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Ann Thorac Surg 2007;84:789-794
© 2007 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, Division of Biostatistics, Mount Sinai School of Medicine, New York, New York
b Department of Neurosurgery, Division of Biostatistics, Mount Sinai School of Medicine, New York, New York
c Department of Anesthesiology, Division of Biostatistics, Mount Sinai School of Medicine, New York, New York
Accepted for publication April 16, 2007.
* Address correspondence to Dr Halstead, Department of Cardiothoracic Surgery, Mount Sinai School of Medicine, One Gustave L. Levy Pl, New York, NY 10029 (Email: jameschalstead{at}yahoo.co.uk).
Presented at the Basic Science Forum of the Fifty-third Annual Meeting of the Southern Thoracic Surgical Association, Tucson, AZ, Nov 8–11, 2006.
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Abstract |
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Methods: Twelve juvenile Yorkshire pigs (mean weight, 22.3 kg) were randomized to segmental artery sacrifice at 32°C or 37°C. Cord integrity was assessed with myogenic-evoked potential (MEP) monitoring. Stepwise craniocaudal sacrifice of segmental arteries was continued until MEP diminution occurred; the last segmental artery was then reopened. Fluorescent microspheres were used to measure spinal cord blood flow (SCBF) at baseline, 5 minutes, 1 hour, and 3 hours after segmental artery sacrifice. Hind limb function was monitored for 5 days.
Results: All animals recovered normal hind limb function. At 32°C, more segmental arteries, 16.5 versus 15 (p = 0.03), could be sacrificed without MEP loss. Baseline SCBF at 32°C was 50% that at 37°C (p = 0.003) and remained fairly stable throughout. At 37°C, SCBF to the craniocaudal extremes of the cord (C1 to T3 and L2 to L6) increased markedly (p = 0.01) at 1 hour and returned toward normal at 3 hours. Concomitantly, SCBF fell in the middle portion of the cord (T9 to T13) at 1 hour before returning to normal at 3 hours.
Conclusions: Almost all segmental arteries can be sacrificed with preservation of spinal cord function. No major change occurs in the central cord in normothermic animals, but there is significant transient hyperemia in segments adjacent to extrasegmental vessels. Hypothermia reduces SCBF and abolishes this possible steal phenomenon. Metabolic and hemodynamic manipulation should enable routine sacrifice of all segmental arteries without spinal cord injury.
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Introduction |
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At Mount Sinai School of Medicine, the clinical approach to thoracoabdominal aneurysm resection has been dictated by the hypothesis that spinal cord perfusion depends on an integrated collateral network rather than the presence of single important major spinal arteries. The use of motor and somatosensory evoked potential monitoring (MEP/SSEP) has led to a technique that avoids reimplantation of segmental vessels altogether, protecting the spinal cord intraoperatively through the use of hypothermia [5] and a variety of bypass techniques (partial cardiopulmonary, left heart, deep hypothermic circulatory arrest) that are usually determined by anatomic factors [4]. Others, reporting a similarly low incidence of neurologic injury, have espoused the importance of critical vessel reimplantation in response to diminution in MEP signals [6].
We sought to examine the changes in spinal cord perfusion during MEP-monitored serial segmental artery sacrifice in a porcine model, with a focus on the impact of mild hypothermia on spinal cord blood flow (SCBF).
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Material and Methods |
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All animals received humane care in accordance with the guidelines from Principles of Laboratory Animal Care formulated by the National Society for Medical Research, and the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication No. 86–23, revised in 1985). The Mount Sinai Institutional Animal Care and Use Committee approved the protocol for this experiment.
Perioperative Management and Anesthesia
After premedication with intramuscular ketamine (15 mg/kg) and atropine (0.03 mg/kg) to sedate the animals and dry oropharyngeal secretions, an endotracheal tube was inserted, and a 20-gauge catheter was placed in a suitable ear vein. The animals were then transferred to the operating room and were mechanically ventilated with a fraction of inspired oxygen of 0.7, and a minute volume adequate for maintenance of a normal PCO
2 (30 to 40 mm Hg). A crystalloid infusion was started to maintain hydration (12 mL/[kg · hour]). Anesthesia was induced by the bolus intravenous administration of propofol (1 mg/kg) and fentanyl (50 µg/kg) and was maintained with infusions of ketamine (15 mg/[kg · hour]), propofol (7 mg/[kg · hour]), and fentanyl (5 µg/[kg · hour]).
