Clinic
Studies
Myanmar
Myint-Lwin et al. 1985: 123 Vipera russelli siamensis bites (= Daboia russelli siamensis). Identification: morphological 77/123 or immunological (Khin-Ohn-Lwin et al. 1984) 46/123.
Classification
- No signs of envenoming 34/123.
- Local envenoming:
- Extent of the swelling (grade 1–6; scale of Warrell et al. 1974).
- Intensity of the swelling (method of Reid et al. 1963c). Local swelling as the only sign of envenoming: 35/123.
- Systemic envenoming 54/123. Criteria: incoagulable blood, arterial hypotension or renal failure.
The data in the study of Myint-Lwin et al. 1985 refer either to the total number of verified bites (n = 123) or to the number of snakebite patients with systemic envenoming (n = 54).
Study in which the species was not clearly identified or evidence for the identification was lacking
China
Sawai et al. 1992: 50 V. russelli bites are described.
Case reports
Myanmar
Than-Than et al. 1989: 3 patients who died from Vipera russelli siamensis bites (= Daboia russelli siamensis) (autopsy findings).
Signs & symptoms
Autopharmacological effects
Myanmar
Vomiting 3/123, early occurrence of syncope as a consequence of arterial hypotension 2/123, within 90 min after the bite, spontaneous recovery within minutes. 12–24 h after the bite: conjunctival oedema 13/54, conjunctival haemorrhage 3/54, effusions (pleural, peritoneal) 1/54, pulmonary oedema (Myint-Lwin et al. 1985).
Hypovolaemia and shock due to extensive loss of fluid into the tissue (Than-Than et al. 1989).
The underlying pathophysiological mechanism is probably an autopharmacological release of endogenous mediators, histamine, 5-hydroxytryptamine, kinins and prostaglandins, or a direct effect of the venom on the vessel walls. These substances cause increased (generalised) capillary permeability. The altered capillary permeability might also cause brain oedema, which would explain the decreased consciousness, generalised cerebral seizures and focal neurological signs (Than-Than et al. 1989).
Local effects
Myanmar
Local pain 99/123, onset within minutes at the site of the bite.
Local swelling 84/123, maximum 1–4 days after the bite. Degree of swelling: grade 1: 49/123; grade 4 or 5: 9/123; grade 6: 1/123. Mean maximum increase in the circumference of the bitten extremity 4.0 cm ± 6.1%. Local swelling in patients with systemic envenoming more marked than in patients without systemic envenoming. However, 5/123 had systemic envenoming without local signs (Myint-Lwin et al. 1985).
On the whole, local signs of envenoming due to Daboia russelli bites are quite mild compared to those caused by other viperids and in relation to the severity of the systemic envenoming. Daboia russelli is an important exception to the rule that a viper bite can be ruled out in the absence of local swelling (Warrell 1989).
Regional lymph nodes: pain 68/123, painful enlargement 66/123. Painful enlargement in patients with systemic envenoming 40/54 (Myint-Lwin et al. 1985).
China
Local swelling 43/50, necrosis 6/50 (Sawai et al. 1992).
Haemostatic effects
Myanmar
Persistent bleeding from bite marks 38/123, gingival bleeding 11/54, haematemesis 6/54, melaena 4/54, epistaxis 1/54, haematuria 39/54 (Myint-Lwin et al. 1985).
Haemoptysis (rare), menorrhagia and pre- and post-partum hemorrhaging (rare), intracerebral and subarachnoid haemorrhages (Warrell 1989).
Clinical signs of hypopituitarism: acute with severe headache, shock, signs of hypoglycaemia and loss of consciousness, onset 21 h–9 days after the bite (Burke 1990, Tun-Pe et al. 1987b). Chronic with hoarse voice, low drive, reduced libido, oligo/amenorrhoea, impotence, absence of pubic hair, hyperpigmentation, signs of hypothyroidism, Addisonian crisis possible (Tun-Pe et al. 1987b, Warrell 1989).
Pathophysiological cause most likely bleeding and deposition of fibrin microthrombi in the anterior hypophysis (Than-Than et al. 1989).
