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Ann Thorac Surg 2005;80:1829-1833
© 2005 The Society of Thoracic Surgeons

Original article: Cardiovascular

An Epidural Cooling Catheter Protects the Spinal Cord Against Ischemic Injury in Pigs

Atsuo Mori, MD a , * , Toshihiko Ueda, MD b , Takashi Hachiya, MD a , Nobuyuki Kabei, PhD a , Hideyuki Okano, MD c , Ryohei Yozu, MD b , Tatsuumi Sasaki, MD a

a Department of Cardiovascular Surgery, Saitama Cardiovascular and Respiratory Center, Saitama, Japan
b Department of Cardiovascular Surgery, Keio University School of Medicine, Tokyo, Japan
c Department of Physiology, Keio University School of Medicine, Tokyo, Japan

Accepted for publication April 22, 2005.

* Address correspondence to Dr Mori, Department of Cardiovascular Surgery, Saitama Cardiovascular and Respiratory Center, 1696 Itai, Konancho, Osatogun, Saitama, 360–0105, Japan (Email: mori_atsuo{at}hotmail.com).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Using swine, we investigated whether epidural placement of a cooling catheter rather than infusing iced saline solution could protect the spinal cord from ischemia during aortic surgery.

METHODS: We divided 14 domestic pigs into two groups of 7 each. Each underwent epidural catheter placement preceding 30 minutes of aortic cross-clamping distal to the origin of the left subclavian artery. In group 1, cold water was circulated continuously through the lumen of the catheter connected to an external unit. In group 2, animals received catheter placement without cooling. Spinal cord somatosensory evoked potentials were recorded. Neurologic status involving hind limbs was graded sequentially after surgery.

RESULTS: At aortic cross-clamping, spinal temperature in group 1 (31.7° ± 0.6°C) was significantly lower than in group 2 (37.8° ± 0.4°C; p < 0.0001). No significant elevation of intrathecal pressure accompanied cooling with the catheter (group 1, 8.1 ± 1.7 mm Hg; group 2, 8.0 ± 1.5 mm Hg). Mean duration of total loss of potentials was significantly shorter in group 1 (7.4 ± 3.8 minutes) than group 2 (19.7 ± 7.3 minutes; p = 0.0002). Pigs in group 1 exhibited better hind limb function recovery (mean Tarlov score, 4.7 ± 0.5) than group 2 (0.6 ± 0.8; p = 0.0017). Group 1 showed normal histologic characteristics, whereas group 2 showed loss of motor neurons in the ventral horns.

CONCLUSIONS: Epidural cooling catheter without iced saline infusion can cool the spinal cord without elevating intrathecal pressure, protecting the cord against ischemia.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Although cardiovascular surgeons have achieved substantial reductions in the incidence of paraplegia associated with surgery for thoracic aortic and thoracoabdominal aortic aneurysms [1–3], this dreaded complication is yet to be eliminated completely. Since the 1950s, hypothermia has been demonstrated to be beneficial against ischemic spinal cord injury [4]. General body hypothermia, however, involves risks including coagulopathy, arrhythmia, and respiratory dysfunction.

Local spinal cord cooling is intended to avoid the detrimental effects of systemic hypothermia while preserving protective efficacy. Although favorable clinical experience with epidural cooling (EC) by epidurally infusing iced saline solution in thoracoabdominal aortic aneurysm surgery was reported, elevated intrathecal pressure (IP) resulting from the infused saline presented a major concern [5]. To eliminate this elevation, we investigated an alternative method of EC in swine, placing a cooling catheter containing circulating cold water in the epidural space. Both cooling capacity and protection against ischemic injury were assessed.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Continuous Cord Cooling System
The cooling system was composed of three units; a water-filled cooling catheter (Unitika, Tokyo, Japan) with a loop U lumen configuration in the epidural space, connected with an external cooling unit, and an external circulating pump (A.S.T., Co, Ltd, Higashimatsuyama, Japan; Fig 1). The polyurethane cooling catheter had an outer diameter of 19G (1.055 mm). The distilled water used as a coolant was cooled to 4°C before inflow within the catheter, and the pump circulated the water at a constant flow rate of 40 mL/min.



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  		Fig 1. Schematic illustration of the continuous cord cooling system and the experimental setting. The epidural cooling catheter, cooling unit, and circulating pump compose the circuit. Distilled water is not infused into the epidural space, but is circulated by the pump as a coolant wholly within the U-shaped lumen of the epidural catheter and the extracorporeal parts of the circuit.

