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J Thorac Cardiovasc Surg 1994;107:1203-1209
© 1994 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Additive effect of allopurinol and deferoxamine in the prevention of spinal cord injury caused by aortic crossclamping

Vancouver, B.C., Canada

Supported by the Rick Hansen Man in Motion Legacy Fund.

Received for publication March 25, 1993. Accepted for publication Aug. 19, 1993. Address for reprints: A. K. Qayumi, MD, PhD, Assistant Professor of Surgery, Department of Surgery, Room 3100—910 W. 10 Ave., Vancouver, British Columbia, V5Z 4E3.

Abstract

Fourteen domestic swine were divided into two groups. Group A (n= 7) was the control group, in which no pharmacologic intervention was applied. In group B (n= 7), the ischemic-reperfused spinal cord was treated with the combination of allopurinol (50 mg/kg/day for 3 days before the day of operation) and deferoxamine (Desferal, 50 mg/kg administered intravenously over 3 to 4 hours). The administration of deferoxamine was completed 1 hour before crossclamping. The crossclamp was placed on the descending aorta just distal to the left subclavian artery for 30 minutes. Proximal hypertension was controlled with sodium nitroprusside and volume depletion. Methods of assessment included an evaluation of the neurologic status of the animals by quantitative Tarlov criteria, blood flow by radiolabeled microspheres, and histologic examination of the spinal cord. All animals in the control group, group A, were completely paraplegic with 0% recovery by Tarlov criteria at 24 hours after the removal of the crossclamp. In contrast, all animals in group B, in which the combination of allopurinol and deferoxamine was used, completely recovered (100% recovery by Tarlov criteria), and at 24 hours after the ischemic episode they were able to walk with no difficulty and had intact sensation. Functional parameters of these animals fully correlated with the morphologic findings. Widespread acute neuronal injury and vacuolation of neuropil were observed in the control group of animals. In contrast, animals in group B showed much less pronounced morphologic changes after the same period of ischemia. In summary, the combined use of these agents significantly (p< 0.001) reduced the incidence of paraplegia induced by aortic crossclamping with 82% additivity. (J THORAC CARDIOVASC SURG1994;107:1203-9)

Operation for thoracoabdominal aortic aneurysms requires aortic clamping and carries a risk of distal organ ischemia as a result of diminished perfusion. ^1-4 Organs at risk for ischemia include kidneys, liver, spinal cord, and intestines. The spinal cord is the organ most sensitive to ischemia and the resulting ischemic injury can produce paraparesis or paraplegia. Even with substantial progress over the past two decades in the surgical treatment of descending thoracic and thoracoabdominal aneurysms, paraplegia remains the most dreaded complication of aortic operation. ^3-5 The rate of paraplegia is directly related to the length of the aorta being clamped and duration of the resulting ischemia. ^2,6 Simple aortic clamping at the level of the left subclavian artery results in substantial decreases in spinal cord blood flow and oxygen tension below the level of the mid–thoracic aorta. Progress has been made in reducing spinal cord injury with improvements in operative technique and anesthesia management and the use of shunts or bypass techniques to maintain distal perfusion. ^4,5 There remains uncertainty regarding the efficacy of these adjuncts in preventing or reducing the incidence of spinal cord injury. The mechanisms of tissue injury and possible interventional therapies have received limited attention in regard to the spinal cord.

We evaluated a possible mechanism of tissue injury in ischemic-reperfused spinal cord caused by oxygen free radicals. ⁷ Results of former experimentation confirm the possible role of oxygen free radicals in the pathophysiologic development of spinal cord injury induced by aortic crossclamping. Prevention of hydroxyl formation by iron chelating agents such as deferoxamine appears to be the most important mechanism in protecting the spinal cord from ischemia-reperfusion injury (75% recovery). Allopurinol also demonstrated some protective effect (25% recovery). Because allopurinol and deferoxamine both are clinically available agents, we hypothesized that the possible additive effect of these agents would have a scientific and clinical value. The objective of this experimental protocol was to evaluate the combined effect of allopurinol and deferoxamine in the prevention of spinal cord ischemia-reperfusion injury caused by 30 minutes of aortic crossclamping.

