Annals of Vascular Surgery
Volume 24, Issue 2 , Pages 225-232, February 2010

Protective Effect of Etomidate on Spinal Cord Ischemia–Reperfusion Injury Induced by Aortic Occlusion in Rabbits

  • Qijing Yu

      Affiliations

    • Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
    • Corresponding Author InformationCorrespondence to: Qijing Yu, MD, Department of Anesthesiology, Renmin Hospital of Wuhan University, 238 Jie Fang Road, Wuhan, Hubei Province 430060, China
    • ,
  • Qingshan Zhou

      Affiliations

    • Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
    • ,
  • Haibo Huang

      Affiliations

    • Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
    • ,
  • Yanlin Wang

      Affiliations

    • Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
    • ,
  • Shufang Tian

      Affiliations

    • Department of Histopathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
    • ,
  • Daiming Duan

      Affiliations

    • Department of Rehabilitation, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China

published online 11 September 2009.

Article Outline

Background

We conducted a randomized controlled study on the neuroprotective effect of a commonly used anesthetic, etomidate, in an ischemia–reperfusion (IR) injury rabbit model.

Methods

We studied 24 white adult Japanese rabbits at the animal facility at the Medical College of Wuhan University. Rabbits were randomly assigned into a sham-operation group (group I), an IR group (group II), and an etomidate-treated IR group (group III). Rabbits in groups II and III were subjected to 45min of infrarenal aortic cross-clamping to induce spinal cord ischemia, while group I rabbits received the sham operation as a control. Following an initial single-dose intravenous injection at 0.6mg/kg 10min before aortic clamping, etomidate was infused intravenously at 3mg/(kg · hr) in group III rabbits until unclamping, while 0.9% saline was given as the control in group II.

Results

Changes in neurological function scores, histopathology, electromyography, malondialdehyde levels, superoxide dismutase activities, and the concentrations of Ca2+, Mg2+, Cu2+, and Zn2+ ions were measured. Compared with the sham-operation group, group II showed significant IR injury–associated changes in all parameters evaluated (p<0.01), whereas these unfavorable changes were significantly reversed in etomidate-treated animals (p<0.05 or p<0.01). No significant differences were observed between group I and group III animals in all parameters.

Conclusion

Etomidate displayed a potent neuroprotective effect against IR-induced spinal cord injuries. We propose that this effect may be associated with the ability of etomidate to enhance the activities of endogenous antioxidants and maintain the ion balance in IR-affected tissues.

 

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Introduction 

Paraplegia is the impairment in motor and/or sensory function of the lower extremities and often occurs as a serious complication of aortic surgery.1 The pathophysiology of acute spinal cord injury (SCI) due to surgical procedures is complex and not fully understood. It is considered that free radical–induced lipid peroxidation plays a causative role in the development of SCI.2, 3 Studies have shown that inhibition of lipid peroxidation by antioxidants or free radical scavengers may be beneficial for the treatment of SCI.4, 5

Other protective methods used during aortic surgery include cerebrospinal fluid drainage,6, 7, 8 distal perfusion with extracorporeal support,9, 10, 11 and regional hypothermia of the spinal cord.12, 13 Although a variety of drugs have been evaluated for their neuroprotective effects in aortic surgeries, none of them is proven effective in preventing the development of SCI-associated paraplegia.14, 15, 16, 17

Etomidate is a nonbarbiturate intravenous anesthetic that has been used in humans for more than 30 years in various clinical settings, especially in the induction of rapid-sequence intubation in emergency departments.18 Its anesthetic effect is through the activation of gamma-aminobutyric acid (GABA) receptors, thereby promoting the release of potassium chloride–evoked GABA in cortical synaptosomes.19 The neuroprotective effect of etomidate during cerebral ischemia has been indicated in rat studies, where etomidate has been shown to reduce hippocampal neuronal injury after incomplete forebrain ischemia,20 block ischemia-induced increases in extracellular glutamate and glycine in the hippocampus,21 and attenuate posttraumatic functional (motor and cognitive) and histological (CA3 neuron loss and contusion volume) deficits.22 A plausible mechanism underlying the beneficial effects of etomidate is that it decreases neuronal activity, therefore reducing cerebral oxygen and glucose metabolism.23

In this study, the neuroprotective effect of etomidate was evaluated in a rabbit infrarenal ischemia–reperfusion (IR) injury model induced by aortic occlusion, and the neurological outcomes of the postinjury spinal cord were determined. An alternative mechanism for the neuroprotective effects of etomidate was proposed.

