Profound systemic hypothermia protects the spinal cord in a primate model of spinal cord ischemia

Profound systemic hypothermia protects the spinal cord in a primate model of spinal cord ischemia Spinal cord ischemia with resultant paraplegia or paraparesis remains an important clinical problem after operations on the thoracoabdominal aorta. Because hypothermia has a protective effect on ischemic neural tissue, we developed a baboon model of spinal cord ischemia to simulate the situation encountered clinically for resection of aneurysms of the thoracoabdominal aorta and to determine whether profound hypothermia produced by hypothermic cardiopulmonary bypass has a protective effect on spinal cord function. After cardiopulmonary bypass was established, the aorta was clamped distal to the left subclavian artery and proximal to the renal arteries for 60 minutes. Group I animals (n = 9) underwent aortic clamping at normothermia (37 0 C), and group II animals (n = 9) were cooled to a rectal temperature of 15 0 C before aortic clamping and underwent cardiopulmonary bypass at this temperature until the aorta was unclamped. Of the eight operative survivors in group I, six animals were paraplegic and two were paraparetic, whereas all six group II animals that survived the procedure were neurologically intact (p = 0.0002). The protective effect of hypothermia was associated with blunting of the hyperemic response of spinal cord blood flow (determined by the radioactive microsphere technique) in the lower thoracic and the lumbar segments of the spinal cord after unclamping of the aorta. Profound hypothermia produced by hypothermic cardiopulmonary bypass may be an effective method of protection of the spinal cord in patients undergoing repair of aneurysms of the thoracoabdominal aorta and may reduce the prevalence of ischemic injury to the spinal cord. (J THORAC CARDIOVASC SURG 1993;106:1024-35)

Chris K. Rokkas, MD, Sudhir Sundaresan, MD, Todd A. Shuman, MD, Robert S. Palazzo, MD, Takashi Nitta, MD, George J. Despotis, MD, Timothy C. Burns, CCP, Thomas H. Wareing, MD, and Nicholas T. Kouchoukos, MD, St. Louis, Mo.

AortiC clamping during operations on the descending thoracic or the thoracoabdominal aorta reduces the perfusion of organs distal to the occlusion. The neural tissue of the spinal cord, which has a highly variable blood supply,I-S is particularly sensitive to ischemia, and the resulting injury can produce paraparesis or paraplegia.v ? In human beings, the prevalence of spinal cord injury is related primarily to the type and extent of the aortic dis-

From the Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Mo. Supported in part by a grant from the Shoen berg Foundation. Received for publication Oct. 5, 1992. Accepted for publication Dec. 21, 1992. Address for reprints: Nicholas T. Kouchoukos, MD, Department of Surgery, Jewish Hospital at Washington University Medical Center, 216 S. Kingshighway Blvd., St. Louis, MO 63110. Copyright

1993 by Mosby-Year Book, Inc.

0022-5223/93 $1.00

1024

+ .10 12/1/46215

ease and to the duration of aortic clamping.r!? In patients with aortic dissection, paraparesis or paraplegia is reported to occur in up to 40% after repair of extensive thoracoabdominal aneurysms when simple aortic clamping techniques are used. 11 Experimental studies have shown that hypothermia has a protective effect on ischemic neural tissue. 12- 14 Hypothermia produced by cardiopulmonary bypass (CPB) is used for spinal cord protection to increase the tolerable duration of ischemia so that resection and graft replacement of the involved aortic segment and reimplantation of critical intercostal and lumbar arteries can be effected before the onset of permanent neurologic injury. I 5 The purpose of this study was twofold: (1) to develop a baboon model of spinal cord ischemia that simulates the situation encountered clinically for resection of aneurysms of the thoracoabdominal aorta and (2) to evaluate the effect of profound hypothermia induced by hypothermic CPB on spinal cord function in this model.

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MICROSPHERES

I 02 5

MEMBRANE/ OXYGENATOR'\.

-

f

1

-

- --

Fig. 1. Animal preparation.

