Antivenom surveillance: An audit of antivenom stock within South Australia.

OBJECTIVES: Antivenoms are important emergency medications to be held within Australia, particularly in regional and remote locations. We audited current antivenom holdings in hospitals and health services across South Australia (SA) and compared to recommendations in the 'Snakebite and Spiderbite Management Guidelines' from the State's Toxinology service. The process also assessed the feasibility of 'real-time' remote stock monitoring. METHODS: Fifty-three sites listed in the guideline were recommended to hold antivenom, though only 49 are currently operational. Interrogation of antivenom stock for 29 sites was possible using electronic reports generated from the State Pharmacy database. The 20 remaining centres had their stock levels confirmed by calling the centres directly. Data obtained were then compared to recommended levels of antivenom holdings in the guideline with discrepancies and associated costs documented. A separate report verification process was used to determine 'real-time' accuracy of the electronic reports. RESULTS: Thirty-seven sites (75%) held more than the recommended number of antivenom vials, totalling 129 vials in excess with an approximate total cost of $110 000. Twelve sites (24%) held inadequate stock to deliver a treatment dose for 19 envenoming events. The report verification revealed variances in the electronic reports. CONCLUSIONS: This audit has demonstrated a significant disparity between recommended and actual antivenom holdings across most sites in SA and has also revealed that 'real-time' remote monitoring of state antivenom holdings is not currently feasible. Correction of stock levels to that recommended may result in financial benefit for State Health while also addressing inequity in regional and remote healthcare provision.

The Incidence of Infection Complicating Snakebites in Tropical Australia: Implications for Clinical Management and Antimicrobial Prophylaxis.

Objective: To define the incidence of infection following snakebite in tropical Australia and the resulting implications for the routine prescription of prophylactic antibiotics. Methods: A retrospective study of all individuals presenting to Cairns Hospital, a tertiary referral hospital in tropical Australia, after a snakebite between December 2013 and October 2020. Results: There were 732 hospitalisations, 720 (98.4%) patients presented within 8 hours of the snakebite, and 29/732 (4.0%) were envenomated. Envenomated patients were more likely to receive empirical antibiotics than nonenvenomated patients (8/29 (27.6%) versus 14/703 (2.0%), p < 0.001), although this was frequently as a bundle of care for critically ill individuals. Superficial skin infection was diagnosed by clinicians in 6/732 (0.8%) patients during their hospitalisation; infection was diagnosed more commonly in envenomated than in nonenvenomated patients (3/29 (10.3%) versus 3/703 (0.4%), p = 0.001). All 3 envenomated individuals diagnosed with infection were believed to have taipan (genus Oxyuranus) bites. Five (83%) of the six patients diagnosed with infection had received empirical antibiotics at presentation; only 1/710 (0.1%) patients who received no antibiotics developed a (superficial) infection. Conclusion: Infection is a very uncommon complication of snakebite in tropical Australia. Individuals bitten by snakes in tropical Australia should not routinely receive antibiotic prophylaxis.

Clinical toxinology.

Clinical toxinology is a specialized area of clinical medicine focused on the pathophysiology, diagnosis, treatment, and prevention of diseases caused by animal, plant, and fungal toxins. This review focuses on recent developments in snakebite. Snakebite is newly recognized as a Neglected Tropical Disease by the World Health Organization (WHO), reflecting the large human and economic cost of this disease. New WHO guidelines on antivenom production are available. The methods of producing antivenom and dosing are changing as understanding of envenoming improves. Lower antivenom doses in some regions are delivering equal outcomes, but antivenom cannot fully treat all envenoming types. Early antivenom treatment may reduce local tissue damage in some types of snakebite.

Snakebite Envenoming Diagnosis and Diagnostics.

Snakebite envenoming is predominantly an occupational disease of the rural tropics, causing death or permanent disability to hundreds of thousands of victims annually. The diagnosis of snakebite envenoming is commonly based on a combination of patient history and a syndromic approach. However, the availability of auxiliary diagnostic tests at the disposal of the clinicians vary from country to country, and the level of experience within snakebite diagnosis and intervention may be quite different for clinicians from different hospitals. As such, achieving timely diagnosis, and thus treatment, is a challenge faced by treating personnel around the globe. For years, much effort has gone into developing novel diagnostics to support diagnosis of snakebite victims, especially in rural areas of the tropics. Gaining access to affordable and rapid diagnostics could potentially facilitate more favorable patient outcomes due to early and appropriate treatment. This review aims to highlight regional differences in epidemiology and clinical snakebite management on a global scale, including an overview of the past and ongoing research efforts within snakebite diagnostics. Finally, the review is rounded off with a discussion on design considerations and potential benefits of novel snakebite diagnostics.

