- Title
- Snake envenoming in Australia and beyond: investigating clinical presentation, myotoxicity and the role of early antivenom
- Creator
- Johnston, Christopher Ian
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2024
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Background: Over 760 venomous snake species have been identified worldwide. Snake envenoming is an important health issue in many tropical and sub-tropical regions of the world and is a neglected area of research and resource allocation. Australia has an often feared and diverse snake fauna. The epidemiology, clinical presentation, management of snakebite and associated mortality in Australia is poorly described. Little published evidence exists, which lead to care of patients being dependent on guidance from case reports of unconfirmed snake types and overseas experience. Myotoxicity resulting from Australian snake envenoming is of unknown incidence and is not well characterised. Current management of envenoming from two types of snakes known to cause myotoxicity, taipans (Oxyuranus spp.) and sea snakes (Hydrophiini) is based on overseas experience with different species from Papua New Guinea (PNG) and Malaysia, respectively, with need for clinical evidence from Australian cases to confirm management principles. Early antivenom is a goal of therapy to help prevent the establishment of envenoming syndromes in envenomed patients. Additional biomarkers are necessary to help guide the early management of myotoxicity as the current gold standard for diagnosis, creatine kinase (CK), is slow to demonstrate evidence of muscle damage. Snake envenoming is a major health issue in Sri Lanka. The common krait (Bungarus caeruleus) and Russell’s viper (Daboia russelii) are two important snake types in Sri Lanka responsible for many cases of envenoming. The incidence and severity of myotoxicity resulting from envenoming from these snake types is inadequately described. Aims and objectives: 1. To investigate the epidemiology, clinical presentation, investigation, management, outcomes and mortality of snakebite in Australia and any change in these parameters over time. 2. To investigate the incidence, clinical presentation and severity of myotoxicity resulting from Australian snake envenoming and the impact of antivenom therapy. 3. To investigate the clinical effects of Australian taipan (Oxyuranus spp.) envenoming and the impact of antivenom therapy on its severity. 4. To investigate the clinical effects of Australian sea snake (Hydrophiini) envenoming and the impact of antivenom therapy on its severity. 5. To investigate the predictive value of several novel biomarkers in the detection of Australian myotoxic snake envenoming relative to the gold standard current biomarker in an animal mode of myotoxicity. 6. To investigate the incidence and severity of myotoxicity resulting from common krait (B. caeruleus) and Russell’s viper (D. russelii) envenoming in Sri Lanka. Methodology: Patients with snakebite in Australia were recruited to the Australian Snakebite Project (ASP). ASP is a prospective observational study that recruits all patients from age two and up with suspected or confirmed snakebite. Patients are referred for recruitment by the National Poisons Information Centre network or by local investigators in hospitals. Data is collected on demographic, bite circumstance, first aid, clinical presentation, investigation, management, and resolution of envenoming. Signs and symptoms are classified according to pre-defined envenoming syndromes. Patient blood samples are taken and frozen for later analysis. Venom specific enzyme immunoassay is performed to confirm identity of snake venom and quantify venom on presentation, during hospital stay and after antivenom. Snake species confirmation is based on this assay or professional identification of the snake. Data is entered into a Microsoft Access relational database. As of December 2023, over 2574 patients from 390 hospitals have been recruited to ASP. In addition to the analysis detailed within this thesis, I have also been involved with participating in an on-call roster for the study phone (one out of two) to assist the treating hospital with recruitment and laboratory steps, participation in the completion of some of the venom specific enzyme immunoassay and completion of all of the biomarker assays contained within this thesis. Patients were identified from the ASP database and individual study methods are as follows: • 10 years of snakebite in Australia: All patients that were recruited to ASP between July 2005 and June 2015 were included. Outcomes assessed were demographic data, bite circumstances, clinical effects of envenoming, results of laboratory investigations and snake venom detection kits, treatment administration, response and adverse events, time to treatment and discharge, and mortality. In addition to the ASP dataset, the National Coronial Information System was accessed and searched for same period, with cases manually reviewed and included. • Australian snakebite myotoxicity: All patients that were recruited to ASP between January 2003 and December 2016 with envenoming and biochemical evidence of myotoxicity (CK >1000 U/L) were included. For comparison, patients without evidence of envenoming and peak CK >1000 U/L were also analysed. Data analysed included patient demographics, clinical and biochemical characterisation of myotoxicity including specific and non-specific symptoms, biomarker evidence of myotoxicity, characteristics of biomarker deviation, treatment, impact of time to antivenom and health resource utilisation (length of hospital stay, need for management of complications). • Australian taipan (Oxyuranus spp.) envenoming: All cases of potential taipan envenoming were identified from the database. Confirmation of cases occurred with either professional identification or venom-specific enzyme immunoassay, and analysis of demographic, bite circumstance, taipan species, clinical effects, treatment, time to hospital discharge and