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Eur J Cardiothorac Surg 2007;31:643-648. doi:10.1016/j.ejcts.2007.01.023
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
a Department of Cardiothoracic Surgery, Mount Sinai School of Medicine, New York, New York, USA
b Department of Neurophysiology, Mount Sinai School of Medicine, New York, New York, USA
c Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA
Received 10 September 2006; received in revised form 28 December 2006; accepted 5 January 2007.
* Corresponding author. Address: Mount Sinai School of Medicine, Department of Cardiothoracic Surgery, One Gustave L. Levy Place, PO-Box: 1028, New York, NY 10029, USA. Tel.: +1 212 659 6800; fax: +1 212 659 6818. (Email: christian.etz{at}mountsinai.org).
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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Key Words: Spinal cord perfusion/protection • Paraplegia • Segmental artery sacrifice • Thoracoabdominal aortic aneurysm repair (TAA/A)
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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Most often, neurologic injury becomes apparent immediately postoperatively, and is attributed to ischemic injury during intraoperative aortic cross-clamping and/or inadequate postoperative spinal cord perfusion. However, a small fraction of patients awaken from anesthesia neurologically normal, but develop delayed onset paraplegia hours to weeks later. The pathogenesis of both types of paraplegia, but particularly of delayed onset deficit, is still poorly understood [7]. Consequently, the effectiveness of different strategies for minimizing intraoperative spinal cord ischemia, and for managing intercostal and lumbar arteries during repair of thoracic and thoracoabdominal aortic aneurysms (TAA/A) in order to prevent paraplegia remains controversial [3,8–14].
The studies described in this report were undertaken to try to gain a better understanding in an animal model of the impact of extensive sacrifice of segmental arteries (SAs) on spinal cord perfusion intraoperatively and in the immediate postoperative period, under experimental conditions which approximate the circumstances prevailing during clinical thoracoabdominal aortic surgery. Previous studies with this model established the feasibility of routine extensive SA sacrifice without loss of function because of the existence of a dense and complex collateral arterial network feeding the spinal cord [15,16]. It is hoped that further investigation of the usual physiological and functional response of the collateral spinal cord perfusion network to the sacrifice of important contributors to its blood supply – and especially of the time course of the response – will help to elucidate how best to prevent even the rare occurrence of paraplegia after extensive SA sacrifice. Avoiding spinal cord injury despite occlusion of most SAs is critical not only for surgical repair but also for the eventual successful endovascular treatment of large thoracoabdominal aneurysms.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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This experimental model closely simulates the procedure used for resection of descending thoracic and thoracoabdominal aneurysms clinically at our institution. However, it should be noted that the anatomy of the pig differs from that of humans in having 13 thoracic (and five lumbar) segmental arteries, which arise together from the descending aorta and subsequently divide. The subclavian arteries and the median sacral arteries are both important parts of the collateral perfusion of a continuous spinal cord vascular network in both species; in humans, however, the iliac arteries provide a much greater proportion of the flow into the collateral network. In the clinical situation, cross-clamping of the aorta is occasionally required for an open distal anastomosis, and distal perfusion and spinal fluid drainage are routinely utilized to minimize intraoperative spinal cord ischemia. This experimental model is simplified to allow an uncomplicated focus on the input to the collateral network in the wake of segmental artery sacrifice. Previous experiments with this model have demonstrated that the spinal cord collateral flow in the pig behaves in ways very similar to what is observed under comparable circumstances clinically in humans [15,16].
2.2 Perioperative management and anesthesia
All animals received humane care in compliance with the guidelines of ‘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 Institute of Health (NIH Publication No. 88-23, revised 1996). The Mount Sinai Institutional Animal Care and Use Committee approved the protocols for all experiments.
After pretreatment with intramuscular ketamine (15 mg/kg) and atropine (0.03 mg/kg), animals were anesthetized with intravenous sodium thiopenthal (20 mg/kg). Following endotracheal intubation, the pigs were ventilated mechanically with an FiO2 of 0.5 and anesthesia was maintained with an infusion of ketamine 15 mg/kg/h and sufentanil 5 mg/kg/h. This anesthetic regimen has no major effect on MEP responses, and has been described previously [12]. Paralysis for intubation was achieved with intravenous pancuronium (0.1 mg/kg), but no further doses were administered subsequently to avoid interfering with measurement of MEPs.
