| Background:In 1954, published by GIBBON, the cardiopulmonary bypass(CPB) technology was used in cardiac surgery. It has promoted the development of cardiac surgery greatly. With the improvement of surgical technique, extracorporeal circulation apparatus and organs protection measures, the incidence of cardiac insufficiency, hypohepatia and renal insufficiency decreased obviously postoperatively. However, the incidence of central nervous system complications after cardiac surgery in the past 30 years has no change obviously. It’s a significant clinical problem for clincians that CPB leads to central nervous system damage in cardiac surgery. It often cause central nervous system damage during cardiac surgery with CPB, such as the formation of brain micro thrombus, the changes of cerebral perfusion and systemic or local inflammatory cascade reaction. Due to brain oxygen metabolism disorders, it leads to Ca2+ overload in brain cells, excitatory neurotransmitter toxic effects, nitric oxide peroxide and oxygen free radical damages. The inflammation caused by CPB, it products and releases inflammatory markers. According to reports in the literature, the incidence of postoperative severe stroke is 2%～5%, the incidence of pathological encephalopathy is 10%～30%, the incidence of cognitive dysfunction postoperative 1 week is 50%～70%, the incidence of cognitive dysfunction postoperative 2 months is still can be as high as 30%～50%, patients with severe illness will be die. The complications of central nervous system will increase mortality, extend the length of hospital stay, lower the quality of life and consume more medical resources. In a word, it is of great significance to promote cerebral protection during cardiac surgery.How to find an effective manner to assess damage degree timely? The development of modern medical imaging technology for the diagnosis and monitoring of cerebral injury provides a great help. It may have some difficulties to take image examination for critical patients with unstable vital signs, using mechanical ventilation, continuous ECG monitoring and hemodynamic disorder. So, the clinicians pay attention to continuous and dynamic detecting the change of biochemical indexes of neurological damage day by day.This experimental study using detecting neurological damage biochemical indexes, inflammatory markers and mini-mental state examination scale(MMSE) to assess the degree of neurological damage.Up to now, methods of cerebral protection still are hypothermia, improving cerebral blood supply, ischemic preconditioning and so on. The lack of ideal, safe and low cost of cerebral protection drugs is a problem. S100-β protein is a kind of acid protein can be combined with calcium and zinc. As a sensitive marker of early cerebral damage, it is in the central nervous system of stellate glial cells and anterior pituitary cells specifically. Under normal circumstances, it can not through the blood brain barrier. With nervous system damaged, it can enter the cerebrospinal fluid and through the blood brain barrier into the blood stream. Neuron specific enolase(NSE) is the key enzyme of glycolysis pathway. It exists in neurons and neuroendocrine cells specifically. When the cerebral damage factors influence the metabolic changes of neurons and the structure and function of neuron membrane damaged, NSE is released from the cytoplasm into the intercellular space and cerebrospinal fluid. NSE activated can degrade the main components of the blood brain barrier basement membrane, including fiber mucins and laminin, and then destroy the blood brain barrier. Cause increased the permeability of blood brain barrier, prompting elevated serum NSE concentration. Under the physiology condition, interleukin-6(IL-6) mainly comes from Purkinje cells in the cerebellum, vertebral body cell and granulosa cells in hippocampus. High levels of IL-6 through chemotaxis neutrophils to the lesion area a large number of accumulation and release of toxic oxygen free radicals, coordination with other inflammatory cells and cytotoxic effect into full play, lead to brain edema or necrosis. C-reactive protein(CRP) is one of the most valuable acute phase reaction proteins. CRP has varying degrees of increase in patients with cerebral injury incidence. It is positively associated with the degree of illness. The illness is heavier, the higher of serum concentration is more obviously and the peak is higher. The rise of its serum concentration degree can react the extent of the injury and inflammation indirectly. High levels of CRP is closely related with acute cerebral infarction development. CRP can be used as an independent risk factor for patients with acute cerebral damage, and has important clinical significance for diagnosis and predicting prognosis.It is low T3 syndrome that the serum FT3 