Randomised Controlled Double-Blind Non-Inferiority Trial of Two Antivenoms for Saw-Scaled or Carpet Viper (Echis ocellatus) Envenoming in Nigeria

Background

In West Africa, envenoming by saw-scaled or carpet vipers (Echis ocellatus) causes great morbidity and mortality, but there is a crisis in supply of effective and affordable antivenom (ISRCTN01257358).

Methods

In a randomised, double-blind, controlled, non-inferiority trial, “EchiTAb Plus-ICP” (ET-Plus) equine antivenom made by Instituto Clodomiro Picado was compared to “EchiTAb G” (ET-G) ovine antivenom made by MicroPharm, which is the standard of care in Nigeria and was developed from the original EchiTAb-Fab introduced in 1998. Both are caprylic acid purified whole IgG antivenoms. ET-G is monospecific for Echis ocellatus antivenom (initial dose 1 vial) and ET-Plus is polyspecific for E. ocellatus, Naja nigricollis and Bitis arietans (initial dose 3 vials). Both had been screened by pre-clinical and preliminary clinical dose-finding and safety studies. Patients who presented with incoagulable blood, indicative of systemic envenoming by E. ocellatus, were recruited in Kaltungo, north-eastern Nigeria. Those eligible and consenting were randomly allocated with equal probability to receive ET-Plus or ET-G. The primary outcome was permanent restoration of blood coagulability 6 hours after the start of treatment, assessed by a simple whole blood clotting test repeated 6, 12, 18, 24 and 48 hr after treatment. Secondary (safety) outcomes were the incidences of anaphylactic, pyrogenic and late serum sickness-type antivenom reactions.

Findings

Initial doses permanently restored blood coagulability at 6 hours in 161/194 (83.0%) of ET-Plus and 156/206 (75.7%) of ET-G treated patients (Relative Risk [RR] 1.10 one-sided 95% CI lower limit 1.01; P = 0.05). ET-Plus caused early reactions on more occasions than did ET-G [50/194 (25.8%) and 39/206 (18.9%) respectively RR (1.36 one-sided 95% CI 1.86 upper limit; P = 0.06). These reactions were classified as severe in 21 (10.8%) and 11 (5.3%) of patients, respectively.

Conclusion

At these doses, ET-Plus was slightly more effective but ET-G was slightly safer. Both are recommended for treating E. ocellatus envenoming in Nigeria.

Trial Registration

Current Controlled Trials ISRCTN01257358     

Death Adder Envenoming Causes Neurotoxicity Not Reversed by Antivenom - Australian Snakebite Project (ASP-16)

Background

Death adders (Acanthophis spp) are found in Australia, Papua New Guinea and parts of eastern Indonesia. This study aimed to investigate the clinical syndrome of death adder envenoming and response to antivenom treatment.

Methodology/Principal Findings

Definite death adder bites were recruited from the Australian Snakebite Project (ASP) as defined by expert identification or detection of death adder venom in blood. Clinical effects and laboratory results were collected prospectively, including the time course of neurotoxicity and response to treatment. Enzyme immunoassay was used to measure venom concentrations. Twenty nine patients had definite death adder bites; median age 45 yr (5–74 yr); 25 were male. Envenoming occurred in 14 patients. Two further patients had allergic reactions without envenoming, both snake handlers with previous death adder bites. Of 14 envenomed patients, 12 developed neurotoxicity characterised by ptosis (12), diplopia (9), bulbar weakness (7), intercostal muscle weakness (2) and limb weakness (2). Intubation and mechanical ventilation were required for two patients for 17 and 83 hours. The median time to onset of neurotoxicity was 4 hours (0.5–15.5 hr). One patient bitten by a northern death adder developed myotoxicity and one patient only developed systemic symptoms without neurotoxicity. No patient developed venom induced consumption coagulopathy. Antivenom was administered to 13 patients, all receiving one vial initially. The median time for resolution of neurotoxicity post-antivenom was 21 hours (5–168). The median peak venom concentration in 13 envenomed patients with blood samples was 22 ng/mL (4.4–245 ng/mL). In eight patients where post-antivenom bloods were available, no venom was detected after one vial of antivenom.

