Asian Cardiovasc Thorac Ann 2000;8:216-220
© 2000 Asia Publishing EXchange Pte Ltd
Functional Outcome in Model of Spinal Cord Ischemia: Use of Enoximone
A Tulga Ulus, MD,
Ufuk Tütün, MD,
Selçuk Sürücü, MD,1,
Nusret Apaydin, PhD,2,
Perran Gökçe, PhD,2,
S Fehmi Katircio
lu, MD
Department of Cardiovascular Surgery
Turkiye Yüksek  htisas Hospital
Ankara, Turkey
1 Department of Anatomy, Faculty of Medicine
Hacettepe University
Ankara, Turkey
2 Veterinary Faculty
Ankara University
Ankara, Turkey
|
|
For reprint information contact: A Tulga Ulus, MD Tel: 90 532 522 1520 Fax: 90 312 229 0148 email: uluss{at}yahoo.com Nide Sokak Ulus Apt. 20/6, Dikmen, Ankara 06460, Turkey.
|
 |
Abstract
|
|---|
Ten dogs underwent 60 minutes of aortic occlusion; 5 received enoximone 10 µg•kg–1•min–1 and the other 5 served as controls. Distal and proximal aortic pressures were measured during the procedure. Neurological status was assessed after 72 hours. Spinal cord specimens were taken for electron microscopy. During aortic occlusion, cerebrospinal fluid pressure was 17 ± 3 mm Hg in the control group and 14 ± 4 mm Hg in the enoximone group, while distal aortic pressure was 15 ± 4 mm Hg in the control group compared to 47 ± 6 mm Hg in the enoximone group (p < 0.001). Four dogs in the control group suffered paraplegia but there was no paraplegia in the enoximone group (p < 0.01). Electron microscopy scores indicated significantly less ultrastructural damage (p < 0.01) in the enoximone group (2.73 ± 0.79) than in the control group (7.67 ± 0.89). It was concluded that enoximone was effective in reducing the risk of spinal cord injury during aortic crossclamping.
|
Introduction
|
|---|
Spinal cord injury is the most dreaded complication of thoracoabdominal aortic aneurysm surgery because of the risk of paraplegia. Aortic crossclamping reduces arterial pressure distal to the clamp, resulting in reduced blood flow to the spinal cord. Perioperative ischemia and subsequent reperfusion can injure the spinal cord.1,2 Various methods such as pharmacological agents and shunt procedures have been used to protect the spinal cord from ischemia but none have been uniformly successful.3–7 The aim of these techniques is either to increase the spinal cord blood flow or to reduce the risk of ischemia-reperfusion injury. Papaverine has been shown to significantly increase spinal cord blood flow.7 Prosta-cyclin, a drug similar to papaverine, reduced the risk of spinal cord injury in previous studies by our group.3,4 In this study, we selected enoximone to maintain blood flow in the spinal cord during aortic crossclamping because enoximone has both inotropic and vasodilating properties similar to papaverine.
|
Materials and Methods
|
|---|
Ten adult mongrel dogs weighing 23 ± 5 kg were used in this study. The care of these animals complied with the "Principles of Laboratory Animal Care" formulated by the USA National Society for Medical Research and the "Guide for the Care and the Use of Laboratory Animals" prepared by the National Academy of Science and published by the National Institutes of Health (NIH publication no. 85–23, revised 1985). Permission was obtained from the ethics committee of the veterinary faculty of Ankara University, Ankara, Turkey.
The animals were anesthetized with xylazine 2 mg•kg–1 intramuscularly and thiopental sodium 5 mg•kg–1. All animals were placed on volume ventilators. Venous and arterial catheters were placed in the femoral artery and vein for volume replacement, drug administration, and pressure monitoring. A left thoracotomy was performed and the aorta was isolated distal to the left subclavian artery. A thermodilution catheter was inserted in the pulmonary artery and another catheter was placed in the femoral artery for cardiac output, pressure monitoring, and blood gases analyses. Body temperature was main-tained at 35.5°C as monitored by a rectal thermometer. Proximal arterial pressure was monitored by a catheter inserted 3 cm proximal to the clamp. The femoral arterial catheter was used for distal pressure monitoring during aortic occlusion. Both groups had a subarachnoid needle placed in the cisterna cerebellomedullaris for cerebrospinal fluid pressure measurements.
