Clinical Toxicology (2015), 53, 834–839 Copyright © 2015 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2015.1059947
CLINICAL TOXICOLOGY TEACHING CASE
An instructive case of presumed brown snake (Pseudonaja spp.) envenoming Judy Ou,1 Sebastien Haiart,1 Steven Galluccio,1 Julian White,2 and Scott A. Weinstein2 1Flinders
Medical Centre, Bedford Park, Adelaide, South Australia, Australia of Toxinology, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia
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2Department
Context. Several species of medically important Australian elapid snakes are frequently involved in human envenoming. The brown snake group (Pseudonaja spp., 9 species) is most commonly responsible for envenoming including life-threatening or fatal cases. Several Pseudonaja spp. can inflict human envenoming that features minor local effects, but may cause serious systemic venom disease including defibrination coagulopathy, thrombocytopenia, micro-angiopathic hemolytic anemia (MAHA) and, rarely, paralysis. Pseudonaja envenoming is typically diagnosed by history, clinical assessment including occasional active clinical bleeding noted on physical examination (e.g. from venipuncture sites, recent cuts, etc.), and laboratory detection of coagulopathy (prolonged activated partial thromboplastin time [APTT]/ INR, elevated D-dimer, afibrinogenemia and thrombocytopenia). Lack of verified identity of the envenoming snake species is a common problem in Australia and elsewhere. Identification and confirmation of the envenoming Australian snake taxon is often attempted with enzyme sandwich immunoassay venom detection kits (SVDKs). However, the SVDK has limited utility due to unreliable specificity and sensitivity when used to detect venoms of some Australian elapids. Antivenom (AV) remains the cornerstone of treatment, although there is debate concerning the recommended dose (1 vs. 2 or more vials) necessary to treat serious Pseudonaja envenoming. Envenomed patients receiving timely treatment uncommonly succumb, but a proportion of seriously envenomed patients may exhibit clinical or laboratory evidence of myocardial insult. Case details. An 88-year-old woman presented her dog to a veterinarian after it had sustained a bite by a witnessed snake, reportedly an eastern brown snake (Pseudonaja textilis, Elapidae). The woman became suddenly confused, and lost consciousness at the veterinary office. After transport to hospital, she denied any contact with the snake, but developed large haematomas at intravenous (i.v.) catheter insertion sites; blood tests revealed a severe defibrination coagulopathy, consistent with envenoming by a brown snake. An SVDK-tested urine sample was negative. A non-contrast CT of her head showed a minor subacute infarction of the left corona radiata. A twelve-lead ECG was normal, but her troponins were mildly elevated (39 ng/L). A diagnosis of brown snake envenoming was made and she received 2 vials of brown snake AV i.v., without adverse incident. Thirty min post AV her Glasgow Coma Score (GCS) had improved from 13 to 15 (normal). At 3.5 h post AV all bleeding from i.v. sites ceased, although her troponin T level peaked at 639 ng/L, supporting a diagnosis of non-ST elevated myocardial infarction (NSTEMI). Discussion. Severe brown snake envenoming may occur in the absence of a perceived bite, and AV is temporally associated with improvement in clinical findings and coagulopathy. However, severe envenoming by this species can be complicated by cardiovascular events that in the circumstance of incomplete or absent history may confuse the primary diagnosis and affect patient outcome.
Case presentation (Dr Judy Ou)
tion unclear) loss of consciousness just after arriving at a veterinarian’s office. She had taken her dog (female, 6-year-old West Highland Terrier) to the veterinarian, as the dog looked ‘unwell’ after it was found interacting with a reported ‘brown snake’ in her backyard, and was noted to be bleeding from the left hindfoot. She denied being bitten herself, but was unable to recall the specific details of the incident. It was later reported by the veterinarian that her dog had persistent bleeding from the hindfoot wound, and developed macroscopic haematuria. One vial of brown snake monovalent AV (BSAV; bioCSL, Melbourne, Victoria, Australia) was administered to the dog by slow i.v. infusion; pulmonary edema was noted shortly thereafter, and furosemide (25 mg/dose, two doses) was given. There was no change in the dog’s condition, but improvement in cardiorespiratory function was noted 10–15 min after provision of a second vial of BSAV.
An 88-year-old female with a history of ‘sudden collapse’ was retrieved by ambulance to a tertiary center. On arrival in the Emergency Department, she was confused and disorientated with GCS of 13, and her pupils were unequally dilated, 3.5 mm (right), 4.0 mm (left). Her other vital signs were normal, and a history reported by the ambulance officers indicated that she had suffered a sudden onset of confusion followed by unresponsiveness, and brief (dura-
Received 19 March 2015; accepted 28 May 2015. Address correspondence to Scott A Weinstein, PhD, MBBS, MD, Department of Toxinology, Women’s and Children’s Hospital, North Adelaide, South Australia, 5003 Australia. Tel: 61-8-8-161-8044. E-mail: [email protected]
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Australian brown snake (Pseudonaja) envenoming 835
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Discussion (Dr. Judy Ou, Dr. Scott Weinstein) Differential diagnosis Considering the presenting illness (confusion and transient loss of consciousness), the advanced age of the patient, and her denial of any contact with the snake that she observed interacting with her dog, the initial differential diagnosis included cardiac, neurally mediated or orthostatic syncope; myocardial infarction (MI); central nervous system (CNS) infarct; envenoming and anxiety. The patient’s initial examination and evaluation did not fully eliminate any of these possible diagnoses; however, the available history strongly suggested that her dog had been seriously envenomed provided support for the possibility that the patient was unaware of having been bitten by the snake while attending to her dog. This possibility was also concordant with her sudden collapse in the veterinary practice, as early sudden loss of consciousness or ‘collapse’ is reported in a substantial proportion of patients envenomed by several species of Australian elapids. Case continuation (Dr. Judy Ou, Dr. Sebastien Haiart) The patient’s medical and surgical history was remarkable for controlled hypertension, as well as hypercholesterolaemia and smoking (70 pack years); she had bilateral phacoemulsification performed in 2005. Her regular medication includes aspirin 100 mg daily, candesartan 8 mg daily, rosuvastatin 10 mg 3 times per week, calcium/vitamin D 600 mg/400 IU daily and risedronate 35 mg weekly. She reported allergy to topical aminoglycosides, but was unable to recall the reaction to exposure. She lives independently alone in a house in a metropolitan area of South Australia. There was no reported significant dementia or premorbid substantial cognitive deficits. The patient’s remaining clinical examination was unremarkable, aside from some reported subjective weakness on the right side that correlated with mildly reduced power of the right upper extremity, but neurological examination including all cranial nerves was unremarkable. There was no detected evidence of fang punctures, or bite marks. A non-contrast CT of the head showed a subacute infarction in the left corona radiata. Multiple i.v. cannulas were inserted at the conclusion of the initial physical examination. Large haematomas rapidly developed around the insertion sites that required firm pressure and bandage to control the brisk bleeding (Fig. 1). Rotational thromboelastometry was performed to quickly assess the coagulation profile. Initial results were available in 10 mins and showed that the extrinsic and intrinsic pathway clotting times were grossly prolonged with no gross clot formation. After 40 mins, no clot had formed; therefore, the a value (rate of clot production), A5 and A10 values (clot strength at time in minutes) were undetectable. Other laboratory investigations indicated a severe defibrinating coagulopathy: INR 12, APTT 200 sec and fibrinogen 0.3 g/L (Table 1). There was also a mildly raised troponin T level of 39 ng/L, but a 12-lead ECG showed no Copyright © Informa Healthcare USA, Inc. 2015
evidence of acute coronary syndrome, or ischaemia. Her haemoglobin level, platelet count and creatinine level were also within normal limits (Table 1). Urinalysis detected microscopic haematuria (1000 106/L; normal range 0–10) and proteinuria (1886 mg/L, protein/creatinine ratio 93; normal 18). A urine sample sent for SVDK confirmation was later reported to be negative.
Additional discussion Evidence supporting venom-induced coagulopathy (Dr. Scott Weinstein) The results of further physical examination and investigations showed that the patient did not have a haemorrhagic infarct; the minor lacunar infarct may have contributed to her presentation, but did not account for her evolving syndrome. Similarly, she had no evidence of cardiac ischaemia or complaint of chest/jaw/arm pain, and the cardiac enzyme levels (troponin T) were only mildly elevated. However, the patient spontaneously and briskly bled from i.v. cannula insertion sites, and her laboratory results showed a defibrinating coagulopathic picture typically observed in severe brown snake (Pseudonaja spp.) envenoming.1–5 It is also useful to note the utility of the rapidly procured (within 10 min) results of the rotational thromboelastography. These early results added some support to the provisional diagnosis of envenoming by Pseudonaja spp. because there was no detection of gross clot formation in the setting of brisk bleeding from i.v. insertion sites. The combination of these signs and laboratory results provided support for the diagnosis of envenoming, although an extensive dermatological examination with special attention to the extremities and fingers did not reveal any evidence of snakebite (scratches, punctures, small interrupted lacerations, persistently bleed-
Fig. 1. Expanding haematoma that developed at the i.v. cannula insertion site on the medial aspect of the patient’s right forearm (colour version of this figure can be found in the online version at www. informahealthcare.com/ctx).
836 J. Ou et al. Table 1. Summary of serial blood results. A blood film taken with the initial full blood count contained rare red cell fragments, without evidence of haemolysis. Three subsequent blood films were within normal limits. BSAV: monovalent brown snake antivenom. Test (normal range)
On arrival
Haemoglobin (115–155 g/L) Platelet (150–450 109/L) Creatinine (50–100 umol/L) INR (0.9–1.2) APTT (24–38 sec) Fibrinogen (1.5–4.0 g/L) Troponin T (30 ng/L) Rotational Thromboelastometry Parameters* (normal range) Extrinsic pathway clotting time (38–79 sec) Intrinsic pathway clotting time (100–240 sec)
142 181 100 12.0 200 0.3 39
3.5 h post BSAV 7.5 h post BSAV 14 h post BSAV Day 2 Day 3 136 253 93 4.0 52 0.3 624
137 249 97 1.7 36 0.4 428
130 235 92 1.1 29 0.8 N/A
N/A N/A 83 0.9 26 N/A N/A
N/A N/A N/A 0.8 24 2.6 N/A
3174 2875
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* The rotational thromboelastometry results showed a lack of clot formation after 40 min. The a value (rate of clot production), A5 and A10 (clot strength at time in minutes) were undetectable.
Additional discussion (Dr. Scott Weinstein)
ing traumatic lesions, etc.). Bites inflicted by Pseudonaja spp. may appear as multiple scratches of varying depth, dual or single puncture marks that may be accompanied by additional tooth marks, or as subtle, minor lacerations.5 Also, the majority of medically significant Pseudonaja spp. envenoming shows no specific pathological signs on physical examination unless the victim has recently had a coincidental traumatic wound, dental work, surgery, piercings, etc. which predispose to visible sources of bleeding or extensive ecchymoses.1 Under some circumstances, a fragmented history, declared lack of contact with an observed unverified snake species, absence of a visible snakebite and negative result of a SVDK might direct more attention to alternative diagnoses, but given the concurrent veterinary case, absence of any other trauma, reported exposure or potentially relevant co-morbidity, brown snake envenoming was considered the most likely diagnosis. This was also supported because Pseudonaja spp. (eastern brown snake (P. textilis), Fig. 2) is the only snake species found where the incident occurred that could inflict a severe defibrinating envenoming.