venom assays was carried out on confirmed cases. • Australian sea snake (Hydrophiini) envenoming: All cases of potential sea snake bite were extracted from the database. Due to lack of venom specific enzyme immunoassay for all sea snakes, cases of presumed sea snake were included in the analysis based on 1) expert ID of the snake or 2) witnessed bite by a snake with a paddle shaped tail close to, or in, coastal waters. Data analysed included demographics, bite circumstance, clinical presentation, serial laboratory investigation, treatment, and time to discharge. • Novel biomarker analysis was carried out on a rat model of Australian myotoxic snake envenoming. Rats were anaesthetised and provided with ventilatory, circulatory and temperature support. Rats were then administered either tiger snake (Notechis scutatus) venom, red-bellied black snake (Pseudechis porphyriacus) venom or placebo (saline). Blood samples were taken at baseline and every 2 hours until 10 hours. Assays were performed on blood samples including the gold standard for skeletal muscle injury, CK, as well as several novel biomarkers of myotoxic snake envenoming: CK-MM, skeletal troponin-I, skeletal troponin-C, skeletal myosin light chain-1 and myoglobin. Comparison was made of biomarker response between placebo and venom administered rats. Diagnostic value of the biomarkers at detecting myotoxic snake envenoming versus CK was completed with the use of receiver operating characteristic curves and assessment of AUC of these curves. • Biochemical assessment of myotoxicity in patients with Sri Lankan common krait (B. caeruleus) and Russell’s viper (D. russelii) envenoming was carried out on samples from patients that had been recruited via a snakebite study at the Teaching Hospital, Anuradhapura, Sri Lanka between April-October 2014. Outcomes: Over 10 years, 1548 patients (835 envenomed) were recruited to ASP. Definite ID was possible in 718 cases, most common snake types were brown snakes (Pseudonaja spp.), tiger snakes (Notechis spp.) and red-bellied black snakes(Pseudechis porphyriacus). Clinical effects varied across the snake types; the most common envenoming syndrome present was venom induced consumption coagulopathy (VICC). Twenty-three people died during the 10-year period. Seqirus snake venom detection kit (SVDK) results were inaccurate in some cases, giving incorrect results in 5% of envenomed patients. Antivenom was given a median of 4.3 hours post bite and this did not change across the study period. The myotoxicity analysis identified 148 patients with myotoxicity, most caused by tiger snake (Notechis spp.) and red-bellied black snake (P. porphyriacus) bites. Systemic symptoms and white cell count increases were common. It took a median of 11.1 hours for the first abnormal CK to develop and 34.3 hours to peak. Antivenom reduced the severity of myotoxicity if given before abnormal CK developed. Taipan (Oxyuranus spp.) bites were rare. Most patients bitten by a taipan were snake handlers. Taipan envenoming was severe when it occurred and was characterised by VICC and neurotoxicity in most patients. Other features included myotoxicity and venom allergy. Antivenom reduced the incidence and severity of several venom effects. One vial of antivenom was sufficient to bind circulating venom. Coastal taipans (Oxyuranus scutellatus) and inland taipans (Oxyuranus microlepidotus) had a similar pattern of venom effects. Sea snake bites (Hydrophiini) were very rare and occurred predominately in patients who were fishing. Sea snake envenoming was characterised by nonspecific systemic symptoms and myotoxicity that was severe. Severity of myotoxicity appeared to correlate with time to antivenom. In the rat model of Australian snake myotoxicity, there was no difference in CK AUC between the placebo and venom treated rats after 10 hours. CK-MM AUC was significantly higher for rats treated with venom versus placebo, with early rise in the biomarker concentration evidence on the first sample post venom administration. CK-MM had superior diagnostic characteristics as assessed by ROC curve AUC. Sri Lankan common krait (B. caeruleus) envenoming did not lead to the development of myotoxicity, and Sri Lankan Russell’s viper (D. russelii) envenoming led to myotoxicity that was mild biochemically. Conclusion: This thesis adds to a growing body of evidence of confirmed cases of snake envenoming in Australia and Sri Lanka, describing epidemiology, clinical presentation, the toxidrome of myotoxicity and approaches to early antivenom therapy. The viability of a large, long-running multicentre observational study as a method to generate data on a rare and geographically dispersed disease was demonstrated, and the method also allowed monitoring of evidence-based practice change over time. Whilst relatively rare, Australian snake envenoming was shown to be severe in many cases when it occurs, with myotoxicity one of the most common envenoming syndromes described. Taipan (Oxyuranus spp.) and sea snake (Hydrophiini) envenoming cases were extremely rare but often very severe. It was demonstrated that myotoxicity was not a major feature of Sri Lankan Russell’s viper (D. russelii) and common krait (B. caeruleus) envenoming. This thesis adds to growing evidence demonstrating the importance of early treatment with antivenom to reduce the incidence and severity of envenoming syndromes in at-risk patients. It also provides early detail on an approach to help identify these at-risk patients. Future direction of research includes furthering this approach with clinical validation of diagnostic methods available at the bedside to ensure timely diagnosis and treatment of the appropriate patient.
- Subject
- Australian; snake; thesis by publication; Sri Lankan; envenoming; myotoxicity; taipan; sea snake; antivenom; early; biomarkers
- Identifier
- http://hdl.handle.net/1959.13/1511519
- Identifier
- uon:56504
- Rights
- Copyright 2024 Christopher Ian Johnston
- Language
- eng
- Full Text
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