Material and methods Eighteen adult male baboons (Papio anubis) weighing 25 to 35 kg were used. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Science and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985). General anesthesia was induced with ketamine hydrochloride (I mg/kg) administered intramuscularly followed by fentanyl citrate (5 ,ug/kg) and vecuronium bromide (IOO,ug/kg) administered intravenously. Anesthesia was maintained with a continuous intravenous infusion offentanyl citrate (3 ,ug/kg per hour) and vecuronium bromide (30 ,ug/kg per hour). After endotracheal intubation, a positive-pressure mechanical ventilator (model MA-I; Bennett Respiration Products Inc., Santa Monica, Calif.) was used for ventilatory support. Instrumentation. Two peripheral venous lines were inserted for administration of fluids and drugs, and an arterial line was placed in the right brachial artery. A urinary catheter, a nasagastric catheter, and rectal and nasopharyngeal temperature probes (series 400; Yellow Springs Instrument Co., Inc., Yellow Springs, Ohio) were inserted. A cerebrospinal fluid pressure catheter (Perifix; Burron Medical Inc., Bethlehem, Pa.) and a spinal temperature probe (model 520; Yellow Springs Instrument) were inserted intrathecally through the second or third lumbar intervertebral space. A second arterial line was placed in the right femoral artery, and a pulmonary artery catheter was inserted through the right femoral vein. Brachial arterial pressure, femoral arterial pressure, pulmonary arterial pressure, central venous pressure, left atrial pressure, and cerebrospinal fluid pressure were measured with Statham-Gould pressure

transducers (Gould Inc., Test and Measurement Recording Systems Division, Cleveland, Ohio). These pressures and a three-lead electrocardiogram were recorded on a continuous multichannel polygraph 2800S recorder; Gould). The intrathecal temperature probe was connected to a thermometer (model 43TD; Yellow Springs Instrument), and readings were obtained at 10-minute intervals. Surgical preparation. The animals were positioned in the right lateral decubitus position, with the pelvis rotated 45 degrees to the left to facilitate groin cannulation and retroperitoneal dissection for exposure of the abdominal aorta. A left thoracotomy was performed through the fourth intercostal space. A left retroperitoneal incision was made, and the abdominal aorta was exposed. After systemic anticoagulation with porcine-derived heparin sulfate (300 U /kg intravenous bolus), CPB was established at 100 mljkg per minute. A single cannula was inserted in the right atrium for return of venous blood to the pump-oxygenator. Two arterial lines (one in the left femoral artery and one in the aortic arch) attached to separate roller pumps and two membrane oxygenators and filters were used to regulate blood flow to the upper (one third of total flow) and lower (two thirds of total flow) parts of the body (Fig. I). In all animals, the aorta was clamped immediately distal to the left subclavian artery and just proximal to the renal arteries for 60 minutes. The isolated aortic segment was vented to atmospheric pressure, and the upper six pairs of thoracic intercostal arteries were ligated at their origins. Experimental design. In group I animals (n = 9), rectal temperature was maintained at 37° C by the perfusate during the 60-minute interval of aortic occlusion (control group). The aortic clamps were then removed, the vent site in the aorta was secured, and CPB was discontinued. Group II animals (n = 9) were cooled by the perfusate to a rectal temperature of 15° C

The Journal of Thoracic and Cardiovascular Surgery December 1993

I 0 2 6 Rokkas et al.

Table I. Hemodynamic variables Baseline Mean arterial pressure Brachial Femoral Cerebrospinal fluid pressure Central venous pressure

AXC60 min

Group!

Group II

105 ± 14 105 ± 14 8± I 5± 2

90 ± 5 90 ± 5 10 ± 4 4±1

Group! 77 85 19 9

± ± ± ±

12 7 2t I

OjfCPB

Group II 80 76 26 12

± ± ± ±

10 2 3t:j: 5

Group! III III 15 7

± ± ± ±

8 8 2 3

Group II 87 87 9 7

± ± ± ±

10* 10* I 3

Data are expressed as mean ± standard deviation in millimeters of mercury AXC 60 min, At the end of aortic cross clamping; Off CPR, after discontinuation of CPR • p < 0.025, compared with group I. tp < 0.001, compared with baseline. :j:p < 0.05, compared with group I.