The ventilator rate and the tidal volume were adjusted to maintain the arterial carbon dioxide tension at 35–40 mmHg. End-expiratory carbon dioxide (PPG Biomedical Systems, Model 2010-200 R, Lenexa, KS, USA) was monitored continuously. Arterial oxygen tension was maintained >90 mmHg. A bladder catheter (Foley 8–10 F) was inserted for online measurement of urine output, and temperature probes were placed in the esophagus and the rectum. Electrocardiographic measurements were recorded continuously. An arterial line was placed in the right brachial artery for pressure monitoring and blood sampling (pH, oxygen tension, carbon dioxide tension, oxygen saturation, base excess, hematocrit, hemoglobin and glucose, lactate, Blood Gas Analyzer, Ciba Corning 865, Chiron Diagnostics, Norwood, MA, USA).
2.3 Body temperature management
After inducing anesthesia (see protocol above), the pigs were cooled to 32 °C rectal temperature by covering them with packs of artificial refrigerants for a period of 30 min. In addition, a cooling blanket was used even after the target temperature was reached to maintain hypothermia and prevent an upward temperature drift during the procedure. The operating room temperature was reduced to 14 °C. No local cooling of the vertebral column was undertaken. The animals were subsequently warmed using a heating blanket and a heating lamp, usually for 90–100 min, and by raising the operating room temperature to 24 °C. To prevent any intraoperative temperature drift, the small left thoracotomy in the fourth intercostal space was temporarily closed after clamping the thoracic spinal arteries.
2.4 Monitoring of postoperative systemic and spinal cord perfusion pressure (SCPP)
Two arterial lines were placed: one in the descending aorta and another in the distal arm of the segmental artery feeding the first lumbar segment. These lines enabled systemic and lumbar perfusion pressure monitoring and blood sampling (pH, oxygen tension, carbon dioxide tension, oxygen saturation, base excess, hematocrit, hemoglobin and glucose, lactate; Blood Gas Analyzer, Ciba Corning 865, Chiron Diagnostics, Norwood, MA, USA) prior to, during, and after radical sacrifice of all thoracic and abdominal segmental arteries.
2.5 Monitoring technique for motor-evoked potentials (MEPs)
A 5 cm longitudinal incision was made in the scalp overlying the skull, and the periosteum was removed to expose the sagittal and coronal sutures of the calvarium. Four stainless steel screw electrodes with attached wire leads were screwed into the skull 10 mm lateral to the sagittal suture. Two screws were placed on the left side (8 mm anterior and 8 mm posterior to the coronal suture), and two were equally placed on the right. The wire leads were connected to an electrical stimulator (Digitimer Stimulator Model D 180A, Welwyn, Garden City, United Kingdom). Electromyographic recordings were made from sterile stainless steel needle electrodes placed through the skin over the tibialis muscle in the hind leg and the muscles in the foreleg. A stimulation train (three pulses, 200–300 V, 100 ms pulse duration, and 2 ms interstimulus interval) delivered to the skull electrodes was used to elicit MEPs. MEPs were amplified (gain 2000), bandpass filtered (10–1000 Hz), digitized, and stored on an optical disk for subsequent analysis by a Spectrum 32 neurophysiological recording system (Cadwell Laboratories Inc., Kennewick, WA, USA). MEPs were recorded before clamping, during the 3-min interval after clamping of each segmental pair, and after clamping of all thoracic and abdominal segmental arteries for a period of 60 (to 90) min. The baseline value was determined just prior to the start of SA clamping. A lack of response to the stimulus is considered evidence of ischemic spinal cord injury.
Data acquisition and analysis were performed on a computer with an AD converter and software (LabVIEW, National Instruments, Austin, TX) as previously published.
2.6 Neurobehavioral assessment
All animals were videotaped at the same time daily, and a neuroscientist, blinded to the intraoperative course of events, carried out neurological scoring using a modified Tarlov score. The scale is as follows: no voluntary movements (0); perceptible movements at joints (1); good movements at joints but inability to stand (2); ability to get up and stand with assistance <1 min (3); ability to get up with assistance and stand unassisted <1 min (4); ability to get up with assistance and stand unassisted >1 min (5); ability to get up and stand unassisted >1 min (6); ability to walk <1 min (7); ability to walk >1 min (8); complete recovery (9).
