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Eur J Cardiothorac Surg 2003;24:807-816
© 2003 Elsevier Science NL
a Department of Cardiothoracic Surgery, Mount Sinai School of Medicine/New York University, One Gustave L. Levy Place, P.O. Box 1028, New York, NY 10029, USA
b Department of Neurosurgery, Mount Sinai School of Medicine/New York University, New York, NY, USA
c Department of Biomathematics, Mount Sinai School of Medicine/New York University, New York, NY, USA
Received 13 June 2003; received in revised form 24 July 2003; accepted 9 August 2003.
* Corresponding author. Tel.: +1-212-659-6800; fax: +1-212-659-6818
e-mail: ju.strauch{at}gmx.de
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Key Words: Cerebral blood flow • Selective cerebral perfusion • Fluorescent microsphere • Animal model
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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The purpose of SCP is to maintain cerebral blood flow to support metabolism of the brain during ascending aorta and arch surgery, offering the opportunity to carry out complex procedures without strict time constraints, in contrast to the known time limits for safe use of HCA. Clinical evidence suggests that SCP provides better cerebral protection than prolonged HCA [4–6]. However, little is known thus far about cerebral blood flow (CBF) and cerebral metabolism during a long interval of SCP – during which the rest of the body is ischemic – and virtually nothing is known about changes in CBF in different regions of the brain during SCP. We therefore undertook this study in pigs to delineate changes in CBF, cerebral oxygen metabolism, cerebral vascular resistance, and intracranial pressure during SCP and compare these observations with what happens during total body cardiopulmonary bypass at the same temperature (HCPB). The experiments were performed using CPB or SCP at 20 °C for an interval of 90 min. Parenchymal cerebral blood flows were accurately ascertained utilizing repeated injection of fluorescent microspheres.
Use of microspheres that lodge in the microcirculation is the most reliable and precise method for determining regional blood flow in the brain and in other organs [7]. Studies have shown that results using nonradioactive – fluorescent and colored – microsphere techniques correlate very well with the time-honored radioactive microsphere method [8], which is no longer economically feasible in large animal studies. We therefore feel confident that our observations offer an accurate reflection of cerebral physiology during SCP, and add to the growing evidence that SCP is the optimal method for protecting the brain during complex aortic arch surgery.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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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 Institutes of Health (NIH Publication No. 88-23, revised 1985). The protocol for this experiment was approved by the Mount Sinai Institutional Animal Care and Use Committee.
After pretreatment with intramuscular ketamine (15 mg/kg), and atropine (0.03 mg/kg) to induce anesthesia, animals were anesthetized with intravenous sodium thiopenthal (20 mg/kg) and underwent endotracheal intubation. The pigs were ventilated mechanically with an FiO2 of 0.5, and isoflurane 1–2% was used to maintain 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 between 35 and 40 mmHg. End-expiratory carbon dioxide and inspiratory and expiratory isoflurane were monitored continuously (PPG Biomedical Systems, Model 2010-200 R, Lenexa, KS). Arterial oxygen tension was maintained greater than 100 mmHg.
A bladder catheter (Foley 8–10 F) was inserted for online measurement of urine output, and temperature probes were placed not only in the esophagus and rectum but also in the brain via a small burr hole in the skull. 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, glucose and lactate (Blood Gas Analyzer, Ciba Corning 865, Chiron Diagnostics, Norwood, MA)). A thermodilution catheter (Baxter Healthcare Corp., Irvine, CA) for assessment of cardiac output was inserted in the femoral vein and advanced into the pulmonary artery.
2.3. Sagittal sinus cannulation and intracranial pressure (ICP) monitoring
Sagittal sinus cannulation was performed before heparinization and cannulation for CPB. A midline scalp incision was made and the underlying periosteum removed to facilitate identification of the coronal and sagittal sutures. Under 2.5x 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 ICP pressure probe was connected to a transducer (Codman ICP Express, Johnson and Johnson Prof. Inc., Raynham, MA).
