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Eur J Cardiothorac Surg 2002;22:510-516
© 2002 Elsevier Science NL
a Department of Cardiothoracic Surgery, Mount Sinai School of Medicine/New York University, New York, NY, 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 31 August 2001; received in revised form 21 April 2002; accepted 29 April 2002.
* Corresponding author. Present address: Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Tel.: +49-511-532-6581; fax: +49-511-532-5404
e-mail: hagl{at}thg.mh-hannover.de
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Abstract |
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 Top Abstract 1. Introduction2. Material and methods3. Results4. Discussion5. ConclusionsAppendix A. Conference...References |
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Key Words: Cerebral protection • Great vessels • Hypothermic circulatory arrest • Intracranial pressure • Cerebral edema
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1. Introduction |
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TopAbstract1. Introduction2. Material and methods3. Results4. Discussion5. ConclusionsAppendix A. Conference...References |
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The first reports of elevated ICP during reperfusion after HCA were clinical observations in infants by Burrows et al. [1] and Van der Linden [2]. These and subsequent studies [3], which showed that cerebral blood flow velocity was reduced after HCA, led us to wonder whether the extent of brain edema after HCA may generally be underestimated. Recent findings in our porcine model during experiments exploring alternatives to HCA reinforced this impression. We therefore undertook a retrospective review of control animals from studies exploring pharmacological means of improving cerebral protection to examine whether high ICP during reperfusion after HCA in our experimental model is associated with poorer neurological outcome as indicated by neurophysiological evaluation and behavioral scores.
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2. Material and methods |
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TopAbstract1. Introduction2. Material and methods3. Results4. Discussion5. ConclusionsAppendix A. Conference...References |
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Each animal underwent preoperative behavioral assessment, and intraoperative hemodynamic and metabolic monitoring. ICP and quantitative EEG as well as somatosensory evoked potentials (SSEP) were recorded. Daily behavioral/neurological assessment was performed until elective sacrifice according to the protocol, but for at least 3 days for each animal. Animals that died before postoperative day 3 were excluded from the study.
2.1. Perioperative management and anesthesia
Pigs were pretreated with intramuscular ketamine (15 mg/kg) and atropine (0.03 mg/kg) and were anesthetized with intravenous pentobarbital (20 mg/kg). After endotracheal intubation, they were ventilated with 50% oxygen and anesthetized with isoflurane (1–2%). Tidal volume and ventilation rates were adjusted to maintain pCO2 between 35 and 45 mmHg. Intravenous pancuronium (0.1 mg/kg) was used to achieve paralysis. All animals received cephazoline (15 mg/kg) intravenously.
Urine output was measured via a bladder catheter (Foley 8–12 F), and temperature probes were placed in the esophagus, rectum and in the brain (via a small burr hole). A femoral arterial line was placed for pressure monitoring and blood sampling (Blood Gas Analyzer, Ciba Corning 865, Chiron Diagnostics, Norwood, MA, USA). A 7.5-F thermodilution catheter (Baxter Healthcare Corp., Irvine, CA, USA), advanced from the femoral vein into the pulmonary artery, allowed assessment of cardiac output.
2.2. Intracranial pressure (ICP) and neurophysiology
For continuous intracranial pressure monitoring, a parenchymal pressure probe (Codman ICP Express, Johnson and Johnson Prof. Inc., Raynham, MA, USA) was inserted via a small burr hole in the skull. The MicroSensor pressure transducer used in all study animals is a catheter with a miniature silicon strain gauge-type sensor mounted in a titanium housing at the side of the tip of a small flexible nylon catheter. This catheter is widely used clinically, and has been shown to have a temperature drift of only 0.15 mmHgx10-1 °C when temperature variations between 20 and 45 °C are simulated [4]. Transducers were zeroed in a saline solution at the appropriate level prior to insertion and allowed to stabilize for 5 min. Then the catheter was placed approximately 5mm into the brain parenchyma and secured to avoid displacement. Care was taken to avoid any movements of the animal's head which might be associated with a shifting of cerebral mass, causing recording errors.
Cervical and cortical somatosensory evoked potentials (SSEP) in response to stimulation of the median nerve, as well as continuous electroencephalographic activity (EEG) were monitored from stainless steel electrodes mounted into the skull as previously described in detail [5]. Analysis was performed by a neurophysiologist blinded to the protocol and are expressed as percent recovery compared to baseline recordings.