 
Animal Model, Surgical Procedure, and Cooling Protocol
Fourteen domestic pigs (30 to 35 kg) were divided into two groups of 7 each. Swine were preanesthetized with intramuscular ketamine (15 mg/kg), intubated, and anesthetized with 2.0% isoflurane added to a mixture of 50% O2 and 50% N2O. Electrocardiogram, arterial pressure, and rectal temperature were monitored continuously. Normothermic core body temperature (38°C) was maintained by a warming blanket.

Two dorsal midline skin incisions, each 7 cm in length, were made at the levels of T4 and L3. The spinous process and intervertebral ligament were excised to expose the ligamentum flavum, which was incised at L3 to create a small defect for entry into the epidural space. The EC catheter lumen made a U turn at its midpoint at the catheter tip. A tie of 5-0 propylene positioned 2 cm from the tip of the catheter was useful in maintaining the U shape. Use of a straight stylet in each limb of the U from the proximal end to the tip also facilitated insertion. The catheter was introduced into the epidural space at L3 and directed rostrally (Fig 1) along the midline of the space to the T4 level under fluoroscopic control, followed by connection to the external unit to form a circuit. A thermistor probe was placed on the dorsal dural surface at the level of L4 through the defect at L3 to record the epidural temperature. The fascia of the paravertebral muscle was approximated with interrupted 3-0 nylon sutures, followed by skin closure. About 30 minutes was required to place the cooling catheter in the epidural space, including the laminectomy. An IP sensor (Johnson and Johnson Prof Inc, Raynham, MA) and a thermistor probe for spinal temperature were introduced into the subarachnoid space by means of a needle puncture at the L5–L6 interspace (Fig 1).

A left lateral thoracotomy was performed at the fourth intercostal space. Heparin sulfate was administered as a 60-U/kg intravenous bolus. In both groups, animals underwent 30 minutes of aortic cross-clamping (AXC) distal to the origin of the left subclavian artery. In group 1, animals underwent EC with the cooling catheter beginning 30 minutes before AXC. During 30 minutes of AXC, EC by means of the catheter was continued. After release of clamping, EC was continued for 30 minutes to slow the rise of spinal temperature accompanying reperfusion (total, 90 minutes). In group 2, the epidural catheter was placed in the same fashion, but the pigs did not undergo EC at any point in the procedure.

After surgery, the cooling catheter and all measuring probes were removed immediately. Pigs were extubated and returned to cages with free access to water and food. All animals received humane care and treatment in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication no. 85–23, revised 1985). Also, both the experimental and animal care protocols were approved by the Animal Care Committee of Saitama Cardiovascular and Respiratory Center.

Spinal Cord Somatosensory Evoked Potentials
We recorded spinal cord somatosensory evoked potentials (sSEP) directly from the spinal cord. Bipolar electrodes were positioned within the epidural space at the level of L3–L4 for stimulation and at the T3–T4 level for recording. Stimulation variables included a 0.2-millisecond pulse at a 3- to 5-mA intensity with a rate of 5.0 Hz. Potentials were recorded on a time base of 3 milliseconds after passage through a bandpass filter (50 to 1,500 Hz; Nihon Kohden, Tokyo, Japan). Each recording represented an average of 50 repetitions. A baseline sSEP was recorded at initiation of cooling, and the recording was repeated at 60-second intervals.

Neurologic Evaluation
Neurologic status with respect to hind limb function was assessed at 12, 24, and 48 hours after the operation according to a modified Tarlov score (0 = complete paralysis, 1 = minimal movement, 2 = standing with assistance, 3 = standing alone but unable to walk, 4 = weak walking, 5 = full recovery and normal walking) [6].

Histologic Examination
At 48 hours after surgery, animals were killed with an intravenous overdose of pentobarbital. The spinal cord was removed rapidly and then fixed with 4% phosphate-buffered paraformaldehyde. Spinal cord sections were stained with hematoxylin and eosin. Histologic assessment was performed using light microscopy.