2.4. Operative technique
The chest was opened via a small left thoracotomy in the fourth intercostal space. The heart and the great vessels were exposed. After heparinization (300 IU/kg), the ascending aorta was cannulated with a 16-F arterial cannula, and the right atrium with a single 26-F cannula. Non-pulsatile CPB was initiated at a flow rate of 80–100 ml/kg per min and then adjusted to maintain a minimum mean arterial pressure of 45 mmHg. To avoid distension of the left ventricle during CPB and as an injection-port for fluorescent microspheres, a 10-F vent catheter was inserted via the left atrium. After initiation of CPB, the lungs were allowed to collapse. A heat exchanger was utilized for core cooling, and surface cooling was achieved with the use of a cooling blanket.
The cardiopulmonary bypass 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 1000 cc 0.9% NaCl, furosemide (1 mg/kg), heparin (5000 IU) and KCl (1.5 mg/kg). Using alpha-stat principles, the pH was maintained at 7.40 with an arterial pCO2 of 35–40 mmHg uncorrected for temperature, during cooling, perfusion and rewarming.
After initiation, CPB was continued for 30 min to reach a deep brain temperature of 20 °C, and to insure thorough cooling to avoid a possible updrift in temperature during the period of selective cerebral perfusion. The operating room temperature during HCA was maintained at 18–20 °C for the same reason.
In all animals, myocardial protection was afforded by topical cooling, maintaining a solution of iced saline (
4 °C) in the pericardium during the 90-min interval of SCP or total body perfusion; cardioplegia was not used. For SCP, the ascending and descending aorta were both cross clamped so that only the subclavian and carotid arteries were perfused bilaterally. Flow was initiated at 10 ml/kg per min, and then adjusted to maintain a stable arterial pressure greater than 45 mmHg.
After the 90-min interval of SCP, CPB was reinstituted, and core and surface rewarming were begun and continued to an esophageal temperature of approximately 35–36 °C, a process which usually lasted about 45 min. Care was taken to avoid a temperature difference of more than 10 °C between the perfusate and the core temperature. During weaning from CPB, an infusion of 3–5 mg/kg per min dobutamine was frequently utilized. 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.
2.5. Cerebral blood flow
CBF was measured with fluorescent microspheres as described in previous studies [8–10]. In brief, approximately 2 million microspheres 15±0.5 µm in diameter in seven different colors (red-high, red-medium, red-low, orange-high, blue-high, violet-high and violet medium, Interactive Medical Technologies Ltd., Irvine, CA) were injected and flushed with 5 ml of saline solution into a left ventricular catheter before and after CPB, and into the aortic cannula during SCP or HCPB.
Before injection, the fluorescently labeled microspheres, suspended in 10% dextran with 0.05% polyoxyethylenesorbitan monooleate (Tween 80) were mixed, sonicated, and vortexed. To allow calculation of absolute blood flow rates, a reference blood sample was taken from the brachial artery at a rate of 2.9 ml/min with a Harvard withdrawal pump (Harvard Bioscience Inc, Holliston, MA). Withdrawal of blood started 10 s before injection of the microspheres and was continued for 110 s after microsphere injection. Blood pressure measurement was performed simultaneously.
The pig was put to death after the last microsphere injection using intravenous sodium pentobarbital (30 mg/kg) and saturated potassium chloride (6 mEq/kg).
In all animals (including the three who died) the skull was opened, the brain was removed, the two hemispheres divided, and the specimens weighed precisely. Tissue samples (1–3 g) from four different regions – neocortex, cerebellum, hippocampus and brainstem – were taken for microsphere count. Thereafter, the microspheres were recovered from brain tissue by sedimentation, and from the blood utilizing a commercial protocol (NuFlow Extraction protocol 9507.2, Interactive Medical Technologies). Fluorescent analysis was carried out by the same company.
Regional cerebral blood flow was then calculated from the intensity of fluorescence in blood and tissue samples utilizing the following formula:
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2.6. Cerebral metabolism
Cerebral venous – 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 was calculated by using the equation:
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Cerebral metabolic rate (oxygen consumption, CMRO2) was determined as follows:
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Arterial and venous blood pH, oxygen tension, carbon dioxide tension, hematocrit, oxygen saturation and oxygen content as well as glucose and lactate were measured using Ciba-Corning Diagnostics Corp. Analyzer (model 865; Medfield, MA).
