磺胺嘧啶铈对烧伤脓毒症的防治效果及烧伤脓毒症早期诊断

发布时间：2018-05-04 16:30

本文选题：特重烧伤 + 磺胺嘧啶铈　；参考：《南方医科大学》2014年博士论文

【摘要】：研究背景严重烧伤患者易并发脓毒症。严重烧伤患者由于机体皮肤自然屏障不完整,同时治疗中往往需建立人工气道、多次经创面置入深静脉导管,且免疫功能受损。细菌易从创面、呼吸道、各种有创医疗管道等途径侵入机体导致感染、全身炎症反应、脓毒症“三部曲”,所以特重烧伤患者脓毒症发病率高达28%。烧伤脓毒症发病隐匿。86%的医师认为脓毒症的症状不典型导致诊断及治疗的延迟,而烧伤患者脓毒症与非脓毒症的症状和体征尤其不易鉴别,导致“烧伤脓毒症”的诊断更具有隐匿性。烧伤脓毒症治疗困难。严重烧伤患者一旦发生脓毒症后,因皮肤屏障短期内无法重建而难以做到“病因治疗”,很容易进一步发展为严重脓毒症、脓毒性休克甚至死亡,文献报道烧伤脓毒症发病后死亡率高达58.9%。所以尽管已经有众多针对烧伤脓毒症的预防手段如早期创面封闭、广谱抗菌药物应用、外用抗菌药物和敷料,以及脓毒症治疗的支持手段等,但对于烧伤脓毒症的诊治,仍是目前危重烧伤救治中的难点。目的和意义鉴于烧伤脓毒症发病率高、发病隐匿、死亡率高的临床现实,对于特重烧伤患者的救治,早期预防和早期诊断就尤其有意义。外用抗菌药物是烧伤创面处理的一个重要方法。烧伤学界共识烧伤后越早期应用抗生素越可以有效预防感染,从早期创面处理开始就要外用抗菌药物预防感染。并且对于大面积烧伤患者,其创面势必长期裸露缺少有效覆盖,需要长期外用抗菌药物防治感染。所以对于伤后早期和部分全身情况不能耐受手术如休克纠正不佳、脏器功能不全者,或白体皮源奇缺不能提供足够白体皮肤供移植的特重烧伤患者,其创面均需要应用外用敷料或药物(如经典药物磺胺嘧啶银)暂时保护,防治感染。理想的烧伤创面外用药应该具有以下特点：1.可抑制烧伤毒素进入机体：能有效去除或抑制烧伤毒素释放入血。2.抗菌谱广：能杀死或抑制各种病菌；3.穿透组织能力强：能杀死痂下致病菌,防止病菌进入机体。4.作用周期长：可适应临床工作需要,减轻临床医师工作量。5.副作用小。但目前临床上应用的各种消毒制剂、抗菌制剂等,均不能满足以上要求。所以,寻求理想的创面外用药物或敷料,始终是烧伤医务工作者的探索目的。文献中报道铈可以早期固定烧伤毒素,防止烧伤毒素入血损伤脏器[4]、减轻脏器水肿；可改善免疫功能[8];抗菌谱广。国外已有临床试验证实硝酸铈能降低严重烧伤患者病死率,同时国内外均有动物实验、临床试验等证实烧伤创面外涂铈剂具有和切痂等同的抗感染作用,但在国内特重烧伤患者中尚未见应用。目前更多的研究证明硝酸铈其实抗感染能力较磺胺嘧啶银为差,但是镧系金属——铈的多种作用,如固定烧伤毒素、免疫调理等,可能是降低严重烧伤患者病死率的根本原因。综合以上文献报道和查新结论,推测铈剂为理想的烧伤创面外用药,既可以早期保护创面,固定毒素,防治感染,同时可以调理免疫系统,降低脓毒症发病率。国内现有上市消毒剂磺胺嘧啶铈可能兼备磺胺嘧啶的抗感染作用和铈的免疫调理作用,推测其外用于烧伤创面可能具有防治烧伤脓毒症的作用。文献报道81%的医师期待清晰并且更容易被接受的脓毒症临床定义。如何早期识别高危患者及脓毒症的三个阶段(脓毒症、严重脓毒症和脓毒性休克),提高脓毒症诊断的敏感性,合理实施治疗策略,准确评估预后是目前面临的难题。降钙素原(PCT)近年广受关注,可用于鉴别细菌感染导致的严重脓毒症,并指导抗菌药物的应用,但在某些非感染情况如创伤、严重烧伤等也可能导致其升高,所以在特重烧伤救治过程中,如何评价PCT的应用价值,依然需要进一步探讨。鉴于以上原因,我们在特重烧伤患者救治中引入磺胺嘧啶铈外用消毒剂和PCT检测,用来预防烧伤脓毒症和早期诊断。