China
Systemic bleeding, e.g. ecchymosis, gingival bleeding, haematuria 12/50 (Sawai et al. 1992).
Renal effects
Myanmar
Pain in the sides (signs of ischaemia) 9/54, renal bed sensitive to percussion (signs of ischaemia) 21/54, oliguria <400 ml/24 h 24/54; in 21/24 patients, the sensitivity of the renal bed preceded the oliguria and thus represents a valuable criterion for imminent renal failure (sensitivity 0.7, specificity 0.9) (Myint-Lwin et al. 1985).
49/119 (Tun-Pe et al. 1991) and 5/15 (Thein-Than et al. 1991) patients with systemic envenoming developed acute renal failure.
Kidney damage possible due to primary effects of the venom (Ratcliffe et al. 1989) or arterial hypotension (Myint-Lwin et al. 1985). However, the early acute renal failure seems to be primarily a consequence of ischaemia due to microthrombosis in the context of disseminated intravascular coagulation (Than-Than et al. 1989, Thein-Than et al. 1991).
China
Oliguria (Sawai et al. 1992).
Other signs & symptoms
Epigastric pain 10/54 (Myint-Lwin et al. 1985).
Morbidity
Chronic pituitary insufficiency (Tun-Pe et al. 1987b), chronic renal failure.
Case fatality rate
10/123, 15 h–7 days after the bite (Myint-Lwin et al. 1985). Causes: peripheral circulatory failure, intracranial and gastrointestinal bleeding, acute hypophyseal-adrenocortical insufficiency, acute renal failure (Myint-Lwin et al. 1985, Than-Than et al. 1989).
1/50 (Sawai et al. 1992).
Laboratory and physical investigations
1. Haemostasis
Studies
1. Than-Than et al. 1987: 22 patients with Vipera russelli siamensis bites (= Daboia russelli siamensis) (identification: morphological) who showed no signs of systemic envenoming, such as systemic bleeding, local swelling or an abnormal clotting time, on admission to hospital 0.25–4 h after the bite. This patient population separated into 3 groups during the course of the observations. Group 1 (n1 = 5): no activation of the coagulation system that would have been detectable on the tests utilised. Group 2 (n2 = 6): sub-clinical activation of the coagulation system with minor abnormalities of some haemostatic parameters. Group 3 (n3 = 9): developed massive disseminated intravascular coagulation.
2. Than-Than et al. 1988: 42 patients with Vipera russelli siamensis bites (= Daboia russelli siamensis); identification: morphological or immunological (Khin-Ohn-Lwin et al. 1984): spontaneous systemic bleeding 23/42, hypotension 17/42, oliguria 15/42, of whom 5 died.
Type of haemostatic defect
Disseminated intravascular coagulation (Than-Than et al. 1987, 1988).
Haemostatic parameters
| Overview haemostasis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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A
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H
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H
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H
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H
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DH
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DH
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FI
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H | CT | (FSP) | Tc | PT | aPTT | TT | I | FSP | D | II | V | VIII | X | XIII | PC | ATIII | PI | tPA | α2AP | |||||||||||||||||||||||||||||||||||||||||||
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BI
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C
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EH
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EH
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E
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F
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GI
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GI
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Essential bed-side tests |
Tests for full clinical assessment | Tests for research purposes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A |
Clotting time (CT): an abnormal clotting time is a definite indication for administration of antivenom. However, this test is not sensitive enough to detect early but already clinically relevant haemostatic defects. 26 patients who had coagulable blood (clotting time test) at the time of hospitalisation were found to have incoagulable blood 30 min–26 h later. At the time of the initial investigation, certain clotting factors were already reduced, and proteinuria was already present (Myint-Lwin et al. 1985). Incoagulability of the blood can also develop days after the bite (Tun-Pe et al. 1991). Patients must be observed for a sufficiently long period in order to definitely rule out a coagulation disorder. The clotting time test can be performed at 6-hour intervals after the 1st administration of antivenom, in order to monitor the effect of the antivenom and to determine the need for further doses of antivenom (Myint-Lwin et al. 1985). |
