| Background:The third national cause of death in our country found that cerebral vascular disease has been promoted to Chinese first death, accounted for22.45%of the total number of deaths. Ischemic stroke (cerebral infarction or cerebral infarction) accounts for80%in cerebral vascular disease. And researches have shown that more than30%is caused by heart disease.With the blood circulation, thrombosis or neoplasm from the heart into the brain arteries, causing ischemic in the corresponding brain blood supply area, and leading to neurological dysfunction. These cardiac diease resulting in cerebral infarction need a cardiac operation under cardiopulmonary bypass, aimed at removing the mural thrombus or valvular vegetations、replacing valvular and correcting the organic lesions.Than the problem of re-embolism can be solved. Currently, the use of technology of cardiopulmonary bypass makes cardiac mortality decreased significantly after surgery, but postoperative neurological complications is still high. Brain damage may be aggravated finally by the controlled hypotension, hemodilution, heparin, non-physiological bypass micro-embolism and inflammation as consequences of CPB. To reduce brain damage caused by cardiopulmonary bypass, traditional prevention or treatment intervene brain damage by strengthening intraoperative monitoring, reduce surgical embolization, reduce inflammation intensity, increase brain tissue ischemia and hypoxia tolerance and other comprehensive measures. But the effect is still not ideal.In view of the cerebral embolism, the specific pathological conditions, cerebral embolism in itself has caused serious damage to brain tissue, particularly in the acute phase. The degree of low-temperature has a certain protective effect during CPB. CPB is commonly used at room temperature(37), low temperature (28-32℃) and deep hypothermia (18-27℃). Low temperature has a neuroprotective role in focal and global cerebral ischemia in acute experimental models. Despite its neuroprotective mechanism has yet been fully elucidated, low temperature can affect variety of physiological and pathological mechanism of cerebral ischemia. It exerts neuroprotective effects by delaying or blocking the ischemic cell death in focal cerebral ischemia. If reperfusion can be restored timely, cerebral cell can return to normal. In recent years, it is found that neuroprotective effects of low temperature goes far beyond its ability to reduce demand of hypoxia and glucose metabolism. Low temperature can reduce harmful intracellular protein hydrolysis, damage of blood-brain barrier, the inflammatory cascade and production and release of oxygen radicals. Otherwise, hypothermia can reduce ths release of excitatory neurotransmitters (such as glutamate), reducing the damage to surrounding neurons. Meanwhile, it has a good effect of cerebral protection that using hypothermia method to reduce the damage of the brain tissue in aortic arch operation.For therapeutic drugs into brain cells, blood brain barrier opening creates a good environment. Nerve growth factor is one of the important bioactive molecules in the nervous system. It is a kind of regulatory factor, which affects survival and differentiation of the certain neurons in the central nervous system. It can promote maturation and repair of neurons, maintainning survival and function of nerve cell. It can also save ischemic neurons under pathological conditions. Recently, some research found that the expression of NGF is increased in brain tissue after cerebral ischemic injury. And it has certain protection and therapeutic effects on cerebral ischemic injury. The experimental results showed that ths exogenous NGF can inhibit the apoptosis of neural cells after deep hypothermic circulatory arrest and obviously reduce the apoptosis led by cerebral ischemia reperfusion to protect the brain. Generally, NGF is not easy to pass through blood brain barrier(BBB). However, in the case of brain injury and hypothermia CPB, as the increasing the permeability of BBB, NGF can achieve a higher concentration in the brain tissue through BBB. And it play a role in protecting brain effectively.At the same time, it already confirmed by clinical that brain injury can cause the phenomenon of abnormal levels of thyroid hormone. The mechanism of injury is usually complicated as patients with the brain injury and low thyroid hormone. Primary brain injury is heavy, so the prognosis is poor. Levels of thyroid hormone associated with the prognosis of craniocerebral injury in deed. Among them, patients with traumatic brain injury combined low thyroid hormone, its prognosis is significantly lower than the non-poor patients with thyroid levels. The reason may be related to the hypothalamic-pituitary-thyroid axis dysfunction caused by brain injury, thus exacerbating brain injury. Thyroid function was restrained in perioperative period of cardiac operation. It can decrease triiodothyronine and have a certain impact on the recovery of the body after surgery. The supplementation of thyroxine tablets can promote the rapid restoration of normal serum T3in perioperative period and reduce the dosage of postoperative inotropic and vasoactive drugs. It can reduce