before aortic clamping (hypothermia group). The average duration of CPB necessary to achieve this temperature was 35 ± 7 minutes. Flow was gradually reduced during cooling to 60 ml/kg per minute (20 ml/kg per minute through the upper cannula and 40 ml/kg per minute through the lower cannula). The rectal temperature and the total flow were maintained at the previously mentioned levels until the aorta was unclamped. Flow was then gradually increased, and the animals were warmed to 37° C (rectal). The average rewarming period was 50 ± II minutes. After the animals were weaned from CPB, protamine sulfate (3.75 mg/kg) was administered, hemostasis was achieved, thoracostomy tubes were inserted, and the incisions were closed in layers with absorbable sutures. The animals were then allowed to emerge slowly from anesthesia. Buprenorphine hydrochloride (0.15 mg per dose) was administered intramuscularly as needed for analgesia. A hematocrit value of 25% was maintained with homologous blood transfusions. In the perioperative period, group I animals received an average of 311 ± 251 ml of blood and group II animals received 711 ± 251 ml (p = 0.001). The animals were killed on the second postoperative day with an intravenous dose of saturated potassium chloride, and the spinal cord was excised. Blood flow studies. Spinal cord blood flow was determined by injection of radioisotope-tagged microspheres (New England Nuclear, Boston, Mass.) with the technique described by Rudy and Heymann and their associates. 16, 17 The microspheres were 15 ,urn in diameter and were labeled with one of the following gamma ray--emitting radioisotopes: cerium 141, scandium 46, chromium 51, tin 113, niobium 95, or ruthenium 103. They were suspended in a solution of 10% dextran and polyoxyethylene sorbitan monooleate (Tween-80; Sigma Chemical Co., S1. Louis, Mo.). Before each determination, the microspheres were thoroughly agitated for 15 minutes and then were rapidly injected in the left atrial line (approximately 8 X 106 microspheres per injection). The injections of the various isotopes were random to prevent ordering bias. No hemodynamic changes were observed after injection. Reference blood samples were collected from the femoral arterial line with a constant withdrawal pump (Harvard Apparatus, S. Natick, Mass.) at 7.75 ml/rnin, beginning 15 seconds before injection of the microspheres and continuing for 2 minutes after the injection was completed. Measurements of spinal cord blood flow were made before initiation of CPB (baseline) and at 5, 30, 60, 90, and 120 minutes after discontinuation of CPB. In group I animals, CPB was

discontinued shortly after the aorta was unclamped. CPB was maintained in group II animals until their temperature reached 37° C. Post-CPB spinal cord blood flow determinations were made after all animals were normothermic. Spinal cord blood flow measurements were not obtained during the period of aortic clamping because all the animals were supported by CPB during this interval. The excised spinal cord was prepared for counting by removal of the meninges and nerve roots. It was then divided into three sections, consisting of the six upper thoracic, the six lower thoracic, and the five lumbar segments. The tissue samples were weighed and counted for radionuclide activity. Raw counts were obtained with a gamma well counter (Packard Auto-Gamma 5000; Packard Instrument Company, Meriden, Conn.) and were corrected for background, decay, and spillover to obtain final activity (Compusphere; Packard Instrument Company). Spinal cord blood flow (SCBF) in milliliters per 100 grams per minute was calculated as:

SCBF =

Sample ] [7,75 CTScorr ml/rnin ] Reference X Sample X 100 [ blood sample weight CTScorr (gm)

where CTScorr is the corrected raw count for radionuclide activity. Histologic analysis. Representative sections of each segment of the spinal cord were stained with hematoxylin and eosin. The specimens were reviewed by a pathologist in a blinded fashion with respect to the grouping and the neurologic outcome. Neurologic assessment. The Tarlov scale was used for clinical neurologic assessment on the first and second postoperative days: 0 = no movement of legs, I = perceptible movement of the joints of the legs, 2 = good movement but unable to stand, 3 = able to stand and walk, 4 = complete recovery. I 8 A score of o was indicative of paraplegia, and a score of I to 3 was indicative of paraparesis. Statistical analysis. The data obtained were analyzed with the Personal Computer Statistical Analysis Software package (PC SAS, Cary, N.C.). Logarithmic transformation of the blood flow data was used to normalize the distribution and equalize the variances. 19 Differences from baseline within each group were analyzed with a matched-pair t test with statistical

The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 6

Rokkas et al.

