王世軍 林欣欣 陳福偉 楊 旭

眼鏡蛇是我國常見的劇毒蛇之一，主要分布于云南、貴州、浙江、福建等地區(qū)。流行病學資料顯示，福建省是眼鏡蛇咬傷的高發(fā)地區(qū)，每年因眼鏡蛇咬傷入院的患者近百名，主要表現為水皰、灰黑斑及局部壞死等。目前，臨床上多采用中草藥外敷、植皮等方法予以治療，但療效不甚滿意，極易導致咬傷部位進行性壞死而最終導致截肢。為提高眼鏡蛇咬傷的治療效果，筆者將臨床常用于慢性難愈合創(chuàng)面治療的燒傷創(chuàng)瘍再生醫(yī)療技術應用于眼鏡蛇咬傷患者的創(chuàng)面治療，并與重組牛堿性成纖維細胞生長因子凝膠 （貝復新）治療者進行了對比，療效顯著，現報告如下。

1 臨床資料

1.1 一般資料

選取2010年6月至2016年6月福建中醫(yī)藥大學附屬人民醫(yī)院收治的120例眼鏡蛇咬傷后局部皮膚出現灰黑斑的患者作為研究對象，并按照隨機數表法將其隨機分為治療組 （60例）與對照組 （60例），其中治療組男性41例、女性19例，年齡12～75歲 ［（51.05±12.32）歲］，咬傷至就診時間為 2～120 h［（14.60±20.51） h］，咬傷位于上肢者28例、下肢者32例，入院前出現潰瘍者8例、入院后出現潰瘍者52例，輕度腫脹 （腫脹未越過1個大關節(jié)）者8例、中度腫脹 （腫脹越過1個大關節(jié)但未越過2個大關節(jié)）者17例、重度腫脹（腫脹越過2個大關節(jié)）者35例，Ⅰ度潰瘍（潰瘍面積＜4.0 cm ×4.0 cm［1］） 者53例、 Ⅱ度潰瘍 （潰瘍面積≥4.0 cm×4.0 cm且＜8.0 cm×8.0 cm［1］）者7例；對照組男性38例、女性22例，年齡10～74歲 ［（49.08±13.31）歲］，咬傷至就診時間為1.8～115 h［（12.76±19.25）h］，咬傷位于上肢者26例、下肢者34例，入院前出現潰瘍者5例、入院后出現潰瘍者55例，輕度腫脹者11例、中度腫脹者20例、重度腫脹者29例，Ⅰ度潰瘍者51例、Ⅱ度潰瘍者9例。兩組患者性別、年齡等一般資料對比，P均＞0.05，差異無統(tǒng)計學意義，具有可比性 （表1）。本研究經福建中醫(yī)藥大學附屬人民醫(yī)院倫理委員會批準，且所有患者均簽署了知情同意書。

Cobra is one of the common venomous snakes in China，mainly in such provinces as Yunnan， Guizhou， Zhejiang and Fujian.Epide?miological data show that Fujian Province is a high?risk area of cobra bites.In Fujian，nearly 100 people are admitted into hospitals each year due to cobra bites.The main symptoms of cobra bites are blis?ters， gray black skin spots and local necrosis.At present， the external dressing with Chinese herbal medicine and skin grafting are commonly used to treat such injury in clinical practice，but the clinical efficacy is not satisfying because these approaches probably lead to progressive necrosis of the affected sites，resulting in amputation eventually.In order to improve the therapeutic effect of cobra bites，the author tentatively applied MEBT／MEBO ?a commonly used therapy in the treatment of chronic and hard?to?healing wounds ?in the treatment of cobra bites，compared its clinical efficacy with that of the recombined bovine basic fibroblast growth factor （bFGF） gel， and the results showed that the former had much better clinical efficacy than the later.

