Indications for use of antivenom in the United States have not been rigorously defined. Advantages of early administration highlighted (Gold et al 2004).

After bites of the most dangerous rattelsnakes (Crotalus atrox, C.adamanteus, C.viridis, C.oreganus, C.horridus, C.scutulatus), antivenom should be given early, even before systemic envenoming has become obvious (Warrell 2010). See also discussion Kitchens and Eskin 2008.

In patients with coral snake bites (Micruroides euryxanthus, M.fulvius, M.tener) should be given very early (Warrell 2010).

In most cases the cause of autopharmacological reactions is the direct toxin-induced release of biogenic amines. Immediate hypersensitivity reactions (type I) appear to be rare. To date only a few cases have been reported (Hogan and Dire 1990, Schmutz and Stahel 1985). This type of reaction requires sensitisation, i.e. prior exposure to the same venom or a cross-reacting venom (Parrish and Pollard 1959). Apart from bites, sensitisation can occur through working with the dry matter of venoms.
Patients frequently develop arterial hypotension following North American crotalid bites. The causes are anaphylaxis (see above), anaphylactoid reactions and direct effects of the venom on blood vessels during the early phase of envenoming (Mancuso de Mesquita et al. 1991). Arterial hypotension occurring later in the course of envenoming is caused by a reduction in the intravascular fluid volume, in the majority of cases most probably due to increased vascular permeability (Dart et al. 1992). This leads to systemic sequestration of large volumes of fluid, in addition to fluid sequestration within the bitten extremity. Pulmonary and cerebral oedema can also be explained by changes in vascular permeability. Bleeding into the extremity in which venom was injected contributes to the development of hypovolaemia. Untreated, there is a risk of hypovolaemic shock. Of 9 fatalities that were attributable to snakebites according to the registry of deaths in Arizona between 1969 and 1984, 5 were evidently caused by multiple organ failure as a consequence of persistent arterial hypotension. 2 of the victims kept snakes as pets (C. s. scutulatus), and the other 7 bites were attributed to C. atrox or C. s. scutulatus according to epidemiological criteria (Hardy 1986). Adequate intravenous fluid replacement and antivenom administration would very probably have prevented most of these fatalities, if not all of them. It is important to reverse the development of hypovolaemia as early as possible, which may require large volumes of intravenously administered fluids (Hardy 1991).

Tourniquets can cause local swelling and mimic local venom effects.

If this type of first aid measure is applied following North American crotalid bites, the risk of ischaemia distal to the tourniquet is high. Furthermore, as the venom of these crotalids is rich in components with a local cytotoxic effect, this favours the process of necrotisation in the region where venom was injected (Willson 1908, Hardy 1992b).

Swelling that involves large areas of an extremity or the entire extremity and that extends to the trunk carries the risk of development of hypovolaemic shock due to sequestration of large volumes of fluid.

On the whole, local effects of the venom are one of the most crucial aspects of envenoming caused by North American crotalids. There are numerous reports in the North American literature describing locally acting myotoxins, haemorrhagins and dermonecrotic components (Ownby 1990). However, these descriptions deal primarily with the results of animal experiments, which are not directly translatable to the situation in humans. In humans, the local swelling can reach monstrous proportions, involve the entire bitten extremity and even extend to the trunk. If a necrotising process occurs, the entire soft tissue covering can be affected. However, it has become increasingly clear that extensive necrosis of these proportions is associated with contra-indicated local first aid and therapeutic measures, and is to be expected in the (rare) cases in which intramuscular injection of venom occurs. For this reason the potential of these venoms to cause local tissue damage in humans was overestimated.

In a retrospective study of patients bitten chiefly by Crotalus atrox and C. s. scutulatus, those patients given only medical treatment suffered less local morbidity than those given a combination of medical and surgical treatment (Hardy 1988).

Severe local tissue damage including impairment of function and loss of limbs are undoubtedly possible complications of North American crotalid bites but are much less frequent if rational first aid and therapetuic measures are applied (Dart et al. 1992, Hardy 1992b).

The incidence of sequelae of crotalid bites, including those that most treating doctors would not classify as severe, but which are troublesome for the patient, has been underestimated to date (Dart et al. 1992). In the past it was estimated that 10% of patients suffered permanent damage following a bite (Russell 1969, 1983). A prospective study of the consequences of crotalid bites, in which patients themselves evaluated permanent damage, resulted in estimates of >20 % (Dart et al. 1992).

