摘要
现代战争中,由于高科技武器的使用,使战伤更趋于受伤部位多、创面大、伤情复杂等特点。由此而引起的战斗人员出血死亡,感染致畸等发生率也会增高。所以,我科自2003年起一直致力于战伤急救止血剂工作的研究,以期研制出一种快速止血并兼有预防伤口感染功能的新型战伤急救止血剂。本课题是在课题组前期工作的基础上,完成新型战伤急救止血剂的组方研究。其研究的目的是:1、确定新型战伤急救止血剂附载金属离子的量。课题组前期研究表明5A沸石附载金属离子后能够降低沸石放热反应造成的副损伤和预防伤口感染,但未对附载量作进一步研究,故本实验拟筛选并最后确定5A沸石止血剂中附载金属离子的合适剂量;2、确定新型战伤急救止血剂中藻酸盐含量。止血剂中复合藻酸盐可以增强凝血块强度,降低再出血的发生率,提高战伤急救止血的成功率,但过多复合藻酸盐又会降低5A沸石的止血性能,故本实验拟确定其复合比例;3、观察新型战伤急救止血剂在体内的抗菌效果;4、观察新型战伤急救止血剂在体内的放热反应及止血效果。实验共分为四个部分:
1.新型战伤急救止血剂中金属离子含量的实验研究。共分为3个小实分验:1、5A沸石附载金属离子的标准曲线制作,在60℃、pH6~8的条件下,改变金属离子溶液的离子浓度,以液相法合成附载金属离子银、锌及银锌双载的5A沸石,利用火焰原子吸收分光光度计测量5A沸石中附载的金属离子的量,制成标准曲线;2、附载金属离子后5A沸石的抗菌性能,根据标准曲线合成不同金属离子含量的5A沸石,按倍比稀释法测定其对创面检出率最高的格兰阳性、格兰阴性和真菌即金黄色葡萄球菌、绿脓杆菌及白色念珠菌的MIC。结果:5A沸石附载Ag+后对金黄色葡萄球菌、铜绿假单孢菌、白色念珠菌的MIC分别达到了125μg/ml~500μg/ml、31.25μg/ml~500μg/ml、250μg/ml~500μg/ml;附载Zn2+后对金黄色葡萄球菌、铜绿假单孢菌、白色念珠菌的MIC别达到了12.5mg/ml~25mg/ml、6.25mg/ml~ 50mg/ml、25mg/ml;双离子附载后对金黄色葡萄球菌、铜绿假单孢菌、白色念珠菌的MIC分别达到了250μg/ml~500μg/ml、62.5μg/ml~ 500μg/ml、500μg/ml。统计学分析表明:①5A沸石附载金属离子后均具有抗菌作用,且抗菌作用与了附载金属离子的量正相关;②附载相同质量Ag+的5A沸石较附载Zn2+者具有更强的抗菌作用;③双金属离子附载在抗菌上具有协同作用;④三种细(真)菌对Ag+、Zn2+的敏感性为:铜绿假单孢菌>金黄色葡萄球菌>白色念珠菌;⑤2%Ag++8%Zn2+与2%Ag++10%Zn2+及4%载银组与阳性对照组无显著性差异(p>0.05)。3、附载金属离子后5A沸石的水合热,将依标准曲线合成的不同金属离子含量的5A沸石300℃下,完全脱水后,在湿度为0%的条件下,利用微热量热仪测定其水合热。结果:沸石附载Ag+后水合热可以降低到396.873±5.712~598.399±6.377 J/g;附载Zn2+后可使水合热降低到578.937±5.334~622.438±5.763 J/g;双离子附载后可使水合热降低到430.572±8.371~503.344±5.261 J/g。说明Ag+、Zn2+附载均可以降低沸石的水合热,且降低的程度与金属离子附载量密切相关;对相同载量的银型沸石与锌型沸石作比较时发现银型沸石可以降低更多的水合热(p<0.01);其中2%Ag++8%Zn2+的5A沸石组、2%Ag++10%Zn2+的5A沸石组及4%载银沸石组两两比较后,其组间均无显著性差异(p>0.05)。根据既能达到降低放热反应又其有一定的抗菌性能的原则对止血剂中Ag+、Zn2+的量确定为2%Ag++8%Zn2+。
2.新型战伤急救止血剂中藻酸盐复合比例的实验研究。止血剂中添加藻酸盐是为了增强止血过程中形成的凝血块强度,从而提高止血能力。故本实验按止血剂中添加藻酸盐的比例分为0%、5%、10%、15%共4组,每组加入1ml血液后形成凝血块,再利用片剂强度分析仪测定每组凝血块的强度。结果:单纯银锌双载5A沸石组凝血块的强度为10.1±1.51 N/cm2,对银锌双载5A沸石复合5%、10%、15%的藻酸盐后,凝血块的强度分别为12.3±1.22、15.7±1.13、16.5±0.98 N/cm2。统计学分析显示5%组与单纯银锌双载5A沸石组无显著性差异(p>0.05),但10%组或15%组与单纯银锌双载5A沸石组相比凝血块强度显著增加(p均<0.01);同时,10%组与15%组无显著性差异(p>0.05),证明对沸石的复合10%的藻酸盐即可显著增加血凝块的强度。从而将止血剂中藻酸盐的复合比例固定为10%。
3.新型战伤急救止血剂体内抗菌的实验研究。本实验以兔背污染创面为模型,予创面覆盖抗菌止血剂3天后,观察创面表现并检测创内组织中的细菌量,以评价复合止血剂的抗菌功能。结果:创面大体及组织学观察均显示单纯5A沸石止血剂组和Quikclot组较新型战伤急救止血剂组有较重的炎症反应;空白对照组、5A沸石止血剂组、Quikclot组、新型战伤急救止血剂组组织内细菌含量分别为2.28±0.17×109、2.37±0.16×109、2.43±0.15×109、8.11±0.26×104(cfu/g)。单纯5A沸石止血剂组和Quikclot组组织内细菌定量均达到109,与空白对照组相比无显著差异(p>0.05),证明这两种止血剂均无感染作用。新型战伤急救止血剂组织内细菌含量为104,与空白对照组相比有显著性差异(p<0.01)。
