Prof. Tan, Nget Hong

Department of Molecular Medicine

Faculty of Medicine, University of Malaya

Kuala Lumpur, Malaysia

1.  Introduction

       Snakebite is a serious medical problem in Malaysia. During the year 1958 to 1980, there were 55000 cases of snakebites recorded in the hospitals in Malaysia. The mortality rate of snakebite in Malaysia is only 0.3 per 100000 population but the local necrotic effects of some venoms can cause prolonged morbidity or even crippling deformity.

 2. Venomous Snakes of Malaysia

      In Malaysia and the coastal waters of the region, there are at least 18 different species of venomous front fanged land snakes and more than 22 different species of sea snakes. These venomous snakes belong to the following 5 subfamilies:

    1.      Crotalinae: represented by the two genera Calloselasma and Trimeresurus.

2.      Elapinae: represented by the five genera Naja, Bungarus, Ophiophagus, Maticora and Calliophis;

3.      Laticaudinae, represented by the genus Laticauda

4.      Hydrophiini, represented by the six genera Enhydrina, Kerilia, Hydrophis, Thalassophis, Pelamis and Kolpophis

5.      Ephalophiini, represented by the only genus Aipysurus.

The Crotalinae and Elapinae subfamilies are land snakes whereas the other three subfamilies are sea snakes.

     Only a few of the Malaysian venomous snakes can be regarded as of medical importance. Epidemiological studies showed that in Malaysia, bites were mainly due to four species of land snakes (Table 1): Calloselasma rhodostoma (Malayan pit viper), Naja naja (Asian common cobra), Trimeresurus purpureomaculatus (shore pit viper) and Trimeresurus wagleri (Wagler’s pit viper). Other venomous snakes indigenous to Malaysia that are potentially dangerous to human include Bungarus candidus (Malayan krait), Bungarus fasciatus (banded krait), Ophiophagus hannah (king cobra), Trimeresurus sumatranus (Sumatran pit viper), Trimeresurus albolabris (white-lipped pit viper) and the sea snakes.

                                     Table 1: Snakebites in West Malaysia

             Report from monthly statistics of 28 hospitals throughout Malaysia, 1965-1971.

3. Biochemical composition of Snake Venoms

     Dried snake venom contains mainly proteins (70-90%) and small amounts of metals, amino acids, peptides, nucleotides, carbohydrates, lipids and biogenic amines. The protein components include enzymes and non-enzymatic proteins/polypeptides.    The main toxins in the venoms of elapid snakes (cobras, kraits and sea snakes) include: polypeptide postsynaptic neurotoxins, cardiotoxins and phospholipases A that may exhibit presynaptic neurotoxicity or myotoxicity. The main toxins of crotalid (pit viper) snake venoms, on the other hand, are thrombin-like enzymes, hemorrhagic proteases and platelet-aggregation inducers.  

4. Elapid Venom Poisoning

      Elapid venoms (cobras, kraits and sea snakes) generally exhibit neurotoxicity and cardiotoxicity. The earliest symptom of systemic elapid poisoning is a feeling of drowsiness or intoxication, which starts from 15 min to 5 hr after cobra bites. Difficulty in opening the eyes (bilateral ptosis: eyelids may remain completely closed though the patient usually remains conscious until respiratory failure is advanced), speaking, opening the mouth, moving the lips and in swallowing follows within 1 to 4 hrs. Breathing becomes increasingly difficult. In severe poisoning, respiratory failure sets in rapidly.

One week after a cobra bite. Subcutaneous necrosis in cobra bites is always more extensive than visible skin changes would suggest.

           Bilateral ptosis in elapid venom poisoning  

     The neurotoxic effects are mainly at the postsynaptic level of the neuromuscular junction where the neurotoxins block acetylcholine receptors, thereby producing muscular paralysis and respiratory failure. The major neurotoxins are usually basic polypeptides.

     Cardiotoxicity is caused by polypeptide cardiotoxin that affects both excitable and non-excitable cells, causing irreversible depolarization of the cell membrane and consequently impairing the structure and function of various cells, thus contributing to muscle paralysis and leading to circulatory and respiratory failure and systolic arrest.

     Cobra venom also causes extensive local necrosis, which requires treatment. The local necrosis is presumably caused by the combine action of cardiotoxin and phospholipase A₂.

     Sea snake venoms contain both polypeptide neurotoxins (homologous to elapid neurotoxins) and myotoxins, which are basic phospholipase A₂. The venom causes respiratory failure (neurotoxic effect), myonecrosis, myoglobinemia and acute renal failure.

