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Ann Thorac Surg 2007;84:768-774
© 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 13, 2007.
* Address correspondence to Dr Halstead, Department of Cardiothoracic Surgery, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029 (Email: jameschalstead{at}yahoo.co.uk).
Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.
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Abstract |
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Methods: Thirty pigs (26.3 ± 1.4 kg), cooled to 15°C on cardiopulmonary bypass, using alpha-stat pH management (mean hematocrit 30%), were randomly allocated to differing brain protection strategies: 90 minutes of HCA (group A); 30 minutes of HCA, then 60 minutes of SCP (group B); or 90 minutes of SCP (group C). Using fluorescent microspheres and sagittal sinus sampling, cerebral blood flow (CBF [mL · 100g–1 · min–1]) and cerebral metabolic rate for oxygen (CMRO2 [mL · 100g–1 · min–1]) were assessed at baseline, after cooling, during SCP (where applicable), and for 2 hours after cardiopulmonary bypass. Neurobehavioral scores were assessed blindly from standardized videotaped sessions for 7 days postoperatively.
Results: Cerebral blood flow was significantly higher (p = 0.0001) during SCP (60 and 90 minutes) if preceded by HCA. The CMRO2 was also significantly higher in group B versus group C (p = 0.016) at 60 minutes. The CMRO2 in all three groups rebounded promptly toward baseline after weaning from cardiopulmonary bypass. Postoperative neurobehavioral scores were significantly worse in group A.
Conclusions: Continuous SCP provides the best brain protection overall. However, an initial period of HCA does not seem to impair late outcome; perhaps the elevated CBF and CMRO2 observed reflect a beneficial cerebral response to a recoverable insult. Clearly, 90 minutes of HCA induces permanent brain injury, even in this carefully controlled setting.
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Introduction |
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We investigated the impact of a prolonged period (90 minutes) of HCA compared with both a short period of HCA followed by SCP, and continuous SCP. A technique involving a short interval of HCA followed by SCP is advantageous clinically because it enables implementation of strategies aimed at reducing embolic injury during the period of HCA in addition to providing the potential benefits of SCP in averting global ischemic injury [7]. By utilizing a model with both microsphere delivery and postoperative neurologic assessment, we were able to interrogate both the underlying cerebral physiology and its behavioral impact.
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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 1985). The Mount Sinai Institutional Animal Care and Use Committee approved the protocol for this experiment.
Perioperative Management and Anesthesia
The animals were premedicated with intramuscular ketamine (15 mg/kg) and atropine (0.03 mg/kg) to induce sedation and facilitate endotracheal intubation. The pigs were mechanically ventilated with an inspired oxygen fraction of 0.7. During normothermia, the minute volume was adjusted to produce an arterial carbon dioxide tension of 35 to 45 mm Hg. Anesthesia was maintained with isoflurane at 1.5% and paralysis was achieved with intravenous pancuronium (0.1 mg/kg). Arterial oxygen tension was maintained above 100 mm Hg at all times.
An 8F Foley bladder catheter was placed for continuous assessment of urine output. Rectal and esophageal temperatures probes were inserted and electrocardiographic monitoring instituted. A 14G arterial line was placed in the right axillary artery for pressure monitoring, arterial blood gas sampling (Ciba Corning 865; Chiron Diagnostics, Norwood, Massachusetts), and the withdrawal of reference samples for regional blood flow determinations.
Intracranial Monitoring
Before heparinization, a midline scalp incision was made and carried down to the periosteum to reveal the intersection of the sagittal and coronal sutures. A 2-mm cutting tool was used to create a 1-cm diameter burr hole through which the superior sagittal sinus was visualized. The sinus was cannulated with a 24G catheter and used for blood gas analyses and sinus pressure monitoring. An intracranial pressure monitoring probe (Codman ICP Express; Johnson and Johnson Prof, Raynham, Massachusetts) was passed extradurally through this burr hole to allow continuous assessment, and a temperature probe was inserted into the cerebral parenchyma.
Operative Technique
The chest was opened through a small left thoracotomy in the fourth intercostal space. The pericardium was opened and the heart and great vessels were identified. After heparinization (300 IU/kg), the right atrium was cannulated with a 26F single-stage cannula, and the aortic arch with a 16F arterial cannula. Cardiopulmonary bypass was initiated at a flow rate of 80 to 100 mL · kg–1 · min–1 and thereafter adjusted to produce a minimum mean arterial pressure of 45 mm Hg. A 10F left atrial cannula was inserted for venting the left heart and injecting fluorescent microspheres.
