Toxicon 85 (2014) 17–26
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Clinical report
The Australian mulga snake (Pseudechis australis: Elapidae): Report of a large case series of bites and review of current knowledge Shahab Razavi a, b, Scott A. Weinstein a, David J. Bates a, *, Sam Alfred c, Julian White a a b c
Toxinology Department, Women’s & Children’s Hospital, North Adelaide, SA 5006, Australia Medical School, University of Bristol, Bristol BS8 1TH, UK Emergency Department, Royal Adelaide Hospital, North Tce, Adelaide, SA 5000, Australia
a r t i c l e i n f o Article history: Received 20 November 2013 Received in revised form 28 March 2014 Accepted 3 April 2014 Available online 13 April 2014 Keywords: Mulga snake Pseudechis australis Clinical case Envenoming Myotoxicity Local effects
a b s t r a c t Background: The mulga snake (Pseudechis australis) is the largest terrestrial venomous snake in Australia. It is capable of inflicting severe and occasionally fatal envenoming, but there have been few studies of P. australis bites. Objectives: To highlight and reinforce the main features of P. australis envenoming and to provide a clearer picture of the epidemiology of bites from this species. Methods: Selected case records kept by the Toxinology Dept. (Women’s and Children’s Hospital, Adelaide, Australia) were reviewed retrospectively to determine definite P. australis bites. Inclusion criteria: definite cases where the snake was identified by a competent person and/or lab specimens (bite site/urine) tested positive for “black snake” using CSL snake venom detection kit in a locality within the known range of P. australis, but without sympatry with other Pseudechis spp. Exclusion criteria: where the snake could not be clearly identified under criteria above. Epidemiological and clinical information was recorded and analysed for the definite cases. Results: A total of 27 cases were identified as definite P. australis bites; there were no fatalities. The median age was 35.5 years (IQR 51-23) and 80% of bites occurred in males. More bites occurred in the warmer months (Dec–March) and in those handling/interfering with snakes. Seven people were bitten whilst asleep at night. 21/27 patients developed systemic envenoming (based on signs, symptoms and laboratory results) and 17 cases received antivenom. Local bite site pain (18) and swelling (17) were common as were nonspecific generalised symptoms such as nausea, vomiting and headache. Myotoxicity (11) and anticoagulant coagulopathy (10) occurred frequently; haemolysis was seen in fewer cases (3). Two patients developed local tissue injury around the bite site requiring further treatment. Conclusions: This study confirms previous reports about P. australis bites with respect to high rates of envenoming, commonly associated with pain and swelling and systemic effects of rhabdomyolysis and anticoagulant coagulopathy. Systemic envenoming, even severe cases, responds well to antivenom therapy. Compared to other Australian snakes, a
Abbreviations: ASP, Australian Snakebite Project; BSAV, Black Snake Antivenom; PBI, Pressure Bandage Immobilisation; PVAV, Polyvalent Snake Antivenom; SVDK, Snake Venom Detection Kit; Australian States – NSW, New South Wales; NT, Northern Territory; QLD, Queensland; SA, South Australia; VIC, Victoria; WA, Western Australia. * Corresponding author. Tel.: þ61 8 8161 6525. E-mail address: [email protected] (D.J. Bates). http://dx.doi.org/10.1016/j.toxicon.2014.04.003 0041-0101/Ó 2014 Elsevier Ltd. All rights reserved.
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high proportion of bites occur in people asleep at night. Medically significant local tissue injury around the bite site may occur and may be associated with inappropriate first-aid, particularly the vascular occlusive type. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction The mulga snake (Pseudechis australis: Elapidae) is the largest terrestrial venomous snake species in Australia (Fig. 1), with a wide geographical distribution in arid, semiarid and tropical savannah habitats covering most inland and northern mainland Australia. P. australis bites are probably associated with large venom yields (Morrison et al., 1983) and often produce severe envenoming (Sutherland and Tibballs, 2001; White, 1987, 1992). However fatalities have rarely occurred with the last reported fatality more than 40 years ago (Rowlands et al., 1969). In experiments on mice, mulga snakes were found to inject the greatest mean mass of venom (62 mg dry weight during an initial bite) compared with other medically important Australian elapids tested (Morrison et al., 1983); considerably more than the death adder (Acanthophis antarcticus) that delivered the second highest amount (36 mg dry weight). Morrison et al. (1983) also demonstrated that on average, very little of the venom remains on the skin (0.07 mg dry weight), compared to all other tested species. P. australis venom contains a broad variety of toxins (Hodgson and Wickramaratna, 2006) and anticoagulants (Dambisya et al., 1995) including myotoxic and neurotoxic PLA2s, but lacks the potent prothrombin-converting procoagulants found in many medically important Australian elapid venoms with high lethal potency (White, 2005). There have been few studies of bites by P. australis, mostly limited to single cases (Campbell, 1984), or a series within broader studies (Currie, 2004; Isbister and Currie, 2003; White, 1987, 1992). A recent paper (Johnston et al., 2013) reviewed 17 cases from the Australian Snakebite Project (ASP*) with particular focus on envenoming and antivenom therapy.
This paper reviews the clinical experience of the Toxinology Department (Women’s and Children’s Hospital, Adelaide, Australia) with P. australis bites using to date the largest cohort of cases from the past 30þ years. The inclusion criteria used were more encompassing than those of the ASP study, which included cases only where snakes were expertly identified or the presence of mulga snake venom was confirmed by enzyme immunoassay of blood samples (Johnston et al., 2013). The present study therefore provides a broader picture of the clinical spectrum of envenoming caused by P. australis bites. We highlight and reinforce the main features of P. australis envenoming, but also provide a clear and somewhat different overall picture of the circumstances under which bites are encountered. 2. Methods The authors (one or more) have had direct clinical involvement with every case in this study, either through telephone consultation or bedside treatment. The records kept by one of us (JW) prospectively over the last 35 years were searched for cases that might be consistent with P. australis bite, based on snake identification, geographic location, or nature of clinical effects and data recorded in a database created for this purpose. Inclusion/exclusion criteria were then developed and applied, to refine the cases to one of two groups; bites by P. australis that were (A) definite, or (B) possible but unconfirmed. This last group was then excluded. The remaining cases were reviewed, details expanded from the clinical notes where possible, and were analysed retrospectively. A. Inclusion criteria Evidence of definite P. australis bites i.e. (1) cases where the snake causing the bite was caught/killed and identified by a competent person, or (2) cases that occurred in a region known to contain P. australis, but not other members of genus Pseudechis, for which a specimen (bite site or urine) tested positive for black snake/mulga snake venom (positive well 3) using the CSL snake venom detection kit (SVDK). B. Exclusion criteria
Fig. 1. A specimen of the mulga snake, Pseudechis australis.
Possible but unconfirmed mulga snake bites i.e. cases in the correct geographical region exhibiting some clinical features associated with mulga snake bite, but without sufficient data to confirm the identity of the snake. The available clinical notes made at the time of clinical presentation from cases meeting inclusion criteria were studied retrospectively to gain greater detail, specifically considering clinical symptoms and signs (local and
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systemic), with emphasis on local effects at the bite site, presence of systemic rhabdomyolysis, haemolysis and anticoagulant-type coagulopathy. Systemic envenoming was defined as one or more of: significant general symptoms of envenoming (severe headache, vomiting, marked abdominal pain), rhabdomyolysis (elevated CK, >1000 IU/ L), coagulopathy (aPTT > 39s). The epidemiology of bites was considered, with emphasis on whether the bite involved the victim’s intentional handling or killing of the snake, or occurred as a result of the victim’s accidental contact with a snake. For the latter type of bite, the circumstances of the bite were further examined. Treatment and outcomes were also considered. Due to the limited number of cases and heterogeneity of available information, statistical analysis was not applied.