5. Pit Viper Venom Poisoning

      The venom of pit vipers causes local swelling, necrosis and systemic bleeding. Hemorrhage is the outstanding symptom of systemic pit viper poisoning. Clotting defect usually accompanies hemorrhage. The commonest and earliest hemorrhagic manifestation is hemoptysis, which may be seen as early as 20 minutes after the bite. Blessing from the gum is less common and follows later after the bite. Discoid ecchymoses (right picture) appear in the skin an hour or so later. Bleeding into the brain or other vital organ may be fatal. In severe cases, loss of blood may lead to hypovolemic shock.

           Swelling in Malayan pit viper bite            Ecchymoses in Malayan pit viper bite

          Blisters in Malayan pit viper bite      Local necrosis in finger bite by Malayan pit viper

      In Malayan pit viper bite, the clotting defect is primarily due to thrombocytopenia aggravated by defibrination syndrome.

      Thrombocytopenia is presumably due to the actions of platelet aggregation inducers. Aggregoserpentin, a non-enzymatic protein with molecular weight of 28160 has been purified, it activates platelets through the activation of endogenous phospholipase A₂ or C. Anti-platelet protease may be also be involved.

      Defibrination syndrome is due mainly to the action of ancrod and partly to the activation of fibrinolysis causing fibrinogenolysis. Ancrod is a thrombin-like enzyme that acts directly on fibrinogen, releasing only fibrinopeptide A and fibrin monomers that form microclots.  The microclots formed are easily lysed by plasmin digestion. Thus, ancrod causes continual microcoagulation of fibronogen but the microclots are virtually simultaneously lysed. In the presence of sufficient amount of ancrod, the rate of consumption of fibrinogen may exceeed its rate of synthesis in the liver, resulting in defibrination syndrome characterized by non-clotting blood.

Right: Clot-quality observation test in systemic Malayan pit viper venom poisoning. This is a simple test useful for assessing defibrination and the severity of systemic poisoning. The clot quality is graded according to the size of the remaining clot, after 1 hour at room temperature.

Grade 1: Normal

Grade 2: Slight defect, clot size is slightly diminished.

Grade 3: Moderate defect, clot size is about half the size of a contracted normal clot

Grade 4: Severe defect, clot is only a small speck.

6. Death Times and Recovery Times

Generally speaking, deaths are most rapid after cobra bites and most protracted after viper bites:

Recovery times

     In the absence of necrosis, pain after viper bites rarely exceeds 2 weeks. When necrosis develops (in about 10% of cases) pain may remain severe for a month. Swelling usually resolves completely in 2-3 weeks. Healing time of local necrotic lesions varies greatly according to the extent of the lesion and the treatment given, but may requires 1-6 months or longer.

     In patients who do not receive specific antivenin, systemic symptoms generally subside more quickly than local symptoms. Neurotoxic symptoms usually resolve in 2-3 days. Hemorrhagic effects in viper bites are also short-lived and rarely exceed a week but the coagulation defect may persist for 3-4 weeks.

7. First-Aid Measure in Snake Venom Poisoning  

1.      Do not panic and keep calm, reassure the individual as complete recovery is the rule. Lie the patient down to ensure minimum activity

2.      Keep the bitten part at rest, immobilize the bitten limb with splints

3.      Wash bite with care because washing might disfigure or deface the original bite marks. Do not attempt to cut the wound and suck out the venom. This will introduce infection.

4.      Apply a broad and firm bandage to cover the bitten area using any flexible material. Arterial tourniquets can be dangerous

5.      All patients with snake bites must be brought to the hospital for treatment

6.      If the snake has been killed, bring it to the hospital for identification.

8.  Diagnosis of Snakebite Poisoning

       Two major questions in the diagnosis of snakebite poisoning are: the identity of the snake inflicting the bite and the severity of poisoning:

1. Diagnosis of the biting species: This can be ascertained by

i)                    Identification of the snake if the patient brings the snake to the hospital

ii)                  Immunodiagnosis: this is costly and can be performed only in a well-equipped laboratory. Presently not available in Malaysian hospitals

iii)                 Clinical observation and inquiring circumstances of bite:

Systemic pit viper venom poisoning is characterized by non-clotting blood and other hemorrhagic syndrome accompanied by rapid local swelling after the bite

Systemic elapid venom poisoning (due to cobras, kraits): characterized by neurotoxic effects including ptosis, glossopharyngeal palsy, respiratory paresis and sometime cardiac effects.

Systemic sea snake venom poisoning is characterized by myotoxic effects such as myaligia on moving, paresis, myoglobinuria, hyperkalaemia.

2. Diagnosis of severity of snakebite poisoning can generally be made by observation of the extent of local poisoning (swelling)

            Evaluation of severity of poisoning

      In mild cases, there are minimal local signs, no swelling except in the

            immediate vicinity of the wound, no significant systemic symptoms, and

            no laboratory abnormalities.

      In severe cases, pain is great, swelling is massive.

