Ophitoxaemia (Venomous snakebite)

Joseph L. Mathew
Tarun Gera

Address for correspondence:
Dr. Tarun Gera
B - 256, Derawala Nagar,
Delhi-110009,
India
E-mail : jlm@rediffmail.com, tarun256@hotmail.com

* Introduction
* Epidemiology
* Systemic Manifestations
* Local Manifestations
* Unusual and Rare Manifestations



* Factors influencing outcome
* Laboratory features
* Management
* First Aid
* Specific Therapy



* Supportive Therapy
* Mortality
* Conclusion
* References

INTRODUCTION

Ophitoxaemia is the rather exotic term that characterizes the clinical spectrum of snake bite envenomation. Of the 2500-3000 species of snakes distributed world-wide, about 500 are venomous. Based on their morphological characteristics including arrangement of scales, dentition, osteology, myology, sensory organs etc., snakes are categorized into families. The families of venomous snakes are Atractaspididae, Elapidae, Hydrophidae and Viperidae.
The major families in the Indian subcontinent are: Elapidae which includes common cobra, king cobra and krait, Viperidae which includes Russell's viper, pit viper and saw-scaled viper and Hydrophidae (the sea snakes) [1]. Of the 52 poisonous species in India, majority of bites and consequent mortality is attributable to 5 species viz. Ophiophagus hannah (king cobra), Naja Naja (common cobra), Daboia rusellii (Russell's viper), Bungarus caeruleus (krait) and Echis carinatae (saw-scaled viper). There are 14 venomous species in Nepal. These include pit vipers (5 species), Russell's viper, kraits (3 species), coral snake and 3 species of cobra including the king cobra [2].

EPIDEMIOLOGY OF SNAKE BITE

Snake bite remains a public health problem in many countries even though it is difficult to be precise about the actual number of cases. It is estimated that the true incidence of snake envenomation could exceed 5 million per year. About 100,000 of these develop severe sequelae. The global disparity in the epidemiological data reflects variations in health reporting accuracy as well as the diversity of economic and ecological conditions [3].

To complicate matters further, accurate records to determine the exact epidemiology or even mortality in snake bite cases are also generally unavailable [1]. Hospital records fall far short of the actual number owing to dependence on traditional healers and practitioners of witchcraft etc. It has been reported that in most developing countries, upto 80% of individuals bitten by snakes first consult traditional practitioners before visiting a medical centre [4,5]. Owing to the delay several victims die during transit to the hospital. Nevertheless, Swaroop reported about 200,000 bites and 15,000 deaths in India due to snake bite poisoning as far back as 1954 [6]. Based on an epidemiological survey of 26 villages with a total population of nearly 19,000 individuals in Burdwan district of West Bengal state in India, Hati et al worked out an annual incidence of 0.16% and mortality rate of 0.016% per year [7]. In Sri Lanka, the overall annual mortality from a single venomous species ranges from 5.6 per 100,000 to as high as 18 per 100,000 in some areas [8]. Myanmar seems to have the highest mortality in Asia and 70% snakebites are by Russell's viper [9.10]. However, this may only reflect a better reporting system prevalent in that country. Maharashtra, one of the states of India with the highest incidence, reported 70 bites per 100,000 population and mortality of 2.4 per 100,000 per year [11]. The other states with a large number of snakebite cases include West Bengal, Tamil Nadu, Uttar Pradesh and Kerala [1].
It has been estimated that 150 to 200 ophitoxaemia related deaths occur annually in Nepalese hospitals [12]. The WHO estimated over 20,000 cases and 1000 deaths from ophitoxaemia in Nepal [13].

Chippaux has stressed the importance of distinguishing between hazardous snakebites, which occur when humans encounter a snake accidentally and 'illegitimate' snakebites inflicted by an animal kept in captivity, or during snake handling. In industrialized countries the frequency of illegitimate snake bites is increasing while hazardous bites predominate in developing countries [3].

The age and sex incidence of snake bite victims throws light on the vulnerable section of the population. While snake bite is observed in all age groups, the large majority (90%) are in males aged 11-50 years. The predominance of male victims suggests a special risk of outdoor activity [14].

The high incidence of snake bite between 0400 hours to midnight corresponds well with the period of maximum outdoor activity observed in most studies. The incidence of snake bite shows a distinct seasonal pattern closely related to rainfall and temperature which compels the reptiles to come out of their shelter [14].

Most patients are unable to identify the snake species either because of ignorance or poor visibility in darkness. A large number of bites occur in fields, most individuals are unable to spot the snake due to tall grass and crops. The observation that the most frequent site of bite is the lower extremity suggests that in most cases the snake is inadvertently trodden upon.
Among the host factors, people involved in occupations and/or lifestyles requiring movement in dense undergrowth or undeveloped land, are the worst affected. These include farmers, herders and hunters [15] and workers on development sites. Paul reported an incidence of 7-15 percent in children less than10 years [16]. Another study reported 37% incidence in the second decade of life [14]. The sex ratio seems almost uniform all over with males being affected twice or thrice as commonly as females [16]. For obvious reasons, bites are maximal in lower limbs (about two thirds) [17] with 40 percent occurring in feet alone.

