A double-blind, randomized trial of intravenous versus intramuscular antivenom for red-back spider envenoming

Objective: To compare the efficacy of intravenous versus intramuscular antivenom (AV) in the treatment of Red‐back spider (RBS) envenoming. Methods: Randomized, double‐dummy, double‐blind, multicentre trial of patients with red‐back spider envenoming requiring AV treatment recruited from five hospital EDs in Western Australia. Results: Thirty‐five patients were recruited; two were excluded; 33 were available for initial analysis, but two who were unblinded after one ampoule of trial AV and given i.v. AV had limited data; 31 remained in the study and had more complete data. After AV, pain scores for both i.m. and i.v. groups improved rapidly. At 24 h, the i.v. group was better with a 55% absolute difference (76% vs. 21%; 95% CI 25–85% difference) in the proportion pain‐free. There were no safety issues. Conclusions: Red‐back spider antivenom was initially effective by both i.m. and i.v. routes. The study generates the hypothesis that at 24 h, significantly more patients are pain‐free with i.v. administration. Definitive recommendations on the optimal route of administration of RBS AV await the results of further studies.     

Red‐back spider envenomation in children in Central Australia

Objective: To describe the clinical spectrum of Red‐back spider (RBS) envenomation in children up to 12 years of age. Methods: Retrospective case notes review of children with a discharge diagnosis of RBS bite from January 1992 to June 2001. The setting was Alice Springs Hospital, the main paediatric hospital for the whole region of Central Australia. The patients were 54 children, comprising 39 Aboriginal and 15 non‐Aboriginal children. Results: Forty‐six (85%) children had systemic envenomation. The three most common systemic features are irritability, hypertension and sweating; 35 (65%) children had all three systemic features. Forty‐five (83%) received antivenom therapy. The clinical characteristics and outcomes showed no significant difference between children  4 and > 4 years of age. Conclusions: There is a high incidence of systemic envenomation due to RBS bite in children in Central Australia. The triad of irritability, hypertension and sweating in a previously well child is highly suggestive of latrodectism.     

Route of administration of redback spider bite antivenom: determining clinician beliefs to facilitate Bayesian analysis of a clinical trial

Objective: To determine current beliefs of Australasian emergency physicians, to form the basis of ‘stopping rules’ for a clinical trial of intravenous (i.v.) versus intramuscular (i.m.) redback spider antivenom. Methods: An email survey of fellows and trainees of the Australasian College for Emergency Medicine. Results: There were 218 responses; 30% used the i.v. route exclusively, 16% used the i.m route exclusively, 17% used i.m. followed by i.v. if there was a poor initial clinical response, and 38% stated that they had no particular preference. The probability given by respondents that the i.v. route is superior allowed us to differentiate ‘i.v. enthusiasts’ from ‘i.v. sceptics’. Median predicted response rates were 90% versus 80% for the i.v. route and 60% versus 75% for the i.m. route in the enthusiastic and sceptical groups, respectively. The median expected absolute advantage of i.v. compared with i.m. antivenom was 20% versus 5%, respectively. The median number‐needed‐to‐treat threshold that would lead respondents to choose the i.v. route in preference to the i.m. was 5. Conclusion: Australasian emergency physicians have polarized views on the optimal route for administering redback spider antivenom. We were therefore able to define both sceptical and enthusiastic priors for a fully Bayesian trial analysis. Our findings support using a number needed to treat of 5 (20% absolute advantage) for powering a clinical study and for determining the point at which it should be stopped.     

Towards rationalisation of antivenom use in funnel-web spider envenoming: enzyme immunoassays for venom concentrations