the brain injury and promote the recovery of neurological function.Our previous study has successfully established rabbits model of cardiopulmonary bypass in acute cerebral embolism phase. We confirmed that the degree of brain injury of CPB is not obvious difference between24hour and1week after cerebral embolism. We revealed the surgery of cardiopulmonary bypass in acute cerebral embolism phase is not the absolute contraindication, and the risk faced is within the acceptable range. It was found that the mechanism of brain injury is closely related to inflammatory response during CPB and changes of cerebral vasomotor function, but the degree of brain injury is not obvious difference between early24hour and1week after cerebral embolism. This study was designed to investigate the protective effect of brain through the intervention from controlling temperature and perioperative administration of exogenous drug. We expect to develop new theories and methods of cerebral protection of CPB in acute cerebral embolism phase, so as to protect nerve function better in the operation.Part I Cerebral protective effect of middle hypothermia on rabbits model of cardiopulmonary bypass in acute cerebral embolism phaseObjective:To observe what temperature conditions is the best for the brain protetion, through controlling temperature by the water tank of constan temperature in the process of CPB under the specific conditions of acute cerebral embolism phase.Methods:1.24rabbits, Mean body weight of2.3±0.45Kg, were randomly divided into three groups. Group A underwent an operation of CPB room temperature(37℃) at24h after MCAO, Group B middle hypothermia (28℃) and Group C deep hypothermia (20℃).2. Establishment of a rabbit middle cerebral artery occlusion (MCAO) model and neural function test:group rabbits accepted surgeries electrocoagulating the main stem of the left MCA under direct vision through the supraorbital margin approach. After recovery from anesthesia rabbits were scored according to5points score:0points, no symptoms of nervous system;1point, cannot fully extended contralateral forepaw;2, crawling around,3points, to4points, on the side dump; unable to walk, loss of consciousness. Rabbits scored1to3points were enriched. Establishment of a rabbit model of cardiopulmonary bypass in the acute phase of cerebral embolism:The MCAO rabbits received median sternotomy CPB. Ascending aorta and right atrium are respectively sewed fried line, put perfusion tube into the ascending aorta, inserted drainage tube into the right atrium, aorta clamping, inject Thomas’solution20ml through aortic root to achieve the cardiac arrest. During the bypass, temperature and invasive arterial blood pressure were monitored [Group A at room temperature(37), Group B middle hypothermia (28℃) and Group C deep hypothermia (20℃)]. After1hour the aortic root was unclamped, following rewarming, assisted circulation and withdrawal of extracorporeal circulation.3. Collection of specimen and detection of plasma chemical molecules:took the venous blood of rabbits with3ml before CPB,20min after CPB and60min after CPB respectively, and centrifuged at3000rpm for30minutes, drew the supernatant into pyrogen and endotoxin free tube, labeled and kept in the refrigerator in-20℃. Determination the content of S100β protein, plasma tumor necrosis factor (TNF-α), myelin basic protein (MBP) and nitric oxide (NO) in24hours after using the method of ELISA.4. Data analysis:statistical analysis was conducted using SPSS13.0.0software, numerical were described by means and standard deviations (x±SD), data in the chart were described by the mean and the standard deviation (SD) or95%confidence interval(CI), and counted data by relative number.Results: 1、Biochemical markers of brain damage:it is found that the plasma S-100β protein is effective markers for early brain damage, the variation of MBP content reflects the damage of brain and blood brain barrier. There are no significant differences among three groups (P>0.05) at the beginning of CPB. Compared group B with group A at different time points:CPB20min (P<0.05), CPB60min (P<0.05); Compared group B with group C at different time points:CPB20min (P<0.05),CPB60min (P<0.05)2、Inflammation index:TNF-α is the formation of vasogenic brain edema, the destruction of blood brain barrier and neuronal degeneration and necrosis. There are no significant differences among three groups (P>0.05) at the beginning of CPB. Compared group B with group A at different time points:CPB20min (P<0.05), CPB60min (P<0.05); Compared group B with group C at different time points: CPB20min (P<0.05), CPB60min (P<0.05)3、Endothelium-derived relaxing factor:NO is a potent vasodilator, which conducive to the protection of cerebral vasomotor function. There are no significant differences among three groups (P>0.05) at the beginning of CPB. Compared group B with group A at different time points:CPB20min (P<0.05),CPB60min (P<0.05); Compared group B with group C at different time points:CPB20min (P<0.05), CPB60min (P<0.05)Conclusion:Middle hypothermia (28℃) conditions can alleviate cerebral injury, inhibit inflammatory reaction and protect cerebral vasomotor function through controlling temperature by