Morbidity and mortality resulting from snake-bite envenomation also depends on the species of snake involved, since the estimated "fatal dose" of venom varies with species. In the Indian setting, almost two-thirds of bites are attributed to saw-scaled viper (as high as 95% in some areas like Jammu) [18], about one fourth to Russell's viper and smaller proportions to cobra and kraits [19]. In Sri Lanka, Daboia russellii accounts for 40% of bites and Naja naja for another 35% [8,20]. Daboia russellii alone accounts for 70% bites in Myanmar [9,10]. Among the various species, the average yield per bite in terms of dry weight of lyophilised venom is 60 mg for cobras, 63 mg for Russel's viper, 20 mg for krait and 13 mg for saw scaled viper. The respective "fatal doses" are much smaller viz 12 mg, 15 mg, 6 mg and 8 mg [21]. However, clinical features and outcomes are not as simple to predict because every bite does not result in complete envenomation [22]. Epidemics of snake bite following floods owing to human and snake populations getting concentrated together have been noted in Pakistan, India and Bangladesh.

PATHOPHYSIOLOGY OF OPHITOXAEMIA

Snake venom, the most complex of all poisons is a mixture of enzymatic and non-enzymatic compounds as well as other non-toxic proteins including carbohydrates and metals. There are over 20 different enzymes including phospholipases A2, B, C, D hydrolases, phosphatases (acid as well as alkaline), proteases, esterases, acetylcholinesterase, transaminase, hyaluronidase, phosphodiesterase, nucleotidase and ATPase and nucleosidases (DNA & RNA) [1]. The non-enzymatic components are loosely categorized as neurotoxins and haemorrhagens [16]. Different species have differing proportions of most if not all of the above mixtures- this is why poisonous species were formerly classified exclusively as neurotoxic, haemotoxic or myotoxic. The pathophysiologic basis for morbidity and mortality is the disruption of normal cellular functions by these enzymes and toxins. Some enzymes such as hyaluronidase disseminate venom by breaking down tissue barriers. The variation of venom composition from species to species explains the clinical diversity of ophitoxaemia. There is also considerable variation in the relative proportions of different venom constituents within a single species throughout its geographical distribution, at different seasons of the year and as a result of ageing.
The various venom constituents have different modes of action. Ophitoxaemia leads to increase in the capillary permeability which may cause loss of blood and plasma volume into the extravascular space. This accumulation of fluid in the interstitial space is responsible for edema. The decrease in the intravascular volume may be severe enough to compromise circulation and lead on to shock. Snake venom also has direct cytolytic action causing local necrosis and secondary infection, a common cause of death in snake bite patients. The venom may also have direct neurotoxic action leading to paralysis and respiratory arrest, cardiotoxic effect causing cardiac arrest, myotoxic and nephrotoxic effect. Ophitoxaemia also causes alteration in the coagulation activity leading to bleeding which may be severe enough to kill the victim.

CLINICAL MANIFESTATIONS

The clinical manifestations of snake-bite occur in a wide spectrum with some bites resulting in minimal or no symptoms at all, while others are severe enough to result in systemic manifestations and even death. Besides discussing these, we have also tried to include unusual and rare presentations of ophitoxaemia.

SNAKE BITES WITH NO MANIFESTATIONS

The most obvious explanation for a confirmed snake-bite but no clinical manifestations is bite by a non-poisonous species. However, it is well documented that a large number of poisonous species also often do not cause symptoms. In a study of 432 snake-bites in North India, Banerjee noted that 80% of victims showed no evidence of envenomation [1]. This figure correlates almost exactly with a more recent observation from Brazil [24]. Reid also states that over 50% of individuals bitten by potentially lethal venomous snakes escape with hardly any features of poisoning [22]. This is corroborated by Saini's study of 200 cases in Jammu region in India, in which only 117 showed symptom/sign of envenomation [19]. From the relatively low frequency of poisoning following snakebites, it has been suggested that snakes on the defensive when biting humans seldom inject much venom [25]. Other possible explanations include a bite without release of venom (dry bite). In a study of 40 bites by snakes which were captured and identified as poisonous, about one- third showed no clinical or laboratory evidence of systemic envenoming suggesting a high incidence of dry bites [26]. There are also cases wherein venom is spewed into the victim's body as the snake attempts to bite, thereby reducing the overall quantity of venom in the blood stream. Lamb has recorded that almost 30% of cobra bites are "superficial" with minimal envenomation. Other protective factors include the layers of clothing or boot leather through which the snake sometimes strikes [27].