研究内容 1.评价磺胺嘧啶铈对烧伤脓毒症的预防作用。为了证实以上设想,本研究对磺胺嘧啶铈的体外、在体抑菌能力；对烧伤诱导的高血管通透性的影响；对严重烧伤大鼠休克期死亡率和生存时间、感染期死亡率和生存时间的影响,进行了系列研究。并将磺胺嘧啶铈应用于特重烧伤患者,通过观察休克期补液量和休克期并发症、创面感染率、血流感染率、脓毒症发生率、脏器并发症发生率、死亡率及SOFA评分等,评价磺胺嘧啶铈对特重烧伤患者的防治作用。 2.探讨特重烧伤患者脓毒症早期诊断策略和预后判断。本研究纳入63例特重烧伤患者,通过在救治过程中将PCT和临床指标结合,探讨特重烧伤脓毒症的早期诊断策略；探讨PCT、烧伤危险系数(Baux score)、体重指数(BMI)等因素,对特重烧伤患者预后的影响。研究方法和过程第一部分磺胺嘧啶铈对烧伤诱导的高血管通透性影响。 1.磺胺嘧啶铈降低烧伤大鼠血清对单层血管内皮细胞电位变化影响：采用EVOM电压电阻仪测定细胞跨膜电阻抗(TER)变化测定血管内皮细胞间电位变化显示,严重烧伤大鼠血清对血管内皮细胞电位变化影响,高于假烧伤组(P=0.000)；磺胺嘧啶铈外用于严重烧伤大鼠创面后,烧伤大鼠血清对血管内皮细胞电位变化影响,低于磺胺嘧啶银组(P=0.000)。 2.磺胺嘧啶铈没有减轻烧伤后大鼠肺脏水肿：磺胺嘧啶铈外用于严重烧伤大鼠创面后,大鼠休克期肺脏器干湿重比与创面外用磺胺嘧啶银组差异无统计学意义(P=0.05)。 3.磺胺嘧啶铈没有改善大鼠休克期血压：磺胺嘧啶铈外用于严重烧伤大鼠创面后,伤后8小时内其股动脉有创血压与磺胺嘧啶银组无差异(P=0.05)。第二部分磺胺嘧啶铈对烧伤大鼠感染期的影响。 1.磺胺嘧啶铈抑制体外细菌增殖：应用抑菌环法测定磺胺嘧啶铈对金黄色葡萄球菌、微生物的体外抑制作用,磺胺嘧啶铈的抑菌环直径与磺胺嘧啶银的抑菌环直径差异无统计学意义(P值均大于0.31)。 2.磺胺嘧啶铈降低大鼠烧伤创面感染率：磺胺嘧啶铈外用于大鼠中度烧伤创面后,创面感染率较与磺胺嘧啶银组差异无统计学意义(P=0.789)。 3.磺胺嘧啶铈延长严重烧伤大鼠生存时间：磺胺嘧啶铈外用于严重烧伤大鼠(无补液)创面后,其72小时内生存率与应用磺胺嘧啶银组无差异(P0.05),生存时间无差异(P0.05)；磺胺嘧啶铈外用于严重烧伤大鼠(腹腔补液)创面后,其7d内内生存率与磺胺嘧啶银组无差异(P0.05) 4.磺胺嘧啶铈改善严重烧伤大鼠细胞免疫功能：磺胺嘧啶铈外用于严重烧伤大鼠创面后,其伤后7d的IL-6、IgG较磺胺嘧啶银组高(P=0.04,P=0.044)。第三部分磺胺嘧啶铈对特重烧伤患者疗效评价。 1.治疗组烧伤面积较对照组大,Baux score、休克指数较对照组高,吸入性损伤、复合伤、基础疾病、入院时脏器功能比较均无差异。 2.磺胺嘧啶铈对严重烧伤患者休克期输液量影响：磺胺嘧啶银和磺胺嘧啶铈联合外用于烧伤创面,其休克期输液量较单纯应用磺胺嘧啶银组差异无统计学意义(P值大于0.108)。 3.磺胺嘧啶铈对休克期并发症发生率影响：磺胺嘧啶银和磺胺嘧啶铈联合外用于烧伤创面,其并发症发生率与单纯应用磺胺嘧啶银组差异无统计学意义(P值均大于0.383)。 4.磺胺嘧啶铈对严重烧伤患者脓毒症发病率影响：伤后0-7d联用组脓毒症发生率高于单纯应用磺胺嘧啶银组,可能与原发伤情严重有关；但是8-35d两组脓毒症发病率差异无统计学意义(P值均大于0.189)。 5.磺胺嘧啶铈对严重烧伤脏器并发症发生率影响：磺胺嘧啶银和磺胺嘧啶铈联合外用于烧伤创面,其伤后3d、7d、14d、21d、28d与单纯磺胺嘧啶银组脏器并发症发病率差异无统计学意义(P值均大于0.383))。 6.