Statistical Analysis
We used the Mann-Whitney U test to compare the postoperative neurologic status between the two groups of animals. Analysis of variance for repeated measures was carried out for variables assessed at multiple times.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Temperature
Rectal temperature, spinal temperature, and epidural temperature were similar between groups 1 and 2 at baseline. In group 1, spinal temperature (38.3° ± 0.6°C) and epidural temperature (38.3° ± 0.5°C) at baseline fell significantly to 31.7° ± 0.6°C and 29.4° ± 0.7°C, respectively, at AXC (p < 0.0001; Fig 2). At conclusion of AXC, spinal temperature and epidural temperature in group 1 had fallen further, to 30.2° ± 1.0°C and 27.9° ± 0.9°C, respectively. The rectal temperature in group 1 remained constant between baseline (38.1° ± 0.5°C), AXC (37.6° ± 0.6°C), and clamp release (37.5° ± 0.5°C) with no significant difference. A significant difference was evident between spinal temperature and rectal temperature during AXC (p < 0.0001) in group 1. Spinal temperature in this group during AXC also differed significantly from that in control pigs (group 2; 37.8° ± 0.4°C; p < 0.0001).



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  		Fig 2. Time course of spinal, epidural, and rectal temperature (temp.). Open diamonds, squares, and circles represent rectal, spinal, and epidural temperatures, respectively, in the cooling (1) group. Filled diamonds, squares, and circles represent rectal, spinal, and epidural temperatures, respectively, in the control (2) group. (X-clamp = cross-clamp.)

 
In group 2, spinal, epidural, and rectal temperatures remained constant throughout the procedure. Spinal temperature (37.8° ± 0.4°C), epidural temperature (38.1° ± 0.6°C), and rectal temperature (38.0° ± 0.5°C) at AXC did not differ significantly among one another in group 2. Rectal temperatures were similar in groups 1 and 2 throughout the procedure.

Intrathecal Pressure
Intrathecal pressure was similar between groups at baseline (group 1, 8.4 ± 3.3 mm Hg; group 2, 8.1 ± 1.8 mm Hg). No significant elevation of IP was detected at aortic unclamping in group 1 (8.1 ± 1.7 mm Hg) compared with group 2 (8.0 ± 1.5 mm Hg; p = 0.77). Spinal cord perfusion pressure during AXC was calculated as distal mean arterial pressure minus IP. Immediately before aortic unclamping, spinal cord perfusion pressure did not differ between groups (group 1, 9.2 ± 2.9 mm Hg; group 2, 8.9 ± 2.4 mm Hg). Other physiologic variables including mean arterial pressure and heart rate were similar in both groups during AXC.

Spinal Cord Somatosensory Evoked Potentials
In group 1, EC before AXC significantly prolonged latency of sSEP and reduced its amplitude within 5 minutes. Epidural cooling itself did not make the waves diminish to flat ones. The sSEP amplitude was significantly decreased by EC, from 21.1 ± 2.9 µV at baseline to 14.6 ± 5.6 µV at AXC (p = 0.008). The latency of sSEP was also significantly prolonged, changing from 2.60 ± 0.59 to 3.58 ± 0.83 milliseconds between these two times. Configuration of sSEP did not change until 20 minutes after AXC in any pigs in group 1. Subsequently, in 5 of 7 pigs in group 1, the sSEP amplitude gradually decreased with loss of potentials before clamp release. Two pigs in group 1 did not lose sSEP until immediately after unclamping followed after a few minutes by rapid recovery of potentials. During the 30 minutes of cooling after clamp release, potentials returned in all pigs.

In group 2, during the period of clamping, sSEP gradually decreased in amplitude, with prolongation of latency, and eventual complete loss of potentials. After varying intervals, potentials gradually reappeared in all animals.

Mean time from AXC to onset of sSEP loss was significantly longer in group 1 than in group 2. Mean time showing total time of sSEP loss as well as regeneration time was significantly shorter in group 1 than in group 2 (Table 1). The ratio of final amplitude of sSEP to baseline amplitude was 106.9% ± 13.5% in group 1 and 97.1% ± 16.8% in group 2, with no significant difference between groups (p = 0.26). The ratio of final latency to baseline latency was 106.1% ± 5.4% in group 1 and 102.9% ± 7.4% in group 2 (no significant difference; p = 0.37).