3. Results A total of 27 cases met the inclusion criteria and were classed as definite P. australis bites; there were no reported fatalities. Table 1 summarises the clinical findings of these cases, and Fig. 2 shows examples of the local tissue reaction and swelling resulting from bites by P. australis. A further eight cases were identified as possible P. australis bites, but did not satisfy the inclusion criteria. The location of our service in South Australia has resulted in case selection bias towards this state (14/27) so that the data are not indicative of the national distribution of P. australis bite cases. However, all other mainland states and territories are represented with at least one case (up to four), demonstrating both the wide Australian distribution of P. australis, and the extent of interstate referral to our centre. More bites occurred in the warmer months from December to March (Fig. 3). The vast majority of bites (80%) occurred in males and the median age was 35.5 years (IQR 51-23). The highest proportion of bites resulted from intentional contact (e.g. people feeding or handling the snake) (Fig. 4). All bites that resulted from unintentional contact with the snake took place in rural areas, and seven of the 10 cases occurred when the patient was asleep (but not intoxicated) during the early hours of the morning (between midnight and 5:00am). Of these, four occurred whilst the victim was asleep in bed inside a dwelling, one whilst sleeping inside a shearing shed and two whilst sleeping on the ground outside. All bites were inflicted on the limbs, and those involving the upper extremities in particular were commonly a consequence of handling the snake. Some form of first aid was recorded on 15 occasions (Fig. 5b). The recommended pressure bandage immobilisation (PBI) was used in 12 cases. In one episode (case #24) involving an 18-year-old female, a tight PBI was employed and she later developed tissue necrosis around the bite site. This case is described in more detail in the discussion. Twenty-one cases met criteria for systemic envenoming based on signs, symptoms and laboratory findings, and three did not, although one of these cases demonstrated local envenoming. In the remaining three cases, there were insufficient data to make conclusions about whether they were envenomed.
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Nine cases were considered severe based on signs, symptoms and laboratory findings. These cases featured major rhabdomyolysis (CK > 10,000 IU/L) and/or markedly elevated aPTT/INR readings. Serial laboratory data obtained in cases #24 & #25 indicated an anticoagulation coagulopathy (case #24: aPTT 51 s at 4 h; case #25 aPTT 49 s at 8.2 h [normal range 24–38 s)) that respectively resolved within 12–12.5 h post-envenoming. In case #24, a transient thrombocytopenia (platelets 132 109/L [normal range 150–400 109/L]) was noted 24 h post-envenoming, and resolved by day 5. The patient’s haemoglobin decreased to 59 (normal range 115–155 g/L) on day 4, and the patient remained anaemic for over 3 wk with resolution after 6 wk post-envenoming. In case #25, the patient had a borderline normal haemoglobin at 60 h, but did not develop anaemia. However, this 17 yr old male did exhibit a transient mild leucocytosis concomitant with a brief lymphocytopenia (lymphocytes 0.52 at 12.5 h [normal range 1.00–3.50 109/ L]) that were within normal limits by day 3. Most notably, both of these patients showed rapid signs of rhabomyolysis: in case #24, the CK peaked 50,350 U/L at 20 h post-envenoming, and LDH reached 1814 U/L at 31 h; in case #25, CK peaked 25,658 U/L at 12.5 h. As the patient in case #24 was in particular provided with aggressive intravenous resuscitation, the creatinine was low, but renal function remained within normal limits in both patients, and CK gradually declined to normal over 7–10 d postenvenoming. In both cases aPTT returned to normal range following administration of CSL Black Snake Antivenom (BSAV), but as noted, CK levels remained elevated for a number of days. None of the patients developed renal failure secondary to rhabdomyolysis, or developed spontaneous bleeding. Clinical features of the bites are shown in Fig. 6. Local pain, oedema or both were common. In four cases, bruising and/or wound discharge also occurred. Two patients (cases #1 & #24) developed long-term bite site sequelae (see ahead). Non-specific systemic symptoms such as nausea/vomiting, headache, abdominal pain and diarrhoea were common. Specific systemic signs and symptoms suggestive of more severe envenoming, such as myalgia and myoglobinuria also occurred frequently; however, ptosis occurred in only two cases. Fig. 6b includes the abnormal laboratory findings. There was evidence of myotoxicity (CK > 1000 IU/L) in 11 cases. A modestly elevated CK was also noted in four other cases. Myoglobinuria was recorded in seven patients. Blood results indicated the presence of anticoagulant coagulopathy in 10 cases, and there was evidence of haemolysis (haemoglobinaemia, elevated LDH and/or hyperbilirubinaemia) in three cases. In several cases there was also the presence of leucocytosis (N ¼ 6), but thrombocytopenia was less common (N ¼ 3). Antivenom was administered in 17 patients (Fig. 5a). A single vial was used on most occasions; however, two vials were given in five cases. The specific BSAV was used solely in 11 of these cases. In the five cases where two vials of antivenom were administered, three were a combination of CSL Polyvalent Snake Antivenom (PVAV) and BSAV. In these situations, the PVAV was always used first. Adverse
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Table 1 Summary of clinical information for the 27 cases analysed in this study. Case
Age (y) gender: State
Proof of bite
Bite site
Activity
First aid
Local effects
Systemic symptoms
Most abnormal lab results
Anti-venom
Other clinical features
1
24M: NT
Snake ID
R thumb
Catching snake
Tourniquet to base of thumb
Swelling
None reported
Prolonged whole blood clotting time
1 PVAVa
Partial loss of R thumb secondary to gangrene
2
Young adult F: SA
Snake ID
R ankle
PBI < 15 min
Severe pain plus erythema
1 PVAVb
22M: SA
Snake ID
R index finger
PBI < 15 min
Pain & swelling
Prolonged clotting time
2 BSAV (1 h & 6 h)
4
48M: SA
SVDK
R hand
Walking/trod-on
None
Pain & swelling
11M: SA
SVDK
R thumb
Trying to catch snake
None
Swelling
6
33M: SA
Snake ID
L thumb
Feeding pet snake
Constrictive bandage
Pain up L arm
Abdominal pain, vomiting & diarrhoea
7
M: SA
SVDK
Upper Limb
In garden
ND
Pain & swelling
Vomiting & diarrhoea
8
8M:SA
Snake ID
Upper Limb
ND
ND
Pain
Vomiting, abdominal pain & headache
9
54F: QLD
Snake ID & SVDK
Upper Limb (?)