磺胺嘧啶铈对特重烧伤脓毒症患者SOFA评分影响：磺胺嘧啶银和磺胺嘧啶铈联合外用于烧伤创面,其伤后0、3d、7d、14d、21d、28d与单纯磺胺嘧啶银组SOFA评分差异无统计学意义(P值均大于0.209),但是伤后4-7日治疗组SOFA评分大于11分者比例低于对照组(P=0.038)。 7.磺胺嘧啶铈对特重烧伤患者感染期内生存时间影响：以患者脱离感染期(创面面积小于5%TBSA)为截尾时间,发现磺胺嘧啶铈组患者生存时间较磺胺嘧啶银组长(P=0.048),但生存率差异无统计学意义(P=0.446)。第四部分特重烧伤患者烧伤脓毒症的早期诊断和危险因素分析 1.PCT可早期诊断细菌感染导致的烧伤脓毒症：用早期拟诊断和最终确诊的策略,通过对89人次烧伤脓毒症的发病诊断回顾确诊,应用Logistic回归分析和ROC曲线法,分析792组PCT、WBC、CRP、PLT数据发现,PCT和临床体征结合可早期诊断烧伤脓毒症,对于严重烧伤患者,PCT值达到1.035或24h内PCT升至原基础值1倍以上,需调整治疗措施。 2. Baux score、BMI、PCT值可预测严重烧伤早期预后：通过分析63例成人特重烧伤救治过程和预后,结合Baux score、BMI、PCT值等指标,用COX分析统计方法,发现Baux score、BMI、PCT48h/PCT24h高,死亡可能性越大。综上所述,磺胺嘧啶铈改善烧伤诱导血管高通透性,可降低严重烧伤患者感染期内死亡率,提示烧伤创面应用磺胺嘧啶铈是治疗严重烧伤的有效方法；PCT和临床体征结合可提前早期诊断脓毒症；PCT值越高,死亡可能性越大。结论 1.磺胺嘧啶铈可改善严重烧伤血清诱导的血管内皮细胞高通透性。 2.磺胺嘧啶铈具有和磺胺嘧啶银近似的抑菌能力,并且可以改善严重烧伤导致的免疫功能异常。 3.磺胺嘧啶铈能延长严重烧伤大鼠(无补液)72小时内生存时间和严重烧伤大鼠(补液)14d内生存时间；磺胺嘧啶铈结合磺胺嘧啶银能降低特重烧伤患者感染期SOFA评分,延长特重烧伤患者生存时间。 4.PCT结合临床体征可早期诊断细菌感染导致的烧伤脓毒症,24h内PCT如果升至原基础值1倍以上或达至1.035ng/ml,需调整抗感染治疗措施。 5. Baux score、BMI、伤后48小时内PCT值越高,特重烧伤患者死亡可能性越大。
[Abstract]:Research background
Patients with severe burns are prone to sepsis. Patients with severe burns are not complete because of the natural skin barrier of the body. At the same time, artificial airway is often set up in the treatment, and the deep venous catheter is inserted through the wound many times, and the immune function is damaged. The bacteria are easily invaded from the wound, respiratory tract, and various invasive medical pipes and other ways to cause infection and systemic inflammation. Should be sepsis trilogy, so the incidence of sepsis in severely burned patients is as high as 28%.