Context: Funnel-web spider (Atrax and Hadronyche spp.) envenoming is rare but causes severe neuromuscular, autonomic, and cardiac effects. A rabbit-derived IgG antivenom is available, but venom detection in patients has not been reported. Objective: To use serial venom and antivenom concentrations to better define envenoming and antivenom effectiveness. Materials and methods: Serum was collected from nine patients with suspected funnel-web spider bites and clinical effects were recorded. Venom-specific enzyme immunoassays were developed to measure funnel-web spider venom and antivenom concentrations. Goat anti-rabbit whole serum was coupled to UltraLink resin and added to samples to remove bound venom and measure free venom. Antivenom efficacy was defined as antivenom binding all free venom and antivenom effectiveness as resolution of clinical features. Results: Venom was detectable in samples from six of nine patients. In three patients without venom detected, there were only moderate effects, which did not completely respond to antivenom in all cases and no spider was identified. In five of six cases, a male Atrax spp. (Sydney funnel-web) spider was identified. Three patients had moderate envenoming which responded to antivenom. Three patients had severe envenoming and developed catecholamine-induced myocarditis and acute pulmonary oedema. Although cholinergic and non-specific clinical features appeared to respond to antivenom, myocarditis and pulmonary oedema lasted 2–4 days. Median venom concentration pre-antivenom in five patients with samples was 5.6 ng/ml (3–35 ng/ml), and immediately post-antivenom decreased to a median of 0 ng/ml (0–1.8 ng/ml). Post-antivenom venom concentrations decreased when bound venom was removed; median, 0 ng/ml (0–0.9 ng/ml), indicating that most venom detected post-antivenom was bound. There was recurrence of venom and clinical features in one patient when a pressure bandage was removed. Conclusions: Detection of venom in suspected funnel-web spider bites identified definite cases with characteristic envenoming and a spider was identified. Measurement of venom concentrations pre- and post-antivenom demonstrated that venom was bound by antivenom, but in severe cases cardiac toxicity was not reversed.     

Evolution in the choice of therapies used to treat latrodectism: Redback spider antivenom or standard analgesic medications. Nothing to rave about

Objectives

Redback spider (RBS) antivenom (RBSAV) use appears to have decreased since the results of the RAVE-2 antivenom efficacy study were released. The aims of this study were to assess change in RBSAV use over time and compare responses to treatment for antivenom and other analgesics.

Methods

Retrospective audit of RBS bite referrals to a toxicology unit, from January 2010 to January 2022. Data included demographics, pain severity, treatment (analgesia or RBSAV), response to treatment, re-presentation rate, adverse events, change in antivenom use over time.

Results

Of 270 presentations, 157 with moderate or severe pain were included (RBSAV n = 51, analgesia n = 106). Median age was 39 years, n = 81 (51%) female. Those receiving antivenom were more likely to report severe pain n = 46/51 (84%) versus n = 68/106 (58%) (P = 0.006). Eighty-three percent of antivenom doses were administered between 2010 and 2013. Analgesia-only group received various combinations of paracetamol, NSAIDs, and opioids. In those receiving RBSAV, 17/48 (35%), 26/48 (54%), 5/48 (10%) reported a partial, complete or no reduction in pain, respectively, versus 30/77 (39%), 43/77 (58%) and 4/77 (5%), for analgesia-only group. Post-treatment pain was not recorded in three RBSAV and 28 analgesia-only patients. Pain reduction was no different for intravenous and intramuscular antivenom. Re-presentation for ongoing pain was more common in the analgesia-only group, 16/106 (15%) versus 1/51 (2%) for antivenom (P = 0.013).

Conclusion

Antivenom use fell over the study period. There was no difference in pain relief between RBSAV and analgesia-only groups. RBSAV, regardless of route of administration, was no better than standard analgesics in pain reduction in the present study.     

Successful treatment of presumed death‐adder neurotoxicity using anticholinesterases

We present the first reported case in Australia of anticholinesterases being used successfully in conjunction with antivenom to treat neurotoxicity following death‐adder envenomation. A 49‐year‐old man was bitten by his pet death adder. He developed significant neurotoxicity due to delayed presentation and suboptimal first aid. Following one ampoule of polyvalent antivenom which produced an allergic reaction, administration of neostigmine and atropine facilitated aeromedical evacuation without the need for mechanical ventilation. After three ampoules of monovalent death‐adder antivenom at the receiving hospital, antivenom supplies were exhausted. Further neostigmine and atropine resulted in complete resolution of paralysis, allowing discharge. Anticholinesterases may reduce the dose of antivenom required to treat death‐adder envenomation. They may also be of use in cases of allergic reactions to antivenom, and in reducing the need for endotracheal intubation.     