ND
ND
None reported
10
57M:WA
Snake ID
Hand
ND
Tourniquet < 15 min
Swelling
Headache, nausea & cramping pain in arms & shoulders ND
CK 13758 LDH 961 AST 400 APTT 33 PT 15 CK 400 Early unclotted whole blood sample, CK 304 LDH 295 WCC 17.6 Haematuria APTT 31 INR 2.1 Plt 140 Myoglobinuria CK 400 APTT 37 Plt 235 Normal
None
5
Blurred vision, paraesthesia lower leg Headache, vomiting & stomach cramps Nausea & hypotension (90/65) Vomiting, abdominal pain
Normal (Antivenom used within 30 min)
3
Asleep outside in a swag at army training depot Feeding pet snake
ND
11 12
M:VIC 23M:SA
Snake ID Snake ID & SVDK
Hand L thumb
Pet snake Asleep in bed inside (bitten at 4.30am)
ND PBI within 15 min
Pain & swelling Pain, swelling & bruising
ND Headache, vomiting, abdominal pain, myalgia, diplopia
13
50F:NT
Snake ID & SVDK
Lower limb
ND
PBI within 15 min
Pain
Confusion
14
38M: WA
PBI within 15 min ND
Pain & swelling
ND
46M:VIC
Arm, hung on for >10 s 1st toe
ND
15
Snake ID & SVDK Snake ID
CK 1405 APTT 39 INR 1.3 CK 2750 CK 23,790 (peak 33 h) INR 1.2 APTT 28 WCC 38.3 Plt 153 Hb 123 Red urine CK 25,000 INR 1.3 APTT 44 WCC 38 Haemolysis (?) Myoglobinuria CK 4000
Discharging wound. Pain, swelling & bruising
Abdominal pain, diarrhoea, myalgia & malaise
CK 573 APTT 66 INR 1.3
1 PVAV (1 h) 1 BSAV (4 h) 1 BSAV (6 h)
Cellulitis L hand successfully treated with antibiotics
ND
1 PVAV (1 h) 1 BSAV None
Under influence of alcohol
1 BSAV 1 PVAV (3 h) 1 BSAV
2 BSAV
1 BSAV 1 BSAV (3 h)
Past history of autoimmune haemolytic anaemia. NFD
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Pet snake
Skin peeled 3 weeks post-bite but healed
Asleep in bed inside (bitten at midnight) Sleeping in shearing shed (bitten at 4am)
ND
Pain & swelling
Ptosis, myalgia, abdominal pain, diarrhoea
CK 1900 APTT 49 Dark urine
1 BSAV (5 h)
Sucked wound plus PBI after 1 h
Swelling, bruising & discharge
Vomiting, abdominal pain, diarrhoea, headache & myalgia
1 BSAV (16 h)
Asleep in bed inside (bitten at 1am) Pet snake
ND
Pain & swelling
Nausea, headache & abdominal pain
CK 12,000 APTT 43 INR 1.2 Myoglobinuria Normal
PBI
ND
None reported
CK 300
None
Asleep outside in a swag when woken at 5am by pain in arm
None
Pain & swelling
Nausea, abdominal pain, myalgia, diarrhoea
1 PVAV (10 h)
L middle finger
Snake keeper
PBI within 15 min
None reported
None reported
Snake ID & SVDK
R forearm
In garden playing with snake
PBI within 15 min
Pain & swelling
Vomiting, abdominal pain & diarrhoea
CK 1054 (post-AV) INR 1.5 APTT 36 LDH 545 Plt 103 WCC 13.9 Lymph 0.66 Hb 126 Initial tests normal CK 126 APTT 28 INR 1 CK 600 APTT 47
28M: QLD
Snake ID
Finger
Snake keeper handling snake
ND
ND
Vomiting, abdominal pain
ND
24
18F: SA
Snake ID & SVDK
L thigh
Asleep in bed inside (awoke at 3am to find a large snake >1.5 m in her bed)
PBI (tight application)
Severe pain, swelling & bruising
Abdominal pain, vomiting, headache, myalgia (ptosis & nystagmus resolved post antivenom)
25
17M:SA
SVDK
R hand
Fell on snake; bitten twice
PBI
Pain & swelling
26 27
M: SA SA
Snake ID Snake ID & SVDK
Upper Limb Lower Limb
Handling in zoo
PBI ND
ND ND
Headache, vomiting, diarrhoea, muscle pain & weakness. Tender axilla ND ND
CK 156 INR 1.8 APTT 93 CK 50,350 INR 1.2 APTT 51 LDH 1756 Bilirubin 81 Hb 65 Plt 107 Lymph 0.87 WCC 41.4 Myoglobinuria CK 25,658 APTT 49 WCC 26.1 Myoglobinuria ND ND
27M:QLD
Snake ID & SVDK
L foot
17
65M:SA
Snake ID
R middle finger
18
70M: SA
Snake ID & SVDK
L index finger
19
Adult M:VIC
Snake ID
20
60M: NSW
SVDK
Upper Limb plus hung-on R arm
21
39M: NT
Snake ID
22
9M: NT
23
None
None
1 BSAV
Skin swelling & discolouration around bite site plus fever: treated with flucloxacillin
1 BSAV (2 h)a
Full thickness necrosis around bite site requiring debridement & grafting; extensive post-envenoming rehab required
1 BSAV (9 h)c
Under influence of alcohol
None None
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ND ¼ No data; NFD ¼ No further data. a Generalised rash; no further complications. b Patient developed cough, breathlessness & bronchospasm requiring adrenaline. c Bronchospasm & rash, treated with adrenaline, promethazine & salbutamol.
Swelling & malaise lasted for weeks but recovered fully
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Fig. 2. Examples of local tissue reaction and swelling resulting from mulga snake bites, including cases used in this study; A, B. case #12, C. case #17, D. case #18, E. case #22, F. case #25.
reactions were reported on four occasions; two anaphylactic reactions were more severe and required adrenaline. 4. Discussion Consistent with previous studies (Johnston et al., 2013), our results show that documented P. australis bites occur across a wide geographical area and that most bites occur on the upper limbs of males. It should be noted that the 17 cases included for analysis by Johnston et al. (2013) were
completely different to the 27 cases included in our study. Our data are also concordant with the observation (Currie, 2004), that bites occur more frequently during the warmer months. Previously published information suggests that bites by P. australis most commonly occur as a result of handling/ interfering with snakes or walking/performing activities near snakes (Currie, 2004; Johnston et al., 2013). Bites resulting from intentional contact with snakes were also common in this study; however, seven patients were bitten
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Fig. 3. Monthly case distribution of cases of P. australis bite. The range of average maximum temperatures ( C) within the geographical spread of the cases is shown at the top of each bar. There is a clear predominance during the warmest months (December–March).
when asleep. This is noteworthy since it represents 70% of identified cases involving bites without intentional contact, and suggests that bites sustained during sleep may be more common than previously reported. In our experience in Australia, the only venomous snake bites occurring at night while the patient was asleep, where the snake responsible was identifiable, were caused by P. australis. There are three taxa of venomous snakes that have repetitively been associated with inflicting envenoming in sleeping victims, several species of kraits (Bungarus spp., Elapidae), African spitting cobras (Naja nigricollis and Naja mossambica, Elapidae) and the colubrine colubrid, Boiga irregularis (brown
Fig. 4. Human activity associated with P. australis bites. Note the predominance of cases involving intentional handling, but also the high frequency amongst cases involving unintentional contact of nocturnal bites occurring while the patient is asleep.
Fig. 5. (a) Antivenom use in P. australis bites (N ¼ 27); (b) Type and frequency of first aid in P. australis bites (N ¼ 27).
