Clinic
Studies
Brazil (São Paulo)
Cardoso et al. 1993: 121 Bothrops bites; identification: morphological (B. jararaca 43/121; B. jararacussu 1/121) or immunological (Bothrops 77/121) with ELISA (Theakston et al. 1977, Ho et al. 1986a). This study is a good approach to B. jararaca envenoming, under the following assumptions: 43/44 of the snakes brought in by the patients were morphologically identified as B. jararaca. 97% of patients treated for snakebite in the past at the 'Hospital Vital Brazil', where the study was conducted, had been bitten by B. jararaca (Jorge and Ribeiro 1990). Inclusion criteria: morphological or immunological identification of the snake as Bothrops and incoagulable blood or local swelling involving ≥2 segments.
Exclusion criteria: patients <7 years, >70 years, pregnant women, >48 h since the bite, patients who had already received antivenom, patients with signs of severe envenoming: kidney failure, systolic blood pressure <70 mmHg at at least 2 time points with an interval of 10 min at the initial investigation, swelling involving the entire extremity and extending to the trunk, difference in swelling between the two sides of the body of >30%.
Classification
- Local envenoming:
- extent of the swelling (grade 1–6; scale of Warrell et al. 1974);
- intensity of the swelling (measurement method of Reid et al. 1963c);
- necrosis.
- Systemic envenoming
Criteria: spontaneous systemic bleeding (gingival, epistaxis, cutaneous, gastrointestinal, urogenital), shock (arterial hypotension with peripheral hypoperfusion), cardiac arrhythmias. Incoagulability on the clotting time test.
Case reports
Milani et al. 1997: 29 cases; identification: morphological 28/29, immunological 1/29.
Kouyoumdjian 1990: 2 cases, cited; identification of B. jararaca and B. jararacussu stated to be certain.
Wolff 1958 (cited in Kouyoumdjian 1990): 1 case; identification of B. jararacussu stated to be certain.
Regional differences in symptoms of envenoming
No data available.
Ontogenetic differences in symptoms of envenoming
Patients bitten by juvenile snakes appear to have a more severe course of envenoming with regard to the haemostatic effects (Franca et al. 1993, Furtado et al. 1991, Maruyama et al. 1990).
Signs & symptoms
Local effects
Local pain 116/121, local swelling 121/121 (reached a maximum within 24 h after hospitalisation), lymphadenopathy 92/121, no local bleeding 59/121, local bleeding 30/121, ecchymosis 72/121, local purpura 52/121.
Further course (after antivenom treatment): local blistering 24/121, local necrosis 7/121, local abscesses 12/121, local purpura 61/121 (Cardoso et al. 1993).
Local pain 28/29, local swelling 27/28, necrosis 6/28 (all snakes > 50cm) (Milani et al. 1997).
Haemostatic effects
Gingival bleeding 29/121, purpura 14/121, bleeding from recent wounds 17/121, conjunctival bleeding 2/121, macrohaematuria 2/121, uterine bleeding 1/121, haemoptysis 1/121 (Cardoso et al. 1993).
Intracranial haemorrhage with hemiplegia (2/2) (Kouyoumdjian 1990).
Intracranial haemorrhage with pituitary insufficiency (Wolff 1958).
Sponataneus systemic bleeding 2/28 (Milani et al. 1997).
Renal effects
Acute renal failure; secondary causes: arterial hypotension, shock, microthrombosis (DIC); primary causes: nephrotoxic venom components.
Renal failure 4/28 (all snakes > 50cm): acute renal tubular necrosis (autopsy result), bilateral cortical necrosis (in patient with chronic renal failure) (Milani et al. 1997).
Morbidity
The incidence of chronic morbidity is not known. It is estimated to be >1% (Cardoso et al. 1993). Of 121 patients with moderately severe envenoming, who were all successfully treated with antivenom with regard to their systemic signs of envenoming, 12/121 developed a local abscess, 7/121 local necrosis, 1 of these 7 had to have their thumb amputated (Cardoso et al. 1993). In 88/121 who were followed up 20–30 days after treatment, 62.5% were completely free of signs and symptoms, 4.5% had persistent pain, 23% still had local swelling, 5% necrosis, 6% abscesses (Cardoso et al. 1993). The average length of the hospital stay for the 121 patients with moderately severe envenoming treated with antivenom was 3–5 days (Cardoso et al. 1993).