LOCAL MANIFESTATIONS

With the possible exception of the psychological trauma of being bitten, local changes are the earliest manifestations of snake bites [28]. Features are noted within 6-8 minutes but may have onset up to 30 minutes [21,29]. Local pain with radiation and tenderness and the development of a small reddish wheal are the first to occur. This is followed by oedema [16], swelling and appearance of bullae - all of which can progress quite rapidly and extensively even involving the trunk [19]. Tingling and numbness over the tongue, mouth and scalp and paraesthesias around the wound occur mostly in viper bites [21]. Local bleeding including petechial and/or purpuric rash is also seen most commonly with this family. Regional lymphadenopathy has been reported as an early and reliable sign of systemic poisoning [30]. The local area of bite may become devascularized with features of necrosis predisposing to onset of gangrenous changes. Generally Elapid bites result in early gangrene-usually-wet type whereas vipers cause dry gangrene of slower onset; though one of the authors (JLM) has also seen the reverse pattern. There are two interesting case reports of Raynaud's phenomenon and gangrene in a limb different from the one bitten - both bites were by Russell's viper [31]. Secondary infection including tetanus and gas gangrene may also result [1].

SYSTEMIC MANIFESTATIONS

As mentioned previously, the most common and earliest symptom following snake bite (poisonous or non poisonous) is fright [28], particularly of rapid and unpleasant death [21]. Owing to fright, a victim attempts 'flight' which unfortunately results in enhanced systemic absorption of venom. These emotional manifestations develop extremely rapidly (almost instantaneous) and may produce psychological shock and even death. Fear may cause also transient pallor, sweating and vomiting. The time onset of poisoning is similar in different species. Cobra produces symptoms as early as 5 minutes [16] or as late as 10 hours [28] after the bite. Vipers take slightly longer - the mean duration of onset being 20 minutes [16]. However, symptoms may be delayed for several hours. Sea snake bites almost always produce myotoxic features within 2 hours so that they are reliably excluded if no symptoms are evident within this period [16].

Other systemic manifestations depend upon the pathophysiological changes induced by the venom of that particular species (See Fig. 1). As mentioned previously, based on the predominant constituents of venom of a particular species, snakes were loosely classified as neurotoxic (notably cobras and kraits), hemorrhagic (vipers) [2] and myotoxic (sea snakes). However it is now well recognized that such a strict categorization is not valid as each species can result in any kind of manifestations. Neurotoxic features are a result of selective d-tubocurarine like neuro-muscular blockade which results in flaccid paralysis of muscles [16]. Cobra venom is however 15-40 times more potent than tubocurarine [1]. Ptosis is the earliest [1] neuroparalytic manifestation followed closely by opthalmoplegia. Paralysis then progresses to involve muscles of palate, jaw, tongue, larynx, neck and muscles of deglutition-but not strictly in that order [16]. Generally muscles innervated by cranial nerves are involved earlier [1]. However, pupils are reactive to light till terminal stages [1]. Muscles of chest are involved relatively late with diaphragm being the most resistant. This accounts for the respiratory paralysis, which is often terminal. Reflex activity is generally not affected in ophitoxaemia and deep tendon jerks are preserved till late stages [1]. Onset of coma is variable, however several cases of cobra bite progress to coma within 2 hours of bite. Symptoms that portend paralysis include repeated vomiting, blurred vision, paraesthesiae around the mouth, hyperacusis, headache, dizziness, vertigo and signs of autonomic hyperactivity.

Cardiotoxic features include tachycardia, hypotension and ECG changes. Cardiotoxicity occurs in about 25% viperine bites and includes rate, rhythm and blood pressure fluctuations [32]. In addition, sudden cardiac standstill may also occur owing to hyperkalemic arrest. Non dyselectrolytemic acute myocardial infarction has also been reported [33]. Tetanic contraction of heart following a large dose of cobra venom has been documented in vivo and in vitro [34]. There is a single case report of non-bacterial thrombotic endocarditis following viper bite [35]. Myalgic features are the most common presentation of bites by sea snakes. Muscle necrosis may also result in myoglobinuria.

Snake venoms cause haemostatic defects by a number of different mechanisms. Some cause activation of intravascular coagulation and result in consumption coagulopathy. Notable in this group is Daboia russelli which has procoagulant activating factors V and X. Certain other venoms cause defibrinogenation by activating endogenous fibrinolytic system [35,36]. Besides direct effects on the coagulation cascade, venoms also can cause qualitative and quantitative defects in platelet function [39]. In India and Sri Lanka, Russell's viper envenomation is often associated with massive intravascular haemolysis [37]. Haematological changes - both local as well as systemic - are some of the commonest features of snake bite poisoning. Bleeding may occur from multiple sites including gums [17], GIT (haematemesis and melaena), urinary tract, injection sites and even as multiple petechiae and purpurae [28]. Subarachnoid haemorrhages were documented in 5 of 200 cases in Saini's series of patients in Jammu region [19]. In addition cerebral haemorrhage [39] and extradural haematoma [40] have also been reported. Almost every species of snake can cause renal failure. It is fairly common following Russell's viper bite and is a major cause of death [41] In a series of 40 viper bites, renal failure was documented in about a third [42]. The extent of renal abnormality in them correlated well with the degree of coagulation defect; however in a majority renal defects persisted for several days after the coagulation abnormalities normalised: suggesting that multiple factors are involved in venom induced ARF.