tree snake) (Fritts et al., 1994; Warrell, 2010; World Health Organisation, 2010). While the latter has caused several medically serious but non-fatal bites that may have been complicated by physical trauma (constriction of infant victims; Weinstein et al., 2011), the former two have caused numerous fatalities. Commonly in these previously reported cases, the victim is sleeping on the floor or near a low-lying window accessible to outside foliage. By contrast, in only two of the cases in the present study were the persons sleeping in a vulnerable position outside, and most often the bite occurred in the early hours of the morning whilst the victim was asleep in a bed inside a building, indicating that the snake had entered intentionally. The reason for this can only be speculated, but in one case (#24) for which we have most detail concerning the circumstances, the patient reported that she had placed several large bags on her front porch during a particularly hot day (approximately 41 C) in order to move her bed from the inner bed room to under the sole air conditioner that was located above the front door. She moved the bags back into this area shortly before retiring. It is possible that the snake had entered one of the bags left on the front porch and was inadvertently brought into the house. However, as is the likely case with Bungarus in India and Sri Lanka, these snakes may also seek rodent prey around human dwellings. The patient in case #24 reported that her rubbish bin was within 5 m of her front
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door, and thus may have attracted rodents close to her home. It is also possible that the snake may have been attracted to the victim’s body heat. Bite site pain, oedema, rhabdomyolysis, anticoagulant coagulopathy and haemolysis are recognised effects of P. australis bite, all concordant with our observations. In cases where systemic envenoming took place, antivenom was used in most cases, as it was in the two previous large group studies (Currie, 2004; Johnston et al., 2013). Where laboratory results were available for analysis, administration of antivenom was shown to reverse coagulopathy, as previously noted by Johnston et al. (2013). It appears that local complications were increased in severity due to the inappropriate application of first aid in two cases. In case #6 involving a constrictive bandage, it is unclear whether secondary infection occurred or if a direct venom effect caused the local pathology at the bite site. However, the patient’s hand healed without sequelae. Case #1 was also reported by Vines (1978) and later published by White (1981). In this case, it is likely that inappropriate first-aid contributed to tissue necrosis and subsequent amputation of the digit. Vines‘ report indicated that a tourniquet was placed on the upper arm. However, one of the authors (JW) recalls that after talking with the patient soon after the event, the victim reported that he had applied a tight narrow tourniquet (perhaps a rubber band) to the base of the thumb for around two hours. Although localised signs and symptoms of pain and swelling around the bite site have been well reported in the literature in the past (Currie, 2004; White, 1987, 1992), tissue necrosis is infrequently reported. Case #24 was previously reported by White et al. (2010) and is an unusual case involving an 18-year-old female who developed full thickness skin necrosis on her limb around the bite site, which required debridement and grafting. The development of the wound over days 1, 2 and 6 post-injury is shown in Fig. 7 (panels A, B, C respectively). She was bitten in bed by a large P. australis; examination of the bite site by one of the authors (SAW) shortly after the patient’s arrival in hospital suggested she might have been bitten more than once. The PBI was applied tightly, but not so tight as to constrict blood flow. She was severely envenomed suggesting that a large volume of venom had been injected by the snake. The autopsy report of the fatal case reported by Rowlands et al. (1969) stated that the patient had developed ‘severe subcutaneous oedema, haemorrhage and infiltration with neutrophils and eosinophils’. The patient had been bitten at least twice. In another case (Sutherland and Tibballs, 2001), a four-year-old child who was bitten multiple times on the lower leg had a tourniquet put in place. The patient later developed an abscess at the bite site that required draining. Venom-induced tissue damage was the considered primary cause of this complication. In an unpublished, but popularly publicised case of P. australis envenoming from the Northern Territory in 1998 (Adlam, 2009), a man who had received an estimated 9–12 bites developed such severe local tissue injury that a forequarter amputation of the affected upper limb was required. The clinical details of this case are unclear, but judging by the number of times he was bitten, it is likely that he had received a large volume of venom.
Fig. 6. (a) Local and non-specific systemic clinical features of P. australis bites (N ¼ 22); (b) Specific clinical features in P. australis bites (N ¼ 22).
The contribution to the local adverse effects of the tight PBI in case #24 is difficult to determine; however, it is unlikely to be the only causal factor (White et al., 2010). Tissue destruction secondary to P. australis envenoming, not directly attributed to inappropriate first aid, may have occurred and cannot be ruled out. It is possible that a very large volume of venom sequestered locally in a limb contributed to tissue destruction and further complications. In the early period after introduction of the PBI first aid method in 1978, there were several published reports of adverse local effects around the bite site in cases where the PBI was applied for a prolonged period (Frost, 1981; Harvey et al., 1982). These mostly involved tiger snakes (Notechis scutatus) bites. One of the authors (JW) has managed cases of bites by other Pseudechis spp. and by Notechis spp., where local tissue injury occurred around the bite area in association with either some form of restrictive, tourniquet-like bandage as first aid, or prolonged use of PBI. 5. Conclusions This study is concordant with earlier studies and case reports, indicating that P. australis bites in humans are associated with a high rate of medically significant envenoming. P. australis envenoming is characterised by pain, marked swelling and, occasionally, tissue damage around
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bites. However, there are insufficient cases in our study to confirm this association. Although this study is insufficient to determine appropriate antivenom doses for treating P. australis systemic envenoming, based on our clinical experience with many such cases, and largely supported by the literature, a single vial of CSL Black Snake Antivenom (or CSL Polyvalent Snake Antivenom, if BSAV is unavailable) is likely to be sufficient in most cases. However, we strongly caution against advising limitation of dosing to a single vial, as clinical circumstances of individual presentations should determine dosing and in severe cases a higher dose might be needed, as in our case #24. Funding None. Ethical statement All cases included in this study were analysed retrospectively using data taken from the personal records made by the treating clinician (i.e. not taken from medical case files), after de-identification. Clinical photos show only parts of the body affected by bites, without identifying features, and permission was given by all subjects for the photos to be taken and for them to be used in publications. Acknowledgement The authors thank their many colleagues who have participated in treating the patients included in the cases listed here. Conflict of interest statement The authors declare that there are no conflicts of interest. References
Fig. 7. Progression of the local necrotic tissue damage following P. australis bite in case #24; A. 1 day post-injury, B. 2 days post-injury, C. 6 days postinjury.
the bite site, with systemic effects featuring principally rhabdomyolysis and anticoagulant-type coagulopathy (e.g. significant elevation of aPTT). Unlike cases involving other medically important venomous Australian snakes, cases of envenoming by P. australis may occur while the patient is asleep at night. Use of inappropriate or prolonged first aid, particularly vascular-restrictive first aid, appears to be associated with extensive local tissue injury around the site of P. australis
Adlam, N., Feb. 13th 2009. How I Let a King Brown Bite Me Nine Times, Northern Territory News. www.ntnews.com.au (viewed May 2013). Campbell, C.H., 1984. Myotoxic paralysis and haemolytic anaemia due to king brown snake bite. Aust. N. Z. J. Med. 14, 169. Currie, B.J., 2004. Snakebite in tropical Australia: a prospective study in the “Top End” of the Northern Territory. Med. J. Aust. 181, 693–697. Dambisya, Y.M., Lee, T.L., Gopalakrishnakone, P., 1995. Anticoagulant effects of Pseudechis australis (Australian king brown snake) venom on human blood: a computerized thromboelastography study. Toxicon 33, 1378–1382. Fritts, T.H., McCoid, M.J., Haddock, R.L., 1994. Symptoms and circumstances associated with bites by the brown tree snake (Boiga irregularis). J. Herpetol. 28, 27–33. Frost, J., 1981. Tiger snake envenomation and muscle spasm. Med. J. Aust. 2, 579. Harvey, P.M., Tabrett, D.G., Solomons, B.J., Thomas, M.A.B., 1982. Envenomation by a King Island tiger snake (Notechis ater humphreysi). Med. J. Aust. 2, 192–193. Hodgson, W.C., Wickramaratna, J.C., 2006. Snake venoms and their toxins: an Australian perspective. Toxicon 48, 931–940. Isbister, G.K., Currie, B.J., 2003. Suspected snakebite: one year prospective study of emergency department presentations. Emerg. Med. 15, 160– 169. Johnston, C.I., Brown, S.G.A., O’Leary, M.A., Currie, B.J., Greenberg, R., Taylor, M., Barnes, C., White, J., Isbister, G.K., Investigators, A.S.P., 2013. Mulga snake (Pseudechis australis) envenoming: a spectrum of
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myotoxicity, anticoagulant coagulopathy, haemolysis and the role of early antivenom therapy – Australian Snakebite Project (ASP-19). Clin. Toxicol. 51, 417–424. Morrison, J.J., Pearn, J.H., Charles, N.T., Coulter, A.R., 1983. Further studies on the mass of venom injected by elapid snakes. Toxicon 21, 279–284. Rowlands, J.B., Mastagli, F.L., Kakulas, B.A., Hainswor., D., 1969. Clinical and pathological aspects of a fatal case of mulga (Pseudechis australis) snakebite. Med. J. Aust. 1, 226. Sutherland, S.K., Tibballs, J., 2001. Australian Animal Toxins: the Creatures, Their Toxins and Care of the Poisoned Patient, second ed. Oxford University Press, Melbourne. Vines, A., 1978. Severe local reaction to bite of king brown snake. Med. J. Aust. 1, 657. Warrell, D.A., 2010. WHO Guidelines for the Management of Snake-bites in South East Asia. World Health Organisation, Regional Office for South East Asia, New Delhi. Weinstein, S.A., Warrell, D.A., White, J., Keyler, D.E., 2011. Venomous Bites from Non-Venomous Snakes: a Critical Analysis of Risk and Management of Colubrid Snake Bites. Elsevier, London.