Tiger‐snake antivenom for suspected small‐eyed snake envenomation

Despite its relative frequency and widespread distribution throughout eastern Australia, bites by the nocturnal eastern small‐eyed snake, Cryptophis nigrescens, have seldom been recorded. There is no standard laboratory test or proven antidote for its venom, which is capable of causing life‐threatening myolysis in humans. A 39‐year‐old man presenting to hospital with acute abdominal and limb muscle pains, was noted to have a pair of puncture wounds on his leg. No venom was detected in the urine with the Commonwealth Serum Laboratories’ Venom Detection Kit. The only blood abnormality was a grossly elevated creatine kinase at 48 000 IU/L. A presumptive diagnosis of Cryptophis nigrescens envenomation was made and the patient treated with tiger‐snake antivenom (3000 U). Creatine kinase levels started to fall almost immediately and the patient made a full recovery. We believe this is the first time tiger‐snake antivenom has been used specifically for suspected Cryptophis nigrescens envenomation.     

Suspected snakebite: One year prospective study of emergency department presentations

Aim: Snakebite is an uncommon, but potentially life‐threatening condition. The more common clinical scenario is suspected snake‐bite. Our aim was to characterise the epidemiology, diagnosis and management of patients with suspected snakebites. Methods: Prospective cohort study of patients presenting with suspected snakebites to a tertiary referral hospital serving a large rural region in tropical northern Australia where a standard admission protocol for suspected snakebites is used. Results: Of 70 suspected snakebite cases, there were 45 definite bites: three severe envenomings (two western brown snakes [Pseudonaja nuchalis] and one mulga snake [Pseudechis australis]); seven mild/moderate envenomings by other snakes, two non‐envenomings by identified P. nuchalis, five bites by identified non‐venomous snakes and 28 definite bites without envenoming. The remaining 25 cases were either suspected bites (8), unlikely bites (15) and two people hit by snakes. Definite snake‐bites occurred throughout the year, peaking in May and December. There were three severe envenomings (mainly coagulopathy), requiring antivenom treatment, but no deaths or major complications. Most patients had appropriate investigations. Of 47 venom detection kit swabs collected, 34 were not tested, venom was not detected in nine and was positive in the three envenomings with one false‐positive tiger snake. Whole blood clotting time was highly sensitive for procoagulant coagulopathy and envenoming in this study. Median length of time from the bite to discharge was 20 h (interquartile range: 12–27). Conclusions: The study shows that although suspected snakebite was common, severe envenoming occurred in less than 5% of cases. The study supports the proposition that a structured approach and admission policy of suspected snakebites leads to the appropriate management of severe envenoming, with no cases discharged early and no cases of non‐envenoming treated with antivenom.     

Mild snake envenomation

Snake bite envenomation typically requires treatment with effective first aid and antivenom. There is a spectrum of envenomation seen, which includes mild envenomation, but this has not been reported previously. We report two cases of mild envenomation and describe the changes in laboratory coagulation values. The patients had a benign clinical course without receiving antivenom. We strongly recommend that if clinicians are considering not treating any envenomated patients with antivenom, they do so only on expert advice.     

Recurrent,persistent, or late,new-onset hematologic abnormalities in Crotaline snakebite

Background.?Hematologic effects from rattlesnake envenomation exhibit a phenomenon of recurrent, persistent or late, new onset (late) abnormalities in some Fab antivenom‐treated patients 4 or more days post‐envenomation. Indicators that reliably identify or exclude those patients at risk of late hematologic effects have not been developed.

Methods.?This was a retrospective, observational case series of rattlesnake bite records at two US poison centers. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for D‐dimer, fibrinogen, platelets, platelet count trend, INR and PTT associated with late hematologic abnormalities, were determined.

Results.?Three hundred seventy six cases were reviewed. Sixty cases met inclusion criteria. Overall, 17 of 60 patients (28%) had a hematologic abnormality as a result of envenomation. Eleven of 60 patients (65% of those with a hematologic abnormality; 18% overall) developed late hematologic abnormalities 4 or more days post‐envenomation. Four patients had late, new onset hypofibrinogenemia and/or thrombocytopenia. All were associated with early D‐dimer elevation and/or platelet rise in response to FabAV treatment, respectively. Normal hematologic parameters in the first 48 h post‐envenomation and the lack of a greater than 20% rise in platelets within 4 h post‐antivenom administration had a 100% NPV for late hematologic effects.

