The Clinical Management of Snake Bites in the South East Asian Region

Management of Snake bites in South East Asia - Part 2

5.6.8 Administration of antivenom
      

Freeze-dried (lyophilised) antivenoms are reconstituted, usually with 10 ml of sterile water for injection per ampoule. The freeze-dried protein may be difficult to dissolve. Two methods of administration are recommended:

     Intravenous "push" injection: reconstituted freeze-dried antivenom or neat liquid antivenom is given by slow intravenous injection (not more than 2 ml/minute). This method has the advantage that the doctor/nurse/dispenser giving the antivenom must remain with the patient during the time when some early reactions may develop. It is also economical, saving the use of intravenous fluids, giving sets, cannulae etc.

     Intravenous infusion: reconstituted freeze-dried or neat liquid antivenom is diluted in approximately 5-10 ml of isotonic fluid per kg body weight (ie 250-500 ml of isotonic saline or 5% dextrose in the case of an adult patient) and is infused at a constant rate over a period of about one hour.

5.6.8.1 Local administration of antivenom at the site of the bite is not recommended!

Although this route may seem rational, it should not be used as it is extremely painful, may increase intracompartmental pressure and has not been shown to be effective.

5.6.8.2 Intramuscular injection of antivenom

Antivenoms are large molecules (F(ab0)₂ fragments or sometimes whole IgG) which, after intramuscular injection, are absorbed slowly via lymphatics. Bioavailability is poor, especially after intragluteal injection and blood levels of antivenom never reach those achieved rapidly by intravenous administration. Other disadvantages are the pain of injection of large volumes of antivenom and the risk of haematoma formation in patients with haemostatic abnormalities.

Situations in which intramuscular administration might be considered :

     at a peripheral first aid station, before a patient with obvious envenoming is put in an ambulance for a journey to hospital that may last several hours;

     on an expedition exploring a remote area very far from medical care;

     when intravenous access has proved impossible.

Although the risk of antivenom reactions is less with intramuscular than intravenous administration, epinephrine (adrenaline) must be readily available.

Under these unusual circumstances, the dose of antivenom should be divided between a number of sites in the upper anterolateral region of both thighs. A maximum of 5-10 ml should be given at each site by deep intramuscular injection followed by massage to aid absorption. Local bleeding and haematoma formation is a problem in patients with incoagulable blood.

Finding enough muscle mass to contain such large volumes of antivenom is particularly difficult in children.

5.6.9 Dose of antivenom

Manufacturers’ recommendations are usually based on inappropriate animal tests in which venom and antivenom are incubated before being injected into the test animal. The recommended dose is often the amount of antivenom required to neutralise the average venom yield when captive snakes are milked of their venom. In practice, the choice of an initial dose of antivenom is usually empirical.

Since the neutralising power of antivenoms varies from batch to batch, the results of a particular clinical trial may soon become obsolete if the manufacturers change the strength of the antivenom.

5.6.10 Antivenom reactions

A proportion of patients, usually more than 20%, develop a reaction either early (within a few hours) or late (5 days or more) after being given antivenom.

Early anaphylactic reactions: usually within 10-180 minutes of starting antivenom, the patient begins to itch (often over the scalp) and develops urticaria, dry cough, fever, nausea, vomiting, abdominal colic, diarrhoea and tachycardia. A minority of these patients may develop severe life-threatening anaphylaxis: hypotension, bronchospasm and angio-oedema. Fatal reactions have probably been under-reported as death after snake bite is usually attributed to the venom.

In most cases, these reactions are not truly "allergic". They are not IgE-mediated type I hypersensitivity reactions to horse or sheep proteins as there is no evidence of specific IgE, either by skin testing or radioallergosorbent tests (RAST). Complement activation by IgG aggregates or residual Fc fragments or direct stimulation of mast cells or basophils by antivenom protein are more likely mechanisms for these reactions.

Pyrogenic (endotoxin) reactions: usually develop 1-2 hours after treatment. Symptoms include shaking chills (rigors), fever, vasodilatation and a fall in blood pressure. Febrile convulsions may be precipitated in children. These reactions are caused by pyrogen contamination during the manufacturing process. They are commonly reported.

Late (serum sickness type) reactions : develop 1-12 (mean 7) days after treatment. Clinical features include fever, nausea, vomiting, diarrhoea, itching, recurrent urticaria, arthralgia, myalgia, lymphadenopathy, periarticular swellings, mononeuritis multiplex, proteinuria with immune complex nephritis and rarely encephalopathy. Patients who suffer early reactions and are treated with antihistamines and corticosteroid are less likely to develop late reactions.