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Materials and Methods 

Animals and Experimental Groups 

The study was approved by the Institutional Review Board of Wuhan University for animal research. Twenty-four white adult Japanese rabbits of either sex, weighing 2.2-2.7kg, were supplied by Experimental Animal Institute of Wuhan University (certification SYXK [e] 20040027). All animals were housed in standard cages and randomly assigned to one of three groups with eight rabbits in each group: group I, sham-operation group; group II, IR group; group III, IR with etomidate treatment group. There were no significant differences in animal weight or sex among the three groups before the surgery.

Surgical Procedure 

Before surgery, all rabbits were tested to ensure that all motor functions were normal. Rabbits were intravenously infused with 3% pentobarbital (15mg/kg in 5mL 0.9% saline) at the rate of 2.5mL/min, endotracheally intubated, and then connected to a small-animal respirator machine (model DH140B; Zhe Jiang Medical Instrument Factory, Zhe Jiang Medical University, Hangzhou, China). The respiration of the rabbits was controlled at 30 breaths/min, with a 1.5:1 ratio of inspiration to expiration. Partial pressure of carbon dioxide (PaCO2) levels were maintained at 4.67-6 kPa. Ringer's solution was infused at 10mL/(kg·hr) through an ear vein during the procedure, and additional doses of 3% pentobarbital and 0.5mg/kg recuronium were administered at regular intervals throughout the experiment. Following intravenous heparin (3mg/kg of animal weight) administration, the right femoral artery was exposed, and a catheter with an arterial line connected to a pressure/heart transducer (LIFESCOPEE9; Light and Electricity Company, Tokyo, Japan) was inserted for continuous monitoring of aortic pressure. The arterial pressures both distal and proximal to the cross-clamp were measured, and the mean arterial pressure (MAP) was calculated. The cardiogram was recorded. The rectal body temperature was maintained at approximately 38°C with the aid of a heating pad during the study.

Aortic Occlusion 

To create IR SCI by aortic occlusion,24 the rabbit's skin was incised along the lateral vertical side of the erector spinal muscle below the left costal verge, the abdominal aorta was exposed outside the peritoneum, and a small-diameter silicone plastic tube was placed around the abdominal aorta at the distal side 1cm below the left artery. Aortic occlusion was induced by pulling and clamping the surrounding plastic tubing until the distal MAP reached 0mm Hg. The proximal MAP increased to some degree after aortic occlusion in both group II and group III animals, but no significant difference was observed between these two groups (Table I).

Table I. MAP of rabbits before and after aortic occlusion
MAP (mm Hg)Number of rabbits1min before aortic occlusion1min after aortic occlusion
Group II864.12±5.3167.41±4.72
Group III863.74±7.0266.17±4.56

IR Injury and Etomidate Treatment 

Spinal cord ischemia was induced in groups II and III by infrarenal aortic cross-clamping for 45min and confirmed by the decrease of the distal blood pressure and the disappearance of the pulse immediately after the aortic occlusion. Reperfusion was initiated upon removal of the clamp and continued for 7 days. Etomidate (Enhua Pharmacological, Xuzhou, China; H20020511) was intravenously injected to the group III rabbits at a single dose of 0.6mg/kg 10min before aortic clamping and then infused at a rate of 3mg/(kg · hr) until unclamping. Saline at 0.9% was given to group II animals in the same manner as etomidate, serving as the control. Sham-operated animals were subjected to similar operative dissections but without aortic occlusion and were not given either etomidate or 0.9% saline. Immediately after the operation, penicillin (400,000 U) was administered intramuscularly in all animals. The wounds were then sutured and the rabbits returned to their home cages for observation.

Hindlimb Motor Function 

During the reperfusion period, rabbits were assessed for hindlimb motor function once daily by an observer who was unaware of the experimental conditions. Each animal was evaluated once daily for a total of 7 days. Each group had eight rabbits. Therefore, motor function was assessed 56 times for each group. The modified Tarlov criteria were used to score the observed neurological functions on a scale of 0-4:25 0, paraplegia with no lower extremity motor function; 1, poor lower extremity motor function (flicker of movement or weak antigravity movement only); 2, some lower extremity motor function with good antigravity strength but inability to draw legs under the body and/or hip; 3, ability to draw legs under the body and hip but not normally; and 4, normal motor function as seen in normal animals.