Rarer systemic manifestations including hypopituitarism [43,44], bilateral thalamic haematoma [45] and hysterical paralysis [46] have also been reported.

MORTALITY

While there are many factors influencing the outcome in victims of snake-bite, there is an overall agreement in the case fatality rate - generally varying from 2-10%[16,47-51]. The mortality rate is higher in children owing to larger amount of toxin per kg body weight absorbed [27]. There is significantly higher mortality among victims who develop neurotoxicity [47,51]. On an average - cobras and sea snakes result in about 10% mortality [28]-ranging from 5-15 hours following bite. Vipers have a more variable mortality rate of 1-15% and generally more delayed (up to 48 hours) [22].

UNUSUAL AND RARE MANIFESTATIONS OF OPHITOXAEMIA
Delayed manifestations

Authors are all uniform in their opinion that delayed onset of signs is rare. In their series of 56 cases, Saini et al documented 4 patients who had normal clinical and laboratory coagulation profile at admission shortly following bite, but started bleeding as late as 4-6 days after the bite [9]. Reid has noted that haemorrhage in the brain may be delayed up to one week after bite [28]. The possible explanation for these manifestations is that local blebs constitute a venom depot which is suddenly released into the blood stream, especially when the wound is handled surgically [29]. Further, these depots are generally inaccessible to antivenom. Nevertheless we have experience of a case showed good response to antivenom injected twice (24 hour and 36 hour after bite) and still developed features of systemic neurotoxicity on the 7th day, despite remaining well for 51/2 days (unpublished observation). This occurred without any interference at the local site. There is also the interesting report of a zookeeper bitten on the finger following which he was administered antivenom. This prevented the development of systemic poisoning but had no effect on the extent of local complications. This individual developed compartment syndrome and spontaneous rupture of the extensor tendon of the involved finger several weeks after the bite suggesting a delayed manifestation even in the absence of systemic poisoning [52]. Kumar et al have reported a singular occurrence of unconsciousness 6 days after an individual was bitten- he remained symptom free for the first 5 days [53].
Recurrent manifestations
Recurrence of manifestations has not been discussed in most of the published literature. The only record is Warrell's assertion that signs of systemic envenomation may recur hours or even days after initially good response to antivenom. This has been explained by ongoing absorption of venom from the blood - which has a half life of 26-95 hours [17]. He therefore suggests daily evaluation of patients for at least 3-4 days. This theory would probably not be able to account for our experience of recurrence of neurotoxic manifestations in a 10 year old child bitten by a cobra, that occurred 12 hours after a relatively large dose of antivenom (10 vials). This child responded well to an additional dose of 10 more vials (Unpublished observations). Available literature suggests the use of antivenom till symptoms and signs are controlled, with some authors recommending its use as and when necessary [17]. Nevertheless, recurrence of signs of envenomation is still a rarity.

Long term effects of snake bite [22]

In most cases, swelling and oedema resolve within 2 to 3 weeks. However, they may occasionally persist up to 3 months. In exceptional circumstances, they may also be permanent. There are records, which suggest that coagulation disturbances [28] and neurotoxicity may persist beyond 3 weeks. Necrosis of the local tissue, resultant gangrene and the consequent cosmetic defects are obvious long term effects of ophitoxaemia [28].

Manifestations of snake bite not because of toxemia

Cases have been reported wherein the clinical manifestations of snake bite are not because of the poisoning, but due to venom hypersensitivity [27]. This has been noted, irrespective of a history of previous bite by the same or different species. Such patients may manifest with anxiety, cutaneous sensitivity or tightness in the throat. They may also present with features of anaphylactic shock. In a study of victims of Bothrops bite in rural Argentina, it was noted that individuals bitten twice developed hives and angioedema within 15 minutes of the second bite. Specific antibodies - both IgE and IgG were detectable in their serum . The crossreactivity among the venom of Bothrops sp suggests that these signs are because of specific IgE antibodies against venom and must not be interpreted with toxic effects that appear late [55].

Toxemia without bite

Naja nigricollis (spitting cobra) is a species which can eject venom with considerable accuracy even from a distance of 6-12 feet [17]. The exact range and target of this snake's venom is a matter of considerable debate among herpetologists. Most are in agreement that the venom is aimed at the victim's eyes resulting in conjunctivitis and corneal ulceration. The latter may be deep enough to cause anterior uveitis and hypopyon [56]. There are patients who have required enucleation of both eyes following a vicious attack by the spitting cobra. Besides the local manifestation, a dull headache persisting beyond 72 hours is a common feature. Spitting cobra is an exotic species since even the king cobra does not eject venom in this manner.

