- Email: [email protected]
Spinal cord protection during aortic cross-clamping using retrograde venous perfusion
Spinal Cord Protection During Aortic CrossClamping Using Retrograde Venous Perfusion Patrick E. Parrino, MD, Irving L. Kron, MD, Scott D. Ross, MD, Kimberly S. Shockey, MS, Michael J. Fisher, BA, John R. Gaughen, Jr, BA, John A. Kern, MD, and Curtis G. Tribble, MD Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia
Background. Paraplegia remains a devastating complication following thoracic aortic operation. We hypothesized that retrograde perfusion of the spinal cord with a hypothermic, adenosine-enhanced solution would provide protection during periods of ischemia due to temporary aortic occlusion. Methods. In a rabbit model, a 45-minute period of spinal cord ischemia was produced by clamping the abdominal aorta and vena cava just below the left renal vessels and at their bifurcations. Four groups (n 5 8/group) were studied: control, warm saline, cold saline, and cold saline with adenosine infusion. In the experimental groups, saline or saline plus adenosine was infused into the isolated cavae throughout the ischemic period. Clamps were removed and the animals to recovered for 24 hours before blinded neurological evaluation.
Results. Tarlov scores (0 5 paraplegia, 1 5 slight movement, 2 5 sits with assistance, 3 5 sits alone, 4 5 weak hop, 5 5 normal hop) were (mean 6 standard error of the mean): control, 0.50 6 0.50; warm saline, 1.63 6 0.56; cold saline, 3.38 6 0.26; and cold saline plus adenosine, 4.25 6 0.16 (analysis of variance for all four groups, p < 0.00001). Post-hoc contrast analysis showed that cold saline plus adenosine was superior to the other three groups (p < 0.0001). Conclusion. Retrograde venous perfusion of the spinal cord with hypothermic saline and adenosine provides functional protection against surgical ischemia and reperfusion.
P
gated experimentally, including perfusion of the subarachnoid space with cold solutions or oxygenated perfluorocarbons [10, 11]. The procedures that most consistently demonstrated protection of the spinal cord have been those that cooled the threatened segment of spinal cord. Cold cord perfusion during aortic cross-clamping has been most frequently obtained in an antegrade fashion. Cold antegrade perfusion can be accomplished by partial bypass cooling circuits or by direct infusion of a cold solution into the isolated segment of aorta [12]. Other techniques that achieve similar levels of protection include the perfusion of the subarachnoid space with cold infusates and whole-body cooling using total cardiopulmonary bypass. Those methods of spinal cord protection use spinal cord cooling as the protective intervention. However, these methods also share other, less desirable characteristics. Use of these interventions requires additional invasive procedures time beyond those required for the operation, and each intervention is associated with significant risks and complications inherent to its clinical use. These risks greatly limit the clinical applicability and diminish the likelihood that they will ever gain widespread clinical use. We developed a spinal cord cooling technique that was effective, easy to use, and had a minimum of associated
araplegia after repair of thoracic or thoracoabdominal aneurysms is a devastating and unpredictable complication. Despite advances in surgical technique, spinal cord injury after aneurysm repair can occur in as many as 21% of patients [1]. In certain high-risk populations the incidence of neurologic impairment can be as high as 40% [2]. Neurologic injury is a result of the ischemia brought on by aortic cross-clamping in the absence of adequate collateral flow, and increases with the duration of occlusion. This injury can be exacerbated by continued ischemia if critical intercostal vessels are excluded from the repair or by reperfusion injury. Efforts to dampen this cascade of events have focused on methods to protect the spinal cord during ischemia or to reestablish the blood supply to the spinal cord [3]. Efforts to protect the spinal cord during ischemia have ranged from purely mechanical, such as cerebrospinal fluid drainage or perfusion of the aorta beyond the cross-clamp, to purely pharmacologic, such as the use of vasodilators, neutrophil-blocking antibodies, or free radical scavengers [4 –9]. Other, more exotic means of protecting the ischemic spinal cord have also been investi-
Presented at the Forty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 12–14, 1998. Address reprint requests to Dr Tribble, Department of Surgery, University of Virginia Health Sciences Center, Box 181-95, Charlottesville, VA 22908; e-mail: [email protected].
© 1999 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
(Ann Thorac Surg 1999;67:1589 –95) © 1999 by The Society of Thoracic Surgeons
0003-4975/99/$20.00 PII S0003-4975(99)00307-0
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risks. We hypothesized that the ischemic spinal cord could be protected by cooling with retrograde venous perfusion, similar to cerebral retrograde perfusion commonly used during circulatory arrest. This technique does not require access to the subarachnoid space or epidural space and does not incur the risks of partial or total bypass.
Material and Methods All protocols in this study were reviewed and approved by the Animal Review Committee of the University of Virginia. All animals received humane care in compliance with the “Principles of Laboratory Animal Care” as described by the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” (NIH publication 85-23, revised 1985). Adult New Zealand white rabbits of either sex were used throughout this study.
Preparation of Experimental Animals New Zealand white rabbits (2.8 to 3.2 kg) were anesthetized by intramuscular injection of xylazine (10 mg) and ketamine (100 mg). Once the animals were sedated adequately, an ear vein catheter was placed for administration of additional medications and intravenous fluids. The animals were then intubated, placed supine on a heated operating table, and ventilated (Harvard Rodent Ventilator Model 683, Harvard Apparatus, South Natick, MA) with a mixture of 98% oxygen and 2% halothane. An ear arterial catheter was placed for continuous monitoring of arterial pressure. Heparin sodium (2,000 units) was administered intravenously and allowed to circulate for 5 minutes. During this interval, the abdomen was prepared and draped in a sterile manner. A midline laparotomy was made and the viscera reflected to the right. After opening the retroperitoneum, the abdominal aorta and inferior vena cava (IVC) were identified and isolated with soft vessel loops just inferior to the left renal artery and vein and just proximal to their bifurcations.