1.Clinical data

1.1 .General data

One hundred and twenty patients with gray black spots on their skin caused by cobra bites， admitted to The Affiliated People’s Hos?pital of Fujian University of Traditional Chinese Medicine from June 2010 to June 2016， were selected as the study subjects and were di?vided， according to the random number table， into a treatment group（60 cases） and a control group （60 cases）.In the treatment group：41 males and 19 females，aged 12-75 years old ［ （51.05±12.32）years］，time from being bitten to admission 2-120 h ［ （14.60 ±20.51） h］， 28 cases of upper limb bites， 32 cases of lower limb bites， 8 cases with ulcers before admission， 52 cases with ulcers after admission， 8 cases of mild swelling （smaller than 1 large joint）， 17 cases of moderate swelling（larger than 1 large joint but smaller than 2） ， 35 cases of severe swelling （larger than 2 large joints）， 53 ca?ses of degreeⅠ ulcer（ulcer area ＜4.0 cm ×4.0 cm［1］）， 7 cases of degreeⅡulcer（ulcer area≥4.0 cm×4.0 cm and ＜8.0 cm×8.0 cm）.In the control group：38 males and 22 females， aged 10-74 years old［ （49.08±13.31） years］， time from being bitten to admission 1.8-115 h［ （12.76±19.25） h］，26 cases of upper limb bites， 34 cases of lower limb bites， 5 cases with ulcers before admission， 55 cases with ulcers after admission， 11 cases of mild swelling，20 cases of moderate swelling，29 cases of severe swelling，51 cases of degreeⅠulcer，9 cases of degreeⅡulcer.The general data including gender，age and etc.were compared between the two groups and the results showed no statistically significant difference（all P ＞0.05）， presenting the comparability between the two groups（Table 1）.The study was approved by the Ethics Committee of The Affiliated People’s Hospital of Fujian University of Traditional Chi?nese Medicine and all patients signed the informed consent.

表1 兩組患者一般資料對比Table 1 Comparison of general data between the two groups

1.2 納入標準

（1）明確眼鏡蛇咬傷史且符合眼鏡蛇咬傷臨床表現者；（2）符合 《中國毒蛇學》中毒蛇咬傷所致皮膚潰瘍的診斷標準［2］者；（3）咬傷部位位于四肢者；（4）潰瘍程度為Ⅰ～Ⅱ度者；（5）年齡在10～75歲之間者；（6）對本研究知情，并自愿簽署知情同意書者。

1.3 排除標準

（1）對本研究所用藥物過敏者；（2）入院前1周內使用過潰瘍相關外用藥物者；（3）妊娠期婦女；（4）患有惡性腫瘤或嚴重心腦血管、肝、腎等系統(tǒng)原發(fā)性疾病者；（5）潰瘍程度為Ⅲ度 （潰瘍面積≥8.0 cm ×8.0 cm［1］） 或已深達骨骼并引發(fā)骨髓炎者。

1.2 .Inclusion criteria

Those who （1） have a history of cobra bite and the clinical mani?festations of cobra bites； （2） meet the diagnostic criteria for skin ulcers caused by poisonous snake bites in China Poisonous Snake Research［2］；（3） have the snake bites at four limbs； （4） suffer from degreeⅠ -Ⅱulcer； （5） aged between 10 and 75 years old； （6） are well informed of this study and voluntarily sign the informed consent.

1.3 .Exclusion criteria

Those who （1） are allergic to the drug used in this study； （2）have used ulcer?related topical drugs within 1 week before admission；（3） women in pregnancy； （4） have malignant tumors or severe primary diseases of cardiovascular system，cerebrovascular system，liver，kidney and etc.； （5） suffer from degreeⅢ ulcer（ulcer area≥8.0 cm ×8.0 cm［1］） or ulcers extending to bone and resulting in osteomyelitis.

2 方法

2.1 治療方法

治療組：在給予患者肌肉注射破傷風抗毒素、靜脈滴注抗眼鏡蛇毒血清+地塞米松+5%葡萄糖注射液、口服蛇傷膠囊和三草湯 （福建中醫(yī)藥大學附屬人民醫(yī)院內部制劑）以及加減蛇傷十三味方等全身綜合治療的同時，局部依次予以灰黑斑切開減壓、清除壞死組織、生理鹽水沖洗、消毒干紗布拭凈后均勻涂抹濕潤燒傷膏 （汕頭市美寶制藥有限公司生產，國藥準字Z20000004），厚約0.5 cm（有潛腔者予以濕潤燒傷膏藥紗填塞），并覆蓋無菌敷料固定包扎，每天換藥1～2次，直至創(chuàng)面完全愈合。

