Ann Thorac Surg 2005;79:S2254-S2256
© 2005 The Society of Thoracic Surgeons
Supplement
Neuroprotection in Cardiac Surgery
William A. Baumgartner, MD*
Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland
Accepted for publication February 21, 2005.
* Address reprint requests to Dr Baumgartner, Department of Surgery, The Johns Hopkins Hospital, 600 N Wolfe St, Blalock 618, Baltimore, MD 21287 (E-mail: wbaumgar{at}csurg.jhmi.jhu.edu).
Presented at the 4th Annual Lillehei Heart Institute Symposium Celebrating the 50th Anniversary of Open-Heart Surgery by Cross Circulation, Minneapolis, MN, Oct 19–20, 2004.
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Introduction
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Several hundred thousand patients in the United States undergo cardiac surgery. The most common procedures include those for coronary artery disease, valvular heart disease, aortic disease, surgery for heart failure, congenital heart disease, transplantation, and a variety of other combined procedures. Neurologic injury is a significant risk factor for patients undergoing cardiac surgery. Although stroke, with an incidence of 1% to 6%, is the most serious complication, cognitive impairment (25% to 65%) and impaired level of consciousness (approximately 10%) can be significantly troublesome for patients and lead to potential further complications [1]. This latter complication can consist of encephalopathy, delirium, confusion, and depression. Atherosclerotic emboli from the aorta and great vessels and hypoperfusion to watershed regions of the brain are the predominant causes of stroke (or cerebrovascular accident). The cause of cognitive impairment and impaired level of consciousness is multifactorial and has been attributed to hypoperfusion, microemboli, metabolic derangements, general anesthesia, and initiation of a proinflammatory state.
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Development of Neuroprotective Strategies
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At our institution we believe there is sufficient direct and indirect evidence to support neuroprotective strategies outlined in Table 1. The fact that the overall stroke rate for most cardiac surgical procedures has not increased during the past several years, despite a steady increase in the number of elderly patients, is in part attributed to the successful application of these strategies.
The majority of these strategies are designed to reduce potential microemboli as well as relative hypoperfusion and ischemia, which could play a role in reducing overall neurologic injury, particularly that of encephalopathy. In our own experience looking at 2,244 consecutive patients (all procedures) who did not have a stroke or encephalopathy, the hospital mortality was 1.4%. Patients who sustained a cerebrovascular accident had a mortality of 22%, whereas those with encephalopathy had a hospital mortality of 7.5%. These outcomes have been a stimulus for us to not only carefully follow our patients who have had neurologic injury but also develop a basic laboratory strategy to understand the mechanism of neurologic injury.
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Summary of Laboratory Experience
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Since 1992, we have had continuous National Heart, Lung, and Blood Institute funding (NS31238-10) to investigate the mechanism of neurologic injury in a clinically relevant canine model of cardiopulmonary bypass and hypothermic circulatory arrest (HCA). Dogs undergo 2 hours of HCA at 18°C followed by resuscitation and recovery for 3 days. We have had wonderful collaboration with our neuroscientists, cardiologists, and radiologists.
Figure 1 summarizes our current thoughts regarding the role of excitotoxicity in the mechanism of injury. Excitotoxicity is the excessive activation of glutamate receptors that mediates neuronal injury or death [2]. We have demonstrated the damaging role of excessive glutamate in this model. We have shown there is an elevation of glutamate above baseline levels and that when an N-methyl-D-aspartate (NMDA; glutamate) receptor antagonist (MK801) or 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist (NBQX) is administered, the excitotoxic response can be significantly blocked [3]. We have also demonstrated that neuronal nitric oxide plays a significant neurotoxic role in the injury induced by HCA. Nitric oxide synthase converts oxygen plus arginine to citrulline plus nitric oxide. Using a microdialysis technique, elevations of citrulline in the cerebrospinal fluid correlated with increased levels within cortical homogenates during HCA and reperfusion [4, 5]. This proof of concept was further validated when a number of inhibitors to neuronal nitric oxide synthase were used in this investigative model. Two specific neuronal nitric oxide synthase inhibitors (7-nitroindazole and Astra 17477AR) resulted in superior neurologic function compared with untreated HCA dogs [6].