Five of the 10 dogs did not receive any special protective treatment and were considered as controls. The other group of 5 animals received 10 µg•kg–1•min–1 of enoximone (Perfan; Marion Merrel Dow Ltd., Uxbridge, Middlesex, England, UK). Enoximone was administered for 5 minutes before aortic crossclamping, during crossclamping, and for 5 minutes after declamping. After baseline measurements, the aorta was crossclamped distal to the subclavian artery for 60 minutes. Neurological status was assessed at 72 hours and graded according to the Tarlow8 method: 0 = no movement of hind limbs (paraplegia); 1 = slight movement of hind limbs (spastic paraplegia); 2 = good movement of hind limbs but inability to stand; 3 = ability to stand but not to walk normally; 4 = complete recovery. Animals with a score of 0 were paraplegic, those with a score of 1 to 3 were paraparetic, and those with a score of 4 were normal.
Full cross-section spinal cord specimens were taken from the thoracic region and fixed in 2.5% glutaraldehyde solution, post-fixed in osmium tetroxide dehydrated with alcohol, and embedded in epoxy resin. Ultrathin sections (60 to 90 nm) were prepared with an ultratome and contrasted with uranyl acetate and lead citrate. The specimens were examined with a JEM 1200 electron microscope (JEOL, Tokyo, Japan). The spinal cord damage in each sample was scored according to the criteria in Table 1
.
Pressure values were calculated as the mean ± standard deviation. Pressures were analyzed by one-way analysis of variance. The difference in Tarlow's scores between the groups was determined by nonparametric statistical analysis using the Kruskal-Wallis test. A p value less than 0.05 was considered statistically significant.
|
Results
|
|---|
All animals tolerated the operation well. There were no differences between the groups with regard to baseline and reperfusion pressures, but during aortic occlusion, distal arterial pressures were significantly different in the control group compared to the enoximone group (Table 2). Cerebrospinal fluid pressure did not show any significant differences during the observation period. Cardiac index was higher and systemic vascular resistance was lower in the enoximone group compared to the control after 15 and 60 minutes of crossclamping and at 3 hours after declamping (Table 3). There were 4 paraplegic animals in the control group but there was none in the enoximone group 72 hours after aortic occlusion (Table 4). Neurological outcome at 72 hours showed a statistical difference between the groups, based on Tarlow's scores (p < 0.01).
Electron microscopy of spinal cord samples from the control group revealed axoplasmic edema in all axons, neurofilament density was very much reduced, many of the fibers showed axonal displacement, and the mito-chondria were edematous (Figure 1). The myelin sheaths of the axons were thinner and clefts were observed between the myelin layers. Many of the axons displayed vesicular degeneration giving a honeycomb appearance. In the enoximone group, some recovery of the ultrastructure was observed (Figure 2). The myelin structure and the neurofilament density appeared normal in most of the axons but there were some myelin clefts and edematous mitochondria. The cytoplasm exhibited some mild edema but most of the membranes seemed intact. The mean electron microscopy score was 2.73 ± 0.79 for the enoximone group and 7.67 ± 0.89 for the control group (p < 0.01).
View larger version (148K):
[in this window]
[in a new window]
|
Figure 1. Electron microscopic appearance of the thoracic spinal cord from an enoximone-treated dog. There was no significant change in spinal cord ultrastructure (uranyl acetate and lead citrate stain, original magnification x2000).
|
|
View larger version (172K):
[in this window]
[in a new window]
|
Figure 2. Electron microscopic appearance of the thoracic spinal cord from a control dog. Almost all of the axons had myelin sheet degeneration and severe edema (uranyl acetate and lead citrate stain, original magnification x2000).
|
|
|
Discussion
|
|---|
Spinal cord injury may result from temporary or permanent perioperative ischemia caused by preoperative hypotension or distal aortic hypotension after aortic occlusion.9 After application of an aortic crossclamp, changes in ventricular function are associated with increased venous return that exacerbates myocardial dysfunction and leads to a reduced ejection fraction. As a result of these changes, distal parts of the body receive less blood, resulting in decreased distal blood pressure.
