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The Effects of Dexmedetomidine on HMGB-1Expression of Peripheral Blood Mononuclear Cells and Renal Function Indicators during the CPB

Author: LiuLinLin
Tutor: GuMiaoNing
School: Southern Medical University,
Course: Anesthesiology
Keywords: dexmedetomidine HMGB-1 renal function CPB
CLC: R614
Type: Master's thesis
Year: 2013
Downloads: 54
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IntroductionCardiopulmonary Bypass (CPB) is the foundation and guarantee of safe cardiac surgery. But at the same time, cardiopulmonary bypass was born as "a huge trauma platform for treatment". In the artificial physiological state during the cardiopulmonary bypass, a range of factors including blood contact with artificial materials pipeline, ischemia-reperfusion, hypothermia, etc can stimulate the immune system to release a great number of inflammatory factors and cytokines, which can lead to a systemic inflammatory response syndrome (SIRS), and may develop to multiple organ dysfunction syndrome (MODS). Acute renal injury (AKI) is a common complication after cardiopulmonary bypass, which could affect the prognosis and prolong hospitalization of patients. When the AKI develop to the acute renal failure (ARF), the mortality of patients would increase to a high level. Based on the increasing evidence, researchers believe that systemic inflammatory response syndrome and ischemia-reperfusion injury is the primary reasons which can cause organ dysfunction after CPB. When AKI or ARF occurred following the ischemia reperfusion injury, how to design a reasonable anti-inflammatory treatment is important for clinical. Clinically, ARF usually occur from1day to several days after CPB, merely occur immediately. Corticosteroids such as dexamethasone are used in the beginning of the cardiopulmonary bypass aim to suppress the inflammatory response, but the effect is unsatisfactory. According the accumulating evidence, we considered that the severe inflammatory response after cardiopulmonary bypass is probably a delayed inflammatory response after CPB. And the time of its onset is match with the high mobility group protein box1(HMGB-1), a powerful proinflammatory cytokine which is found in the late of the inflammatory response accordingly, how to choose reasonable medicines and treatment is the key in preventing and therapy of SIRS caused by lethal proinflammatory cytokines produced during the cardiopulmonary bypass.Dexmedetomidine, a new type of highly selective α2receptor agonist is used widely in recent years. Several researches have demonstrated its ability in activate the anti-apoptotic signaling pathways to produce protective effect in several cell lines and organs, including brain, heart, lung and kidney. In this study, HMGB-1expression level of peripheral blood mononuclear cells and serum/urine renal function indicators during the cardiopulmonary bypass with or without dexmedetomidine will be observed. Based on these data, the dynamic changes with or without dexmedetomidine of HMGB-1and renal function indicators will be analyzed, which may elucidate the effect of HMGB-1in CPB-induced inflammation and the protective effects of dexmedetomidine in renal function.Materials and Methods60cases of ASA grade Ⅱ-Ⅵ undergoing cardiac valve replacement under CPB were randomly chosen for this trial. And then were randomly divided into two groups:the saline control group (30cases, NS group), the dexmedetomidine set treatment group (30cases, Dex group). The inclusive criteria are list as following: without history of hormone application before operation in a week; liver, lung, kidney function is normal; NYHA grade is II-IV, EF>35%; non-rheumatoid activity (ESR and the ASO is normal preoperatively.). Acute infection, diabetes, immunological diseases, psychic disease, tuberculosis, hepatitis, syphilis and other infectious diseases are excluded. All the cases received intramuscular injection of10mg diazepam and lmg penehyclidine30mins before the operation. All patients were anesthetized by total intravenous anesthesia combined with propofol, sufentanil and cis-atracurium. ECG, blood pressure, pulse oxygen saturation, end-tidal carbon dioxide, nasopharyngeal temperature, invasive arterial pressure, central venous pressure, and BIS values were monitored as usual.30min NS group and DEX group were respectively given normal saline (NS) and or0.6μg/(kg-h) dexmedetomidine30min before the induction of anesthesia saline till the end of surgery. Blood and urine samples at T1(before induction of anesthesia), T2(at the end of CPB), T3(6h after CPB), T4(24h after CPB), T5(48h after CPB) were collected respectively. The expression level of HMGB-1of peripheral blood mononuclear cells were analyzed by Western blot, the serum BUN, serum Cr, urinary NAG/Cr ratio, urinary β2-microglobulin/Cr ratio were detected separately.ResultsIn NS group, HMGB-1of peripheral blood mononuclear cells has already existed before induction of anesthesia (T1), and gradually increased at the end of the CPB (T2) then reached the peak6hours after CPB(T3), After a slightly lower24hours after CPB (T4), then continue to rise at48hours after CPB (T5),. In DEX group, HMGB-1of peripheral blood mononuclear cells has the same trend with the NS group, and the change of HMGB-1is