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Ann Thorac Surg 2003;76:1972-1981
© 2003 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, New York, New York, USA
b Department of Neurosurgery, New York, New York, USA
c Department of Biomathematics, Mount Sinai School of Medicine/New York University, New York, New York, USA
Accepted for publication June 6, 2003.
* Address reprint requests to Dr Strauch, Mount Sinai School of Medicine, Department of Cardiothoracic Surgery, One Gustave L. Levy Pl, PO Box 1028, New York, NY 10029, USA.
e-mail: ju.strauch{at}gmx.de
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Abstract |
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METHODS: In this blinded study, 30 pigs (20 to 22 kg) were randomized after cooling to 20°C. Pigs in the HCA-CPB group (n = 10) underwent 30 minutes of HCA followed by 60 minutes of total body perfusion (CPB); HCA-SCP pigs (n = 10) underwent 30 minutes of HCA followed by 60 minutes of SCP, and SCP pigs (n = 10) had 90 minutes of SCP without prior HCA. Fluorescent microspheres enabled calculation of cerebral blood flow during perfusion and recovery. Hemodynamics, intracranial pressure, cerebrovascular resistance, and cerebral oxygen consumption were also monitored. Daily behavioral scores were obtained for 7 days postoperatively.
RESULTS: In all groups, cerebral oxygen consumption fell significantly with cooling (p < 0.0001), remained low during perfusion, and rebounded promptly with rewarming; cerebral oxygen consumption was significantly (p = 0.027) greater during SCP than during HCA-CPB. Cerebral blood flow was significantly higher throughout SCP in the HCA-SCP group (p < 0.0001) than with CPB. Cerebrovascular resistance during SCP and HCA-SCP was significantly lower (p = 0.036) than during CPB. Behavioral scores were significantly better with SCP than with HCA-CPB throughout recovery, but did not differ between SCP and HCA-SCP.
CONCLUSIONS: This study suggests that a short period of HCA preceding SCP provides global cerebral protection comparable to continuous SCP, implying that in clinical practice, a short period of HCA to reduce risk of embolization will not compromise the superior cerebral protection provided by SCP.
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Introduction |
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Although HCA and SCP are used clinically, both separately and in combination [1–3], there has been little systematic study of SCP, and the physiology of SCP after HCA has never been investigated. Both hypothermic cardiopulmonary bypass (CPB) and HCA have been shown to cause a decrease of cerebral blood flow (CBF) for several hours after rewarming—at a time when the brain's demand for oxygen is already back to normal—increasing the likelihood of ischemic injury during reperfusion and recovery [4]. Such maladaptive responses of cerebral physiology may be implicated in the occurrence of the cognitive dysfunction that is often observed at least transiently in patients undergoing procedures involving prolonged HCA [5]. It is not known whether similar disturbances in cerebral autoregulation occur after SCP alone, or when a short interval of HCA is followed by an interval of SCP. In fact, we know very little about the physiology of CBF during SCP, especially if cerebral protection time is prolonged. In an earlier study, we were surprised to discover that cerebral oxygen consumption (CMRO2) and CBF were higher with SCP than with hypothermic CPB [6]. In this study, we have tried to evaluate the efficacy of cerebral protection provided by prolonged SCP, and to compare it with the response to a combination of HCA and SCP, which is similar to the strategy used clinically for aortic arch replacement.
This study was therefore undertaken in a chronic animal model to allow us to investigate how a short, clinically relevant interval of HCA preceding SCP affects not only CBF and metabolism, but also behavioral recovery. Animals undergoing HCA followed by SCP were compared with animals subjected to HCA followed by hypothermic CPB and with pigs subjected to SCP without prior HCA. Our earlier study suggested that SCP might provide better cerebral protection than total body perfusion at low temperatures [6], but whether neurologic outcome is adversely affected when SCP is preceded by an interval of HCA has not previously been investigated.
