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Clinic

 

Echis ocellatus

Studies

Nigeria
Warrell et al. 1977: 115 Echis ocellatus bites; identification: morphological 47/115, immunological (Greenwood et al. 1974) 15/115 or other indirect criteria: description of the snake by the patient plus incoagulable blood at the time of hospitalisation (inclusion criterion, as at that time no case of incoagulability of the blood caused by other species of snakes had been observed) 53/115.

Classification:

  • Local envenoming
    a) Extent of the swelling (grade 1–6; scale of Warrell et al. 1974).
    b) Intensity of the swelling (according to the method of Reid et al. 1963c).
  • Systemic envenoming
    Criteria:
    Clinical: spontaneous systemic bleeding (gingival, epistaxis, conjunctival, retinal, cutaneous, pulmonary, gastrointestinal, urogenital).
    Laboratory: clotting time.

Pugh and Theakston 1987a: 26 Echis ocellatus bites; identification: morphological 8/26; on the basis of the criteria of spontaneous bleeding and incoagulable blood (inclusion criterion, see above) 14/26; clinical, supported by immunological findings 4/26.

Case reports

Reid 1977: 1 Echis ocellatus bite; identification: morphological.

Signs & symptoms

Autopharmacological effects

Vomiting within the first 30 min after the bite 2/13 (Pugh and Theakston 1987a).

Local effects

Pain 114/115, onset within 10 min after the bite at the site of the bite in 80% of patients.

Swelling (study inclusion criterion) 115/115, onset within 30 min after the bite at the site of the bite in 60% of patients. Local swelling maximum of grade 3, i.e. involving the segment affected by the bite and the neighbouring segment. No difference between patients with and without bleeding. Therefore it is not an indicator of the severity of systemic envenoming.

Blisters 15/115; blister contents: Echis venom in 5/7 of the studied patients. This finding supports the notion of ongoing absorption of venom from the region around the site at which the venom entered the body.

Painful regional lymph nodes 88/115, in 23% within 30 min after the bite; painful enlargement of the regional lymph nodes 57/115 (Warrell et al. 1977).

Haemostatic effects

Spontaneous bleeding beyond the region of the bite wound 66/115. Bleeding from the bite mark/incision 92/115, duration of less than 10 min in 80% of patients. Subcutaneous and intramuscular haematomas. Gingival bleeding 40/115, bloody saliva 25/115, haematemesis 5/115, melaena 1/115, bloody stool 1/115. Epistaxis 10/115, haemoptysis (in the absence of another source of bleeding in the nose-throat region) 1/115, sublingual haematoma. Haematuria 32/115 (in 7/32 also S. haematobium eggs). Subconjunctival haemorrhage. Subarachnoid haemorrhage 3/115, of these 1/3 diagnosed post mortem, 1/3 clinical suspicion, 1/3 xanthochromic fluid (Warrell et al. 1977).

Renal effects

Acute renal failure 1/115, this patient had been hypotensive for a long time (Warrell et al. 1977). Thus there is no indication of primary nephrotoxicity.

Morbidity

Necroses 13/115, which appeared on average on the 6th (1st–13th) day after the bite and involved the skin, hypodermis and musculature. Osteomyelitis 1/115 (Warrell et al. 1977).

Necroses (3/26) (Pugh and Theakston 1987a).

Case fatality rate

Spontaneous bleeding is the most clinically significant consequence of envenoming and was the cause of death in all 5 fatalities from amongst the 115 patients who were bitten by Echis ocellatus; intracranial haemorrhage 2/5, of which 1/2 subarachnoid haemorrhage, 1/2 intracerebral haemorrhage; haemorrhagic shock 3/5, of which 1/3 gastrointestinal haemorrhage. 2 of these patients did not receive Behring antivenom, while the other 3 did. Without treatment the mortality rate is 10–20%; in a group of patients (n = 107) who received 10 and 110 ml of specific antivenom, it was reduced to 2.8% (Warrell et al. 1977).

Mortality 2/26, of which 1/2 subarachnoid haemorrhage, 1/2 complications of a tourniquet that was applied too tightly (Pugh and Theakston 1987a).

Severe (fatal) haemorrhaging occurs 1(2)–12 days after the bite (Warrell et al. 1977).