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Fig 1. Diagram illustrating the excitotoxicity mechanism of neuronal cell injury and points of intervention. NBQX is an -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist; MK801 is an N-methyl-D-aspartate (NMDA) receptor antagonist; 7-nitroindazole, monosialoganglioside GM1, and Astra 17477AR are pharmacologic drugs that exhibit inhibition of nitric oxide (NO) synthase. (Reprinted from Baumgartner WA. Neurologic injury after cardiopulmonary bypass surgery. J Neurosurg Anesthesiol 2004;16:102–4 by permission of Lippincott Williams & Wilkins.)
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Figure 2 further elaborates our investigations into the mechanism of injury on the subcellular level. Nitric oxide and peroxynitrite injure the mitochondria, leading to a proliferation of free radicals, which further break down cellular membranes resulting in necrosis. Apoptosis is also produced when cytochrome c is activated on injury to the mitochondrion, which then triggers the caspase system leading to DNA fragmentation and resultant programmed cell death.
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Fig 2. Diagram illustrating the role of the mitochondria in neuronal cell injury and the mechanism of pharmacologically induced preconditioning. Diazoxide influences the opening of the adenosine triphosphate-sensitive potassium (KATP) channels on the inner membrane of mitochondria. (NMDA = N-methyl-D-aspartate; NO = nitric oxide; NOS = nitric oxide synthase.) (Reprinted from Baumgartner WA. Neurologic injury after cardiopulmonary bypass surgery. J Neurosurg Anesthesiol 2004;16:102–4 by permission of Lippincott Williams & Wilkins.)
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On the basis of previous cardiac investigations with ischemic preconditioning, we performed a series of experiments with the aim that preischemic conditioning could be activated using pharmacologic agents. Certain pharmacologic agents can open adenosine triphosphate (ATP)-sensitive potassium channels on the inner membrane of the mitochondria, thereby chemically producing preconditioning leading to neuronal cell protection. Diazoxide has been shown to be a mitochondrial potassium-channel opener. By administrating this drug before and during cardiopulmonary bypass, we demonstrated significant improvement in both functional scoring and histopathologic analysis in these animals compared with control animals [7].
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Summary of Laboratory Experience and Future Investigative Plans
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Using an animal model with significant neuronal cell injury (HCA), the following conclusions can be drawn:
- Glutamate excitotoxicity occurs and contributes to the injury [3]
- Inhibition of glutamate excitotoxicity significantly reduces this injury (functionally, receptor autoradiographically, and histopathologically) [3]
- Nitric oxide is induced by hypothermic circulatory arrest [4–6]
- Inhibition of neuronal nitric oxide synthase reduces neuronal cell injury [4–6]
- Mitochondrial ATP-dependent potassium channels are involved in neuroprotection [7]
Our focus in the laboratory will continue to further define the mechanism of neuronal cell injury as well as investigating pharmacologic agents that block the pathway of injury at different levels. The more that is understood about the molecular and cellular pathways, the more likely we will be able to develop a specific pharmacologic approach to reducing this injury as well as a gene-screening approach to identify the high-risk patient.
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Clinical Research Into Neurologic Injury
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Along with our colleagues in neurology, we have been evaluating neurocognitive outcomes in patients undergoing coronary artery bypass grafting (CABG). In a four-arm nonrandomized study, patient groups included those with conventional CABG with cardiopulmonary bypass, nonsurgical control patients with a diagnosis of coronary artery disease, those patients undergoing off-pump CABG, and a normal control group without known risk factors for cerebrovascular disease. We have not completed follow-up of our patients who underwent off-pump CABG, but evidence suggests that this modification of CABG might be beneficial to reducing neurologic injury in high-risk patients [8].