Experimental Protocol We studied four groups of 8 animals each. To induce distal spinal cord ischemia, atraumatic vascular clamps were used to isolate the infrarenal portions of the aorta and IVC proximally and distally. In all groups clamps were applied rapidly to the aorta just distal to the left renal artery and just above the bifurcation, and on the IVC just proximal to the confluence of the iliac veins and just distal to the left renal vein. These clamps were left in place for 45 minutes. In the three experimental groups, a 24-gauge intravenous catheter (Johnson and Johnson Medical Inc, Arlington, TX) was inserted into the midportion of the IVC immediately after application of the clamps. This catheter was used to administer saline or saline plus drug during the 45-minute ischemic period. We studied three experimental groups using the following infusates: warm saline (22°C), cold saline (4°C), and
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cold saline with adenosine (4°C, 0.74 mg/mL). All infusates were delivered at a constant rate of 1 mL/kg per minute using an infusion pump (Syringe infusion pump 22; Harvard Apparatus, South Natick, MA). The infusion was begun immediately after placement of the catheter and continued throughout the 45-minute ischemic period. An inline cooling coil (Model 158822; Radnoti Glass Technology Inc, Monrovia, CA) connected to a cold water bath (Fisher Scientific Isotemp Refrigerated Circulator Model 900; Fisher Scientific, Pittsburgh, PA) was used in the two groups that received cold infusates to achieve and maintain the desired temperature. At the conclusion of the 45-minute ischemic interval, the catheter was withdrawn and the veinotomy quickly closed using a 7-0 stitch, taking care not to compromise the lumen of the IVC. The clamps were then removed rapidly, and the abdomen closed. The animals were allowed to recover from anesthesia before being returned to the holding area, where they could move freely about their cages and were provided with food and water ad libitum. After 24 hours, the animals were evaluated for hindleg function by a blinded observer and graded based on the Tarlov scale (0 5 complete paralysis; 1 5 minimal movement; 2 5 stands with assistance; 3 5 stands alone; 4 5 weak hop; 5 5 normal hop). The animals were then sacrificed using an overdose injection of sodium pentobarbital.
Data Acquisition During Aortic and Caval Cross-clamping Arterial blood pressure data were collected and recorded before application of the clamps, during the ischemic interval, and for 5 minutes after release of the clamps by customized digital data acquisition software (Workbench PC; Strawberry Tree Inc, Sunnyvale, CA). In three of the eight animals in each group, rectal temperature was measured just before release of the clamps to determine the average postprocedure temperature in each group.
Angiographic Verification of Regional Infusion One animal was prepared exactly as described above. This animal was then transported to the angiography suite where contrast medium (Omnipaque, 25 mL) was injected through the venous catheter immediately after all clamps were placed. Angiographic images were obtained of the animal as contrast was injected to demonstrate filling of the epidural veins and small venules around the spinal cord.
Statistical Analysis All results are expressed as the mean 6 standard error of the mean. Data were analyzed for between-group differences using analysis of variance. Tukey’s Honestly Significant Different (HSD) multiple comparisons test was used to determine significant differences. Specific hypotheses were tested using contrast analysis. Significance was defined as a p value less than 0.05. All analyses were done using SPSS Software (SPSS Inc, Chicago, IL).
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Table 1. Statistical Comparison of Tarlov Scores Between All Groups Group
Control
Control Warm saline Cold saline Cold saline 1 adenosine
p , 0.231 p , 0.0001 p , 0.0001
Warm Saline
Cold Saline
Cold Saline 1 Adenosine
p , 0.231
p , 0.0001 p , 0.025
p , 0.0001 p , 0.001 p , 0.441
p , 0.025 p , 0.001
p , 0.441
Values represent p for comparison between the two groups that intersect at that point, calculated using Tukey’s Honestly Significant Different (HSD) multiple comparisons test.
Results The control group, which did not receive an infusion during the ischemic period, had an average Tarlov score of 0.50 6 0.50. Tarlov scores demonstrated graduated improvement in the other groups, with infusion of warm saline alone providing some degree of spinal cord protection, as shown by the score of 1.63 6 0.56. The administration of cold saline further improved these results, as animals in the cold saline group had an average Tarlov score of 3.38 6 0.26. Animals in the cold saline plus adenosine group, however, did significantly better than all others, with an average Tarlov score of 4.25 6 0.16. Analysis of variance of these four groups demonstrated a p value less than 0.00001, and contrast analysis of cold saline plus adenosine versus the other groups clearly indicated that this intervention was superior ( p , 0.0001). Contrast analysis of cold saline plus adenosine versus cold saline alone demonstrated that the former was more protective ( p , 0.016). Further analysis was done using Tukey’s HSD multiple comparisons test to evaluate for between-group differences (Table 1), which confirmed spinal cord protection with cold saline plus adenosine. There was no significant difference between the baseline mean arterial pressure (MAP) among the four groups. There was also no significant difference in MAP 5 minutes after release of the vascular clamps ( p 5 0.41, Table 2). MAP throughout the 45-minute ischemic period and the first 5 minutes of reperfusion is illustrated in Figure 1. Rectal temperature was measured in three animals in
each group. There were no significant differences between any groups (Table 2). Digital subtraction radiographs were obtained of an animal prepared in the exact same fashion as the experimental animals to demonstrate retrograde venous perfusion of the spinal cord. Figures 2 and 3 are digital subtraction angiograms of the abdomen of the rabbit taken while contrast was injected with all clamps in place. The clamps were placed just before injection of the contrast medium to duplicate the conditions of the experiment. Both radiographs demonstrate filing of the lumbar veins and the anterior longitudinal sinus, and the lateral view (Fig 3) clearly demonstrates the opacification of small venules in the region of the spinal cord. The contrast in the anterior longitudinal sinuses extends well into the thoracic spine.
Comment Spinal cord hypoperfusion might be an unavoidable consequence of thoracic aortic operations. Clamping of the thoracic aorta has been shown to reduce spinal blood flow in a variety of animal models, and this effect has been documented in humans as well [13]. The precise mechanisms by which this low flow state induces permanent injury, however, are not known. Numerous efforts have been made to identify factors that can be controlled or modified to reduce the incidence of permanent spinal cord injury. Although some have been more effective than others, no single therapeutic intervention has emerged as clearly beneficial. Interventions found to be helpful in one report are shown to have no effect, or even
Table 2. Average Tarlov Scores, Rectal Temperature, and Mean Arterial Pressure 5 Minutes After Release of Clamps
Group Control Warm Saline Cold Saline Cold Saline 1 Adenosine
Tarlov Score
Mean Arterial Pressure (mm Hg)
Temperature (°C)
0.50 6 0.50 1.63 6 0.56 3.38 6 0.26 4.25 6 0.16
61.31 6 5.99 64.62 6 7.42 54.97 6 5.23 51.40 6 5.76
34.33 6 0.33 34.66 6 0.33 34.33 6 0.33 34.33 6 0.33
For Tarlov score, analysis of variance for all four groups demonstrated p , 1 3 10 25 . Contrast analysis showed that cold saline 1 adenosine was significant versus cold saline alone ( p , 0.016). There were no significant differences for mean arterial pressure or temperature.