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Material and methods |
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All animals were randomized to one of three study groups:
Randomization was carried out before the start of the protocol by an independent member of the Department of Biomathematics, and was revised after half of the animals had been studied to replace animals that died before completion of the protocol.
Perioperative management and anesthesia
After pretreatment with intramuscular ketamine (15 mg/kg) and atropine (0.03 mg/kg) to induce anesthesia, animals were anesthetized with intravenous sodium thiopental (20 mg/kg). Endotracheal intubation was carried out, and the pigs were mechanically ventilated with an inspired oxygen fraction of 0.5 and isoflurane 1% to 2% to maintain sufficient anesthesia. Paralysis was achieved with intravenous pancuronium (0.1 mg/kg). The ventilator rate and the tidal volume were adjusted to maintain the arterial carbon dioxide tension at about 35 to 40 mm Hg. End-expiratory carbon dioxide and inspiratory and expiratory isoflurane were monitored continuously (PPG Biomedical Systems, model 2010 to 200 R, Lenexa, KS). Arterial oxygen tension was maintained greater than 100 mm Hg. A bladder catheter (Foley 8F to 10F) was inserted for online measurement of urine output, and temperature probes were placed in the esophagus and rectum, and in the brain through a small burr hole in the skull. An arterial catheter was placed in the right axillary artery for pressure monitoring and blood sampling (pH, oxygen tension, carbon dioxide tension, oxygen saturation, base excess, hematocrit, hemoglobin, glucose, and lactate; Blood Gas Analyzer, Ciba Corning 865, Chiron Diagnostics, Norwood, MA).
Intracranial pressure
Before cannulation for CPB, the sagittal sinus was cannulated. A midline scalp incision was made, and the underlying periosteum was removed to facilitate exposure of the coronal and sagittal sutures. At less than x2.5 magnification, a 3-mm cutting burr was used to remove the bone over the sinus. A 24-gauge catheter was inserted into the sagittal sinus to permit both sampling of cerebral venous blood and monitoring of cerebral venous pressure. An intracranial pressure (ICP) pressure probe was connected to a transducer (Codman ICP Express, Johnson and Johnson Prof Inc, Raynham, MA).
Operative technique
The chest was opened through a left thoracotomy in the fourth intercostal space. The pericardium was opened, and the heart and great vessels were exposed. After heparinization (300 IU/kg) and preparation with 4-0 pursestring sutures, the aortic arch was cannulated with a 16F arterial cannula. Venous return was drained with a single-stage 26F cannula in the right atrium. Nonpulsatile CPB, using 
-Stat pH management, was initiated at a flow rate of 80 to 100 mL · kg-1 · min-1 and then adjusted to maintain a minimum mean arterial pressure of 45 mm Hg. To avoid distension of the left ventricle during CPB and as an injection port for fluorescent microspheres, a 10F vent catheter was inserted into the left atrium.
After initiation of CPB, atelectasis was prevented by providing continuous positive pressure in the bronchial system. A heat exchanger (Hemotherm Cooler/Heater, Cincinnati Sub-Zero, Cincinnati, OH) was used for core cooling, and surface cooling was achieved with the use of a cooling blanket. The CPB circuit included roller pumps, a cardiotomy reservoir, and a membrane oxygenator (VPCML Plus, Cobe Cardiovascular Inc, Arvada, CO), which was primed with a bloodless solution consisting of 1,000 mL of 0.9% saline solution, furosemide (1 mg/kg), heparin (5,000 IU), and potassium chloride (1.5 mEq/kg). The pH was maintained, by means of -Stat principles, at 7.40 with an arterial carbon dioxide partial pressure of 35 to 40 mm Hg, uncorrected for temperature, and hematocrit was maintained between 22% and 28%. After initiation, CPB was continued for 30 minutes to reach a deep brain temperature of 20°C, to guarantee thorough cooling, and to avoid an upward drift of the temperature during the interval of circulatory arrest. For the same reason the operating room temperature was maintained at 18° to 20°C. In all animals, myocardial protection was afforded by applying iced saline (approximately 4°C) topically in the pericardium during HCA and the interval of SCP or total body perfusion. For all study groups, the ascending aorta was cross-clamped, and coronary artery perfusion was interrupted for 90 minutes. No cardioplegic solution was given.