Laboratory and physical investigations

1. Haemostasis

Studies

Warrell et al. 1977 (see above for description of study)

Edgar et al. 1980

 

Type of haemostatic defect

Disseminated intravascular coagulation induced by direct activation of prothrombin and reactive (secondary) hyperfibrinolysis. Thrombopaenia (although this seemed to occur mainly in patients with severe envenoming). Little intravascular fibrin deposition (this is reflected in the low incidence of renal function impairment and microangiopathic haemolysis). Fibrin clearance appears to be very efficient. Haemorrhagic activity is present, which together with the coagulation defect is responsible for the systemic bleeding (Warrell et al. 1977, Edgar et al. 1980).


Haemostatic parameters


Overview haemostasis
 
A
+
 
B
 
            
C
 
C
 
                    
 
 H CT (FSP) Tc PT aPTT TT I FSP D II V VIII X XIII PC ATIII PI tPA α2AP
       
 
D
      
 
E
    
 
F
 
F
 
F
  
 
F
          
 

Essential

bed-side

tests

 Tests for full clinical assessment Tests for research purposes
H haemorhagic effects
+ definite evidence in
human envenoming
CT full blood clotting test
(FSP)  FSP rapid test
Tc platlets
PT prothrombin time
aPTT partial thromboplastin time
TT thrombin time
I fibrinogen
FSP  fibrinogen split products
D D-dimer
II, V, VII, X, XIII
  clotting factors
PC protein C
ATIII antithrombin III
PI plasminogen
tPA tissue plasmin activator
α2AP α2-antiplasmin
 
In this overview, the deviations from normal
are recorded for those haemostasis para-
meters only, for which good evidence is
documented in the literature.

 

A

Haemorrhagic activity: the venom contains an active haemorrhagic component that contributes to the bleeding risk. Additional endothelial damage due to venom-induced activation of complement is likely (Warrell et al. 1977).
B

Clotting time: clotting time was analysed at the time of hospitalisation in 86/115. 95% of them had incoagulable blood, in 5% coagulation occurred after 3–6 min (Warrell et al. 1977).

The haemostatic defect caused by an Echis ocellatus bite can appear within 75 min–27 h after the bite. Hence the necessity of observing such patients for a sufficient period of time before systemic envenoming can be excluded. Incoagulability of the blood can persist for up to 10 days after the bite, and ongoing spontaneous bleeding has been observed (up to 144 h after the bite). If the haemostatic defect is only mild [blood coagulable on clotting time test, small to normal clot on clot observation test, FSP 160–2,560 μg/ml (5/115)], normalisation of the haemostatic parameters occurs after 2–4 days (Warrell et al. 1977).
C

FSP, D-dimers: in a random sample of 18 patients on average 1,711 μg/ml (1 SD = 904 μg/ml) (normal range <4 μg/ml). FSP were also ≥160 μg/ml in 5/115 patients who had incoagulable blood according to the test criteria and who were not treated with antivenom (Warrell et al. 1977). Fibrin/fibrinogen split products consist mainly of D-fragments. In some patients significant amounts of D-dimers were found, which indicates factor XIII activation (Edgar et al. 1980).
D

Platelets: thrombopaenia, defined as a platelet count <102,958 mm³ (mean value minus 2 SD in a northern Nigerian population) (10/96), whereby 8 of these 10 patients had spontaneous bleeding and 9/10 had a concurrent fibrinogen level <5% of the normal value (Warrell et al. 1977).
E

Fibrinogen: in a random sample of 18 patients on average 33.5 mg/100 ml (1 SD = 46 mg/100 ml) (normal range 200–400 mg/100 ml) (Warrell et al. 1977).
F Factors II, V, VIII, XIII:
II on average 49.5% (1 SD 21%) (normal: 50–150),
V on average 9.5% (1 SD 14%) (normal: 50–150),
VIII on average 33.7% (1 SD 28%) (normal: 50–150),
XIII on average 105 (reciprocal titre) (1 SD 147) (normal: 256–512) (Warrell et al. 1977).


2. Leucocytes

Neutrophilic leucocytosis, on average 11,380/mm³ in 73% of patients at the time of hospitalisation (Warrell et al. 1977).

3. Haemoglobin/haematocrit

Haematocrit at the time of hospitalisation on average 37.6% (19–49.5%). The lowest haematocrit level was measured on average 3 days (0–9 days) after the bite (Warrell u. Mitarb. 1977).