Hindlimb Needle Electromyography 

At the end of the 7-day reperfusion, hindlimb needle electromyography (EMG) of quadriceps femoris muscles and biceps muscles of both hindlimbs was performed twice in all rabbits with the 3202 type EMG apparatus (Nihon Kohden, Tokyo, Japan) by a physician who was unaware of the study groups. Spontaneous potential appearance and motor unit potential (MUP) were measured. Spikes were used to define the degree of spontaneous potential appearance, with one spike defined as rarely visible, two spikes as sometimes visible, and three spikes or more as visible in a great quantity. MUP score was assessed using the following criteria: 1, interference pattern; 2, mixed-interference pattern; 3, mixed pattern; 4, mixed-simple pattern; 5, simple pattern. MUP score 1 or 2 indicated normal hindlimb motor function. For scores of 3-5, the higher the MUP score, the worse the hindlimb motor function.

Histopathology of the Spinal Cord 

After scoring of neurological function for 7 days, all animals were killed by exsanguination, and the spinal cord tissues from L1 to L3 vertebrae were quickly removed, immersed in 4% paraformaldehyde in 0.1M phosphate buffer, and stored at 4°C for 2 weeks. Spinal cord tissues from the L3 vertebra were used to prepare cross sections for microscopy. Tissues were embedded in paraffin, then cut into 5μm sections and stained with hematoxylin–eosin (H&E). Histology was evaluated under a light microscope (×400) for potential neurological injury by an experienced histopathologist who was unaware of the experimental conditions and the neurological outcomes. Ischemic neurons were identified by cytoplasmic eosinophilia with loss of Nissl substance and by the presence of pyknotic homogenous nuclei. Histopathological changes were graded based on the standard of Naslund et al.:24 grade I, neurons were normal, or the vacuole and granule denaturation of cytoplasm in neurons were observed occasionally; grade II, normal neurons and ischemic neurons coexisted in similar amounts; grade III, massive quantities of ischemic neurons were crimpled with nuclei dissolved and myelin swollen. Five serial sections from each animal and a total of 40 sections from each group were used for histopathological analysis.

Malondialdehyde Levels and Superoxide Dismutase Activities 

Levels of the lipid peroxidation end product malondialdehyde (MDA) and activities of superoxide dismutase (SOD) in spinal cord tissues were determined. Following death, about 1cm spinal cord tissues from L3 to L5 vertebrae around the injured region were collected, washed twice with cold saline solution, and then stored at –30°C until analysis. Tissue MDA levels were measured by the method described by Wasowicz et al.26 Total SOD activities, including both Cu-ZnSOD and MnSOD activities, were measured by their abilities to reduce nitroblue tetrazolium in the xanthine–xanthine oxidase system. One unit of enzyme activity was defined as the amount of SOD that causes 50% inhibition of oxidation in 25min. Results were expressed as units per milligram protein.27 Protein concentrations were determined using the method of Lowry et al.28

Measurement of Metal Ion Concentrations in Spinal Cord Homogenates 

At death, about 1-cm-long spinal cord tissues in the injured region (L3–L5) were collected and washed with triply distilled water to remove the spinal dura mater and the remnant blood. Then the tissue was dried, weighed, and homogenized in triply distilled water. After centrifugation, the supernatant was collected and stored in a –70°C freezer until analysis. Concentrations of Ca2+, Mg2+, Cu2+, and Zn2+ ions in the spinal cord homogenates were determined by flame atomic absorption spectrophotometry (L-type spectrAA-40 atomic absorption spectrum apparatus, hollow cathode light; Varian, Palo Alto, CA).

Statistical Analysis 

Statistical analysis was performed using SPSS 13.0 software (SPSS, Inc., Chicago, IL). MDA levels, SOD activities, and concentrations of Ca2+, Mg2+, Cu2+, and Zn2+ ions among the groups were determined by analysis of variance with the post hoc test. Neurological scores, EMG, and histopathological changes among the groups were analyzed with nonparametric methods (Kruskal-Wallis and Nemenyi tests). Data were expressed as mean ± standard deviation (SD), and p<0.05 was considered statistically significant.