Conclusions/Significance

Death adder envenoming is characterised by neurotoxicity, which is mild in most cases. One vial of death adder antivenom was sufficient to bind all circulating venom. The persistent neurological effects despite antivenom, suggests that neurotoxicity is not reversed by antivenom.     

不明蛇种咬伤的急诊救治

目的探讨不明蛇种咬伤的诊断方法、临床特点及急诊救治措施。方法对64例不明蛇种咬伤患者的诊断方法、临床表现、程序化综合救治方法及疗效评价进行分析。结果蛇种判定基本准确,治疗及时,总有效率100%,伤口渗血、肿胀明显减少。结论急诊救治的关键是早期诊断、早期预测、早期治疗,其中早期诊断是重中之重。需要早期评估病情的发展,加强蛇伤知识的普及,提高对毒蛇的认识,建议群众尽可能把伤人之蛇打死带来医院以便于及早确诊。     

Antivenoms for the treatment of snakebite envenomings: The road ahead

The parenteral administration of antivenoms is the cornerstone of snakebite envenoming therapy. Efforts are made to ensure that antivenoms of adequate efficacy and safety are available world-wide. We address the main issues to be considered for the development and manufacture of improved antivenoms. Those include: (a) A knowledge-based composition design of venom mixtures used for immunization, based on biochemical, immunological, toxicological, taxonomic, clinical and epidemiological data; (b) a careful selection and adequate management of animals used for immunization; (c) well-designed immunization protocols; (d) sound innovations in plasma fractionation protocols to improve recovery, tolerability and stability of antivenoms; (e) the use of recombinant toxins as immunogens to generate antivenoms and the synthesis of engineered antibodies to substitute for animal-derived antivenoms; (f) scientific studies of the contribution of existing manufacturing steps to the inactivation or removal of viruses and other zoonotic pathogens; (g) the introduction of novel quality control tests; (h) the development of in vitro assays in substitution of in vivo tests to assess antivenom potency; and (i) scientifically-sound pre-clinical and clinical assessments of antivenoms. These tasks demand cooperative efforts at all main stages of antivenom development and production, and need concerted international partnerships between key stakeholders.     

毒蛇咬伤的社区医院处理对策

目的总结39例毒蛇咬伤患者的社区医院处理经验。方法对39例毒蛇咬伤患者的临床资料进行回顾性分析。结果39例中,治愈20例,好转13例,无死亡病例}转送上级医院6例,转诊率15．38％,治愈率51．28％,总有效率84．62％。结论毒蛇咬伤社区医院处理对策,关键在于准确地辨别蛇种和判断病情,熟练使用相应的抗蛇毒血清和中医中药治疗。     

Snake Envenoming: A Disease of Poverty

Background

Most epidemiological and clinical reports on snake envenoming focus on a single country and describe rural communities as being at greatest risk. Reports linking snakebite vulnerability to socioeconomic status are usually limited to anecdotal statements. The few reports with a global perspective have identified the tropical regions of Asia and Africa as suffering the highest levels of snakebite-induced mortality. Our analysis examined the association between globally available data on snakebite-induced mortality and socioeconomic indicators of poverty.

Methodology/Principal Findings

We acquired data on (i) the Human Development Index, (ii) the Per Capita Government Expenditure on Health, (iii) the Percentage Labour Force in Agriculture and (iv) Gross Domestic Product Per Capita from publicly available databases on the 138 countries for which snakebite-induced mortality rates have recently been estimated. The socioeconomic datasets were then plotted against the snakebite-induced mortality estimates (where both datasets were available) and the relationship determined. Each analysis illustrated a strong association between snakebite-induced mortality and poverty.

Conclusions/Significance

This study, the first of its kind, unequivocally demonstrates that snake envenoming is a disease of the poor. The negative association between snakebite deaths and government expenditure on health confirms that the burden of mortality is highest in those countries least able to deal with the considerable financial cost of snakebite.     