An 8F Foley catheter was placed in the bladder for continuous monitoring of urine output, and temperature probes were placed in the rectum and esophagus. Electrocardiographic monitoring was continuous. Systemic arterial pressure was monitored by using a 14-gauge right brachial artery catheter, through which blood gas analyses were also regularly monitored (Ciba Corning 865, Chiron Diagnostics, Norwood, MA) and reference samples for regional blood flow determinations were withdrawn.
Monitoring for Motor-Evoked Potentials
A 3-cm midline scalp incision was made, through which the periosteum was elevated to reveal the sagittal and coronal skull sutures. Four stainless steel electrodes were screwed into the skull: 2 were placed 1 cm to the left and 2 1 cm to the right of the sagittal suture; the anterior one of each pair was sited 0.8 cm in front of the coronal suture, the other 0.8 cm behind the suture. The electrodes were connected to an electrical stimulator (Digitimer Stimulator Model D 180A, Welwyn Garden City, UK).
Electromyographic recordings were made from stainless steel needle electrodes placed into the anterior and posterior muscle compartments of both fore and hind limbs. A stimulation train (3 pulses: 200 to 300 V, 100-µs pulse duration with a 2-millisecond interstimulus pause) was delivered to the skull electrodes, and the MEPs were recorded in the limbs. The MEP signal was amplified (x2000), bandpass filtered (10 to 1000 Hz), and displayed using a Spectrum 32 neurophysiologic recording system (Cadwell Laboratories Inc, Kennewick, WA).
Operative Technique for Motor-Evoked Potentials–Monitored Segmental Artery Sacrifice
A left posterolateral thoracotomy was made through the seventh intercostal space. The thoracic aorta was mobilized, from the left brachiocephalic artery (the pig has 2 brachiocephalic vessels) proximally down to the aortic opening behind the diaphragm distally, to expose its segmental vessels at their origins. These vessels arise on the left side dorsolaterally as a single vessel that later divides into right and left branches.
A linear left flank incision was made from the costovertebral angle cranially to the posterior aspect of the iliac crest caudally. Through this incision, the abdominal aorta was exposed from the distal extent of the thoracic dissection down to the vessel’s trifurcation (the pig has a median sacral artery of similar calibre to its common iliac arteries), without entering the peritoneum, to expose its segmental vessels at their origins.
During the above preparations, we allowed the temperature of group A pigs to drift down to 32°C by keeping a normal ambient room temperature (active cooling was not used). Heating blankets were used to maintain a temperature of 37°C in the group B pigs.
Once the target temperature had been attained, heparin (300 IU/kg) was administered into the ear vein catheter. A tiny opening was made into the pericardium over the left atrial appendage and an 8F catheter was placed through this into the body of the left atrium for microsphere delivery. Baseline MEPs were assessed, and a baseline SCBF measurement was obtained.
The segmental vessels were then sacrificed, one at a time, in the craniocaudal direction. The vessels were clamped for 5 minutes, with MEPs taken at 1, 3, and 5 minutes to assess whether each vessel was critical. If there was no MEP diminution (>75%), the vessel was clipped, divided, and its caudal neighbor clamped, and the MEPs repeated. This process was repeated down the aorta until a critical vessel was identified by a MEP diminution exceeding 75%. Once identified, this vessel was promptly reopened. MEP return occurred within 5 minutes in all animals. Once the critical vessel had been identified, microsphere SCBF measurements were taken at 5 minutes, 1 hour, and 3 hours after it had been reopened. The Yorkshire pig has 17 segmental vessels (11 thoracic and 6 lumbar) that arise directly off the aorta.
After the final microsphere injection, the left atrial catheter was removed, the scalp electrodes were detached, and the incisions were closed. Anesthesia was discontinued, the remaining catheters were removed, and the pig was weaned from the ventilator.
Fluorescent Microsphere Spinal Cord Blood Flow Measurement
Fluorescent microspheres were used to determine SCBF, as detailed in previous studies [7–9]. This study used four colors, with one injected at each specific time point given above. For each injection, 2.5 million microspheres (15.5 µm diameter, Interactive Medical Technologies Ltd, Irvine, CA) were administered into the left atrial catheter. To allow calculation of SCBF rates, a reference sample was withdrawn from the brachial artery catheter at a rate of 2.91 mL/min with a Harvard pump (Harvard Bioscience Inc, Holliston, MA).