White, J., 1981. Ophidian envenomation: a South Australian perspective. In: Records of the Adelaide Children’s Hospital 1980–1981, vol. 2, pp. 311–421. White, J., 1987. A review of 105 cases of suspected snakebite in South Australia. In: Gopalakrishnakone, P., Tan, C. (Eds.), Progress in Venom and Toxin Research. Proceedings of the First Asia-Pacific Congress on Animal, Plant and Microbial Toxins Held in Singapore, June 24–27. National University of Singapore, pp. 15–19. Faculty of Medicine. White, J., 1992. A review of snakebites and suspected snakebites treated in South Australia with particular reference to reptile handlers. In: Gopalakrishnakone, P., Tan, C. (Eds.), Recent Advances in Toxinology. Venom and Toxin Research Group, Singapore. White, J., 2005. Snake venoms and coagulopathy. Toxicon 45, 951–967. White, J., Alfred, S., Weinstein, S., 2010. Local tissue injury after Australian snakebite. Clin. Toxicol. 48, 308–309. World Health Organisation, 2010. Guidelines for the Prevention and Clinical Management of Snake Bite in Africa. World Health Organisation, Regional Office for Africa, Brazzaville.
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Toxicon journal homepage: www.elsevier.com/locate/toxicon
Clinical report
The Australian mulga snake (Pseudechis australis: Elapidae): Report of a large case series of bites and review of current knowledge Shahab Razavi a, b, Scott A. Weinstein a, David J. Bates a, *, Sam Alfred c, Julian White a a b c
Toxinology Department, Women’s & Children’s Hospital, North Adelaide, SA 5006, Australia Medical School, University of Bristol, Bristol BS8 1TH, UK Emergency Department, Royal Adelaide Hospital, North Tce, Adelaide, SA 5000, Australia
a r t i c l e i n f o Article history: Received 20 November 2013 Received in revised form 28 March 2014 Accepted 3 April 2014 Available online 13 April 2014 Keywords: Mulga snake Pseudechis australis Clinical case Envenoming Myotoxicity Local effects
a b s t r a c t Background: The mulga snake (Pseudechis australis) is the largest terrestrial venomous snake in Australia. It is capable of inflicting severe and occasionally fatal envenoming, but there have been few studies of P. australis bites. Objectives: To highlight and reinforce the main features of P. australis envenoming and to provide a clearer picture of the epidemiology of bites from this species. Methods: Selected case records kept by the Toxinology Dept. (Women’s and Children’s Hospital, Adelaide, Australia) were reviewed retrospectively to determine definite P. australis bites. Inclusion criteria: definite cases where the snake was identified by a competent person and/or lab specimens (bite site/urine) tested positive for “black snake” using CSL snake venom detection kit in a locality within the known range of P. australis, but without sympatry with other Pseudechis spp. Exclusion criteria: where the snake could not be clearly identified under criteria above. Epidemiological and clinical information was recorded and analysed for the definite cases. Results: A total of 27 cases were identified as definite P. australis bites; there were no fatalities. The median age was 35.5 years (IQR 51-23) and 80% of bites occurred in males. More bites occurred in the warmer months (Dec–March) and in those handling/interfering with snakes. Seven people were bitten whilst asleep at night. 21/27 patients developed systemic envenoming (based on signs, symptoms and laboratory results) and 17 cases received antivenom. Local bite site pain (18) and swelling (17) were common as were nonspecific generalised symptoms such as nausea, vomiting and headache. Myotoxicity (11) and anticoagulant coagulopathy (10) occurred frequently; haemolysis was seen in fewer cases (3). Two patients developed local tissue injury around the bite site requiring further treatment. Conclusions: This study confirms previous reports about P. australis bites with respect to high rates of envenoming, commonly associated with pain and swelling and systemic effects of rhabdomyolysis and anticoagulant coagulopathy. Systemic envenoming, even severe cases, responds well to antivenom therapy. Compared to other Australian snakes, a
Abbreviations: ASP, Australian Snakebite Project; BSAV, Black Snake Antivenom; PBI, Pressure Bandage Immobilisation; PVAV, Polyvalent Snake Antivenom; SVDK, Snake Venom Detection Kit; Australian States – NSW, New South Wales; NT, Northern Territory; QLD, Queensland; SA, South Australia; VIC, Victoria; WA, Western Australia. * Corresponding author. Tel.: þ61 8 8161 6525. E-mail address: [email protected] (D.J. Bates). http://dx.doi.org/10.1016/j.toxicon.2014.04.003 0041-0101/Ó 2014 Elsevier Ltd. All rights reserved.
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high proportion of bites occur in people asleep at night. Medically significant local tissue injury around the bite site may occur and may be associated with inappropriate first-aid, particularly the vascular occlusive type. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction The mulga snake (Pseudechis australis: Elapidae) is the largest terrestrial venomous snake species in Australia (Fig. 1), with a wide geographical distribution in arid, semiarid and tropical savannah habitats covering most inland and northern mainland Australia. P. australis bites are probably associated with large venom yields (Morrison et al., 1983) and often produce severe envenoming (Sutherland and Tibballs, 2001; White, 1987, 1992). However fatalities have rarely occurred with the last reported fatality more than 40 years ago (Rowlands et al., 1969). In experiments on mice, mulga snakes were found to inject the greatest mean mass of venom (62 mg dry weight during an initial bite) compared with other medically important Australian elapids tested (Morrison et al., 1983); considerably more than the death adder (Acanthophis antarcticus) that delivered the second highest amount (36 mg dry weight). Morrison et al. (1983) also demonstrated that on average, very little of the venom remains on the skin (0.07 mg dry weight), compared to all other tested species. P. australis venom contains a broad variety of toxins (Hodgson and Wickramaratna, 2006) and anticoagulants (Dambisya et al., 1995) including myotoxic and neurotoxic PLA2s, but lacks the potent prothrombin-converting procoagulants found in many medically important Australian elapid venoms with high lethal potency (White, 2005). There have been few studies of bites by P. australis, mostly limited to single cases (Campbell, 1984), or a series within broader studies (Currie, 2004; Isbister and Currie, 2003; White, 1987, 1992). A recent paper (Johnston et al., 2013) reviewed 17 cases from the Australian Snakebite Project (ASP*) with particular focus on envenoming and antivenom therapy.
