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J Thorac Cardiovasc Surg 2007;133:942-948
© 2007 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Controlled low-pressure perfusion at the beginning of reperfusion attenuates neurologic injury after spinal cord ischemia

Enyi Shi, MD, PhDa,c,1,*,*, Xiaojing Jiang, MDb,*, Teruhisa Kazui, MD, PhDa, Naoki Washiyama, MD, PhDa, Katsushi Yamashita, MD, PhDa, Hitoshi Terada, MD, PhDa, Abul Hasan Muhammad Bashar, MBBS, PhDa

a First Department of Surgery, Hamamatsu, Japan
b Department of Anesthesiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
c Department of Cardiac Surgery, the First Affiliated Hospital, China Medical University, Shenyang, China.

Received for publication October 16, 2006; revisions received November 27, 2006; accepted for publication December 13, 2006.

* Address for reprints: Enyi Shi, MD, PhD, Attending doctor, Department of Cardiac Surgery, the First Affiliated Hospital, China Medical University, 155 Nanjingbei Street, Shenyang, 110001, China. (Email: shienyi2002{at}hotmail.com).


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Objective: Paraplegia caused by spinal cord ischemia remains a serious complication after surgical repair of thoracoabdominal aortic aneurysms. This study tests the hypothesis that controlled low-pressure perfusion at the beginning of reperfusion can attenuate neurologic injury of the spinal cord after transient ischemia.

Methods: Spinal cord ischemia was accomplished in rabbits by occlusion of the infrarenal aorta with a balloon catheter for 25 minutes. In the normal reperfusion group, reperfusion was completely restored immediately after ischemia, whereas perfusion pressure was controlled between 45 and 55 mm Hg during the first 10 minutes followed by complete reperfusion in the low-pressure reperfusion group. Functional evaluation with the Tarlov score during a 14-day observation period, histopathologic assessment of the lumbar spinal cord, and measurements of malondialdehyde levels and amyloid precursor protein immunoreactivity were performed.

Results: Neurologic impairment was remarkably attenuated in the low-pressure reperfusion group (compared with the Tarlov scores of the normal reperfusion group, P < .05 at day 2; P < .01 at days 1, 7, and 14). Compared with the normal reperfusion group, malondialdehyde levels were significantly lower in the low-pressure reperfusion group (P < .05), and the large motor neurons of the low-pressure reperfusion group were preserved to a much greater extent (P < .05). White matter injury of the low-pressure reperfusion group was also markedly attenuated as evidenced by reduction of vacuolation area of the white matter (P < .05) and decrease of the amyloid precursor protein immunoreactivity (P < .05).

Conclusion: Reperfusion initiated with low-pressure perfusion exerts neuroprotective effects on the spinal cord against ischemia/reperfusion injury.

Abbreviations and Acronyms APP = amyloid precursor protein; LR = low-pressure reperfusion group; MDA = malondialdehyde; NR = normal reperfusion group


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

Figure 1
Drs Kazui and Shi (left to right)


Paraplegia or paralysis remains a major devastating and unpredictable complication after surgical repair of descending and thoracoabdominal aortic aneurysms. Multiple factors contribute to this complication, but the principal root is temporary or permanent interruption of the blood supply to the spinal cord. Although the neurologic deficits have significantly decreased in recent times with the progress of surgical adjuncts and pharmacologic interventions, this complication still cannot be prevented completely.1,2Go

Reperfusion has the potential to introduce additional injury that is not evident at the end of ischemia, expressed as endothelial and microvascular dysfunction, impaired blood flow, metabolic dysfunction, cellular necrosis, and apoptosis, which is known as reperfusion injury.3Go An endogenous form of cardioprotection with targeted reduction of reperfusion injury, termed as "postconditioning," was recently reported, in which a series of brief mechanical interruptions of reperfusion were applied immediately at the onset of reperfusion.4Go Subsequent studies further confirmed postconditioning as a powerful cardioprotective strategy.5-7Go In addition, a clinical report demonstrated that postconditioning after coronary angioplasty and stenting protected the human heart during acute myocardial infarction.8Go The latest reports showed that postconditioning also induced powerful neuroprotective effects. In a rat model of cerebral ischemia, postconditioning reduced infarct size and blocked apoptosis and free radical generation.9Go In our previous study, postconditioning attenuated neurologic injury resulting from spinal cord ischemia, and the first few minutes of reperfusion were crucial to its neuroprotection.10Go These data indicate that intervention of the blood flow at the beginning of reperfusion can engage endogenous mechanisms to attenuate reperfusion injury specifically. In the current study, we tried to control the perfusion pressure to a comparative low degree at the beginning of reperfusion, which also can be regarded as a modified postconditioning, and sought to investigate whether this method can attenuate neurologic injuries after spinal cord ischemia.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
Animal Care and Surgical Procedure
Japanese white rabbits weighing 1.9 to 2.4 kg were used in the study. The animal protocol was approved by the Ethics Review Committee for Animal Experimentation of Hamamatsu University School of Medicine and was in accordance with the National Institutes of Health "Guide for the Use and Care of Laboratory Animals" (Bethesda, Md).