Presumed envenoming, cardiovascular complications and management of venom-induced defibrinating coagulopathy The provision of BSAV resulted in a temporally associated therapeutic response, as the patient’s spontaneous bleeding ceased abruptly, her serial laboratory results indicated reversal of the coagulopathy and her clinical condition visibly improved. In the absence of verified contact with a Pseudonaja spp., administration of BSAV constitutes an empirical treatment and its clinical effectiveness also confirmed the diagnosis. It is important to note that in cases of defibrinating coagulopathy induced by Australian elapid envenoming, declination of the INR is commonly an indicator of reversed coagulopathic effects, and in most cases the reversal will not be accelerated by additional AV. Fibrinogen levels are often undetectable for some 12–24 h postenvenoming, but usually become detectable 24–36 h post envenoming.2–4 In patients who develop thrombocytopenia, platelet levels may remain below 50,000 (normal adult range:
Case continuation (Dr. Judy Ou, Dr. Steven Galluccio, Dr. Scott Weinstein) After consulting one of the authors (SAW), the patient was given 2000 units (2 vials) of BSAV. There were no adverse reaction to the AV, and approximately 30 min post BSAV infusion her GCS improved to 15; neurological– ophthalmological examination were within normal limits. Serial laboratory tests demonstrated reversal of the coagulopathy (e.g. declining INR) within 3.5 h after receiving AV (Table 1), during which time all bleeding ceased at the i.v. insertion sites. She was transferred to the Intensive Care Unit for continuous monitoring. The troponin T level peaked at 639 ng/L at 3.5 h post AV administration (Table 1), but, as she was asymptomatic and still exhibited abnormal laboratory results indicating a resolving coagulopathy, no further action was taken. Over the next 24 h, she continued to show improvement without any bleeding or neurological complications.
Fig 2. Eastern brown snake (P. textilis, Elapidae), head profile, South Australian specimen. Pseudonaja spp. especially P. textilis, P. nuchalis (Northern brown snake) and P. mengdeni (Western brown snake) are the venomous snake taxa most commonly involved in envenoming in Australia (photograph copyright to Julian White; used with permission) (colour version of this figure can be found in the online version at www.informahealthcare.com/ctx). Clinical Toxicology vol. 53 no. 8 2015
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Australian brown snake (Pseudonaja) envenoming 837 150,000–400,000) mm3 for as long as a week or even more.5 Platelet infusions rarely shorten or notably improve the duration of snake venom-induced thrombocytopenia,6 but the provision of infused platelets are necessary if the patient spontaneously bleeds. The threshold for prophylactic provision of platelets varies on circumstances and patient morbidities, and can range between 5,000 and 100,000 mm3.7,8 Patients with marked and persistent thrombocytopenia require frequent neurological monitoring because these patients are at increased risk for a fatal outcome. Non-contrast CT of the head should be performed in any patient with altered sensorium in the setting of a severe envenoming such as this because of the increased risk of CNS bleeding. The patient had troponin T levels consistent with an NSTEMI. However, the patient was not a candidate for acute interventional therapy due to her coagulopathy, absence of ischaemic changes and clinical improvement post BSAV; likewise, there was no provision of any beta-blocker or angiotensin-converting enzyme inhibitor because the patient’s improvement and lack of any evidence of ischaemia suggested that the risks per sudden blood pressure changes would outweigh the potential minimal benefits offered by the medications.
Case continuation (Dr Judy Ou) The following day she reported blurred vision that she had noticed during her initial presentation, but only reported it when it interfered with her trying to read newspapers the next day. Visual field testing suggested a right homonymous hemianopia. Retinal bleeding was excluded by slit lamp examination, and a repeated CT of her head excluded intracranial bleeding; there were no changes in the CT in comparison to that performed shortly after her presentation. There was also no evidence of atrial fibrillation, and bilateral carotid ultrasound showed no critical stenosis. She was provided with a short non-tapered course (4 d) of prednisone, 40 mg, p.o., discharged home six days post envenoming with appointments for the transient ischaemic attack (TIA) clinic, an MRI of the head, Holter monitoring and a trans-thoracic echocardiogram. She was also advised not to drive a vehicle until a satisfactory driving assessment could be completed, and to see her GP within the following week. The patient presented again 4 days post discharge with abdominal pain. A CT of the abdomen was performed, but no acute pathology was identified. Urine culture grew 1 106/mL of Enterococcus faecalis and urinary tract infection was diagnosed; the patient was treated with i.v. amoxicillin (1 g, q.i.d). The pre-arranged MRI without gadolinium detected a tiny acute small vessel infarct in the left corona radiata with a background of moderate to severe chronic small vessel ischaemic change. The stroke team reviewed her and at that time she reported that she had occasional ‘flashes’ in the right lower quadrant of her right eye. She denied any language disturbance, weakness or sensory loss. Full neurological examination was unremarkable. Clinically, the MRI findings were not consistent with her right homonymous Copyright © Informa Healthcare USA, Inc. 2015
hemianopia. She was discharged and advised to continue aspirin and candesartan.
Additional discussion (Dr. Scott Weinstein, Dr. Julian White, Dr. Judy Ou) Factors influencing diagnosis of elapid envenoming This case contained several features, some of which may commonly occur, that can complicate diagnosis and management of serious snakebite envenoming including an absence of reported linkage between the patient and a presumed, unverified highly venomous species, as well as an initially unclear history of initial symptoms/signs. Furthermore, the patient was of advanced age and experienced an early sudden loss of consciousness or ‘collapse’, as is reported in some 27–45% of patients envenomed by several species of Australian elapids.9,10 However, without a careful detailed history including the description of the reported ‘brown snake’ that bit the patient’s dog, given the patient’s age, known co-morbidities and lack of clear evidence of contact with a snake, a differential diagnosis might have been considered without the inclusion of possible envenoming. The limiting sensitivity and specificity of SVDK in diagnosing human envenoming The patient’s clinical signs (e.g. active bleeding) and laboratory results (e.g. markedly prolonged APTT/INR and the thromboelastography results) supported a diagnosis of Pseudonaja envenoming despite a negative SVDK urine sample, which in a recent series was noted in 5/45 (11%) urine samples from patients envenomed by Pseudonaja spp.10 False-negative SVDK results have theoretically been assigned to high venom content in some tested samples, the ‘high dose hook effect’11, which refers to the biphasic dose–response curve observed in sandwich immunoassays. Sutherland and Tibbals1 reported an association between ‘occasional’ false-negative SVDK results when the test is ‘overwhelmed by a massive concentration’ of venom, with an ‘equivocal’ (negative) reaction when the tested sample contains 100 mg/mL, a level stated to be some ‘10,000 fold the limit of detection’.1 However, this remains independently unconfirmed, and high concentrations of venom including amounts from experimentally envenomed rodents that likely would exceed many human clinical samples (1 mg/mL) were easily detected during testing of a very similar sandwich enzyme immunoassay developed for North American pit viper venoms,12,13 although this does not obviate the possibility that this might occur in other assays, or those used to detect venoms of other taxa. The failure of the SVDK to detect venom in some cases such as this might be more likely due to assay conditions such as non-specific binding, sample-specific limitations/interference, or bite site washing, delayed urine sampling missing the period for venom clearance in urine or sample levels of venom being below the SVDK’s detectable level.12,14 Results may be notably influenced by the clinical specimen tested (e.g. urine vs. wound swab15). SVDK interpretation may also