24 hours after operation

•• • • ••e I

I

2

3

4

5 6 7

8 9

~

®

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® 0 0 0 0 ® ® 0 0

I027

48 hours after operation

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• TarloY 0 • TarlaY I ~ Tarlov 2 TarlaY 3 Tarlov 4 death

o

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Fig. 2. Postoperative neurologic assessment of spinalcord function. Tarlov 0, No movementofiegs; Tarlov 1, perceptiblemovement of jointsof legs; Tarlov 2, goodmovement but unable to stand; Tarlov 3, able to stand and walk; Tarlov 4, complete recovery. significance based on a p value of <0.05. Differences among groups at each time period were analyzedwith one-way analysis ofvariance. When p < 0.05, Tukey's procedurewas used to testall possible pairwise comparisons among the means. Fisher'sexact test was used for comparison of neurologic outcome. Results Spinal cord function. Six of the eight group I (control) animals that survived the surgical procedure were paraplegicand two were paraparetic on the first postoperative day. One of the paraplegic animals showed a mild improvement on the second postoperative day. In group II (hypothermia), all six animals that survived the procedure were neurologically intact (Fig. 2). The difference between the two groups when compared by Fisher's exact test was highly significant (p = 0.0002). Hemodynamics and cerebrospinal fluid pressure. All animals were weaned successfully from CPB without inotropic support (Table I). One animal in group I and twoanimals in group II died of respiratory complications 6 to 18hours after the operation. Another animal in group II, which died 20 hours after the operation, was found at autopsy to have a large hemothorax. Mean arterial pressure was significantly lower in group II than in group I immediately after discontinuation of CPR A marked increase in cerebrospinal fluid pressure in both groups occurred during the 60 minutes of aortic clamping, with group II exhibiting a significantly higher cerebrospinal fluid pressure (p = 0.05). However, group II animals demonstrated a faster rate of normalization of cerebrospinal fluid pressure after unclamping of the aorta (Fig. 3). Spinal cord blood flow. No statistically significant differencewas found between the two groups with regard to baseline flows in the entire spinal cord and in the upper thoracic,lower thoracic, and lumbar segments when data obtainedfrom all 18 animals were analyzed (Table II). A pronouncedhyperemia occurred in the lower thoracic and lumbarsegments in both groups. The hyperemic response was significantly higher in group I at 5 and 30 minutes

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Fig. 3. Cerebrospinal fluid pressures (CSFP) at baseline, 60 minutes after aortic crossclamping (AXC-60 min), and after discontinuation of CPB (Off CPB). after discontinuation ofCPB compared with that of group II. When spinal cord blood flows in group I were analyzed in two subgroups (paraplegic and paraparetic animals), the paraparetic subgroup demonstrated a pattern of hyperemia similar to that of group II animals. The upper thoracic segment showed a mild but significant hyperemia 5 minutes after termination of CPB, without significant differences among the three groups (Fig. 4). At the same time interval, all animals demonstrated marked hyperemia in the lower thoracic and lumbar segments. The hyperemia was greatest among the paraplegic control animals, in whom the blood flow was significantly greater than that in paraparetic control or group II animals. In these segments, the hyperemia persisted in the paraplegic baboons at 30 and 60 minutes after discontinuation of CPB, whereas, in the paraparetic

I 02 8

The Journal of Thoracic and Cardiovascular Surgery December 1993

Rokkas et al.

80

... C'

i

~

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30min

60 min

90min

Fig. 4. Spinal cord blood flows (SCBF) in upper thoracic segment (mean ± standard deviation). p-CPB, After termination of CPB.