The physicians of the occult.86% in the onset of burn sepsis believe that the symptoms and signs of sepsis and non sepsis are especially difficult to differentiate between the symptoms and symptoms of sepsis, and the diagnosis of "burn sepsis" is more occult.
It is difficult to treat severe burn sepsis. Once the sepsis occurs in severe burn patients, it is difficult to achieve "etiological treatment" because the skin barrier can not be rebuilt in the short term. It is easy to further develop into severe sepsis, septic shock and even death. The mortality rate of sepsis after burn is up to 58.9%.
Therefore, there are many preventive measures for burn sepsis, such as early wound closure, broad spectrum antibiotic use, external use of antibiotics and dressings, and support for the treatment of sepsis, but the diagnosis and treatment of burn sepsis is still a difficult point in the treatment of critical burn.
Purpose and significance
In the light of the clinical reality of high incidence of burn sepsis, concealment and high mortality, early prevention and early diagnosis of severe burn patients is of particular significance.
The external use of antibiotics is an important method for the treatment of burn wounds. It is common understanding that the more early application of antibiotics is the more effective prevention of infection, and the use of antibiotics to prevent infection from the early wound treatment. It is necessary to apply external dressings or drugs (such as the classic drug sulfadiazine silver) for the early and partial general conditions after the injury, such as the poor correction of the shock, the dysfunction of the organs, or the deficiency of the white body skin source that can not provide sufficient white body skin for the special burn patients. Time protection, prevention and treatment of infection.
Ideal burn wound medication should have the following characteristics: 1. can inhibit burn toxin into the body: can effectively remove or inhibit the release of burn toxin into the blood.2. antibacterial spectrum: can kill or inhibit various pathogens; 3. penetrating tissue ability is strong: can kill the eschar pathogenic bacteria, prevent germs into the body.4. long period of action: can adapt to the body The clinical work needs to reduce the side effect of the clinician's workload.5., but the clinical application of various disinfection preparations, antibacterial agents, etc., can not meet the above requirements. Therefore, the search for the ideal external use of drugs or dressings is always the goal of the burn medical workers.
It is reported that cerium can fix the burn toxin in early stage, prevent the burn toxin into the blood damage organ [4], reduce the organ edema, improve the immune function [8], and have a wide spectrum of antimicrobial spectrum. The clinical trials abroad have confirmed that cerium nitrate can reduce the mortality of severely burned patients, and both domestic and foreign animal experiments and clinical trials confirm the burn wound coating. Cerium has the same anti infection effect as eschar, but it has not been used in the severe burn patients in China. At present, more studies have shown that cerium nitrate is in fact less resistant to infection than sulfadiazine, but the various roles of lanthanide metal, such as fixed burn toxin and immunization, may reduce the death of severely burned patients. The root cause of the rate.
According to the above literature and the new conclusions, it is conjectured that cerium is an ideal drug for the burn wound. It can protect the wound, fix the toxin, prevent the infection, and regulate the immune system and reduce the incidence of sepsis. The current listed disinfectant, sulfadiazine, can also protect the anti infection effect of sulfadiazine and the immune modulation of cerium. It is presumed that it may be used to treat burn sepsis.