4. ELISA

Identification of the snake that caused the bite: 3 Causus maculatus bites and 2 Bitis arietans bites could be distinguished from Echis ocellatus bites using this method (Pugh and Theakston 1987a).

First aid

A thromboembolic complication with a fatal outcome was observed in connection with a very tight tourniquet that was left on for a long time (Pugh and Theakston 1987a).

Treatment (symptomatic)

  1. Pain in the region of the bite: codeine phosphate per os (Warrell et al. 1977).
  2. Arterial hypotension (systolic BP <60 mmHg) 5/115. Cause of arterial hypotension: blood loss (minimum Hb 2.5 g/100 ml). Most important cause of blood loss: incision prior to hospitalisation. Course of the 5 patients with arterial hypotension: fatal 3/5, restoration of adequate blood pressure after transfusion and administration of antivenom 2/5. 7/115 received blood transfusions due to shock, anaemia or persistently incoagulable blood for >24 h after the bite (Warrell et al. 1977).
  3. Haemostatic defect: heparin does not have a positive influence on the course of envenoming (Warrell et al. 1976d).

Treatment (specific)

Antivenoms

  1. MicroPharm "EchiTAb G" antivenom (monospecific, Echis ocellatus, caprylic acid purified whole IgG antivenom)
  2. Instituto Clodomiro Picado "EchiTAb-Plus-ICP" antivenom (polyspecific, Echis ocellatus, Naja nigricollis, Bitis arientans, caprylic acid purified whole IgG antivenom)
  3. Echis antivenom, SAIMR (SAVP), Johannesburg, South Africa
  4. African Antivipmyn®, freeze-tried polyvalent equine F(ab')2 antivenom (Bitis gabonica, B.arietans, Echic ocellatus, E.leucogaster, E.pyramidum, Naja haje, N.melanoleuca, N.nigricollis, N.pallida, Dendroaspis polylepis)
  5. Bitis-Echis-Naja antivenom, Pasteur Institute, France
  6. North Africa antivenom, Behringwerke, Marburg, Germany
  7. 'Ipser Afrique', Pasteur Institute, France
  8. Ipser Afrique™ antivenom, Pasteur Mérieux Connaught, Lyon, France (polyvalent equine F(ab')2 antivenom, Bitis arietans, B. gabonica, Echis leucogaster , Naja melanoleuca, N.haje, N.nigricollis, Dendroaspis viridis, D.jamesoni, D.augusticeps)
  9. Monospecific ovine Fab antivenom (EchiTab™), Therapeutic Antibodies, Ltd.


Studies / clinical trials

Abubakar et al 2010a

Abubakar et al 2010b

Chippaux et al 1998

Chippaux et al 1999

Chippaux et al 2007

Daudu and Theakston 1988

Meyer et al 1997

Warrell et al. 1974
Warrell et al. 1976d
Warrell et al. 1977
Warrell et al. 1980

Antivenom indications and control parameters for antivenom dosage

Incoagulable blood (as a sign of systemic envenoming): antivenom is even indicated days after the bite if the blood is still incoagulable at this time point. Intracerebral haemorrhage with fatal consequences up to 12 days after the bite has been described; in contrast, death due to envenoming in the first 24 h after the bite is unusual (Warrell et al. 1977).

Indication and dosage interval for antivenom according to the results of the following simple coagulation test: several millilitres of blood are left to stand for 20 min in a clean, dry test tube. Then by tilting the tube it can be seen if the blood has coagulated. This coagulation test and administration of antivenom are repeated every 6 h until coagulation has been restored according to the criteria of this test. Subsequent daily monitoring for 3 days, in order to exclude a recurrent haemostatic defect due to delayed absorption of venom from the region of the bite (Warrell et al. 1977).

Not all bleeding that recurs after initial neutralisation of the venom requires further antivenom treatment. Among other factors, lysis of unstable clots at the initial sites of bleeding (e.g. gingiva) may be the cause of such recurrence of bleeding. Repeat evaluation of the coagulability of the blood (clotting time) determines whether further administration of antivenom is required (Swinson 1976).