Fig 1. Mean arterial pressure during the 45-minute ischemic period and the first 5 minutes of reperfusion.
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by which distal spinal cord perfusion can be maintained and the spinal cord cooled in patients who have thoracoabdominal aortic operations [6]. However, this technique also carries its own associated complications. Cannulation of diseased vessels can lead to distal embolic events, and although the hypothermic complications associated with partial bypass and maintenance of intrinsic cardiac rhythm might not be as significant as those associated with total bypass, they are not negligible. A third technique, infusion of cold perfusate into an isolated aortic segment, has been shown to be beneficial in animal models [12, 17, 18]. This technique has the added benefit of inducing only local hypothermia, thereby avoiding the recognized problems associated with whole body cooling. Unfortunately, this method of spinal cord cooling requires a period of perfusion during which the aorta is clamped but repair of the aneurysm is delayed [17]. Although this approach to spinal cord
Fig 2. Anterior-posterior digital subtraction angiogram showing filling of the inferior vena cava, lumbar veins, and epidural sinuses.
to be harmful, in other series. This ambiguity, combined with the inherent risks associated with the use of some methods, has led to little consensus regarding what procedures, if any, efficaciously prevent spinal cord injury in the setting of thoracic aortic operations. Although it has been nearly 50 years since it was first reported that hypothermia reduces the neurologic complications of aortic operation [14], no consistent and reliable mechanism for induction of spinal cord hypothermia has been identified that is effective, rapid, and safe. Four modalities have been used most frequently both experimentally and clinically. The first, whole body cooling during total cardiopulmonary bypass, has been shown clinically to reduce the incidence of postoperative paraplegia [15]. Problems with dysrhythmias, coagulopathy, and increased metabolic demands after rewarming are all significant detriments to the use of deep hypothermia for thoracic aortic operations. Hypothermia has also been shown to be associated with an increased risk of myocardial ischemia postoperatively [16]. Partial bypass has also been advocated as a mechanism
Fig 3. Lateral digital subtraction angiogram with the vertebral bodies, spinal cord, and opacified venules identified.
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cooling has not been studied clinically, it is unlikely that this delay in operative repair of an aneurysm in older, less hardy patients would be without complication. Last, perfusion of paraspinal spaces has been shown to provide spinal cord protection [10, 11]. This technique requires both inflow and outflow access to the spinal cord and is dependent on significant flows through the intrathecal spaces. Although this method has protected the spinal cord in experimental models, increased intraspinal pressure has been implicated as a mechanism of spinal cord injury in humans [19]. This concern, combined with the additional risk of complications associated with doubly accessing the spinal cord, has limited clinical utilization of this technique. These studies clearly show that hypothermia appears to protect the spinal cord, but no innocuous and rapid means to induce it currently exists. The utility of retrograde cerebral perfusion for neurologic protection during operations requiring circulatory arrest has been clearly demonstrated. We hypothesized that retrograde perfusion of the spinal cord with a cold solution would result in effective cooling of the cord, would avoid the systemic effects of hypothermia, and would be protective against ischemic injury. Our results support our hypothesis. The assessment of neurologic function 24 hours after the ischemic event allowed all residual anesthetic effects to resolve and resulted in an accurate assessment of the degree of impairment present in each group. The animals in the cold saline plus adenosine group had a mean Tarlov score of 4.25 6 0.16. This score indicates a functional status between a weak hop and normal activity. Conversely, animals in the control group had a mean Tarlov score of 0.50 6 0.50, indicating nearly complete paraplegia. This difference both validates this model and demonstrates the effectiveness of this technique. The serial improvement seen when the four groups are compared together permits analysis of the factors in retrograde venous perfusion that combine to provide the protection ultimately seen in the cold saline plus adenosine group. Animals in the warm saline group derived some benefit from the perfusate compared with control animals (Table 2). This improvement might have resulted from a number of factors, including a washout of intravascular elements, such as neutrophils and platelets that might cause injury during stasis and ischemia, and relative cooling, as the warm saline was at room temperature (22°C). Animals in the cold saline group can be presumed to receive these benefits as well, and any benefit obtained from marginal cooling in the warm saline group would be expected to be amplified in the cold saline group. This assumption was supported by the additional improvement in function in this group, with an average Tarlov score of 3.38 6 0.26. Rabbits in the cold saline plus adenosine group were able to hop about their cages, unlike animals in the other groups. With an average score of 4.25 6 0.16, these animals improved significantly more than animals in the other groups ( p , 0.0001). The effect of adding adenosine to cold saline most likely represents the benefits of cooling the spinal cord, resulting in decreased metabolic demand and decreased re-
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lease of excitatory neurotransmitters, combined with the theoretical and known actions of adenosine. The choice of adenosine as the infused drug was based on previous studies from our laboratory and its known pharmacologic properties [12, 20]. Adenosine has been shown to have specific neuroprotective effects [21], to prevent platelet adherence, to prevent of accumulation of white blood cells, and it has been used in solutions for cold organ preservation in transplantation [22]. Probably most significantly, adenosine is a potent vasodilator [23]. This property likely contributed the most to our results, as the vasodilation induced by the adenosine allowed the cold saline to more adequately perfuse the ischemic spinal cord. The dose of adenosine was extrapolated from an earlier study at our institution in which a dose of 100 mg of adenosine was administered into an isolated aortic segment in a rabbit model of spinal cord ischemia [20]. The rabbits used in that study weighed approximately 3 kg, and they received the dose as a bolus. On the basis of encouraging results from that previous work, the same dose of adenosine was used in the present retrograde perfusion model. An infusion rate of 1 mL/kg per minute was chosen empirically. For a 3-kg rabbit, this results in a total volume infused of 135 mL during the 45-minute ischemic period, with a concentration of 0.74 mg/mL of adenosine. Adenosine has significant potentially detrimental side effects, including profound hypotension and complete heart block. However, neither of those effects was seen, possibly because of the slow washout of adenosine from the ill-perfused spinal cord and distal circulation combined with the short half-life of adenosine in the circulation (5 seconds). Figure 1 shows the mean systolic blood pressures of the animals in the four groups. Although the animals in the cold saline plus adenosine group had lower mean systolic blood pressures than the other animals, both at the beginning and 5 minutes after the end of the experiment, there were no significant differences between the mean systolic blood pressures of the groups. No episodes of acute hypotension or arrhythmia occurred. To demonstrate that these results were not due to inadvertent whole animal cooling, rectal temperatures were measured at the end of the ischemic interval in three of eight animals in each group. There were no significant differences in temperature between the control and experimental groups ( p 5 0.86, Table 2). The radiographs confirm the validity of our assumption that solutions infused into the IVC will pass through the lumbar veins and into the vertebral veins, and then into the paravertebral venous plexi, reaching the spinal cord. Figures 2 and 3 clearly show perfusion of the epidural veins (anterior longitudinal sinuses) which lie within the spinal canal. These data show the effectiveness of retrograde venous perfusion of the spinal cord in preventing injury during surgically induced ischemia. However, in this experiment the site used to deliver the perfusate, the inferior vena cava, is unlikely to be used clinically because of the difficulty of obtaining access to the IVC from a standard
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thoracoabdominal incision. Although these data clearly demonstrate the effectiveness of this technique, an alternative route of administration is required. Other avenues for accomplishing the same end might be the superior intercostal vein or the accessory hemiazygous vein. Preliminary work in a porcine model using these vessels has been encouraging.