Table II. Spinal cord blood flows Time after termination of CPB (min) Control group Paraplegic Upper thoracic Lower thoracic Lumbar Para paretic Upper thoracic Lower thoracic Lumbar Hypothermic group Upper thoracic Lower thoracic Lumbar

Baseline

5

30

60

90

120

15 ± 8 15 ± 7 24 ± 9

30 ± 10 47 ± 7 93 ± 8

25 ± 7 37 ± 13 78 ± 17

22 ± 14 34 ± 15 47 ± 7

19 ± 1 22 ± 2 36 ± 4

17 ± I 18 ± I 31 ± 2

21 ± 9 18 ± 6 26 ± 12

37 ± 21 29 ± 13 49 ± 35

18 ± 6 17 ± 3 28 ± 13

17 ± 10 13 ± 6 26 ± 13

18 ± 6 14 ± 1 31 ± 6

19 ± 6 20 ± 3 32 ± 4

13 ± 4 15 ± 4 24 ± 7

28 ± 9 28 ± 9 49 ± 13

15 ± 3 17 ± 3 29 ± 6

16 ± 7 16 ± 8 30 ± 15

12 ± 4 13 ± 4 24 ± 5

17 ± 8 18 ± 8 31 ± 6

Data are expressed as mean ± standard deviation in milliliters per minute per 100 gm.

control and hypothermic baboons, the flows returned to baseline (Figs. 5 and 6). The neurologically intact group II animals and the control animals, which retained some degree of neurologic function, exhibited similar patterns of spinal cord blood flow. The areas at greatest risk for ischemic injury, the lower thoracic and lumbar segments of the spinal cord, had mean reperfusion flows approximately three to four times the mean baseline flows in the paraplegic control animals. In the paraparetic control and group II animals, the hyperemic response was approximately twice the baseline flow (Fig. 7). Blood flows returned to baseline levels 30 minutes after termination of ePB for the para paretic control and group II animals and 2 hours

after termination of ePB for the paraplegic control animals. Temperatures. In group II animals, the temperature in the spinal cord fell more rapidly during coolingand rose more rapidly during rewarming than did the rectal and nasopharyngeal temperatures (Fig. 8). At the time of aortic clamping, when the rectal temperature was 150 C, the mean spinal cord temperature was 11.50 ± 0.40 C. Although rectal temperature was maintained at 150 C, spinal cord temperature equilibrated with rectal temperature approximately 20 minutes after aortic crossclamping and continued to rise at a faster rate than did the nasopharyngeal temperature, reaching 170 ± 0.60 C at the end of the aortic crossclamp interval (Fig. 9).

The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 6

Rokkas et al.

°

1 29

80

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60

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Histologic analysis. No significant abnormalities in the microscopic appearance of the anterior horn cells or the surrounding neural tissue were observed in either group I or group II animals. Discussion In 1944, van Harreveld and Tyler/" showed that damage to the spinal cord in cats, as indicated by changes in

reflex activity, metabolism, and histologic structure, was more severe after 35 minutes of ischemia at 38° ethan after 120 minutes of ischemia at 27° C. In 1950, Bigelow and associates-l-F showed that hypothermia reduces total body oxygen consumption. In 1954, Rosomoff and Holaday'? showed that cerebral oxygen consumption varies proportionately with body temperature during hypothermia. It was subsequently shown by several

The Journal of Thoracic and Cardiovascular Surgery December 1993

1 0 3 0 Rokkas et al.

Upper Thoracic Segment 300

Lower Thoracic Segment Q) c

300

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400

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5 min

30 min

GOmin

90min

120 min

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Fig. 7. Spinal cord blood flows (SCBF) expressed as percentage of baseline (mean ± standard deviation). p-CPB, After termination of CPB.

investigators that hypothermia reduces the oxygen consumption of neural tissue by about 5% for each degree that temperature falls, reaching 25% of normal consumption at 22° C. l2 , 24-27 A variety of methods designed to protect the spinal cord during clamping of the thoracic aorta has had minimal impact on reducing the prevalence of ischemic injury to the spinal cord. 28-33 The use of hypothermia for spinal cord protection during operations on the thoracoabdominal aorta was first investigated by Beattie and associates'" in 1953. In a series of experiments, paraplegia did not develop in dogs externally cooled to 25 ° to 30° Cafter

60 or 90 minutes of aortic occlusion distal to the left subclavian artery. In contrast, 40% of control animals became paraplegic. In 1954, Pontius and associates-' determined the prevalence of paraplegia after a variety of interventions on the thoracic aorta in dogs. Occlusion of the aorta just distal to the left subclavian artery in normothermic (control) animals for a period of 1 hour produced ischemic injury to the spinal cord in 30% of animals. When the aorta was simultaneously occluded just distal to the left subclavian artery and at the level of the diaphragmatic hiatus, the prevalence of paraplegia was 90%. They also showed that interruption of the

The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 6

Rokkas et al.