2.7 Histopathological evaluation
The spinal cords were removed en bloc immediately after the pigs were euthanized. They were fixed in 10% formalin solution, embedded in paraffin, and then serially sectioned transverse to the craniocaudal axis at 0.5-cm intervals. Sections 6 µm in thickness were stained with hematoxylin and eosin, and examined by an experienced neuropathologist.
2.8 Data analysis
All data are described by means and standard deviations. Since this was an exploratory study, no formal comparative statistical analysis was performed. The few comparisons cited and p-values given were obtained by Student's t-tests.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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4 (able to stand without assistance) – were considered to have recovered function. Those pigs with a score <4 by the fifth day postoperatively were considered to have sustained spinal cord injury (paraplegia/paraparesis). Four pigs did not fully regain the ability to stand, and constituted the spinal cord injury group. Six animals – of which two could stand and four could walk – were considered to have recovered.
3.2 Intraoperative and postoperative systemic and spinal cord perfusion pressures
Target mean aortic pressure was 90 mmHg intra- and postoperatively. Only volume infusions but no pharmaceuticals were used to maintain aortic pressures.
The mean aortic pressures intraoperatively were similar between the spinal cord injury group and the pigs that recovered, so the mean aortic pressures for the group as a whole are shown in Fig. 1 .
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Postoperatively (Fig. 2 ), SCPP continued to drop further: to 21 ± 4 mmHg at 1 h, and to its lowest point – 19 ± 4 mmHg – 5 h after sacrifice of the last segmental artery. Thereafter, there was recovery, reaching (in mmHg) 33 ± 6 at 24 h; 42 ± 10 at 48 h; 56 ± 14 at 72 h; 62 ± 15 at 96 h, and returning to baseline (63 ± 20) at 120 h. There was no difference in the SCCP between the groups which recovered and which did not recover function postoperatively at any of the postoperative time points.
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3.4 Behavioral score
The pattern of behavioral scores is shown in Fig. 4
. These scores, as previously noted, were assessed on the basis of videotapes of postoperative behavior taken at the same time each day, and interpreted in a blinded format by a neurophysiologist. After the final assessment on the fifth postoperative day, the animals were sacrificed and their spinal cords were harvested for histopathological examination.
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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The severity of the acute intraoperative ischemic insult – the duration of aortic cross-clamping, for example, and the temperature at which it is carried out – certainly plays a critical role in whether acute spinal cord injury occurs [16]. However, the ways in which the spinal cord collateral circulation responds to intraoperative injury – how it compensates for the sacrifice of large numbers of SAs, and the time required for full recovery – remain largely unknown [19,20]. The observations in this study document that the recovery of spinal cord perfusion pressure in the presence of an adequate mean arterial pressure takes longer than 24 h. Very low SCPPs are present, beginning 1 h after sacrifice of the last SA: these pressures remain very low for at least 5 h, and are still well below baseline values at 24 h. Since not all of the pigs recovered function in the presence of these very low pressures, it seems reasonable to suppose that these pressures are very close to the threshold for intolerable ischemia during the recovery phase postoperatively. The discovery, upon histopathological examination, of evidence of minute areas of ischemia even in pigs with apparent complete functional recovery confirms the precariousness of the blood supply under current operative conditions. Determination of the minimal amplitude of blood pressure/flow which will assure recovery of spinal cord function and of the duration for which this minimum perfusion requirement needs to be sustained, will require further investigation.
Within the first few hours postoperatively, any fall in arterial pressure could make a critical difference, as is suggested by the graph in Fig. 3, which shows slightly but significantly higher arterial pressures at the critical 5-h nadir of SCPP in the group which eventually recovered. The observations suggest that it is very likely that meticulous attention to preserving good perfusion pressures – including pharmacological manipulations – not only intraoperatively but for at least the first 24 h postoperatively may be effective in further reducing the incidence of spinal cord injury. The very low measured pressures in the collateral circulation to the spinal cord make it quite conceivable that the small contribution in lowering outflow resistance provided by cerebrospinal fluid (CSF) drainage could have a considerable impact in improving functional outcome by helping to improve SCPP, as has been documented in both clinical and experimental studies [21–23].