| B |
Platelet count: on average 104,000/μl (25,000–197,000/μl). Thrombopaenia at the time of defibrin(ogen)ation 5/10: 25,000-89,000/μl. At this time point also platelet aggregation, especially in thrombocytopaenic patients (Than-Than et al. 1988). |
| C | Fibrinogen: in 32 patients on average 0.09 g/l (0–0.6 g/l) (Than-Than et al. 1988). |
| D |
FSP and D-dimers: FSP in 32 patients on average 1,614 μg/ml (350–3,500 μg/ml) (normal value <10 μg/ml); D-dimers in 12 patients on average 1,058 μg/ml (38–3,000 μg/ml) (normal value <0.2 μg/ml) (Than-Than et al. 1988). FSP >80 μg/ml could be used as a marker for imminent defibrin(ogen)ation. As an indicator for administration of antivenom, however, this laboratory parameter has only limited value, as the test is too time-consuming and kidney damage due to microthrombosis can already develop before defibrin(ogen)ation is detectable in the laboratory. There is an urgent need for tests that are able to detect systemic envenoming early on (Than-Than et al. 1987). A clear increase in D-dimers suggests secondary hyperfibrinolysis in reaction to disseminated intravascular coagulation (Woodhams et al. 1989). Serum FSP levels were monitored in 50 patients who had coagulable blood at the time of hospitalisation. Antivenom was administered as soon as FSP was ≥80 μg/ml. 28 of these patients developed incoagulable blood (20-min clotting time test). In 11 the incoagulability occurred between 2 h and 20 min and 4 h and 50 min after the bite, and in 7 between 6 h and 12 h and 30 min after the bite (Tun-Pe et al. 1991). This underlines the importance of a sufficiently long period of observation after a bite with repeated haemostatic investigations. |
| E |
Clotting factors: ↓ factor V, ↓ factor X, ↓ factor XIIIa (Than-Than et al. 1988). |
| F |
Inhibitors: ↓ protein C, ATIII normal (see I below) (Than-Than et al. 1988). |
| G |
Fibrinolysis parameters: ↓ plasminogen, ↓ α2-antiplasmin (Than-Than et al. 1988). |
| H |
Laboratory parameters that showed abnormal trends within the first 5 h after the bite and are suitable to identify those patients with a risk of defibrination. Factors V and X are also suitable for this purpose (Than-Than et al. 1987). |
| I |
Laboratory parameters that showed irregular abnormal trends within the first 5 h after the bite and are thus not suitable markers in the early phase of envenoming. Furthermore, ATIII and α2-antiplasmin are not suitable for this purpose (Than-Than et al. 1987). In theory, ATIII, as an inhibitor of thrombin and factor X, should be decreased. However, as ATIII is an acute-phase protein and thus may be initially elevated as a reaction to envenoming, the increased consumption of ATIII is often masked. Measurement of ATIII at two different time points allows consumption to be determined (Than-Than et al. 1988). |
2. Leucocytes
In patients with systemic envenoming >10,000/μl (18/26) (Myint-Lwin et al. 1985).
3. Renal function
Studies
- Thein-Than et al. 1991: 24 Vipera russelli siamensis bites (= Daboia russelli siamensis); identification morphological; prospective study. All patients had coagulable blood at the time of hospitalisation (0.5–6.5 h after the bite). 15/24 developed severe defibrin(ogen)ation within 3–5 days. 10 of these 15 had mild renal dysfunction; however, this returned to normal with antivenom treatment. The other 5, who were all already oliguric at the time of hospitalisation, developed acute renal failure despite administration of antivenom. Acute renal failure developed very rapidly after the bite. Albuminuria is already present in the first 24 h after the bite, sometimes even much earlier. In the 5 patients with acute renal failure, the albuminuria preceded the oliguria and is thus a suitable early indicator of acute renal failure.
- Tin-Nu-Swe et al. 1993: 52 patients with V. r. siamensis bites who developed acute renal insufficiency (serum creatinine >1.3 mg/dl). Identification morphological and/or detection of specific venom antigen in the serum with ELISA; prospective study. Oliguria 32/52, urine output >400 ml/24 h 18/52. Oliguric patients more commonly had gastrointestinal bleeding, renal bed sensitive to percussion and conjunctival oedema, and the maximum serum creatinine values were significantly higher than in non-oliguric patients. The most likely cause of the renal dysfunction is proximal tubular necrosis.