毒蛇咬伤早期集束化治疗

目的探讨毒蛇咬伤早期集束化治疗对病情的影响。方法收集我院2011年4月~2014年11月资料完整的70例五步蛇咬伤患者的临床资料,统计分析患者的就诊时间、清洗伤口时间、伤口切开时间、使用抗蛇毒血清时间、使用激素时间与病情严重程度、肢体肿胀程度及住院时间的关系。结果就诊时间、清洗伤口时间、伤口切开时间、使用抗蛇毒血清时间、使用激素时间与病情严重程度、肢体肿胀程度及住院时间明显相关(均P0.001)。以各指标中位数为截点进行危险分层,大于中位数组的病情严重程度、肢体肿胀程度重于小于中位数组,大于中位数组的住院时间长于小于中位数组,差异具有统计学意义(均P0.01)。结论毒蛇咬伤预后受多因素影响,在短时间内完成集束化治疗可减轻病情严重程度及缩短住院时间,改善预后。     

Current Treatment for Venom-Induced Consumption Coagulopathy Resulting from Snakebite

Venomous snakebite is considered the single most important cause of human injury from venomous animals worldwide. Coagulopathy is one of the commonest important systemic clinical syndromes and can be complicated by serious and life-threatening haemorrhage. Venom-induced consumption coagulopathy (VICC) is the commonest coagulopathy resulting from snakebite and occurs in envenoming by Viperid snakes, certain elapids, including Australian elapids, and a few Colubrid (rear fang) snakes. Procoagulant toxins activate the clotting pathway, causing a broad range of factor deficiencies depending on the particular procoagulant toxin in the snake venom. Diagnosis and monitoring of coagulopathy is problematic, particularly in resource-poor countries where further research is required to develop more reliable, cheap clotting tests. MEDLINE and EMBASE up to September 2013 were searched to identify clinical studies of snake envenoming with VICC. The UniPort database was searched for coagulant snake toxins. Despite preclinical studies demonstrating antivenom binding toxins (efficacy), there was less evidence to support clinical effectiveness of antivenom for VICC. There were no placebo-controlled trials of antivenom for VICC. There were 25 randomised comparative trials of antivenom for VICC, which compared two different antivenoms (ten studies), three different antivenoms (four), two or three different doses or repeat doses of antivenom (five), heparin treatment and antivenom (five), and intravenous immunoglobulin treatment and antivenom (one). There were 13 studies that compared two groups in which there was no randomisation, including studies with historical controls. There have been numerous observational studies of antivenom in VICC but with no comparison group. Most of the controlled trials were small, did not use the same method for assessing coagulopathy, varied the dose of antivenom, and did not provide complete details of the study design (primary outcomes, randomisation, and allocation concealment). Non-randomised trials including comparison groups without antivenom showed that antivenom was effective for some snakes (e.g., Echis), but not others (e.g., Australasian elapids). Antivenom is the major treatment for VICC, but there is currently little high-quality evidence to support effectiveness. Antivenom is not risk free, and adverse reactions can be quite common and potentially severe. Studies of heparin did not demonstrate it improved outcomes in VICC. Fresh frozen plasma appeared to speed the recovery of coagulopathy and should be considered in bleeding patients.     

蛇伤药酒抗毒抗菌作用的实验研究

目的探讨蛇伤药酒抗眼镜蛇毒、内毒素及细菌的效果。方法抗眼镜蛇毒和内毒素试验采用鲎试剂法．抗菌试验采用纸片法。结果眼镜蛇毒与0．5EU／ml鲎试剂产生凝集反应的浓度在5．0ug／ml以上;蛇伤药酒浓度1ml／ml时有抗5倍量眼镜蛇毒的凝集反应;有抗2．5倍量内毒素的凝集反应;对多种细菌有抑制作用。结论蛇伤药酒有抗眼镜蛇毒、抗内毒素和多种病原菌的作用。     

毒蛇咬伤病人的血小板聚集功能初探

目的为了探讨血液毒及混合毒类毒蛇咬伤病人的血小板功能情况,了解临床中毒发病机理。方法对近年来在本院急诊科确诊的五步蛇(Da.),蝮蛇(Ah.),眼镜蛇(Nn.),眼镜王蛇(Oh.),蝰蛇(Vr.),烙铁头(Tm.)和竹叶青(Ts.)等各种血液毒及混合毒类毒蛇咬伤17例病人25个血样,进行最大血小板聚集率(MAR)的检查和分析研究。结果除了Da未见MAR下降外(仅1例1个样品),其余各蛇种咬伤的样品均有下降。在获得未经治疗(抗蛇毒血清)的15个样品的检查结果中,进行统计分析,Vr、Tm以及Ah的MAR比正常人对照组(51.3±16.0)%明显下降。结论蛇毒中的血小板集聚抑制因子,可引起蛇伤患者体内血小板聚集功能下降,血小板处于无用状态,结果有些蛇伤病人DIC样综合征时出现严重出血而无明显微循环血栓形成致器官受损的临床症状。     