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11. 12.
We appreciate the invaluable technical assistance of Mr Anthony J. Herring.
13.
References
14.
1. Cox GS, O’Hara PJ, Hertzer NR, Piedmonte MR, Krajewski LP, Beven, EG. Thoracoabdominal aneurysm repair: a representative experience. J Vasc Surg 1992;15:780– 8. 2. Crawford ES, Crawford JL, Safi HJ, et al. Thoracoabdominal aortic aneurysms: preoperative and intraoperative factors determining immediate and long-term results of operations in 605 patients. J Vasc Surg 1986;3:389 – 404. 3. Ross SD, Kron IL, Parrino PE, Shockey KS, Kern JA, Tribble CG. Reimplantation of intercostal arteries during thoracic aneurysm surgery reduces the incidence of paraplegia. J Thorac Cardiovasc Surg 1999;(in press). 4. Kazama S, Masaki Y, Mayuyama S, Ishihara A. Effect of altering cerebrospinal fluid pressure on spinal cord blood flow. Ann Thorac Surg 1994;58:112–5. 5. Crawford ES, Svensson LG, Hess KR, et al. A prospective randomized study of cerebrospinal fluid drainage to prevent paraplegia after high-risk surgery on the thoracoabdominal aorta. J Vasc Surg 1991;13:36– 45. 6. Frank SM, Parker SD, Rock P, et al. Moderate hypothermia, with partial bypass and segmental sequential repair for thoracoabdominal aneurysm. J Vasc Surg 1994;19:687–97. 7. Barone GW, Joob AW, Flanagan TL, Dunn CE, Kron IL. The effect of hyperemia on spinal cord function after temporary thoracic aortic occlusion. J Vasc Surg 1988;8:535– 40. 8. Forbes AD, Slimp JC, Winn RK, Verrier ED. Inhibition of neutrophil adhesion does not prevent ischemic spinal cord injury. Ann Thorac Surg 1994;58:1064– 8. 9. Agee JM, Flannigan T, Blackbourne LH, Kron IL, Tribble CG. Reducing postischemic paraplegia using conjugated superoxide dismutase. Ann Thorac Surg 1991;51:911–5. 10. Berguer R, Porto J, Fedoronko B, Dragovic L. Selective deep
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hypothermia of the spinal cord prevents paraplegia after aortic cross-clamping in the dog model. J Vasc Surg 1992;15: 62–72. Maughan RE, Mohan C, Nathan IM, et al. Intrathecal perfusion of an oxygenated perfluorocarbon prevents paraplegia after aortic occlusion. Ann Thorac Surg 1992;54:818–25. Herold JA, Kron IL, Langenburg SE, Blackbourne LH, Tribble CG. Complete prevention of postischemic spinal cord injury by means of regional infusion with hypothermic saline and adenosine. J Thorac Cardiovasc Surg 1994;107: 536– 42. Grum DF, Svensson LG. Changes in cerebrospinal fluid pressure and spinal cord perfusion pressure prior to crossclamping of the thoracic aorta in humans. J Cardiothorac Vasc Anesth 1991;5:331– 6. DeBakey M, Cooley DA, Creech O. Resection of the aorta for aneurysms and occlusive disease with particular reference to the use of hypothermia: analysis of 240 cases. Trans Am Coll Cardiol 1955;5:153–7. Rokkas CK, Kouchoukos NT. Profound hypothermia for spinal cord protection in operations on the descending thoracic and thoracoabdominal aorta. Semin Thorac Cardiovasc Surg 1998;10:57– 60. Frank SM, Beattie C, Christopherson R, et al. Unintentional hypothermia is associated with postoperative myocardial ischemia. The Perioperative Ischemia Randomized Anesthesia Trial Study Group. Anesthesiology 1993;78:468–76. Colon R, Frazier OH, Cooley DA, McAllister HA. Hypothermic regional perfusion for protection of the spinal cord during periods of ischemia. Ann Thorac Surg 1987;43:639– 43. Ueno T, Furukawa K, Katayama Y, Itoh T. Protection against ischemic spinal cord injury: one shot perfusion cooling and percutaneous topical cooling. J Vasc Surg 1994;19:882–7. Berendes JN, Bredee JJ, Schipperheyn JJ, Mashour YA. Mechanisms of spinal cord injury after cross-clamping of the descending thoracic aorta. Circulation 1982;66(part 1):112– 6. Seibel PS, Theodore P, Kron IL, Tribble CG. Regional adenosine attenuates postischemic spinal cord injury. J Vasc Surg 1993;18:153– 60. Marangos PJ, von Lubitz DAG, Daval JL, Deckert J. Adenosine: its relevance to the treatment of brain ischemia and trauma. Prog Clin Biol Res 1990;361:331– 49. Southard JH, van Gulik TM, Ametani MS, et al. Important components of the UW solution. Transplantation 1990;49: 251–7. Collis MG. The vasodilator role of adenosine. Pharmacol Ther 1989;41:143– 62.