Various methods such as distal perfusion techniques and vasodilating or anti-ischemic pharmacological agents have been assessed for prevention of spinal cord injury.5,10 Distal perfusion techniques failed to increase blood flow to the lumbar or thoracic spinal cord. Svensson and colleagues7 demonstrated that shunt techniques did not increase blood flow to the spinal cord because of the high resistance of the anterior spinal artery above the arteria radicularis magna which supplies the lower-thoracic spinal cord. They demonstrated that a functioning shunt may not be adequate for perfusion of the lower-thoracic spinal cord. To increase lower-thoracic spinal cord blood flow, the artery supplying this segment must be dilated pharmacologically. Accordingly, it was postulated that paraplegia would not occur if the anterior spinal artery was large or dilated enough to satisfy the metabolic needs of this segment. In a previous study, papaverine was used to increase spinal cord blood flow because of its beneficial effect on spasm of the basilar artery.11 We have also demonstrated that prostacyclin can reduce the risk of spinal cord injury.3,4 These drugs increase the spinal cord blood flow, whereas sodium nitroprusside used as a vasodilator lowered spinal cord perfusion pressure and increased the risk of neurologic injury.12 It is our belief that any vasodilator that increases cyclic adenosine monophosphate levels, reduces the incidence of neuro-logical injury.
Patients undergoing aortic surgery may have concomitant aortic disease and limited coronary reserve.13 In this group, left ventricular decompensation occurs in response to an increase in afterload following crossclamping. When the aorta is clamped, the stroke volume does not increase or only slightly increases, but isoproterenol therapy during aortic crossclamping significantly increases the stroke volume.1 This suggests that inotropic therapy associated with vasodilation exerts beneficial effects on the myo-cardium to support the circulation during aortic cross-clamping.
Enoximone is a phosphodiesterase inhibitor that shows both inotropic and vasodilatory properties. Its use leads to an improvement in cardiac function without increasing myocardial oxygen consumption.14 It increases the intracellular cyclic adenosine monophosphate level. In this study, enoximone significantly raised the distal arterial pressure compared to the control group. This action was associated with slightly increased proximal arterial pressure but the pressure rise was not statistically significant compared to the control group. In both groups, cerebrospinal fluid pressure did not rise due to the proximal hypertension. However, spinal cord perfusion pressure was significantly higher in the enoximone group than in the control group. Whether there are any neurological effects of enoximone on the spinal cord remains to be elucidated.6,15
The importance of distal arterial pressure during clamping should be noted. Laschinger and colleagues5 demonstrated that the spinal cord is very susceptible to ischemia if the distal aortic pressure is lower than 40 mm Hg, whereas Wadouh10 found that a pressure of 40 mm Hg in the abdominal artery between the first lumbar and first sacral vertebrae to be borderline and recommended techniques to maintain it at 50 mm Hg. In this study, distal aortic pressures stayed above 40 mm Hg in the enoximone group where paraplegia did not occur at all, while in the control group, with corresponding pressures below 20 mm Hg during occlusion, every animal was severely affected.
Enoximone is a powerful agent that enhances myocardial contractility and has strong vasodilating properties. These features lead to increased cardiac output associated with a minimal increase in myocardial oxygen tension.16 Crossclamping the thoracic aorta increases systemic vascular resistance suddenly, which reduces myocardial contractility. Enoximone increases myocardial contractility while it dilates the arterial wall. Dilatation of the arterial wall increases the distal arterial blood flow with an increase in cardiac output. In this study, enoximone was observed to increase the distal arterial pressure and reduce systemic vascular resistance compared to the control group. We believe that these changes increased the spinal cord perfusion pressure with a resultant reduction in neu-rological injury. This was confirmed by ultrastructural findings in the spinal cord indicating that enoximone significantly reduced ultrastructural damage. Thus, it was concluded that enoximone can effectively preserve spinal cord function during aortic occlusion.