Case fatality rate
0/121 patients treated with antivenom due to moderately severe envenoming (Cardoso et al. 1993).
Generally mortality in treated patients is estimated to be 0.8% (Ministerio da Saude 1990, cited in: Cardoso et al. 1993). The most important cause of death appears to be acute renal failure (Amaral et al. 1986), but also shock (Ministerio da Saude 1990, cited in: Cardoso et al. 1993). 2/2 (intracranial haemorrhage) (Kouyoumdjian 1990).
3/28 (all snakes > 50cm) (Milani et al. 1997).
Laboratory and physical investigations
1. Haemostasis
Studies
Kamiguti et al. 1991: 34 patients from a group of 89 who had been bitten by Bothrops (B. jararaca under the same assumptions as above: study of Cardoso et al. 1993) were investigated in detail.
Maruyama et al. 1990: 9 verified B. jararaca bites; identification: morphological 9/9: juvenile 5/9, adult 4/9. Patients with severe envenoming (hypotension, shock, massive haemorrhaging and marked oedema) were not included in the study.
Kamiguti et al. 1986: 78 B. jararaca bites (no information regarding how the snakes were identified).
Type of haemostatic defect
Defibrin(ogen)ation via direct fibrinogen-coagulating ("thrombin-like") activity, factor X activation (Nahas et al. 1979, Kamiguti et al. 1991).
Haemostatic parameters
| Overview haemostasis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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A
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B
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C
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C
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E
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F
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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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G
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D
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H
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Essential bed-side tests |
Tests for full clinical assessment | Tests for research purposes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A |
Haemorrhagic effects: damage to the endothelial cell layer by haemorrhagins plays a critical role in envenoming due to B. jararaca. This is suggested by the observation that patients with coagulable blood and thrombopaenia show systemic haemorrhaging (systemic bleeding in 6/18 patients with thrombopaenia and coagulable blood) (Kamiguti et al. 1991). Three haemorrhagins have been detected in B. jararaca venom (Mandelbaum et al. 1976, Assakura et al. 1986). They destroy the basal membrane of vessel walls (Ohsaka 1979). Locally they attack the endothelial cell layer of vessel walls from the outside, systemically from the luminal side. There are indications that α2-macroglobulin is a critical factor with regard to systemic effects of the venom, as this inhibitor controls the haemorrhagin activity of the venom (Kamiguti et al. 1993); the same may apply to cysteine protease inhibitors (Gonçalves et al. 1993). |
| B |
Clotting time: 50/89 had incoagulable blood, whereby 35/50 had systemic bleeding and 9/50 only local bleeding (Kamiguti et al. 1991). See also D for correlation of systemic bleeding – coagulability – thrombopaenia and A for the relationship between systemic bleeding – coagulability – thrombopaenia – vessel damage. |
| C | PT, aPTT: PT and aPTT outside the normal range (14/34) (Kamiguti et al. 1991). |
| D |
Fibrinogen: at the initial investigation 0.1–0.25 g/l in patients with incoagulable blood, 1.06–2.9 g/l in patients with coagulable blood (Kamiguti et al. 1991). Approx. 90 g/l (mean value, n = 99) (Cardoso et al. 1993). Bites caused by juvenile (<50 cm) *B. jararaca* led to more marked defibrinogenation and activation of the fibrinolytic system. Restoration of minimal haemostatic capacity (fibrinogen ≥100 mg%) occurred 12 h after antivenom administration in patients bitten by juvenile and adult *B. jararaca*; normal levels (>200 mg%) were achieved after 24 h (Franca et al. 1993).