After the 5-day period of daily neurologic assessment, the animals were euthanized by exsanguination under anesthesia, and their spinal cords were removed. The spinal cords were cut into 12 similar-sized segments for subsequent analysis: C1 to C2, C2 to C4, C4 to C8, C8 to T3, T3 to T5, T5 to T7, T7 to T9, T9 to T11, T11 to T13, T13 to L2, L2 to L4, and L4 to filum terminale. Microspheres were recovered from the samples by sedimentation and counted using a fluorescent spectrophotometer. SCBF was then determined from the fluorescent intensities of the tissue and blood reference samples using the formula SCBF (mL/[100 g · min)] = 100 x [(R x It)/(Ibr x Wt)], where R is the blood reference withdrawal rate (2.91 mL/min), It and Ibr are the tissue and blood reference samples’ fluorescent intensities, and Wt is the weight of the tissue sample in grams.
Hemodynamic and Metabolic Data
In addition to the injection of microspheres, various hemodynamic and arterial blood gas data were collected. These comprised rectal and esophageal temperature, mean arterial pressure (MAP), heart rate, pH, PO
2, PCO
2, hemoglobin, and glucose concentrations.
Postoperative Neurologic Outcome
Neurologic examination using a modified Tarlov score [5, 7] was done daily at the same time by an investigator blinded to the grouping. The scoring system was as follows: 0 = no voluntary movement; 1 = perceptible movements at joints; 2 = good movements at joints but inability to stand; 3 = ability to stand and walk, and 4 = complete recovery. On postoperative day 5, the animals were euthanized.
Statistical Methods
The animals were randomized to one of the two temperature groups in accordance with a schedule prepared by the study statistician. The group assignment was revealed just before the induction of anesthesia.
Hemodynamic and intraoperative variables were summarized by means and standard errors for each group at each time point. Repeated measures analysis of variance (ANOVA) was used to compare groups during the four time points. Changes from baseline values for each group at each time were tested for significance by one-sample t tests.
Flow data for the two temperature groups were compared at three distinct regions: segments C1 to T3 (top), segments T9 to T13 (middle section), and segments L2 to filum terminale (bottom). Repeated measures ANOVA was used to compare the groups’ average baseline values over the three segment regions. Changes from baseline flow were averaged over the component segments and tested for significance using one-sample t tests for paired data. Between-temperature group and between-region comparisons of changes from baseline flow were tested in a repeated measures mixed model with unstructured covariance matrix, separately at each of the time points, and contrasts testing specific segment comparisons were constructed within these models.
The numbers of vessels sacrificed were compared by the Wilcoxon rank sum test, using exact one-sided p values. All other tests were two-sided. Values of p < 0.05 were considered statistically significant. Analyses were performed using SAS software (SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Number of Segmental Vessels Sacrificed
In group A (32°C), the median number of segmental vessels that could be sacrificed before significant MEP diminution occurred was 16.5. In group B (37°C), it was 15 (p = 0.03).
Spinal Cord Blood Flow
The changes observed in SCBF are depicted in Figures 1 and 2.
The statistical analyses comparing the groups’ changes from baseline flow in the three segment regions showed significant differences (p = 0.008, p = 0.007, p = 0.02 at 5 minutes, 1 hour, and 3 hours, respectively). There were no significant differences in overall average flow between the two groups (p = 0.99, p = 0.29, p = 0.30), but the group-segment interaction at 1 hour was significant (p = 0.84, p = 0.02, p = 0.91).
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At 37°C (Fig 2), no significant change from baseline was seen at 5 minutes. At 1 hour, SCBF to the craniocaudal extremes of the cord (C1 to T3 and L2 to filum terminale) increased. These values were significantly greater than baseline values in the cranial segment (p = 0.04), and SCBF at both extremes of the cord was significantly higher than SCBF in the midsection of the cord at the 1-hour time point (p = 0.004, p = 0.005). SCBF fell slightly—but not significantly—from its baseline value in the middle cord at the 1-hour time point. All segments returned toward normal at 3 hours, although the cranial cord continued to show SCBF significantly above baseline values (p = 0.02).
Pig Survival and Neurologic Recovery
All pigs survived the procedure and the 5-day observation period. On the first day, the median hind limb function score was 3.5 in group A (maximum 4); in group B it was 3 (p = 0.6). Thereafter, median scores were 4 in each group until euthanasia.