5.6.11 Treatment of early anaphylactic and pyrogenic antivenom reactions

Epinephrine (adrenaline) is given intramuscularly (into the deltoid muscle or the upper lateral thigh) in an initial dose of 0.5 mg for adults, 0.01 mg/kg body weight for children. Severe, life-threatening anaphylaxis can evolve very rapidly and so epinephrine (adrenaline) should be given at the very first sign of a reaction, even when only a few spots of urticaria have appeared or at the start of itching, tachycardia or restlessness. The dose can be repeated every 5-10 minutes if the patient’s condition is deteriorating.

5.6.11.1 Additional treatment

After epinephrine (adrenaline), an anti H₁ antihistamine such as chlorpheniramine maleate (adults 10 mg, children 0.2 mg/kg by intravenous injection over a few minutes) should be given followed by intravenous hydrocortisone (adults 100 mg, children 2 mg/kg body weight). The corticosteroid is unlikely to act for several hours, but may prevent recurrent anaphylaxis.

There is increasing evidence that anti H₂ antihistamines such as cimetidine or ranitidine have a role in the treatment of severe anaphylaxis. Both drugs are given, diluted in 20 ml isotonic saline, by slow intravenous injection (over 2 minutes).

Doses: cimetidine - adults 200 mg, children 4 mg/kg;  ranitidine - adults 50 mg, children 1 mg/kg.

In pyrogenic reactions the patient must also be cooled physically and with antipyretics (for example paracetamol by mouth or suppository). Intravenous fluids should be given to correct hypovolaemia.

5.6.12 Treatment of late (serum sickness) reactions

Late (serum sickness) reactions usually respond to a 5-day course of oral antihistamine. Patients who fail to respond in 24-48 hours should be given a 5-day course of prednisolone.

Doses:

Chlorpheniramine: adults 2 mg six hourly, children 0.25 mg/kg /day in divided doses Prednisolone: adults 5 mg six hourly, children 0.7 mg/kg/day in divided doses for 5-7 days

5.6.13 Observation of the response to antivenom

If an adequate dose of an appropriate antivenom has been administered, the following responses may be seen.

     General: the patient feels better. Nausea, headache and generalised aches and pains may disappear very quickly. This may be partly attributable to a placebo effect.

     Spontaneous systemic bleeding (eg from the gums) usually stops within 15-30 minutes.

     Blood coagulability (as measured by 20WBCT) is usually restored in 3-9 hours. Bleeding from new and partly healed wounds usually stops much sooner than this.

     In shocked patients, blood pressure may increase within the first 30-60 minutes and arrhythmias such as sinus bradycardia may resolve.

     Neurotoxic envenoming of the post-synaptic type (cobra bites) may begin to improve as early as 30 minutes after antivenom, but usually take several hours. Envenoming with presynaptic toxins (kraits and sea snakes) is unlikely to respond in this way.

     Active haemolysis and rhabdomyolysis may cease within a few hours and the urine returns to its normal colour.

5.6.14 Recurrence of systemic envenoming

In patients envenomed by vipers, after an initial response to antivenom (cessation of bleeding, restoration of blood coagulability), signs of systemic envenoming may recur within 24-48 hours.

This is attributable to:

     continuing absorption of venom from the "depot" at the site of the bite, perhaps assisted by improved blood supply following correction of shock, hypovolaemia etc, after elimination of antivenom (range of elimination half-lives: IgG 45 hours; F(ab0)2 80-100 hours; Fab 12-18 hours);

     a redistribution of venom from the tissues into the vascular space, as the result of antivenom treatment.

Recurrent neurotoxic envenoming after treatment of cobra bite has also been described.

5.6.15 Criteria for repeating the initial dose of antivenom

If the blood remains incoagulable (as measured by 20WBCT) six hours after the initial dose of antivenom, the same dose should be repeated. This is based on the observation that, if a large dose of antivenom (more than enough to neutralise the venom procoagulant enzymes) is given initially, the time taken for the liver to restore coagulable levels of fibrinogen and other clotting factors is 3-9 hours.

In patients who continue to bleed briskly, the dose of antivenom should be repeated within 1-2 hours.

In case of deteriorating neurotoxicity or cardiovascular signs, the initial dose of antivenom should be repeated after 1-2 hours, and full supportive treatment must be considered.

5.6.16 Conservative treatment when no antivenom is available

This will be the situation in many parts of the region, where supplies of antivenom run out or where the bite is known to have been inflicted by a species against whose venom there is no available specific antivenom (for example for bites by the Malayan krait (Bungarus candidus), coral snakes - genera Calliophis and Maticora), sea snakes, the mangrove/shore pit viper T purpureomaculatus and the mountain pit viper Ovophis monticola.