I03 I

40

e-;;;

30

25

_Spinal ...... Nasopharyngeal

~

20

(I experiment)

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15

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60

120

180

TIME (min)

Fig. 8. Temperaturecurves during cooling, aortic crossclamping (X-clamped), and rewarming from a representative hypothermia experiment. intercostal vessels increased the severity of the ischemic injury beyond that produced by aortic occlusion. None of the animals in the experimental group (surface cooling from 240 ton° C) had paraplegia. In 1955, Parkins, Ben, and Vars'" induced hypothermia-26° to 30 0 C-by application of ice inside the abdomen and cooling of blood in a carotid artery-internal jugular vein shunt in dogs and observedno paraplegia after balloon catheter occlusion of the proximal aorta for 30 to 120 minutes. Owens, Prevedel, and Swan '" observed a 50% prevalence of paraplegia in normothermic dogs after 20 to 30 minutes of clamping of the thoracic aorta. No animals cooled by immersion to 23 0 to 26 0 C had paraplegia after 90 to 120 minutes of aortic occlusion. Systemic cooling for protection of the spinal cord during aortic aneurysmectomy in human beings was reported by Julian and associates'! in 1955. They described two patients who successfully underwent repair of aneurysms of the descending thoracic aorta after surface cooling to a rectal temperature of 28 0 C. No evidence of spinal cord injury was observed in the postoperative period. DeBakey, Cooley, and Creech" described eight patients treated similarly with no evidence of spinal cord injury. Adams and Van Geertruyden''" clamped the aorta proximal to the left subclavian artery and repaired aneurysms of the descending thoracic aorta in four patients undergoing moderate hypothermia, also produced by surface cooling, without neurologic deficit. In these patients, the upper thoracic intercostal arteries were sacrificed. During this early period, the only documented case of failure of hypothermia to protect the spinal cord was reported by Eiseman and Summers.i! Their patient was cooled to 28 0 to 30 0 C, and the aorta was clamped at the levels of the eighth and twelfth thoracic vertebrae for 63 minutes. The

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t

10

20

30

40

50

TIME (min)

Fig. 9. Spinal, nasopharyngeal, and rectal temperatures (mean ± standard deviation) during 60-minuteperiodof aortic crossclamping. overall clinical experience with the use of hypothermia during this period (1954 to 1960) was generally unsatisfactory because of high mortality and complication rates. In 1983, Coles and associatesf reported a method for perfusion cooling of the spinal cord by infusion of 50 C lactated Ringer's solution into an excluded segment of the descending thoracic aorta in dogs. The initial spinal cord temperatures were between 18 0 and 30 0 C. No paraplegia was observed after 30 minutes of aortic occlusion. A similar method for regional cooling of the spinal cord was reported in 1987 by Colon and associates.f This technique involved perfusion cooling of the excluded aortic segment with blood that was obtained from the aortic arch and cooled in a heat exchanger. A disadvantage of

1 0 3 2 Rokkas et al.