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Results 

At the end of the animal study, all 24 rabbits survived and were used for data collection and analysis.

Neurological Functions of Hindlimbs 

After the surgery, changes in neurological functions were scored in all animals (Table II). Compared to those in groups I and III, neurological function scores were significantly lower in group II (p<0.01). No significant difference was observed in neurological function scores between groups I and III (p>0.05). A score of 0 indicates paraplegia, as assessed by loss of lower extremity motor function. Paraplegia was found in none of the animals in the sham-operation group (group I, 0/8) but was found in all animals in group II (8/8) and in one animal in group III (1/8). The neurological function of the group III animal that displayed paraplegia was partially recovered during the observation period (only five observations of score 0).

Table II. Comparison of neurological function scores of hindlimbs
Scoring frequencies
GroupsTotal score times01234
Group I56000056
Group IIa56435413
Group IIIb56501248

D stands for the test statistic between compared groups.

aD=4,589, p<0.01 compared with group I.

bD=3,970, p<0.01 compared with group II.

Hindlimb EMG 

As evidence of IR injury, spontaneous potential was not found in any of the animals in group I, whereas it occurred at high frequencies in all eight animals of group II but in only two animals in the etomidate-treated group III, with one at a high frequency and the other at a very low frequency. The interference pattern or mixed-interference pattern of the MUP is an indicator of normal motor function. It was observed in all animals in group I (8/8) and in most of the animals in group III (7/8) but in none of the animals in group II (0/0). In comparison with either group I or group III, group II showed significant unfavorable changes of MUP (p<0.01). No significant change was observed in MUP between groups I and III (p>0.05) (Table III).

Table III. Comparison of MUP scores of hindlimbs
Scoring frequencies
GroupsTotal score times12345
Group I16160000
Group IIa16000115
Group IIIb16132001

D stands for the test statistic between compared groups.

aD=399, p<0.01 compared with group I.

bD=342, p<0.01 compared with group II.

Histological Changes of the Spinal Cords 

No sign of histological abnormalities was observed in sham-operated rabbits, and all 40 sections of spinal cord tissues from this group were scored as grade I (Fig. 1A). However, sections from group II exhibited dramatic necrotic changes with karyolysis and neurophil vacuolation (Fig. 1B) and were mostly grade III except three sections of grade II. In group III, only mild degrees of destruction, such as triangular shape and Nissl granule loss, were observed in some motor neurons (Fig. 1C); and these changes were mostly grade I. The damage of neurons observed in group II was significantly attenuated by etomidate treatment in group III (D=1970, p<0.01). There were no significant differences in the histological scores of the spinal cords between groups I and III (D=515, p>0.05).

  • View full-size image.
  • Fig. 1 

    Histology of spinal cord tissue sections. Images of H&E-stained sections of spinal cord tissues from animals in groups I (A), II (B), and III (C) under the light microscope at ×400 magnification. A Tissue from a sham-operated rabbit showing normal cells. B Tissue from a group II rabbit showing necrotic changes with karyolysis and neurophil vacuolation. C Spinal cord from a group III rabbit showing only a mild degree of destruction such as triangular shape and Nissl granule loss in some motor neurons.

Changes of MDA Levels and SOD Activities in Spinal Cord Tissues 

As shown in Table IV, compared with those in group I, MDA levels in spinal cord tissues were significantly increased in group II (p<0.01). However, this increase was significantly reversed in the etomidate-treated group III (p<0.01). At the same time, SOD activities in the same tissues were significantly decreased in group II over those of the controls (p<0.01), but this decrease was significantly inhibited by etomidate treatment in group III (p<0.01). There were no significant differences in MDA levels and SOD activities in spinal cord tissues between groups I and III (p>0.05).

Table IV. MDA levels and SOD activities in spinal cord tissues
GroupsMDA (nmol/g)SOD (μ/mg)
Group I15.36±1.281.07±0.08
Group II24.15±1.29a0.68±0.11a
Group III17.02±1.27b1.07±0.10b

Data are expressed as mean±SD (n=8).

t stands for the test statistic between compared groups.

at=14.12 (MDA) or 7.69 (SOD), p<0.01 compared with group I.

bt=14.92 (MDA) or 9.85 (SOD), p<0.01 compared with group II.