|
Acknowledgments
|
|---|
Supported in part by the Özel Yasam Hospital (Ankara) grant.
|
References
|
|---|
-
Bugge-Asperheim B, Kiil F. Cardiac response to increased aortic pressure: changes in output and left ventricular pressure pattern at various levels of inotropy. Scand J Clin Lab Invest 1969;24:345–60.[Medline]
-
Crawford ES, Rubio P. Reappraisal of adjuncts to avoid ischemia in the treatment of aneurysms of the descending thoracic aorta. J Thorac Cardiovasc Surg 1973;66:693–704.[Medline]
-
Katirciog lu SF, Gökçe P, Özgencil E, Sarita
Z, 
ener E, Yilmazkaya B, et al. Prostacyclin usage for spinal cord protection during experimental aortic cross-clamping. Vasc Surg 1996;30:97–101.
-
Katirciog lu SF, Küçükaksu S, Küplülü S, Vuran R, Bayazit M, Tademir O, et al. Effects of prostacyclin on spinal cord ischemia: an experimental study. Surgery 1993; 114:36–9.[Medline]
-
Laschinger JC, Cunningham JN Jr, Nathan IM, Knopp EA, Cooper MM, Spencer FC. Experimental and clinical assessment of the adequacy of partial bypass in maintenance of spinal cord blood flow during operations on the thoracic aorta. Ann Thorac Surg 1983;36:417–26.[Abstract]
-
Mauney MC, Blackbourne LH, Langenburg SE, Buchanan SA, Kron IL, Tribble CG. Prevention of spinal cord injury after repair of the thoracic or thoracoabdominal aorta. Ann Thorac Surg 1995;59:245–52.[Abstract/Free Full Text]
-
Svensson LG, Von Ritter CM, Groeneveld HT, Rickards ES, Hunter SJ, Robinson MF, et al. Cross-clamping of the thoracic aorta. Ann Surg 1986;204:38–47.[Medline]
-
Tarlow IM. Spinal cord compression: mechanisms of paralysis and treatment. Springfield: Charles, 1957:147–55.
-
Lim KH, Connolly M, Rose D, Siegman F, Jacobowitz I, Acinapura A, et al. Prevention of reperfusion injury of the ischemic spinal cord: use of recombinant superoxide dismutase. Ann Thorac Surg 1986;42:282–6.[Abstract]
-
Wadouh F. New surgical techniques for the prevention of paraplegia during aortic surgery. Thorac Cardiovasc Surg 1992;40:26–32.[Medline]
-
Ogata MB, Marshall M, Lougheed WM. Observations on the effects of intrathecal papaverine in experimental vasospasm. J Neurosurg 1973;38:20–5.[Medline]
-
Marini CP, Grubbs PE, Toporoff B, Woloszyn TT, Coons MS, Acinapura AJ, et al. Effect of sodium nitroprusside on spinal cord perfusion and paraplegia during aortic cross-clamping. Ann Thorac Surg 1989;47:379–83.[Abstract]
-
Whittemore AD, Clowes AW, Hetchman HB, Mannick JA. Aortic aneurysm repair: reduced operative mortality associated with maintenance of optimal cardiac per-formance. Ann Surg 1980;192:414–21.[Medline]
-
Dage RC, Okerholm RA. Pharmacology and pharmaco-kinetics of enoximone. Cardiology 1990;77(Suppl 3): 2–13.
-
Svensson LG, Klepp P, Hinder LA. Spinal cord anatomy of the baboon—comparison with man and implications of spinal cord blood flow during thoracic aortic cross-clamping. S Afr J Surg 1986;24:32–4.[Medline]
-
Katirciolu SF, Sarita Z, Ulus AT, Yamak B. Comparison of the effects of enoximone and isoproterenol on protamine cardiotoxicity in the anesthetized dogs. Jpn Circ J 1998; 62:122–6.[Medline]
TOP
Abstract
Introduction