Evaluation of the efficacy of antivenom with regard to local effects, such as swelling and in particular necrosis, is controversial. However, there is agreement on the fact that the time that normally elapses between the bite and administration of antivenom represents a significant factor that can limit the chances for success of antivenom treatment with regard to local effects (Hardy 1992b). In one prospective study (n = 131), this interval was 81 min on average (Dart et al. 1992), and in 227 patients investigated in California, it was 1 h (median) (0.5–27 h) (Wingert and Chan 1988). In animal experiments antivenom only prevented local necrosis if venom and antivenom were administered simultaneously or if antivenom was administered immediately after the venom (Russell et al. 1973, Ownby and Colberg 1986).

In North America, local signs of envenoming, particularly swelling, are a reliable parameter of possible systemic envenoming in most crotalid bites. Important exceptions are some populations of Crotalus scutulatus ("type A"), C. mitchelli, C. lepidus and C. tigris, which can cause systemic envenoming without significant local effects (Minton 1987a). C. adamanteus can cause incoagulability of the blood without significant local findings (Kitchens and Van Mierop 1983).

Micrurus fulvius: local swelling does not develop at all or is insignificant.

Even extensive swelling of the extremities is not necessarily an indication of compartment syndrome.

In a retrospective study of patients who were primarily bitten by Crotalus atrox and C. s. scutulatus, 64 had swelling that extended as far as the axilla or inguinal region. None of these patients required surgical intervention. None of them developed symptoms that could have been attributed to compartment syndrome. All patients regained full functionality of the affected limb (Hardy 1991).

In a prospective study in which the majority of patients had been bitten by C. atrox and a smaller number by C. s. scutulatus, C. m. molossus and C. cerastes (snakes identified according to geographical criteria), patients were investigated using non-invasive angiological methods (pulse volume amplitude, blood pressure, skin temperature). In only one case was a reduced pulse volume amplitude recorded. This patient also had a decrease in blood pressure and the skin temperature of the bitten extremity. On angiography, thrombosis of the popliteal artery and the deep femoral artery was seen. The patient had applied a tourniquet following the bite, which may have caused the thrombosis. The thrombus was successfully removed using a Fogarty catheter (Curry et al. 1985).

Following C. adamanteus bites there is almost never the need to perform fasciotomy. Local necrosis is rare, even with bites that cause massive swelling (Kitchens 1992, pers. comm.).

In 700 patients who had suffered a rattlesnake bite, the need for surgical decompression was extremely rare, using objective criteria for the determination of increased intra-compartmental pressure (pressure >30–40 mmHg, measured with a Wick catheter). In this study surgical decompression was evidently only necessary in one patient. None of the patients experienced a neurological or functional deficit of the affected extremity that could have been attributed to increased intra-compartmental pressure (Garfin 1982).

These clinical and experimental findings indicate that following crotalid bites, intra-compartmental pressure does not increase to such an extent that ischaemia occurs. Massive swelling with restricted movement of the fingers and severe pain can, however, mimic compartment syndrome.

The decision to perform surgical decompression should only be made when the risk of ischaemia has been established objectively. There needs to be evidence of increased intra-compartmental pressure and reduced arterial blood flow, as well as exclusion of the possibility of arterial thrombosis (Curry et al. 1985, Hardy 1991). See also Compartment syndrome.

Even coagulation disorders that are severe according to laboratory tests may only be clinically apparent to a slight degree or not at all (see Biomedical database entry Crotalus admanteus). Although defibrinogenation, caused by the direct fibrinogen-coagulating activity of the venom, generally has a benign course, there is nonetheless a risk of spontaneous haemorrhage with extensive loss of blood or focal bleeding (e.g. intracranial; Kitchens and Eskin 2008) as long as the haemostatic defect is not corrected (untreated, i.e. without antivenom treatment, days to weeks). The risk is even greater if a patient does not receive appropriate treatment at a hospital and is then exposed to trauma, even very minor trauma (Boyer et al 2001). Loss of large volumes of blood can occur due to blood oozing from the bite wound or from injuries or due to medical or paramedical intervention.
If antivenom is effective, spontaneous systemic bleeding should cease within 15–30 min, and blood coagulability should be restored within 1–6 h. The clotting time test is a simple means to regulate the antivenom dose. The initial dose should be repeated if the blood is still not coagulable 6 h after the first dose (Warrell 1990b).
Treatment of the haemostatic defect with blood product replacement should only be carried out if it is clearly indicated, i.e. there is already bleeding or there is an immediate risk of critical bleeding. In all other cases administration of antivenom should be a sufficiently effective and quick means of correcting the haemostatic defect (Burgess and Dart 1991). FabAV has been evaluated in two clinical trial (Dart et al 1997, 2001). Venom-induced abnormalities of the coagulation was reversible following antivenom treatment with recurrences as an important problem (Gold et al 2004). See clinical entry 'Crotalus sp.'