After the previously described cannulation of the aortic arch, the proximal and distal aortic arch was cross-clamped for antegrade SCP. This allows the perfusate to flow only into the subclavian and carotid arteries. The subclavian arteries were included in the SCP circuit to allow arterial pressure monitoring from the upper extremities, and to permit withdrawal of a reference blood sample for microsphere flow calculations. We tried to maintain a stable pump flow rate of 10 to 20 mL · kg-1 · min-1 for the period of SCP. The pressure in the axillary artery was maintained at about 50 mm Hg.
After HCA or SCP, total body perfusion was reinstituted in all groups; core and surface rewarming were initiated, and continued to an esophageal temperature of 35° to 36°C. Care was taken to avoid a temperature difference between the perfusate and core temperature of more than 10°C. During weaning from CPB, an infusion of 3 to 5 mg · kg-1 · min-1 dobutamine was frequently used. When necessary, cardiac defibrillation was performed after administration of lidocaine (1 mg/kg). After decannulation, protamine sulfate (5 mg/kg) was administered to reverse heparinization.
Cerebral blood flow
Cerebral blood flow was measured with fluorescent microspheres as described in previous studies [7]. In brief, approximately 2 million microspheres 15 ± 0.5 µm in diameter in seven different colors were injected and flushed with 5 mL of saline solution into a left atrial catheter before and after CPB and into the aortic cannula during SCP or CPB.
Before injection, the fluorescently labeled microspheres, suspended in 10% dextran with 0.05% polyoxyethylene sorbitan monooleate (Tween 80) were mixed, sonicated, and vortexed. To allow calculation of absolute blood flow rates, a reference blood sample was taken from the axillary artery at a rate of 2.9 mL/min with a Harvard withdrawal pump (Harvard Bioscience, Inc, Holliston, MA). Withdrawal of blood started 10 seconds before injection of the microspheres, and was continued for 110 seconds after microsphere injection [8, 9].
In all animals, the brain was removed, the two hemispheres were cut in the middle, and the specimens were weighed. Tissue samples (1 to 3 g) from four different regions, neocortex (gyrus precentralis), cerebellum, hippocampus, and brainstem, were taken for microsphere count. Thereafter, the microspheres were recovered from brain tissue by sedimentation and from the blood using a commercial protocol (NuFlow Extraction protocol 9507.2, Interactive Medical Technologies Ltd, Irvine, CA). Fluorescent analysis was carried out by the same company.
Cerebral blood flow was then calculated from the intensity of fluorescence in blood and tissue samples using the following formula:
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Cerebral metabolism
Cerebral sagittal sinus and arterial samples were obtained simultaneously for calculation of cerebral oxygen extraction (arteriovenous oxygen content difference), sagittal sinus oxygen saturation, and cerebral oxygen saturation extraction (arteriovenous oxygen saturation difference). Cerebral vascular resistance (CVR) was calculated by using the following equation:
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Cerebral metabolic rate of oxygen consumption was determined as follows:
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Study protocol
Cerebral blood flow and CVR were determined at six (seven in group SCP) points throughout the experiment by microsphere injection. Simultaneously, hemodynamic variables, ICP, and sagittal sinus pressures were recorded, and arterial and venous blood samples were obtained. The experimental protocol is shown in Figure 1, and the sampling points listed below:
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Behavior and postoperative neurologic outcome
Pigs were scored on a 12-point behavioral scale before surgery, and daily for 7 days postoperatively. An independent veterinarian not aware of the protocol evaluated the animals at the same time each day, scoring mental status, movement, and appetite, as described in earlier reports [10, 11]. The scale allows a maximum of 12 points for the behavior of a healthy pig, and allows sensitive grading of impairment of consciousness, motor function, and coordination. Previous studies have validated the correlation of this behavioral index with histologic evidence of brain injury [12].
