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.

The venom of vipers in particular can cause clinical symptoms of anaphylaxis in patients within minutes after the bite.

Autopharmacological effects of venom such as arterial hypotension and hypovolaemic shock as a consequence of sequestration of large amounts of fluid in the extravascular space occur with Bitis arietans, Vipera palaestinae and Macrovipera sp.? in particular (Efrati 1979, Leviton et al. 1992, Warrell et al. 1975).

Tourniquets can cause local swelling and thus mimic local venom effects.

For some species of snakes local signs of envenoming, in particular swelling, are a reliable parameter for possible systemic envenoming, while for other species they provide no indication at all.

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.

The efficacy of antivenom with regard to local effects, such as swelling and necrosis, has not been proven. The small amount of data that is available is not sufficient to assess this (Warrell et al. 1975, 1976b, 1977, Tilbury 1982).

Atractaspis sp.: as a rule there is generally at least mild local swelling following injection of venom (Warrell et al. 1976c).

Bitis arietans: marked local swelling that often extends to the trunk and causes necrosis (Warrell et al. 1975, Marsh and Whaler 1984).

Causus sp.: local swelling generally appears to occur following injection of venom, but is only marked in a small proportion of cases (Warrell et al. 1976c).

Echis sp.: local swelling always occurs if venom has been injected, but may be only mild (Porath et al. 1992, Warrell et al. 1977).

Daboia palaestinae and Macrovipera lebetina: extensive swelling that may extend to the trunk, necrosis possible but rarely severe as long as the bite is not on the fingers or toes (Efrati 1979, Leviton et al. 1992).

Naja nigricollis and N. pallida: local swelling may be very extensive, possibly involving the trunk, necrosis (Warrell et al. 1976b).
Naja haje: local signs of envenoming usually absent or insignificant (Warrell et al. 1976b, Blaylock et al. 1985, Visser and Chapman 1978).

Walterinnesia aegyptia: local swelling (Yayon et al. 1988).
Eyes:
Naja nigricollis, N. pallida, N. katiensis and N. nubiae can cause lesions in the eye (Warrell and Ormerod 1976).

Even extensive swelling, such as occurs following Bitis arietans, V. palaestinae and Macrovipera lebetina bites, is not usually a manifestation of compartment syndrome. The decision to perform a fasciotomy must have a rational basis (evidence of increased intra-compartmental pressure; reduced or absent arterial blood flow).

Even coagulation disorders that are severe according to laboratory tests may only be clinically apparent to a slight degree, or not at all (e.g. Echis sp. bites). There is a threat of spontaneous haemorrhage with extensive loss of blood or focal bleeding (e.g. intracranial) as long as the haemostatic defect exists (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, for example while working. 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 and venom-induced coagulation disorders are present, 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).

If antivenom treatment is not successful, it is always necessary to consider the possibility of treatment failure or misidentification of the snake that caused the bite.

Haematuria (especially microhaematuria) is not a reliable sign of a venom-induced haemorrhage in those regions where urinary schistosomiasis (Schistosoma haematobium) is prevalent.

There are no controlled clinical studies of the efficacy of antivenoms for snakebites in this region that cause neurological effects. In Southeast Asia the efficacy of antivenom with regard to neurological effects (Cobras, Kraits) has been more thoroughly investigated. The effect is not convincing and, if present at all, is slow to occur (Warrell 1990b).

Apart from the problem of antivenom efficacy, the possibility of misidentification of the snake that caused the bite must always be considered if the expected treatment effect does not occur.

Due to the highly questionable efficacy of antivenom against neurotoxic symptoms of envenoming, the other two available treatment approaches need to be used concurrently and in a timely manner:

• Endotracheal intubation and artificial respiration: endotracheal intubation is certain to prevent any form of aspiration. Manual or mechanical ventilation, 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) (Watt 1992).
  

In 4 definite cases of Walterinnesia aegyptia bites no signs of paralysis were observed (Yayon et al. 1988). Corkill (1931–33) reported neurotoxic symptoms following bites by Walterinnesia morgani; however, the snakes that caused the bites were not identified with certainty.

ECG changes have been observed following Echis coloratus bites (Fainaru et al. 1974).

Cardiac dysrhythmias and cardiac insufficiency and failure are probably usually secondary effects (hyperkalaemia, in the context of shock).

• Antivenom,
• symptomatic treatment:
  
  • treatment of the acute renal failure.

According to the available data, acute renal failure following a snakebite in North Africa and the Near and Middle East generally appears to be a secondary effect (arterial hypotension, shock, DIC).

For Bitis arietans and Cerastes cerastes venom a primary nephrogenic effect is discussed (Warrell et al. 1975, Schneemann et al. 2004).

In many regions of North Africa and the Near and Middle East, polyspecific antivenoms are available that cover the medically relevant snake species; however, sometimes monospecific antivenoms need to be utilised as well.

If the snake that caused the bite needs to be identified at the species level in order to choose the appropriate antivenom, indirect criteria must often be used, as in the majority of cases the snake is not available for identification or the patient's description of the snake is not conclusive.

Differentiation according to symptom complexes can aid regional identification (see Clinical flowchart: North Africa, Near and Middle East):

• Signs of paralysis of the cranial nerves, extremities and respiratory musculature:
  Elapids: Naja haje, N. arabica?, N. melanoleuca?, N. senegalensis?, N. oxiana?, Walterinnesia aegyptia?

• Incoagulable blood (clotting time test), spontaneous bleeding, local swelling:
  Viperids: Echis sp., Cerastes cerastes
  
• Marked local swelling that may involve the trunk, necrosis, hypovolaemic shock, spontaneous bleeding (clotting time normal):
  Viperids: Bitis arietans, (Cerastes cerastes)
• Marked local swelling that may involve the trunk, hypovolaemic shock, (spontaneous bleeding), (necrosis):
  Viperids: Vipera palaestinae, Macrovipera lebetina
• Marked local swelling that may affect the entire extremity and the trunk, (necrosis):
  Elapids: Naja nigricollis, N. pallida, N. katiensis?, N. nubiae?
  
• Mild swelling (→ necrosis):
  Viperids: Causus sp. (no antivenom available!); Atractaspis sp. (no antivenom available!).
• Local signs of envenoming in the eye:
  Spitting cobras: N. nigricollis,  N. pallida, N. katiensis, N. nubiae.

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 efficacy of the antivenom;
3. incorrect identification of the cause → revision of identification.

Controlled clinical studies of antivenom efficacy only exist for a small number of antivenoms (see Biomedical database).

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.

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.

Local treatment.

In particular with Cobra bites that cause local effects (N. nigricollis, N. pallida, N. katiensis, N. nubiae), the true extent of the necrosis is often only discernible after some time, and thus it is essential that the patient is observed for a sufficiently long period in order to ensure the necessary treatment.

Corneal lesions and lesions of the anterior chambers of the eye need to be either definitively excluded or treated systematically in order to avoid damage due to secondary infections.