The CPB circuit consisted of nonpulsatile roller heads, a membrane oxygenator (VPCML Plus; Cobe Cardiovascular, Arvada, Colorado), and heat exchanger (Hemotherm Cooler/Heater; Cincinnati Sub-Zero, Cincinnati, Ohio); cardiotomy suction was used. The circuit was rinsed with 1,000 mL 0.9% saline and then primed with 800 mL donor whole pig blood, together with 4,000 IU heparin. Once stable CPB was established, cooling to 15°C was undertaken (alpha-stat pH management, 6). CPB was continued for a minimum of 30 minutes after initiation to ensure thorough cooling (defined as sagittal sinus oxygen saturation > 94%), and the operating room was kept between 15°C and 18°C to minimize upward temperature drift.
Just before the commencement of HCA or SCP, diastolic cardiac arrest was achieved by adding 1 mEq/kg potassium chloride to the venous reservoir. Then, for group A and group B animals, HCA was initiated. For group C animals, clamps were placed across the ascending aorta and the proximal descending aorta to isolate the arch, and SCP was started and maintained at a mean pressure of 50 mm Hg. Group B animals underwent these maneuvers after 30 minutes. Myocardial protection was supplemented by the irrigation of the pericardium with iced saline (approximately 4°C).
After the 90-minute interval, the clamps were removed and CPB with whole-body perfusion reinstituted. Rewarming was undertaken and carried through to a brain temperature of 36.5°C. Care was taken to avoid a temperature difference of more than 10°C between the perfusate and brain/rectal measurements. Cardiac defibrillation was achieved electrically without the need for pharmacologic adjuncts.
Cerebral Blood Flow and Metabolism
Fluorescent microspheres were used to determine cerebral blood flow (CBF), as detailed in previous studies [7–9]. This study utilized seven colors, with each one injected at a specific time point: at baseline, after 30 minutes of cooling (15°C), 15 minutes post-CPB, and 2 hours post-CPB in all animals. In addition, group B animals had injections after 30 and 60 minutes of SCP, and group C animals after 30, 60, and 90 minutes of SCP. For each injection, 2.5 million microspheres (15.5 µm diameter; Interactive Medical Technologies, Irvine, California) were administered into the left atrial catheter at baseline and post-CPB, and directly into the arterial catheter for the measurements after cooling and during SCP. To allow calculation of regional blood flow rates, a reference sample was withdrawn from the axillary catheter at a rate of 2.91 mL/min with a Harvard pump (Harvard Bioscience, Holliston, Massachusetts).
After the 1-week period of daily neurobehavioral assessment, the animals were sacrificed by exsanguination under anesthesia, and their brains were removed. The two hemispheres were divided and the samples (1 to 3 g in weight) were taken from the right hemisphere at four locations: hippocampus, neocortex, cerebellum, and brainstem. Microspheres were recovered from the samples by sedimentation and counted using a fluorescent spectrophotometer. Cerebral blood flow was then determined from the fluorescent intensities of the tissue and blood reference samples using the formula:
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Hemodynamic and Metabolic Data
In addition to the injection of microspheres detailed above, various hemodynamic and arterial and sagittal sinus blood gas data were collected. These were taken for the following time points: at baseline; after 15 and 30 minutes of cooling; after 30, 60, and 90 minutes of either HCA or SCP; after 15 and 30 minutes of rewarming; and 15 minutes and 2 hours post-CPB. The following data were recorded: brain temperature, mean arterial pressure, intracranial pressure, sagittal sinus pressure, cardiopulmonary bypass flow (where appropriate), pH, pO2, pCO2, O2 content, hemoglobin, hematocrit, and lactate concentrations.
Behavior and Postoperative Neurologic Outcome
In the early recovery phase (defined as the first 3 hours after extubation), the animals were scored according to a six-point scale reflecting both early mental alertness and activity [10].