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| E |
FSP: 0.5–2,048 μg/ml (normal <32 μg/ml) (Maruyama et al. 1990). Approx. 400 μg/ml (mean value, n = 97) (Cardoso et al. 1993). Fibrinogen split products were no longer detectable 24 h after antivenom treatment in patients bitten by juvenile and adult *B. jararaca* (Franca et al. 1993). |
| F | D-dimers: 0.5–64.0 μg/ml (normal <0.5 μg/ml) (Maruyama et al. 1990). Approx. 110 μg/ml (mean value, n = 82) (Cardoso et al. 1993). |
| G |
Platelets: in a group of 34 patients bitten by B. jararaca, 10/20 patients with incoagulable blood and 3/14 with coagulable blood had thrombopaenia, sometimes only in a mild form (28,000–135,000/μl) (Kamiguti et al. 1991). Thrombopaenias after B. jararaca bites have multifactorial origins, of which one element can probably be attributed to the aggregation-promoting activity of coagglutinin (Kamiguti et al. 1991). Another element is the platelet-aggregating activity of thrombin, which is generated by prothrombin and factor X activators (Kamiguti et al. 1986). Systemic bleeding after B. jararaca bites is correlated with the presence of thrombocytopaenia and is independent of the degree of coagulability of the blood. Two further factors that may contribute to systemic bleeding are damage to vessel walls (see A) and platelet function defects. Of those patients who had incoagulable blood and thrombopaenia, 22/27 had systemic bleeding, and in contrast, of those who had no thrombopaenia, only 13/23 had systemic bleeding. Of those patients who had coagulable blood and thrombopaenia, 6/18 had bleeding, and in contrast, of those who had no thrombopaenia, 0/21 had bleeding (these observations are drawn from a population of 89 patients bitten by *B. jararaca*) (Kamiguti et al. 1991). This correlation was not found for trauma-induced local bleeding outside the region of the bite marks (e.g. ecchymosis) (Kamiguti et al. 1991). |
| H | Inhibitors: α2-antiplasmin: approx. 0.2 IU/ml (mean value, n = 86) (Cardoso et al. 1993). |
2. Leucocytes
Mean values of the individual groups between 9,800 and 14,500/μl (Cardoso et al. 1993).
3. Haemoglobin
Within the normal range in 105 patients with moderately severe envenoming (Cardoso et al. 1993).
4. Histological examination of the kidneys
Acute tubular necrosis and renal cortical necrosis; mostly acute tubular necrosis (Da Silva et al. 1979; however, no details given regarding the method used to identify the snakes that had caused the bites); renal cortical necrosis (Amaral et al. 1985; however, the snakes that had caused the bites identified on the basis of statements by patients or their companions and clinical signs).
5. ELISA
With regard to their specificity, the ELISAs presently used for research purposes are suitable for indirect identification of the cause of a venomous snakebite at the genus level but not at the species level (Warrell 1993, pers. comm.). For further use of the ELISA method, see below, paragraph "Pharmacokinetics".
Dynamics of systemic envenoming
Signs of systemic envenoming may appear very late: incoagulability of the blood >12 h after admission to hospital (Cardoso et al. 1993).
Treatment (symptomatic)
Haemodialysis.
Treatment (specific)
Antivenoms
Polyspecific Bothrops antivenom Instituto Butantan (AIB);
polyspecific Bothrops antivenom Instituto Vital Brazil (AIVB);
polyspecific Bothrops antivenom Fundacao Ezequiel Dias (FUNED).
Studies (Brazil)
Cardoso et al. 1993: randomised comparative study of three antivenoms: polyspecific Bothrops antivenom Instituto Butantan (AIB), polyspecific Bothrops antivenom Instituto Vital Brazil (AIVB), polyspecific Bothrops antivenom Fundacao Ezequiel Dias (FUNED) (all three antivenoms are produced using more or less the same method and are pepsin-digested, purified, polyspecific liquid antivenoms from horse serum) in 3 groups of patients with moderately severe envenoming. Each of the three patient groups was further divided into a subgroup with "more severe" envenoming (criteria: <7 and >60 years, local swelling involving 4 or 5 segments, hospitalisation <2 hours after the bite) and a subgroup with "milder" envenoming.
The time between the bite and administration of antivenom was on average 5 h.
Initial dose
Patients with "milder" envenoming: 40 ml. Patients with "more severe" envenoming: 80 ml.
Indication for a second dose (40 ml): blood still incoagulable >6 h after the initial dose or if the swelling has extended to 2 or more segments or if the percentage difference in the circumference of the affected extremity compared to the unaffected extremity exceeds 30%.