對照組：在給予患者全身綜合治療的同時 （治療方法同治療組），局部依次予以灰黑斑切開減壓、清除壞死組織、生理鹽水沖洗、消毒干紗布拭凈后均勻涂抹貝復新 （珠海億勝生物制藥有限公司生產，國藥準字S20040001），30 IU／cm2（有潛腔者予以貝復新紗條填塞），并覆蓋無菌敷料固定包扎，每天換藥1～2次，直至創(chuàng)面完全愈合。

2.2 觀察指標及療效判定標準

分別于治療30、60 d時參照國家中醫(yī)藥管理局發(fā)布的 《中醫(yī)病證診斷療效標準》［3］中蛇咬傷的療效判定標準判定兩組患者的治療效果：治愈，創(chuàng)面完全愈合，患肢功能恢復；顯效，肉芽組織生長良好，愈合創(chuàng)面面積＞70%，局部癥狀明顯改善；有效，肉芽組織生長較好，愈合創(chuàng)面面積＞30%且≤70%，局部癥狀有所改善；無效，愈合創(chuàng)面面積≤30%，甚至擴大，局部癥狀無改善或加重；總有效率= （痊愈例數+顯效例數+有效例數） ／總例數×100%。

2.3 統(tǒng)計學處理

采用SPSS 22.0統(tǒng)計軟件對所得數據進行統(tǒng)計學分析，其中計量資料以 （x ± s） 表示，采用t檢驗或t＇檢驗；計數資料以頻數或百分比表示，采用卡方檢驗或秩和檢驗；均以P＜0.05為差異具有統(tǒng)計學意義。

2.Methods

2.1 .Management methods

Treatment group： in addition to systemic comprehensive treatments，such as intramuscular injection of tetanus antitoxin，intravenous drip of Naja Antivenin+dexamethasone+5%glucose injection， oral adminis?tration of snake bite capsule and Sancao decoction （pharmaceutical prep?aration of The Affiliated People’s Hospital of Fujian University of Tradi?tional Chinese Medicine） and thirteen?ingredient Chinese herbs， the fol?lowing procedures were given to manage the local wounds including inci?sion and decompression of gray black spots， removal of necrotic tissues，normal saline rinsing， wiping with sterile dry gauze in turn before the ap?plication of MEBO（manufactured by Shantou MEBO Pharmaceutical Co.， Ltd.with China approval No.Z20000004）， about 0.5 cm in thick?ness （in case of hidden cavity， MEBO?impregnated gauze was filled in）， and the local wound was then covered and fixed with sterilized dressing.Dressing change was performed 1-2 times per day until the wound was healed completely.

Control group： in addition to systemic comprehensive treatments，such as intramuscular injection of tetanus antitoxin（same as that in the treatment group）， the local wound was given incision and decompression of gray black spots， removal of necrotic tissues， normal saline rinsing，wiping with sterile dry gauze in turn，followed by the application of bFGF （manufactured by Essex Bio?Technology Limited （Zhuhai） with China approval No.S20040001）， 30 IU／cm2（hidden cavity， if any，was filled with bFGF?impregnated gauze）， and the local wound was then covered and fixed with sterilized dressing.Dressing change was also per?formed 1-2 times per day until the wound was healed completely.

2.2 .Observational indexes and assessment criteria of clinical efficacy

After 30 and 60 days of treatment，the clinical efficacy of the two groups was assessed by reference to the clinical efficacy assessment standards for snake bites in Criteria of Diagnosis and Therapeutic Effect of Diseases and Syndromes in Traditiona1 Chinese Medicine［3］issued by State Administration of Traditional Chinese Medicine.Cured：complete wound healing and good recovery of the injured limb； markedly effec?tive： granulation tissues grow well， the healed area is ＞70%and local symptoms get improvement substantially； effective： granulation tissues grow well，the healed area ＞30%and≤70%，and local symptoms get improvement；ineffective：the healed area≤30%， or the wound area has no change or even becomes larger，no improvement can be seen in local symptoms or symptoms are aggravated.Total effective rate=（number of healed cases+number of markedly effective cases+num?ber of effective cases） ／total number of cases×100%.