The following conservative measures are suggested:

Neurotoxic envenoming with respiratory paralysis: assisted ventilation. This has proved effective, and has been followed by complete recovery, even after being maintained for periods of more than one month. Manual ventilation (anaesthetic bag) by relays of doctors, medical students, relatives and nurses has been effective where no mechanical ventilator was available. Anticholinesterases should always be tried (see below 5.7.2.1, p 51).

Haemostatic abnormalities - strict bed rest to avoid even minor trauma; transfusion of clotting factors and platelets; ideally, fresh frozen plasma and cryoprecipitate with platelet concentrates or, if these are not available, fresh whole blood. Intramuscular injections should be avoided.

Shock, myocardial damage: hypovolaemia should be corrected with colloid/crystalloids, controlled by observation of the central venous pressure. Ancillary pressor drugs (dopamine or epinephrine-adrenaline) may also be needed. Patients with hypotension associated with bradycardia should be treated with atropine.

Renal failure: conservative treatment or dialysis (see below 5.7.4, p).

Dark brown urine (myoglobinuria or haemoglobinuria): correct hypovolaemia and acidosis and consider a single infusion of mannitol (see below 5.7.4.2).

Severe local envenoming: local necrosis, intracompartmental syndromes and even thrombosis of major vessels is more likely in patients who cannot be treated with antivenom. Surgical intervention may be needed but the risks of surgery in a patient with consumption coagulopathy, thrombocytopenia and enhanced fibrinolysis must be balanced against the life-threatening complications of local envenoming. Prophylactic broad spectrum antimicrobial treatment is justified (see below 5.8.1).

5.7 Supportive/ancillary treatment

Antivenom treatment can be expected to neutralise free circulating venom, prevent progression of envenoming and allow recovery. However, these processes take time and the severely envenomed patient may require life support systems such as assisted ventilation and renal dialysis until the severely damaged organs and tissues have had time to recover.

5.7.1 Dangers of venepuncture in patients with haemostatic abnormalities

In patients with incoagulable blood, any injection (subcutaneous, intramuscular) and, particularly venepuncture, carries a risk of persistent bleeding and haematoma formation. Arterial puncture is contraindicated in such patients.

Repeated venepuncture can be avoided by using an indwelling cannula and three-way tap system. When blood coagulability has been restored, the dead space should be filled with heparinised saline, but beware! If this is not flushed out before blood sampling, misleading results will be obtained in clotting tests, including the 20WBCT.

In patients with coagulopathy, sites of venous access and placement of intravenous cannulae or catheters should be chosen where haemostasis by external pressure is most likely to be effective, eg the antecubital fossa. If possible, avoid jugular, subclavian and femoral vein puncture. A pressure pad must be applied at the site of any venepuncture.

5.7.2 Neurotoxic envenoming

Death may result from aspiration, airway obstruction or respiratory failure. A clear airway must be maintained. Once there is loss of gag reflex and pooling of secretions in the pharynx, failure of the cough reflex or respiratory distress, a cuffed endotracheal tube should be inserted. If this is impossible for any reason, a tracheostomy should be performed and a snugly-fitting or cuffed tracheostomy tube inserted.

Anticholinesterase drugs have a variable, but potentially very useful effect in patients with neurotoxic envenoming, especially those bitten by cobras.

A trial of anticholinesterase (eg "Tensilon test") should be performed in every patient with neurotoxic envenoming, as it would be in any patient with suspected myasthenia gravis.

5.7.2.1 Trial of anticholinesterase

Ideally, a short acting anticholinesterase, such as edrophonium ("Tensilon"), should be used.

Baseline observations or measurements are made against which to assess the effectiveness of the anticholinesterase. Atropine sulphate (adults 0.6 mg, children 50 µg/kg body weight) is given by intravenous injection (to prevent the undesirable muscarinic effects of acetylcholine such as increased secretions, sweating, bradycardia and colic) followed immediately by edrophonium chloride (adults 10 mg, children 0.25 mg/kg body weight) given intravenously over 3 or 4 minutes. The patient is observed over the next 10-20 minutes for signs of improved neuromuscular transmission. Ptosis may disappear (Fig 43) and ventilatory capacity (peak flow, FEV₁ or maximum expiratory pressure) may improve.

If edrophonium chloride is not available, any other anticholinesterases (neostigmine - "Prostigmine", distigmine, pyridostigmine, ambenomium) can be used for this assessment but a longer period of observation will be needed (up to 1 hour).

Patients who respond convincingly can be maintained on a longer-acting anticholinesterase such as neostigmine methylsulphate combined with atropine. Maintenance doses are atropine sulphate 50 mcg/kg, neostigmine methylsulphate 50-100 mcg/kg both by subcutaneous injection every four hours.Patients able to swallow tablets may be maintained on atropine 0.6 mg twice each day, neostigmine 15 mg four times each day or pyridostigmine 60 mg four times each day (initial adult doses).