level declined in patients with cardiac surgery under cardiopulmonary bypass. There is a significantly correlation that the extent of FT3 decrease and degree of cerebral injury. Research shows that there is a cerebral damage after CPB, include blood brain barrier damage, a large amount of inflammatory factors (such as S100-β protein, NSE, TNF-a and IL-6) released into the bloodstream, the inflammatory factors increase negative correlation with serum FT3 level declined significantly. In addition, through studying the serum thyroid hormone levels in patients with acute cerebral injury, show that the concentration of serum FT3 declined significantly. The study shows that low serum FT3 level will further aggravate the cerebral damage and the close correlation between the mortality of the patients with acute cerebral damage and low concentration of serum FT3.At present, domestic and international researches show that measures are still hypothermia, ensure cerebral blood supply and ischemic preconditioning. Lack of ideal, safe and low cost of cerebral protection drugs. Low T3 syndrome often appears in patients with cardiac surgery. TH can improve postoperative concentration of serum FT3 significantly and reduce the incidence of postoperative cardiac insufficiency. At present, TH is often applied in the heart donors of the brain death. The main reason is that TH can improve the function of the transplant heart effectively, at the same time TH is good for cerebral protection. Besides, TH is considered has obvious cerebral protection in ischemic cerebral disease. TH can inhibit the cerebral ischemic disease in the process of the production of inflammatory factors, inhibit the body’s inflammatory response, reduce cerebral edema and reduce the permeability of blood brain barrier, so as to achieve the purpose of reduce cerebral damage. It has attracted much attention that clinical intervention of TH in the treatment of traumatic cerebral damage and improve the patients’ prognosis. However, there is very few research of TH in prevention and treatment of cerebral damage during cardiac operations, and the mechanism of TH in cardiac surgery with CPB is still not clear in the process of cerebral injury.By randomized controlled clinical trial to observe preoperative oral levothyroxine sodium piece 1 week for serum cerebral damage inflammatory factors in patients with cardiac surgery. Explore the cerebral protection of TH in patients with cardiac operation under CPB, in order to further reduce the postoperative complications of central nervous system, improve the outcomes of patients with cardiac surgery, put forward better treatment strategies and provide clinicians with safe and effective cerebral protection drug choice.Objective:Research the influence of thyroid hormone(TH) on the intraoperative and postoperative the serum concentrations of neurological damage specific indicators and inflammatory factors and postoperative cognitive function in patients with cardiac surgery with CPB. To explore protective effect of TH on neurological damage in cardiopulmonary bypass. Provide new ideas for clinical application of cerebral protection drugs.Methods:1. Study object:One hundred and fifty-two patients performed with heart valve replacement in Cardiothoracic Surgery department were randomly divided into treatment group (n=76) and control group (n=76).2. In treatment group,50μg levothyroxine sodium (Euthyrox, Merck, Germany) was taken everyday from a week before surgery to the morning of surgery. The control group was not special treatment.3. Anesthesia:Two groups of patients with tracheal intubation compound vein anesthesia.4. Establish CPB:The extracorporeal circulation machine is produced by Germany Stella medical instrument company. The extracorporeal membrane oxygenator is produced by America Medtronic company. We adopt lcrystoloid solution to reduce blood sticky and vascular resistance, blood cell damage and visible part within the capillary blood sedimentation and adjust acid-base and electrolyte balance in the body. Our research observe the patients’ electrocardiogram, arterial pressure, central venous pressure, nasopharyngeal temperature, blood gas analysis index, whole blood activated clotting time (ACT) and hematocrit (HCT) closely. Intravenous heparin when cut pericardium, the heparin injection quantity should be 3mg/kg. The injection quantity can not only avoid insufficient anticoagulation, but also avoid heparinization caused by.excessive dosage of heparin. Temperature at 28-32℃ in patients with shallow low temperature, oxygen flow rate control between 0.6-0.9, to protect the myocardial function can infusion 20 mmol/L of potassium stopped fluid.5. Surgical procedures:The operation was performed under general anesthesia with endotracheal intubation, moderate hypothermic