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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.54 no.4 Campinas July/Aug. 2004
Pathophysiology of neurological injuries during heart surgery*
Lesión neurológica en cirugía cardíaca: aspectos fisiopatológicos
Rólison Gustavo Bravo Lelis, M.D.I; José Otávio Costa Auler Júnior, TSA, M.D.II
IGraduando de Medicina da FMUSP. Bolsista
de Iniciação Científica pela FAPESP (Processo nº 02/06790-9)
IIProfessor Titular da Disciplina de Anestesiologia, Departamento de Cirurgia da FMUSP
BACKGROUND AND OBJECTIVES:
Since neurological injuries are very concerning and important postoperative
complications following cardiac surgeries, the purpose of this study was to
discuss the pathophysiology of these injuries, what measures can be taken to
decrease their incidence and the possible genetic origin of such brain injuries.
CONTENTS: This study is a review of papers which address the pathophysiology of heart surgery-related neurological injuries and their possible genetic origin, as well as some proposals for their prevention.
CONCLUSIONS: A lot has been said about cognitive function disorders after heart surgeries, such as myocardial revascularization, which are present causes of increased morbidity and mortality, in addition to longer hospital stay. Major advances to decrease such rates have been observed in this field, and others are still expected aiming at neurological injuries prevention.
Key Words: COMPLICATIONS, Neurologic: injuries; SURGERY, Cardiac: myocardial revascularization
JUSTIFICATIVA Y OBJETIVOS:
En virtud de las lesiones neurológicas que ocupan un papel importante en
el contexto de las complicaciones pós-operatorias, cuando comparadas a
las demás, el presente estudio tentó discutir los principales factores
envueltos en la lesión neurológica peri-operatoria en cirugía
cardíaca, las intervenciones que buscan disminuir la incidencia de lesiones
neurológicas, enfocando de manera simple, y la probable génesis genética
en tales lesiones cerebrales.
CONTENIDO: Este trabajo contiene la revisión de artículos que enfocan la fisiopatología de las lesiones neurológicas relacionadas a procedimientos cardíacos, su posible origen genético, bien como una propuesta para su prevención.
CONCLUSIONES: Mucho se habló de las disfunciones cognitivas de pacientes después de cirugía cardíaca, como la revascularización del miocardio que es motivo del aumento de la morbimortalidad observada actualmente y factor de mayor tiempo de hospitalización. Es un hecho que ya hubo grandes avanzos en esa área con la finalidad de disminuir eses índices, previniendo aún otros que visan la profilaxis de lesiones neurológicas.
Recent technological advances have led to decreased morbidity and mortality during heart surgeries. Neurological complications, however, are still important causes of postoperative morbidity and respond for great part of postoperative deaths.
Cardiopulmonary bypass (CPB) was introduced 50 years ago, and since then, reports have been published about patients developing some type of neurological sequela, fostering extensive researches on these sequela and CPB itself. It is believed that the overall incidence of such complication is up to 75%1, and may vary from transient psychological changes, such as attention and memory deficits, to more severe events, such as extensive stroke. It is currently known that such complications after heart surgery may involve different brain areas and present a variety of clinical manifestations.
Many factors play different roles on perioperative neurological injury origin during heart surgeries, like older age, previous brain or atheromatous disease, diabetes mellitus, intracardiac procedures, changes in body temperature during CPB and maybe a genetic predisposition, among others.
This review aimed at discussing major factors involved in heart surgery-related neurological injuries and their possible genetic origin, as well as proposing some measures for their prevention.
INCIDENCE AND PATHOPHYSIOLOGY
The literature shows a wide variation in the incidence of neurological complications after heart surgeries. Discrepancy of results is attributed to different study designs (whether prospective or retrospective, for example), the nature of the surgery (open or closed heart surgeries), the presence of co-morbidity and the method used to evaluate type and degree of neurological dysfunctions. Studies on postoperative neurological dysfunctions are primarily related to myocardial revascularization because it represents most heart surgeries. Although there are discrepancies regarding the methods, the incidence of neurological complications varies from 0.4% to 5.4%1.