Bite by a killed snake
There are instances on record wherein a recently killed snake and even those with severed heads have ejected venom into those handling them. This is the basis for the absolute ban on handling and extreme caution in transportation which is usually advocated for killed snakes [17].

FACTORS AFFECTING SEVERITY AND OUTCOME IN OPHITOXAEMIA

There are several agent, host and environmental factors that modify the clinical presentation and resultant mortality of ophitoxaemia.

Children overall fare worse than adults owing to greater amount of toxin injected per unit body mass [16]. For the same age, individuals in a better state of health fare better than more debilitated counterparts [27]. Patients bitten on the trunk, face and directly into bloodstream have a worse prognosis [16]. Reid however asserts that the age of the victim and part of body bitten have no relation to outcome [29]. Exercise and exertion following bite results in enhanced systemic absorption of venom. This is why individuals who panic and flee from the scene of bite generally have a worse outcome [57]. The protection afforded by layers of clothing or shoes sometimes mitigates the effects of envenomation to a considerable extent [27]. Sensitivity of individual to venom naturally modifies the clinical picture as explained earlier [27]. Victims of ophitoxaemia who develop secondary infection at the site of bite fare worse than those uninfected [57].

The number and depth of the bites inflicted by the snake is a relative index of the amount of venom injected [16]. Indirect evidence for this is also available by studying the volume of venom remaining in the glands and fangs. The condition of fangs, intact or broken, is also an indirect indicator of amount of envenomation. The species of snake which has bitten alters outcome since the amount of venom injected and the 'lethal dose' varies with species [21]. The length of time a snake clings to its victim and the presence or absence of pathogenic organisms in its mouth are two other agent factors affecting outcome. The time of bite (day or night) and breeding habits of the snake are not related to outcome in any way [27]. The size of snake does not appear to be related to the efficacy of envenomation since several small specimens also have lethal capacity.

Among the environmental factors, the nature of first-aid and the time elapsed before administration is perhaps the single most important factor affecting outcome [27]. The circumstances that provoked the snake to bite may also have a bearing on clinical presentation and survival of victims.

APPROACH TO AN INDIVIDUAL ' ALLEGEDLY BITTEN' BY A SNAKE

This section is included here because of the importance of confirming an alleged bite by a snake. This has relevance on the management issues. Quite often, the victim who has ventured into open fields or dense undergrowth is bitten by a species which is not immediately identifiable. In addition, the psychological reaction generated by this unexpected event impels him/her to flee: thereby further reducing the probability of confirming the snake-bite. Therefore, in a patient presenting with history suggestive of snake-bite, it is important to address the following questions .



1. Is it actually a snake bite?

The classical setting for a snake bite has been described above. Bite is identified by the presence of 2 puncture wounds which may vary in distance from a few millimeters to as much as 4 cms, depending on the species. The depth of the bite varies anywhere from 1-8 millimeter [2]. In some cases, fang puncture sites are not easily visible. They may be brought to view by Bailey's method of injecting lignocaine through a fine gauge needle and observing the sites where it oozes from [27]. In some cases of bite, fang marks may not be visible at all. This has been attributed to a glancing strike or protection by clothing or foot wear. For the same reason, puncture wounds may even be single at times. There are instances wherein a snake has attacked repeatedly leaving multiple puncture marks [27]. Non-poisonous snakes generally leave a row of tooth impressions, but not fangs marks [21]. However, it is advocated that too much stress should not be laid on this rather variable feature.

2. Could it be anything else?

Russell contends that the marks left by snakes may be so variable as to make it difficult to distinguish from bites of rats, mice, cats and even lizards. They may also be confused with insect and scorpion bites/stings. Scratches or penetration by thorns or cactus may also leave marks like those of fangs; all these may be accompanied by local changes further compounding the problem of correct diagnosis [27].



3. Is it likely to be a poisonous species?

There is no simple, reliable method to distinguish poisonous from non-poisonous species. Poisonous species generally have fangs but these may be very small in elapids and not easily visible in vipers. Tails are usually not compressed and belly scales are small in non-venomous species - all of which are opposite in poisonous species [21]. Short of identifying the offending reptile, the only way to determine the poisonous nature of a species is to watch for features of envenomation viz local changes and/or systemic features.