838 J. Ou et al.
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be complicated by cross-reactivity with venoms and other oral secretions of venomous and non-venomous snakes.16 Clinical veterinary results have reported 100% specificity using canine and feline urine specimens.17 However, this case re-emphasises that a negative SVDK does not exclude envenoming, and that it should not be used as a screening test for suspected snakebite. Presumed envenoming, establishment of the diagnosis, controversies about management and complications of Pseudonaja envenoming Our patient was diagnosed on the basis of the patient’s available history, clinical presentation, laboratory findings and the fact that Pseudonaja is the only naturally occurring venomous taxon that can cause defibrination coagulopathy that is found in the patient’s geographic area. Also, there was a concomitant veterinary case involving the patient’s dog in which Pseudonaja spp. envenoming was independently diagnosed and treated with two vials of BSAV. The patient’s active bleeding from i.v. cannula and venipuncture sites abruptly ceased in less than 2 h post BSAV administration, and her APTT/INR became detectable within 3.5 h (Table 1). This supports an efficient pharmacotherapeutic response of the coagulopathy to BSAV. A recent prospective observational study of 136 patients with systemic Pseudonaja envenoming suggested that ‘giving more than one vial of AV is unnecessary in brown snake envenoming’.10 In our view, this is premature and a precariously narrow clinical strategy because patient co-morbidities, habitus and related volume of distribution, individual venom component metabolism, and other patient-centred factors may unpredictably influence the clinical course of envenoming. In particular, the most important subgroup of patients included those with signs/symptoms suggesting more severe envenoming, as it is these patients who are at most risk for serious complications or fatal outcomes. It is for this reason we generally choose to use 2 vials of BSAV as the initial dose, not the minimal dose of 1 vial suggested elsewhere.10 Several fatal outcomes have been assigned to intracranial bleeding, intracerebral events or pre-hospital cardiac arrest/collapse,10,18,19 and some rare fatalities occur despite provision of AV.20 Our patient developed serious cardiovascular complications including notably elevated troponins consistent with a NSTEMI, and a minor TIA/lacunar stroke involving a minor blood vessel in the corona radiata. She also developed a right homonymous hemianopia. Although we consider it likely that these complications were directly a result of the envenoming, it is possible that these coincidentally occurred as a result of stress and/or exacerbation of occult cerebrovascular and coronary artery disease. The ‘brown snake paradox’: potent venom neurotoxins and rare paralytic features in human envenoming Although P. textilis venom contains textilotoxin, the presynaptic neurotoxin with the highest experimental (murine) lethal potency reported so far (0.6–1 mg/kg21,22) of any
studied snake venom, human envenoming rarely presents with paralytic features. The recent series reported by Allen et al.10 reported neurotoxicity in 2/136 patients with definitive Pseudonaja envenoming, and one of the two may have exhibited indirect neurotoxicity due to prodrome associated with an impending intracerebral haemorrhage. This apparent confounding clinical discrepancy has been termed the ‘brown snake paradox’, and has been assigned by some investigators to the relatively low percentage of textilotoxin in some assayed venom samples (3–5.7% of total venom protein23–25), as well as its reported lower in vitro neurotoxicity in comparison with the higher percentage and more potent experimental neurotoxicity of taipoxin, the major presynaptic neurotoxin from coastal taipan (Oxyuranus scutellatus) venom22, another medically important Australian elapid. However, the early provision of AV has been associated with a possible decrease in the historically reported higher frequency of described ‘slowly developing’ neurotoxicity from Pseudonaja spp. envenoming.7 Additionally, some venom toxins exhibit marked prey specificity and can have significantly varied impact in different vertebrates; this can include the observed in vitro effects of a given toxin in nerve–muscle preparations from different test species.6,26 Some other Australian elapid venoms also have similar proportions of potent presynaptic neurotoxins that clearly cause some of the dominant paralytic clinical effects in human envenoming such as notexin (6% of crude venom protein27) from the common tiger snake (Notechis scutatus).
Summary (Dr. Scott Weinstein, Dr. Judy Ou) In summary, we have described an unusual case of presumed Pseudonaja envenoming in which an 88-year-old woman was unknowingly bitten, as she came to the aid of her dog while her dog was bitten by a snake highly likely to be a P. textilis. The patient had a sudden onset of confusion followed by loss of consciousness, coagulopathy with active, brisk bleeding, signs and symptoms consistent with those present in Pseudonaja spp. envenoming. She also developed a right homonymous hemianopia, and cardiovascular complications including a NSTEMI and minor TIA, both likely due to thromboembolic events. Fortunately, she recovered without any major disabling sequela. This ‘instructive’ case emphasises the central importance of procuring a detailed history that, in combination with clinical acumen, can guide patient-centered management and provide the best chance for a positive outcome.
Final diagnosis Eastern brown snake (P. textilis) envenoming, severe, with cardiovascular complications.