In addition, the animals were also taken daily from their holding areas and allowed to explore a larger environment in a specially designed room baited with strategically placed apple pieces. Animals were videotaped over a standard 3-minute period, and their performance scored in a blinded manner (5 = normal, 0 = coma or death) by a neuroscientist skilled in assessing pig behavior. The videotapes were not identified with the pig’s group or even day of convalescence, assuring maximal objectivity; scores were based on gait, balance, and ease of movement.
Statistical Methods
The animals were randomly allocated to one of the three groups according to a randomization schedule prepared by the study statistician. The group assignment was revealed just before the institution of CPB. Hemodynamic and intraoperative variables were compared at baseline using analysis of variance (ANOVA) or Kruskal-Wallis tests between groups. Later comparisons were based on measured values, or on changes from baseline if deemed more relevant. For data that were consistent with the requisite assumptions, groups were compared by repeated measures ANOVA separately for periods of cooling (after 15 minutes and at end cooling), HCA/SCP (at 30, 60, and 90 minutes), rewarming (15 minutes and 30 minutes), and recovery post-CPB (15 minutes and 2 hours). Pairwise comparisons between groups were conducted if the corresponding average difference or time-by-group interaction was statistically significant. For other variables, the three groups were compared by Kruskal-Wallis tests at relevant time points. Wilcoxon tests were used for pairs of tests comparing average behavioral or early recovery scores of group A with groups B and C combined, and group B with group C, with the Bonferroni multiple testing correction to control for an overall 0.05 significance level. Analyses were performed using SAS software (SAS Institute, Cary, North Carolina).
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Results |
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Hemodynamic and CPB-Related Data
Baseline brain temperature was in close agreement among the three groups. Moreover, the temperature changes during cooling were almost identical among the groups. During HCA/SCP group A had a lower brain temperature and, although this averaged only 0.5°C colder across the three time points, it was statistically significant. During rewarming group C’s brain temperature was significantly lower, averaging around 3°C colder over the two time points. After the end of CPB there was close agreement between the groups’ brain temperatures (Table 1).
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In terms of blood gas management, an 
-stat strategy was consistently employed, and the resulting pH and pCO2 values were in close agreement among the groups; as noted previously [11], the pig demonstrates a mild metabolic alkalosis at baseline (Table 1).
Arterial O2 saturation analyses reveal that all animals were more than 99% saturated at baseline, during perfusion (CPB or SCP), and after bypass. Sagittal sinus O2 saturation analyses reveal close agreement between groups at baseline, during cooling, SCP, and post-CPB. However, during rewarming, while there were no statistically significant between-group differences, the time-by-group interaction was significant because the group A animals maintained their saturation while the animals in groups B and C recorded lower levels at the 30-minute time point (Table 1).
Hematocrit values were also similar in all the groups at baseline (10 to 11 mg/dL) and were maintained at this level during cooling and SCP through the use of whole donor pig blood prime. That was followed by progressive hemoconcentration to values above baseline during rewarming and after CPB. All the data were consistent across the groups (Table 1).
Cerebral Blood Flow
As seen in Figure 1, the baseline CBF values of the three groups were similar (p = 0.11), and fell similarly during cooling. After this, the animals undergoing HCA experienced total cessation of cerebral perfusion. Those in group B underwent SCP from 30 minutes onward (HCA/SCP), whereas those in group C had ongoing SCP. The repeated measures ANOVA results for the period during HCA/SCP were p less than 0.0001, p = 0.002, and p = 0.02 for the group, time, and time-by-group interaction effects, respectively. Of note, the animals in group B had significantly higher changes from baseline levels of CBF than those in group C at both the 60- and 90-minute time points (p < 0.0001 and p = 0.0001, respectively): the levels of CBF afforded by SCP were far higher if SCP was preceded by a period of HCA.
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Cerebral Metabolic Rate for Oxygen
The baseline cerebral metabolic rate for oxygen (CMRO2) values (Fig 2) were in close agreement among the groups (p = 0.34), and similar to values observed in previous studies involving the pig model. During cooling, there was a marked decrease in CMRO2 in all groups, reflecting effective metabolic suppression. During monitoring of SCP, the group, time, and time-by-group interaction effects of the ANOVA had p values of 0.05, 0.05, and 0.10, respectively. The animals in group B had higher CMRO2s than those in group C at the HCA/SCP 60-minute time point (p = 0.016), but not at 90 minutes (p = 0.14). After CPB, the CMRO2 had increased toward but had not reached baseline in all three groups at 2 hours. The post-CPB levels remained somewhat depressed in group A, but not significantly so; none of the ANOVA effects was statistically significant in this period (p = 0.14, 0.92, 0.40).