DISCUSSION DR WILLIAM A. BAUMGARTNER (Baltimore, MD): I would like to congratulate Dr Parrino and his colleagues on this novel work. As you know, we have also been interested in a similar porcine model of retrograde vena caval administration of cold blood in conjunction with left atrial femoral bypass. This work is primarily that of Dr John Doty, a resident in our lab, and Dr Vince Gott. We have also demonstrated that the perfusate does reach the venules of the spinal cord. Injected gelatin dye can be seen in the venules of both the gray and the white matter at the level of the L3 vertebra. We support your conclusions in that we think that this circuit represents an excellent delivery method and needs to be further evaluated. The inferior vena caval retroperfusion circuit is easy to set up, especially in combination with left atrial femoral artery bypass. I have just a couple of questions. Do you have the histology of the spinal cord to better define the protective effect of your © 1999 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
method, and what would be your method to reproduce this technique clinically? DR PARRINO: Thank you Dr Baumgartner. We have had some trouble with our pathologists in getting data. In order for our study to be approved by the Animal Research Committee, we were limited to a 24-hour postoperative survival time. This resulted in the presence of only subtle changes in the spinal cord tissue, which have been difficult to quantify using standard staining techniques. We are now looking at getting some special immunohistochemical stains to look for early markers of apoptosis to determine whether this method will allow better characterization of the changes. In order to develop methods to use this technique clinically, we have also done some work in a porcine model as well. This small animal experiment was an initial step to verify that this technique would work. Our approach in the porcine model has 0003-4975/99/$20.00 PII S0003-4975(99)00308-2
Background. Paraplegia remains a devastating complication following thoracic aortic operation. We hypothesized that retrograde perfusion of the spinal cord with a hypothermic, adenosine-enhanced solution would provide protection during periods of ischemia due to temporary aortic occlusion. Methods. In a rabbit model, a 45-minute period of spinal cord ischemia was produced by clamping the abdominal aorta and vena cava just below the left renal vessels and at their bifurcations. Four groups (n 5 8/group) were studied: control, warm saline, cold saline, and cold saline with adenosine infusion. In the experimental groups, saline or saline plus adenosine was infused into the isolated cavae throughout the ischemic period. Clamps were removed and the animals to recovered for 24 hours before blinded neurological evaluation.
Results. Tarlov scores (0 5 paraplegia, 1 5 slight movement, 2 5 sits with assistance, 3 5 sits alone, 4 5 weak hop, 5 5 normal hop) were (mean 6 standard error of the mean): control, 0.50 6 0.50; warm saline, 1.63 6 0.56; cold saline, 3.38 6 0.26; and cold saline plus adenosine, 4.25 6 0.16 (analysis of variance for all four groups, p < 0.00001). Post-hoc contrast analysis showed that cold saline plus adenosine was superior to the other three groups (p < 0.0001). Conclusion. Retrograde venous perfusion of the spinal cord with hypothermic saline and adenosine provides functional protection against surgical ischemia and reperfusion.
P
gated experimentally, including perfusion of the subarachnoid space with cold solutions or oxygenated perfluorocarbons [10, 11]. The procedures that most consistently demonstrated protection of the spinal cord have been those that cooled the threatened segment of spinal cord. Cold cord perfusion during aortic cross-clamping has been most frequently obtained in an antegrade fashion. Cold antegrade perfusion can be accomplished by partial bypass cooling circuits or by direct infusion of a cold solution into the isolated segment of aorta [12]. Other techniques that achieve similar levels of protection include the perfusion of the subarachnoid space with cold infusates and whole-body cooling using total cardiopulmonary bypass. Those methods of spinal cord protection use spinal cord cooling as the protective intervention. However, these methods also share other, less desirable characteristics. Use of these interventions requires additional invasive procedures time beyond those required for the operation, and each intervention is associated with significant risks and complications inherent to its clinical use. These risks greatly limit the clinical applicability and diminish the likelihood that they will ever gain widespread clinical use. We developed a spinal cord cooling technique that was effective, easy to use, and had a minimum of associated
araplegia after repair of thoracic or thoracoabdominal aneurysms is a devastating and unpredictable complication. Despite advances in surgical technique, spinal cord injury after aneurysm repair can occur in as many as 21% of patients [1]. In certain high-risk populations the incidence of neurologic impairment can be as high as 40% [2]. Neurologic injury is a result of the ischemia brought on by aortic cross-clamping in the absence of adequate collateral flow, and increases with the duration of occlusion. This injury can be exacerbated by continued ischemia if critical intercostal vessels are excluded from the repair or by reperfusion injury. Efforts to dampen this cascade of events have focused on methods to protect the spinal cord during ischemia or to reestablish the blood supply to the spinal cord [3]. Efforts to protect the spinal cord during ischemia have ranged from purely mechanical, such as cerebrospinal fluid drainage or perfusion of the aorta beyond the cross-clamp, to purely pharmacologic, such as the use of vasodilators, neutrophil-blocking antibodies, or free radical scavengers [4 –9]. Other, more exotic means of protecting the ischemic spinal cord have also been investi-
Presented at the Forty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 12–14, 1998. Address reprint requests to Dr Tribble, Department of Surgery, University of Virginia Health Sciences Center, Box 181-95, Charlottesville, VA 22908; e-mail: [email protected].
© 1999 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
(Ann Thorac Surg 1999;67:1589 –95) © 1999 by The Society of Thoracic Surgeons
0003-4975/99/$20.00 PII S0003-4975(99)00307-0
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risks. We hypothesized that the ischemic spinal cord could be protected by cooling with retrograde venous perfusion, similar to cerebral retrograde perfusion commonly used during circulatory arrest. This technique does not require access to the subarachnoid space or epidural space and does not incur the risks of partial or total bypass.
Material and Methods All protocols in this study were reviewed and approved by the Animal Review Committee of the University of Virginia. All animals received humane care in compliance with the “Principles of Laboratory Animal Care” as described by the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” (NIH publication 85-23, revised 1985). Adult New Zealand white rabbits of either sex were used throughout this study.