2.3 .Statistical analysis

The software SPSS 22.0 was adopted to analyze the study data，in which t test or t＇test was used to manage the measurement data expressed with（x± s） while Chi?square test or rank sum test was used to manage the count data expressed with frequency or percentage.P＜0.05 was considered as statistically significant difference.

3 結果

3.1 兩組患者臨床療效對比

治療30 d時，治療組患者中治愈13例、顯效21例、有效8例、無效18例、總有效率為70.00%；對照組患者中治愈8例、顯效15例、有效8例、無效29例、總有效率為51.67%，兩組對比，P＜0.05，差異具有統(tǒng)計學意義。治療60 d時，治療組患者中治愈53例、顯效3例、有效2例、無效2例、總有效率為96.67%；對照組患者中治愈41例、顯效4例、有效7例、無效8例、總有效率為86.67%，兩組對比，P＜0.05，差異具有統(tǒng)計學意義 （表2）。

3.Results

3.1 .Comparison of clinical efficacy between the two groups

After 30 days of treatment，the total effective rate was 70.00%，with 13 cases cured， 21 cases markedly effective， 8 cases effective， and 18 cases ineffective in the treatment group， while in the control group，the total effective rate was 51.67%，with 8 cases cured，15 cases markedly effective， 8 cases effective and 29 cases ineffective， between which the comparison showed statistically significant difference（P＜0.05）.After 60 days of treatment， the total effective rate was 96.67%，with 53 patients cured， 3 cases markedly effective， 2 cases effective and 2 cases ineffective in the treatment group， which showed statistically sig?nificant difference as compared with the total effective rate 86.67%，41 cases cured， 4 cases markedly effective， 7 cases effective and 8 cases ineffective in the control group （P ＜0.05） （Table 2）.

表2 兩組患者臨床療效對比 （例，%）Table 2 Comparison of clinical efficacy between the two groups（n，%）

3.2 兩組患者創(chuàng)面愈合時間對比

治療過程中，兩組患者均未發(fā)生創(chuàng)面感染、過敏等不良反應，最終創(chuàng)面均完全愈合，其中治療組患者的創(chuàng)面愈合時間為14～120 d［（43.63±20.48） d］，對照組患者的創(chuàng)面愈合時間為18～161 d ［ （66.93±36.45） d］，兩組對比方差不齊采用t＇檢驗，t＇=-4.317，P=0.000，P＜0.05，差異具有統(tǒng)計學意義。

4 討論

中醫(yī)學認為，眼鏡蛇蛇毒為風火毒，患者被咬傷后因火毒熾盛，熱盛肉腐，腐肉化膿，導致局部組織潰爛、壞死［4］。火毒內襲入血分，熱盛則迫血妄行，血行脈外，離經之血聚而成瘀，瘀血郁而化熱，進而加重組織損傷?，F代醫(yī)學研究顯示，眼鏡蛇蛇毒中含有的透明質酸酶、蛋白水解酶、肌肉毒素、細胞毒素及磷脂酶A2等可導致細胞消融，局部組織缺血、缺氧及微循環(huán)障礙，血管壁通透性增加等，從而引發(fā)局部組織水腫及壞死［5］。

3.2 .Comparison of wound healing time between the two groups

During the treatment course，no adverse reactions such as wound infection and allergic reaction once occurred in the two groups and all the wounds of the two groups were completely healed at the end.The wound healing time was 14-120 （43.63±20.48） d in the treatment group while 18-161 （66.93±36.45） d in the control group，between which t＇test was used for the comparison given the unequal variance， and the results showed statistically significant difference （t＇=-4.317， P=0.000， P ＜0.05）.

4.Discussion

Traditional Chinese medicine holds that cobra venom is wind?fire toxin.After the patient is bitten by cobra，the fire toxin in the body leads to heat exuberance，as a result of which the injured muscle will rot and fester， eventually resulting in local tissue ulceration and necrosis［4］； The fire toxin will invade the blood， causing frenetic movement of blood，blood overflowing from the veins and arteries，and forming congestion.The stagnated blood in turn produces more heat，further aggravating the tissue damage.Modern medical research shows that hyaluronidase， pro?teolytic enzymes， myotoxin， cytotoxins and phospholipase A2contained in cobra venom can cause cell ablation，ischemia and hypoxia of local tissues， microcirculation disorders， increased permeability of vascular wall and etc.， further leading to local tissue edema and necrosis［5］.

