Silva, A., Maduwage, K. and Buckley, N.A., 2017. Antivenom for snake venom-induced neuromuscular paralysis (Protocol).
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of antivenom on neuromuscular paralysis in people with neurotoxic snake envenoming.
Description of the condition
Snakebite leads to significant morbidity and mortality globally, with an estimated burden of 421,000 to 1,841,000 envenomings and 20,000 to 94,000 deaths per year. Of this, more than 90% of envenomings are reported from tropical Asia, sub-Saharan Africa, and Latin America (Kasturiratne 2008). Venom-induced neuromuscular paralysis is one of the major clinical manifestations of envenoming, predominately by elapid snakes. In some neurotoxic snakebites, such as by kraits (genus Bungarus) in Asia, life-threatening paralysis occurs in more than 50% of patients (Kularatne 2002; Hung 2009).
Neurotoxic snake venoms primarily affect the neuromuscular junction causing a disruption of neurotransmission, resulting in paralysis of the skeletal muscles (Harris 2009; Ranawaka 2013). Snake venom neurotoxins target multiple sites in the neuromuscular junction. The majority of the snake venom neurotoxins either act on the motor nerve terminals (presynaptic) or the nicotinic acetylcholine receptor on the motor end-plate (postsynaptic).
Presynaptic toxins initially lead to a depletion of the synaptic vesicles and ultimately cause structural damage to the motor nerve terminals (Logonder 2008; Prasarnpun 2005). This type of insult is most likely to be treatment resistant, and recovery depends on the natural regeneration of the nerve terminal, as shown from experimental studies using presynaptic toxins isolated from krait and viper venoms (Dixon 1999; Logonder 2008; Prasarnpun 2004; Prasarnpun 2005). Snake venom postsynaptic neurotoxins competitively bind to the agonist-binding sites of the nicotinic acetylcholine receptors on the motor end-plate with high affinity and poor reversibility, blocking neuromuscular transmission (Ishikawa 1985; Vincent 1998). Some neurotoxic snake venoms, as in kraits, contain both types of toxins (Rusmili 2014). Several snake venom toxins act on specific ion channels or affect acetylcholinesterase activity in the neuromuscular junction (Harris 2009).
Whatever the mechanism, all of these toxins result in the same clinical effect: neuromuscular weakness, which can range from a mild weakness of the eyelid and facial muscles to fatal paralysis of bulbar and respiratory muscles (Connolly 1995; Isbister 2012; Johnston 2012; Kularatne 2000; Kularatne 2002; Silva 2016). In extreme cases, complete neuromuscular paralysis involving all skeletal muscles of the body can occur (Silva 2016). To sustain life, mechanical ventilation is essential in people with respiratory paralysis. Depending on the snake species involved, neuromuscular paralysis can co-exist with other clinical manifestations of envenoming, such as local tissue necrosis seen in cobras, Kularatne 2009, and venom-induced consumptive coagulopathy in vipers, Sano-Martins 2001, and some Australasian elapids (Isbister 2012).
The detection and monitoring of the neuromuscular paralysis in people with snakebite in the clinical setting as well as for research purposes are almost entirely dependent on the clinical examination. For this, patients are constantly monitored for clinical features of neurotoxicity such as ptosis, ophthalmoplegia, and facial, neck, bulbar, respiratory, and limb weakness (Isbister 2012; Johnston 2012; Kularatne 2000; Kularatne 2002). Neurophysiological tests such as single-fibre electromyography have also been used for this purpose (Silva 2016). However, such tests require equipment and skills beyond the reach of rural settings, where snakebites are mostly prevalent.
Description of the intervention
Antivenoms have been used for the treatment of snakebite for more than a century (Gutiérrez 2011; WHO 2010). They are polyclonal whole immunoglobulin (IgG) or immunoglobulin fractions (Fab or F(ab’)2) raised against venom from one (monovalent) or several (polyvalent) snake species in other animals, most commonly horses. The immunised animals are periodically bled and the immunoglobulins are separated from the blood using ammonium sulphate or caprylic acid to produce whole IgG antivenom. During the production of many commercial antivenoms, the whole immunoglobulins are fractionated by papain or pepsin digestion to make Fab or F(ab’)2, respectively (Chippaux 2006; Gutiérrez 2011; WHO 2010). Depending on the production protocol, the immunoglobulins or fractions may be subject to further purification involving chromatographic steps and pasteurisation (León 2013). Antivenoms are available in freeze-dried powdered form (where the powder is reconstituted with sterile water prior to use) or liquid form. Snake antivenoms are almost always delivered to the patients via the intravenous route. Antivenom therapy is associated with adverse reactions, and frequent life-threatening reactions are a major problem associated with some antivenoms (de Silva 2011; de Silva 2015; León 2013).
How the intervention might work
In doses used in the clinical setting, antivenom molecules (polyclonal antibodies) likely outnumber the venom molecules (toxins) in the circulation (Allen 2012; Isbister 2015). The polyclonal nature of the antivenoms means that they contain a range of antibodies or antibody fractions against a range of neurotoxins (both pre- and postsynaptic), relevant to this review, as well as non-neurotoxic toxins. These antivenom molecules bind with circulating toxins, forming large venom-antivenom complexes, trapping the venom molecules in the circulation (O’Leary 2006; O’Leary 2014). The antibodies likely act via a number of mechanisms, including blocking the active site of the neurotoxin molecules, preventing the toxins from interacting with the target site (neuromuscular junction) by restricting the movement of the neurotoxins to the extravascular target sites, and also increasing the elimination of the toxins (Maduwage 2015). In addition, if the antivenom molecules are able to distribute from the circulation, they might be able to reach the neuromuscular junctions and neutralise the neurotoxins at their target site. However, it is unclear how effectively the whole IgG, F(ab’)2, or Fab molecules in the antivenoms can distribute to the neuromuscular junctions.
Presynaptic neurotoxins result in structural damage to the motor nerve terminals that is irreversible (in the short term). Antivenom is therefore unlikely to be able to reverse already established presynaptic neurotoxic injury (Harris 2013; Logonder 2008; Prasarnpun 2005). In contrast, postsynaptic neurotoxins act in a similar way to reversible non-depolarising type neuromuscular blockers or muscle relaxants. The reversibility of the binding of postsynaptic toxins to the nicotinic acetylcholine receptor varies based on the structural properties of the individual toxins (Barber 2013). Experimental evidence suggests that specific immunoglobulins are able to increase the recovery of the neuromuscular junctions from postsynaptic toxin-mediated neuromuscular block (Gatineau 1988).
Why it is important to do this review
Although antivenom therapy is commonly utilised for neurotoxic snake envenoming, its effectiveness in preventing or reversing neurotoxicity is less clear and has been questioned in several studies conducted in different regions (Johnston 2012; Richardson 2007; Theakston 1990; Silva 2016). Recovery of the neurotoxicity in snake envenoming without antivenom has also been reported (Hung 2009; Pochanugool 1997). In practice, it is doubtful whether the antivenom could be delivered early enough to prevent the neurotoxins from reaching neuromuscular junctions. Furthermore, it is unclear whether the antivenoms can speed recovery of already established neurotoxicity. A recent study of common krait envenoming demonstrated that even in the patients who received early antivenom (median 3.5 hours postbite) in an adequate dose to bind with all circulating venom antigens, antivenom was unable to prevent the subsequent development of life-threatening paralysis (Silva 2016). In contrast, a study of taipan bites in Papua New Guinea found that early administering of antivenom prevented intubation in a proportion of patients (Connolly 1995).