the water tank of constan temperature in the process of CPB under the specific conditions of acute cerebral embolism phase. It is the best for the brain protetion. Part Ⅱ Cerebral protective effect of NGF on rabbits model ofcardiopulmonary bypass in acute cerebral embolism phaseObjective:To observe the brain protetion of administration of exogenous nerve growth factor in the process of CPB under the specific conditions of acute cerebral embolism phase.Methods:1.16rabbits, Mean body weight of2.3±0.45Kg, were randomly divided into two groups. Group D underwent an operation of CPB temperature at24h after MCAO (non-treatment), Group B underwent an operation of CPB temperature at24h after MCAO (treatment).2. The methods of establishment of the CPB model with acute cerebral embolism are the same. The most common low temperature (28℃-32℃) as the temperature control standard in the heart operation. Join the "mouse nerve growth factor for injection"(2mL;40mg) in the priming solution in Group E during CPB. In the D group with normal saline as control.3. Collection of specimen and detection of plasma chemical molecules:took the venous blood of rabbits with3mL before CPB,20min after CPB and60min after CPB respectively, and centrifuged at3000rpm for30minutes, drew the supernatant into pyrogen and endotoxin free tube, labeled and kept in the refrigerator in-20℃. Determination the content of S100p protein, plasma tumor necrosis factor (TNF-α), myelin basic protein (MBP) and nitric oxide (NO) in24hours after using the method of ELISA.4. Data analysis:statistical analysis was conducted using SPSS13.0.0software, numerical were described by means and standard deviations (x±SD), data in the chart were described by the mean and the standard deviation (SD) or95%confidence interval(CI), and counted data by relative number.Results:1.. Biochemical markers of brain damage:Compared group D with group E at different time points:CPB20min (P<0.05), CPB60min (P<0.05). S100β protein concentration increased rapidly. There are no significant differences in MBP at different time points.2、Inflammation index:Compared group D with group E at different time points: CPB20min (P<0.05), CPB60min (P<0.05). TNF-α concentration increased rapidly.3、Endothelium-derived relaxing factor:Compared group D with group E at different time points:CPB20min (P<0.05), CPB60min (P<0.05). NO concentration descended rapidly.Conclusion:Administration of exogenous nerve growth factor can alleviate cerebral injury, inhibit inflammatory reaction and protect cerebral vasomotor function through controlling temperature by the water tank of constan temperature in the process of CPB under the specific conditions of acute cerebral embolism phase. It takes on the brain protetion in the process.Part Ⅲ Cerebral protective effect of thyroid hormone(TH) on rabbits model of cardiopulmonary bypass in acute cerebral embolism phaseObjective:To observe the brain protetion of administration of thyroid hormone in the process of CPB under the specific conditions of acute cerebral embolism phase.Methods:1.16rabbits, Mean body weight of2.3±0.45Kg, were randomly divided into two groups. Group F underwent an operation of CPB temperature at24h after MCAO (non-treatment), Group G underwent an operation of CPB temperature at24h after MCAO (treatment).2. The methods of establishment of the CPB model with acute cerebral embolism are the same. The most common low temperature (28℃-32℃) as the temperature control standard in the heart operation. Join the "thyroid hormone"(50μg) in the priming solution in Group G during CPB. In the F group with normal saline as control. Monitoring of heart rate, blood pressure of air temperature in operation.3. Collection of specimen and detection of plasma chemical molecules:took the venous blood of rabbits with3ml before CPB,20min after CPB and60min after CPB respectively, and centrifuged at3000rpm for10minutes, drew the supernatant into pyrogen and endotoxin free tube, labeled and kept in the refrigerator in-20℃. Determination the content of S100β protein, plasma tumor necrosis factor (TNF-α), myelin basic protein (MBP) and nitric oxide (NO) in24hours after using the method of ELISA.4. Data analysis:statistical analysis was conducted using SPSS13.0.0software, numerical were described by means and standard deviations (x±SD), data in the chart were described by the mean and the standard deviation (SD) or95%confidence interval(CI), and counted data by relative number.Results:1、Biochemical markers of brain damage:Compared group F with group G at different time points:CPB20min (P<0.05), CPB60min (P<0.05). S100β protein and MBP concentration increased rapidly. 2、Inflammation index:Compared group F with group G at different time points: CPB20min (P>0.05), CPB60min (P>0.05). There are no significant differences bewteen them.3、Endothelium-derived relaxing factor:Compared group F with group G at different time points:CPB20min (P>0.05), CPB60min (P>0.05).There are no significant differences bewteen them.Conclusion:Administration of thyroid hormone can alleviate cerebral injury in the process of CPB under the specific conditions of acute cerebral embolism phase. |
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