Treatment (specific)

Antivenoms

1. Crotalidae Polyvalent Immune Fab Antivenom, ovine (immunized with Crotalus adamanteus, Crotalus atrox, Crotaus scutulatus ssp. and Agkistrodon piscivorus) / CroFab™, Savage Laboratories, Melville, New York (since 2000).
   See also individual Crotalus sp. clinical entries.
2. Wyeth (Crotalidae) Polyvalent Antivenom (ACP), equine (immunized with Crotalus adamanteus, Crotalus atrox, Crotaus durissus terrificus, Bothrops atrox), Wyeth Laboratories (Philadelphia), USA (since 1994, no longer in use).
   See also individual Crotalus sp. clinical entries.

For the characterists of 1. and 2., see Gold et al. 2002.

1. Crotalidae Polyvalent Immune Fab Antivenom, ovine (immunized with Crotalus adamanteus, Crotalus atrox, Crotaus scutulatus ssp. and Agkistrodon piscivorus) / CroFab™, Savage Laboratories, Melville, New York

Studies / clinical trials

Boyer et al. 1999, 2001

Clark et al. 2002

Dart et al. 1997b, 2001

Offerman et al. 2002

Ruha et al. 2002

Antivenom indications and control parameters for antivenom dosage

Crotalid snake bite severity score (Dart et al. 1997a).

Efficacy / effectiveness of the antivenom

• Prospective multicentre clinical trial of Crotalinae polyvalent immune Fab (ovine) (N=11). Severity score (see below) decreased or remained the same after 4 hours in all patients. However, in 2/11 patients local swelling and in 1/11 coagulopathy recurred (discovered at the 1-week follow-up visit) (Dart et al. 1997b).
• Randomised multicentre trial (N=31) of Crotalinae polyvalent immune Fab (ovine) comparing a group (n=15) receiving an initial treatment (6 vials plus 6 vials if needed) to achieve initial control plus further doses (2 vials each) as needed with a group (n=16) receiving an initial treatment (6 vials plus 6 vials if needed) to achieve initial control plus a fixed schedule of 2 vials 6 hourly for a total dose of 6 vials (18 hours) plus additional doses if the investigator detected worsening of envenoming. Inclusion criteria: (1) minimal to moderate envenoming by a North American crotaline snake within 6 hours preceding administration of the antivenom, (2) age ≥10 years, (3) progression of the envenoming syndrome. Exclusion criteria: (1) lack of progression of the envenoming, (2) severe envenoming, (3) bites by a copperhead snake (Agkistrodon contortrix), (4) infusion of >1 vial of polyvalent (Crotalidae) antivenom before enrolment, other non-specific criteria. The mean severity score (see below) decreased from 4.35 at baseline to 2.39 12 hours after initial control of envenoming was achieved with no difference between the two groups. Recurrence of coagulopathy was frequent, requiring additional antivenom doses in the "as needed" group (Dart et al. 2001).
• Postmarketing data from patients receiving Crotalinae polyvalent immune Fab (ovine) (n=28). Initial control of coagulopathy was difficult to achieve. In some patients recurring coagulopathy required large amounts of antivenom, and, even then, only moderate increases in fibrinogen concentration were achieved. Recurrence of coagulopathy at follow-up visits in 3/28 and of thrombocytopenia in 1/28. 2/28 had delayed-onset severe thrombocytopenia (Ruha et al. 2002).
• Coagulopathy was controlled (fasciculations, haemorrhage, hypotension, progression of swelling) after 4 vials of Crotalinae polyvalent immune Fab (ovine); thereafter the patient received further vials up to a total of 12 vials within 24 hours. On day 5 his coagulation parameters (PT, PTT, fibrinogen, platelets; severely depleted plasminogen consistent with selective defibrination and hyperfibrinolysis) were again found to be abnormal after initial normalization (apart from a marginally prolonged PT). There were no clinical signs of envenoming (fasciculations, hypotension, bleeding, renewed swelling). On day 6 deterioration of the patient's mental status and brain haemorrhage on CCT (coagulopathy meanwhile improved after 4 further vials of antivenom). Died on day 7 (Kitchens and Eskin 2008).
• Prospective and retrospective case series of paediatric patients ≤13 years with signs of envenoming at presentation (n=12). Snakebite severity score (see below) 2–9 (mean 5.3). Coagulation abnormalities (fibrinogen, platelets) at presentation: 2/12; on day 3 (platelets), 1/12. Total antivenom dose 4–22 vials (mean 12.7). Initial control achieved with 4–16 vials (mean 7.7). Recurrence (local swelling) despite scheduled dosing of antivenom: 1/12 (Offerman et al. 2002).