Preparation of Experimental Animals New Zealand white rabbits (2.8 to 3.2 kg) were anesthetized by intramuscular injection of xylazine (10 mg) and ketamine (100 mg). Once the animals were sedated adequately, an ear vein catheter was placed for administration of additional medications and intravenous fluids. The animals were then intubated, placed supine on a heated operating table, and ventilated (Harvard Rodent Ventilator Model 683, Harvard Apparatus, South Natick, MA) with a mixture of 98% oxygen and 2% halothane. An ear arterial catheter was placed for continuous monitoring of arterial pressure. Heparin sodium (2,000 units) was administered intravenously and allowed to circulate for 5 minutes. During this interval, the abdomen was prepared and draped in a sterile manner. A midline laparotomy was made and the viscera reflected to the right. After opening the retroperitoneum, the abdominal aorta and inferior vena cava (IVC) were identified and isolated with soft vessel loops just inferior to the left renal artery and vein and just proximal to their bifurcations.
Experimental Protocol We studied four groups of 8 animals each. To induce distal spinal cord ischemia, atraumatic vascular clamps were used to isolate the infrarenal portions of the aorta and IVC proximally and distally. In all groups clamps were applied rapidly to the aorta just distal to the left renal artery and just above the bifurcation, and on the IVC just proximal to the confluence of the iliac veins and just distal to the left renal vein. These clamps were left in place for 45 minutes. In the three experimental groups, a 24-gauge intravenous catheter (Johnson and Johnson Medical Inc, Arlington, TX) was inserted into the midportion of the IVC immediately after application of the clamps. This catheter was used to administer saline or saline plus drug during the 45-minute ischemic period. We studied three experimental groups using the following infusates: warm saline (22°C), cold saline (4°C), and
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cold saline with adenosine (4°C, 0.74 mg/mL). All infusates were delivered at a constant rate of 1 mL/kg per minute using an infusion pump (Syringe infusion pump 22; Harvard Apparatus, South Natick, MA). The infusion was begun immediately after placement of the catheter and continued throughout the 45-minute ischemic period. An inline cooling coil (Model 158822; Radnoti Glass Technology Inc, Monrovia, CA) connected to a cold water bath (Fisher Scientific Isotemp Refrigerated Circulator Model 900; Fisher Scientific, Pittsburgh, PA) was used in the two groups that received cold infusates to achieve and maintain the desired temperature. At the conclusion of the 45-minute ischemic interval, the catheter was withdrawn and the veinotomy quickly closed using a 7-0 stitch, taking care not to compromise the lumen of the IVC. The clamps were then removed rapidly, and the abdomen closed. The animals were allowed to recover from anesthesia before being returned to the holding area, where they could move freely about their cages and were provided with food and water ad libitum. After 24 hours, the animals were evaluated for hindleg function by a blinded observer and graded based on the Tarlov scale (0 5 complete paralysis; 1 5 minimal movement; 2 5 stands with assistance; 3 5 stands alone; 4 5 weak hop; 5 5 normal hop). The animals were then sacrificed using an overdose injection of sodium pentobarbital.
Data Acquisition During Aortic and Caval Cross-clamping Arterial blood pressure data were collected and recorded before application of the clamps, during the ischemic interval, and for 5 minutes after release of the clamps by customized digital data acquisition software (Workbench PC; Strawberry Tree Inc, Sunnyvale, CA). In three of the eight animals in each group, rectal temperature was measured just before release of the clamps to determine the average postprocedure temperature in each group.
Angiographic Verification of Regional Infusion One animal was prepared exactly as described above. This animal was then transported to the angiography suite where contrast medium (Omnipaque, 25 mL) was injected through the venous catheter immediately after all clamps were placed. Angiographic images were obtained of the animal as contrast was injected to demonstrate filling of the epidural veins and small venules around the spinal cord.
Statistical Analysis All results are expressed as the mean 6 standard error of the mean. Data were analyzed for between-group differences using analysis of variance. Tukey’s Honestly Significant Different (HSD) multiple comparisons test was used to determine significant differences. Specific hypotheses were tested using contrast analysis. Significance was defined as a p value less than 0.05. All analyses were done using SPSS Software (SPSS Inc, Chicago, IL).
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Table 1. Statistical Comparison of Tarlov Scores Between All Groups Group
Control
Control Warm saline Cold saline Cold saline 1 adenosine
p , 0.231 p , 0.0001 p , 0.0001
Warm Saline
Cold Saline
Cold Saline 1 Adenosine
p , 0.231
p , 0.0001 p , 0.025
p , 0.0001 p , 0.001 p , 0.441
p , 0.025 p , 0.001
p , 0.441
Values represent p for comparison between the two groups that intersect at that point, calculated using Tukey’s Honestly Significant Different (HSD) multiple comparisons test.
Results The control group, which did not receive an infusion during the ischemic period, had an average Tarlov score of 0.50 6 0.50. Tarlov scores demonstrated graduated improvement in the other groups, with infusion of warm saline alone providing some degree of spinal cord protection, as shown by the score of 1.63 6 0.56. The administration of cold saline further improved these results, as animals in the cold saline group had an average Tarlov score of 3.38 6 0.26. Animals in the cold saline plus adenosine group, however, did significantly better than all others, with an average Tarlov score of 4.25 6 0.16. Analysis of variance of these four groups demonstrated a p value less than 0.00001, and contrast analysis of cold saline plus adenosine versus the other groups clearly indicated that this intervention was superior ( p , 0.0001). Contrast analysis of cold saline plus adenosine versus cold saline alone demonstrated that the former was more protective ( p , 0.016). Further analysis was done using Tukey’s HSD multiple comparisons test to evaluate for between-group differences (Table 1), which confirmed spinal cord protection with cold saline plus adenosine. There was no significant difference between the baseline mean arterial pressure (MAP) among the four groups. There was also no significant difference in MAP 5 minutes after release of the vascular clamps ( p 5 0.41, Table 2). MAP throughout the 45-minute ischemic period and the first 5 minutes of reperfusion is illustrated in Figure 1. Rectal temperature was measured in three animals in
each group. There were no significant differences between any groups (Table 2). Digital subtraction radiographs were obtained of an animal prepared in the exact same fashion as the experimental animals to demonstrate retrograde venous perfusion of the spinal cord. Figures 2 and 3 are digital subtraction angiograms of the abdomen of the rabbit taken while contrast was injected with all clamps in place. The clamps were placed just before injection of the contrast medium to duplicate the conditions of the experiment. Both radiographs demonstrate filing of the lumbar veins and the anterior longitudinal sinus, and the lateral view (Fig 3) clearly demonstrates the opacification of small venules in the region of the spinal cord. The contrast in the anterior longitudinal sinuses extends well into the thoracic spine.