The majority of reports clearly demonstrate that there is a subset of patients who suffer postoperative cognitive decline [9]. Our own studies as well as those from Duke University document decline at 5 years from preoperative levels [10, 11]. The majority of studies, including our own, have focused on defining incidence and cause, but not duration.
The question is whether these early cognitive changes continue long after the operation and are the direct result of cardiopulmonary bypass. In previous studies there were no comparable groups that were controlled for cardiopulmonary bypass, anesthesia, normal aging, and vascular and other comorbid diseases as well as dementia.
In a previously published study [12], results were presented comparing 140 patients who underwent CABG with standard cardiopulmonary bypass with a demographically similar nonsurgical control group with documented coronary artery disease. There was no difference in mean test scores between groups at baseline, 3 months, or 1 year. Our preliminary analysis at 3 years would suggest there is no difference in change in cognitive performance between the two groups and that there is a mild decline seen between 1 and 3 years that is most likely caused by a combination of normal aging and a progression of underlining cerebrovascular disease.
Multidisciplinary translational research is the cornerstone to reducing neurologic injury in patients undergoing cardiac surgery. Targeted therapies and emerging imaging technology will help to reduce this injury. Further work in the laboratory with its eventual translation to the patient’s bedside will lead to improved care of our cardiac surgical patients. Ultimately gene screening will be able to identify those patients at greater risk and allow specific interventional strategies to be used in this high-risk group of patients.
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References
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- Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery N Engl J Med 1996;335:1857-1864.[Abstract/Free Full Text]
- Olney JW, Ho OL, Rhee V, et al. Neurotoxic effects of glutamate N Engl J Med 1973;289:1374-1375.
- Redmond JM, Gillinov AM, Zehr KJ, et al. Glutamate excitotoxicitya mechanism of neurologic injury associated with hypothermic circulatory arrest. J Thorac Cardiovasc Surg 1994;107:776-787.[Abstract/Free Full Text]
- Tseng EE, Brock MV, Kwon CC, et al. Quantitative analyses of intracerebral excitatory amino acids and citrulline following hypothermic circulatory arrest Surg Forum 1997;48:297-299.
- Brock MV, Blue ME, Lowenstein CJ, et al. Induction of neuronal nitric oxide following hypothermic circulatory arrest Ann Thorac Surg 1996;62:1313-1320.[Abstract/Free Full Text]
- Tseng EE, Brock MV, Lange MS, et al. Neuronal nitric oxide synthase inhibition reduces neuronal apoptosis after hypothermic circulatory arrest Ann Thorac Surg 1997;64:1639-1647.[Abstract/Free Full Text]
- Shake JG, Peck EA, Marban E, et al. Pharmacologically induced preconditioning with DiazoxideA novel approach to brain protection. Ann Thorac Surg 2001;72:1849-1854.[Abstract/Free Full Text]
- Yokoyama T, Baumgartner FJ, Gheissari A, et al. Off-pump versus on-pump coronary bypass in high risk subgroups Ann Thorac Surg 2000;70:1546-1550.[Abstract/Free Full Text]
- Selnes OA, Goldsborough MA, Borowicz LM, et al. Neurobehavioural sequelae of cardiopulmonary bypass Lancet 1999;353:1601-1606.[Medline]
- Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudinal assessment of neurocognitive function after coronary artery bypass surgery N Engl J Med 2001;344:395-402.[Abstract/Free Full Text]
- Selnes OA, Royall RM, Grega MA, et al. Cognitive changes 5 years after coronary artery bypass graftingis there evidence of late decline?. Arch Neurol 2001;58:598-604.[Abstract/Free Full Text]
- Selnes OA, Grega MA, Borowicz LM, et al. Cognitive changes with coronary artery diseasea prospective study of coronary artery bypass graft patients in nonsurgical controls. Ann Thorac Surg 2003;75:1377-1386.[Abstract/Free Full Text]
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Introduction
Development of Neuroprotective...