4. Which species is involved?

Among the commonest poisonous species in India, the cobra (nag) is easiest to identify owing to a mental picture well entrenched in most peoples minds. Technically, however it is described as having a hood bearing a single or double spectacle shaped mark on its dorsal aspect. A white band in the region where the body touches the hood is another identifying feature. The common krait (karayat) is steel blue, often shining and has a single or double white band across the back. The head is covered with large shields. In general, elapidae have relatively short, fixed front fangs; as do the Hydrophidae. Russell's viper (daboia, kander) is identified by its flat, triangular head with a white 'V' shaped mark and three rows of diamond-shaped black or brown spots along the back. The sawscaled viper (afai) is distinguished from the other species by a white mark on the head resembling a bird's footprint or an arrow. The fangs of vipers are long, curved, hinged, front fangs, which have a closed venom channel, giving them a structure akin to a hypodermic needle. Besides these, there are several other differentiating characteristics among the poisonous snakes, which are of more interest to an expert than medical personnel. It has been claimed that most venomous species produce characteristic sounds, which may help in identification. These include hissing (Russell's viper), rasping (saw-scaled viper) and 'growling' (king cobras).

LABORATORY AIDS IN OPHITOXAEMIA

The laboratory serves rather poorly in the diagnosis of snake-bite, with the exception of ELISA studies which are now available to identify the species involved, based on antigens in the venom [22]. These tests are expensive and not freely available-hence of limited value; except for epidemiological study [16]. Laboratory tests are useful for monitoring, prognosticating victims of ophitoxaemia, as well as determining stages of intervention. Recently emphasis is being laid on the value of immuno-enzymatic tests to identify the offending species accurately [58].
Blood changes include anaemia, leucocytosis and thrombocytopenia [16]. In addition, peripheral smear may show evidence of haemolysis, particularly in viperine bites [19]. Deranged coagulant activity manifested by prolonged clotting time and prothrombin time may also be evident [28]. The quality of clot formed may be a better indicator of coagulation capability than the actual time required for formation, since clot lysis has been observed in several patients who had normal clotting time [19]. Hypofibrinogenemia may also be evident [16]. Among the metabolic changes, hyperkalaemia and hypoxemia with respiratory acidosis, especially with neuroparalysis may be present [16].
Urine examination could reveal haematuria, proteinuria, haemoglobinuria or myoglobinuria. In cases of ARF, all features of azotemia are also present. CSF haemorrhage has been documented in a minority of victims [16,19].

ECG changes are generally non-specific and include alterations in rhythm (predominantly bradycardia) and atrioventricular block with ST segment elevation or depression. T wave inversion and QT prolongation [1] have also been noted. Tall T waves in lead V2 and patterns suggestive of acute anterior wall infarction have been reported as well [32]. In addition, cases who develop hyperkalaemia manifest typical changes of this dyselectrolytaemia [17].
Serum cholesterol at admission has been found to correlate negatively with severity of envenomation. Rabbits exposed to snake venom in an experimental setting were noted to have a dose dependent decrease in serum cholesterol. This fall which is independent of the fall in serum albumin can only partially be explained by transcapillary lipoprotein leakage. It is more likely an indication of change in lipoprotein transport and metabolism as a result of phospholipase A2 in venom [59].

Recently EEG changes have been noted in up to 96% of patients bitten by snakes; starting within hours of the bite. Interestingly none of them showed any clinical features suggestive of encephalopathy. 62% showed grade I changes defined as decrease in (activity or/and increase in -activity or presence of sharp waves. 31% cases manifested grade II changes viz. sharp waves or spikes and slow waves; classified as moderate to severe abnormality. The remaining 4% showed severe abnormality with diffuse (activity (grade III). These abnormal EEG patterns were picked up mainly in the temporal lobes [60].

MANAGEMENT OF OPHITOXAEMIA

A review of literature pertaining to management of snake bite makes interesting reading, particularly with respect to traditional methods [27]. However, even a brief review of these novel practices is beyond the scope of the present discussion. Management aspects are fraught with controversy with experts differing over most, if not all facets of therapy. Owing to the variables involved in therapy, an ideal prospective clinical trial will likely never be done [61]. This article attempts to discuss management under the following heads:

a) First aid
b) Specific therapy
c) Supportive therapy

First aid

Most physicians are in disagreement with regard to nature, duration and even necessity of first aid. Russell advises minimal wastage of time with first-aid measures which often end up doing more harm than good [27]. Nevertheless, it is felt that reassurance and immobilization of the affected limb with prompt transfer to a medical facility are the cornerstones of first-aid care [16,22]. Most experts also advocate the application of a wide tourniquet or crepe bandage over the limb to retard the absorption and spread of venom [16,28]. The tourniquet should be tight enough to occlude the lymphatics, but not venous drainage [1]; though some also prefer to occlude the veins. Enough space to allow one finger between the limb and bandage is most appropriate. Should the limb become edematous, the tourniquet should be advanced proximally [16]. Tourniquets should never be left in place too long for fear of distal avascular necrosis [27]. In a recent report from Brazil, two cases were reported to have increased local envenoming subsequent to a tourniquet [62].