MATERIALS AND METHODS

The efficacy of pharmacologic agents for prevention and control of oxygen free radical damage in an ischemic-reperfused spinal cord was assessed in a swine model of thoracoabdominal aortic crossclamping. Experiments were done with 14 female domestic swine (Sus serota domesticus) weighing from 20 to 22 kg. The animals were divided into two groups of seven each: group A (n = 7) was the control group in which no pharmacologic intervention was introduced. In group B (n = 7) animals were pretreated with allopurinol, 50 mg/kg/day, for 3 days and, in addition, deferoxamine in a dose of 50 mg/kg was administered intravenously over a period of 3 to 4 hours before ischemia. All animals were subjected to 30 minutes of ischemia, and neurologic status was assessed at 4 hours after recovery from anesthesia and 24 hours after the crossclamping.

Anesthesia was induced with ketamine (20 mg/kg body weight) and maintained with isoflurane (0.5% to 2.0%). Ventilation was maintained with a volume ventilator and inflatable cuffed endotrachial tube.

The animals were hemodynamically controlled by monitoring the systemic blood pressure (systolic, diastolic, mean) and heart rate. Electrocardiographic monitoring was also conducted throughout the procedure. Proximal hypertension was controlled with 20 to 40 mg sodium nitroprusside and volume depletion (300 to 500 ml). The nitroprusside was administered at a dosage of 100 µg/ml and a flow rate of 1 ml/kg/min during the first 15 minutes of ischemia. There were indications of volume depletion when the systemic pressure and heart rate were more than double the original value. The cardiovascular system in swine is very sensitive. Therefore the use of both methods (volume depletion and vasodilation) is important to control the proximal hypertension.

Under sterile conditions a limited fourth intercostal space left thoracotomy was done to provide exposure of the proximal and midportion of the descending thoracic aorta. The aorta distal to the left subclavian vein was exposed for clamping. Proximal and distal arterial monitoring lines for pressure were introduced via the right carotid artery and right femoral artery. The pericardium was opened for exposure of the left atrial appendage and placement of the polyethylene catheter for microsphere infusion. The external jugular vein was cannulated for intravenous access for the administration of nitroprusside to control proximal hypertension during aortic clamping and for volume replacement during the declamping phase. After aortic declamping, the thoracotomy was closed and the animal was permitted to regain consciousness for neurologic assessments over a period of 2 to 3 hours. The animals received appropriate sedation during the recovery period. Acid-base status was monitored throughout the procedure and metabolic acidosis was corrected with sodium bicarbonate, if necessary. Animals were sedated after extubation and kept warm in the recovery room with direct control of the vital signs. At 24 hours after the crossclamping, neurologic assessment was done for grading of the Tarlov criteria.

After 24 hours of observation, animals were reanesthetized and the thoracotomy wound was reopened. A 2-0 silk pursestring suture was placed on the medial part of the thoracic aorta, which was cannulated with a 16-gauge catheter. The aorta was doubly crossclamped at the first and eleventh thoracic vertebrae. The animals were then killed with an overdose of sodium pentobarbitol. The spinal cord was perfused with 500 ml 10% solution of formaldehyde. A laminectomy was done at the level of the eighth thoracic vertebra to obtain spinal cord specimens for quantitation of microspheres and pathomorphologic analysis. The experimental protocol was designed and performed in accordance with the principles of the Canadian Council on Animal Care and the University of British Columbia Animal Care Committee regulations.

The end points of evaluation were neurologic status, spinal cord blood flow assessment, and morphologic analysis.

Neurologic status
Neurologic assessment included physical findings of hind limb neurologic function at 4 hours after reperfusion. The neurologic status was determined when the animals were fully conscious. The assessment comprised clinical criteria of hind limb neurologic function according to the modified Tarlov criteria. The Tarlov criteria were quantitated as follows: grade 0, no voluntary function (complete paralysis), 0% recovery; grade I, movement of joints perceptible, 25% recovery; grade II, active movement of joints (inability to stand), 50% recovery; grade III, able to stand (unable to walk), 75% recovery; and grade IV, complete recovery (able to stand, walk, run), 100% recovery.

Spinal cord blood flow assessment
Blood flow assessment was done by radiolabeled microsphere techniques. The blood flow assessment was used to determine the residual spinal cord blood flow, including collateral flow, for each of the study groups. The blood flow assessment was done at three time periods: at time one (preischemia) gadolinium 153 was administered; at time two (during ischemia, 5 minutes before reperfusion) tin 113 was administered; and at time three (postischemia, within 30 minutes after reperfusion, at the time of reestablishment of hemodynamic parameters) ruthenium 103 was administered. The radiopharmaceuticals were injected into the left atrium through the left atrial cannula and blood samples were collected simultaneously from the femoral artery. Quantitation of the blood flow was done by a method described by Heyman and colleagues. ⁸

Morphologic analysis
Specimens from thoracic spinal cords previously fixed by perfusion were embedded in paraffin and sectioned for routine light microscopic examination. Sections from three different levels of each spinal cord were stained with hematoxylin-eosin and Luxol, fast blue, and crystal violet stains. Before histologic examination the labeling on the slides was masked so that morphologic evaluation of control and experimental spinal cords was done blindly. The control (group A) and experimental (group B) specimens were also compared with sections obtained from intact animals with no ischemic episode.