Statistical analysis
The animals were randomized into three study groups by an independent party. The group assignment was revealed immediately after the second sampling point, and the experiment then continued following the specific protocol for the assigned group.
Before the statistical analysis of outcome data (CBF, CVR, CMRO2, ICP, O2 extraction, arterial and venous lactate, sagittal sinus pressure), baseline values were compared by one-way analysis of variance (or Kruskal-Wallis test, as appropriate). Differences among groups were found for baseline measurements of ICP and sagittal sinus pressure; thus, changes from baseline were used for further comparisons of all the variables. Measurements during SCP, CPB, and off bypass were analyzed by two-way analysis of variance, including tests for mean differences among groups and among points, and for changes of differences among groups throughout the duration of the experiment (interaction effects). Dunnett's test was used for pair-wise comparisons of groups HCA-CPB versus SCP and HCA-SCP versus SCP to identify significant differences in changes from baseline among the groups.
The level for all sets of tests was set at 0.05. Statistical analysis was performed using SAS (SAS Institute, Cary, NC) on a personal computer.
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Results |
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Mortality
Four HCA-SCP animals and 3 SCP animals did not reach the final measurement point or could not be weaned from mechanical ventilation: none showed evidence of neurologic injury. There was no mortality among the HCA-CPB animals: the better myocardial protection in these animals may be secondary to better cooling, with more cold blood returning to the heart through the atrium and through noncoronary collaterals. Among the nonsurvivors, 2 pigs showed signs of left ventricular failure despite administration of catecholamines; another could not be defibrillated after CPB, and 3 had pulmonary edema. We think that these deaths, which occurred early in the series, were all related to inadequate myocardial protection—which relied entirely on topical hypothermia—during the interval of HCA-SCP. To allow reliable statistical analysis, animals that died before completing the protocol were replaced in a rerandomized fashion.
Cerebral blood flow and cerebral vascular resistance
Cerebral blood flow did not show significant differences among the groups at baseline or after cooling to 20°C (Table 2,
Fig 2).
Fifteen minutes after the start of perfusion, the highest blood flow was seen in the HCA-SCP animals, with CBF significantly exceeding baseline levels, and differing significantly from corresponding measurements in SCP animals, in which CBF had fallen significantly below baseline; CBF with HCA-CPB was also significantly below baseline. Toward the end of the perfusion interval, CBF diminished in all groups, reaching values below baseline. Animals in the HCA-SCP group showed the highest CBF among the groups before the start of rewarming. During rewarming, CBF increased slightly in all groups, but stayed significantly below baseline in SCP and HCA-CPB animals. Two hours after discontinuation of bypass, CBF had not reached baseline in any of the study groups, perhaps in part because of continuing mild hypothermia. Overall, both groups with selective perfusion showed higher CBF than the HCA-CPB group throughout the experiment.
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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An alternative approach is to cannulate the cerebral vessels without an interval of HCA, so that the entire operation can be performed using antegrade SCP, as advocated by Bachet and associates[16], Kazui and coworkers [17], and Tanaka and colleagues [18]. This approach has the potential theoretical advantage of avoiding HCA altogether, but requires insertion of cannulas into the cerebral vessels, risking embolization [19]. The current study was designed to investigate whether cerebral protection consisting of a short interval of HCA followed by a long period of SCP provides benefits equivalent to those seen using cerebral protection with SCP alone.