The rabbits were anesthetized with intravenous sodium pentobarbital (25 mg/kg). Core body temperature was continuously monitored with a rectal probe and was maintained at 38.5°C ± 0.5°C with the aid of a heating lamp. A 4F balloon-tipped catheter (Goodtec Inc, Huntington Beach, Calif) was inserted through an arteriotomy in the left femoral artery and advanced 15 cm forward into the abdominal aorta. Preliminary investigations confirmed that the balloon should be positioned 0.5 to 1.2 cm distal to the left renal artery.11Go After systemic heparinization (200 U/kg), spinal cord ischemia was induced by inflation of the balloon. Complete aortic occlusion was confirmed by reduction in distal aortic blood pressure to less than 20 mm Hg, which was measured through the side hole of the balloon catheter. At the end of the operation, the catheter was removed and the femoral artery was reconstructed.

Experimental Protocol
All rabbits were subjected to 25 minutes of spinal cord ischemia and then were randomly divided into the following 2 groups. In the normal reperfusion group (NR, n = 11), blood flow was completely restored immediately after ischemia. In the low-pressure reperfusion group (LR, n = 11), during the first 10 minutes of reperfusion, blood flow was partially restored and the mean blood pressure of the distal aorta was controlled between 45 and 55 mm Hg by adjusting the volume of the balloon. Then, complete reperfusion was performed. For measurement of malondialdehyde (MDA) levels, 3 rabbits from each group were sacrificed 24 hours after reperfusion. The other 8 rabbits of each group were sacrificed 14 days after the transient ischemia for histologic study.

Neurologic Assessment
During a 14-day recovery after ischemia, hind-limb motor function was assessed by 2 blinded observers using the modified Tarlov scale:12Go 0, no movement; 1, slight movement; 2, sit with assistance; 3, sit alone; 4, weak hop; and 5, normal hop.

Malondialdehyde Measurement
As a marker of oxidative stress and free oxygen radical-mediated damage, MDA levels of lumbar spinal cords (L4-6) were measured 24 hours after reperfusion using the Malondialdehyde Assay Kit (Northwest Life Science Specialties, Vancouver, Wash) according to the procedure recommended by the manufacturer. MDA concentration was calculated in nanomoles per gram of protein.

Histologic Study
Paraffin-embedded sections (4 µm) of lumbar spinal cords (L4-6) were stained with hematoxylin-eosin. In cases in which the cytoplasm was diffusely eosinophilic, the large motor neuron cells were considered to be "necrotic or dead." When the cells demonstrated basophilic stippling (containing Nissl substance), the motor-neuron cells were considered to be "viable or alive."13Go The intact motor neurons in the ventral gray matter were counted by a blinded investigator in 3 sections for each rabbit, and the results were then averaged.

White matter injury was assessed by evaluation of the vacuolation in ventral, ventrolateral, and lateral white matter using National Institutes of Health image software. The percentage of vacuolation of the 3 target areas was calculated, and the data were averaged.14Go

Immunohistochemical Staining
Immunohistochemical staining of amyloid precursor protein (APP) was used to label injured axons. Briefly, after deparaffinization, sections were blocked in normal serum and treated with the antibody against APP (Chemicon, Temecula, Calif). Then the sections were incubated with biotinylated secondary antibody followed by high-sensitivity streptavidin conjugated to horseradish peroxidase (R&D System, Minneapolis, Minn). Diaminobenzidine was used as a chromogen for light microscopy. APP immunoreactivity was assessed in 3 areas of ventral, ventrolateral, and lateral white matter with a dimension of 200 µm. Each area was divided into 9 squares, and a score of 0 (no APP accummulation) or 1 (APP accummulation in axonal awelling) was assigned to each square.14,15Go The total score of both sides in each animal was calculated (0-54).

Statistical Analysis
Values were expressed as mean ± standard deviation. Mann–Whitney U test for nonparametric values and unpaired t test for parametric values were used.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
Physiologic Parameters
The body weight and rectal temperature are shown in Table 1. All rabbits had a slight decrease in rectal temperature after aortic occlusion followed by elevation back to the preocclusion level after the start of reperfusion. There was no significant difference in the weights of the animals (P > .05), and the rectal temperature was not significantly different between the 2 groups at each time point (P > .05). The mean blood pressure of the distal aorta of the LR group during the first 10 minutes of reperfusion was significantly lower than that of the NR group (Figure 1).