4. Hypopituitarismus
Acute: hypoglycaemia, low levels of serum cortisol, plasma growth hormone and plasma prolactin (Tun-Pe et al. 1987b, Antonypillai et al. 2010).
Chronic: decreased levels of testosterone and thyroxine, diminished response of cortisol and growth hormone to hypoglycaemia (Tun-Pe et al. 1987b, Antonypillai et al. 2010).
5. ELISA
ELISA tests have been used in a number of studies in Myanmar for indirect identification of the cause of snakebite accidents (Khin-Ohn-Lwin et al. 1984, Myint-Lwin et al. 1985, Than-Than et al. 1988).
An improved ELISA test was used in a large study in Myanmar for indirect identification of the cause of snakebite accidents, in order to correlate the serum venom concentration with the severity of the envenoming and to investigate the dynamics of envenoming (Tun-Pe et al. 1991):
In 175 patients who did not bring the snake with them for identification, V. russelli was indirectly identified as the cause of the bite by an ELISA test in 101.
The serum venom antigen concentrations were higher in patients with systemic envenoming than in those with local symptoms of envenoming or an absence of symptoms. At the onset of the coagulation defect, they were higher the earlier after the bite the coagulation defect developed, and they increased as the coagulation defect developed. However, serum venom antigen concentrations cannot be directly correlated with the coagulability of the blood, as the assay does not only detect the fraction of the venom with a procoagulative action.
Furthermore, the measured serum venom antigen concentrations do not represent the actual amount of venom injected, as the venom undergoes tissue binding (Maung-Maung-Thwin et al. 1988). Venom is slowly released from a depot at the site of injection, so that the amount of venom measured in the serum also depends on the speed of absorption, which is influenced by various factors, including the muscular pump, which accelerates the transport of high-molecular weight venom components. The amount of venom measured is also dependent on the time period between the injection of venom and its measurement (Tun-Pe et al. 1991).
First aid
According to the information currently available, tourniquets appear to be largely ineffective and even caused additional damage in some cases (Warrell 1989, Tun-Pe et al. 1987a).
Treatment (symptomatic)
- Arterial hypotension (systolic blood pressure <80 mmHg for >10 min): patient characteristics: 19/123 became hypotensive within 4–38 h after the bite (on average 18.9 h). Mean lowest blood pressure after admission to hospital 60.2 mmHg (0–76 mmHg). 11 of the 19 hypotensive patients had clinical signs of bleeding: only gingival bleeding or bleeding from venipunctures or incisions (6/11), haematemesis (3/11), melaena (2/11). 10 of the 19 hypotensive patients developed oliguric renal failure (Myint-Lwin et al. 1985).
Treatment: holding the head lower than the rest of the body and dextran 40 i.v., physiological salt solution and whole blood until the central venous pressure is 0 to +5 cmH2O. Improvement of blood pressure through volume replacement therapy (11/19). If blood pressure did not improve with volume replacement therapy: dopamine 2–15 μg/kg body weight/min i.v. (infusion). Improvement of blood pressure with this treatment (6/7); in 1 of these patients blood pressure was not measurable beforehand (Myint-Lwin et al. 1985). - Acute hypopituitarismus: patient characteristics: shock in combination with strong headache, impaired consciousness and other neurological signs of hypoglycaemia (Warrell 1989, Antonypillai et al. 2010).
Treatment: Glucose and hydrocortisone (50–100 mg) i.v. (no i.m. administration due to concurrent coagulopathy) (Warrell 1989, Burke 1990, Antonypillai et al. 2010). - Chronic hypopituitarismus: Replacement of deficient hormones. Those who develop diabetes insipidus can be managed with vasopressin or desmopressin (Antonypillai et al. 2010).
- Renal failure: patient characteristics: 24/123 developed oliguria. 21/123 patients who were hospitalised on average 5 h after the bite became oliguric on the 1st day in hospital, 3/123 on the 2nd and 3rd day (Myint-Lwin et al. 1985).