Even admitting that cardiopulmonary bypass is the major factor involved in neurological complications during heart surgeries, there have always been some questions about the potential noxious effect of the anesthetic-surgical procedure on the central nervous system. To verify this possibility, an European study2 has evaluated brain function of 1218 elderly patients submitted to non-cardiac surgeries. Neuro-cognitive tests through simple questionnaires with direct questions about name, birth date, current date, job, address, data on relatives, were applied in three periods: before surgery, at hospital discharge and three months later. There has been a relatively high incidence of postoperative cognitive dysfunction (26%), made evident by confusion of dates and facts, as well as by memory lapses persisting for up to three months in 10% of studied patients2. The study tried to attribute this cognitive dysfunction to the anesthetic-surgical procedure, in the absence of cardiopulmonary bypass. Shaw et al.3, following the same line of investigation and also employing neuro-cognitive tests based on simple questionnaires, have compared two groups of patients: one submitted to myocardial revascularization with cardiopulmonary bypass, and the other submitted to peripheral vascular surgery. Results are shown in table I and reveal higher incidence of cognitive dysfunction in the first group. What can be drawn from this and other investigations is that, for sure, cardiopulmonary bypass is a predisposing factor for cognitive dysfunctions, but that they are also present in non-cardiac surgeries, especially in patients with history of arterial vascular disease.
The impact of cognitive changes on morbidity and mortality of patients submitted to heart surgery with cardiopulmonary bypass is not severe. The same is not true for more severe events, since injuries generically defined as strokes may lead to comma, permanent sequela or death. There has always been some confusion in the literature regarding names, classification and pathophysiology of more severe neurological events. It was up to a group of investigators led by Roach et al.4, studying a large series of patients, to propose a classification shown in chart I. Using the classification proposed by these investigators4, Wolman et al.5 have evaluated a group of patients submitted to myocardial revascularization and have classified neurological events in: type I, defined as focal injuries with stupor or comma; and type II, with intellectual function deterioration, memory deficits or seizures5.
This study has shown that 6.1% of patients had some neurological complication, being 3.1% type I, and 3% type II5.
Still in this investigation, Wolman et al.5 have shown that, parallel to the surgical technique, age would also be a risk factor for neurological complications. Patients aged 70 years or above had a mean incidence of 4% to 9% postoperative stroke or comma, differently from patients below 70 years of age, who had an incidence of 1%.
Other mechanisms to explain these complications have also been exhaustively studied. CPB itself has been considered the major cause for more severe postoperative cognitive changes. However, a study by Taggart et al.6 to establish the real impact of CPB on neurological complications has shown that patients submitted to heart surgeries with or without CPB had similar neuro-psychological test results. These patients, who had been evaluated before surgery, were submitted to simple questions and answers tests evoking memory in two moments: hospital discharge and three months later. Results have shown that CPB was not the major cause of neuro-psychological dysfunctions. Another speculation would be that such neuro-psychological disorders are partially associated to transient changes in brain auto-regulation as a consequence of artificial ventilation, anesthetic drugs and blood pressure changes6.
Today it is known that postoperative cognitive changes are multifactorial. Older age, diffuse vascular disease, intraoperative embolization, hypoperfusion and consequent inflammation, as well as reperfusion injury inherent to this type of procedure may, together, determine more or less cognitive deficits.