these techniques is that the spinal cord may become ischemic before it is adequately cooled because the aortic clamps are applied before cooling is initiated. Furthermore, because maintenance of profound hypothermia is not feasible after the aorta is opened, the spinal cord will eventually attain the temperature of the surrounding tissues, which could have a detrimental effect on spinal cord function if long periods of aortic occlusion are necessary. Selective hypothermia of the canine spinal cord, with the use of epidural catheters, was used by Negrin and Klauber44 in 1960 with favorable results. Several studies 45-47 established the effectiveness of regional profound hypothermia for spinal cord protection after spinal cord injury. More recently, Berguer and associates's achieved spinal cord temperatures of 120 to 19 0 C by infusing 50 C saline solution into the subarachnoid space of dogs. After aortic occlusion for 45 minutes, all control animals were paraplegic and all experimental animals were neurologically normal. This technique involvescatheterization of the cisterna magna and the exchange of the cerebrospinal fluid with a nonphysiologic solution. These conditions could be difficult to accomplish and are potentially hazardous in human beings. In these experimental studies involving regional cooling of the spinal cord, the intercostal arteries were not ligated and were reperfused when the aortic clamps were removed. Profound hypothermia and circulatory arrest induced with CPB have been used for the treatment of aneurysms and dissections of the descending thoracic aorta. Mahfood and associates'? reported no neurologic dysfunction in three patients who survived the repair of aneurysms of the descending thoracic aorta with the use of hypothermic circulatory arrest. Massimo and associates'? observed normal spinal cord function in four patients with aortic dissections who were similarly treated. Crawford, CoselIi, and Safi 51 reported paraplegia in 2 of 18 patients in whom hypothermic circulatory arrest was used for treatment of aneurysms of the descending thoracic aorta. However, it was used primarily because of complications encountered in attempts to expose the aorta. The depth of hypothermia and the extent of resection in these patients were not stated. Caramutti and associatesf treated 10 patients with type B dissecting aortic aneurysms that were confined to the descending thoracic aorta by using profound hypothermia induced by CPB; they observed intact spinal cord function after the operation. Kouchoukos and associates-' reported no spinal cord dysfunction in five patients requiring replacement of the thoracoabdominal aorta. In these patients, cooling to a rectal temperature of 15 0 to 19 0 C was achieved with an extracorporeal circuit with the use of two separate arterial systems to regulate flow to the upper and lower parts of the body.

The Journal of Thoracic and Cardiovascular Surgery December 1993

The lower intercostal and upper lumbar arteries were routinely reimplanted. Westaby'" used hypothermic CPB (20 0 C) with or without circulatory arrest to treat six patients with thoracoabdominal aortic aneurysms or type B aortic dissections. One patient with a massive thoracoabdominal aneurysm and excessive postoperative bleeding had paraplegia. In that patient, a large intercostal artery at T-ll, approximately two to three times the diameter of neighboring intercostal vessels, was reimplanted in the graft. In our study, the clinical situation of resection of the thoracoabdominal aorta was simulated in an animal model with a spinal cord blood supply similar to that of the human being. 2-5, 55 The excluded aortic segment was vented to allow free retrograde bleeding from the intercostal and lumbar arteries, which simulates the situation during operations on this segment of the aorta in human beings. These arteries, which usually give origin to the arteria radicularis magna, were preserved. This preservation simulates the reimplantation of these arteries into the aortic graft in human beings. Although all control animals demonstrated neurologic dysfunction of some degree, hypothermia adequately protected spinal cord function in all experimental animals after double aortic crossclamping for 60 minutes. In a series of experiments on baboons, Svensson and associates'" showed that the development of paraplegia was inversely correlated with the spinal cord blood flow, measured by the microsphere technique, during aortic occlusion. In animals that became paraplegic, thoracic and lumbar spinal cord blood flows during aortic clamping were significantly lower than they were in animals that did not become paraplegic. Furthermore, an inverse relationship existed between spinal cord blood flow measured during 60 minutes of aortic crossclamping and the subsequent magnitude of reactive hyperemia after unclamping the aorta. In the baboons that became paraplegic, the hyperemic response of the spinal cord in the thoracic and lumbar spinal cord segments 30 minutes after reperfusion was significantly greater than that in the animals that did not become paraplegic. Bower and associates'? demonstrated in dogs that both low spinal cord blood flow during aortic crossclamping and reperfusion hyperemia were associated with a worse neurologic outcome. Animals with complete recovery or minimal paraparesis showed little hyperemic response. Barone and associates's reported a threefold greater flow in the lower thoracic and lumbar spinal cord in dogs with paraplegia after 30 minutes of aortic occlusion, whereas animals without paraplegia showed a twofold increase in spinal cord blood flow. The findings from our study are consistent with these results. We have shown that the absence of paraplegia or the