Acknowledgement We gratefully acknowledge our patient’s cooperation and informed consent for documenting her case. Clinical Toxicology vol. 53 no. 8 2015
Australian brown snake (Pseudonaja) envenoming 839
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
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CLINICAL TOXICOLOGY TEACHING CASE
An instructive case of presumed brown snake (Pseudonaja spp.) envenoming Judy Ou,1 Sebastien Haiart,1 Steven Galluccio,1 Julian White,2 and Scott A. Weinstein2 1Flinders
Medical Centre, Bedford Park, Adelaide, South Australia, Australia of Toxinology, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia
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2Department
Context. Several species of medically important Australian elapid snakes are frequently involved in human envenoming. The brown snake group (Pseudonaja spp., 9 species) is most commonly responsible for envenoming including life-threatening or fatal cases. Several Pseudonaja spp. can inflict human envenoming that features minor local effects, but may cause serious systemic venom disease including defibrination coagulopathy, thrombocytopenia, micro-angiopathic hemolytic anemia (MAHA) and, rarely, paralysis. Pseudonaja envenoming is typically diagnosed by history, clinical assessment including occasional active clinical bleeding noted on physical examination (e.g. from venipuncture sites, recent cuts, etc.), and laboratory detection of coagulopathy (prolonged activated partial thromboplastin time [APTT]/ INR, elevated D-dimer, afibrinogenemia and thrombocytopenia). Lack of verified identity of the envenoming snake species is a common problem in Australia and elsewhere. Identification and confirmation of the envenoming Australian snake taxon is often attempted with enzyme sandwich immunoassay venom detection kits (SVDKs). However, the SVDK has limited utility due to unreliable specificity and sensitivity when used to detect venoms of some Australian elapids. Antivenom (AV) remains the cornerstone of treatment, although there is debate concerning the recommended dose (1 vs. 2 or more vials) necessary to treat serious Pseudonaja envenoming. Envenomed patients receiving timely treatment uncommonly succumb, but a proportion of seriously envenomed patients may exhibit clinical or laboratory evidence of myocardial insult. Case details. An 88-year-old woman presented her dog to a veterinarian after it had sustained a bite by a witnessed snake, reportedly an eastern brown snake (Pseudonaja textilis, Elapidae). The woman became suddenly confused, and lost consciousness at the veterinary office. After transport to hospital, she denied any contact with the snake, but developed large haematomas at intravenous (i.v.) catheter insertion sites; blood tests revealed a severe defibrination coagulopathy, consistent with envenoming by a brown snake. An SVDK-tested urine sample was negative. A non-contrast CT of her head showed a minor subacute infarction of the left corona radiata. A twelve-lead ECG was normal, but her troponins were mildly elevated (39 ng/L). A diagnosis of brown snake envenoming was made and she received 2 vials of brown snake AV i.v., without adverse incident. Thirty min post AV her Glasgow Coma Score (GCS) had improved from 13 to 15 (normal). At 3.5 h post AV all bleeding from i.v. sites ceased, although her troponin T level peaked at 639 ng/L, supporting a diagnosis of non-ST elevated myocardial infarction (NSTEMI). Discussion. Severe brown snake envenoming may occur in the absence of a perceived bite, and AV is temporally associated with improvement in clinical findings and coagulopathy. However, severe envenoming by this species can be complicated by cardiovascular events that in the circumstance of incomplete or absent history may confuse the primary diagnosis and affect patient outcome.
Case presentation (Dr Judy Ou)
tion unclear) loss of consciousness just after arriving at a veterinarian’s office. She had taken her dog (female, 6-year-old West Highland Terrier) to the veterinarian, as the dog looked ‘unwell’ after it was found interacting with a reported ‘brown snake’ in her backyard, and was noted to be bleeding from the left hindfoot. She denied being bitten herself, but was unable to recall the specific details of the incident. It was later reported by the veterinarian that her dog had persistent bleeding from the hindfoot wound, and developed macroscopic haematuria. One vial of brown snake monovalent AV (BSAV; bioCSL, Melbourne, Victoria, Australia) was administered to the dog by slow i.v. infusion; pulmonary edema was noted shortly thereafter, and furosemide (25 mg/dose, two doses) was given. There was no change in the dog’s condition, but improvement in cardiorespiratory function was noted 10–15 min after provision of a second vial of BSAV.
An 88-year-old female with a history of ‘sudden collapse’ was retrieved by ambulance to a tertiary center. On arrival in the Emergency Department, she was confused and disorientated with GCS of 13, and her pupils were unequally dilated, 3.5 mm (right), 4.0 mm (left). Her other vital signs were normal, and a history reported by the ambulance officers indicated that she had suffered a sudden onset of confusion followed by unresponsiveness, and brief (dura-
Received 19 March 2015; accepted 28 May 2015. Address correspondence to Scott A Weinstein, PhD, MBBS, MD, Department of Toxinology, Women’s and Children’s Hospital, North Adelaide, South Australia, 5003 Australia. Tel: 61-8-8-161-8044. E-mail: [email protected]
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Australian brown snake (Pseudonaja) envenoming 835