Embolus formation, caused by aortic wall atheromas, platelets aggregation and air bubbles from the oxygenator and cardiac chambers, may be the primary cause of brain injury or worsening of preexisting injuries. Intraoperative gas microembolism is difficult to detect and is considered the major cause for cognitive disorders. There are three main mechanisms for micro-bubbles formation. The first one is related to the oxygenator itself, when membrane material may rupture due to increased transmembrane pressure by excessive gas flow. This way, small amounts of air may directly reach the blood stream. The second cause is blood cooling and heating, which can modify gases' physical properties (oxygen, nitrogen and carbon dioxide). Solubility changes may predispose to micro-bubbles formation. Finally, cardiac chambers opening leads to air entrance into them and pulmonary vessels as well. This air, in small amounts, may get to arterial circulation and reach brain circulation next. Several measures have been proposed to overcome this problem. The most important is focused on the surgeon, and consists of careful air removal from cardiac cavities and pulmonary vessels before aortic unclamping. Preventing spontaneous heartbeats with open aorta before being sure that all air has been removed is also an important approach. For the anesthesiologist, pulmonary hyperventilation when air is being removed by the surgeon may determine decreased brain blood flow. Vessels caliber decreasing by vasoconstriction may reduce micro-emboli impactation, as shown by Linder et al.7.
Aortic atheroembolism is also a risk for patients submitted to heart surgeries. It is known that severe aortic atheromatous disease is worsened with age, being detected up to 80% of patients aged 80 years or above. Patients with previous cerebral vascular disease or transient ischemic attack, with proven atheromatous disease in extracranial brain arteries, have a higher chance of developing intraoperative stroke. Similar to age, diabetes mellitus and hypertension are independent factors which may affect neurological complications. So, patients with these diseases are at additional risk during heart surgery with CPB. Microembolization and brain perfusion changes due to arterial hypotension, which is frequent in this type of surgery, are other aggravating factors able to cause neurological injuries. It should also be considered that diffuse atherosclerotic disease, promoting brain vessels narrowing, affects its auto-regulation which, in face of blood pressure changes and possible embolization, makes some brain areas more susceptible to ischemia8.
Inflammatory response, as shown in figure 1, may contribute to brain injury, especially in brain areas with bad perfusion, a mechanism known as post-reperfusion injury. During CPB, blood exposure to non-endothelial surfaces activates the coagulation cascade, the fibrinolytic and complement systems, being able to induce leukocytes degranulation and free radicals release as well. Brain regions which might have suffered some degree of microembolization-induced hypoperfusion or ischemia would have a higher chance of worsening the injuries due to overimposed inflammatory events, with significant clinical consequences8,9.
As seen, the surgery itself, in addition to older age of patients submitted to heart surgeries and other factors above discussed, increases the risk for some type of neurological sequela. It is also a fact that most candidates to this type of surgical procedure already present with several conditions which may increase the risks for neurological disorders. Therefore, many methods have been proposed to reduce such sequela and patients' morbidity.
This way, Arrowsmisth et al.9 have classified protective measures during heart surgeries in two types: physical and pharmacological. Physical protective measures are mainly related to the intraoperative period, and include fast and effective surgery, adequate temperature and MBP, as well as glycemia and CO2 control. Temperature management has been highlighted among physical measures, being hypothermia considered by some authors a useful tool for brain protection. Two studies10,11, summarized in Table II, have investigated the effect of temperature during CPB. In a study of Martin et al.10, patients submitted to CPB were divided in two groups: in the first group, temperature was maintained at 35 ºC or above, and in the second, temperature was maintained at 28 ºC or below. Results have indicated that, in the hypothermal group, the incidence of neuro-cognitive complications was three times lower as compared to the warmer group10. Another similar study of a different group of investigators11 was unable to show similar results.
Mean blood pressure (MBP) during surgery has also been an issue for scientific speculations. As summarized in table III, a study of Gold et al.12 has shown that mean blood pressure maintained above 80 mmHg is related to a lower incidence of neurological injuries. The authors have compared two groups of patients: one of them with MBP kept between 50 and 60 mmHg during CPB, and the other with MBP equal to or above 80 mmHg. Postoperative neurological tests have shown a lower rate of neurological complications in the group with MBP above 80 mmHg.