Studies have shown that MEBO ?the core drug of MEBT／MEBO，has the effects of clearing heat，promoting blood circulation to improve blood stasis， and enhancing tissue regeneration［6-7］.Some active ingre?dients contained in MEBO can activate the potential regenerative cells in the wound tissues and transform them into stem cells which then prolifer?ate and differentiate in situ into tissue cells of all layers in the wound to regenerate and restore the wounded skin［8-9］.MEBO contains multiple nutrients such as polysaccharides， fatty acids， amino acids， vitamins，electrolytes and microelements，providing material guarantee for the regenerative restoration of wound tissues［10-12］.Therefore， the author applied MEBO in the treatment of cobra bite in this study and compared its clinical efficacy with that of bFGF.The results showed that after 30 days of treatment，the total effective rate was 70.00%in the treatment group and 51.67%in the control group，between which the comparison showed statistically significant difference（P ＜0.05）.After 60 days of treatment，the total effective rate was 96.67%in the treatment group and 86.67%in the control group，between which the comparison also showed statistically significant difference （P ＜ 0.05）.Finally， the wounds of patients in both groups were all completely healed.The wound healing time was（43.63±20.48） d in the treatment group and（66.93±36.45） d in the control group， between which the comparison showed statistically significant difference （P ＜0.05）.Thus， MEBT／MEBO can effectively promote the wound healing of patients with cobra bites， short?en the wound healing time and improve wound healing effect，of which the reason probably is that bFGF can only promote capillary regenera?tion， improve local blood circulation and accelerate wound healing，while， in contrast， besides the above same effects， MEBO can also clear heat and promote blood circulation to remove blood stasis，presenting better clinical efficacy than bFGF.

In summary， MEBT／MEBO in the treatment of cobra bite wounds can realize remarkable curative effects including shortening wound heal?ing time and improving wound healing effect，showing much high clinical application value.

研究顯示，燒傷創(chuàng)瘍再生醫(yī)療技術的核心藥物濕潤燒傷膏具有清熱解毒、活血化瘀、生肌收斂之效［6-7］，其內含有的有效成分可激活創(chuàng)面組織中的潛能再生細胞，并將其轉化為干細胞，再在原位增殖、分化為創(chuàng)面各層組織細胞，再生修復創(chuàng)面［8-9］；其含有的多糖、脂肪酸、氨基酸、維生素、電解質、微量元素等營養(yǎng)物質，可為創(chuàng)面的再生修復提供物質保障［10-12］。鑒于此，筆者于本研究中將其應用于眼鏡蛇咬傷患者的創(chuàng)面治療，并與貝復新治療者進行了對比。結果顯示，治療30 d時，治療組患者的總有效率為70.00%，對照組患者的總有效率為51.67%，兩組對比，P＜0.05，差異具有統(tǒng)計學意義；治療60 d時，治療組患者的總有效率為96.67%，對照組患者的總有效率為86.67%，兩組對比，P＜0.05，差異具有統(tǒng)計學意義；最終兩組患者創(chuàng)面均完全愈合，其中治療組患者的創(chuàng)面愈合時間為 （43.63±20.48）d，對照組患者的創(chuàng)面愈合時間為（66.93±36.45） d， 兩組對比， P＜0.05，差異具有統(tǒng)計學意義。可見燒傷創(chuàng)瘍再生醫(yī)療技術可有效促進眼鏡蛇咬傷患者的創(chuàng)面愈合，縮短創(chuàng)面愈合時間，提高創(chuàng)面愈合效果。其原因可能為，貝復新僅具有促進毛細血管再生，改善局部血液循環(huán)，加速創(chuàng)面愈合等作用，而濕潤燒傷膏還兼具中醫(yī)學中清熱解毒、活血化瘀等功效，故療效明顯優(yōu)于貝復新。

綜上所述，燒傷創(chuàng)瘍再生醫(yī)療技術治療眼鏡蛇咬傷創(chuàng)面，可縮短創(chuàng)面愈合時間，提高創(chuàng)面愈合效果，療效顯著，臨床應用價值較高。

（收稿日期：2018?12?14）