cardiopulmonary bypass and blood oxygenation by membrane oxygenator in vitro. Keep the mean aortic perfusion pressure at 60-80mmHg. The incision into the chest is center of the chest. The mitral valve replacement incision is from the right atrium-the interatrial septum into heart. The aortic valve replacement incision is ascending aorta root oblique abdominal. Include 103 cases of mitral valve replacement,29 cases of aortic valve replacement and 20 cases of double valve replacement (mitral valve combined aortic valve replacement).6. Specimen collection and target detection:To take blood samples for detection of S100-β protein, neuron specific enolase (NSE), interleukin-6 (IL-6), C-reactive protein (CRP) and free triiodothyronine (FT3) in times of before opearation (Time1),30 min after beginning of CPB (Time2), the end of CPB (Time3),6h (Time4) and 24h (Times) after CPB, respectively.7. Assessment of cognitive function:To assess the patients’cognitive function with mini-mental state examination (MMSE) before operation and 1,3 and 7d postoperative.8. Data analysis:Statistical analysis was conducted using SPSS 19.0 software. Data were expressed as mean±standard deviation(x±s). Comparisons between groups were conducted with unpaired t-test, and linear correlations were assessed between independent and dependent variables. P<0.05 was considered statistically significant.Results:1. Serum FT3 levels:There was no statistically significant difference of serum FT3 concentration in two groups (P=0.273). Two groups of serum FT3 concentration started to decline with CPB beginning. The serum FT3 concentration was lowest at Time3 (3.40±0.38 vs 3.07±0.28, P=0.000). The serum FT3 concentration rised gradually after CPB. The serum FT3 concentration in intervention group was still higher than the control group (3.73±0.38 vs 3.32±0.28, P=0.000)2. Cerebral damage biochemical indicators:S100-β protein is a sensitive early biomarkers of acute cerebral damage. It has important diagnostic value. NSE specificity exist in neurons and neuroendocrine cells. After cerebral damage, NSE can be released from cells, through the damage of blood brain barrier into the blood circulation. It Is considered to be reflected a sensitive monitoring indicators of cerebral damage. There was no statistically significant difference of serum S100-β protein and NSE concentration in two groups at Time1 (P=0.598, P=0.068). The concentration of serum S100-β protein started to rise gradually with CPB beginning, and reached a maximum amounting at Time3(0.79+0.07 vs 0.93±0.08, P=0.000). The serum S100-β protein concentration gradually declined after CPB. There was no statistically significant difference of serum S100-β protein concentration in two groups at Times (P=0.149). The concentration of serum NSE started to rise gradually with CPB beginning, and reached a maximum amounting at Time3 (39.48±2.71 vs 44.50±3.77, P=0.000). It gradually declined after CPB.3. Inflammation factors:IL-6 mainly comes from Purkjuje cells in the cerebellum, hippocampus vertebral body cell and granulosa cells. High concentrations of IL-6 through chemotaxis neutrophils to the lesion area a large number of accumulation, the release of toxic oxygen free radicals, and coordination with other inflammatory cells playing a role of cytotoxicity, and lead to cerebral edema or necrosis. CRP is a kind of typical acute phase proteins, CRP synthesis and cause inflammatory reaction of cytokines have close relationship, the levels of inflammatory reaction is an important biochemical indicators. There was no statistically significant difference of serum IL-6 and CRP concentration in two groups at Time1 (P=0.126、P=0.073). The concentration of serum IL-6 started to rise gradually with CPB beginning, and reaches a maximum amounting at Time4 (69.43±7.95 vs 79.88±9.37, P=0.000). Then it declined gradually. The concentration of serum CRP started to rise gradually with CPB beginning, and reached a maximum amounting at Time3 (71.04±8.26 vs 79.80±7.27, P=0.000). It started to decline gradually after CPB.4. Mini-mental state examination scale (MMSE):There was no statistically significant difference of MMSE score in two groups at operational morning (P=0.762). The MMSE score was higher in the treatment group than that in the control group one week postoperatively (P<0.05).Conclusion:The serum concentrations of neurological damage specific indicators and inflammatory factors are increased and postoperative cognitive function is declined in patients with cardiac surgery by CPB. Preoperative application of TH can effectively improve the perioperative serum thyroid hormone concentrations and improve the low T3 syndrome. It may produce certain cerebral protection by inhibiting the inflammatory factors in patients with CPB. |
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