2.3. Cardiopulmonary bypass and hypothermic circulatory arrest
After systemic heparinization (300 IU/kg), nonpulsatile CPB was instituted via a single cannula (26–28 F) in the right atrium, with return to the ascending aorta (16 F). A 10-F flexible cannula was passed from the right superior pulmonary vein into the left ventricle to permit decompression. Surface cooling was used in all animals; the head was not packed in ice during HCA. For cardiopulmonary bypass (CPB), a membrane oxygenator (VPCML Plus, Cobe Cardiovascular Inc., Arvada, CO, USA) was primed with a bloodless solution consisting of 1000 cc 0.9% NaCl, furosemide (1 mg/kg), heparin (5000 IU) and potassium chloride (1.5 mEq/kg). CPB using alpha-stat principles was continued to reach a deep brain temperature of 20 °C. Prior to HCA, all animals received 20 mg/kg of methylprednisolone intravenously.
Myocardial protection during HCA was achieved by topical cooling. After HCA, rewarming was continued to an esophageal temperature of approximately 35–36 °C, avoiding a temperature gradient exceeding 10 °C between the perfusate and core temperature. During weaning from CPB, 3–5 mg/kg per min dobutamine was frequently utilized, and norepinephrine was occasionally necessary in cases of low resistance.
All pigs received intramuscular cephalosporine (15 mg/kg) as well as pain killers (buterophenol 0.1 mg/kg) for the first 3 postoperative days (POD). For behavioral evaluation the animals were kept in separated pens for the entire observation period.
2.4. Behavioral score
From POD 1 until elective sacrifice, all animals were scored on a gross behavioral grading scale by a veterinarian blinded to the experimental protocol, as described in earlier reports [5]. Daily scores were determined after inspections in the morning, at noon and in the evening. A score of 9 is normal, and 0 indicates coma or death.
2.5. Animal care
All animals received humane care in compliance with the guidelines 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, 1996). The protocol for these experiments was approved by The Mount Sinai Institutional Animal Care and Use Committee.
2.6. Statistics
The data were entered in an Excel spreadsheet and analyzed using SPSS software on a personal computer. Data are described as mean and standard deviation, median and range, or percent, as appropriate. Differences across time points were analyzed by repeated-measures analysis of variance, followed by individual paired contrasts. Agreement between pairs of values was estimated by Pearson product-moment correlation coefficients. Predictors of the behavioral scores at days one, two, and three each were tested by stepwise linear regression.
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3. Results |
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TopAbstract1. Introduction2. Material and methods3. Results4. Discussion5. ConclusionsAppendix A. Conference...References |
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In the survivors, basic hemodynamic data showed only minor variations (as indicated by the small standard deviations): there were no clinically relevant inter-individual differences in heart rate, mean arterial pressure, central venous pressure or pulmonary artery pressure, Table 1. A slightly lower cardiac output one to three hours after HCA probably reflects slightly depressed cardiac contractility due to HCA. Total cardiopulmonary bypass time was comparable in all animals. The upward drift of the intracranial temperature during HCA was less than 1.2 °C in all animals.
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3.3. Behavioral evaluation
Median standard behavioral scores – including the ranges – are depicted graphically in Fig. 2
. Pigs showed the poorest performance on POD 1, with progressive recovery over the subsequent 2 days.
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4. Discussion |
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TopAbstract1. Introduction2. Material and methods3. Results4. Discussion5. ConclusionsAppendix A. Conference...References |
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To simulate the clinical situation, we have established a porcine model which can be used for acute and also chronic laboratory studies [10] of HCA and its alternatives. Several studies of the effects of retrograde cerebral perfusion (RCP) [11], which ultimately demonstrated that only an insignificant amount of blood pumped via the superior vena cava reaches brain capillaries, made it apparent that there is a marked increase in ICP during and following RCP, but that this phenomenon is also seen, albeit in milder form, even after HCA.
Since monitoring of ICP was instituted, Ehrlich et al. [12] showed that an interval of cold reperfusion after HCA can attenuate the rise in ICP usually seen after HCA, and can also reduce the amount of histopathological damage. In another study [5] in which the potential neuroprotective effect of the anti-apoptotic drug cyclosporine A was being examined, lower ICP during reperfusion was seen in the treated group as compared with untreated controls. Behavioral scores were also higher in the drug-treated group for the first 4 days postoperatively. But the histopathology, evaluated 7 days after HCA, did not show any differences [13]. Based on a suspicion that the peak of apoptotic cell death might have been missed, some additional CsA-treated animals were killed at the peak of neuropathological changes, 72 h after HCA; in these animals [14], a significant reduction in necrotic and ischemic cell death was found, albeit no change in apoptosis. Taking all the data together, we hypothesize that CsA may protect the brain via its known anti-inflammatory effects, which may reduce capillary leakage and thereby reduce the amount of cerebral edema after HCA.