This paper reviews the clinical experience of the Toxinology Department (Women’s and Children’s Hospital, Adelaide, Australia) with P. australis bites using to date the largest cohort of cases from the past 30þ years. The inclusion criteria used were more encompassing than those of the ASP study, which included cases only where snakes were expertly identified or the presence of mulga snake venom was confirmed by enzyme immunoassay of blood samples (Johnston et al., 2013). The present study therefore provides a broader picture of the clinical spectrum of envenoming caused by P. australis bites. We highlight and reinforce the main features of P. australis envenoming, but also provide a clear and somewhat different overall picture of the circumstances under which bites are encountered. 2. Methods The authors (one or more) have had direct clinical involvement with every case in this study, either through telephone consultation or bedside treatment. The records kept by one of us (JW) prospectively over the last 35 years were searched for cases that might be consistent with P. australis bite, based on snake identification, geographic location, or nature of clinical effects and data recorded in a database created for this purpose. Inclusion/exclusion criteria were then developed and applied, to refine the cases to one of two groups; bites by P. australis that were (A) definite, or (B) possible but unconfirmed. This last group was then excluded. The remaining cases were reviewed, details expanded from the clinical notes where possible, and were analysed retrospectively. A. Inclusion criteria Evidence of definite P. australis bites i.e. (1) cases where the snake causing the bite was caught/killed and identified by a competent person, or (2) cases that occurred in a region known to contain P. australis, but not other members of genus Pseudechis, for which a specimen (bite site or urine) tested positive for black snake/mulga snake venom (positive well 3) using the CSL snake venom detection kit (SVDK). B. Exclusion criteria
Fig. 1. A specimen of the mulga snake, Pseudechis australis.
Possible but unconfirmed mulga snake bites i.e. cases in the correct geographical region exhibiting some clinical features associated with mulga snake bite, but without sufficient data to confirm the identity of the snake. The available clinical notes made at the time of clinical presentation from cases meeting inclusion criteria were studied retrospectively to gain greater detail, specifically considering clinical symptoms and signs (local and
S. Razavi et al. / Toxicon 85 (2014) 17–26
systemic), with emphasis on local effects at the bite site, presence of systemic rhabdomyolysis, haemolysis and anticoagulant-type coagulopathy. Systemic envenoming was defined as one or more of: significant general symptoms of envenoming (severe headache, vomiting, marked abdominal pain), rhabdomyolysis (elevated CK, >1000 IU/ L), coagulopathy (aPTT > 39s). The epidemiology of bites was considered, with emphasis on whether the bite involved the victim’s intentional handling or killing of the snake, or occurred as a result of the victim’s accidental contact with a snake. For the latter type of bite, the circumstances of the bite were further examined. Treatment and outcomes were also considered. Due to the limited number of cases and heterogeneity of available information, statistical analysis was not applied.
3. Results A total of 27 cases met the inclusion criteria and were classed as definite P. australis bites; there were no reported fatalities. Table 1 summarises the clinical findings of these cases, and Fig. 2 shows examples of the local tissue reaction and swelling resulting from bites by P. australis. A further eight cases were identified as possible P. australis bites, but did not satisfy the inclusion criteria. The location of our service in South Australia has resulted in case selection bias towards this state (14/27) so that the data are not indicative of the national distribution of P. australis bite cases. However, all other mainland states and territories are represented with at least one case (up to four), demonstrating both the wide Australian distribution of P. australis, and the extent of interstate referral to our centre. More bites occurred in the warmer months from December to March (Fig. 3). The vast majority of bites (80%) occurred in males and the median age was 35.5 years (IQR 51-23). The highest proportion of bites resulted from intentional contact (e.g. people feeding or handling the snake) (Fig. 4). All bites that resulted from unintentional contact with the snake took place in rural areas, and seven of the 10 cases occurred when the patient was asleep (but not intoxicated) during the early hours of the morning (between midnight and 5:00am). Of these, four occurred whilst the victim was asleep in bed inside a dwelling, one whilst sleeping inside a shearing shed and two whilst sleeping on the ground outside. All bites were inflicted on the limbs, and those involving the upper extremities in particular were commonly a consequence of handling the snake. Some form of first aid was recorded on 15 occasions (Fig. 5b). The recommended pressure bandage immobilisation (PBI) was used in 12 cases. In one episode (case #24) involving an 18-year-old female, a tight PBI was employed and she later developed tissue necrosis around the bite site. This case is described in more detail in the discussion. Twenty-one cases met criteria for systemic envenoming based on signs, symptoms and laboratory findings, and three did not, although one of these cases demonstrated local envenoming. In the remaining three cases, there were insufficient data to make conclusions about whether they were envenomed.
19
Nine cases were considered severe based on signs, symptoms and laboratory findings. These cases featured major rhabdomyolysis (CK > 10,000 IU/L) and/or markedly elevated aPTT/INR readings. Serial laboratory data obtained in cases #24 & #25 indicated an anticoagulation coagulopathy (case #24: aPTT 51 s at 4 h; case #25 aPTT 49 s at 8.2 h [normal range 24–38 s)) that respectively resolved within 12–12.5 h post-envenoming. In case #24, a transient thrombocytopenia (platelets 132 109/L [normal range 150–400 109/L]) was noted 24 h post-envenoming, and resolved by day 5. The patient’s haemoglobin decreased to 59 (normal range 115–155 g/L) on day 4, and the patient remained anaemic for over 3 wk with resolution after 6 wk post-envenoming. In case #25, the patient had a borderline normal haemoglobin at 60 h, but did not develop anaemia. However, this 17 yr old male did exhibit a transient mild leucocytosis concomitant with a brief lymphocytopenia (lymphocytes 0.52 at 12.5 h [normal range 1.00–3.50 109/ L]) that were within normal limits by day 3. Most notably, both of these patients showed rapid signs of rhabomyolysis: in case #24, the CK peaked 50,350 U/L at 20 h post-envenoming, and LDH reached 1814 U/L at 31 h; in case #25, CK peaked 25,658 U/L at 12.5 h. As the patient in case #24 was in particular provided with aggressive intravenous resuscitation, the creatinine was low, but renal function remained within normal limits in both patients, and CK gradually declined to normal over 7–10 d postenvenoming. In both cases aPTT returned to normal range following administration of CSL Black Snake Antivenom (BSAV), but as noted, CK levels remained elevated for a number of days. None of the patients developed renal failure secondary to rhabdomyolysis, or developed spontaneous bleeding. Clinical features of the bites are shown in Fig. 6. Local pain, oedema or both were common. In four cases, bruising and/or wound discharge also occurred. Two patients (cases #1 & #24) developed long-term bite site sequelae (see ahead). Non-specific systemic symptoms such as nausea/vomiting, headache, abdominal pain and diarrhoea were common. Specific systemic signs and symptoms suggestive of more severe envenoming, such as myalgia and myoglobinuria also occurred frequently; however, ptosis occurred in only two cases. Fig. 6b includes the abnormal laboratory findings. There was evidence of myotoxicity (CK > 1000 IU/L) in 11 cases. A modestly elevated CK was also noted in four other cases. Myoglobinuria was recorded in seven patients. Blood results indicated the presence of anticoagulant coagulopathy in 10 cases, and there was evidence of haemolysis (haemoglobinaemia, elevated LDH and/or hyperbilirubinaemia) in three cases. In several cases there was also the presence of leucocytosis (N ¼ 6), but thrombocytopenia was less common (N ¼ 3). Antivenom was administered in 17 patients (Fig. 5a). A single vial was used on most occasions; however, two vials were given in five cases. The specific BSAV was used solely in 11 of these cases. In the five cases where two vials of antivenom were administered, three were a combination of CSL Polyvalent Snake Antivenom (PVAV) and BSAV. In these situations, the PVAV was always used first. Adverse
20
Table 1 Summary of clinical information for the 27 cases analysed in this study. Case
Age (y) gender: State
Proof of bite
Bite site
Activity
First aid
Local effects
Systemic symptoms
Most abnormal lab results
Anti-venom
Other clinical features
1
24M: NT
Snake ID
R thumb
Catching snake
Tourniquet to base of thumb
Swelling
None reported
Prolonged whole blood clotting time
1 PVAVa
Partial loss of R thumb secondary to gangrene
2
Young adult F: SA
Snake ID
R ankle
PBI < 15 min
Severe pain plus erythema
1 PVAVb
22M: SA
Snake ID
R index finger
PBI < 15 min
Pain & swelling
Prolonged clotting time
2 BSAV (1 h & 6 h)
4
48M: SA
SVDK
R hand
Walking/trod-on
None
Pain & swelling
11M: SA
SVDK
R thumb
Trying to catch snake
None
Swelling
6
33M: SA
Snake ID
L thumb
Feeding pet snake
Constrictive bandage
Pain up L arm
Abdominal pain, vomiting & diarrhoea
7
M: SA
SVDK
Upper Limb
In garden
ND
Pain & swelling
Vomiting & diarrhoea
8
8M:SA
Snake ID
Upper Limb
ND
ND
Pain
Vomiting, abdominal pain & headache
9
54F: QLD
Snake ID & SVDK
Upper Limb (?)