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  		TABLE 1 Physiologic parameters
 

Figure 1
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  		Figure 1. Mean distal aortic pressure. NR, Normal reperfusion group; LR, low-pressure reperfusion group.

 
Neurologic Assessment
The individual neurologic scores of the 2 groups 1, 2, 7, and 14 days after reperfusion are shown in Figure 2. A 25-minute period of aortic occlusion resulted in severe lower-extremity neurologic deficits in the rabbits that received complete reperfusion after spinal cord ischemia, whereas low-pressure perfusion in the first 10 minutes of reperfusion remarkably enhanced the motor function of hind limbs after spinal cord ischemia (the average Tarlov scores at day 1, NR = 0.9 ± 1.0 vs LR = 2.9 ± 1.8, P < .01; at day 2, NR = 0.9 ± 1.1 vs LR = 2.9 ± 1.6, P < .05; at day 7, NR = 0.5 ± 0.8 vs LR = 2.8 ± 1.7, P < .01; and at day 14, NR = 0.5 ± 0.8 vs LR = 2.8 ± 1.7, P < .01).


Figure 2
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  		Figure 2. Neurologic function assessed with Tarlov score at 1, 2, 7, and 14 days after ischemia. Individual rabbits (triangles). NR, Normal reperfusion group; LR, low-pressure reperfusion group.

 
Malondialdehyde Levels
The MDA level in the lumbar spinal cord of the LR group was significantly lower compared with the NR group (group NR = 83.4 ± 14.5 nmol/g vs group LR = 60.1 ± 21.1 nmol/g, P < .05, Figure 3).


Figure 3
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  		Figure 3. MDA levels of lumbar spinal cords 24 hours after reperfusion. NR, Normal reperfusion group; LR, low-pressure reperfusion group; MDA, Malondialdehyde.

 
Histologic Assessment
Representative sections of lumbar spinal cords stained with hematoxylin-eosin are shown in Figure 4, A, and the results of counting viable motor neurons are summarized in Figure 4, B. A 25-minute aortic occlusion induced severe neuronal damage in the animals of the NR group 14 days after ischemia, as indicated by vacuolization, frank necrosis, and almost a total loss of the motor neurons. In contrast, slighter histologic changes were found in the lumbar spinal cords of animals in the LR group, and the intact motor neurons were preserved to a much greater extent (P < .05, vs NR group).


Figure 4
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  		Figure 4. Histologic assessment of the spinal cord 14 days after transient ischemia. A, Representative sections of lumbar spinal cords stained with hematoxylin-eosin (magnification 100x). B, Number of large motor neurons in the ventral gray matter. NR, Normal reperfusion group; LR, low-pressure reperfusion group.

 
Vacuolation was apparent in the white matter of the NR group but was not so notable in the white matter of the LR group (Figure 5, A). The percentage of the vacuolation area of the NR group was significantly higher than that of the LR group (P < .05, Figure 5, B).


Figure 5
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  		Figure 5. Vacuolation in white matter of lumbar spinal cords. A, Representative photomicrographs of the ventrolateral white matter in hematoxylin-eosin–stained sections (magnification 200x). B, Percentage of vacuolation area in white matter. NR, Normal reperfusion group; LR, low-pressure reperfusion group.

 
Amyloid Precursor Protein Immunoreactivity
Immunohistochemical staining revealed that APP was concentrated within axon bundles in the ventral, ventrolateral, and lateral white matter 14 days after spinal cord ischemia. Representative photographs of immunohistochemical staining for APP in the ventrolateral region of white matter are shown in Figure 6, A. As summarized in Figure 6, B, the APP scores of lumbar spinal cords of the NR group were significantly higher than those of the LR group (P < .05).


Figure 6
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  		Figure 6. Expression of APP in white matter of lumbar spinal cord. A, Photomicrographs of the immunohistochemical staining for APP in the ventrolateral white matter (magnification 200x). B, APP scores of the 2 groups. NR, Normal reperfusion group; LR, low-pressure reperfusion group; APP, amyloid precursor protein.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
The salient finding conveyed by the current study is that partial restoration of blood flow during the first 10 minutes of reperfusion by control of the perfusion pressure to 45 to 55 mm Hg protects spinal cords against transient ischemia, as evidenced by improvement of motor function, survival of large motor neurons, and attenuation of white matter injuries.

