Antivenom treatment

Antivenom administration: practical approach

Treatment step	Procedure	Comments
Sensitivity test	no	Apart from the rare cases of a pre-existing sensitivity, e.g. to horse serum, sensitivity tests (intradermal, intraconjunctival) have no predictive value for an antivenom reaction (Malasit et al. 1986)
Pre-medication	adrenaline s.c.	see 'Prevention' below.
Timing of antivenom	When indicated, as quickly as possible. It is, however, "never too late if signs of systemic envenoming persist" (Warrell 2023)	Local evenoming is most likely not reversible or preventable by antivenom if delayed by a few hours (Warrell 2023).
Mode of administration	i.v.	Antivenoms are most effective when administered i.v. - even F(ab) small fragment antivenoms; in rare cases antivenoms can be administered i.m.; however, this is associated with a loss of efficacy, and there is a danger of intramuscular bleeding in the case of envenoming with haemostatically active venom components; i.m. administration should thus only be applied if i.v. administration is not possible for technical reasons and pressure dressing appied after injection to control bleeding(Warrell 1990b); further exceptions: Chironex antivenom.
Route and speed of administration	i.v. infusion with isotonic saline solution over 30–60 min i.v. "push"-injection over 10-20 minutes	No difference in the incidence or severity of antivenom reactions. In the rural tropics the "push" injections has the advantage that it needs less equippment. (Warrell 2023)
Dose	Children receive the same or a larger dose than adults. Repeated doses may be necessary.	Information from the manufacturer is often based on mouse assays, which can differ from clinical results. Repeated doses may be necessary, even if there is initial normalisation of crucial parameters; this can be explained by continued absorption of venom from a depot in the region of venom application. Recurrent envenoming was common when rapidly cleared Fab antivenoms were introduced: EchiFab, Micropharm, London, UK for envenoming by Nigerian saw-scaled viper, ProlongaTab, Micropharm for envenoming by Sri Lankan Russell's viper (D. russelli), and CroFab, BTG, London, UK for envenoming by American rattlesnakes. Possible mechanisims: (a) continued absorption of antivenom from the bite site after antivenom has been cleared or has complexed with venom and (b) redistribution of venom after dissociation of the venom-antivenom complexes (Warrell 2023). Repetition of the initial dose with snakebites if, for example, severe cardiovascular or neurological symptoms persist for longer than 30 min and if blood is incoagulable for more than 6 h (Warrell 2023).
Precautions	Monitoring of the patient during and after antivenom administration; constant monitoring during the first 10–15 min after the start of antivenom administration, continued for 3 hours at regular intervals (see below 'Antivenom reactions'); In the case of envenoming with impaired haemostasis ensuring that there is no persistent bleeding from the site of venipuncture, possibly compression bandage	The likelihood of the occurrence of early severe antivenom reactions is greatest after the start of antivenom administration, however, so-called "early" reactions may also first appear after a period of hours; thus it is necessary to monitor the patient for several hours following antivenom administration
Identification and treatment of antivenom reactions	see below 'Antivenom reactions'
Quality of and access to antivenoms	see published clinical trials and WHO Snakebite Information and Data PlatformThere is a multitude of antivenoms produced on various levels of standards. Quality of and access to antivenoms at an appropriate standard vary widely globally.	Great efforts are being undertaken to secure appropriate standards (GMP) and access for people in need: WHO: Snakebite envenoming -- A strategy for prevention and control WHO: Antivenoms WHO Snakebite Information and Data Platform

Antivenom reactions: types, mechanisms, treatment

Type/Characteristics	Mechanism	Treatment
Early anaphylactoid/anaphylactic reactions approx. 10–180 minutes after starting antivenom treatment (Warrell 2023)	The mechanisms have not yet been clearly elucidated; Complement activation by immune complexes (aggregates)? Rarely a type I hypersensitivity reaction to horse sera	Adrenaline (epinephrine) in an initial dose of 0.5 mL of a 0.1% solution (1:1000, 1 mg/mL) for adults (0.01 mL/kg BW for children) should be given at the first sign of a reaction. followed by Antihistamines, e.g. chlorpheniramine maleate: adults 10 mg, children 0.2 mg/kg BW, slowly i.v. (Warrell 2023) If a patient continues to deteriorate despite this treatment, additional treatment, see WHO-ICRC Basic Emergency Care: approach to the acutely ill and injuredEarly anaphylactoid reactions, which make up the great majority of the early reactions, cannot be predicted with a sensitivity test (Malasit et al. 1986)
Mild reactions: urticaria, nausea, vomiting, diarrhoea, headache, fever (Malasit et al. 1986) Severe (systemic) reactions: bronchospasm, arterial hypotension, angio-oedema (Malasit et al. 1986) The more purified the antivenom used, the lower the incidence of such reactions.
Pyrogenic reactions approx. 1 –2 hours after starting antivenom treatment (Warrell 2023)	Contamination of the antivenom during the manufacturing process.	Reducing fever through cooling and antipyretics such as paracetamol (Warrell 2023).
Signs and symptoms: fever, chills, vasodilatation, arterial hypotension (febrile seizures can occur in children)
Late reactions (serum sickness) approx. 7 days (5–24 days) after antivenom treatment (Warrell 2023)	Type III hypersensitivity	Mild reaction Histamine H₁-blockers such as chlorpheniramine: adults 4 × daily 2 mg, children 0.2 mg/kg BW/day in divided doses. Severe reactions Prednisolone: adults 4 × 5 mg per day for 5 days, children 0.7 mg/kg BW/day in divided doses for 5 days (Warrell 2023)
Signs and symptoms: pruritus, urticaria, fever, arthralgia, lymphadenopathy, peri-articular swelling, albuminuria, neurological impairment (mononeuritis multiplex, rarely encephalopathy); The incidence and speed with which the reaction develops are greater the higher the dose of antivenom administered (Warrell 2023)

Prevention

de Silva et al. (2011) Low-Dose Adrenalin, Promethazine, and Hydrocortisone in the Prevention of Acute Adverse Reactions to Antivenom Snakebite: A Randomized, Double-Blind, Placebo-Controlled Tria (PLoS Med 8(5):e1000435.doi:10.1371/journal.pmed.1000435): In total, 1,007 patients were randomized, using a 2×2×2 factorial design, in a double-blind, placebo-controlled trial of adrenaline (0.25 ml of a 1:1,000 solution subcutaneously), promethazine (25 mg intravenously), and hydrocortisone (200 mg intravenously), each alone and in all possible combinations.

In total, 752 (75%) patients had acute reactions to antivenom: 9% mild, 48% moderate, and 43% severe; 89% of the reactions occurred within 1 h; and 40% of all patients were given rescue medication (adrenaline, promethazine, and hydrocortisone) during the first hour. Compared with placebo, adrenaline significantly reduced severe reactions to antivenom by 43% (95% CI 25–67) at 1 h and by 38% (95% CI 26–49) up to and including 48 h after antivenom administration; hydrocortisone and promethazine did not. Adding hydrocortisone negated the benefit of adrenaline.

Conclusions: Pretreatment with low-dose adrenaline was safe and reduced the risk of acute severe reactions to snake antivenom. This may be of particular importance in countries where adverse reactions to antivenom are common, although the need to improve the quality of available antivenom cannot be overemphasized.