Although this study's results leave no doubt about the value of higher MBP during heart surgery to decrease neurological complications, one should keep in mind that this is particularly true for older patients or those with carotid obstructive injuries and/or history of severe hypertension. It should also be highlighted the role of carbon dioxide (PaCO2) and glycemia. As mentioned above, lower PaCO2 levels would play some role in microembolization prevention when heartbeats are restarted8. Also, glycemia levels above 120 mg% seem to potentiate ischemic injuries, a mechanism which involves cell calcium metabolism during reperfusion injury development. Hence, the strict control of glycemia by anesthesiologists in the intraoperative period is a basic recommendation today8,9.
Pharmacological measures aim at modulating neuronal activity by means of substances of proven action, such as ischemic pathway inhibitors and/or metabolic suppressors9. Among these substances, special attention has been given to propofol for its effect on EEG spikes suppression. A question has been raised whether such effect could play a role in decreasing brain metabolism during CPB, thus acting as neuronal protector. According to Souter et al.13, propofol in doses suppressing EEG waves during CPB has not decreased brain venous oxygen saturation below 50% during reheating, measured in internal jugular vein bulb.
Cell ischemia pathway inhibitors, such as calcium antagonists are being evaluated as potential protectors. Antidepressant agents could aid for a new strategy aiming at leukocytes inhibition, endothelial protection and excitatory aminoacid receptors inhibition, among others, promoting some degree of organic protection during CPB9. However, clinical confirmation of such results still requires further investigations.
Even with protective methods and the proper care during pre, intra and postoperative periods, there are still patients who, submitted to similar risks, present different clinical evolutions, making us believe in a case-by-case genetic influence. Currently, with the development of genetic research labs, it is possible to identify neuronal function markers. These markers would be involved in brain protection or a higher trend for cell injury after an aggression, or would even help patient's screening for more accurate prognosis or diagnosis. One of the several investigations in this area has targeted S100 protein, which may be a promising neuronal injury marker. S100 protein is not an usual part of blood plasma substances, but it is present in plasma after stroke, subarachnoid hemorrhage, brain trauma and CPB14. Trying to understand how this protein is released after CPB, Johnson et al.15 have observed 515 patients submitted to MR and have monitored S100 concentration at CPB completion, after 5, 15 and 48 hours, together with clinical-neurological follow-up. Data have shown that early S100 release was related to age and longer CPB time, with no correlation with neurological tests. Late S100 release, however, was associated to positive neurological tests and the incidence of brain injuries. Although being a possible indicator of brain injury severity, S100 protein is unable to inform its anatomic extension or clinical consequences. While investigations progress toward finding effective substances to improve diagnosis, there are speculations about other already well-known substances, among them glutamate, which could be a brain injury marker. Reynolds et al.16, however, in an attempt to know whether glutamate would correlate to neuronal injuries, have developed a simple and reliable method to quantify its plasma concentration during MR with CPB. Glutamate concentration changes were obtained during surgery. Neuro-cognitive tests were applied before and after surgery. It has been observed that glutamate concentration during surgery would vary according to each patient and with time. Based on intraoperative serum glutamate concentrations and neurological tests, Reynolds et al. have concluded that plasma glutamate changes were not predictive of neurological disorders observed after MR16.