Changes in Ion Concentrations in Spinal Cord Homogenates 

There were no significant differences between groups I and III in Ca2+, Mg2+, Cu2+, and Zn2+ ion levels in spinal cord tissues (p>0.05). Group II showed a significant increase in Ca2+ and Cu2+ ion levels (p<0.05 and p<0.01, respectively) and a significant reduction in Zn2+ and Mg2+ ion levels (p<0.05 and p<0.01, respectively) compared to those in group I (Table V).

Table V. Changes of metal elements in spinal cord homogenate (n=8, mg/L)
GroupsCaMgCuZn
Group I0.376±0.0785.220±0.3480.079±0.0120.568±0.124
Group II1.821±0.461a3.281±0.430a0.234±0.096a0.417±0.052a
Group III0.394±0.052b5.010±0.425b0.088±0.019b0.572±0.083b

Data are expressed as mean±SD.

ap<0.05 or p<0.01 compared with group I.

bp<0.05 or p<0.01 compared with group II.

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Discussion 

SCI and its resulting paraplegia following thoracoabdominal aortic surgeries can be devastating due to ischemia in the spinal cord caused by aortic occlusion followed by postsurgical blood reperfusion. In our animal model, SCI was induced by infrarenal aortic cross-clamping (1cm below the left artery) for 45min, followed by reperfusion for 7 days, and the occlusion was high enough to induce spinal cord ischemia, although there was collateral circulation in the animal.

To reduce IR-induced SCI, a variety of drugs have been evaluated. Barbiturates and calcium channel blockers have been shown to provide significant protection against IR-induced SCI in animal models.14, 16, 17 For the first time, we demonstrated that etomidate, a commonly used nonbarbiturate intravenous anesthetic, also effectively prevents SCI and subsequent neurological damage in a rabbit IR injury model.

Free radical–induced lipid peroxidation has been shown to contribute to tissue injuries during IR by attacking critical biological molecules, such as membrane lipids, essential cellular proteins, and DNA.29, 30 An increase in free radicals in IR-affected tissues is associated with a reduction in the activity of the endogenous antioxidant SOD, and SOD administration has been shown to significantly reduce free radical–triggered lipid peroxidation.31, 32 We showed that etomidate significantly reversed the increase in the end product of lipid peroxidation MDA in IR-injured tissues and prevented the reduction of SOD activities. Our results indicate that the neuroprotective effect of etomidate in spinal cord IR may be correlated with its ability to promote the activities of antioxidants in IR-affected tissues.

The activation of cation channels has also been suggested to play an important role in IR-induced SCI.33 Shen et al.34 have shown that redistribution of extracellular and intracellular metal ions is correlated with cell damage during IR. Kouchi et al.35 indicated that changes in multi-ion channels or cell membrane permeability are critical in ischemic preconditioning (IPC)–induced ischemia tolerance. We showed that, in comparison with control animals, IR-injured animals displayed significantly higher levels of Ca2+ and Cu2+ ions and significantly lower levels of Mg2+ and Zn2+ ions in spinal cord tissues and that etomidate treatment inhibited these adverse changes and maintained the normal ion balance. It is unknown whether these observed effects of etomidate on tissue ion levels are associated with multi-ion channels; however, one can speculate that some agents may have been released from the tissues as a result of the etomidate treatment and affected the cell membrane permeability and function.

Although changes in antioxidant levels and ion balance have been correlated with SCI, whether these changes are the cause of the SCI or merely the result of it remains unknown. We postulate that they could be both the causative and downstream events of SCI. On the one hand, changes in antioxidant levels and ion balance may lead to the occurrence of SCI; on the other hand, SCI may further reduce antioxidant levels and change the ion balance. Therefore, maintaining normal antioxidant levels and ion balance is crucial for the physiological function of the spinal cord. However, more work has to be done to evaluate this hypothesis.