4.新型战伤急救止血剂体内放热及止血功能的实验研究。本实验以猪腹股沟部股动、静脉横断为模型,对新型战伤急救止血剂体内放热及止血功能进行了观察。方法:健康家猪38头,体重40~47kg,实验前3天标准喂养,实验前一晚禁食,不禁水。以17.5mg/kg苯巴比妥钠+0.1ml /kg速眠新颈部肌注麻醉动物后,仰卧位固定于手术台上,颈部及左腹股沟区备皮后碘伏消毒,常规铺单,暴露颈部和左腹股沟部,行气管切开插管后接动物呼吸机。实验过程中每20分钟追加速眠新0.1ml/3kg体重,以维持麻醉。动物麻醉平稳后,取右侧颈部中正切口约4~5cm,分离出右侧颈动脉和颈外静脉,分别置管,颈外静脉接输液瓶,暂不输液,颈动脉插管接压力传感器,并和多导生理记录仪连接。同时连接好多导生理记录仪的心电图等导联。取腹股沟部纵行切口约10cm.分离腹四头肌在腹股沟韧带下找到股动静脉后,将数字型电子测温仪探头固定于距腹股韧带下约2cm处的股动静脉后方。观察实验动物心率、血压等生命体征平稳后,于腹股沟韧带下约2cm处横断股动静脉。任其出血3min后,轻轻吸出血池内的血液,然后施加各组治疗,并以纱布轻压腹股沟部5分钟。在股血管横断15分钟后进行复苏,从颈外静脉快速补液(平衡盐)1000ml。在股血管横断15分钟内每5分钟(温度测量为1次/min)记录一次观察指标,以后每15分钟测量一次,持续观测180分钟或直到动物死亡。180分钟后对存活动物常规行创面清创,8/0显微外科缝线缝合股动脉,关闭伤口,手术过程中补液500ml,术后予动物肌肉注射青霉素80万单位后送回动物房,单栏喂养。术后7日内,每日肌注青霉素80万单位并检视伤口。于术后14日麻醉动物后行腹股沟部股动脉B超检查,观察股动脉吻合后的通畅率。实验分为5组,即空白对照组、标准敷料组、单纯5A沸石组、Quikclot组和新型战伤急救止血剂组。观测指标包括平均动脉压、心输出量、血红蛋白、乳酸含量、创面温度、动物死亡率、股动脉通畅率等。结果:股动静脉横断后动物平均动脉和心输出量最低下降为20.3±8.6mmHg、2.1±0.5L/min,血红蛋白量也逐渐下降,乳酸值逐渐上升。使用3组止血剂后均获得100%动物存活率,与ND组的0%和SD组的33.3%相比差异显著;新型战伤急救止血剂组的创面温度为39.1±1.6,与Quikclot组、单纯5A沸石组的68.7±3.0、65.3±1.8相比差异显著(p均<0.01);Quikclot组、单纯5A沸石组、新型战伤急救止血剂组的股动脉通畅率分别为16.7%、28.6%、100%,3组相比差异显著(p均<0.01)。
结论:
1、综合考虑附载金属离子后沸石的水合热及抗菌性能,新型战伤急救止血剂中最佳金属离子附载量为银2%+锌8%。
2、新型战伤急救止血剂中复合医用藻酸盐的量应为10%。
3、新型战伤急救止血剂可预防伤口感染,从而改善战伤的预后。
4、新型战伤急救止血剂具有良好的止血功能。
5、新型战伤急救止血剂在止血过程中不会造成热损伤。
In the modern war, the usage of high-tech weapon make the combat injuries characterized by multiple injury location, large wound area, and complicated wound situation, et al. Therefore, the subsequent mortality caused by bleeding and morbidity caused by infection is higher than it was in the past. Our department has been concentrating on the study of hemostat for combat injury since 2003, in order to develop a new type of hemostat which has anti bacteria function. Based on the previous study of our department, this project is aim to specify the components of a new type of hemostat for combat injury. The purposes of this project are: 1, Specify the concentration of the metal ion. Our previous data showed that addition metal ion to the zeolite decreased tissue injury caused by the heat release reaction of zeolite and prevented infection. The optimal concentration of metal ion is not specified yet. This project will try to find the optimal concentration of Ag+ in the zeolite. 2, Determine the concentration of alginates in the hemostat. Addition of alginates to the zeolite increased the stability of the blood clot, decreased the incidence of the rehaemorrhagia, and increased the survival rate of the combat injury. But too much alginate will decrease the haemostatic function of zeolite. This project will specify the optimal concentration of alginates. 3, Observe the anti bacteria effect of the new type of hemostat. 4, Observe the heat release and homeostasis efficacy of the new hemostat. The experiment can be divided into four parts:
1. Determination of the metal ion concentration of the new type of hemostat for combat injury. This part is composed of three small experiments: 1, Standard curve of metal ion: set the temperature at 60℃and ph value at 6~8, determine the absorbance of metal ion solutions with different concentration and make the standard curve. 2, Antibiotic effect of zeolite type 5 A with metal ion. Based on the standard curve, the zeolites types 5A with different concentration of metal ion were produced. The zeolites were diluted and co-cultured with Gram positive bacteria, Gram negative bacteria, and fungus (Staphylococcus aureus, pseudomonas aeruginosa, and Candida albicans), and the MIC was determined. Results: the MIC of zeolite mixed with Ag+ to Staphylococcus aureus, pseudomonas aeruginosa, and Candida albicans was 125μg/ml~500μg/ml, 31.25μg/ml~500μg/ml, and 250μg/ml~500μg/ml respectively; MIC of zeolite mixed with Zn2+ to Staphylococcus aureus, pseudomonas aeruginosa, and Candida albicans was 12.5mg/ml~25mg/ml, 6.25mg/ml~ 50mg/ml, and 25mg/ml respectively; MIC of zeolite mixed with Ag+ and Zn2+ to Staphylococcus aureus, pseudomonas aeruginosa, and Candida albicans was 250μg/ml~500μg/ml, 62.5μg/ml~ 500μg/ml, and 500μg/ml respectively. These data indicated that addition of metal ion to the zeolite increased the antibiotic effect of zeolite and this effect was proportional to the concentration of metal ion; addition of Ag+ to the zeolite had stronger antibiotic effect than the addition of Zn2+; the addition of Ag+ and Zn2+ to zeolite had synergistic effect on the antibiotic effect.; the MIC of metal ion to pseudomonas aeruginosa is smaller than Staphylococcus aureus, and both of them were smaller than Candida albicans; and zeolite mixed with 2%Ag+ and 8% Zn2+ has no significant difference compared with zeolite mixed with 2% Ag+ and 10% Zn2+ or with 4% Ag+ (P>0.0.5). 