ND
ND
None reported
10
57M:WA
Snake ID
Hand
ND
Tourniquet < 15 min
Swelling
Headache, nausea & cramping pain in arms & shoulders ND
CK 13758 LDH 961 AST 400 APTT 33 PT 15 CK 400 Early unclotted whole blood sample, CK 304 LDH 295 WCC 17.6 Haematuria APTT 31 INR 2.1 Plt 140 Myoglobinuria CK 400 APTT 37 Plt 235 Normal
None
5
Blurred vision, paraesthesia lower leg Headache, vomiting & stomach cramps Nausea & hypotension (90/65) Vomiting, abdominal pain
Normal (Antivenom used within 30 min)
3
Asleep outside in a swag at army training depot Feeding pet snake
ND
11 12
M:VIC 23M:SA
Snake ID Snake ID & SVDK
Hand L thumb
Pet snake Asleep in bed inside (bitten at 4.30am)
ND PBI within 15 min
Pain & swelling Pain, swelling & bruising
ND Headache, vomiting, abdominal pain, myalgia, diplopia
13
50F:NT
Snake ID & SVDK
Lower limb
ND
PBI within 15 min
Pain
Confusion
14
38M: WA
PBI within 15 min ND
Pain & swelling
ND
46M:VIC
Arm, hung on for >10 s 1st toe
ND
15
Snake ID & SVDK Snake ID
CK 1405 APTT 39 INR 1.3 CK 2750 CK 23,790 (peak 33 h) INR 1.2 APTT 28 WCC 38.3 Plt 153 Hb 123 Red urine CK 25,000 INR 1.3 APTT 44 WCC 38 Haemolysis (?) Myoglobinuria CK 4000
Discharging wound. Pain, swelling & bruising
Abdominal pain, diarrhoea, myalgia & malaise
CK 573 APTT 66 INR 1.3
1 PVAV (1 h) 1 BSAV (4 h) 1 BSAV (6 h)
Cellulitis L hand successfully treated with antibiotics
ND
1 PVAV (1 h) 1 BSAV None
Under influence of alcohol
1 BSAV 1 PVAV (3 h) 1 BSAV
2 BSAV
1 BSAV 1 BSAV (3 h)
Past history of autoimmune haemolytic anaemia. NFD
S. Razavi et al. / Toxicon 85 (2014) 17–26
Pet snake
Skin peeled 3 weeks post-bite but healed
Asleep in bed inside (bitten at midnight) Sleeping in shearing shed (bitten at 4am)
ND
Pain & swelling
Ptosis, myalgia, abdominal pain, diarrhoea
CK 1900 APTT 49 Dark urine
1 BSAV (5 h)
Sucked wound plus PBI after 1 h
Swelling, bruising & discharge
Vomiting, abdominal pain, diarrhoea, headache & myalgia
1 BSAV (16 h)
Asleep in bed inside (bitten at 1am) Pet snake
ND
Pain & swelling
Nausea, headache & abdominal pain
CK 12,000 APTT 43 INR 1.2 Myoglobinuria Normal
PBI
ND
None reported
CK 300
None
Asleep outside in a swag when woken at 5am by pain in arm
None
Pain & swelling
Nausea, abdominal pain, myalgia, diarrhoea
1 PVAV (10 h)
L middle finger
Snake keeper
PBI within 15 min
None reported
None reported
Snake ID & SVDK
R forearm
In garden playing with snake
PBI within 15 min
Pain & swelling
Vomiting, abdominal pain & diarrhoea
CK 1054 (post-AV) INR 1.5 APTT 36 LDH 545 Plt 103 WCC 13.9 Lymph 0.66 Hb 126 Initial tests normal CK 126 APTT 28 INR 1 CK 600 APTT 47
28M: QLD
Snake ID
Finger
Snake keeper handling snake
ND
ND
Vomiting, abdominal pain
ND
24
18F: SA
Snake ID & SVDK
L thigh
Asleep in bed inside (awoke at 3am to find a large snake >1.5 m in her bed)
PBI (tight application)
Severe pain, swelling & bruising
Abdominal pain, vomiting, headache, myalgia (ptosis & nystagmus resolved post antivenom)
25
17M:SA
SVDK
R hand
Fell on snake; bitten twice
PBI
Pain & swelling
26 27
M: SA SA
Snake ID Snake ID & SVDK
Upper Limb Lower Limb
Handling in zoo
PBI ND
ND ND
Headache, vomiting, diarrhoea, muscle pain & weakness. Tender axilla ND ND
CK 156 INR 1.8 APTT 93 CK 50,350 INR 1.2 APTT 51 LDH 1756 Bilirubin 81 Hb 65 Plt 107 Lymph 0.87 WCC 41.4 Myoglobinuria CK 25,658 APTT 49 WCC 26.1 Myoglobinuria ND ND
27M:QLD
Snake ID & SVDK
L foot
17
65M:SA
Snake ID
R middle finger
18
70M: SA
Snake ID & SVDK
L index finger
19
Adult M:VIC
Snake ID
20
60M: NSW
SVDK
Upper Limb plus hung-on R arm
21
39M: NT
Snake ID
22
9M: NT
23
None
None
1 BSAV
Skin swelling & discolouration around bite site plus fever: treated with flucloxacillin
1 BSAV (2 h)a
Full thickness necrosis around bite site requiring debridement & grafting; extensive post-envenoming rehab required
1 BSAV (9 h)c
Under influence of alcohol
None None
21
ND ¼ No data; NFD ¼ No further data. a Generalised rash; no further complications. b Patient developed cough, breathlessness & bronchospasm requiring adrenaline. c Bronchospasm & rash, treated with adrenaline, promethazine & salbutamol.
Swelling & malaise lasted for weeks but recovered fully
S. Razavi et al. / Toxicon 85 (2014) 17–26
16
22
S. Razavi et al. / Toxicon 85 (2014) 17–26
Fig. 2. Examples of local tissue reaction and swelling resulting from mulga snake bites, including cases used in this study; A, B. case #12, C. case #17, D. case #18, E. case #22, F. case #25.
reactions were reported on four occasions; two anaphylactic reactions were more severe and required adrenaline. 4. Discussion Consistent with previous studies (Johnston et al., 2013), our results show that documented P. australis bites occur across a wide geographical area and that most bites occur on the upper limbs of males. It should be noted that the 17 cases included for analysis by Johnston et al. (2013) were
completely different to the 27 cases included in our study. Our data are also concordant with the observation (Currie, 2004), that bites occur more frequently during the warmer months. Previously published information suggests that bites by P. australis most commonly occur as a result of handling/ interfering with snakes or walking/performing activities near snakes (Currie, 2004; Johnston et al., 2013). Bites resulting from intentional contact with snakes were also common in this study; however, seven patients were bitten
S. Razavi et al. / Toxicon 85 (2014) 17–26
23
Fig. 3. Monthly case distribution of cases of P. australis bite. The range of average maximum temperatures ( C) within the geographical spread of the cases is shown at the top of each bar. There is a clear predominance during the warmest months (December–March).
when asleep. This is noteworthy since it represents 70% of identified cases involving bites without intentional contact, and suggests that bites sustained during sleep may be more common than previously reported. In our experience in Australia, the only venomous snake bites occurring at night while the patient was asleep, where the snake responsible was identifiable, were caused by P. australis. There are three taxa of venomous snakes that have repetitively been associated with inflicting envenoming in sleeping victims, several species of kraits (Bungarus spp., Elapidae), African spitting cobras (Naja nigricollis and Naja mossambica, Elapidae) and the colubrine colubrid, Boiga irregularis (brown
Fig. 4. Human activity associated with P. australis bites. Note the predominance of cases involving intentional handling, but also the high frequency amongst cases involving unintentional contact of nocturnal bites occurring while the patient is asleep.