2.7. Study protocol
Measurements of hemodynamics (heart rate, central venous pressure, mean arterial pressure, mean sagittal sinus pressure) arterial blood gases, hematocrit, glucose and lactate, as well as temperatures, CBF, CVR, CMRO2 and ICP were recorded at seven time-points during the experiments, Fig. 1
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Groups were compared separately at baseline, during CPB, during SCP or total body perfusion (HCPB), and after CPB. The t-test or the Mann–Whitney test, as appropriate, were used for comparisons at baseline. When the data were consistent with normality and equal variance assumptions, the measurements at the various time points were compared using repeated measures analysis of variance, with tests for average differences between groups and for group-time interactions (change in the difference between groups over time). Otherwise the groups were compared separately at each time point using the Mann–Whitney or Fisher exact tests. We report P-values unadjusted for multiple testing: their purpose is not for an exact global assessment but rather as a guide to help interpret the pattern of differences between groups at different times. The Bonferroni correction was not utilized because we expect these tests at successive time points to be highly correlated. Analyses were implemented with SAS software on a VAX computer and StatXact 4 for Windows.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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3.2. Comparability of experimental groups
A comparison of preoperative animal weights (SCP: 20.4±1.2 kg vs. HCPB: 20.1±1.5 kg) and age (in weeks, SCP: 12.2±0.8 vs. HCPB: 12.0±0.7) showed no differences between the groups.
As intended by the design of the study, basic hemodynamic data showed no significant differences between groups in heart rate, mean arterial pressure, central venous pressure or cardiac output. There were also no significant differences in rectal, esophageal or brain temperatures between the groups; the mean brain temperature of 20 °C corresponded to a mean esophageal temperature ranging from 20.2 to 21.3 °C in the different groups, and a mean rectal temperature from 22.3 to 22.9 °C. Table 1 shows the hemodynamic variables measured at the seven different times that data were collected for calculation of CBF and cerebral metabolism in each group.
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3.5. Intracranial pressure
Intracranial pressure, Fig. 5
, was markedly reduced by cooling to 20 °C in both groups. In the SCP group, ICP continued to decline during perfusion, remaining significantly lower than in the HCPB group and than baseline throughout perfusion (P=0.006). In contrast, ICP increased in the HCPB group after 15 min of total body perfusion, and remained consistently higher than with SCP thereafter. After SCP, ICP rose during rewarming and recovery, and reached baseline levels after 2 h, but remained significantly below ICP levels following HCPB.
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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The intent of this study in young pigs was to discern possible intraoperative and postoperative differences in CBF, metabolism and vascular responses between animals undergoing 90 min of hypothermic SCP and animals undergoing hypothermic total body CPB for the same duration at the same temperature. Our results indicate that SCP provides significantly more flow to all sampled regions of the brain than HCPB, but that flow gradually declines with prolonged SCP. The increase in cerebral oxygen consumption and decrease in ICP with SCP compared with total body HCPB suggest that the increased CBF seen with SCP is a positive finding, but further studies to confirm the benefit of SCP using postoperative behavioral evaluation are currently under way.
We started with all parameters at comparable baseline levels in both groups. As expected, there was a reduction in CBF at 20 °C after 30 min of cooling. This is in accord with theoretical predictions and the experimental work of others [13,14]. With HCPB, CBF decreased gradually over the 90-min interval, reaching 55% of baseline; CBF in the SCP group showed some diminution over time, but dropped no lower than 80% of baseline. Thus, our calculation of CBF during SCP is considerably higher than the 40 to 50% of baseline reported by Sakurada and colleagues [3]. CBF was significantly higher upon rewarming after SCP than after HCPB, with minimal decreases during the ensuing 2 h. We saw almost complete return of CBF to baseline values by 2 h after resumption of CPB, as have others [15]. Regionally, the same patterns of CBF with SCP were apparent, with flow highest in the neocortex and lowest in the hippocampus.