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  		Table 1. Loss and Recovery of Spinal Cord Somatosensory Evoked Potentials, by Group: Onset of Loss, Total Time of Loss, and Regeneration Time a
 
Recovery of Motor Functions
Neurologic outcome in group 2, 4 of 7 pigs exhibited complete paraplegia at both 24 and 48 hours after surgery. In contrast, no group 1 animals showed irreversible paraplegia or paraparesis. Five of 7 animals in group 1 had recovered fully at 48 hours. Animals in group 1 showed significantly better recovery in hind limb function than pigs in group 2 (p = 0.0017; Table 2).


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  		Table 2. Neurologic Outcome a
 
Histologic Examination
Neither group showed any axonal injury in the dorsal portion of the spinal cord to suggest a space-occupying effect from the epidural catheter. Group 1 showed normal histologic characteristics (Fig 3A). Group 2 showed loss of motor neurons in anterior horns, with no evidence of white matter degeneration (Fig 3B).



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  		Fig 3. Photomicrographs of histologic sections of spinal cord from pigs in cooling (A; group 1) and control (B; group 2) groups. (Hematoxylin-eosin, x100.)

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Several experimental studies demonstrated that regional cooling by infusing cold saline solution into the intrathecal or epidural space was protective against ischemic spinal cord insults [7, 8]. Yet elevation of IP during these procedures provoked concerns; because spinal cord perfusion pressure represents the difference between mean arterial pressure and IP, elevation of IP could impair blood supply to spinal cord neurons. In our experiment, no significant elevation of IP was detected throughout the period of EC. Additionally, histologic study ruled out spinal cord injury from compression by the catheter.

Our system cooled the spinal cord to 8.1°C below core body temperature at aortic unclamping without resort to epidural perfusion of iced saline solution. During this experiment we came to appreciate the degree to which the spinal canal insulates the spinal cord from heat-producing tissues such as muscle. The canal itself is composed of tissues producing little heat such as bones and ligaments. This enhanced the catheter's cooling ability within the spinal canal in protecting the spinal cord despite the small catheter surface area. Improvement of heat conductance of the cooling catheter or an increased flow rate of circulating coolant may achieve further lowering of cord temperature by this technique.

Because our cooling catheter removes heat from the spinal cord through the dorsal dura surface, we were concerned about effects of a thermal gradient between dural temperature and spinal temperature, especially ventrally. The current study indicated that spinal cord temperature was effectively lowered by EC, preserving ventral horn cells. The diffuse nature of cord cooling may reflect cooling of, and by, freely circulating cerebrospinal fluid.

Although somatosensory evoked potentials have been used commonly in thoracoabdominal aortic aneurysm surgery [9–11], we used sSEP, which are more reproducible than somatosensory evoked potentials in a porcine model. We found that moderate hypothermia induced by EC delayed deterioration and loss of sSEP from spinal cord ischemia rather than accelerating the complete loss of sSEP. Regional hypothermia acts against ischemic stress by decreasing metabolic demands, thus delaying deterioration and loss of sSEP.

We demonstrated that EC significantly shortened total time of sSEP loss and facilitated recovery of sSEP after unclamping. It was reported that during clinical thoracoabdominal aortic aneurysm surgery, total time of sSEP loss predicted risk of postoperative paraplegia more reliably than amplitude of the recovered wave [12].

No pigs exhibited permanent loss of sSEP lasting to the end of the experiment in either group. In the control group, pigs with recovery of sSEP at the end of surgery exhibited paraplegia or paraparesis postoperatively, possibly because neuronal somata are more vulnerable to ischemic stress than axons. Histologically, we demonstrated loss of motor neurons with relative sparing of white matter in group 2.

Animals in group 1 showed significantly better recovery of hind limb function than animals in group 2. Histologic outcome also indicated that epidural catheter cooling protected spinal cord against ischemic injury induced by AXC. Because porcine spinal cord is known to be less tolerant to ischemia from AXC than the humans, a protection time of 30 minutes in swine may correspond to some 40 to 50 minutes in humans [13, 14]. Further experimental studies against ischemia induced by double AXC or venting from an isolated segment will be needed before the clinical application of our catheter [15].

Drawbacks of our system include a need for an open laminectomy to place the cooling catheter in the epidural space. Fluoroscopic guidance and use of stylets may enable us to introduce the catheter in the clinical setting using a single laminectomy. Further, changes in design of the cooling catheter should be possible to permit percutaneous introduction by puncture.