Fig. 5. (a) Antivenom use in P. australis bites (N ¼ 27); (b) Type and frequency of first aid in P. australis bites (N ¼ 27).
tree snake) (Fritts et al., 1994; Warrell, 2010; World Health Organisation, 2010). While the latter has caused several medically serious but non-fatal bites that may have been complicated by physical trauma (constriction of infant victims; Weinstein et al., 2011), the former two have caused numerous fatalities. Commonly in these previously reported cases, the victim is sleeping on the floor or near a low-lying window accessible to outside foliage. By contrast, in only two of the cases in the present study were the persons sleeping in a vulnerable position outside, and most often the bite occurred in the early hours of the morning whilst the victim was asleep in a bed inside a building, indicating that the snake had entered intentionally. The reason for this can only be speculated, but in one case (#24) for which we have most detail concerning the circumstances, the patient reported that she had placed several large bags on her front porch during a particularly hot day (approximately 41 C) in order to move her bed from the inner bed room to under the sole air conditioner that was located above the front door. She moved the bags back into this area shortly before retiring. It is possible that the snake had entered one of the bags left on the front porch and was inadvertently brought into the house. However, as is the likely case with Bungarus in India and Sri Lanka, these snakes may also seek rodent prey around human dwellings. The patient in case #24 reported that her rubbish bin was within 5 m of her front
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door, and thus may have attracted rodents close to her home. It is also possible that the snake may have been attracted to the victim’s body heat. Bite site pain, oedema, rhabdomyolysis, anticoagulant coagulopathy and haemolysis are recognised effects of P. australis bite, all concordant with our observations. In cases where systemic envenoming took place, antivenom was used in most cases, as it was in the two previous large group studies (Currie, 2004; Johnston et al., 2013). Where laboratory results were available for analysis, administration of antivenom was shown to reverse coagulopathy, as previously noted by Johnston et al. (2013). It appears that local complications were increased in severity due to the inappropriate application of first aid in two cases. In case #6 involving a constrictive bandage, it is unclear whether secondary infection occurred or if a direct venom effect caused the local pathology at the bite site. However, the patient’s hand healed without sequelae. Case #1 was also reported by Vines (1978) and later published by White (1981). In this case, it is likely that inappropriate first-aid contributed to tissue necrosis and subsequent amputation of the digit. Vines‘ report indicated that a tourniquet was placed on the upper arm. However, one of the authors (JW) recalls that after talking with the patient soon after the event, the victim reported that he had applied a tight narrow tourniquet (perhaps a rubber band) to the base of the thumb for around two hours. Although localised signs and symptoms of pain and swelling around the bite site have been well reported in the literature in the past (Currie, 2004; White, 1987, 1992), tissue necrosis is infrequently reported. Case #24 was previously reported by White et al. (2010) and is an unusual case involving an 18-year-old female who developed full thickness skin necrosis on her limb around the bite site, which required debridement and grafting. The development of the wound over days 1, 2 and 6 post-injury is shown in Fig. 7 (panels A, B, C respectively). She was bitten in bed by a large P. australis; examination of the bite site by one of the authors (SAW) shortly after the patient’s arrival in hospital suggested she might have been bitten more than once. The PBI was applied tightly, but not so tight as to constrict blood flow. She was severely envenomed suggesting that a large volume of venom had been injected by the snake. The autopsy report of the fatal case reported by Rowlands et al. (1969) stated that the patient had developed ‘severe subcutaneous oedema, haemorrhage and infiltration with neutrophils and eosinophils’. The patient had been bitten at least twice. In another case (Sutherland and Tibballs, 2001), a four-year-old child who was bitten multiple times on the lower leg had a tourniquet put in place. The patient later developed an abscess at the bite site that required draining. Venom-induced tissue damage was the considered primary cause of this complication. In an unpublished, but popularly publicised case of P. australis envenoming from the Northern Territory in 1998 (Adlam, 2009), a man who had received an estimated 9–12 bites developed such severe local tissue injury that a forequarter amputation of the affected upper limb was required. The clinical details of this case are unclear, but judging by the number of times he was bitten, it is likely that he had received a large volume of venom.
Fig. 6. (a) Local and non-specific systemic clinical features of P. australis bites (N ¼ 22); (b) Specific clinical features in P. australis bites (N ¼ 22).
The contribution to the local adverse effects of the tight PBI in case #24 is difficult to determine; however, it is unlikely to be the only causal factor (White et al., 2010). Tissue destruction secondary to P. australis envenoming, not directly attributed to inappropriate first aid, may have occurred and cannot be ruled out. It is possible that a very large volume of venom sequestered locally in a limb contributed to tissue destruction and further complications. In the early period after introduction of the PBI first aid method in 1978, there were several published reports of adverse local effects around the bite site in cases where the PBI was applied for a prolonged period (Frost, 1981; Harvey et al., 1982). These mostly involved tiger snakes (Notechis scutatus) bites. One of the authors (JW) has managed cases of bites by other Pseudechis spp. and by Notechis spp., where local tissue injury occurred around the bite area in association with either some form of restrictive, tourniquet-like bandage as first aid, or prolonged use of PBI. 5. Conclusions This study is concordant with earlier studies and case reports, indicating that P. australis bites in humans are associated with a high rate of medically significant envenoming. P. australis envenoming is characterised by pain, marked swelling and, occasionally, tissue damage around
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bites. However, there are insufficient cases in our study to confirm this association. Although this study is insufficient to determine appropriate antivenom doses for treating P. australis systemic envenoming, based on our clinical experience with many such cases, and largely supported by the literature, a single vial of CSL Black Snake Antivenom (or CSL Polyvalent Snake Antivenom, if BSAV is unavailable) is likely to be sufficient in most cases. However, we strongly caution against advising limitation of dosing to a single vial, as clinical circumstances of individual presentations should determine dosing and in severe cases a higher dose might be needed, as in our case #24. Funding None. Ethical statement All cases included in this study were analysed retrospectively using data taken from the personal records made by the treating clinician (i.e. not taken from medical case files), after de-identification. Clinical photos show only parts of the body affected by bites, without identifying features, and permission was given by all subjects for the photos to be taken and for them to be used in publications. Acknowledgement The authors thank their many colleagues who have participated in treating the patients included in the cases listed here. Conflict of interest statement The authors declare that there are no conflicts of interest. References
Fig. 7. Progression of the local necrotic tissue damage following P. australis bite in case #24; A. 1 day post-injury, B. 2 days post-injury, C. 6 days postinjury.
the bite site, with systemic effects featuring principally rhabdomyolysis and anticoagulant-type coagulopathy (e.g. significant elevation of aPTT). Unlike cases involving other medically important venomous Australian snakes, cases of envenoming by P. australis may occur while the patient is asleep at night. Use of inappropriate or prolonged first aid, particularly vascular-restrictive first aid, appears to be associated with extensive local tissue injury around the site of P. australis
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