81% of the doctors in the literature are looking forward to a clear and more acceptable clinical definition of sepsis. How to identify early high-risk patients and three stages of sepsis (sepsis, severe sepsis and septic shock), improve the sensitivity of the diagnosis of sepsis, the rational implementation of the treatment strategy, and the accurate assessment of the prognosis is a difficult problem. Calcitonin PCT has been widely concerned in recent years. It can be used to identify the severe sepsis caused by bacterial infection and to guide the application of antibiotics. However, in some non infection cases such as trauma and severe burns, it may also lead to its rise. So it is still necessary to discuss how to evaluate the application value of PCT during the treatment of special severe burns.
In view of the above reasons, we introduced the sulfadiazine cerium external disinfectant and PCT in the treatment of severe burn patients to prevent burn sepsis and early diagnosis.
research contents
1. to evaluate the preventive effect of sulfadiazine Cerium on burn sepsis.
In order to confirm the above idea, the effect of sulfadiazine Cerium on the body bacteriostasis in vitro, the effect of the high vascular permeability induced by burn, the mortality and survival time, the mortality and the survival time of the severely burned rats in the shock period were studied. The effect of sulfadiazine on the treatment of severe burn patients was evaluated by observing the volume of fluid infusion and shock stage complications, the rate of wound infection, the rate of blood flow infection, the incidence of sepsis, the incidence of organ complications, the mortality and SOFA score.
2. to explore the early diagnosis strategy and prognosis of sepsis in severely burned patients.
In this study, 63 patients with severe burn were combined to explore the early diagnosis strategy of severe burn sepsis by combining PCT with clinical indicators in the treatment process, and to explore the influence of PCT, Baux score, body mass index (BMI) and other factors on the prognosis of severe burn patients.
Research methods and processes
The first part is the effect of sulfadiazine Cerium on burn induced high vascular permeability.
The effect of 1. sulfadiazine Cerium on the changes of the potential of the monolayer vascular endothelial cells was reduced by the serum of the burned rats. The changes in the intercellular electrical potential of the vascular endothelial cells were measured by the EVOM voltage resistor (TER), and the effect of the serum on the changes of the vascular endothelial cell potential in severely burned rats was higher than that of the false burn group (P=0.000); The effect of pyrimidine Cerium on the potential changes of vascular endothelial cells in burn rats after burn wounds was lower than that in sulfadiazine group (P=0.000).
2. sulfadiazine cerium did not alleviate the pulmonary edema in rats after burn: after the use of sulfadiazine cerium in the wound of severely burned rats, there was no significant difference between the dry and wet weight ratio of the lung organs in the shock stage of the rats and the sulfadiazine silver group outside the wound (P=0.05).
3. sulfadiazine cerium did not improve the blood pressure in the shock stage of rats. After the use of sulfadiazine cerium in the wound of severely burned rats, there was no difference in the blood pressure between the femoral artery and the sulfadiazine group within 8 hours after injury (P=0.05).
The second part is the influence of sulfadiazine Cerium on the infection period of burn rats.
1. sulfadiazine cerium inhibited the proliferation of bacteria in vitro: the inhibitory effect of sulfadiazine Cerium on Staphylococcus aureus, microorganism, the diameter of sulfadiazine cerium and the diameter of bacteriostasis ring of sulfadiazine silver were not statistically significant (P value was greater than 0.31).
2. sulfadiazine cerium reduced the infection rate of burn wound in rats: the infection rate of the wound was no significant difference compared with the sulfadiazine group (P=0.789) after the sulfadiazine cerium was used in the rats with moderate burn wounds.
3. sulfadiazine cerium prolongs the survival time of severely burned rats: there is no difference in survival rate within 72 hours (P0.05) and no difference (P0.05) in the survival time of sulfadiazine (sulfadiazine) after burn wounds in severely burned rats (P0.05), and the internal birth of sulfadiazine after external use in the wound of severely burned rats (peritoneal fluid) There was no difference between the survival rate and the group of silver sulfadiazine (P0.05)
4. sulfadiazine cerium improves the cellular immune function of severely burned rats: after the use of sulfadiazine cerium in severely burned rats, the IL-6 and IgG of the injured rats are higher than those of the sulfadiazine silver group (P=0.04, P=0.044).