Previously, we reported that four cycles of IPC (5min of ischemia followed by 5min of reperfusion) effectively prevented SCI.25 Here, we show that treatment with etomidate had a similar protective effect against SCI induced by 45min of ischemia and 7 days of reperfusion. The drug treatment may offer an advantage over IPC since it is much easier to operate, not only in experimental animals but also potentially in human subjects. In our pilot study, pretreatment with etomidate before IR enhanced the tolerance of the spinal cord to ischemia to only a limited degree for less than 20min (data not shown). In this study, we demonstrated that etomidate infusion started 10min before IR and continued during the entire clamping provided potent protection of tissues during prolonged ischemia up to 45min. The benefit occurred when the infusion was maintained for the duration of ischemia, implying that a reasonable collateral circulation or a sufficient blood concentration has an effect at reperfusion. The reason we reperfused the animals for 7 days is that our preliminary data suggested that the first 7 days of reperfusion following 40min of ischemia were the critical time for SCI and that rabbits subjected to 45min of ischemia with longer reperfusion (15 days) did not display any additional severity of the injury compared with the 7-day reperfusion group (four rabbits each, data not shown).

In humans, the recommended dose of etomidate is 0.1-0.6mg/kg when infused intravenously. In this study, etomidate was given to the rabbits at a higher dosage for obvious effects. Future studies with lower doses are necessary to confirm the beneficial effect of etomidate observed in the current study. When the drug is applied to humans for its potential protective function against IR-related injuries, the dose and administration route may even need to be further optimized to avoid any potential side effects while achieving the neuroprotective effect. Alternatively, it can be given in combination with other drugs to enhance its protective potency at lower doses.

In summary, etomidate displayed a significant neuroprotective effect in a rabbit infrarenal IR injury model. We proposed that this beneficial effect of etomidate may be associated with its ability to promote the activities of endogenous antioxidants such as SOD and maintain the ion balance in IR-affected tissues. Our proof of concept animal study warrants further evaluation of etomidate in humans to provide a simpler and more effective method for the prevention of SCI in aortic clamp operations.

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We thank Guixian Xiong from Renmin Hospital of Wuhan University for her constant assistance during the entire study.

