Ann Thorac Surg 2006;81:910-917
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Effect of Temporary Visceral Ischemia on Spinal Cord Ischemic Damage in the Rabbit
Paul W.G. Elbers, MD
a
,
Peter de Haan, MD, PhD
b
,
*
,
Ivo Vanicky, DVM, PhD
c
,
Dink Legemate, MD, PhD
d
,
Misa Dzoljic, MD, PhD
e
a Department of Anesthesiology, St. Antonius Ziekenhuis Nieuwegein, Nieuwegein
b Department of Anesthesiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands
c Institute of Neurobiology, Slovak Academy of Sciences, Kosice, Slovak Republic
d Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
e Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Accepted for publication September 9, 2005.
* Address correspondence to Dr de Haan, Department of Anesthesiology, Onze Lieve Vrouwe Gasthuis, PO Box 95500, 1090 HM, Amsterdam, the Netherlands (Email: p.dehaan{at}olvg.nl).
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Abstract
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BACKGROUND: Spinal cord ischemia and visceral ischemia may occur simultaneously during thoracoabdominal aortic aneurysm repair. The present rabbit study investigated the effect of a temporary interruption of the visceral perfusion on the development of ischemia-reperfusion injury of the spinal cord.
METHODS: Spinal cord ischemia was induced by occlusion of the infrarenal aorta for variable durations (6 to 20 minutes) in 32 rabbits. In the visceral ischemia group, 20-minute concurrent clamping of the celiac trunk and mesenteric arteries was performed. At 24, 48, and 72 hours after ischemia, neurologic outcome was assessed in the control and visceral ischemia group. The PD50 (the duration of ischemia that produces lower limb neurologic deficits in 50% of the animals) was determined by quantal bioassay analysis. At 72 hours, histologic evaluation of spinal cord infarct size was performed.
RESULTS: Compared with control animals, PD50 was significantly longer in the visceral ischemia group at 48 hours and 72 hours after ischemia. Neurologic and histologic outcomes correlated well (r = –0.90).
CONCLUSIONS: The results of the present rabbit study suggest that concurrent temporary visceral ischemia does not aggravate spinal cord ischemic injury in the rabbit. Moreover, the results suggest that concurrent visceral ischemia may increase the tolerance of the spinal cord to ischemic damage.
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Introduction
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Surgical repair of thoracoabdominal aortic aneurysms (TAAA) necessitates prolonged aortic cross clamping. The resulting interruption of blood flow may evoke ischemic complications, probably the most devastating of which is paraplegia. Significant advances in the understanding of the pathogenesis of spinal cord ischemic injury have resulted in many adaptations to the surgical and anesthetic management of TAAA repair [1–5]. Although protective strategies reduced the incidence of paraplegia, the procedure is still associated with an incidence of irreversible lower limb neurologic deficit of as many as 10% [1–5].
Visceral ischemia/reperfusion injury is an obligatory component of TAAA repair, and appears to play a central role in the development of multiple organ failure, which is an important cause of death in the postoperative phase of TAAA repair [4]. The pathophysiologic mechanism is theorized to include bacterial translocation and consequently the release of proinflammatory cytokines leading to an inflammatory response both locally and systemically [6]. Remote damage induced by intestinal ischemia has been shown for the lung, in which it can generate alveolar damage and edema, probably mediated by cytokine and leukocyte activation [7]. Inflammatory mechanisms are also part of the neurodestructive cascade in experimental spinal cord ischemia [8]. Moreover, recent evidence suggests that an inflammatory component may play a role in late onset paraplegia after TAAA repair [9]. Therefore, visceral ischemia/reperfusion during TAAA repair may modulate the pathogenesis of spinal cord ischemic injury.
The present rabbit study was designed to evaluate the effect of a temporary interruption of visceral blood flow on neurologic and histopathologic outcomes after concurrent transient spinal cord ischemia.
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Material and Methods
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Experimental procedures and animal care were performed in compliance with the Law on Animal Experiments and the Decision on Animal Experiments in the Netherlands. The study protocol was approved by the Animal Research Committee of the Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. We used 32 New Zealand white rabbits weighing 3.22 ± 0.32 kg. Animals were allowed free access to standard rabbit chow and tap water.