The risk of haemorrhagic complications following bites from North American crotalids whose venoms have direct fibrinogen-coagulating activity (Crotalus. adamanteus, C. horridus, juvenile C. atrox) depends on whether additional platelet defects and haemorrhage-induced effects are present. Defibrinogenation caused by direct fibrinogen-coagulating activity is per se benign. Predictions regarding the risk of bleeding  can only be made following C. adamanteus bites in North America, as the only prospective study of haemostatic defects that has been performed involved bites by this species (Kitchens and Van Mierop 1983). From this study, the following indications for antivenom administration can be derived: for patients who have been bitten by C. adamanteus, the presence of defibrinogenation is not per se an indication for antivenom administration, as long as the patient is young and healthy, has a platelet count of >50 000/mm³, has nothing in his/her history that indicates a risk of haemorrhage and has no clinical signs of venom-induced bleeding, such as ecchymosis, discoid bleeds into the skin, gingival bleeding, haemoptysis, haematemesis or blood in the urine or stools. If these recommendations are followed and the patient does not fulfill the indications for antivenom treatment, he/she is kept in hospital until the defibrinogenation and thrombopaenia have returned to haemostatically safe levels (thrombin time ≤25 s) (Van Mierop and Kitchens 1980, Kitchens and Van Mierop 1983, Kitchens 1992, pers. comm.). A fatlity in a patient bitten by Crotalus adamanteus is of concern and raises questions about the currently held view (see above) on the nature and course of rattle snake bites which cause predominately defibrinogenation (Kitchens and Eskin 2008). See clinical entry 'Crotalus sp.'
According to available empirical and experimental data, bites by juvenile C. atrox and C. horridus carry a higher risk of haemorrhage. The same is probably also true for C. viridis bites. Agkistrodon sp. bites carry an extremely low risk of bleeding.

Due to the problems with reversing neurotoxic envenoming with antivenom, the other two available treatment approaches need to be used concurrently and in a timely manner (Watt 1992):

• Endotracheal intubation and artificial respiration: endotracheal intubation is certain to prevent any form of aspiration. Artificial respiration, even though it may have to be employed over a long period of time, can ensure survival of a patient with neurotoxin-induced respiratory failure.
• The edrophonium (Tensilon®) test should be performed immediately in every patient with signs of paralysis, in order, if the result is positive, to make the most of the improvement in neuromuscular transmission that can be achieved through use of a longer-acting acetylcholinesterase inhibitor (neostigmine). In some cases this may avoid the need for artificial respiration (see the Biomedical database entry for Micrurus sp.).

Paraesthesias of the extremities and perioral paraesthesias as well as muscle fasciculations are reported surprisingly frequently following rattlesnake bites (paraesthesias in 63%, fasciculations in 41% of cases; Russell 1983). Limb and perioral paraesthesias could be due to hyperventilation. However, an argument that is raised to counter this explanation is that this type of symptom is seen much less frequently following bites by other species of snakes.

Electrophysiological investigations in patients who had suffered a Crotalus horridus bite showed that the clinical observations can be explained by a reversible effect of the venom on the excitability of peripheral nerves (see the Biomedical database entry for C. horridus).

With one exception, neurological manifestations following North American crotalid bites are limited to the signs and symptoms discussed above. In addition to local swelling and haemostatic defects, C. s. scutulatus ("type A") bites can also cause neurological symptoms of envenoming, including paralysis. However, there are very few reports of obvious neurotoxic symptoms of envenoming following bites from this geographical variant of a single subspecies (Minton 1990a).

Micrurus fulvius causes paralysis that can progress to paralysis of the respiratory musculature and to respiratory failure.

The venom of Micruroides euryxanthus also contains neurotoxic components. However, to date only insignificant symptoms of envenoming have been reported following bites by this species, or none at all.

There have been no clinical trials on the efficacy of antivenom in the treatment of Micrurus fulvius and C. s. scutulatus ("type A") bites. Empirical data on the course of envenoming following Micrurus bites give the impression that established symptoms of paralysis are not influenced by antivenom treatment (Kitchens and Van Mierop 1987). Likewise, there is no significant effect of the polyvalent Wyeth anti-crotalid antivenom on the neurotoxic course of envenoming following C. s. scutulatus bites (Glenn and Straight 1978). This is not surprising, as neither "type A" venom nor Mojave toxin is included in the manufacturing process of the polyvalent Wyeth anti-crotalid antivenom.