Conclusions.?Patients with early onset hypofibrinogenemia, a positive D‐dimer, thrombocytopenia, or a 20% increase in platelet count within 4 h post‐treatment had a significant likelihood of late hematologic effects. Patients in whom fibrinogen, D‐dimer, INR, PTT, and platelet counts remained normal throughout the first 48 h post‐envenomation, and who did not exhibit a >20% increase in platelet count within 4 h post‐antivenom administration, did not develop late hematologic effects.     

Cutaneous loxoscelism caused by Loxosceles anomala

A previously healthy 35-year-old female was bitten on the anterior right thigh by a brown spider while dressing her trousers; the spider was stored and later identified as an adult female Loxosceles anomala. Clinical evolution involved a relatively painless bite with mild itching, followed by local, indurated swelling and a transient, generalized erythrodermic rash at 24 h post-bite. The local discomfort was progressive, and involved changes in the lesion pattern, with pain of increasing intensity. The patient was admitted 60 h post-bite, showing an irregular blue plaque surrounded by an erythematous halo lesion, located over an area of indurated swelling. Considering the presumptive diagnosis of cutaneous loxoscelism, she was treated with five vials of anti-arachnidic antivenom i.v. without adverse effects. There was progressive improvement, with no dermonecrosis or hemolysis; complete lesion healing was observed by Day 55. The clinical features and outcome were compatible with cutaneous loxoscelism and similar to those reported for other Loxosceles species.     

The clinical effects of spider bites in southern Tasmania

Objectives: To analyse the clinical features and outcomes of patients with spider bites who presented to the Department of Emergency Medicine, Royal Hobart Hospital, Tasmania, Australia. Methods: A retrospective study of all patients with an emergency department discharge diagnosis of confirmed spider bite during a 5 year period was performed. Results: Twenty-two cases were identified, 15 of which involved unidentified spiders. Most victims were in the 15–34 years age group and were bitten in the home. Identified spiders included: redback (Latrodectus hasselti), white-tailed house (Lampona cylindrata), black house (Badumna insignis) and huntsman (Delena cancerides). Pain, swelling and erythema were the main presenting symptoms; main presenting signs were erythema, swelling, bite marks, local tenderness, lymphadenopathy and blistering. In 23% of cases, no clinical signs were detectable. Treatment consisted of antihistamines (36%) and antibiotics (32%). Four patients had signs consistent with necrotizing arachnidism; two of the four healed with hyperbaric oxygen after antibiotic treatment failed. Redback antivenom was administered to four patients. Three patients required in-patient treatment for local complications. Conclusions: Most spider bites presenting to Royal Hobart Hospital were uncomplicated; redback bites were uncommon. Treatment strategies were ill-defined and microbiological specimens were taken infrequently. Patients’ tetanus immunization status was poorly documented. There is a need for a national register of spider bites in Australia.     

Intradermal Anti-Loxosceles Fab Fragments Attenuate Dermonecrotic Arachnidism

OBJECTIVE: Bites from the brown recluse spider and other arachnids from the genus Loxosceles frequently induce necrotic skin lesions that can be recalcitrant to treatment and disfiguring. The authors used a rabbit model of dermonecrotic arachnidism to address the therapeutic efficacy of intradermal (id) polyclonal anti-Loxosceles Fab fragments (alphaLoxd Fab) raised against Loxosceles deserta spider venom. METHODS: Fab fragments were prepared by papain digestion and affinity chromatography from the IgG fraction of L. deserta antivenom raised in rabbits. Eighteen inbred New Zealand white rabbits were assigned to six groups of three. The rabbits received L. deserta venom (3 microg, id) injections into each flank. Cohorts of rabbits received single id injections (at one venom site/rabbit) of 30 microg alphaLoxd Fab at different times (T = 0, 1, 2, 4, 8, and 12 hours) after venom injection. In each rabbit the opposite flank was left untreated. As an additional control, one group of rabbits (T = 0) received nonspecific Fab (30 microg, id) in the opposite flank. Dermal lesions were quantified as a function of time through the use of a series of digital photographs and imaging software. In addition, myeloperoxidase (MPO) activity, a measure ofneutrophil accumulation, was determined in lesion biopsies. Lesion areas and MPO activities were analyzed by repeated-measures analysis of variance (ANOVA). RESULTS: Lesion areas and MPO activity were markedly reduced when alphaLoxd Fab was administered very early after venom injections. As the interval between venom inoculation and antivenom treatment increased, the therapeutic benefit of alphaLoxd Fab decreased. The final time tested that demonstrated therapeutic efficacy of alphaLoxd Fab was T = 4 hours. Lesion attenuation was no longer apparent when alphaLoxd Fab was given 8 hours post inoculation. CONCLUSIONS: Intradermal administration of alphaLoxd Fab attenuates Loxosceles-induced dermonecrotic lesion formation when given up to 4 hours after venom inoculation in this rabbit model.     