Efficacy / effectiveness of individual antivenoms

  1. MicroPharm "EchiTAb G" antivenom and Instituto Clodomiro Picado "EchiTAb-Plus-ICP" antivenom: On the basis of pre-clinical and preliminary dose-finding and safty studies of 2 licenced and 6 candidate antivenoms tested "EchiTAb G" and "EchiTAb-Plus-ICP" were selected for comparison in a RCT (Abubakar 2010a).
  2. MicroPharm "EchiTAb G" (ET-G, current standrad of care in Nigeria, developed from EchiTAb-Fab introduced in 1998) antivenom) (n=206) versus Instituto Clodomiro Picado "EchiTAb-Plus-ICP" (ET-Plus) (n=194) antivenom: Randomized controlled double-blind non-inferiority trial.  Enrolment of patiens who presented with incoagualable blood, indicative of systemic envenoming by Echis ocellatus in Kaltungo, north-eastern Nigeria. Initial antivenom dose: ET-G 1 vial, ET-Plus 3 vials. Primary outcome: permanent restauration of blood coagulability 6 hours after the start of teatment, assessed with a simple 20 minutes whole blood clotting test (20WBCT) repeated 6, 12, 18, 24 and 48 hours after treatment. Permanently restored blood coagulability at 6 hours ET-Plus 161/194 (83%), ET-G 156/206 (75.7%). Permanent restoration of blood coagulability (20WBCT) 24 hours after first dose, having received a total of 1-4 doses: ET-Plus 184/194 (94.8%), ET-G 192/206 (93.2%). Recurrent blood incoagulability after initial restoration of blood coagulability: ET-Plus 7/194 (3.6%), ET-G  17/206 (8.3%). Patients requiring rescue treatment bacause their blood was incoagulable 24 hours after first dose:  ET-Plus 2/194 (1%), ET-G 2/206 (0.97%). Secondary (safty) outcomes: see section "adverse reactions below. Fatalities: 0. Length of hospital stay (hours): median ET-Plus 120, ET-G 120  (Abubakar 2010b).

  3. Echis antivenom, SAIMR (SAVP), Johannesburg, South Africa: of 48 patients who received on average 18.5 ml of SAIMR antivenom, none died and none failed to respond to treatment (defined as persistent incoagulability of the blood over a period of >24 h after antivenom treatment was commenced). In 45 of these 48 patients, blood coagulability was actually restored within 6 h with 10–20 ml of SAIMR antivenom. In 8 patients who failed to respond to Behring antivenom and 2 who failed to respond to Bitis-Echis-Naja antivenom, Pasteur Institute, the haemostatic defect was also corrected by administration of SAIMR antivenom. They are included in the group of 48 patients (Warrell et al. 1977).

    In 23/23 patients normalisation of blood coagulability was achieved with an average dose of 15.2 ml of SAIMR antivenom. The average time between the beginning of treatment and permanent restoration of coagulability was 11.8 h (Warrell et al. 1974).