On the basis of these various findings, we decided to review all our observations from concurrent studies of cerebral protection in our chronic porcine model to try to determine whether high ICP during reperfusion after HCA correlates with other evidence of suboptimal cerebral protection. Since all the experiments reported herein were performed by a single surgeon, and all pigs underwent the same protocol – 90 min of HCA at a brain temperature of 20 °C – we feel confident that it is appropriate to pool the data from control animals in several experiments. Using these combined data, we are now able to confirm unequivocally that ICP increases significantly during reperfusion following HCA. There is a strong correlation between ICP and neurological recovery on POD 1+2. There is also a positive correlation between lower ICP and better EEG recovery 3 h postoperatively.
Although the current study provides no real evidence of the nature of the pathophysiological link between elevated ICP and worse outcome, we speculate that, regardless of its etiology, high ICP – especially in conjunction with reduced cardiac output – can then cause depression of cerebral blood flow and ultimately, if severe, destruction of brain tissue. It is well known that cardiopulmonary bypass can cause a capillary leak syndrome as the result of stimulation of acute phase reactants [15]. Although CPB-induced edema may be tolerated reasonably well in most tissues, it may cause severe problems in the brain, where the edematous tissue is encased in a solid vault which limits its expansion. Once cerebral edema begins, it can initiate a vicious cycle. The microvascular system becomes compressed, which decreases blood flow and results in cerebral ischemia. Ischemia then causes arteriolar dilation, and the increased capillary pressures predisposes toward further edema. Ischemia also increases the permeability of the capillaries, causing more leakage of fluid, and turns off the sodium pumps of the tissue cells, allowing them to swell [16]. Because the brain is not capable of anaerobic metabolism, even short periods of ischemia or anoxia can cause permanent injury.
There is experimental [17] and clinical [18] evidence that there is a vulnerable interval after HCA which lasts for at least several hours, during which cerebral blood flow is diminished, and oxygen delivery may be compromised. To our knowledge, the etiology of this phenomenon is not known, and it is not clear whether changes in ICP may be involved in the mechanism of this characteristic compromise in cerebral blood flow late after HCA. In the clinical literature, an ICP between 5 and 15 mmHg is considered normal, and an ICP>40 mmHg is thought to be dangerous [19]. But it is possible that smaller vessels are more sensitive, and that areas of the brain with borderline blood supplies or high metabolic rates (e.g. hippocampus) may be vulnerable to damage at much lower levels of ICP.
Our hypothesis is that the role of even small elevations in ICP may be especially critical in the hours following HCA, during which contractility of the heart is characteristically compromised. There is often a decrease in cardiac output for several hours after HCA. In this study, cardiac output as well as ICP during the first few hours after HCA correlated significantly with behavioral outcome. Since cerebral perfusion pressure is the difference between arterial pressure and ICP, it makes sense that subtle changes in each of these could act synergistically to reduce cerebral blood flow and thereby affect cerebral recovery.
The colloid osmotic pressure may also play a role in the formation of cerebral edema after HCA. Higher hematocrit, which has been shown to improve outcome after HCA, may be protective not only by enhancing oxygen delivery, but also by keeping fluid in the intravascular space. A positive effect of higher hematocrit during reperfusion has been demonstrated [20] in a piglet model of HCA, but ICP was not monitored. In the current studies, hemodilution with saline to a hematocrit of 20% was carried out to avoid sludging during hypothermia, but the low osmotic pressure during recovery may have contributed to the rising ICP postoperatively.
The central observation of this study raises almost more questions than it answers, and will require further study Although we can speculate as to why an elevated ICP often occurs following HCA, it remains unclear what causes variations in its severity in animals undergoing exactly the same protocol. Is there a level of ICP above which there is usually irreversible neurological damage, or is the relative change of ICP from baseline values a more reliable indicator of cerebral injury? The most important unanswered question is whether higher ICP is simply a reflection rather than a cause of neurological injury.