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References 

  1. Flores J, Shiiya N, Kunihara T, et al. Risk of spinal cord injury after operations of recurrent aneurysms of the descending aorta. Ann Thorac Surg. 2005;79:1245–1249
  2. Barut S, Canbolat A, Bilge T, et al. Lipid peroxidation in experimental spinal cord injury: time-level relationship. Neurosurg Rev. 1993;16:53–59
  3. Anderson DK, Hall ED. Pathophysiology of spinal cord trauma. Ann Emerg Med. 1993;22:987–992
  4. Anderson DK, Dugan LL, Means ED, et al. Methylprednisolone and membrane properties of primary cultures of mouse spinal cord. Brain Res. 1994;637:119–125
  5. Saruhashi Y, Matsusue Y, Hukuda S, et al. Effects of seratonin 1A agonist on acute spinal cord injury. Spinal Cord. 2002;40:519–523
  6. Kahn RA, Stone ME, Moskowitz DM. Anesthetic consideration for descending thoracic aortic aneurysm repair. Semin Cardiothorac Vasc Anesth. 2007;11:205–223
  7. Trowbridge C, Bruhn T, Arends B. Selective deep spinal hypothermia with vacuum-assisted cerebral spinal fluid drainage for thoracoabdominal aortic surgery. J Extra Corpor Technol. 2003;35:152–155
  8. Safi HJ, Hess KR, Randel M, et al. Cerebrospinal fluid drainage and distal aortic perfusion: reducing neurologic complications in repair of thoracoabdomonal aortic aneurysm types I and II. J Vasc Surg. 1996;23:223–228
  9. Takagi H, Hirose H, Mori Y, et al. Antegradely insertable aortic balloon occlusion catheter for aortic arch repair. Heart Vessels. 2003;18:75–78
  10. Duhaylongsod FG, Glower DD, Wolfe WG. Acute traumatic aortic aneurysm: the Duke experience from 1970-1990. J Vasc Surg. 1992;15:331–342
  11. Fukumoto Y, Mori Y, Takagi H, et al. Protective effect of prostaglandin E1 against ischemia of spinal cord during aortic cross clamping. J Vasc Surg. 2003;37:156–160
  12. Sugawara Y, Sueda T, Orihashi K, et al. Trans-vertebral regional cooling for spinal cord protection during thoracoabdominal aortic surgery: an experimental study. Hiroshima J Med Sci. 2003;52:35–41
  13. Cambria RP, Davison JK, Zannetti S, et al. Clinical experience with epidural cooling for spinal cord protection during thoracic and thoracoabdominal aneurysm repair. J Vasc Surg. 1997;25:234–241
  14. Nylandder WA, Plunkett RJ, Hammon JW, et al. Thiopental modification of ischemic spinal cord injury in the dog. Ann Thorac Surg. 1982;33:64–68
  15. Hsieh YC, Cheng H, Chan KH, et al. Protective effect of intrathecal ketorolac in spinal cord ischemia in rats: a microdialysis study. Acta Anaesthesiol Scand. 2007;51:410–414
  16. Burns LH, Jin Z, Bowersox SS. The neuroprotective effects of intrathecal administration of the selective N-type calcium channel blocker ziconotide in a rat model of spinal ischemia. J Vasc Surg. 1999;30:334–343
  17. Danielisova V, Chavko M. Comparative effects of the N-methyl-d-aspartate antagonist MK-801 and the calcium channel blocker KB-2796 on neurologic and metabolic recovery after spinal cord ischemia. Exp Neurol. 1998;149:203–208
  18. Bergen JM, Smith DC. A review of etomidate for rapid sequence intubation in the emergency department. J Emerg Med. 1987;15:221–230
  19. Murugaiah KD, Hemmings HC. Effects of intravenous general anesthetics on [3H] GABA release from cat cortical synaptosomes. Anesthesiology. 1998;89:919–928
  20. Watson JC, Drummond JC, Patel PM, et al. An assessment of the cerebral protective effects of etomidate in a model of incomplete forebrain ischemia in the rat. Neurosurgery. 1992;30:540–544
  21. Patel PM, Goskowicz RL, Drummond JC, et al. Etomidate reduces ischemia induced glutamate release in the hippocampus in rats subjected to incomplete forebrain ischemia. Anesth Analg. 1995;80:933–939
  22. Dixon CE, Ma X, Kline AE, et al. Acute etomidate treatment reduces cognitive deficits and histopathology in rats with traumatic brain injury. Crit Care Med. 2003;3:2222–2227
  23. Levy ML, Aranda M, Zelman V, et al. Propylene glycol toxicity following continuous etomidate infusion for the control of refractory cerebral edema. Neurosurgery. 1995;37:363–371
  24. Naslund TC, Hollier LH, Money SR, et al. Protecting the ischemic spinal cord during aortic clamping. The influence of anesthetics and hypothermia. Ann Surg. 1992;215:409–515
  25. Yu QJ, Wang YL, Zhou QS, et al. Effect of repetitive ischemic preconditioning on spinal cord ischemia in a rabbit model. Life Sci. 2006;79:1479–1483
  26. Wasowicz W, Neve J, Peretz A. Optimized steps in fluorometric determination of thiobarbituric acid-reactive substances in serum: importance of extraction pH and influence of sample preservation and storage. Clin Chem. 1993;39:2522–2526
  27. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1988;34:497–500
  28. Lowry OH, Rosebrough NJ, Farr AL, et al. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:265–275
  29. Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84
  30. D'Autreaux B, Toledano MB. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol. 2007;8:813–824
  31. Erten SF, Kocak A, Ozdemir I, et al. Protective effect of melatonin on experimental spinal cord ischemia. Spinal Cord. 2003;41:533–538
  32. Segui J, Gil F, Gironella M, et al. Down-regulation of endothelial adhesion molecules and leukocyte adhesion by treatment with superoxide dismutase is beneficial in chronic immune experimental colitis. Inflamm Bowel Dis. 2005;11:872–882
  33. Paolo B, Fabrizio G, Sara B, et al. Expression of AMPA and NMDA receptor subunits in the cervical spinal cord of wobbler mice. BMC Neurosci. 2006;7:71–78
  34. Shen C, Jiang S, Dong Y. Changes of trace element in the acute spinal cord injury. Chin J Trad Med Traumatol Orthop. 2001;9:14–16
  35. Kouchi I, Murakami T, Nawada R, et al. KATP channels are common mediators of ischemic and calcium preconditioning in rabbits. Heart Circ Physiol. 1998;274:1106–1112

PII: S0890-5096(09)00160-5

doi:10.1016/j.avsg.2009.06.023

Annals of Vascular Surgery
Volume 24, Issue 2 , Pages 225-232, February 2010

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