肌内效贴对离心收缩诱发的踝关节肌肉疲劳后的肌力和平衡能力的影响

目的:探讨肌内效贴贴扎对离心运动诱发的踝关节周围肌群疲劳后肌肉力量以及静态平衡能力的即刻影响。方法:受试对象为45名健康男性大学生,将受试者随机分成3组各15例进行不同测试(正常组、肌肉疲劳组以及肌内效贴组)。其中,正常组直接进行肌力与平衡测试;肌肉疲劳组在BIODEX等速训练仪的离心/离心的训练方式下进行连续的踝背伸及跖屈进而诱导肌肉疲劳,当疲劳出现时立即进行肌力与平衡测试;肌内效贴组采用与肌肉疲劳组相同的训练方法,在疲劳后即刻接受肌内效贴贴扎随后进行肌力与平衡测试,包括：向心模式60°/s和180°/s速度下的等速肌力和睁眼/闭眼状态下的静态平衡测试。结果:在等速肌力方面,肌肉疲劳组60°/s与180°/s跖屈、背伸各项肌力指标均较正常组降低(均P<0.05);肌内效贴组60°/s跖屈峰力矩与平均功率、60°/s背伸峰力矩、平均峰力矩、平均功率均较肌肉疲劳组增加(均P<0.05)。180°/s跖屈平均峰力矩、背伸平均峰力矩、平均功率均较肌肉疲劳组增加(均P<0.05),肌内效贴组背伸峰力矩较正常组降低(P<0.05)。在静态平衡方面,在睁眼状态下肌肉疲劳组Y...     

Clotting factor replacement and recovery from snake venom-induced consumptive coagulopathy

Introduction  Using clotting factors (fresh frozen plasma and/or cryoprecipitate) to treat snake venom-induced consumptive coagulopathy (VICC) is controversial. We aimed to determine if factor replacement after antivenom is associated with an earlier return of coagulation function. Methods  We retrospectively analysed VICC cases due to brown snake (genus Pseudonaja), tiger snake (Notechis, Tropidechis, and Hoplocephalus), and taipan (Oxyuranus) envenoming. Recovery of international normalized ratio (INR)/prothrombin time (PT) was compared between patients who did not receive factor replacement and those who did, and between patients who received factor replacement ≤ 4 h of commencing antivenom and those who received factor replacement later or not at all. Results  There was no significant difference between cases receiving clotting factors and cases that did not, however in 21 cases having factor replacement within 4 h, the median time to coagulation recovery was 4.6 h (interquartile range [IQR] 3.5–8.8), versus 9.5 h (IQR 7.3–13) in 106 cases who had clotting factors later or not at all (P < 0.001). No serious adverse effects attributed to clotting factors were recorded. Recovery by 6 h after starting antivenom was also more likely in those who were younger, in tiger snake envenoming, and where the interval between bite and starting antivenom was longer. The initial dose of antivenom did not appear to influence the likelihood of recovery at 6 h. Conclusion  Early factor replacement after antivenom is associated with earlier improvement of coagulation function. Randomised controlled clinical trials to determine the efficacy and safety of factor replacement for VICC after venom neutralisation are required. On behalf of the ASP investigators. This article is discussed in the editorial available at: doi:.     