In conclusion, our present experiment in swine demonstrated that our EC system cooled the spinal cord selectively and continuously, protecting it against ischemia without changing core body temperature. We believe that it will be an adjunctive device to reduce risk of paraplegia associated with thoracic aortic aneurysm and thoracoabdominal aortic aneurysm surgery.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
We express special thanks to Shigeyuki Takeuchi, MD, Hideyuki Shimizu, MD, Akihiro Yoshitake, MD, Katsuhisa Onoguchi, MD, Hiromitsu Takakura, MD, Michio Yoshitake, MD, Shingo Taguchi, MD, Yasunori Cho, MD, Shinya Inoue, MD, Tashiro Ryoichi, PhD, Shinobu Negishi, Takashi Kimura, Kazunori Yoshinaga, Shinji Matsuo, Kumi Takeda, Atsushi Saito, Ryota Wada, Norio Koike, Tatsuya Takagi, Fumie Oyama, Akemi Misawa, and Takeshi Yokomura for their technical assistance. This work was financially supported by the scientific research fund of Saitama prefecture.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Svensson LG, Crawford ES. Cardiovascular and vascular disease of the aorta. Philadelphia: WB Saunders; 1997.
  2. Coselli JS, LeMaire SA, Conklin LD, Köksoy C, Schmittling ZC. Morbidity and mortality after extent II thoracoabdominal aortic aneurysm repair Ann Thorac Surg 2002;73:1107-1116.[Abstract/Free Full Text]
  3. Griepp RB, Ergin MA, Galla JD, et al. Looking for the artery of Adamkiewicza quest to minimize paraplegia after operations for aneurysms of the descending thoracic and thoracoabdominal aorta. J Thorac Cardiovasc Surg 1996;112:1202-1215.[Abstract/Free Full Text]
  4. DeBakey ME, Cooley DA, Creech Jr O. Resection of the aorta for aneurysms and occlusive disease with particular reference to use of hypothermia; analysis of 240 cases Trans Am Coll Cardiol 1955;5:153-157.
  5. Cambria RP, Davison JK, Zannetti S, L' Italian G, Atamian S. Thoracoabdominal aneurysm repairperspectives over a decade with the clamp-and-sew technique. Ann Surg 1997;226:294-305.[Medline]
  6. Tarlov IM. Spinal cord compression. mechanisms of paralysis and treatment. Springfield, IL: Charles C Thomas; 1957. pp. 1-147.
  7. Berguer R, Porto J, Fedoronko B, et al. Selective deep hypothermia of the spinal cord prevents paraplegia after aortic cross-clamping in the dog model J Vasc Surg 1992;15:62-71.[Medline]
  8. Tabayashi K, Niibori K, Konno H, Mohri H. Protection from postischemic spinal cord injury by perfusion cooling of the epidural space Ann Thorac Surg 1993;56:494-498.[Abstract]
  9. Crawford ES, Mizrahi EM, Hess KR, Coselli JS, Safi HJ, Patel VM. The impact of distal perfusion and somatosensory evoked potential monitoring on prevention of paraplegia after aortic aneurysm operation J Thorac Cardiovasc Surg 1988;95:357-367.[Abstract]
  10. Svensson LG, Crawford ES, Patel V, et al. Spinal oxygenation, blood supply localization, cooling and function with aortic clamping Ann Thorac Surg 1992;54:74-79.[Abstract]
  11. Galla JD, Ergin A, Lansman SL, et al. Use of somatosensory evoked potentials for thoracic and thoracoabdominal aortic resections Ann Thorac Surg 1999;67:1947-1952.[Abstract/Free Full Text]
  12. Grabitz K, Sandmann W, Stuhmeier K, et al. The risk of ischemic spinal cord injury in patients undergoing graft replacement for thoracoabdominal aortic aneurysms J Vasc Surg 1996;23:230-240.[Medline]
  13. 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;43:639-643.[Abstract]
  14. Strauch JT, Lauten A, Spielvogel D, et al. Mild hypothermia protects the spinal cord from ischemic injury in a chronic porcine model Eur J Cardiothorac Surg 2004;25:708-715.[Abstract/Free Full Text]
  15. Dapunt OE, Midulla PS, Sadeghi AM, et al. Pathogenesis of spinal cord injury during simulated aneurysm repair in a chronic animal model Ann Thorac Surg 1994;58:689-697.[Abstract]



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Ann. Thorac. Surg., November 1, 2005; 80(5): 1833 - 1834.
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