Anesthesia
After premedication with ketamine (50 mg · kg–1 intramuscularly) and xylazine (7 mg · kg–1 intramuscularly), anesthesia was induced with isoflurane 2%. The rabbits were intubated and isoflurane concentration was kept at 1.5%. End-tidal CO2 was continuously measured using a mainstream capnograph (Hewlett-Packard, Boeblingen, Germany). Rectal temperature was maintained at 38°C by means of a heating lamp and heating pad. A catheter was placed in an ear artery for measuring proximal arterial pressure (PAP) and blood withdrawal. An ear vein was catheterized for administration of fluids. Throughout surgery, normal saline was administered at a rate of 5 mL · kg–1 · h–1. Lactated Ringers, fenylefrine (0.5 mg · mL–1), efedrine (5 mg · mL–1), and NaHCO3 (1 M) were administered to keep PAP at 60 mm Hg. After the surgical procedure and hemodynamic stabilization, isoflurane administration was stopped and animals were allowed to emerge from anesthesia. When adequate respiration was shown, monitoring and intravenous access were discontinued. All animals received buprenorfine (0.3 mg · mL–1; 0.03 mg · kg–1; intramuscularly) for postoperative analgesia.
Surgical Procedure
Under sterile conditions, a median laparotomy was performed. After transposition of the viscera towards the right, careful dissection was used to expose the celiac trunk, the superior mesenteric artery (SMA), and the inferior mesenteric artery at their aortic origins. The aortic segment just below the origin of the left renal artery was also exposed. Special care was taken to avoid damage to the mesenteric lymph duct, which is intimately associated with the abdominal aorta. After a stabilization period of 10 minutes, the exposed vessel segments were clamped using miniature vascular clips for the celiac trunk, SMA, and inferior mesenteric artery, and a mosquito clamp with the legs covered by polyethylene tubing for the infrarenal aortic segment. The experimental design determined whether all vessels were clamped and the duration of clamping in each animal. When clamps were in place, the viscera were repositioned, and the abdomen was provisionally closed. After the experimental procedures, all clamps were released simultaneously and restoration of blood flow was confirmed visually. The abdomen was closed in layers.
Experimental Design and Randomization
Animal randomization was performed with a draw after all vessel segments had been exposed. The duration of spinal cord ischemia was predetermined, different for each animal, and indicated on the randomization ticket drawn. These predetermined durations are given in Table 1
and were chosen to include a full range of outcomes ranging from paraparesis to normal function based on pilot experiments and previous reports. Animals were allocated to one of two groups: control and visceral ischemia. In both groups, spinal cord ischemia was induced by clamping the aorta just below the origin of the left renal artery. In the visceral ischemia group, the mesenteric trunk, the SMA, and the inferior mesenteric artery were also clamped. The duration of visceral ischemia was 20 minutes. The timing of splanchnic ischemia onset was chosen so that the end of the 20-minute period coincided with the end of the spinal cord ischemia. Thus, in every rabbit all clamps were removed at the same moment. Intravenous sodium nitroprusside (SNP) was administered in the visceral ischemia group to control PAP at approximately 60 mm Hg, and to prevent a rise in PAP after clamping the mesenteric arteries, which might increase spinal cord perfusion pressure. It was determined beforehand that should a rabbit die before all time points of neurologic evaluation had passed, it would be replaced once, up to the maximum number (32) of animals allowed by the Animal Research Committee.
Neurologic Evaluation
At 24, 48, and 72 hours after the surgical procedure, an observer masked to the randomization procedure determined the neurologic status of the animals. Hind limb function was assessed according to a modified Tarlov score, which is a 5-point grading scale: 0 = paraplegia with no lower extremity function; 1 = poor lower extremity motor function, weak antigravity movement only; 2 = some lower extremity motor function with good antigravity strength but inability to draw hind limbs under the body or hop; 3 = ability to draw legs under the body and hop but not normally; 4 = normal motor function. If required, bladder and sigmoid contents were removed by manual expression in paraplegic animals.
Histologic Evaluation
Immediately after the final neurologic assessment, animals underwent anesthesia as described above. After ligation of the SMA, the aorta and vena cava were cannulated proximal to the level of the right renal artery. After administration of heparin (2,500 IU, intravenously), at least 1 L normal saline was infused to remove the blood distal to the cannulation site. Pentobarbital (50 mg · kg–1 intravenously) was administered, and the animals were perfused with 750 mL formalin 3.6%. The lumbosacral part of the spinal cord was removed en bloc and immersed in formalin for at least 10 days. The spinal cord was sampled systematically [10]. Twelve equidistant 1-mm-thick transverse slices were dissected and embedded in paraffin. From each paraffin block, randomly selected 4-µm-thick sections were cut and stained with hematoxyline and eosine. At low magnification, one section from each block was digitized. Total gray matter as well as infarcted gray matter was measured using interactive image analysis software (Qwin; Leica, Cambridge, United Kingdom) by an observer masked to group allocation. To further specify the localization of infarctions, gray matter area was separated into dorsal, intermediate, and ventral zones by dividing the dorsoventral axis of gray matter into three equal parts.