蛇伤药酒抗眼镜蛇毒的药效学研究

目的探讨蛇伤药酒对眼镜蛇毒中毒的治疗效果。方法用中华眼镜蛇毒于家兔制作的病理模型并用蛇伤药酒于注毒局部外敷治疗,再进行中毒表现和血液指标等观察。结果与蛇毒组相比,药酒组局部和全身症状均较轻,死亡率较低;WBC、CK和CRP变化没有那么明显,PLT、PT和FBG水平基本没有变化。结论蛇伤药酒能减轻炎症反应,防止急性DIC发生和保护机体组织受损,故有较好的对抗眼镜蛇毒的作用。     

广西的蛇类资源与蛇伤调查

报道作者在广西壮族自治区 (中国的一个省 )进行蛇类资源和蛇咬伤情况的调查结果。至今为止发现栖息在广西境内的蛇类有 7科 4 2属 96种 ,其中盲蛇科( Typhloidae)、 1种、蟒科 ( Boidae) 1种、闪鳞蛇科( Xenopheltidae) 1种、游蛇科 ( Colubridae) 71种、眼镜蛇科 ( Elapidae) 6种、海蛇科 ( Hydrophiidae) 7种、蝰科( Viperidae) 9种 ,其中有毒蛇 33种。经蛇伤流行病学调查推算 ,广西每年蛇伤病人约 376 0 0例 ,其中约 1 0 1 9例死亡 ,而蛇伤死亡率最高为眼镜王蛇咬伤 ( 5 7.1 % ) ;其次为银环蛇 ,由于抗蛇毒血清供应不足 ,很多边远地区病人因不能及时接受抗蛇毒血清治疗是造成死亡的主要原因之一。     

抗蛇毒血清治疗毒蛇咬伤1569例

本所于1999年6月～2004年10月用抗蛇毒血清(上海赛伦生物技术有限公司生产)配合青青蛇药治疗蝮蛇、眼镜蛇、竹叶青蛇、五步蛇和银环蛇咬伤1569例,获得满意效果。现报道如下。     

蛇伤溃疡的诊治及预防措施

蛇伤溃疡是国内外蛇伤防治领域的一个研究热点,也是临床外科多年来的研究课题.治疗毒蛇咬伤,不仅要抢救生命,还要认真保护肢体的完整及功能.蛇伤后伤口感染或化脓,组织坏死,溃疡久治不愈引起的肢体畸形、残废,目前在国内外还是比较棘手的一大难题.我院经过多年的潜心研究,制成蛇创溃疡散.该药用于治疗376例蛇伤溃疡患者,治愈率达91.5%,总有效率为97.6%[1].由于该药的应用,使我院蛇伤后残肢率明显下降,使许多患者免除了截肢(终身残废)的痛苦.蛇创溃疡散的科研成果已被中国中医药学会、中国中医研究院确认,为此谨就蛇伤溃疡的诊断,治疗和预防等有关问题概述如下.     

东北地区蛇伤的发病特点及救治

我国东北地区属典型温带气候,四季分明,大部分为良田沃土,丘陵山地,雨水调和,植被茂盛,不仅为人类的繁衍生息提供了良好条件,同时也为蛇类的繁衍生息创造了有利环境。不同地区繁衍不同的民族,有典型的地域性,蛇类也一样。我国东北地区同南方相比,蛇的种类较少,特别是毒蛇种类更少。因此,就流行病学角度而言,构成其固有规律及特点。笔者根据多年从事蛇伤防治,蛇毒的研究,生态考察及与相关学者共同探讨,现将东北地区的毒蛇、蛇伤特点及救治原则阐述如下,供同行参考。