Blood flow assessments were analyzed for the effect of time and for comparison among the groups by a repeated-measure analysis of variance model. The difference in Tarlov criteria among the groups was determined by nonparametric statistical analysis of Mann-Whitney pairwise comparison and Kruskal-Wallis ² test. Asterisks on each figure represent the significant differences among the groups; the significance was assessed at 95% and 98% confidence levels as indicated in the figures. The additivity of the pharmacologic agents was calculated as follows:

I_{1, 2} = I₁ + I₂ - (I₁ x I₂)

where I₁ is the effect of allopurinol (obtained from the previous experiments and equals 0.25) and I₂ is the effect of deferoxamine (obtained from the previous experiments and equals 0.75). The additivity for the combination of allopurinol and deferoxamine is I_{1, 2} = 0.25 + 0.75 – (0.25 x 0.75); I_{1, 2} = 0.82 or 82%.

RESULTS

The equally and significantly (p < 0.001) reduced blood flow for both groups during the ischemic interval (time 2) indicates a true ischemic episode for these groups (Fig. 1). It also confirms the insufficiency of collateral circulation to the swine spinal cord during the ischemic episode. Fig. 1 illustrates the significant (p < 0.001) fall in spinal cord blood flow during the ischemic interval. The blood flow count at this time was 3.2 ± 0.6 ml/min/100 gm for the control group of animals and 2.8 ± 1.0 ml/min/100 gm for group B in which pharmacologic intervention was applied, compared with the initial (time 1) values of 27.4 ± 6.1 ml/min/100 gm for group A and 27.0 ± 4.2 ml/min/100 gm for the experimental group. After the release of the crossclamp at time 3 a hyperemic response was evident for both groups (55.2 ± 8.4 ml/min/100 gm for group A and 50.6 ± 5.2 ml/min/ 100 gm for group B). The alteration of spinal cord blood flow was not significant between the groups at each time interval, which indicated an equivalent blood flow for both groups at each time.

View larger version (47K): [in this window] [in a new window]   Fig. 1. Spinal cord blood flow (mean plus or minus standard deviation) assessed by radioactive microsphere technique with specific microspheres used at each time interval. Time 1, Before ischemia; Time 2, during ischemia; Time 3, 30 minutes after ischemia.

Table I

View larger version (41K): [in this window] [in a new window]   Fig. 2. Quantified Tarlov criteria at 24 hours of reperfusion. Group A falls in Tarlov grade 0 with 0% recovery; group B falls in Tarlov grade IV with100% recovery (asterisk indicates p < 0.001). Three-dimensional view is shown at 20% elevation.

View larger version (112K): [in this window] [in a new window]   Fig. 3. Ventral horns of lower thoracic spinal cord. A, Normal motorneurons, glia, and neuropil in intact animal. B, Abnormal motor neurons of control (group A) animal with shrunken and dense cytoplasm lie within vacuolated neuropil. Two necrotic eosinophilic neurons (arrowhead) are adjacent to small focus of leukocyte extravasation (arrow). C, Neurons of experimental (group B) animal are well-preserved and morphologically similar to nerve cells in intact animals. There is slight vacuolation of neuropil; however, a large number of vacuoles represent distended lumina of microvessels. (Hematoxylin and eosin stain; original magnification x200.)

DISCUSSION

The causes of spinal cord ischemia during operations on the descending thoracic and thoracoabdominal aorta are complex. ⁹ The temporary interruption of spinal cord blood supply by simple crossclamping of the aorta can be critical to spinal cord perfusion. ¹⁰