Statistical Analysis
Hemodynamic data, blood gas values, and temperatures are expressed as means ± SD. Neurologic outcome scores were converted to one of two endpoints: normal motor function for Tarlov score 4, and impaired motor function for Tarlov scores 0 to 3. From these binary outcomes, quantal dose response curves were constructed for each group and each evaluation timepoint using iterative fitting of a logistic function, resulting in a sigmoid curve. This analysis has been described in detail, and its utility has been repeatedly demonstrated in both pharmacologic and neurologic studies [11]. The resulting sigmoid curve represents the calculated percentage of animals with impaired motor function at any given duration of spinal cord ischemia. This curve is shifted to the right if neuroprotective measures are applied.
The paraplegic duration-50 (PD50) is the duration of spinal cord ischemia, which leads to a calculated average of 50% lower limb neurologic deficits. The PD50 was calculated for both groups at all neurologic evaluation time points. As the statistical approach only yields standard errors of the mean (SEM) for a calculated PD50, these are given instead of SD. All further statistical analysis was performed using GraphPad Prism software version 3.00 for Windows (GraphPad Software, San Diego, California [www.graphpad.com]). The PD50s were analyzed using two-way analysis of variance (TANOVA), time point and group allocation being the factors. If variance was found to be significantly (p < 0.05) inattributable to chance, Student's t tests for intergroup comparisons were carried out, applying Tukey-Kramer's correction for multiple comparisons. Physiologic parameters were also analyzed using Student's t test with Tukey-Kramer's correction. All p values of 0.05 or less were considered significant. Correlation between neurologic and histopathologic outcome was assessed using Spearman's nonparametric test. Differences between means and the corresponding 95% confidence interval (CI) are given where possible and appropriate.
Although power analysis is cumbersome for this type of statistics, we did perform one based on t-test power analysis for PD50 values [11]. Based on pilot experiments, we expected a baseline PD50 value of about 13 minutes for the control group, and considered a 3-minute deviation from this in the splanchnic ischemia group, although arbitrarily, to be a relevant difference. With an assumed standard deviation of 2.5 minutes, an alpha level of 0.05, and a power (1-beta) of 0.80, this yielded a minimum group size of 14.
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Results
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Inclusion and Premature Mortality
A total of 32 rabbits underwent randomization. Nine rabbits did not survive until final neurologic scoring could be performed (control, 5 [27%]; visceral ischemia, 4 [28%]). Three rabbits died before the first neurologic scoring at 24 hours after the surgical procedure (control, 1; visceral ischemia, 2). Another three rabbits died before the 48-hour neurologic scoring could be performed (control, 2; visceral ischemia, 1). The remaining 3 rabbits died between 48 and 72 hours postoperatively (control, 2; visceral ischemia, 1). In all rabbits the cause of death was respiratory insufficiency except in 1 rabbit (control, less than 24 hours) in which the cause of death could not be identified. According to the protocol, rabbits that died prematurely were replaced once by having the treatment allocation reenter the randomization as long as the number of rabbits used would not exceed the number allowed by the Animal Committee. This resulted in replacement of 3 rabbits in the control group.
Neurologic Evaluation
Table 1 shows functional neurologic outcomes for individual rabbits. Figure 1
shows the computed quantal dose response curves at 72 hours. In the visceral ischemia group, PD50 (the duration of spinal cord ischemia, which leads to a calculated 50% of lower limb neurologic deficits) at 72 hours after ischemia was significantly longer as compared with the control group (3 minutes, 4 seconds longer than 10 minutes, 14 seconds; 95% CI: 1 minute, 20 seconds to 4 minutes, 48 seconds). The same was true for neurologic evaluation 48 hours postoperatively (2 minutes, 43 seconds longer than 10 minutes, 35 seconds; 95% CI: 58 seconds to 4 minutes, 29 seconds). Figure 2
shows the development of PD50 durations over time in both groups. Although the control group shows a trend of neurologic deterioration over time, the effect was not statistically significant.
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Fig 1. The sigmoid curves represent the calculated percentage of animals with impaired motor function as a function of the duration of spinal cord ischemia (subrenal aortic cross-clamping) at 72 hours of reperfusion. The PD
50
is the duration of ischemia that produces lower limb neurologic deficits in 50% of the animals in the control and visceral ischemia group. The horizontal error bars represent standard error of the mean (SEM). The curve labeled splanchnic ischemia is shifted to the right, implying that visceral ischemia increases the tolerance of spinal cord ischemia. *Indicates a statistically significant difference between groups (p < 0.05). (Black line = splanchnic ischemia; gray line = control.)