Characteristics and significance of "green snake" bites in Myanmar, especially by the pit vipers Trimeresurus albolabris and Trimeresurus erythrurus.

Snakebite is an important problem in Myanmar. Regionally, bites by Eastern Russell's vipers, Daboia siamensis (Viperidae, Viperinae), and monocled cobras, Naja kaouthia are considered medically important, but those categorised as "green snake" bites are not. However, these may include bites by green pit vipers, Trimeresurus spp. (Viperidae, Crotalinae) for which no antivenom is available in Myanmar. Elsewhere in Southeast Asia, these snakes are reported to cause local and systemic envenoming. As part of the Myanmar Snakebite Project, prospective case data were collected over 3 years from five hospitals in the Mandalay region. These included 3803 snakebite cases reported from Mandalay region. Of these, 355 were listed as bites by a witnessed green-coloured snake. In 22 cases, the snakes responsible were retained and preserved, then expertly identified; 21 were medically important white-lipped pit vipers (Trimeresurus albolabris), and one as an Asian vine snake, Ahaetulla prasina (Colubridae, Ahaetuliinae) which is not of medical importance. Among confirmed Trimeresurus albolabris bites, 15/21 developed swelling of the bitten limb, and 3/21 coagulopathy, defined as a positive 20-min whole blood clotting test (20WBCT). None developed necrosis, blistering, thrombocytopenia or acute kidney injury (AKI). Of the remaining 333 patients bitten by green snakes that were not specifically identified, 241 (72%) developed swelling of the bitten limb, and 62 (19%) coagulopathy. AKI occurred in 21/333 patients, but only one required dialysis. At least 10/21 of the cases with AKI in this study were more likely to represent bites from Trimeresurus spp. than D. siamensis because the snake responsible was brought into the hospital, examined and described by the treating physician as "green-coloured". This study describes a previously unpublished case of AKI from envenoming by T. erythrurus in Yangon, and reviews cases of AKI following bites by this species and T. albolabris in Myanmar. This confirms that, at least on rare occasions, Trimeresurus spp. envenoming can cause AKI. This has important implications for snakebite management in Myanmar as the finding of local swelling, coagulopathy and AKI is generally considered pathognomonic of D. siamensis envenoming. Further collection of confirmed Trimeresurus spp. bites is required in Myanmar in order better to define the syndrome of envenoming and to assess the possible need for antivenom against Trimeresurus spp. in this country.

Venomous animals: clinical toxinology.

Venomous animals occur in numerous phyla and present a great diversity of taxa, toxins, targets, clinical effects and outcomes. Venomous snakes are the most medically significant group globally and may injure >1.25 million humans annually, with up to 100 000 deaths and many more cases with long-term disability. Scorpion sting is the next most important cause of envenoming, but significant morbidity and even deaths occur following envenoming with a wide range of other venomous animals, including spiders, ticks, jellyfish, marine snails, octopuses and fish. Clinical effects vary with species and venom type, including local effects (pain, swelling, sweating, blistering, bleeding, necrosis), general effects (headache, vomiting, abdominal pain, hypertension, hypotension, cardiac arrhythmias and arrest, convulsions, collapse, shock) and specific systemic effects (paralytic neurotoxicity, neuroexcitatory neurotoxicity, myotoxicity, interference with coagulation, haemorrhagic activity, renal toxicity, cardiac toxicity). First aid varies with organism and envenoming type, but few effective first aid methods are recommended, while many inappropriate or frankly dangerous methods are in widespread use. For snakebite, immobilisation of the bitten limb, then the whole patient is the universal method, although pressure immobilisation bandaging is recommended for bites by non-necrotic or haemorrhagic species. Hot water immersion is the most universal method for painful marine stings. Medical treatment includes both general and specific measures, with antivenom being the principal tool in the latter category. However, antivenom is available only for a limited range of species, not for all dangerous species, is in short supply in some areas of highest need, and in many cases, is supported by historical precedent rather than modern controlled trials.

Clinical importance of the Mandalay spitting cobra (Naja mandalayensis) in Upper Myanmar - Bites, envenoming and ophthalmia.

