmer HE. Localized spinal cord hypthermia—anesthetic effects and application to spinal cord injury. Anesth Analg 1967;46:8–16. Arrica M, Bissonnette B. Therapeutic hypothermia. Semin Cardiothorac Vasc Anesth 2007;11:6–15. Association, A.S.I. Standards for neurological classification of spinal injured patients. in American Spinal Injury Association Annual Meeting. 1984. Chicago. Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 1990;322:1405–1411. Bracken, MB, Shepard MJ, Collins WF Jr, Holford TR, Baskin DS, Eisenberg HM, Flamm E, et al. Methylprednisolone or naloxone treatment after acute spinal cord injury: 1-year follow-up data. Results of the second National Acute Spinal Cord Injury Study. J Neurosurg 1992;76:23–31. Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. Jama 1997;277:1597– 1604. Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, et al. Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up. Results of the third National Acute Spinal Cord Injury randomized controlled trial. J Neurosurg 1998;89: 699–706. Busto R, Dietrich WD, Globus MY, Valde´s I, Scheinberg P, Ginsberg MD. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 1987;7:729–738. Erecinska M, Thoresen M, Silver IA. Effects of hypothermia on energy metabolism in Mammalian central nervous system. J Cereb Blood Flow Metab 2003;23:513–530. Faciszewski T, Winter RB, Lonstein JE, Denis F, Johnson L. The surgical and medical perioperative complications of anterior spinal fusion surgery in the thoracic and lumbar spine in adults. A review of 1223 procedures. Spine (Phila Pa 1976) 1995;20:1592–1599. Fawcett JW, Curt A, Steeves JD, Coleman WP, Tuszynski MH, Lammertse D, et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 2007;45:190–205. Fielding JW. Complications of anterior cervical disk removal and fusion. Clin Orthop Relat Res 1992;284:10–13. Globus MY, Alonso O, Dietrich WD, Busto R, Ginsberg MD. Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem 1995;65:1704–1711. Hachimi-Idrissi S, Van Hemelrijck A, Michotte A, Smolders I, Sarre S, Ebinger G, et al. Postischemic mild hypothermia reduces neurotransmitter release and astroglial cell proliferation during reperfusion after asphyxial cardiac arrest in rats. Brain Res 2004;1019:217–225. Inamasu J, Suga S, Sato S, Horiguchi T, Akaji K, Mayanagi K, et al. Post-ischemic hypothermia delayed neutrophil accumulation and microglial activation following transient focal ischemia in rats. J Neuroimmunol 2000;109:66–74.

192 Kwon BK, Mann C, Sohn HM, Hilibrand AS, Phillips FM, Wang JC, et al. Hypothermia for spinal cord injury. Spine J 2008;8:859–874. Lammertse D, Tuszynski MH, Steeves JD, Curt A, Fawcett JW, Rask C, et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design. Spinal Cord 2007;45:232–242. Lei B, Tan X, Cai H, Xu Q, Guo Q, Effect of moderate hypothermia on lipid peroxidation in canine brain tissue after cardiac arrest and resuscitation. Stroke 1994;25:147–152. Levi AD, Casella G, Green BA, Dietrich WD, Vanni S, Jagid J, Wang MY. Clinical outcomes using modest intravascular hypothermia after acute cervical spinal cord injury. Neurosurgery 2010;66:670–677. Levi AD, Green BA, Wang MY, Dietrich WD, Brindle T, Vanni S, Casella G, Elhammady G, Jagid J. Clinical application of modest hypothermia after spinal cord injury. J Neurotrauma 2009;26:407–415. Ohmura A, Nakajima W, Ishida A, Yasuoka N, Kawamura M, Miura S, et al. Prolonged hypothermia protects neonatal rat brain against hypoxic-ischemia by reducing both apoptosis and necrosis. Brain Dev 2005;27:517–526. Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH, Ditunno JF, et al. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord 2007;45:206–221. Tuszynski MH, Steeves JD, Fawcett JW, Lammertse D, Kalichman M, Rask C, et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics. Spinal Cord 2007;45:222–231.

MADHAVAN ET AL. Vale FL, Burns J, Jackson AB, Hadley MN. Combined medical and surgical treatment after acute spinal cord injury: results of a prospective pilot study to assess the merits of aggressive medical resuscitation and blood pressure management. J Neurosurg 1997;87:239–246. Wang H, Olivero W, Lanzino G, Elkins W, Rose J, Honings D, et al. Rapid and selective cerebral hypothermia achieved using a cooling helmet. J Neurosurg 2004;100:272–277. Westergren H, Yu WR, Farooque M, Holtz A, Olsson Y. Systemic hypothermia following spinal cord compression injury in the rat: axonal changes studied by beta-APP, ubiquitin, and PGP 9.5 immunohistochemistry. Spinal Cord 1999;37:696–704. Yu WR,Westergren H, Farooque M, Holtz A, Olsson Y. Systemic hypothermia following spinal cord compression injury in the rat: an immunohistochemical study on MAP 2 with special reference to dendrite changes. Acta Neuropathol 2000; 100:546–552. Zornow MH. Inhibition of glutamate release: a possible mechanism of hypothermic neuroprotection. J Neurosurg Anesthesiol 1995;7:148–151.

Address correspondence to: Allan D. Levi, M.D., Ph.D. The Miami Project to Cure Paralysis Department of Neurological Surgery University of Miami MILLER School of Medicine 1095 NW 14th Terrace (D4-6) Miami, FL 33136 E-mail: [email protected]