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Fig 2. Results of neurologic evaluation at the different time points are shown. The PD
50
is the duration of subrenal aortic cross-clamping at which 50% of the animals had impaired lower limb motor function. Error bars represent standard error of the mean (SEM). *Indicates a statistically significant difference between groups (p < 0.05). (Black bars = splanchnic ischemia; gray bars = control; h = hours.)
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Histopathologic Evaluation
Visual inspection of the bowel before the start of perfusion fixation demonstrated no evidence of infarction. A total of 23 spinal cords were harvested for histopathologic analysis (13 control, 10 visceral ischemia). None of the cords showed thrombosis of spinal arteries. Figure 3
shows scatter diagrams of Tarlov scores at 72 hours postoperatively versus anterior horn gray matter infarction percentage for both group and for both groups combined. Analysis with the Spearman correlation test showed good correlation between these variables in both groups (control, r = –0.90, 95% CI: –0.97 to –0.69; visceral ischemia, r = –0.83, 95% CI: –0.95 to –0.79; both groups combined, r = –0.90, 95% CI: –0.96 to –0.77).
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Fig 3. For individual rabbits, the percentage of anterior horn gray matter infarct is plotted against Tarlov scores. See text for details and correlation coefficients. (Black dots = splanchnic ischemia; gray dots = control.)
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Physiologic Parameters
The physiologic parameters are given in Table 2. No significant intergroup differences were found except for the following: postoperative PAP was significantly lower in the control group (–8 mm Hg; 95% CI: –14 to –1), and serum glucose content after the surgical procedure was significantly higher in the splanchnic ischemia group (7.6 mM; 95% CI: 3.9 to 11.3). No changes in the PAP pressure tracings were observed during SNP infusion. The blood gas analysis (Table 3) showed that pH (0.10; 95% CI: 0.06 to 0.14) and base excess (5.33; 95% CI: 2.27 to 8.39) were significantly lower after the surgical procedure in the visceral ischemia group.
Anesthetic Management
The variables associated with anesthetic management are given in the lower part of Table 3. No significant difference was found between groups except for the volume of administration of Lactated Ringers solution immediately after the release of clamps. This was significantly greater in the control group (11.0 mL; 95% CI: 2.8 to 19.1).
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Comment
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In the present study, concurrent temporary visceral ischemia did not aggravate spinal cord ischemic injury in the rabbit. Moreover, 20 minutes of visceral ischemia offered protection against transient spinal cord ischemia at 48 and 72 hours of reperfusion. Functional outcomes showed significant improvement at both time points as compared with controls. Functional and histologic outcomes correlated well. This finding falsified our hypothesis and contrasts with findings that show that splanchnic ischemia is deleterious for other remote organ systems, for example, the lung [7, 12]. The absence of neuroprotection at 24 hours after ischemia suggests that a possible mechanism of protection acts on late onset ischemia-reperfusion injury. As far as we are aware, there is only one other study that described the effect of mesenteric ischemia on spinal cord ischemic injury [13]. The authors used snares to clamp the infrarenal aorta and the SMA in a rabbit model of temporary spinal cord ischemia. In contrast to the present results, SMA clamping worsened neurologic outcome. In that study, however, hemodynamic alterations were not controlled. Clamping the SMA led to small bowel ischemia only. In the present study, the mesenteric trunk and the inferior mesenteric artery were clamped in addition to the SMA. This leads to small and large bowel ischemia and liver ischemia. Although speculative, that could mean that interruption of hepatic blood flow may be responsible for the observed protective effect of splanchnic ischemia in the present study.
Possible Confounders
The rabbit spinal cord blood supply is segmental [14], and recent studies showed residual flow to the spinal cord in aortic clamping to be on the order of 2% or less [15]. However, there is still some debate regarding the complete absence of collateral circulation [16]. Proximal arterial pressure will increase as a result of clamping the mesenteric arteries. As a consequence, collateral perfusion of the spinal cord might increase, confounding the results. In the dog and the pig, the ultrashort-acting vasodilator SNP is known to shunt blood away from the spinal cord. As a result, SNP is thought to have a deleterious effect on the development of spinal cord ischemic damage [17, 18]. The underlying mechanism might be a lowering of the distal aortic pressure while increasing cerebrospinal fluid pressure, which leads to a decrease in spinal cord perfusion pressure [19, 20]. Because we thought that a beneficial effect of the increased PAP might outweigh a possible detrimental effect of the SNP, we chose SNP to control proximal arterial pressure. The results in the present study demonstrated that neuroprotection in the visceral ischemia group occurred despite SNP administration.