3, Enthalpy of hydration of Zeolite mixed with metal ion. The zeolites mixed with different concentration of metal ion were heated to 300oC and dehydrated completely, the enthalpy of hydration was determined with microcalorimeter. Results: addition of Ag+ decreased the enthalpy of hydration to 396.873±5.712~598.399±6.377 J/g, addition of Zn2+ decreased the enthalpy of hydration to 578.937±5.334~ 622.438±5.763 J/g, while addition of Zn2+ and Ag+ decreased the enthalpy of hydration to 430.572±8.371~503.344±5.261 J/g. These data indicated that addition of Ag+ or Zn2+ decreased the enthalpy of hydration, and this effect was proportional to the concentration of metal ion, zeolite with Ag+ decreased the enthalpy of hydration more intensely than the one with same concentration of Zn2+, and there were no significant dirfference among the zeolite mixed with 2% Ag+ and 8% Zn2+, the zeolite mixed with 2% Ag+ and 10% Zn2+, and zeolite mixed with 4% Ag+ (P>0.05). since the zeolite mixed with 2% Ag+ and 8% Zn2+ decreased the enthalpy of hydration and had antibiotic effect, this type of zeolite was chosen in this project.
2. Determination of the alginates concentration of the new type of hemostat for combat injury. Additions of alginates to the zeolite enhanced the strength of the blood clot and therefore enhance their hemostasis effect. In this experiment, zeolites mixed with 5%, 10%, 15% and no alginates were examined by tablet strength analyzer after the zeolites were mixed with blood and formed blood clot. Results: the strength of zeolithes mixed with 5%, 10%, 15% and no alginates were 12.3±1.22, 15.7±1.13, 16.5±0.98, and 10.1±1.51 N/cm2 respectively. There were significant difference between the zeolithes mixed with 10% alginates and the zeolites with no alginates. Therefore the zeolite mixed with 10% alginates was chosen in this experiment.
3. Study on antibacterial ability of the new type of hemostat for combat injury in vivo. Using the animal models of contaminated wound of rabbit's back, the bacterial contents of wound tissues were counted 3 days after covering the wound with antibiotic hemostat. Antibacterial abilities of all kinds of hemostats were evaluated by bacterial contents. Results: The gross morphological and histological observation showed that inflammation occurred in 5A and Quikclot groups. The bacterial contents in the control group, 5A, Quikclot and the new type of hemostat for combat injury groups were 2.28±0.17×109, 2.37±0.16×109 , 2.43±0.15×109, 8.11±0.26×104 (cfu/g) respectively. The bacterial content in 5A and Quikclot both reached 109, demonstrating that the two kinds of hemostat showed no antibacterial effect. The bacterial contents in the new type of hemostat for combat injury group was 104, exhibiting a significant difference from the control group (p<0.01).