In the search for brain injury predictors, others substances were identified which could influence prognosis. Toward this goal, attentions were turned to apoliprotein E (ApoE). Some studies already indicate that it could be involved with cognitive decrease after heart surgery. It is certain that the presence of one of the ApoEs alleles is an important risk factor for late onset Alzheimer's disease, in addition to its potential association with increased risk for atherosclerosis. ApoE is genetically coded in men under three isoforms: ApoEe2, ApoE e3 and ApoE e417. A multi populational study18 has shown that ApoE e4 allelic variation increases the risk for Alzheimer's disease, while e2 allele has a protective effect. It has been postulated that allele e4 could be involved in brain blood flow auto-regulation. A study by Ti et al.19 has compared brain blood flow auto-regulation, brain O2 metabolic rate and arterial/venous difference in blood O2 concentrations in 154 patients with or without allele e4 submitted to MR. Brain blood flow was measured during surgery using Xe133 and brain metabolic rate was calculated by the difference between O2 concentrations in arterial and mixed venous blood obtained in the jugular bulb. The conclusion was that allele e4 had no global effect on brain blood flow, O2 supply and extraction, suggesting that allele e4 effects on brain injuries are due to different mechanisms. One of them could be increasing substances which act on inflammatory response activation, such as Interleukin 8 (IL-8) and Tumor Necrosis Factor Alpha (TNF-a). With that in mind, Drabe et al.20 have decided to verify the possible relationship between cytokines and the allele e4 after MR with CPB. Drabe's group has studied 22 patients by monitoring IL-8 and TNF-a concentrations thru radioimmunoassay in 48-hour intervals after surgery, at the same time that they determined the presence of ApoE e4 allele. Their results have shown 6 patients (27%) with this allele. When comparing CPB time, aortic clamping time and cytokines concentration (IL=8 and TNF-a), there has been significant difference for these 27% of patients as they had those parameters increased. The conclusion was that the presence of allele e4 could be associated to increased IL-8 and TNF-a during CPB.
Heart surgery has experienced major technological advances in recent years, not only with the advent of new anesthetic-surgical techniques, but also with the development of different drugs, which knowingly decrease the incidence of short and long-term cardiovascular complications. Nevertheless, it has been observed that, even with good results in long-term follow-ups, there are still some complications for which it is not possible to determine, with a reasonable level of certainty, the predisposing event leading to morbidity. Postoperative neurological dysfunction is an important source of problems, which may vary from transient distress such as disorientation or attention deficits, to irreversible central nervous system injuries, such as brain hemorrhage and ischemia.
It is known that there are some risk factors for central nervous system related problems in the postoperative period of heart surgeries, such as CPB, severe ascending aorta and carotid atheromatous disease, inadequate anticoagulation during surgery with CPB, older age, induction of intraoperative body temperature changes, hyperglycemia, intraoperative acid-base correction methods, micro and macroembolization in CPB, intracardiac procedures, advanced cerebrovascular disease and previous cardiac disease. Even so, these risk factors are still under investigation to determine their actual impact on postoperative neurological prognosis. Genetic predisposition to many diseases has been extensively studied. As an example, we have been developing a study together with the Genetic Laboratory of the Heart Institute, Hospital das Clínicas, where patients undergoing MR are being followed-up. Results of a simple neurological evaluation, known as mini-mental, are compared to ApoE phenotyping to detect whether patients with phenotype for ApoE e4 are prone to postoperative neurological complications. Sampling test suggests that an expressive number of patients is needed to achieve any result, still in the early stage of the study. This mini-mental evaluation is composed of a questionnaire with simple questions to test recent and late memory, before, at 48 hours and at hospital discharge. If more severe complications or mini-mental changes are detected, the neurologist is called for specialized tests. The confirmation that some individuals present hereditary trends to develop some morbid states will allow new therapies to be earlier instituted, as shown in figure 2, before the aggressing factor, what could have a significant impact on life quality and morbidity/mortality. Therefore, it is necessary to establish, as accurately as possible, which are the factors predisposing to pathogenic processes and their effects.
The significant risk of adverse neurological events during heart surgery explains the renewed interest on protective strategies, injuries pathophysiology and, more recently, on the genetics likely to be involved in main central nervous system injuries21.
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Prof. Dr. José Otávio Costa Auler Júnior
Address: Av. Dr. Enéas de Carvalho Aguiar, 44 Cerqueira César
ZIP: 05403-000 City: São Paulo, Brazil
Submitted for publication July 25,
Accepted for publication November 26, 2003
* Received from Serviço de Anestesiologia e Terapia Intensiva Cirúrgica do Instituto do Coração da Faculdade de Medicina da Universidade de São Paulo, InCor (FMUSP), São Paulo, SP