Possible Mechanisms for the Salutary Effect of Visceral Ischemia
The present study suggests that visceral ischemia increases the tolerance to spinal cord ischemia in the rabbit. The mechanism involved is unknown, and was not investigated in this study. However, the concept shows some resemblance to ischemic preconditioning. The latter, originally described for the heart [21], represents the protection against ischemia by an earlier period of sublethal ischemia and has been shown to exist in many organ systems including liver, kidney, bowel, brain, and interestingly, spinal cord. Subsequently, it has been shown that ischemic preconditioning can be induced by a first ischemic event in another part of the same organ [22] or even in remote organs [23–25].
In the present study, there was no perfusion phase between the two ischemic events. That implies that, even though the mechanism involved may resemble remote ischemic preconditioning, it would only be active in the reperfusion phase. The responsible pathophysiologic mechanism cannot be deduced from the present study. However, postperfusion acidosis may provide an explanatory clue. The visceral ischemia group showed a significant decline in pH as compared with the control group after release of clamps. Expressed as serum hydrogen ion concentration, this yields 39 nM in the control group versus 49 nM in the splanchnic ischemia (+26%).
Traditionally, postischemic acidosis has been suggested to worsen neurologic outcome, implying that neuroprotection was afforded by the splanchnic ischemia group despite raised serum proton concentration. However, some reports contradict the destructive effects of postischemic acidosis, although at a lower pH than was observed in the present study. For example, in lambs, ischemic myocardium recovers better when acidosis is present in the reperfusion phase [26]. Moreover, acidosis shifts the hemoglobin-oxygen dissociation curved to the right, which may increase the oxygen available to tissue [27]. Acidosis is also known to interfere with leukocyte superoxide mutation, neuronal apoptosis, phospholipase A2 activity, and expression of cell adhesion molecules [28]. All of these are thought to play a role in ischemia-reperfusion injury. Therefore, it could be hypothesized that the observed postischemic acidosis could be a protective mechanism rather than an injurious one.
Another explanation for the neuroprotective effect in the visceral ischemia group might be provided by the increased serum glucose values in the reperfusion phase. Although elevated serum glucose levels have paradoxically been shown to exacerbate neuronal damage after spinal cord ischemia [29], few experimental studies have shown that lactate and glucose supported neuronal survival after ischemia [30]. Especially, a low lactate/glucose ratio is thought to be beneficial for neuronal survival.
Limitations
During TAAA repair, cross-clamping the aorta might result in spinal cord and visceral ischemia. The importance of visceral ischemia in the development of complications after TAAA surgery has been hypothesized [4, 31, 32]. Inflammatory mechanisms are involved in the neurodestructive cascade leading to irreversible neuronal injury. Consequently, the systemic inflammatory response to visceral ischemia is thought to aggravate spinal cord ischemic injury. Unexpectedly, our data did not support this hypothesis. The present study was mainly designed to evaluate the effect of concomitant visceral ischemia on spinal cord ischemic injury. However, a limitation is that the rabbit model of spinal cord ischemia does not represent a valid model of the clinical situation during TAAA repair. There are substantial differences between the segmental blood supply to the spinal cord in the rabbit and the complex and unpredictable anatomy of the spinal cord blood supply in humans. Therefore, it is currently inappropriate to extrapolate the present findings to the clinical circumstances of TAAA repair. For confirmation of the observed phenomenon, a similar study in another species (the pig or the rat) with a spinal cord anatomy with close resemblance to humans is desirable.
Conclusion
Concurrent temporary visceral ischemia did not aggravate spinal cord ischemic injury in the rabbit. Moreover, the results of the present study suggest that ischemia reperfusion injury to the spinal cord is diminished by concurrent visceral ischemia as shown by significantly better functional and histopathologic outcomes at 72 hours post ischemia. The increased glucose concentration and the lower pH during reperfusion or a factor resulting from the liver ischemia may explain the salutary effect of visceral ischemia.
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Acknowledgments
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We acknowledge the Department of Clinical Epidemiology and Biostatistics for statistical advice; Marloes Klein, Biotechnician, Surgical Laboratory, Department of Surgery, for surgical assistance; Hanneke Beaumont, MS, and Arnout Harwig, MS, for varied assistance during the experiments; and Johan Haumann, MS, and Wouter te Riele, MS, for neurologic evaluation, all affiliated with the Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
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Abstract
Introduction