4.Study on exothermic reaction and the ability of controlling hemorrhage of the new type of hemostat for combat injury in vivo. In this experiment, we used the transsection on the femoral artery and vein of swine as animal models. Methods: A total of 38 swine with body weight 40~47 kg were selected for this study, fed respectively with standard diet 3 days before surgery, which was operated after fasting for 12 hours but water was given. The swine were anesthetized with pentobarbital (17.5 mg/kg) by intramuscular injection on neck part, and fixed in supine position. Preoperative skin preparations, iodophor disinfectant, route sheet–pavement were done, the neck and groin were exposed, tracheotomy and mechanical ventilation were operated. Superaddition Su Miansin 0.1ml/3kg every 20 min during the experiment procedure to maintain anesthesia. Being stably anesthetized, the operation was performed to isolate the right artery and vein in the neck through 4~5cm incision of the right neck part under sterile conditions, tube indwelled respectively, a infusion pump was inserted into external jugular vein, without temporary infusion. Carotid artery cannula was connected to pressure sensor, polygraph also being connected. Meanwhile, the electrocardiographic leads of polygraph were well connected. The femoral artery and vein were exposed by seperating quadriceps; the probe of the digital electronic thermoscope was fixed 2 cm below the inguinal ligament behind femoral artery and vein. The heart rate and blood pressure of the animals were tested showing stable vital signs. Then, they received lateral transsection on femoral artery and vein 2 cm below the inguinal ligament. After 3 minutes of free bleeding(simulating the response time of the helper), slightly exsucted the blood in the blood pool, then impose respective treatments in each group, lightly pressed the inguinal regiong with auze for 5 min. Resuscitations were performed 15 min after femoral blood vessels transsection, rapid infusion through external jugular vein. Observation indexes were recorded 15 min after femoral blood vessels transsection, with the temperature measured once per min; afterword, the observation indexes were measured every 15 min for 180 min or the animal death. 180 min later, route debridement was done on survival animals, femoral artery were sutured using the surgical microscope. Incisions were closed. 500 ml fluid was infused during surgery; the animals were given intramuscular injection of of 800 000 unit penicillin, sent back to animal room and single-column fed. 7 days after surgery, the animals were given intramuscular injection of of 800 000 unit penicillin and the wound was observered every day. The animals received B-ultrasonic examination on inguinal femoral artery to assess the patency rate after anastomosis in swine femoral arteries. The animals were randomized into five groups: (1) No dressing, (2) Standard dressing, (3) 5A hemostatic group, (4) Quikclot group, (5) new type of hemostat for combat injury group. Observation index comprises mean arterial pressure (MAP), cardiac output, hemoglobin, lactic acid content, mortality rate and femoral artery patency rate. Results: mean arterial pressure and cardiac output dropped to 20.3±8.6 mm Hg, 2.1±0.5 L/min, the hemoglobin content was grasually reduced, levels of lactic acid were gradually increased. Survival rates of animals reached 100% after administration hemostatic in 5A, Quikclot and the new type of hemostat groups, demonstrating significant differences v.s. 0% in ND group and 33.3% in SD group. The wound temperature in 5A, Quikclot and the new type of hemostat groups was 68.7±3.0、65.3±1.8, and 39.1±1.6 respectively, there are significant differences among three groups (p<0.01). The femoral artery patency rate in the three groups was 16.7%, 28.6% and 100% respectively, significant differences occurred (p<0.01).
Conclusions:
1, For the purpose of minimal enthalpy of hydration and maximal antibacterial ability, 2% Ag+ and 8% Zn2+exchanged zeolite will be optimal choice.
2, The concentration of alginates in the new type of hemostat for combat injury should be 10%.
3, The new type of hemostat for combat injury can prevent wound infection and improve prognosis of wounded soldier.
4, Using of the new type of hemostat for combat injury can control hemorrhage and dramatically reduce mortality.
5, The new type of hemostat for combat injury did not cause any thermal injury when it was applied.
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