Examination of 18 cobras brought to three hospitals in the Mandalay Region by patients bitten or spat at by them distinguished 3 monocled cobras (Naja kaouthia) and 15 Mandalay spitting cobras (N. mandalayensis), based on their morphological characteristics. We confirm and extend the known distributions and habitats of both N. mandalayensis and N. kaouthia in Upper Myanmar. Clinical symptoms of local and systemic envenoming by N. mandalayensis are described for the first time. These included local swelling, blistering and necrosis and life-threatening systemic neurotoxicity. More information is needed about the clinical phenotype and management of bites by N. mandalayensis, the commoner of the two cobras in Upper Myanmar. Since the current cobra antivenom manufactured in Myanmar has lower pre-clinical efficacy against N. mandalayensis than N. kaouthia, there is a need for more specific antivenom therapy.

Envenomations: an overview of clinical toxinology for the primary care physician.

About 4,000 to 6,000 venomous snakebites occur each year in the United States. Although these envenomations (also known as envenomings) are rarely fatal, about 70 percent require antivenom therapy. Few evidence-based guidelines are available for the management of envenomation. Antivenom therapy is the cornerstone of management for hemorrhagic or coagulopathic envenomation from pit vipers (with or without paralytic features), and for paralytic envenomation from coral snakes. Early intubation and ventilation may be required after bites from pit vipers whose venoms contain presynaptic neurotoxins. Although relatively controversial, antivenom therapy seems to be effective for the management of severe envenomation from widow spiders. Conversely, little evidence supports any specific management strategy for necrotic envenomation from recluse spiders. Cytotoxic fish stings, cnidarian stings, and traumatic penetrative envenomation by stingrays are typically managed symptomatically. Private collection of nonnative venomous animals in the United States is another source of medical risk.

Mushroom poisoning: A proposed new clinical classification.

Mushroom poisoning is a significant and increasing form of toxin-induced-disease. Existing classifications of mushroom poisoning do not include more recently described new syndromes of mushroom poisoning and this can impede the diagnostic process. We reviewed the literature on mushroom poisoning, concentrating on the period since the current major classification published in 1994, to identify all new syndromes of poisoning and organise them into a new integrated classification, supported by a new diagnostic algorithm. New syndromes were eligible for inclusion if there was sufficient detail about both causation and clinical descriptions. Criteria included: identity of mushrooms, clinical profile, epidemiology, and the distinctive features of poisoning in comparison with previously documented syndromes. We propose 6 major groups based on key clinical features relevant in distinguishing between poisoning syndromes. Some clinical features, notably gastrointestinal symptoms, are common to many mushroom poisoning syndromes. Group 1 - Cytotoxic mushroom poisoning. Syndromes with specific major internal organ pathology: (Subgroup 1.1; Primary hepatotoxicity); 1A, primary hepatotoxicity (amatoxins); (Subgroup 1.2; Primary nephrotoxicity); 1B, early primary nephrotoxicity (amino hexadienoic acid; AHDA); 1C, delayed primary nephrotoxicity (orellanines). Group 2 - Neurotoxic mushroom poisoning. Syndromes with primary neurotoxicity: 2A, hallucinogenic mushrooms (psilocybins and related toxins); 2B, autonomic-toxicity mushrooms (muscarines); 2C, CNS-toxicity mushrooms (ibotenic acid/muscimol); 2D, morel neurologic syndrome (Morchella spp.). Group 3 - Myotoxic mushroom poisoning. Syndromes with rhabdomyolysis as the primary feature: 3A, rapid onset (Russula spp.); 3B, delayed onset (Tricholoma spp.). Group 4 - Metabolic, endocrine and related toxicity mushroom poisoning. Syndromes with a variety of clinical presentations affecting metabolic and/or endocrine processes: 4A, GABA-blocking mushroom poisoning (gyromitrins); 4B, disulfiram-like (coprines); 4C, polyporic mushroom poisoning (polyporic acid); 4D, trichothecene mushroom poisoning (Podostroma spp.); 4E, hypoglycaemic mushroom poisoning (Trogia venenata); 4F, hyperprocalcitoninemia mushroom poisoning (Boletus satanas); 4G, pancytopenic mushroom poisoning (Ganoderma neojaponicum). Group 5 - Gastrointestinal irritant mushroom poisoning. This group includes a wide variety of mushrooms that cause gastrointestinal effects without causing other clinically significant effects. Group 6 - Miscellaneous adverse reactions to mushrooms. Syndromes which do not fit within the previous 5 groups: 6A, Shiitake mushroom dermatitis; 6B, erythromelagic mushrooms (Clitocybe acromelagia); 6C, Paxillus syndrome (Paxillus involutus); 6D, encephalopathy syndrome (Pleurocybella porrigens).

A comprehensive approach to managing a neglected, neglected tropical disease; The Myanmar Snakebite Project (MSP).