    SAIMR antivenom in a single dose of 10–20 ml restored blood coagulability in 7/7 patients, and also in 2 who continued to bleed despite administration of Berhing antivenom (Pugh and Theakston 1987a).
  4. African Antivipmyn®, freeze-tried polyvalent equine F(ab')2 antivenom: Open multi-center trial in Benin (n=289). The whole blood clotting test (WBCT) was performed in 275 patients of which 216 (79 %) were positive. 168 patients had a positive WBCT on admission, 40 with a delay and 18 relapsed. Initial antivenom dose: one dose (=2 vials); repeated according to clinical criteria (persistence of edma or bleeding) or abnormal WBCT results. A total of 551 doses (=1102 vials) of antivenom (3.8±2.6 vials) were given to 289 patients. Incoagulable blood 24 hours after initiatian of treatment: 18%; delay of restoration of blood coagulability beyond 60 hours: 6%. Recurrent coagulopathy: 25%. Arrest of bleeding within 2 hours: 60%; within 24 hours: 80%.  Fatalities: 9. (Chippaux et al 2007).
  5. Bitis-Echis-Naja, Pasteur Institute, France: 20–40 ml of this antivenom restored blood coagulability within 12 h in 7/7 patients (Warrell et al. 1980).
  6. North Africa, Behringwerke, Marburg, Germany: of 65 patients who received on average 36.9 ml of Behring antivenom, 3 died and in 10 cases the haemostatic defect was not corrected (criteria see 1.) (Warrell et al. 1977).
    In 18/23 patients restoration of blood coagulability was achieved with an average dose of 37.9 ml of Behring antivenom (Warrell et al. 1974), in 4/7 with doses of 60–180 ml (Warrell et al. 1980). The average time between the beginning of treatment and permanent restoration of coagulability was 27.2 h (Warrell et al. 1974).
  7. 'Ipser Afrique', Pasteur Institute, France: in 24 patients with systemic Echis ocellatus envenoming (incoagulable blood), restoration of coagulability was achieved within 6 h with an average dose of 23.3 ml (20–60 ml) of antivenom (Daudu and Theakston 1988).
  8. Ipser Afrique™ antivenom, Pasteur Mérieux Connaught, Lyon, France (polyvalent equine F(ab')2 antivenom): In 223 patients clinically with obvious snakebite, predominantely due to Echis ocellatus, have been enrolled in 7 centres in North Cameroon. Culprit identified by herpetologist: 59% (however, 64/223???), 55/ 64 (86%) as Echis ocellatus, 5/64 as Atractaspismicrolepidota, 1/64 each as Naja haje and Causus maculatus and 6/64 as Bitis arietans. All other culprits (159/223) were classified "probable" Echis ocellatus on the basis of its prevalence, the patient's description and the clinical picture. On admission before antivenom treatment was started: oedema (93.7%),  haemorrhage (48.9%), 30WBCT (65.4%) of patients. Initial antivenom dose: 2 vials. On average 4.6 (±3.7) vials were administered per patient. Recovered after a single dose of 2 vials: 43%. Overall cure rate: 96.8%. When strict oucome measures were applied (no signs of bleeding and WBCT<30 minutes) (158 of 223 patients of which 35 did not manifest any clotting disorders, 12 developed a relapse, 18 had missing or incomplete data) 111 showed restoration of blood coagulability within the 5 days of the monitoring period with a mean time of 24 hours (range 1-109 hours); 25% (first quartile) less than 2.2 hours and 25% (third quartile) 27 hours to 5 days. In the remaining 47 patients restoration of blood coagulability occured after the monitoring period of 5 days. The precise time is not known. Fatalities: 3/223 (1.3%) (Chippaux et al 1998).
  9. Monospecific ovine Fab antivenom (EchiTab™), Therapeutic Antibodies, Ltd.: Randomized comparative trial of one vial (10ml) of EchiTab (n=22) versus 4 ampoules (40 ml) of Institue Pasteur Serum (Ipser) Africa polyspecific F(ab'2) antivenom (n=17). Only 36% and 35% of patients, respectively, showed permanent restoration of coagulability. The remainder required further doses (Meyer et al 1997).


Efficacy of antivenoms with regard to individual effects of the venom

(evaluated on the basis of patient populations who were treated with SAIMR and/or Bitis-Echis-Naja antivenom, Pasteur Institute, or Behringwerke antivenom)

  1. With regard to local signs of envenoming: uncertain (Warrell et al. 1974) or none (Warrell et al. 1977).
  2. With regard to spontaneous bleeding: observable bleeding, as, for example, epistaxis, ceased in all cases at the latest 10 h, and usually already 2 h after the first dose of antivenom (Warrell et al. 1977).
  3. With regard to the haemostatic defect: blood coagulability was restored 2–39 h (on average 11.75 h) after administration of antivenom (Warrell et al. 1977). Increase in fibrinogen from a mean value of 35 mg/100 ml before antivenom treatment to 95 mg/100 ml after 24 h and 130 mg/100 ml after 7 days (Warrell et al. 1977). At the same time points, factor V: 10/30/52%, factor VIII: 23/40/53%, factor II: 46/60/78% (Warrell et al. 1976d). Mean FSP decreased from a pre-treatment level of 1,711 μg/ml to 271 μg/ml after 24 h, 72 μg/ml after 48 h and 6 μg/ml after 1 week (Warrell et al. 1977).