9.  Management Principles in Snake Venom Poisoning

    General management of snakebite

       General management of snakebite poisoning includes the following measures:

• adequate reassurance
• immobilize the patient, particularly the bitten limb. If a tourniquet has been applied, it should be released upon admission to hospital
• Treatment of local lesion: the site of the bite and blisters should be let strictly alone. Sloughs should be excised when local necrosis is obvious
• Treatment of shock
• Tetanus prophylaxis: Tetanus antitoxin should be given in victims in whom local necrosis developed
• Specific antivenom should be given to patient with systemic poisoning
• All bitten patients, even without symptom of poisoning, should be admitted to hospital for observation of at least 24 hours.

    Antivenom Therapy

      Antivenom is the only specific treatment for snake venom poisoning that is of proved value. If used correctly, it can reverse systemic poisoning even when given hours and even days after the bite. However, it should not be given routinely in all cases of snakebite because it is very expensive and can cause reactions. Antivenom, however, is generally ineffective in preventing or lessening local effects of snake venom poisoning.

      Monospecific (monovalent) antivenoms are more effective and less likely to cause reactions than polyspecific (polyvalent) antivenoms.  At present, however, monospecific antivenoms are available only against the three common types of Malaysian poisonous snakes (anti-Malayan pit viper, anti-Malayan cobra and anti-Enhydrina schistosa). Some commercially available polyvalent antivenoms (in particular, polyvalent Trimeresurus antivenom and polyvalent Elapid antivenom from National Institite of Preventive Medicine, Taiwan, R.O.C.) may be useful for the treatment of snake venom poisoning caused by other Malaysian poisonous snakes. However, these have not been evaluated clinically.

     Early (anaphylactic), pyrogenic and late (serum sickness) reactions can occur after antivenom treatment. Reported incidence of early reactions following intravenous antivenom ranges from 3 to 5%. About 40% of these reactions involve severe systemic anaphylaxis (bronchospasm, hypotension or angioneurotic oedema), though few fatal cases have been reported.  Most authorities have recommended that antivenom should be diluted in isotonic fluid and given by slow intravenous infusion.

     Supportive Treatment

1. Maintain clear airway. If there is danger or bulbar or respiratory paralysis, intubate or ventilate via tracheostomy.
2. Surgical debridement, split skin grafting and broad spectrum antibiotic cover are indicated where signs of local tissue necrosis are present. Occasionally fasciotomy may be needed in cases of fascial compartment syndromes.

Literatures:

1.      Reid, H.A. (1964). Cobra bites. Br. Med. J. 2, 540-545.

2.      Reid, H.A., Chan, K.E. and Thean, P.C. (1963). Prolonged coagulation defect (defibrination syndrome) in Malayan viper bite. Lancet, i, 621-626.

3.      Reid, H.A., Thean, P.C., Chan, K.E. and Baharom, A.R. (1963). Clinical effects of bites by Malayan viper.  Lancet i, 617-621.

4.      Reid, H.A. and Lim, K.J. (1957). Sea-snake bite. Br. Med. J. 2, 1266-1272.

5.      Reid, H.A., Theakston, R.D.S. (1983) The management of snake bite. Bull. W.H.O., 61, 885-895.

6.      Mitrakul, C. (1973). Effects of green pit viper venoms on blood coagulation, platelets and the fibrinolytic enzyme systems: studies in vivo and in vitro. Am. J. clin. Pathol. 60, 654-662.

7.      Warrell, D.A., Looareesuwan, S., White, N.J., Theakston, R.D.G., Warrell, M.J., Kosakarn, W., and Reid, H.A. (1983). Severe neurotoxic envenoming by the Malayan krait, Bungarus candidus: response to antivenom and anti-cholinesterase. Br. Med. J. 286, 678-689.

8.      Warrell, D.A., Theakston, R.D.G., Phillips, R.E., Chanthavanich, P., Viravan, C., Supanaranond, W., Karbwang, J., Ho, M., Hutton, R.A. and Vejcho, S. (1986). Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in southern Thailand: clinical and laboratory correlations. Am. J. Trop. Med. Hyg. 35, 1235-1247.

9.      Lim, B.L. (1982)   Poisonous Snakes of Peninsular Malaysia. 2^nd Ed. Malayan Nature Society, Kuala Lumpur, 72pp.

10.  Reid, H.A. (1968) Symptomatology, pathology and treatment of land snake bites in India and Southeast Asia. In: Venomous Animals and Their Venoms. Vol.1. (Buckely, E.D., Bucheri, W., and Deulofeu, V. Eds.), Academic Press, New York. Pp. 611-642.

11.  Tan, N.H. (1991) The biochemistry of venoms of some venomous snakes of Malaysia. – A Review. Tropical Biomedicine 8, 91-103.