5.7.3 Hypotension and shock

This is usually the result of hypovolaemia (from loss of circulating volume into the swollen limb, or internal/external haemorrhage), venom-induced vasodilatation or direct myocardial effects with or without arrhythmias. Ideally, treatment with plasma expanders (colloids or crystalloid) should be controlled by observation of the central venous pressure (jugular venous pressure or direct measurement of pressure in the superior vena cava via a catheter connected to a saline manometer, see Annex 4). Excessive volume replacement may cause pulmonary oedema when plasma extravasated in the bitten limb and elsewhere is reabsorbed into the circulation.

In patients with evidence of a generalised increase in capillary permeability, a selective vasoconstrictor such as dopamine may be given by intravenous infusion, preferably into a central vein (starting dose 2.5-5 µg/kg/minute).

In victims of Russell’s viper bites in Myanmar and South India, acute pituitary adrenal insufficiency resulting from haemorrhagic infarction of the anterior pituitary may contribute to shock. Hydrocortisone is effective in these cases.

5.7.4 Oliguria and renal failure

In patients with any of these features, the following should be monitored

     pulse rate

     blood pressure, lying and sitting, to detect postural hypotension

     respiratory rate

     temperature

     height of jugular venous pulse

     auscultation of lung bases for crepitations

5.7.4.1 Oliguric phase of renal failure

Most, but not all, patients with acute renal failure are oliguric, defined as a urine output of less than 400 ml/day or less than 20 ml/hour. Conservative management may tide the patient over, avoiding the need for dialysis. If the patient is hypovolaemic, indicated by supine or postural hypotension, empty neck veins, sunken eyeballs, loss of skin turgor and dryness of mucosae, proceed as follows:

     Establish intravenous access

     Insert a urethral catheter (full sterile precautions!)

     Determine the central venous pressure : This can be achieved either by observing the vertical height of the jugular venous pulsation above the sternal angle with the patient propped up on pillows at 45o; or by direct measurement of central venous (superior vena caval) pressure through a long catheter preferably inserted at the antecubital fossa (see Annex 4). The catheter is connected to a saline manometer, the 0 point of which must be placed at the same level as the right atrium (that is, at the sternal angle when the patient is propped up at 45o). In someone who is obviously volume-depleted, resuscitation should start immediately, and not be delayed until a central venous line has been inserted.

     Fluid challenge: depending on the initial state of hydration/dehydration, an adult patient can be given two litres of isotonic saline over one hour or, until the jugular venous pressure/central venous pressure has risen to 8-10 cm above the sternal angle (with the patient propped up at 45o). The patient must be closely observed while this is being done. The fluid challenge must be stopped immediately if pulmonary oedema develops. If the urine output does not improve, try furosamide challenge.

     Furosamide (frusemide) challenge: 100 mg of furosamide is injected slowly (4-5 mg/minute). If this does not induce a urine output of 40 ml/hour, give a second dose of furosamide, 200 mg. If urine output does not improve, try mannitol challenge.

     Mannitol challenge: 200 ml of 20% mannitol may be infused intravenously over 20 minutes but this must not be repeated as there is a danger of inducing dangerous fluid and electrolyte imbalance. An improvement in urine output to more than 40 ml/hr or more than 1 litre/day is considered satisfactory.

     Conservative management: If the urine output does not improve, despite these challenges, no further diuretics should be given and fluid intake should be restricted to a total of the previous day’s output plus "insensible losses" (500-1000 ml/day). If possible, the patient should be referred to a renal unit. The diet should be bland, high in calories (1700/day), low in protein (less than 40g/day), low in potassium (avoid fruit, fruit juices and potassium-containing drugs) and low in salt. Infections will cause tissue breakdown and increase urea levels. They should be prevented or treated promptly with non-nephrotoxic antibiotics (ie avoid aminoglycosides such as gentamicin).

     Biochemical monitoring: Serum potassium, urea, creatinine and, if possible, pH, bicarbonate, calcium and phosphate should be monitored frequently. If this is not possible the electrocardiogram (ECG) should be examined for evidence of hyperkalaemia, especially following bites by sea snakes, or Sri Lankan or South Indian Russell’s vipers or if the patient is passing dark brown urine, indicating rhabdomyolysis or intravascular haemolysis.

These emergency treatments will control hyperkalaemia for 3-6 hours only. If the patient is hypotensive and profoundly acidotic(deep sighing "Kussmaul" respirations, very low plasma bicarbonate concentration or very low pH - <7.10), 40 ml of 8.4% sodium bicarbonate (1 mmol/ml) may be infused intravenously over 30 minutes. If this leads to circulatory improvement, the dose can be repeated.

Caution: Intravenous bicarbonate may precipitate profound hypocalcaemia and fitting, especially in patients with rhabdomyolysis.

      Dialysis