There is biochemical, physiologic, and pharmacologic evidence to support the role of oxygen free radical–induced lipid peroxidation in posttraumatic spinal cord degeneration, but little attention has been paid to the spinal cord injury caused by ischemia and reperfusion. ^11-13 The role of oxygen-derived free radicals, namely superoxide anion, hydrogen peroxide, and, most important, hydroxyl radicals, has also received limited attention in lipid peroxidation caused by ischemia-reperfusion injury, as pertains to the interruption of spinal cord blood flow during aortic crossclamping for large thoracic and thoracoabdominal aneurysm operation. Svenson and colleagues ¹⁴ investigated the effect of allopurinol and superoxide dismutase on spinal cord blood flow and paraplegia caused by 60 minutes of crossclamping of the thoracic aorta. These investigators did not find a protective effect of allopurinol and superoxide dismutase. In contrast, Lim and associates ¹⁵ investigated the time-response relationship of recombinant superoxide dismutase in the ischemic spinal cord within 30 minutes of ischemia. The significant protective effect of superoxide dismutase was demonstrated within 30 minutes of spinal cord ischemia by the latter investigators, and these findings agree with the findings of our previous study (Qayumi and associates ⁷). In addition, results of our previous study demonstrated the role of oxygen free radicals in the pathogenesis of ischemia-reperfusion injury and also confirmed that the formation of hydroxyl radicals, via Haber-Weiss reaction, catalyzed by ferric ions, is the most important pathway in ischemia-reperfusion injury. It also showed that the prevention of hydroxyl formation by iron chelating agents such as deferoxamine is the most effective mechanism (75% recovery) to protect ischemic-reperfused spinal cords from lipid peroxidation. Allopurinol, a xanthine oxidase inhibitor also has been proved to be effective in the prevention of ischemia-reperfusion injury. ^16-18 During the ischemic episode, degradation of adenosine triphosphate and the formation of oxygen free radicals via the hypoxanthine to xanthine reaction are believed to be important in ischemia-reperfusion injury. ¹⁹ The negative results on the protective effect of allopurinol obtained by Svenson and colleagues ¹⁴ were most likely a result of the administration protocol. It has been shown that allopurinol is effective only with chronic administration of at least 3 days before the ischemic interval. ¹⁷ In our previous study, ⁷ chronic administration of allopurinol provided some degree of protection (25% recovery). Despite the controversy about the presence of xanthine oxidase in different species or organs, ^20,21 other protective mechanisms of allopurinol, such as the direct scavenging properties, have been proved by others. ^22-25

Considering that allopurinol and deferoxamine act on two independent pathways of the same pathologic process, we postulated that the combination of these agents is most likely to provide an additive effect. Allopurinol and deferoxamine both are used in clinical practice routinely. Clinical availability of these agents provided an additional interest for the experimental evaluation of these pharmacologic substances. Results of this experimental protocol prove the validity of our hypothesis, and the calculated additive effect is as high as 82% for this combination. The experimental group of animals, in which the combination of allopurinol and deferoxamine was used, had a 100% recovery at 24 hours after the 30-minute ischemic interval and 24 hours of reperfusion. These animals were standing and walking with no difficulty and had intact sensory and motor reflexes. In contrast, animals in the control group were paraplegic with no sensory or motor reflexes. The homogenicity of data in each group clearly proves the superiority of the proposed method of treatment without the consideration of mathematical proof for degree of significance. The outstanding results of this combination provoked interest in clinical investigation and practice. The simplicity and effectiveness of this method are advantageous to those proposing complex shunts ⁵ and bypass techniques. ⁴ Furthermore, this pharmacologic interaction may increase the safety limits for complex surgical procedures such as resection of thoracoabdominal aneurysms. There are many etiologic factors that affect the neurologic outcome of patients who undergo large thoracic and thoracoabdominal aortic crossclamping. ^26,27 These factors mainly include preoperative occlusion of the posterior branches, hypotension, increased cerebrospinal fluid pressure, permanent occlusion of the posterior branches because of surgical procedures, absence of efficient collateral circulation, and duration of the crossclamping time. This experimental model was designed to evaluate the effect of crossclamping time only and does not deal with other etiologic factors of spinal cord injury caused by surgical treatment of large thoracic and thoracoabdominal aortic aneurysm resection.

In summary, the combined effect of allopurinol (50 mg/kg/day orally for 3 days) and deferoxamine (50 mg/kg slow intravenous infusion an hour before crossclamping) demonstrated as high as 82% additivity. This combination provides a significantly (p < 0.001) better protection for the ischemic-reperfused spinal cord after 30 minutes of crossclamping and 24 hours of reperfusion.

Acknowledgments

We thank Fern Rushton, Vicki Chor, and Gail Newell for preparation of the manuscript.

References

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Michael T. Janusz Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qayumi, A. K. Articles by Nikbakht-Sangari, M. Search for Related Content PubMed PubMed Citation Articles by Qayumi, A. K. Articles by Nikbakht-Sangari, M.