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Discussion (Dr. Judy Ou, Dr. Scott Weinstein) Differential diagnosis Considering the presenting illness (confusion and transient loss of consciousness), the advanced age of the patient, and her denial of any contact with the snake that she observed interacting with her dog, the initial differential diagnosis included cardiac, neurally mediated or orthostatic syncope; myocardial infarction (MI); central nervous system (CNS) infarct; envenoming and anxiety. The patient’s initial examination and evaluation did not fully eliminate any of these possible diagnoses; however, the available history strongly suggested that her dog had been seriously envenomed provided support for the possibility that the patient was unaware of having been bitten by the snake while attending to her dog. This possibility was also concordant with her sudden collapse in the veterinary practice, as early sudden loss of consciousness or ‘collapse’ is reported in a substantial proportion of patients envenomed by several species of Australian elapids. Case continuation (Dr. Judy Ou, Dr. Sebastien Haiart) The patient’s medical and surgical history was remarkable for controlled hypertension, as well as hypercholesterolaemia and smoking (70 pack years); she had bilateral phacoemulsification performed in 2005. Her regular medication includes aspirin 100 mg daily, candesartan 8 mg daily, rosuvastatin 10 mg 3 times per week, calcium/vitamin D 600 mg/400 IU daily and risedronate 35 mg weekly. She reported allergy to topical aminoglycosides, but was unable to recall the reaction to exposure. She lives independently alone in a house in a metropolitan area of South Australia. There was no reported significant dementia or premorbid substantial cognitive deficits. The patient’s remaining clinical examination was unremarkable, aside from some reported subjective weakness on the right side that correlated with mildly reduced power of the right upper extremity, but neurological examination including all cranial nerves was unremarkable. There was no detected evidence of fang punctures, or bite marks. A non-contrast CT of the head showed a subacute infarction in the left corona radiata. Multiple i.v. cannulas were inserted at the conclusion of the initial physical examination. Large haematomas rapidly developed around the insertion sites that required firm pressure and bandage to control the brisk bleeding (Fig. 1). Rotational thromboelastometry was performed to quickly assess the coagulation profile. Initial results were available in 10 mins and showed that the extrinsic and intrinsic pathway clotting times were grossly prolonged with no gross clot formation. After 40 mins, no clot had formed; therefore, the a value (rate of clot production), A5 and A10 values (clot strength at time in minutes) were undetectable. Other laboratory investigations indicated a severe defibrinating coagulopathy: INR 12, APTT 200 sec and fibrinogen 0.3 g/L (Table 1). There was also a mildly raised troponin T level of 39 ng/L, but a 12-lead ECG showed no Copyright © Informa Healthcare USA, Inc. 2015
evidence of acute coronary syndrome, or ischaemia. Her haemoglobin level, platelet count and creatinine level were also within normal limits (Table 1). Urinalysis detected microscopic haematuria (1000 106/L; normal range 0–10) and proteinuria (1886 mg/L, protein/creatinine ratio 93; normal 18). A urine sample sent for SVDK confirmation was later reported to be negative.
Additional discussion Evidence supporting venom-induced coagulopathy (Dr. Scott Weinstein) The results of further physical examination and investigations showed that the patient did not have a haemorrhagic infarct; the minor lacunar infarct may have contributed to her presentation, but did not account for her evolving syndrome. Similarly, she had no evidence of cardiac ischaemia or complaint of chest/jaw/arm pain, and the cardiac enzyme levels (troponin T) were only mildly elevated. However, the patient spontaneously and briskly bled from i.v. cannula insertion sites, and her laboratory results showed a defibrinating coagulopathic picture typically observed in severe brown snake (Pseudonaja spp.) envenoming.1–5 It is also useful to note the utility of the rapidly procured (within 10 min) results of the rotational thromboelastography. These early results added some support to the provisional diagnosis of envenoming by Pseudonaja spp. because there was no detection of gross clot formation in the setting of brisk bleeding from i.v. insertion sites. The combination of these signs and laboratory results provided support for the diagnosis of envenoming, although an extensive dermatological examination with special attention to the extremities and fingers did not reveal any evidence of snakebite (scratches, punctures, small interrupted lacerations, persistently bleed-
Fig. 1. Expanding haematoma that developed at the i.v. cannula insertion site on the medial aspect of the patient’s right forearm (colour version of this figure can be found in the online version at www. informahealthcare.com/ctx).
836 J. Ou et al. Table 1. Summary of serial blood results. A blood film taken with the initial full blood count contained rare red cell fragments, without evidence of haemolysis. Three subsequent blood films were within normal limits. BSAV: monovalent brown snake antivenom. Test (normal range)
On arrival
Haemoglobin (115–155 g/L) Platelet (150–450 109/L) Creatinine (50–100 umol/L) INR (0.9–1.2) APTT (24–38 sec) Fibrinogen (1.5–4.0 g/L) Troponin T (30 ng/L) Rotational Thromboelastometry Parameters* (normal range) Extrinsic pathway clotting time (38–79 sec) Intrinsic pathway clotting time (100–240 sec)
142 181 100 12.0 200 0.3 39
3.5 h post BSAV 7.5 h post BSAV 14 h post BSAV Day 2 Day 3 136 253 93 4.0 52 0.3 624
137 249 97 1.7 36 0.4 428
130 235 92 1.1 29 0.8 N/A
N/A N/A 83 0.9 26 N/A N/A
N/A N/A N/A 0.8 24 2.6 N/A
3174 2875
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* The rotational thromboelastometry results showed a lack of clot formation after 40 min. The a value (rate of clot production), A5 and A10 (clot strength at time in minutes) were undetectable.
Additional discussion (Dr. Scott Weinstein)
ing traumatic lesions, etc.). Bites inflicted by Pseudonaja spp. may appear as multiple scratches of varying depth, dual or single puncture marks that may be accompanied by additional tooth marks, or as subtle, minor lacerations.5 Also, the majority of medically significant Pseudonaja spp. envenoming shows no specific pathological signs on physical examination unless the victim has recently had a coincidental traumatic wound, dental work, surgery, piercings, etc. which predispose to visible sources of bleeding or extensive ecchymoses.1 Under some circumstances, a fragmented history, declared lack of contact with an observed unverified snake species, absence of a visible snakebite and negative result of a SVDK might direct more attention to alternative diagnoses, but given the concurrent veterinary case, absence of any other trauma, reported exposure or potentially relevant co-morbidity, brown snake envenoming was considered the most likely diagnosis. This was also supported because Pseudonaja spp. (eastern brown snake (P. textilis), Fig. 2) is the only snake species found where the incident occurred that could inflict a severe defibrinating envenoming.