An earlier study demonstrated that CBF during prolonged hypothermic SCP is higher than during an equivalent period of hypothermic conventional CPB, and does not decline as quickly with time as does flow during hypothermic CPB [6]. Oxygen consumption is somewhat higher during SCP than during CPB, and ICP—which has been correlated with outcome [20]—is lower. During recovery, both groups show prompt return to baseline levels of metabolism, but ICP remains somewhat lower after SCP, and the inappropriate rise in CVR seen after CPB is not apparent after SCP. All these observations suggest that cerebral protection during SCP is better than during hypothermic CPB. Hypothermic CPB, in turn, has been shown in previous studies to be superior to the protection afforded by prolonged HCA [6, 21].
The current study confirms some of the physiologic observations seen in our initial study of what happens during prolonged SCP: oxygen consumption is higher with SCP than with CPB at the same temperature, and does not decline markedly with time; CBF is more than adequate for the level of metabolism (there is, in fact, what has been termed luxury perfusion); recovery of metabolism and blood flow occur promptly after rewarming; and ICP does not rise during prolonged SCP, as it does with prolonged CPB [6]. In addition to confirming our earlier findings, this study shows that the benefits of SCP are not significantly mitigated by instituting a short period of HCA before SCP: there were no significant differences between the HCA-SCP group and the SCP group at the end of SCP with regard to CBF, CVR, CMRO2, or ICP, and only minor early differences in lactate accumulation. Most important, behavioral outcome was not significantly worse after HCA-SCP than with SCP alone. In contrast, HCA followed by hypothermic CPB did not result in as favorable a physiologic profile or neurobehavioral outcome as continuous SCP, or HCA followed by SCP.
This study suggests that a clinical technique that combines a short interval of HCA with SCP should provide excellent global cerebral protection. As this strategy also allows open anastomoses with optimal visibility during circulatory arrest, it should also minimize embolization, a major source of neurologic morbidity during aortic arch surgery.
Why SCP results in a higher oxygen consumption and better cerebral perfusion than hypothermic CPB is not clear from these studies. We suspect that some degree of cerebral autoregulation is at work even at hypothermic temperatures, and that cerebral vasodilation occurs in response to ischemic metabolites from the lower body recirculating to the brain during SCP, which are not present when the entire body is being perfused during CPB. Certainly the marked increase in CBF in the HCA-SCP group after the period of HCA suggests an appropriate reflex hyperemia. It seems likely, given the behavioral outcome, that the failure of the CPB group to respond with cerebral vasodilation after HCA should be considered pathologic rather than that the increase in flow to the brain when SCP is used after HCA should be considered suspect. It is possible that CPB activates some inflammatory mediators not provoked by SCP, which result in inappropriate cerebral vasoconstriction after HCA, and a rise in ICP [7].
It is interesting that apart from the mortality encountered in some pigs because of inadequate surface cooling of the heart during SCP, no obvious morbidity seems to result as a consequence of failure to perfuse the lower body during the interval of circulatory arrest. Lactate levels are higher and persist longer after both SCP strategies than after HCA-CPB. But no animals exhibited renal failure or spinal cord dysfunction postoperatively, suggesting that hypothermia alone may be adequate protection for organs other than the brain during SCP. If SCP or HCA-SCP were carried out using more moderate hypothermia, however, we suspect that such long intervals of SCP would not be without systemic sequelae.
In any case, this study suggests that HCA followed by SCP is as safe a strategy for global cerebral protection as continuous SCP. The superiority of continuous SCP over CPB in terms of CBF and cerebral metabolism demonstrated in our initial study of SCP was confirmed in this study, and were shown to be associated with an excellent behavioral outcome. Although the neurologic recovery in the HCA-SCP group was slightly slower, it was nevertheless complete. We think that the marginal difference in terms of global cerebral protection between continuous SCP and HCA-SCP strategies is a small price to pay in the clinical setting if this approach to aortic arch replacement leads to a reduction in the incidence of stroke by allowing dissection, debridement, and anastomosis of often severely atherosclerotic brachiocephalic vessels under direct visualization during an interval of HCA.
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