Snakebite is predominantly an occupational disease affecting poor rural farmers in tropical regions and was recently added to the World Health Organisation list of Neglected Tropical Diseases (NTD). We document an overview of methodologies developed and deployed in the Myanmar Snakebite Project, a foreign aid project largely funded by the Australian Government, with the core aim to "improve outcomes for snakebite patients". A multidisciplinary team of experts was assembled that worked in a collaborative manner with colleagues in Myanmar, first to identify problems related to managing snakebite and then develop interventions aimed to improve selected problem areas. A broad approach was adopted, covering antivenom production, antivenom distribution and health system management of snakebite. Problems identified in antivenom production included poor snake husbandry resulting in poor survival of captive specimens, lack of geographical diversity; poor horse husbandry, resulting in high mortality, inadequate stock acquisition protocols and data collection, and inappropriate immunisation and bleeding techniques; and inadequate production capacity for freeze dried antivenoms and quality control systems. These problems were addressed in various ways, resulting in some substantial improvements. Antivenom distribution is being reorganised to achieve better availability and utilisation of stock. Health system management of snakebite was assessed across all levels within the area selected for the study, in Mandalay region. A comprehensive community survey indicated that hospital statistics substantially underestimated the snakebite burden, and that access to care by local villagers was delayed by transport and cost issues compounded by lack of antivenom at the most peripheral level of the health service. A health system survey confirmed under-resourcing at the local village level. Prospective case data collection initiated at tertiary hospitals indicated the extent of the snakebite burden on health resources. Interventions initiated or planned include training of health staff, development of a core of senior trainers who can "train the trainers" nationwide in a sustainable way, development and deployment of management guidelines and algorithms for snakebite and a distribution of solar powered fridges to remote health facilities to allow storage of antivenom and prompt treatment of snakebite cases before transfer to major hospitals, thereby reducing the "bite to needle" time.

Twelve month prospective study of snakebite in a major teaching hospital in Mandalay, Myanmar; Myanmar Snakebite Project (MSP).

The Myanmar Snakebite Project is an Australian government (Department of Foreign Affairs and Trade) supported foreign aid project in collaboration with the Myanmar government with the aim of improving outcomes for snakebite patients in Myanmar. As part of the project a case record database was established to document prospective cases of snakebite presenting to Mandalay General Hospital, in Upper Myanmar. The study period was 12 months (1-2-2016 to 31-1-2017). Snake identity was based on a mixture of identified dead snakes brought with patients, doctor's clinical opinion and patient identification. 965 patients were enrolled during the 12 month period, of whom 948 were included for analysis. The male: female ratio was 1.58:1. Most cases involved bites to the lower limbs (82.5%) and adults involved in farm work, confirming snakebite as an occupational disease in this community. Motorised transport was by far the most common form of transport to health care and most patients sought care from the health system (87.7%), not traditional healers (11.5%) as their first point of contact. The officially promoted application of a pressure pad, bandage and immobilisation as first aid for snakebite was almost never used, while most patients used some form of tourniquet (92.0%). 85.4% of cases where a snake ID was listed were bitten by Russell's vipers. Russell's viper bites were responsible for all fatalities (9.8% of cases) and all cases of Acute Kidney Injury (AKI). For all cases, clinical features included local swelling (76.5%), local pain (62.6%), AKI (59.8%), incoagulable blood (57.9%), regional lymphadenopathy (39.8%), nausea/vomiting (40.4%), thrombocytopenia (53.6%), abdominal pain (28.8%), shock (11.8%), secondary infection (8.6%), panhypopituitarism (2.1%). AKI required renal replacement therapy (RRT) in 23.9% of cases, all ascribed to Russell's viper bite. Green pit viper bites were the next most common cause of bites (7.6%) and were associated with incoagulable blood (29%) and occasionally shock (5%) and local necrosis (3%), and in one case AKI not requiring RRT. In contrast to Russell's viper bites, green pit viper bite was most likely to occur in the home (49%). Some green pit viper patients were treated with Russell's viper antivenom (15%), presumably because they had incoagulable blood, although this antivenom is not effective against green pit viper envenoming. For the entire patient group, antivenom was given in 80.5% of cases. The most common indications were presence of coagulopathy/non-clotting blood (59.8%), local swelling (47.4%), oliguria/anuria (19.8%), heavy proteinuria (19.4%). A febrile reaction to antivenom was reported in 47.9% of cases, while anaphylaxis, occurred in 7.9% of cases.

Inadequate knowledge about snakebite envenoming symptoms and application of harmful first aid methods in the community in high snakebite incidence areas of Myanmar.