Mulga snake (Pseudechis australis) envenoming: a spectrum of myotoxicity,anticoagulant coagulopathy,haemolysis and the role of early antivenom therapy – Australian Snakebite Project (ASP-19)

Context. Mulga snakes (Pseudechis australis) are venomous snakes with a wide distribution in Australia. Objective. The objective of this study was to describe mulga snake envenoming and the response of envenoming to antivenom therapy. Materials and methods. Definite mulga bites, based on expert identification or venom-specific enzyme immunoassay, were recruited from the Australian Snakebite Project. Demographics, information about the bite, clinical effects, laboratory investigations and antivenom treatment are recorded for all patients. Blood samples are collected to measure the serum venom concentrations pre- and post-antivenom therapy using enzyme immunoassay. Results. There were 17 patients with definite mulga snake bites. The median age was 37 years (6–70 years); 16 were male and six were snake handlers. Thirteen patients had systemic envenoming with non-specific systemic symptoms (11), anticoagulant coagulopathy (10), myotoxicity (7) and haemolysis (6). Antivenom was given to ten patients; the median dose was one vial (range, one–three vials). Three patients had systemic hypersensitivity reactions post-antivenom. Antivenom reversed the coagulopathy in all cases. Antivenom appeared to prevent myotoxicity in three patients with high venom concentrations, given antivenom within 2 h of the bite. Median peak venom concentration in 12 envenomed patients with samples was 29 ng/mL (range, 0.6–624 ng/mL). There was a good correlation between venom concentrations and the area under the curve of the creatine kinase for patients receiving antivenom after 2 h. Higher venom concentrations were also associated with coagulopathy and haemolysis. Venom was not detected after antivenom administration except in one patient who had a venom concentration of 8.3 ng/ml after one vial of antivenom, but immediate reversal of the coagulopathy. Discussion. Mulga snake envenoming is characterised by myotoxicity, anticoagulant coagulopathy and haemolysis, and has a spectrum of toxicity that is venom dose dependant. This study supports a dose of one vial of antivenom, given as soon as a systemic envenoming is identified, rather than waiting for the development of myotoxicity.     

Review article: Let us talk about snakebite management: A discussion on many levels

We want to discuss antivenom use in snakebite clinical practice guidelines. Coronial reviews in Victoria of two cases of snakebite envenomation, one described in detail below, prompted us to submit this paper for a wider audience and debate. Venom and antivenom levels were measured in the case detailed below, but not in the other. The coroner received conflicting and varied advice from experts regarding the dose of antivenom. The Victorian Department of Health and Human Services and the Australasian College for Emergency Medicine were instructed to review snakebite management guidelines, particularly with respect to antivenom dosage. The discussion that took place among medical experts led to considerable media attention. We discuss the potential fallout when there is no consensus among medical experts.     

Safety profile of snake antivenom (use) in Hong Kong – a review of 191 cases from 2008 to 2015

Introduction: The mainstay of treatment for significant envenoming from snakebites is antivenom. However, there is insufficient data regarding the safety of antivenom used in Hong Kong. We describe the incidence of hypersensitivity reactions from antivenom use and review the frequency and reasons for intensive care unit (ICU) admission.

Methods: The Hong Kong Poisons Information Centre database was reviewed. All patients given snake antivenom between 2008 and 2015 were included. Patient demographics, species of snake involved, details of antivenom used, treatment location, use of pre-treatment, reasons for ICU admission (where applicable) and details of early and late antivenom reactions were extracted.

Results: There were 191 patients who received snake antivenom. Most (93%) were treated with either the green pit viper antivenom from Thailand or the Agkistrodon halys antivenom from China. The incidences of early hypersensitivity reactions to green pit viper antivenom and Agkistrodon Halys antivenom were 4.7% and 1.4%, respectively. Most patients (69%) were managed in the ED observation ward or general ward. There were 59 patients managed in ICU, most (90%) of whom were admitted for close monitoring during antivenom administration. There were no cases of significant morbidity from antivenom administration. Eight patients (5.6%) had features suggestive of mild serum sickness.

Conclusions: The incidence of immediate hypersensitivity reaction to antivenom commonly used in Hong Kong is low. Majority of patients were managed safely in the emergency department observation ward or general ward. Serum sickness appears to be uncommon and possible cases presented with mild features.