Adverse reactions

  1. MicroPharm "EchiTAb G" (ET-G) antivenom (monospecific, Echis ocellatus, caprylic acid purified whole IgG antivenom) and Instituto Clodomiro Picado "EchiTAb-Plus-ICP" (ET-Plus) antivenom (polyspecific, Echis ocellatus, Naja nigricollis, Bitis arientans, caprylic acid purified whole IgG antivenom): Incidence of anaphylactic, pyrogenic and late serum sickness-type antivenom reactions (secondary (safty) outcomes of RCT (see above)): Early reactions on more occasions ET-Plus 50/194 (25.8%), ET-G 39/206 (18.9%) classified as severe ET-Plus 21/194 (10.8%), ET-G 11/206 (5.3%).  Pyrogenic reactions: none. Late serum sickness-type reactions (107 at follow-up) ET-Plus 5/49, ET-G 3/58. "EchiTAb-Plus-ICP" (3 vials)  was slightly mor effective and "EchiTAb G" (1 vial) was slightly safer (Abubakar 2010b
  2. Echis antivenom, SAIMR (SAVP), Johannesburg, South Africa  and North Africa antivenom, Behringwerke, Marburg, Germany: Immediate hypersensitivity occurred in 20.6% of treated patients, usually 6–30 min after the beginning of treatment (significantly more often after SAIMR than after Behring antivenom) and was quickly controlled using the following treatment schedule: chlorpheniramine 10 mg and hydrocortisone 100 mg i.v., adrenalin 0.5 ml (1:1,000) s.c. (Warrell et al. 1977). Delayed hypersensitivity (serum sickness) occurred in 1/107 (60 ml Behring, 50 ml SAIMR antivenom) and responded to 10 mg prednisone and 20 mg promethazine daily (Warrell et al. 1977).
  3. African Antivipmyn®, freeze-tried polyvalent equine F(ab')2 antivenom (Bitis gabonica, B.arietans, Echic ocellatus, E.leucogaster, E.pyramidum, Naja haje, N.melanoleuca, N.nigricollis, N.pallida, Dendroaspis polylepis): "Unexpected events" were observed in 39/289 (13%) patients after first dose of antivenom, in 55/289 (19%) ater all doses. They included low blood pressure (1%) and dyspnoe (5%). (Chippaux et al 2007).
  4. Ipser Afrique™ antivenom, Pasteur Mérieux Connaught, Lyon, France (polyvalent equine F(ab')2 antivenom, Bitis arietans, B. gabonica, Echis leucogaster , Naja melanoleuca, N.haje, N.nigricollis, Dendroaspis viridis, D.jamesoni, D.augusticeps): Early adverse reactions: 6.3%, 1 (0.4%) severe. Serum sickness: 1 patient (Chippaux et al 1998).


Assessment and recommendations by authors who conducted the trials

  1. "EchiTAb-Plus-ICP" (3 vials)  was slightly mor effective and "EchiTAb G" (1 vial) was slightly safer. Both antivenoms are recommended for treating Echis ocellatus envenoming in Nigeria (Abubakar 2010b).
  2. SAIMR (SAVP) antivenom is an effective antivenom for neutralisation of Echis ocellatus-induced haemostatic defects in the studied regions of Nigeria. Bitis-Echis-Naja antivenom, Pasteur Institute, is less effective than SAIMR antivenom (Warrell et al. 1980).
  3. African Antivipmyn®: Arrest of bleeding within 2 hours: 60%. Satisfactory tolerance ("Unexpected events") (Chippaux et al 2007).
  4. The ability of the Behring antivenom to neutralise active venom components in Nigeria is unreliable and unpredictable and clearly inferior to that of SAIMR (SAVP) antivenom and Bitis-Echis-Naja antivenom, Pasteur Institute (Warrell et al. 1980).
  5. 'Ipser Afrique', Pasteur Institute, is a sufficiently effective antivenom for the treatment of mild cases of systemic envenoming due to Echis ocellatus. Due to the small number of patients in this category, no conclusion can be drawn regarding the efficacy of this antivenom in cases of severe envenoming (Daudu and Theakston 1988).
  6. Ipser Afrique™ antivenom, Pasteur Mérieux Connaught, Lyon, France (polyvalent equine F(ab')2 antivenom) given by repeated intravenous infusion (20 ml antivenom ampoules) is a safe and effective treatment (Chippaux et al 1998).
  7. Monospecific ovine Fab antivenom (EchiTab™), Therapeutic Antibodies, Ltd.: With one vial (10ml) of EchiTab only 36% of patients showed permanent restoration of coagulability. Higher dosis (2 vials) caused early anaphylactic reactions in 57% of the cases which was unexpected and possibly due to complement activation which should not occur with pure Fab antivenoms. The particular batch used in the trial was found to be contaminated with Fab aggregates and Fc fragments. The low permanent restoration of coagulability of Fab antivenom is due to  its rapid clearance from the blood stream. The antivenom was used in Nigeria from 1998-2000 and, to overcome this problem, replaced by EchiTAb-G (see above) (Meyer et al 1997, Abubakar et al 2010).