Efficacy/effectiveness of antivenoms with regard to individual effects of the venom

Most noticeable on outcomes involving the coagulation system, central nervous system, gastrointestinal system and cardiovascular system but not the local venom effects (Dart et al. 1997a, 2001) as measured by the crotalid snake bite severity score (Dart et al. 1997a).

Adverse reactions

• Acute reactions: 6/31 patients (19%); 3 in each study group. 4 mild cases (transient urticaria), 2 moderate cases (1 patient had wheezing and dyspnoea, 1 patient had cough and urticaria). Serum sickness: 6/26 (23%) (26/31 returning to the 14-day follow-up visit). Mild/moderate/severe 2 patients each, with the most severe form being diffuse hives and urticaria; responded well to outpatient antihistamines and steroids; 5/6 had a Fab AV batch which contained an excess of Fc fragments (Dart et al. 2001).
• 4 patients treated with Crotalinae polyvalent immune Fab (ovine) presented with antivenom reactions (anaphylaxis, urticaria, angio-oedema, serum sickness). All responded well to combinations of antihistamines, epinephrine and steroids (Clark et al. 2002).
• 0/12 (Offerman et al. 2002).

Assessment and recommendations from the authors who conducted the trials

Crotalidae Polyvalent Immune Fab Antivenom, ovine (immunized with Crotalus adamanteus, Crotalus atrox, Crotaus scutulatus ssp. and Agkistrodon piscivorus) / CroFab™, Savage Laboratories, Melville, New York:

• An initial dose of 6 vials, with further 6-vial doses until initial control of the envenoming syndrome. After initial control has been established, additional 2-vial doses every 6 hours for a total of 3 doses may be needed. Additional 2-vial doses may be needed on the basis of close follow-up for late recurrences of coagulopathy (Dart et al. 2001).
• Prolonged or recurrent coagulopathy may occur. Patients may benefit from periodic rather than single-bolus dosing. Close monitoring for 2 weeks after the bite is recommended for patients with coagulopathy (Boyer et al. 1999).
• Considerations for retreatment: (a) fibrinogen levels less than 50 μg/ml, platelet count < 25,000/mm³, INR >3.0, PTT >50 seconds, (b) multicomponent coagulopathy with abnormal laboratory values of a lesser degree, (c) clear worsening trend in patients with prior severe coagulopathy, (d) high-risk behaviour for trauma, (e) comorbid conditions with an increased hemorrhagic risk. Prevention of local recurrence: repeated administration of antivenom for at least 18 hours after the bite. Prevention of severe recurrent coagulopathy: additional doses may be needed. There are, however, insufficient data to show that recurrent coagulopathy causes a significant risk of haemorrhage and that recurrence can be prevented by scheduled doses of antivenom (Boyer et al. 2001).
• "It is clear that late recurrence, especially involving late defibrinogenation, may occur after unambiguous control of the envenomation syndrome achieved by the initial aggressive antivenom treatment. Whether defibrinogenation itself causes remote delayed hemorrhage is uncertain but, if so, it seems to be exceedingly rare." (C. adamanteus bite; Kitchens and Eskin 2008).
  "It is unclear what course of action to recommend." (C. adamanteus bite; Kitchens and Eskin 2008).