Comment Spinal cord hypoperfusion might be an unavoidable consequence of thoracic aortic operations. Clamping of the thoracic aorta has been shown to reduce spinal blood flow in a variety of animal models, and this effect has been documented in humans as well [13]. The precise mechanisms by which this low flow state induces permanent injury, however, are not known. Numerous efforts have been made to identify factors that can be controlled or modified to reduce the incidence of permanent spinal cord injury. Although some have been more effective than others, no single therapeutic intervention has emerged as clearly beneficial. Interventions found to be helpful in one report are shown to have no effect, or even
Table 2. Average Tarlov Scores, Rectal Temperature, and Mean Arterial Pressure 5 Minutes After Release of Clamps
Group Control Warm Saline Cold Saline Cold Saline 1 Adenosine
Tarlov Score
Mean Arterial Pressure (mm Hg)
Temperature (°C)
0.50 6 0.50 1.63 6 0.56 3.38 6 0.26 4.25 6 0.16
61.31 6 5.99 64.62 6 7.42 54.97 6 5.23 51.40 6 5.76
34.33 6 0.33 34.66 6 0.33 34.33 6 0.33 34.33 6 0.33
For Tarlov score, analysis of variance for all four groups demonstrated p , 1 3 10 25 . Contrast analysis showed that cold saline 1 adenosine was significant versus cold saline alone ( p , 0.016). There were no significant differences for mean arterial pressure or temperature.
Fig 1. Mean arterial pressure during the 45-minute ischemic period and the first 5 minutes of reperfusion.
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by which distal spinal cord perfusion can be maintained and the spinal cord cooled in patients who have thoracoabdominal aortic operations [6]. However, this technique also carries its own associated complications. Cannulation of diseased vessels can lead to distal embolic events, and although the hypothermic complications associated with partial bypass and maintenance of intrinsic cardiac rhythm might not be as significant as those associated with total bypass, they are not negligible. A third technique, infusion of cold perfusate into an isolated aortic segment, has been shown to be beneficial in animal models [12, 17, 18]. This technique has the added benefit of inducing only local hypothermia, thereby avoiding the recognized problems associated with whole body cooling. Unfortunately, this method of spinal cord cooling requires a period of perfusion during which the aorta is clamped but repair of the aneurysm is delayed [17]. Although this approach to spinal cord
Fig 2. Anterior-posterior digital subtraction angiogram showing filling of the inferior vena cava, lumbar veins, and epidural sinuses.
to be harmful, in other series. This ambiguity, combined with the inherent risks associated with the use of some methods, has led to little consensus regarding what procedures, if any, efficaciously prevent spinal cord injury in the setting of thoracic aortic operations. Although it has been nearly 50 years since it was first reported that hypothermia reduces the neurologic complications of aortic operation [14], no consistent and reliable mechanism for induction of spinal cord hypothermia has been identified that is effective, rapid, and safe. Four modalities have been used most frequently both experimentally and clinically. The first, whole body cooling during total cardiopulmonary bypass, has been shown clinically to reduce the incidence of postoperative paraplegia [15]. Problems with dysrhythmias, coagulopathy, and increased metabolic demands after rewarming are all significant detriments to the use of deep hypothermia for thoracic aortic operations. Hypothermia has also been shown to be associated with an increased risk of myocardial ischemia postoperatively [16]. Partial bypass has also been advocated as a mechanism
Fig 3. Lateral digital subtraction angiogram with the vertebral bodies, spinal cord, and opacified venules identified.
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cooling has not been studied clinically, it is unlikely that this delay in operative repair of an aneurysm in older, less hardy patients would be without complication. Last, perfusion of paraspinal spaces has been shown to provide spinal cord protection [10, 11]. This technique requires both inflow and outflow access to the spinal cord and is dependent on significant flows through the intrathecal spaces. Although this method has protected the spinal cord in experimental models, increased intraspinal pressure has been implicated as a mechanism of spinal cord injury in humans [19]. This concern, combined with the additional risk of complications associated with doubly accessing the spinal cord, has limited clinical utilization of this technique. These studies clearly show that hypothermia appears to protect the spinal cord, but no innocuous and rapid means to induce it currently exists. The utility of retrograde cerebral perfusion for neurologic protection during operations requiring circulatory arrest has been clearly demonstrated. We hypothesized that retrograde perfusion of the spinal cord with a cold solution would result in effective cooling of the cord, would avoid the systemic effects of hypothermia, and would be protective against ischemic injury. Our results support our hypothesis. The assessment of neurologic function 24 hours after the ischemic event allowed all residual anesthetic effects to resolve and resulted in an accurate assessment of the degree of impairment present in each group. The animals in the cold saline plus adenosine group had a mean Tarlov score of 4.25 6 0.16. This score indicates a functional status between a weak hop and normal activity. Conversely, animals in the control group had a mean Tarlov score of 0.50 6 0.50, indicating nearly complete paraplegia. This difference both validates this model and demonstrates the effectiveness of this technique. The serial improvement seen when the four groups are compared together permits analysis of the factors in retrograde venous perfusion that combine to provide the protection ultimately seen in the cold saline plus adenosine group. Animals in the warm saline group derived some benefit from the perfusate compared with control animals (Table 2). This improvement might have resulted from a number of factors, including a washout of intravascular elements, such as neutrophils and platelets that might cause injury during stasis and ischemia, and relative cooling, as the warm saline was at room temperature (22°C). Animals in the cold saline group can be presumed to receive these benefits as well, and any benefit obtained from marginal cooling in the warm saline group would be expected to be amplified in the cold saline group. This assumption was supported by the additional improvement in function in this group, with an average Tarlov score of 3.38 6 0.26. Rabbits in the cold saline plus adenosine group were able to hop about their cages, unlike animals in the other groups. With an average score of 4.25 6 0.16, these animals improved significantly more than animals in the other groups ( p , 0.0001). The effect of adding adenosine to cold saline most likely represents the benefits of cooling the spinal cord, resulting in decreased metabolic demand and decreased re-