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The data from the blinded analysis of the daily videotaped sessions in the maze room are shown as Figure 3. There is a highly significant association between group allocation and neurobehavioral score (p < 0.0001 for the average scores over days 1 to 3; p = 0.0002 for the average over days 4 to 7, Kruskal-Wallis tests).
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Comment |
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We have previously used our porcine model to look at the physiology of SCP compared with whole body perfusion (CPB) at the same hypothermic temperature [7]. This study showed that SCP results in significantly greater levels of cerebral blood flow and smaller rises in intracranial pressure. A subsequent study [8] compared HCA followed by CPB (HCA/CPB), HCA followed by SCP (HCA/SCP), and SCP alone over a 90-minute interval at 20°C. It corroborated the prior finding of enhanced cerebral blood flow with SCP, and also showed a significant behavioral benefit from the use of SCP (HCA/SCP or SCP alone) relative to the group undergoing HCA/CPB. These studies gave us insight into the physiology of SCP, but given that continuous whole body perfusion during clinical aortic arch surgery is seldom undertaken, we planned the present study to directly compare SCP with HCA at 15°C, a more clinically relevant temperature for use of HCA alone. The cerebral blood flow results with continuous SCP showed the anticipated slight increase relative to CPB at the same temperature and pressure. However, the most dramatic finding was the hyperemia seen at 60 minutes in those receiving SCP after a short HCA interval, which was double the baseline perfusion at 37°C. This increase in CBF was not associated with an increase in intracranial pressure, and may represent part of a beneficial mechanism reversing the effects of the 30-minute interval of HCA. The elevation of CMRO2 at the same time point, albeit more modest, may likewise be a reflection of a recovery process after HCA. Both cerebral blood flow and metabolism in group B were closer to the group C values by 90 minutes, and the animals in group B had neurobehavioral outcomes comparable with those in group C by 7 days. The acute physiologic measurements after HCA in group A did not provide direct insight into the nature of the more severe insult this group sustained.
The behavioral analysis certainly supports the widely held notion that SCP is better than HCA alone for prolonged procedures, even in the presence of quite profound hypothermia. The group receiving 30 minutes HCA followed by SCP had results more akin to continuous SCP than HCA alone. As a result, it would seem reasonable to recommend either the continuous use of SCP through balloon-tipped catheters [16], which can be quickly inserted, or use of a trifurcated or other branched graft [2], which requires about 30 minutes to place. We prefer the latter approach, believing that it may reduce the risk of macroparticulate embolization by avoiding manipulation of the brachiocephalic vessels—which are often affected by severe atherosclerosis at their origins in aneurysm patients—during perfusion.
Clearly, there are issues regarding the details of how best to provide SCP. Ongoing work in our laboratory is assessing this question. From work completed, and the reports of others, we would suggest using an alpha-stat strategy in the adult vasculopathic population [6], probably at 15°C [17], with a hematocrit of 30% [18]. The current study suggests that the protection from embolization provided by a short interval of HCA before SCP does not impair ultimate behavioral recovery, although it may slow it. It has also demonstrated that SCP and HCA/SCP provide cerebral protection superior to that of prolonged HCA alone, even with careful cooling to 15°C.
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Discussion |
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DR HALSTEAD: Yes, we have always tended to focus on sort of direct clinical outcome of the animals rather than the histopathologic correlates, and I think that is really for a variety of historical reasons perhaps. But for this particular study we have actually kept the contralateral hemispheres, so that is the left cerebral hemispheres of all of these pigs, preserved, and we hope down the line to be able to provide you with some histologic data. I think that as we move forward now, though, we will probably be presenting more data really relating just to the optimal provision of SCP, and there we have in some pilot studies noted that we have different functional outcomes in animals for whom there is hardly any histopathologically detectable damage because they have all had some form of selective cerebral perfusion. So while it is true that histopathology is, of course, a key part of these presentations, or should be a key part of these data, I think we are actually finding that the results that we get from the maze are able to give us a finer level of differentiation of outcome than histopathology does in the context of selective cerebral perfusion—obviously not, though, in the context of hypothermic circulatory arrest.
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References |
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