It was formerly believed and therefore advocated that incision over the bite drains out venom. However, it has now been established from animal experiments that systemic venom absorption starts almost instantly; this form of 'therapy' is therefore being questioned [27,28]. Some experts suggest that longitudinal incisions within fifteen minutes of the bite may be beneficial [1].
Suction of the local area, a staple of snake-bite management in Indian cinema, also has its advocates and detractors. While most have rejected it for its questionable efficacy [63], there are others who advise this method on the grounds of rapidly removing a large amount of venom [64]. There is a patented device, the Sawyer extractor available in the United Kingdom for this purpose [64]. It's suggested use has generated controversy with a series of letters to the editor of NEJM justifying or condemning its use [64,65].

Reid has advised that the wound site be minimally handled. Most authors recommend saline cleaning and sterile dressing [28]. Some however advise that the wound be left open [1,29].
There is disagreement over the use of drugs as part of first-aid care. It has been suggested that NSAIDS particularly aspirin may be beneficial to relieve local pain. Russell however dissuades use of analgesic and in particular aspirin for fear of precipitating bleeding [27]. In Reid's experience, pain relief with placebo was as effective as NSAID [22]. Codeine may be useful in some cases [1]. Similarly there are proponents as well as opponents for use of sedatives [27].
Almost all experts agree that the offending snake must not be provoked further by attempts to capture or kill it [27]. This is for fear of provoking an already enraged reptile to strike again. However, Gellert insists that in the United States, carnivorous bats and animals which bite man are captured as per guidelines of CDC to examine for rabies; therefore a snake should be treated no differently and every effort should be made to capture/kill it [65].

Specific therapy - Antivenom

Antivenoms are prepared by immunizing horses with venom from poisonous snakes and extracting the serum and purifying it. Antivenoms or antivenins may be species specific (monovalent) or effective against several species (polyvalent). Monovalent antivenom is ideal [1], but the cost and non-availability, besides the difficulty of accurately identifying the offending species - makes its use less common [17].

Indications for use

There are specific indications for use of antivenom [11,17]. Every bite, even if by poisonous species does not merit its use. This caution against the empirical use of antivenom is due to the risk of hypersensitivity reactions [28,29]. Therefore, antivenom is indicated only if serious manifestations of envenomation are evident viz coma, neurotoxicity, hypotension, shock, bleeding, DIC, acute renal failure, rhabdomyolysis and ECG changes [16]. In the absence of these systemic manifestations, swelling involving more than half the affected limb [1], extensive bruising or blistering and progression of the local lesions within 30-60 minutes [1] are other indications.
In a study of Elapid ophitoxaemia from India, victims with neuromuscular paralysis were administered anticholinesterase/neostigmine. Four of the patients did not receive any antivenom; all survived. Of 8 who received antivenom 3 were given less than 50 units; all 3 survived. The other 5 were administered more than 50 units; however 2 died. The authors concluded that antivenom has no definite role in Elapid ophitoxaemia [66]. They emphasized the role of anticholinesterase and supportive care as cornerstones of management. In view of the large number of dry bites observed in a Brazilian study, the authors recommended that antivenom be postponed or not administered to victims presenting with no manifestations of local or systemic envenomation [67].

Dose

Despite widespread use of antivenom, there are virtually no clinical trials to determine the ideal dose [68]. Conventionally 50 ml (5 vials) is infused for mild manifestations like local swelling with or without lymphadenopathy, purpura or echymosis. Moderate envenomation defined by presence of coagulation defects or bradycardia or mild systemic manifestations, merits the use of 100 ml (10 vials). 150 ml (15 vials) is infused in severe cases, which includes rapid progression of systemic features, DIC, encephalopathy and paralysis [16].
Thomas and Jacob have attempted to study the effect of a lower dose in a randomized controlled trial and established that, in a cohort of patients who received half the conventional dose, there is no significant difference in the time taken for clotting time to normalize [68]. Philip also advocates using lower doses than conventionally used [1].
Based on a study of 24 cases of demonstrated Russell's viper venom antigenemia, wherein the mean amount of monospecific antivenom correcting blood incoagualability was 165 (59.3 ml, it has been recommended that 60 ml be administered intravenously at 6 hourly intervals till blood coagulability is restored [69]. This dose appears to have been appropriate in a group of Nepalese patients, wherein 71% received less than 6 vials per patient [14]. Theoretically, there does not seem to be an upper dose limit and even 45 vials (4500 units) have been used successfully in a patient [14].

Administration

The freeze dried powder is reconstituted with 10 ml of injection water or saline or dextrose . A test dose is administered on one forearm with 0.02 ml of 1:10 solution intradermally. Similar volume of saline in the other forearm serves as control. Appearance of erythema or wheal greater than 10 mm within 30 min is taken as a positive test [16]. In this event, desensitization is advised starting with 0.01 ml of 1:100 solution and increasing concentration gradually at intervals of 15 minutes till 1.0 ml s.c can be given by 2 hours [16]. Infusion is started at 20 ml/kg per hour initially and slowed down later [16].