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lease of excitatory neurotransmitters, combined with the theoretical and known actions of adenosine. The choice of adenosine as the infused drug was based on previous studies from our laboratory and its known pharmacologic properties [12, 20]. Adenosine has been shown to have specific neuroprotective effects [21], to prevent platelet adherence, to prevent of accumulation of white blood cells, and it has been used in solutions for cold organ preservation in transplantation [22]. Probably most significantly, adenosine is a potent vasodilator [23]. This property likely contributed the most to our results, as the vasodilation induced by the adenosine allowed the cold saline to more adequately perfuse the ischemic spinal cord. The dose of adenosine was extrapolated from an earlier study at our institution in which a dose of 100 mg of adenosine was administered into an isolated aortic segment in a rabbit model of spinal cord ischemia [20]. The rabbits used in that study weighed approximately 3 kg, and they received the dose as a bolus. On the basis of encouraging results from that previous work, the same dose of adenosine was used in the present retrograde perfusion model. An infusion rate of 1 mL/kg per minute was chosen empirically. For a 3-kg rabbit, this results in a total volume infused of 135 mL during the 45-minute ischemic period, with a concentration of 0.74 mg/mL of adenosine. Adenosine has significant potentially detrimental side effects, including profound hypotension and complete heart block. However, neither of those effects was seen, possibly because of the slow washout of adenosine from the ill-perfused spinal cord and distal circulation combined with the short half-life of adenosine in the circulation (5 seconds). Figure 1 shows the mean systolic blood pressures of the animals in the four groups. Although the animals in the cold saline plus adenosine group had lower mean systolic blood pressures than the other animals, both at the beginning and 5 minutes after the end of the experiment, there were no significant differences between the mean systolic blood pressures of the groups. No episodes of acute hypotension or arrhythmia occurred. To demonstrate that these results were not due to inadvertent whole animal cooling, rectal temperatures were measured at the end of the ischemic interval in three of eight animals in each group. There were no significant differences in temperature between the control and experimental groups ( p 5 0.86, Table 2). The radiographs confirm the validity of our assumption that solutions infused into the IVC will pass through the lumbar veins and into the vertebral veins, and then into the paravertebral venous plexi, reaching the spinal cord. Figures 2 and 3 clearly show perfusion of the epidural veins (anterior longitudinal sinuses) which lie within the spinal canal. These data show the effectiveness of retrograde venous perfusion of the spinal cord in preventing injury during surgically induced ischemia. However, in this experiment the site used to deliver the perfusate, the inferior vena cava, is unlikely to be used clinically because of the difficulty of obtaining access to the IVC from a standard
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thoracoabdominal incision. Although these data clearly demonstrate the effectiveness of this technique, an alternative route of administration is required. Other avenues for accomplishing the same end might be the superior intercostal vein or the accessory hemiazygous vein. Preliminary work in a porcine model using these vessels has been encouraging.
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11. 12.
We appreciate the invaluable technical assistance of Mr Anthony J. Herring.
13.
References
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1. Cox GS, O’Hara PJ, Hertzer NR, Piedmonte MR, Krajewski LP, Beven, EG. Thoracoabdominal aneurysm repair: a representative experience. J Vasc Surg 1992;15:780– 8. 2. Crawford ES, Crawford JL, Safi HJ, et al. Thoracoabdominal aortic aneurysms: preoperative and intraoperative factors determining immediate and long-term results of operations in 605 patients. J Vasc Surg 1986;3:389 – 404. 3. Ross SD, Kron IL, Parrino PE, Shockey KS, Kern JA, Tribble CG. Reimplantation of intercostal arteries during thoracic aneurysm surgery reduces the incidence of paraplegia. J Thorac Cardiovasc Surg 1999;(in press). 4. Kazama S, Masaki Y, Mayuyama S, Ishihara A. Effect of altering cerebrospinal fluid pressure on spinal cord blood flow. Ann Thorac Surg 1994;58:112–5. 5. Crawford ES, Svensson LG, Hess KR, et al. A prospective randomized study of cerebrospinal fluid drainage to prevent paraplegia after high-risk surgery on the thoracoabdominal aorta. J Vasc Surg 1991;13:36– 45. 6. Frank SM, Parker SD, Rock P, et al. Moderate hypothermia, with partial bypass and segmental sequential repair for thoracoabdominal aneurysm. J Vasc Surg 1994;19:687–97. 7. Barone GW, Joob AW, Flanagan TL, Dunn CE, Kron IL. The effect of hyperemia on spinal cord function after temporary thoracic aortic occlusion. J Vasc Surg 1988;8:535– 40. 8. Forbes AD, Slimp JC, Winn RK, Verrier ED. Inhibition of neutrophil adhesion does not prevent ischemic spinal cord injury. Ann Thorac Surg 1994;58:1064– 8. 9. Agee JM, Flannigan T, Blackbourne LH, Kron IL, Tribble CG. Reducing postischemic paraplegia using conjugated superoxide dismutase. Ann Thorac Surg 1991;51:911–5. 10. Berguer R, Porto J, Fedoronko B, Dragovic L. Selective deep
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DISCUSSION DR WILLIAM A. BAUMGARTNER (Baltimore, MD): I would like to congratulate Dr Parrino and his colleagues on this novel work. As you know, we have also been interested in a similar porcine model of retrograde vena caval administration of cold blood in conjunction with left atrial femoral bypass. This work is primarily that of Dr John Doty, a resident in our lab, and Dr Vince Gott. We have also demonstrated that the perfusate does reach the venules of the spinal cord. Injected gelatin dye can be seen in the venules of both the gray and the white matter at the level of the L3 vertebra. We support your conclusions in that we think that this circuit represents an excellent delivery method and needs to be further evaluated. The inferior vena caval retroperfusion circuit is easy to set up, especially in combination with left atrial femoral artery bypass. I have just a couple of questions. Do you have the histology of the spinal cord to better define the protective effect of your © 1999 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
method, and what would be your method to reproduce this technique clinically? DR PARRINO: Thank you Dr Baumgartner. We have had some trouble with our pathologists in getting data. In order for our study to be approved by the Animal Research Committee, we were limited to a 24-hour postoperative survival time. This resulted in the presence of only subtle changes in the spinal cord tissue, which have been difficult to quantify using standard staining techniques. We are now looking at getting some special immunohistochemical stains to look for early markers of apoptosis to determine whether this method will allow better characterization of the changes. In order to develop methods to use this technique clinically, we have also done some work in a porcine model as well. This small animal experiment was an initial step to verify that this technique would work. Our approach in the porcine model has 0003-4975/99/$20.00 PII S0003-4975(99)00308-2