The third part is the evaluation of the efficacy of sulfadiazine cerium in severely burned patients.
In 1. treatment group, the area of burn was larger than that of the control group, Baux score, the shock index was higher than the control group, inhalation injury, compound injury, basic disease, and no difference in organ function at admission.
The effect of 2. sulfadiazine on the volume of transfusion during shock period in severely burned patients: the combination of sulfadiazine silver and sulfadiazine cerium in the burn wound, and there is no significant difference in the volume of transfusion in shock period compared with that of the only group of sulfadiazine silver (P value is more than 0.108).
3. the effect of sulfadiazine Cerium on the incidence of complications in shock stage: the combination of sulfadiazine silver and sulfadiazine was used in burn wounds, and the incidence of complications was not statistically significant (P value was more than 0.383) with the only group of sulfadiazine silver group.
The effect of 4. sulfadiazine on the incidence of sepsis in severely burned patients: the incidence of sepsis in the 0-7d group after injury was higher than that in the only group of sulfadiazine silver group, which may be related to the severity of the primary injury, but there was no significant difference in the incidence of sepsis in the two groups (P value was greater than 0.189).
The effect of 5. sulfadiazine on the incidence of severe burn viscera complications: the combination of sulfadiazine silver and sulfadiazine cerium in the burn wound, the incidence of 3D, 7d, 14d, 21d, 28d and simple sulfadiazine group after injury was not statistically significant (P value was greater than 0.383).
The effect of 6. sulfadiazine on the SOFA score of patients with severe burn sepsis: the combination of sulfadiazine silver and sulfadiazine cerium for burn wounds, and there was no statistical difference between the SOFA scores of 0,3d, 7d, 14d, 21d, 28d and pure sulfadiazine group after the injury (P values were both greater than 0.209), but the proportion of SOFA scores in the treatment group was lower than 11 in 4-7 days after injury. In the control group (P=0.038).
The effect of 7. sulfadiazine on the survival time during the infection period of the patients with severe burn: the time of closure of the patients (less than 5%TBSA of the wound area) was taken as the truncation time, and the survival time of the sulfadiazine group was more than that of the sulfadiazine silver group (P=0.048), but the difference of survival rate was not statistically significant (P=0.446).
The fourth part of early diagnosis and risk factors analysis of burn sepsis in severely burned patients
1.PCT can be used for early diagnosis of bacterial infection caused by burn sepsis: the early diagnostic and final diagnosis strategy, retrospective diagnosis of 89 patients with burn sepsis, Logistic regression analysis and ROC curve method, and 792 groups of PCT, WBC, CRP, PLT data, and the combination of PCT and clinical signs can be used for early diagnosis of burn sepsis. For severely burned patients, the PCT value reaches 1.035 or the 24h PCT rises to more than 1 times the original base value, so the treatment measures need to be adjusted.
2. Baux score, BMI, and PCT values can predict the early prognosis of severe burns: by analyzing the treatment process and prognosis of 63 cases of adult severe burns, combined with the Baux score, BMI, PCT value and so on, the COX analysis statistics show that Baux score, BMI, higher, the greater the possibility of death.
In summary, sulfadiazine cerium can improve the permeability of the blood vessels induced by burn and reduce the mortality of severe burn patients during the infection period. It suggests that the application of sulfadiazine to burn wounds is an effective method for the treatment of severe burns; the combination of PCT and clinical signs can early diagnose sepsis; the higher the PCT value, the greater the possibility of death.
conclusion
1. sulfadiazine cerium can improve the permeability of vascular endothelial cells induced by severe burn serum.
2. sulfadiazine cerium has the similar bacteriostatic ability with silver sulfadiazine, and can improve the immune function abnormality caused by severe burn.
3. sulfadiazine cerium can prolong severely burned rats.

【学位授予单位】：南方医科大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R644

【参考文献】