consistent at each time point. In addition to the time T1, DEX group HMGB-1expression were significantly lower than the saline control group at T2-T5(p<0.05), which demonstrated the effect of dexmedetomidine in lower HMGB-1expression.During cardiopulmonary bypass, after using the dexmedetomidine, Dex group’s concentration of serum BUN, serum Cr, urinary NAG/Cr and urinary β2-MG/Cr were also significantly decreased at time point T2-T5compared with NS group (p<0.05). However, the ration of NAG/Cr in DEX group at T2-T5significantly lower than the NS group (p<0.05). There was no significant statistics difference of urine NAG/Cr between the two groups at T1and T3, where as T2, T4, and T5have significant statistics difference and the but the two groups urinary NAG/Cr at DEX group was significantly lower than the NS group (p<0.05). Suggesting that dexmedetomidine may have a renal protective effect.DiscussionAccording to the dynamic change of HMGB-1during CPB, we found that:1, HMGB-1has already existed in the patients peripheral blood mononuclear cells, which may caused by chronic inflammation of the valvular heart disease;2, To the end of the bypass, HMGB-1expression was significantly increased, which may caused by the trauma during the surgery; HMGB-1reached the peak6hours after CPB which may partly produced by the overlap of the active and passive secretion of HMGB-1.3,24hours after CPB, the application of anti-inflammatory medicines and the metabolism of HMGB-1probably result in the decreased of HMGB-1expression;4, Although24hours after CPB, the expression level of HMGB-1decreased, the expression level of HMGB-1at24hours after CPB still maintained at a relative high level, and the level was increasing at48hours after CPB. The main reason may be related to the pro-inflammatory cytokines TNF-a, IL-6activated the mononuclear macrophages active secretion of HMGB-1.Creatinine (Cr) is the creatine metabolites, and urea nitrogen (BUN) is the end product of protein nitrogen metabolites in vivo. They both are primarily excreted by kidney. They are the main renal function indicators for clinical evaluation, which are not sensitive for early acute renal injury. N-acetyl-β-D glucosaminidase (NAG) is a polymer lysosomal marker of renal tubular damage, which can be detected in the early stages of renal impairment. Thus NAG is a sensitive indicator for early renal function impairment. β2-microglobulin (β2-MG) is widely present in the plasma, urinary, and the secretion amount is traceful in physiological conditions. Measured β2-MG is an useful biomarker which can reflect glomerular function impairment. In order to exclude dilution during CPB, all outcomes were corrected (corrected value=measured value-HCT before CPB/HCT on sample test points).Urine results were corrected by comparing to Cr ratio. According to the observed data, the dynamic changes of HMGB-1is almost consistent with the serum Cr and BUN, thus confirmed the detrimental effect in the process of the renal injury caused increasing of HMGB-1. The peak of ratios of urinary NAG/Cr and the urinary P2-MG/Cr during the CPB is earlier than that of Cr and BUN, which proved the two biomarkers are more sensitive in early renal function injury again.The protective effect of α2agonists in multiple systems and organs makes it become a hot research topic. Many clinical and basic researches confirmed α2agonists can reduce inflammation by regulating the immune system, activating anti-apoptotic signaling pathway to protect cells apoptosis. Dexmedetomidine has a α2agonists and the selective affinity ratio of it to the α2AR, and α1AR is8times than that of clonidine. Additionally, dexmedetomidine has a diuretic effect, which can produce a renal protective effect under ischemic state. The animal studies also found that clonidine and dexmedetomidine can significantly reduce renal injury and play renal protective effect and its mechanism may caused by the improvement of renal outer medullary blood flow. Dexmedetomidine given by the central sympathetic inhibition, which may reduce proinflammatory cytokines, inflammatory level, and increase survival in septic rats. In this study, the application of dexmedetomidine at a infusion rate of6μg/kg·h during the whole CPB is designed to intervention the expression of HMGB-1. The result showed that the expression level of HMGB-1is significantly lower in DEX group than that in NS control group, and the biomarkers related to the renal function in DEX group are also significantly better than that in NS control group. The results of the study demonstrated that the renal protective effect of produced by dexmedetomidine and the mechanism of the effect may result in the regulation of HMGB-1expression by dexmedetomidine.Conclusion1. The HMGB-1expression of peripheral blood mononuclear cells has already existed in the patients with rheumatic heart valve disease.2. The HMGB-1expression of peripheral blood mononuclear cells was obviously increased during the CPB.3. Dexmedetomidine has the ability to reduce the expression level of HMGB-1of peripheral blood mononuclear cells during the CPB.4. Dexmedetomidine has renoprotective effect during the CPB.5. The mechanism of dexmedetomidine in HMGB-1and renal function is still unclear and need further study.

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