Antivenom is administered by the intravenous route [16] and never into fingers or toes [27]. Some authors recommend that 1/3 to 1/2 the dose be given at the local site to neutralize venom there (De Vries) [27]. However, animal experiments have established that absorption begins almost instantly from bite sites. Besides this, systemic administration of antivenom has been shown to be effective at the local site as well. Therefore most experts do not advise local injection of antivenin [27]. Efficacy of intramuscular administration of antivenom followed by standard hospital management has also been evaluated and a definite reduction in the number of patients with systemic envenomation, complications and mortality from Russell's viper toxemia has been noted [71]. This route of administration is likely to have value in a field setting prior to transfer to better facilities.

Timing

There is no consensus as to the outer limit of time of administration of antivenom. Best effects are observed within four hours of bite [16]. It has been noted to be effective in symptomatic patients even when administered up to 48 hours after bite. Reports suggest that antivenom is efficacious even 6-7 days after the bite [72]. This is corroborated by Saini's observations also [73]. In experimental settings, rats injected with antivenom even 3 weeks after the bite showed good response [74]. It is obvious that when indicated, antivenom must be administered as early as possible and data showing efficacy with delayed administration is based on use in settings where patients present late.
Response

Response to infusion of antivenom is often dramatic [16] with comatose patients sitting up and talking coherently within minutes of administration. Normalization of blood pressure is another early response [70]. Within 15 to 30 minutes, bleeding stops though coagulation disturbances may take up to 6 hours to normalize. Neurotoxicity improves from the first 30 minutes but may require 24 to 48 hours for full recovery [8].
If response to antivenom is not satisfactory use of additional doses is advocated. However, no studies establishing an upper limit are available [14] infusion may be discontinued when satisfactory clinical improvement occurs even if recommended dose has not been completed [21]. In experimental settings, normalization of clotting time has been taken as end-point for therapy.

Reactions

Hypersensitivity reactions including the full range of anaphylactic reactions may occur in 3-4% of cases, usually within 10 to 180 minutes after starting infusion. These usually respond to conventional management including adrenaline, anti-histamines and corticosteroids [17].

Availability

Several antivenom preparations are available internationally. In India, polyvalent antivenom prepared by C.R.I., Kasauli is effective against the 4 commonest species [16]. Antivenom produced at the Haffkine Corporation, Parel includes more species as well. This is about 10 times as expensive as the former.
The WHO has designated the Liverpool School of Tropical Medicine as the international collaborating centre for antivenom production and/or testing.

Supportive Therapy

In cases of bleeding, replacement with fresh whole blood is ideal. Fresh frozen plasma and fibrinogen are not recommended.
Volume expanders including plasma and blood are recommended in shock, but not crystalloids [16]. Persistent shock may require inotrope support under CVP monitoring [16]. Early mechanical ventilation is advocated in respiratory failure though dramatic responses have also been observed with edrophonium followed by neostigmine [29]. Cases of acute renal failure generally respond to conservative management. Occasionally peritoneal dialysis may be necessary. In cases of DIC, use of heparin should be weighed against risk of bleeding and hence caution is advocated [1].
Routine antibiotic therapy is not a must [28] though most Indian authors recommend use of broad spectrum antibiotics [16]. Chloramphenicol has been claimed to be useful as a post bite antibiotic even when used orally since it is active against most of the aerobic and anaerobic bacteria present in the mouths of snakes. Alternatives include cotrimoxazole, flouroquinolones with or without metronidazole or clindamycin for anaerobic cover [62]. A study of the organisms isolated from the mouth of the Malayan pit vipers suggests that crystalline penicillin with gentamicin would also be appropriate antibiotic cover following snakebite [75].
Recent studies have reported the beneficial effects of intravenous immunoglobulin (IVlg) in ophitoxaemia. There are suggestions that its administration may improve coagulopathy, though its effect on neurotoxicity is questionable. A pilot study indicates that IVIg with antivenom eliminates the need to repeat antivenom for envenomations associated with coagulopathy [76].
A compound extracted from the Indian medicinal plant Hemidesmus indicus R (2-hydroxy-4 methoxy benzoic acid [77] has been noted to have potent anti-inflammatory, antipyretic and anti-oxidant properties, particularly against Russell's viper venom [78]. These experiments suggest that chemical antagonists from herbs hold promise in the management of ophitoxaemia; particularly when used in the presence of antivenom.
Four cases of tetanus have been documented following snake-bite [27] hence tetanus toxoid is a must. Early surgical debridement is generally beneficial [16,70] though fasciotomy is usually more harmful than useful [16,70]. There is no role for steroid therapy in acute snake bite [27]. Although it delays the appearance of necrosis, it does not lessen the severity of outcome [29].

Conclusion

Snakes do not generally attack human beings unprovoked. They are reputed to be more afraid of man than vice-versa. Nevertheless once bitten, a wide spectrum of clinical manifestations may result. The emphasis for treatment should be placed on early and adequate medical management. Overemphasis on first-aid can be dangerous because its value is debatable and too much valuable time is wasted in its administration.