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Comment |
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We have identified that more dynamic changes in SCBF take place when artery sacrifice is undertaken at conditions of normothermia than at hypothermia and demonstrated that significantly fewer vessels can safely be divided at normothermia. At normothermia, the cranial and caudal segments of the spinal cord experienced a significant transient hyperemia, which persisted in the cranial segment even at 3 hours. It may be that this is a reaction to a transient fall in SCBF below baseline in the central portion of the cord, which calls forth a protective response in the presence of undiminished demand.
Clearly, such a fall in perfusion could not have been critical, because all the animals recovered normal neurologic function, but it may be that temporary increases in SCBF above baseline values are part of an important adaptive mechanism that helps enable extensive arterial sacrifice without spinal cord injury. In this context, it should be borne in mind that this experiment stopped short of permanently sacrificing vessels that had an impact on intraoperative spinal cord function, as measured by the MEP response and confirmed by functional recovery of all the animals postoperatively. Had the insult been more severe, we might have documented a more serious and sustained fall in SCBF in the middle portion of the cord.
During hypothermia, a transient significant fall in blood flow to the middle portion of the cord was documented very shortly after segmental artery sacrifice, but was not sustained and was unaccompanied by hyperemia at the cranial and caudal extremes of the cord. We speculate that the reduced metabolic demands of the spinal cord during hypothermia may considerably lessen the protective hyperemic response in the portions of the cord closest to collateral inputs to its blood supply, making steal from the central portions of the cord less likely to occur. This allows safe sacrifice of a greater number of segmental arteries.
There are obvious anatomic differences between human and pig spinal cord perfusion, although the general features of an extensive collateral network with significant inputs from the subclavian arteries cranially and the internal iliac/median sacral arteries caudally have been shown to be common to both [8]. It is also true that the experimental situation does not allow for differences in baseline flow and likely variations in flow reserve that are likely to accompany aneurysmal vascular disease due to segmental vessel thrombosis, concomitant cardiac disease, and so forth, which make segmental artery sacrifice in a healthy pig different from the clinical situation.
Nevertheless, we believe the experimental result to be instructive with regard to the physiology of spinal cord perfusion, and especially with regard to the blood flow response to segmental artery sacrifice. Specifically, it seems clear that segmental artery sacrifice at hypothermia is accompanied by fewer dramatic and potentially worrisome changes in cord perfusion than when such sacrifice is done at normothermia. Hypothermia clearly allows a significantly greater number of segmental arteries to be sacrificed without any detrimental effects on intraoperative function or neurologic outcome, enabling avoidance of time-consuming intercostal and lumbar vessel reimplantation [9].
In outlining the perhaps unusual demands on the collateral circulation after segmental artery sacrifice, this experiment also adds weight to the argument for the use of distal bypass techniques during operation. Obviously, this model mimics graft replacement of the thoracoabdominal aorta with distal perfusion. If a protective or adaptive hyperemia normally occurs through extrasegmental vessels during aortic cross-clamping, then it seems reasonable to do everything one can to support this perfusion, including the provision of physiologic levels of distal blood pressure and flow and the use of cerebrospinal fluid drainage [10].
The same line of reasoning also favors emphasis on maintaining a constant, generous level of mean arterial pressure in the immediate postoperative period to allow the collateral network to deliver whatever compensatory flow may be needed for adequate spinal cord perfusion in the absence of a normal number of segmental arteries [11]. The dramatic contrast between the intraoperative blood flow response to segmental artery ligation at hypothermia and at normothermia suggests that some degree of hyperemia may be required during the postoperative period even after hypothermic segmental artery sacrifice, once the animals again become normothermic (and also awaken from anesthesia), increasing required SCBF. The possible call for transient hyperemia after segmental artery sacrifice reinforces the need for prolonged attention to maintenance of high perfusion pressures and continued cerebrospinal fluid drainage postoperatively to prevent the onset of delayed paraplegia even when segmental vessels have been sacrificed under optimal conditions.
The ability to undertake extensive segmental artery sacrifice safely is absolutely essential for the successful development of endovascular techniques for treatment of thoracoabdominal aneurysms. We strongly believe that further exploration of this experimental model will provide improved understanding of the physiologic response of the spinal cord circulation to segmental artery sacrifice and the development of better strategies for avoidance of spinal cord injury during and after open and endovascular thoracoabdominal aneurysm repair.
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References |
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