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5. Conclusions |
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TopAbstract1. Introduction2. Material and methods3. Results4. Discussion5. ConclusionsAppendix A. Conference...References |
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Acknowledgments |
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Footnotes |
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Appendix A. Conference discussion |
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TopAbstract1. Introduction2. Material and methods3. Results4. Discussion5. ConclusionsAppendix A. Conference...References |
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Dr Hagl: Our behavioral scale assessed gross neurological behavior: our evaluation includes gait, appetite and mental status of the animals. 0 means death or coma and 9 stands for full recovery. Each animal can reach a maximal score of 3 in each category. If you ask what the score would be for a routine patient after HCA without prolonged ischemia, I would guess that on the first day it would be between 7 and 9. With prolonged total cerebral protection time – more than 60 min – it would be more or less comparable with what we have here in our animal model – between 3 and 4 – and that it would, as in the animals, rise progressively thereafter. It should be noted, however, that there are exceptions to the generally good correlation between duration of total cerebral protection and early behavioral recovery – patients with short durations of HCA and slow behavioral recovery, and patients with long durations of HCA and prompt recovery – suggesting that we still have a lot to learn about cerebral protection during aortic surgery.
Dr Y. Ueda (Nagoya, Japan): I have seen the report from Mount Sinai in the same setting of hypothermic circulatory arrest. I wonder why you choose such a relatively high degree of brain temperature, 20 °C, and the longer duration of the hypothermic circulatory arrest, 90 min under 20 °C, which produces ischemic damage of the brain. Is that the purpose, to make such an ischemic injury during hypothermic arrest? Could you explain about such a fairly different setting from the clinical?
Dr Hagl: It is true that 90 min is a pretty long interval for hypothermic circulatory arrest and is not really comparable with the clinical situation. But, on the other hand, almost all of these animals recover, and if you want to see the effects of possible therapeutic interventions, you have to produce some kind of damage. If you use only 60 min of circulatory arrest at 20 °C in these animals, there is no damage at all: they do fine. With 90 min you have a survival rate of about 80%, which we feel is not bad, and there are observable behavioral changes.
If you look into the histopathology of the hippocampus, which is very sensitive to ischemia, when you carry out 60 or 75 min of HCA at 20 °C, you can barely see any damage. If you extend HCA to 120 min, most of the animals die. Therefore we feel that with 90 min we have the optimal experimental situation, and we now have accumulated a considerable body of data at this temperature. It might be possible to use a model with shorter times at 25 °C, but since many institutions rely on temperatures around 20 °C, our current model seems to make sense. But we would definitely recommend that lower temperatures and shorter durations be used for clinical implementation of HCA. We are therefore searching for more sensitive histological and behavioral assays to detect experimentally the more subtle changes which are likely to occur at more clinically relevant temperatures and durations of HCA.
Dr J. Bachet (Paris, France): Would you conclude from this study that in clinical use every single patient undergoing arch replacement with hypothermic circulatory arrest in your institution should have a catheter in the back and permanent control of the intracranial pressure to maintain it lower than 10 mmHg, for instance?
Dr Hagl: I think that it is a good idea to monitor ICP experimentally, even though the baseline is likely to be quite variable. It might also be a useful marker clinically, not only for patients who are subjected to circulatory arrest but also for those undergoing selective antegrade perfusion, since the details of how we should implement antegrade cerebral perfusion have not been clarified. It may help us to determine what is the ideal pressure, the ideal flow, whether we should rely on pulsatile or nonpulsatile perfusion, and whether alpha-stat or pH-stat management is preferable. In this context, ICP may be useful as an additional indicator of cerebral damage. We plan to use ICP monitoring during studies of selective antegrade perfusion in the laboratory, and are considering its clinical use.
Dr W. Harringer (Braunschweig, Germany): You have demonstrated nice correlations between the ICP and the clinical outcome. Were you able to draw any similar correlations with histological data comparing peak intracranial pressure to any neurological changes like apoptosis or cell death?
Dr Hagl: We were not able to look at the histopathology in this study because these were animals which were retrieved from concurrent studies of cerebral protection in which the day of elective sacrifice was not the same, and so histology could not be used as an endpoint. Some of these animals survived 7 days and others 10 days, which are both late for evaluation of apoptosis. But we do have a correlation between ICP and histology from recent studies in the animal laboratory involving retrograde cerebral perfusion. We were able to show that animals with very high ICPs during retrograde cerebral perfusion had more damage in the brain than pigs whose ICPs were lower. Furthermore, another study by Dr Ehrlich – who also worked in Dr Griepp's laboratory – showed that an interval of cold reperfusion after HCA led to lower postoperative ICPs and less neuronal damage.
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References |
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TopAbstract1. Introduction2. Material and methods3. Results4. Discussion5. ConclusionsAppendix A. Conference...References |
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