INTRODUCTION: Every year millions of people in developing countries suffer from snakebite, causing a large number of deaths and long term complications. Prevention and appropriate first aid could reduce the incidence and improve the health outcomes for those who suffer bites. However, many communities where snakebite is a major issue suffer from a lack of information about prevention and first aid measures that a family or community member could take to prevent severe envenoming, complications and poor outcomes. Myanmar suffers from a high burden of snakebites with a large number of deaths. As part of a health services and community development program, a community survey was conducted to identify communities' knowledge about snakebite and their sequelae, and knowledge and practice about first aid and health services use. METHOD: 4,276 rural residents of Kyaukse and Madaya townships in the Mandalay region were recruited by cluster sampling, involving random selection of 144 villages and random sampling of 30 households from each village. One adult member of each household was interviewed using a structured questionnaire. RESULTS: The incidence of snakebite was 116/100,000 people. Respondents reported 15 different types of snakes in the area, with Russell's Viper, Cobra and Green snakes as the most common. 88% of the people informed that working in the fields and forests was when most of the bites occur. A majority knew about snakebite prevention methods such as wearing long boots. However, only a few people knew about the specific symptoms caused by snakebites. Only 39% knew about the correct methods of first aid. More than 60% mentioned tourniquet as a first aid method, though this may cause significant complications such as ischaemia of the limb. 88% said that they would take a snakebite victim to a government hospital, and 58% mentioned availability of antivenom as the reason for doing this. At the same time, the majority mentioned that traditional methods existed for first aid and treatment and 25% mentioned at least one harmful traditional method as an effective measure that they might use. CONCLUSION: The community is aware of snakebites as a major public health issue and know how to prevent them. However, the high incidence of snakebites point to lack of application of preventive methods. The community recognise the need for treatment with antivenom. However, inadequate knowledge about appropriate first aid methods, and a reliance on using tourniquets require a targeted education program. Existing knowledge in communities, albeit insufficient, provides a good starting point for mass media educational campaigns.

Local morbidity from red-bellied black snake (Pseudechis porphyriacus, Elapidae) envenoming: Two cases and a brief review of management.

The red-bellied black snake (Pseudechis porphyriacus, Elapidae) is one of several species of venomous snakes most commonly implicated in human and domestic animal envenoming in Australia. Human systemic envenoming can present with myotoxicity that may include myoglobinuria; hemoglobinuria and intravascular hemolysis; thrombocytopenia, anticoagulant coagulopathy, and, rarely, mild cranial nerve palsies. Pseudechis porphyriacus envenoming can also feature significant local morbidity such as ecchymoses, bleeding, pain and necrosis. Some envenomed patients may develop progressive thickness necrosis independent of secondary infection, and occasionally require surgical debridement. Uncommonly, some digital envenoming may cause more severe deeper tissue pathology that justifies dermotomy and/or distal phalangeal amputation. Presented are two patients with significant local morbidity from P. porphyriacus envenoming. An 18-month old girl received a protracted envenoming on her right foot, while a 38-year old male professional zoologist was envenomed on the third digit of his right hand. Each patient experienced myotoxicity, one had anticoagulant coagulopathy, and both developed clinically significant local morbidity including persistent bleeding, ecchymoses, local necrosis and pain; each required extensive treatment and variably prolonged admission. Noted also were transiently elevated D-dimer with low-normal or normal fibrinogen levels. The progressive necrosis and subsequent chronic pathologic changes with ischemia of the latter patient's digit eventually required a dermotomy and amputation of the distal phalanx. The pediatric patient did not require extensive wound debridement, but experienced prolonged difficulty in ambulation because of slowly resolving wound discomfort. Factors that may contribute to the severity of local morbidity of P. porphyriacus envenoming are considered, and management of envenoming by this taxon is briefly reviewed.

Development of an ELISA assay to determine neutralising capacity of horse serum following immunisation with Daboia siamensis venom in Myanmar.

Snakebite envenoming is a serious problem in Myanmar. The great majority of snakebite in this country is due to Russell's Viper (Daboia siamensis). For many years, the Burma Pharmaceutical Industry has produced a monovalent antivenom to Russell's Viper in horses. At present, the only way of determining the level of antibody against D. siamensis venom in hyperimmune horse serum is to perform venom neutralisation tests in mice. In this study, we describe the development of an in vitro ELISA assay to estimate neutralising capacity of horse serum. We found a strong correlation between the ELISA assay and the venom neutralisation test in mice (r = 0.982). The assay is robust and has sufficient sensitivity (92%) and specificity (96%) to replace the venom neutralisation test in mice during the immunisation phase in horses.