Presumed envenoming, cardiovascular complications and management of venom-induced defibrinating coagulopathy The provision of BSAV resulted in a temporally associated therapeutic response, as the patient’s spontaneous bleeding ceased abruptly, her serial laboratory results indicated reversal of the coagulopathy and her clinical condition visibly improved. In the absence of verified contact with a Pseudonaja spp., administration of BSAV constitutes an empirical treatment and its clinical effectiveness also confirmed the diagnosis. It is important to note that in cases of defibrinating coagulopathy induced by Australian elapid envenoming, declination of the INR is commonly an indicator of reversed coagulopathic effects, and in most cases the reversal will not be accelerated by additional AV. Fibrinogen levels are often undetectable for some 12–24 h postenvenoming, but usually become detectable 24–36 h post envenoming.2–4 In patients who develop thrombocytopenia, platelet levels may remain below 50,000 (normal adult range:
Case continuation (Dr. Judy Ou, Dr. Steven Galluccio, Dr. Scott Weinstein) After consulting one of the authors (SAW), the patient was given 2000 units (2 vials) of BSAV. There were no adverse reaction to the AV, and approximately 30 min post BSAV infusion her GCS improved to 15; neurological– ophthalmological examination were within normal limits. Serial laboratory tests demonstrated reversal of the coagulopathy (e.g. declining INR) within 3.5 h after receiving AV (Table 1), during which time all bleeding ceased at the i.v. insertion sites. She was transferred to the Intensive Care Unit for continuous monitoring. The troponin T level peaked at 639 ng/L at 3.5 h post AV administration (Table 1), but, as she was asymptomatic and still exhibited abnormal laboratory results indicating a resolving coagulopathy, no further action was taken. Over the next 24 h, she continued to show improvement without any bleeding or neurological complications.
Fig 2. Eastern brown snake (P. textilis, Elapidae), head profile, South Australian specimen. Pseudonaja spp. especially P. textilis, P. nuchalis (Northern brown snake) and P. mengdeni (Western brown snake) are the venomous snake taxa most commonly involved in envenoming in Australia (photograph copyright to Julian White; used with permission) (colour version of this figure can be found in the online version at www.informahealthcare.com/ctx). Clinical Toxicology vol. 53 no. 8 2015
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Australian brown snake (Pseudonaja) envenoming 837 150,000–400,000) mm3 for as long as a week or even more.5 Platelet infusions rarely shorten or notably improve the duration of snake venom-induced thrombocytopenia,6 but the provision of infused platelets are necessary if the patient spontaneously bleeds. The threshold for prophylactic provision of platelets varies on circumstances and patient morbidities, and can range between 5,000 and 100,000 mm3.7,8 Patients with marked and persistent thrombocytopenia require frequent neurological monitoring because these patients are at increased risk for a fatal outcome. Non-contrast CT of the head should be performed in any patient with altered sensorium in the setting of a severe envenoming such as this because of the increased risk of CNS bleeding. The patient had troponin T levels consistent with an NSTEMI. However, the patient was not a candidate for acute interventional therapy due to her coagulopathy, absence of ischaemic changes and clinical improvement post BSAV; likewise, there was no provision of any beta-blocker or angiotensin-converting enzyme inhibitor because the patient’s improvement and lack of any evidence of ischaemia suggested that the risks per sudden blood pressure changes would outweigh the potential minimal benefits offered by the medications.
Case continuation (Dr Judy Ou) The following day she reported blurred vision that she had noticed during her initial presentation, but only reported it when it interfered with her trying to read newspapers the next day. Visual field testing suggested a right homonymous hemianopia. Retinal bleeding was excluded by slit lamp examination, and a repeated CT of her head excluded intracranial bleeding; there were no changes in the CT in comparison to that performed shortly after her presentation. There was also no evidence of atrial fibrillation, and bilateral carotid ultrasound showed no critical stenosis. She was provided with a short non-tapered course (4 d) of prednisone, 40 mg, p.o., discharged home six days post envenoming with appointments for the transient ischaemic attack (TIA) clinic, an MRI of the head, Holter monitoring and a trans-thoracic echocardiogram. She was also advised not to drive a vehicle until a satisfactory driving assessment could be completed, and to see her GP within the following week. The patient presented again 4 days post discharge with abdominal pain. A CT of the abdomen was performed, but no acute pathology was identified. Urine culture grew 1 106/mL of Enterococcus faecalis and urinary tract infection was diagnosed; the patient was treated with i.v. amoxicillin (1 g, q.i.d). The pre-arranged MRI without gadolinium detected a tiny acute small vessel infarct in the left corona radiata with a background of moderate to severe chronic small vessel ischaemic change. The stroke team reviewed her and at that time she reported that she had occasional ‘flashes’ in the right lower quadrant of her right eye. She denied any language disturbance, weakness or sensory loss. Full neurological examination was unremarkable. Clinically, the MRI findings were not consistent with her right homonymous Copyright © Informa Healthcare USA, Inc. 2015
hemianopia. She was discharged and advised to continue aspirin and candesartan.
Additional discussion (Dr. Scott Weinstein, Dr. Julian White, Dr. Judy Ou) Factors influencing diagnosis of elapid envenoming This case contained several features, some of which may commonly occur, that can complicate diagnosis and management of serious snakebite envenoming including an absence of reported linkage between the patient and a presumed, unverified highly venomous species, as well as an initially unclear history of initial symptoms/signs. Furthermore, the patient was of advanced age and experienced an early sudden loss of consciousness or ‘collapse’, as is reported in some 27–45% of patients envenomed by several species of Australian elapids.9,10 However, without a careful detailed history including the description of the reported ‘brown snake’ that bit the patient’s dog, given the patient’s age, known co-morbidities and lack of clear evidence of contact with a snake, a differential diagnosis might have been considered without the inclusion of possible envenoming. The limiting sensitivity and specificity of SVDK in diagnosing human envenoming The patient’s clinical signs (e.g. active bleeding) and laboratory results (e.g. markedly prolonged APTT/INR and the thromboelastography results) supported a diagnosis of Pseudonaja envenoming despite a negative SVDK urine sample, which in a recent series was noted in 5/45 (11%) urine samples from patients envenomed by Pseudonaja spp.10 False-negative SVDK results have theoretically been assigned to high venom content in some tested samples, the ‘high dose hook effect’11, which refers to the biphasic dose–response curve observed in sandwich immunoassays. Sutherland and Tibbals1 reported an association between ‘occasional’ false-negative SVDK results when the test is ‘overwhelmed by a massive concentration’ of venom, with an ‘equivocal’ (negative) reaction when the tested sample contains 100 mg/mL, a level stated to be some ‘10,000 fold the limit of detection’.1 However, this remains independently unconfirmed, and high concentrations of venom including amounts from experimentally envenomed rodents that likely would exceed many human clinical samples (1 mg/mL) were easily detected during testing of a very similar sandwich enzyme immunoassay developed for North American pit viper venoms,12,13 although this does not obviate the possibility that this might occur in other assays, or those used to detect venoms of other taxa. The failure of the SVDK to detect venom in some cases such as this might be more likely due to assay conditions such as non-specific binding, sample-specific limitations/interference, or bite site washing, delayed urine sampling missing the period for venom clearance in urine or sample levels of venom being below the SVDK’s detectable level.12,14 Results may be notably influenced by the clinical specimen tested (e.g. urine vs. wound swab15). SVDK interpretation may also