Timely restoration of blood flow is believed to be the most effective treatment to salvage neural tissue from prolonged ischemia. However, there is convincing evidence that sudden and full restoration of blood flow to ischemic cerebral tissue may paradoxically exaggerate injury that is not present at the end of ischemia. In clinical trials, patients treated with thrombolytic therapy have shown a 6% rate of intracerebral hemorrhage, which was balanced against a 30% improvement in functional outcome over controls. Destruction of the microvasculature and extension of the infarct area occur after cerebral reperfusion.16,17Go To attenuate reperfusion injury, staged or controlled reperfusion with retarded restoration of full coronary blood flow or perfusion pressure has been proposed for many years.18,19Go Postconditioning, which can be thought of as a staged or controlled reperfusion, was recently shown to provide powerful cardioprotection against transient ischemia in experimental studies and clinical works.4-8Go In addition to its cardioprotection, postconditioning also induced neuroprotection against cerebral ischemia.9Go In our previous work, a short series of repetitive cycles of brief reperfusion and reocclusion (lasting 8-12 minutes) applied during the onset of reperfusion were demonstrated to protect the spinal cord against ischemia/reperfusion injury.10Go Here, in a similar model, the reperfusion was initiated with a selective low-pressure perfusion in the first 10 minutes, and the neurologic injuries after transient spinal cord ischemia were therefore reduced. As the neuroprotective effects were evaluated during a 14-day period in the current study, low-pressure perfusion appeared to induce a long-term protection rather than a delay in the inevitable injury. Collectively, more and more evidence indicates that gentle and gradual, instead of sudden and complete, restoration of blood flow during the first few minutes of reperfusion can attenuate reperfusion injury specifically.

A well-established fact is that protection induced by modified reperfusion marshals a variety of endogenous mechanisms that operate at numerous levels and target a broad range of pathologic pathways. The mechanisms leading to neuronal cell death after ischemia are highly complex, to which oxidative stress makes a large contribution. At the onset of reperfusion, there is a "respiratory burst" lasting several minutes that originates from a number of cellular sources. This oxidative burst is followed by a moderately but persistently elevated production of oxygen radicals,20Go which are known to damage cellular lipids, proteins, and nucleic acids, and to initiate cell death signaling pathways after cerebral ischemia.21Go In addition to its direct cytotoxic effects, the burst of free radicals also induces the formation of inflammatory mediators through redox-mediated signaling pathways, leading to post-ischemia/reperfusion inflammatory injury.22Go Reactive free radical species are involved in ischemia-induced spinal cord injury, and free radical scavenger has been shown to limit neurologic deficits after spinal cord ischemia.11,23Go Postconditioning has been reported to significantly reduce superoxide anion (O2 –) generation in vivo in postischemic myocardium4,7Go and attenuate superoxide products during early reperfusion after stroke.9Go Consistently, we also observed that the neuroprotective effect of low-pressure perfusion was associated with a reduction of MDA levels of the spinal cord, which is a presumptive marker of lipid peroxidation secondary to oxidant generation. In opposition to having cytotoxic effects, reactive oxygen species also contribute to intracellular signaling and endogenous protection.24Go It is possible that reactive oxygen species played a dual role in the observed neuroprotection in the current study. The cytotoxic "burst" was attenuated and prevented from overwhelming the cytoprotective signaling function of reactive oxygen species. However, the mechanisms through which low-pressure perfusion induces neuroprotection against spinal cord ischemia remain to be defined in detail.

White matter lesions after spinal cord ischemia have generally been eclipsed by emphasis on gray matter lesions in most studies. However, recent evidence suggests that both gray and white matter injuries contribute to the motor dysfunction after spinal cord ischemia. White matter injury is of equal importance to gray matter injury,14,25,26Go and white matter is even more vulnerable to ischemia in comparison with gray matter.27Go Evaluation of only gray matter injury may underestimate the extent of spinal cord injury, and the true extent of spinal cord injury may only be obtained with the assessment of both white and gray matter injury.25Go Vacuolation and accumulation of APP were used to assess white matter injury in the current study. The vacuolation reflects a segmental swelling of myelinated axons, the formation of spaces between myelin sheaths and axolemma, and astrocyte swelling.28Go APP is transported by fast anterograde axonal transport; therefore, the accumulation of APP at the sites of injury, accompanied by morphologic evidence of axonal damage in the form of axonal swelling or bulbs, has been regarded as evidence of axonal injury.14,29Go Our data demonstrated that low-pressure perfusion attenuated white matter and gray matter injuries resulting from spinal cord ischemia.


   Conclusions
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
Our study demonstrates for the first time that partial restoration of blood flow at the beginning of reperfusion induces robust neuroprotective effects against spinal cord ischemia. The observations of the current study provide compelling evidence of a novel method of spinal cord protection against reperfusion injury specifically. Unlike postconditioning, this method can be performed without additional ischemia, which may be more acceptable for clinicians. As a simple procedure, low-pressure perfusion at the beginning of reperfusion possesses a potential clinical value in the prevention of neurologic injury after thoracic aneurysm surgery.


   Footnotes
 
1 Enyi Shi is supported by the Japan Society for the Promotion of Science. Back

* Enyi Shi and Xiaojing Jiang contributed equally to this work. Back


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

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