Our evidence suggests that cerebral autoregulation is probably not completely lost with this degree of hypothermia, judging from the ratio CBF/CMRO2. This ratio, Fig. 5, which is thought to reflect optimal autoregulation at baseline, indicates substantial luxury perfusion at 20 °C in both groups. The findings of Schwartz and coworkers have demonstrated that CBF is determined by arterial pressure [16] when autoregulation is lost, so we were careful to keep the mean arterial pressure (MAP), the perfusion pressure, and the pump flow rate stable during cooling and recovery, and during the period of differential perfusion, and succeeded in avoiding any significant differences between groups, although mean arterial pressure was at times slightly higher in the SCP group. Nevertheless, we saw an increase of CBF to values >90% of baseline after only 15 min of SCP, while CBF in the HCPB group continued to decrease. Although oxygen consumption was higher in the SCP group, the CBF/CMRO2 ratio indicates that SCP flow was still substantially in excess of what was required to maintain cerebral metabolism. We speculate that the generous CBF may be a response to vasoactive metabolites coming from the ischemic lower body and recirculated by the pump. This suggests that cerebral autoregulation is at least partially preserved at 20 °C in the presence of adequate perfusion pressure, as suggested by Tanaka and others [17]; the inappropriately high flows probably occur during SCP because the brain is unable to discern that ischemic signals are emanating from the body rather than from the brain.
The pattern of CBF may reflect the very stable, nearly unchanged level of CVR in the SCP group, in contrast to an increase in CVR of more than 20% in the HCPB group. A poorly understood period of decreased CBF and increased CVR lasting several hours after hypothermic circulatory arrest and total body perfusion have previously been described [18,19]: this phenomenon has been called the ‘vulnerable interval’ because it puts the recovering brain at risk of ischemia in the event of hypotension or bleeding postoperatively. In contrast to HCPB, there is clearly more marked luxury perfusion during and following SCP, which suggests that a much milder vulnerable interval is present after SCP, if one occurs at all. This would imply an increased margin of safety for cerebral perfusion after SCP if any hemodynamic instability were to occur postoperatively. Our failure to find an increase in CVR after SCP is in contrast to the findings of Lodge and coworkers [20]. Further studies are required to clarify this issue.
Several studies have now documented that lower intraoperative and postoperative intracranial pressures correlate with improved postoperative cerebral recovery, and higher ICP levels with worse outcome [10,21,22], as measured by mortality, behavioral scores and cerebral histology. We found significantly lower intracranial pressures throughout the entire perfusion interval using SCP compared with HCPB. Although ICP in both groups was rising after discontinuation of CPB, levels of ICP continued to be significantly lower after SCP than after HCPB.
Oxygen consumption is widely considered the most reliable measure of metabolic activity in the brain. As expected, we found a significant reduction of CMRO2 in both groups at 20 °C, compared to baseline. During differential perfusion, however, we recorded a significantly higher CMRO2 level in the SCP group than in the HCPB group: this consistent difference in cerebral oxygen consumption in the two groups maintained at the same temperature is an unexpected finding. Temperature is the most significant determinant of CMRO2, but other factors such as catecholamines – which might be released by the ischemic lower body during SCP – can alter cerebral metabolism. In the presence of an intact blood-brain barrier, circulating catecholamines usually do not affect CMRO2, but hypothermia may alter blood–brain barrier permeability to catecholamines, leading to increases in cerebral metabolism comparable to those which occur with direct intracerebral catecholamine injection [23–25]. Although a higher metabolic rate in the brain during SCP – or any cerebral protection strategy – is arguably undesirable, SCP is associated with more generous luxury perfusion than is seen with HCPB, so the higher metabolic rate may simply reflect more adequate substrate delivery and support of an appropriate level of ongoing cerebral metabolism. The observed failure of the CVR to increase significantly during and following SCP seems likely to be beneficial for the brain, optimizing oxygen consumption during SCP and minimizing the fall in CBF thereafter, without a detrimental increase in ICP.
In conclusion, our study reveals that SCP provides significantly more blood flow to all sampled regions of the brain than does HCPB, although flow gradually declines with prolonged SCP. There is a statistically significantly higher cerebral oxygen consumption supported by SCP than with prolonged HCPB, accompanied by significantly lower ICP and CVR. We conclude that the cerebral vasodilatation produced by SCP is possibly beneficial, as evidenced by better recovery of cerebral oxygen consumption postoperatively, and lower ICP in the post-bypass period.
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Acknowledgments |
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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