Treatment: dialysis, if <400 ml urine/24 h despite rehydration, furosemide (up to 500 mg i.v.) and dopamine (2–5 μg/kg body weight/min) and if serum urea increasing. The prognosis for the recovery of renal function is good if the uraemic stage can be controlled with the help of dialysis (Myint-Lwin et al. 1985). In 10/28 oliguric patients treated with furosemide and dopamine, urine ouptut increased to >400 ml/24 h within 24–72 h. In 18/28 this treatment had no effect on urine output. The patients who did not respond to this treatment more frequently had spontaneous gingival bleeding and arterial hypotension (<80 mmHg) at the initial investigation and higher maximum blood urea levels and urine albumin concentrations. In none of the patients who responded to the furosemide/dopamine treatment was the renal bed sensitive to percussion or conjunctival oedema present. The time period between the bite and hospitalisation, as well as the initial venom antigen levels in the blood, were comparable between the two groups (Tin-Nu-Swe et al. 1993). - Bleeding affecting the circulation: see also 1. Arterial hypotension.
Treatment: blood transfusion (Myint-Lwin et al. 1985). - Haemostatic defect: treatment with heparin: restoration of blood coagulability was not essentially affected by additional treatment with heparin. Only in patients who initially had very low fibrinogen levels did this additional heparin treatment speed up the process of normalisation somewhat. If antivenom administration is commenced sufficiently early, the use of heparin is definitely not necessary (Myint-Lwin et al. 1989).
Treatment (specific)
Antivenom
Russell's viper antivenom, Industry and Pharmaceutical Corporation, Rangoon, Myanmar.
Efficacy
- With regard to the haemostatic effect of the venom (coagulability):
Dose: single administration of 10 vials.
In all 18 patients who received this dose, blood coagulability was restored. 7 of them were observed closely. Their blood was coagulable again after 3–6 h (geometric mean 4 h) (clotting time test), a normal clot observation test was observed after 4–48 h (geometric mean 14.5 h) (Myint-Lwin et al. 1985).
Dose: initial dose 4 vials.
9/36 patients who received this dose still had incoagulable blood 6 h later. After this dose was repeated, blood coagulability was also restored in these patients (Myint-Lwin et al. 1985).
- With regard to acute renal failure:
Oliguria developed in 9/22 patients who received 4–10 vials of antivenom within less than 4 h after the bite (Myint-Lwin et al. 1985).
Dosage intevals
Repeated doses at well-timed intervals (haemostatic parameters as a guide, see that section) are better suited to maintaining an optimal serum level of antivenom than a single bolus administration, as the elimination rate of the antivenom is almost twice as high as that of the venom (Maung-Maung-Thwin et al. 1988).
Adverse reactions
Pyrogenic reactions 54/54, 38 ± 10 min after the start of infusion (Myint-Lwin et al. 1985). Severe anaphylactic reactions including bronchospasm within 30 min after the start of antivenom administration (7/54). All of these patients responded immediately to administration of 0.1% adrenaline s.c. and chlorpheniramine i.v. (Myint-Lwin et al. 1985).
Evaluation
Russell's viper antivenom, Industry and Pharmaceutical Corporation, Rangoon, Myanmar, is very efficient with regard to restoring blood coagulability. However, it is apparently not able to prevent oliguria, even if administered less than 4 h after the bite (Myint-Lwin et al. 1985). The antivenom needs to be improved with regard to pyrogenic and anaphylactic reactions.
Antivenom indications
List of antivenom indications (Warrell 1989, 1990b).
- Blood incoagulability (see Haemostatic parameters)
- Spontaneous systemic bleeding
- Impaired consciousness
- Intravascular haemolysis
- Local swelling involving >2 segments of the extremity
- Painful enlargement of regional lymph nodes (Myint-Lwin et al. 1985).
69/123 patients developed no systemic signs of envenoming (Myint-Lwin et al. 1985). Conclusion: administration of antivenom is only justified if unambiguous signs of systemic envenoming are evident after the bite.