The most important and not previously noted observation arising from this study is that the interval of low perfusion pressure following SA sacrifice is limited in duration: perfusion pressures nearly at baseline levels are once again present 48–72 h postoperatively in the absence of any patent SAs. This new observation underlines the clinical importance of maintaining high normal systemic pressures during the first few days postoperatively, and continuing to carefully and frequently monitor spinal cord function during this vulnerable interval. The data suggest that after 48 h, when pressures return to within the preoperative range, loss of spinal cord integrity is much less likely to occur.
Why the lowest SCPP in this experiment occurs quite consistently 5 h after sacrifice of the last SA is not readily apparent from this study. We speculate that it may reflect vasodilatation of the collateral circulation in response to increased metabolic requirements upon rewarming and recovery from anesthesia.
The physiological observations of this study thus hold out hope that some further relatively simple hemodynamic adjustments, sustained until the spinal cord perfusion pressure spontaneously regains baseline values at about 48 h, may enable routine sacrifice of large numbers of SAs – during conventional thoracoabdominal surgery and perhaps with endovascular repairs – without provoking paraplegia.
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Appendix A |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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Dr C. Olsson (Uppsala, Sweden): I have two questions for you.
First of all, are there any important differences in the anatomy of spinal cord supply between pig and man?
And secondly, do you see any way of clinically applying this monitoring in human beings?
Dr Etz: This slide shows a photograph of a vascular cast – which was prepared in our laboratory prior to this study – of the collateral network in the pig. Yorkshire pigs have 15 segmental arteries arising from the thoracoabdominal aorta (TAASA), whereas the first three branches arise from the subclavian artery. Since the Yorkshire pig has one more thoracic segment than man does, one can see the TAASA for the segments T4 to T13 and L1 to L5 here. The next slide displays the collateral network in humans: the gross anatomy – as you can see – is very similar.
With regard to your second question, we can learn from this study that SCPP reaches a nadir 5 h after complete TAASA sacrifice, and that functional recovery is associated with the mean aortic pressure during this period: this is a very important finding. Clinically translated, it means that stable postoperative hemodynamics are particularly crucial during the first 24 (to 48) h, because the collateral network has not yet recovered.
We believe that the drop in segmental artery pressure at 5 h seen in this experiment is potentially preventable using hemodynamic manipulation, and we are currently conducting pilot pharmacological studies with the objective of accelerating the collateral network's local response to segmental artery sacrifice.
Dr C. Rokkas (Athens, Greece): You’re defining spinal cord perfusion pressure as the intra-arterial pressure that supplies the spinal cord. That's not the definition we have so far in the literature. Spinal cord perfusion pressure is defined as the intra-arterial pressure minus the intrathecal pressure of the cerebrospinal fluid.
My question here is whether you measure intrathecal pressures in those animals and whether these changes in the pressures that you measure actually reflect changes within the intrathecal space.
Dr Etz: We agree that the contemporary definition of SCPP is mean aortic pressure (MAP) minus intrathecal pressure, although we think the latter is likely to be reflected not only by cerebrospinal fluid pressure, but also may depend upon central venous pressure. We are not convinced that this definition – a rather theoretical calculation – is applicable after extensive TAASA sacrifice, when direct spinal cord perfusion from the aorta is disrupted and local perfusion pressure may therefore be more divorced from MAP than usual. We, therefore, prefer to put our trust in direct measurement, using a distally inserted TAASA catheter: we believe this comes as close as one can get to reality.
The drop in SCPP occurred acutely after clamping the lower thoracic and abdominal segmental arteries – as was witnessed in the video presentation, and – even more importantly – could be reversed immediately by clip removal. Rising intrathecal pressure – presumably related to spinal cord ischemia and subsequent edema – does not occur in seconds, and would not be likely to be reversed acutely unless by CSF drainage.
CSF drainage in juvenile Yorkshire pigs is difficult in a survival experiment, since the anatomy of the spine requires a laminectomy to reliably place a catheter intrathecally, which potentially adds major risks to the postoperative course (and has thus far not been successfully accomplished in a comparable study). So we did not use CSF drainage in these 10 pigs, as we would have in humans. But we speculate that further reduction of the paraplegia/paraparesis rate below 40% in our animals could be achieved if CSF drainage were possible.
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Footnotes |
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionAppendix AReferences |
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