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presence of an incomplete spinal cord injury is associated with a moderate hyperemic response that subsides after 30 minutes, whereas the development of paraplegia is associated with a marked hyperemic response that persistsfor upto 2 hours. It appears that the pathophysiologic mechanism responsible for the development of paraparesis is associated with a blunted post ischemic hyperemic response. However, it is not clear from our study whether this hyperemia has a role in producing or exacerbating the neurologic injury. Our study shows that when profound hypothermia is induced and maintained with CPB, the spinal cord cools rapidly and remains cool «18 0 C) throughout the 60 minute-period of aortic occlusion. Systemic cooling minimizes the development of temperature gradients among tissues and obviates the need for the continuous monitoringof spinal cord temperature, which would be necessary to assure adequate spinal cord cooling when methods producing regional hypothermia are used. Aortic occlusion resulted in a greater increase in cerebrospinal fluid pressure in group II animals than in group I animals, which suggests that the protective effect of cerebrospinal fluid drainage on spinal cord function that has been previously reported-" 59 may be mediated by a mechanism other than reduction in cerebrospinal fluid pressure. Piano and Gewertz'" measured the compliance of the cerebrospinal fluid space and concluded that the increased cerebrospinal fluid pressure observed after aortic crossclamping was due to increased volume of the venous capacitance beds within the dural space. The radiculospinal veins travel through the dural space and narrow considerably as they pass through the dura. This physiologic valve mechanism protects the spinal cord against sudden increases in peripheral venous pressure. The increased cerebrospinal fluid pressure associated with hypothermia may result from diminished patency ofthese thin-walled intradural veins, which are prone to collapse with vasoconstriction. The relationship of cerebrospinal fluid pressure to hypothermia appears complex and warrants further investigation. The precise mechanism by which hypothermia exerts its protective effect is not known. Recent studies suggest that excitatory neurotransmitters may contribute importantly to neuronal death in hypoxic-ischemic states. 6 1-63 Glutamate, an excitatory neurotransmitter and the major intracellular anion in the central nervous system, appears to be a remarkably potent and rapidly acting neurotoxin. The transient release of only a small fraction of the intracellular stores of glutamate into the extracellular space can damage the neurons. This places glutamate early in the chain of lethal events of hypoxia-ischemia. Busto and associates'r' showed that the protective effect of hypo-

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thermia on rat brain may be due to inhibition of glutamate release. In conclusion, we have shown that profound systemic hypothermia induced by hypothermic CPB provides adequate protection of the spinal cord during occlusion and isolation of the thoracoabdominal aorta in baboons. However, this method likely provides maximal protection only during the period of hypothermia. When the spinal cord becomes normothermic, alterations in spinal cord blood flow resulting from sacrifice of critical intercostal or lumbar arteries or an unstable hemodynamic state could result in injury to neurons that were protected or minimally injured during the period of hypothermia. Our study did not assess the role of the intercostal and lumbar arteries in the production of spinal cord ischemic injury. In our model, only the upper thoracic intercostal arteries were sacrificed, and flow to the lower thoracic and lumbar arteries was restored at the end of the ischemic interval. Experimental and clinical studies have not consistently demonstrated that preservation of the lower thoracic and lumbar arteries is essential for normal spinal cord function after periods of aortic occlusion. I I Spinal cord ischemic injury may occur despite adequate intraoperative protection with hypothermia and reimplantation of the critical lower intercostal or lumbar arteries. Recent clinical studies, in contrast to those reported during the early experience with the use of hypothermia for protection of the spinal cord, have demonstrated that hypothermia induced by CPB can be safely applied to patients who require extensive resections of the thoracic and thoracoabdominal aorta. 53, 65 The number of patients in whom this technique has been used is relatively small. However, this initial experience suggests that the prevalence of spinal cord ischemic injury may be reduced in patients who are at high risk for development of this complication. We thank James L. Cox, MD, for support and advice. We acknowledge the assistance of Richard Torack, MD, with histopathologic analysis and that of Brad Wilson, PhD, with statisticalcomputation. We also thank Donna Marquart, Michael Lischko, Dennis Gordon, and Timothy Morris for technical assistance and assisting with animal care. REFERENCES I. AdamkiewiczA. Die Blutgefaesse des menschlichenRuek-

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