838 J. Ou et al.
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be complicated by cross-reactivity with venoms and other oral secretions of venomous and non-venomous snakes.16 Clinical veterinary results have reported 100% specificity using canine and feline urine specimens.17 However, this case re-emphasises that a negative SVDK does not exclude envenoming, and that it should not be used as a screening test for suspected snakebite. Presumed envenoming, establishment of the diagnosis, controversies about management and complications of Pseudonaja envenoming Our patient was diagnosed on the basis of the patient’s available history, clinical presentation, laboratory findings and the fact that Pseudonaja is the only naturally occurring venomous taxon that can cause defibrination coagulopathy that is found in the patient’s geographic area. Also, there was a concomitant veterinary case involving the patient’s dog in which Pseudonaja spp. envenoming was independently diagnosed and treated with two vials of BSAV. The patient’s active bleeding from i.v. cannula and venipuncture sites abruptly ceased in less than 2 h post BSAV administration, and her APTT/INR became detectable within 3.5 h (Table 1). This supports an efficient pharmacotherapeutic response of the coagulopathy to BSAV. A recent prospective observational study of 136 patients with systemic Pseudonaja envenoming suggested that ‘giving more than one vial of AV is unnecessary in brown snake envenoming’.10 In our view, this is premature and a precariously narrow clinical strategy because patient co-morbidities, habitus and related volume of distribution, individual venom component metabolism, and other patient-centred factors may unpredictably influence the clinical course of envenoming. In particular, the most important subgroup of patients included those with signs/symptoms suggesting more severe envenoming, as it is these patients who are at most risk for serious complications or fatal outcomes. It is for this reason we generally choose to use 2 vials of BSAV as the initial dose, not the minimal dose of 1 vial suggested elsewhere.10 Several fatal outcomes have been assigned to intracranial bleeding, intracerebral events or pre-hospital cardiac arrest/collapse,10,18,19 and some rare fatalities occur despite provision of AV.20 Our patient developed serious cardiovascular complications including notably elevated troponins consistent with a NSTEMI, and a minor TIA/lacunar stroke involving a minor blood vessel in the corona radiata. She also developed a right homonymous hemianopia. Although we consider it likely that these complications were directly a result of the envenoming, it is possible that these coincidentally occurred as a result of stress and/or exacerbation of occult cerebrovascular and coronary artery disease. The ‘brown snake paradox’: potent venom neurotoxins and rare paralytic features in human envenoming Although P. textilis venom contains textilotoxin, the presynaptic neurotoxin with the highest experimental (murine) lethal potency reported so far (0.6–1 mg/kg21,22) of any
studied snake venom, human envenoming rarely presents with paralytic features. The recent series reported by Allen et al.10 reported neurotoxicity in 2/136 patients with definitive Pseudonaja envenoming, and one of the two may have exhibited indirect neurotoxicity due to prodrome associated with an impending intracerebral haemorrhage. This apparent confounding clinical discrepancy has been termed the ‘brown snake paradox’, and has been assigned by some investigators to the relatively low percentage of textilotoxin in some assayed venom samples (3–5.7% of total venom protein23–25), as well as its reported lower in vitro neurotoxicity in comparison with the higher percentage and more potent experimental neurotoxicity of taipoxin, the major presynaptic neurotoxin from coastal taipan (Oxyuranus scutellatus) venom22, another medically important Australian elapid. However, the early provision of AV has been associated with a possible decrease in the historically reported higher frequency of described ‘slowly developing’ neurotoxicity from Pseudonaja spp. envenoming.7 Additionally, some venom toxins exhibit marked prey specificity and can have significantly varied impact in different vertebrates; this can include the observed in vitro effects of a given toxin in nerve–muscle preparations from different test species.6,26 Some other Australian elapid venoms also have similar proportions of potent presynaptic neurotoxins that clearly cause some of the dominant paralytic clinical effects in human envenoming such as notexin (6% of crude venom protein27) from the common tiger snake (Notechis scutatus).
Summary (Dr. Scott Weinstein, Dr. Judy Ou) In summary, we have described an unusual case of presumed Pseudonaja envenoming in which an 88-year-old woman was unknowingly bitten, as she came to the aid of her dog while her dog was bitten by a snake highly likely to be a P. textilis. The patient had a sudden onset of confusion followed by loss of consciousness, coagulopathy with active, brisk bleeding, signs and symptoms consistent with those present in Pseudonaja spp. envenoming. She also developed a right homonymous hemianopia, and cardiovascular complications including a NSTEMI and minor TIA, both likely due to thromboembolic events. Fortunately, she recovered without any major disabling sequela. This ‘instructive’ case emphasises the central importance of procuring a detailed history that, in combination with clinical acumen, can guide patient-centered management and provide the best chance for a positive outcome.
Final diagnosis Eastern brown snake (P. textilis) envenoming, severe, with cardiovascular complications.
Acknowledgement We gratefully acknowledge our patient’s cooperation and informed consent for documenting her case. Clinical Toxicology vol. 53 no. 8 2015
Australian brown snake (Pseudonaja) envenoming 839
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
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