Nor are there any clinical trial results available on the efficacy of acetylcholinesterase inhibitors. C. s. scutulatus venom acts at the presynaptic level of neuromuscular transmission (Gopalakrishnakone et al. 1980), while Micrurus fulvius venom acts post-synaptically to depolarise the muscle fibre membrane (Brazil 1990).

Theoretically the use of acetylcholinesterase inhibitors should have a positive effect on the neurotoxic symptoms caused by Micrurus fulvius bites (Norris and Dart 1989).

Significant systemic rhabdomyolysis is very rarely reported following North American crotalid bites (see Catalogue entry C. horridus). In contrast, local myonecrosis is common if the venom was injected intramuscularly. Local myonecrosis develops as the result of a complex process in which local thromboses and other causes of ischaemic tissue damage are also involved. However, in most bites the venom only reaches the subcutaneous tissue.

Toxins that act on the myocardium have been isolated from the venoms of North American crotalids.

However, there are no reports from North America of cases of envenoming that indicate a primary cardiac effect of the venoms of North American elapids and crotalids. Secondary cardiac disturbances do occur.

There are only a few reports from North America of acute renal failure following crotalid bites (Danzig and Abels 1961, Ahlstrom et al. 1991).

In North America it is necessary to distinguish between crotalid and elapid bites in order to be able to administer the appropriate antivenom. Each of these two groups is covered by a polyvalent antivenom.

• Among the crotalids, rattlesnakes are easily identified by the rattle on the end of their tail (see Find terrestrial snake by morphology (regional).
• The markings and colouring of the elapids (Micrurus fulvius, Micruroides euryxanthus) are likewise easily recognisable even for lay people.

In addition, regional differentiation according to sign and symptom complexes is relatively easy and unambiguous in North America (see Clinical flowchart: North America):

• Local swelling, incoagulable blood (systemic bleeding):
  • Crotalids: Crotalus sp., Sistrurus sp. (Agkistrodon sp.).

• (Local swelling), incoagulable blood (systemic bleeding), signs of paralysis:
  • Crotalids: Crotalus s. scutulatus "type A".

• Signs of paralysis of the cranial nerves, the extremities and the respiratory musculature:
  • Elapids: Micrurus fulvius.

If the selected antivenom is not effective, 3 possible causes need to be considered:

1. correct identification of the cause, but insufficient dose administered;
2. correct identification of the cause, but inadequate effect of the antivenom;
3. incorrect identification of the cause → revision of identification.

Rattlesnakes

The effect of FabAV on local venom effects is not convincing regarding improvement of established damage. After antivenom has been infused local damage did not worsen, however. Validation would have needed a control group, however, which was not included into the trial for obvious reasons (Dart et al 2001; see clinical entry Crotalus sp.).

Response to FabAV is marked with ragard to venom effects on the coagulation, central nervous, gastrointestinal, and cardiovascular systems (Dart et al 2001). Recurrence aisan important problem (Gold et al 2004; see clinical entry Crotalus sp.).

There is evidence from case reports (Clark et al 1997) that neurological envenoming following C. s. scutulatus bites can be successfully treated with FabAV (see clinical entry C. s. scutulatus).

Coral snakes

When paralysis following Micrurus fulvius envenomation is established the effect of antivenom is limited or absent with regard to its reversion. Venom components which enter circulation or are already circulating can, however,  be neutralized. For this reason immediate pain or any other sign or symptom of envenoming after or strong suspicion of a coral snke bite (see clinical entry Micrurus sp.) is an indication for antivenom (Gold et al 2004).

An ELISA test for detection of the venom of North American crotalids has been developed (Minton et al. 1984, 1987b). However, it is not yet commercially available (Norris 2004).

Even if the desired effect of antivenom administration, namely normalisation of the parameters relevant to envenoming (findings on physical examinations, physical and laboratory investigations), is achieved quickly, this does not mean that the symptoms of envenoming may not re-occur due to continued absorption of venom from a depot in the region of the bite. Patients bitten by species of snakes whose venom causes haemostatic defects should be kept in hospital for up to several days after initial treatment, and blood coagulability should continue to be monitored twice daily.

FabAV: IMPORTANT: 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 coagulopaty (Boyer et al 1999)

see clinical entry Crotalus sp.

The same considerations apply to patients suffering from elapid bites.

• Excision of necrotic material,
• surgical debridement under general or regional anaesthesia, 
• skin grafting (split-thickness).

• Physiotherapy,
• surgical correction.

See Antivenom treatment.