(See above for further details of the study design.)
Need for a second dose of antivenom:
- In the group who initially received 40 ml (13/89): 8/13 due to incoagulable blood >6 h after the bite, 2/13 due to delayed occurrence of incoagulability of the blood (12 h after hospitalisation), 2/13 due to recurrent incoagulability, 1/13 due to deterioration of the local symptoms.
- In the group who initially received 80 ml (7/32): 5/7 due to incoagulable blood >6 h after the bite, 1/7 due to delayed occurrence of incoagulability of the blood (18 h after the initial dose), 1/7 due to deterioration of the local symptoms.
In all patients who received a second antivenom dose, coagulability was restored within the subsequent 6 h.
Efficacy
- With regard to local cytotoxicity and necrosis formation: in all of the antivenom groups most patients experienced cessation of local cytotoxic activity. Nonetheless, 9/121 developed local necrosis and 10/121 local abscesses; in this regard, there was no statistically significant difference between the individual antivenom groups. As expected, in this study also there was no significant effect of antivenom treatment on the formation of necrosis (Cardoso et al. 1993).
- With regard to the haemostatic defect: in all of the antivenom groups most patients already experienced cessation of bleeding and normalisation of blood coagulability after the initial dose, at the latest after the second dose (Cardoso et al. 1993); see also above, paragraph Haemostasis.
Pharmacokinetics
Studies
Theakston et al. 1992: investigation of the effect of the three most important polyvalent Brazilian antivenoms on venom clearance in 118 patients (identification criteria, see above; Cardoso et al. 1993).
Clearance of venom and antivenom
Clearance of venom antigenaemia in the investigated patients with moderately severe envenoming took 4 days on average for all 3 antivenoms; in contrast, in the study of Ho et al. 1990, it took only 5 min. There is a range of reasons that could explain this discrepancy: different avidity of the antivenoms, different sensitivity of the assays used or incapacity of the polyspecific Brazilian antivenoms to neutralise all antigens (it is nevertheless unlikely that these antigens are responsible for toxic effects, as the clinical symptoms already started to improve while antigenaemia was still present). In contrast, serum antivenom levels were high for up to approx. 10 days after administration of the antivenom and were still detectable for up to 40 days (Theakston et al. 1992). See below for the consequences for antivenom dosage.
Adverse reactions
Acute antivenom reactions: chills (probably a pyrogenic reaction, this occurred in particular with AIB) 29/121, nausea/vomiting 18/121, urticaria 25/121 (anaphylaxis-like reactions). There were significantly more acute reactions with AIB (87%; AIVB: 37%; FUNED: 56%); serum sickness: 10/91 patients who were followed up (the low incidence of the late antivenom reaction can probably be explained by the fact that very many patients received antihistamines and adrenaline due to acute allergic reactions).
Evaluation and recommendations
All 3 antivenoms gave equally satisfactory results, as assessed by clinical and laboratory criteria (Cardoso et al. 1993).
The official recommendations of the Brazilian Ministry of Health (Secretaria de Estado da Saude 1982, cited in: Cardoso et al. 1993: moderately severe envenoming 6–8 vials of polyspecific Bothrops antivenom, severe envenoming ≥16 vials, at each administration, 1/3 of the dose s.c., 2/3 i.v.) appear to be too high in light of the available controlled clinical efficacy study of the 3 above-named antivenoms (Cardoso et al. 1993). This is supported by an investigation of the pharmacokinetics of venom and antivenom using the ELISA method (Theakston et al. 1992). Among other factors, unnecessarily high doses of antivenom are responsible for the high rate of adverse reactions observed.
Dose recommendations
Patients with moderately severe envenoming should not receive the 8-vial regime. An initial dose of 4 vials should be sufficient in the majority of cases. In future, it may even be possible to reduce the initial dose to 1–2 vials (however, this must be evaluated first) (Theakston et al. 1992). In cases of severe envenoming, an initial dose of 8 vials is sufficient, in this context also it may be possible to reduce this dose in future, depending on the results of further controlled clinical studies.
Effects of polyspecific Bothrops antivenom were not impressive (Milani et al. 1997).