Polyvalent Snake Antivenin in the ICU

 Occasionally we come across a case of snake bite in ICU. Here in this Blog Post I'll discuss in brief about the SNAKE ANTIVENIN (POLYVALENT) I.P. - the antidote we commonly use

Antivenin is a injectable medication made from antibodies which is used to treat certain venomous snake bites. The mechanism of action of this drug is based on that of vaccines developed by Edward Jenner but, in this case immunity is induced in a host animal ( like horse) and the hyperimmunized serum is then transfused into the patient who has been bitten.



Antivenins are of two types:

1. Monovalent (effective against a single snake species)
2. Polyvalent (effective against many snake species) - MOST COMMONLY USED IN INDIA

The SNAKE ANTIVENIN (POLYVALENT) I.P. is supplied in a liquid preparation containing Phenol (0.25% w/v) as preservative. It contains refined globulins, processed by enzyme digestion.It has to be stored between 2 to 8 degrees Celsius and should not be allowed to freeze.

Commercially, antivenin can be produced both in liquid and lyophilized forms. There is no evidence to suggest which form is more effective. Liquid Preparation requires a reliable cold chain and has 2-year shelf life. Lyophilized ASV, in powder form, has 5-year shelf life and requires only to be kept cool.

The antivenin is a preparation from equine plasma of Hyperimmunised Horses and is effective against the four common poisonous snakes found in India:

1. Cobra (Naja naja)
2. Common Krait (Bungarus caeruleus)
3. Russells Viper (Vipera russelli)
4. Sawscaled Viper (Echis carinatus)

It must be noted here that polyvalent antivenin is ineffective against species like Humpnosed Pit Viper (Hypnale hypnale) and also in case of region specific species like Sochurek’s Saw-scaled Viper (Echis carinatus sochureki) in Rajasthan, where the effectiveness of polyvalent antivenin is questionable.
Each ml of the serum neutralizes the following amount of standard venoms:

1. Cobra - 0.6mg
2. Common Krait - 0.45mg
3. Russells Viper - 0.6mg
4. Sawscaled Viper - 0.45mg

PROCEDURE FOR ADMINISTRATION OF ANTIVENIN

Precautions
Before drug administration ask for:

1. History of previous serum administration (if any) before the patient was shifted to the ICU
2. Any history of Asthma, Eczema, Known drug allergy or any other atopic/hypersensitivity disorder

Pre-administration Sensitivity testing:
0.1 ml of Antivenin in 1:10 dilution is injected subcutaneously and the patient is kept under observation for 30 mins for any local and/or generalized reaction.

In allergic and sensitive patients, it is better to administer the serum with antihistamines.

However, the administration of serum in sensitive patients must be weighed against the severity of the Patient's condition and urgency of treatment must over-ride the risk of anaphylaxis. Sensitive cases may the co-administered intravenous antivenin along with 1:1000 adrenaline intramuscularly to reduce the risk of anaphylaxis. Half dose of adrenaline may be repeated after 15mins if required.


Severity of evenomation can be indicated by appearance of systemic symptoms:

• Mild envenomation - (systemic symptoms manifest > 3 hours after bite) neurotoxic/hemotoxic
• Severe envenomation -(systemic symptoms manifest < 3 hours after bite) neurotoxic/hemotoxic 

There is no universal agreement on exact dose of antivenin. Only the polyvalent antivenin can neutralise the venom in circulation. As a first dose, 20ml of antivenin can be administered intravenously at a rate of 5ml/min or diluted in Isotonic Fluid and run over 30-60mins.

Second dose can be repeated 2 hours after the first dose or even earlier if symptoms persist. Further dose can be given depending on the condition of the patient.

In case of viper bite, local infiltration of the antivenin in and around bitten area can be done to prevent gangrene formation - however this has been debated and is controversial.


Response to antivenin
If adequate dose of antivenin has been administered the following responses my be seen:

• A general improvement in patients condition. Nausea, vomiting and ache/pain may disappear quickly - however may be a placebo effect
• Spontaneous systemic bleeding (bleeding gums) stop within 15-30mins.
• Blood coagulability (as measured by 20WBCT) is usually restored in 3 - 9 hours. 
• In shocked patients, BP may increase within 30-60 mins and arrhythmias like Brady-arrhythmia may disappear. 
• 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.
  
  
  

Criteria for giving more antivenom:

• Persistence or recurrence of blood incoagulability after 6 hr of bleeding after 1-2 hr
• Deteriorating neurotoxic or cardiovascular signs after 1-2 hr 

 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 antivenin (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.

Govt. Of India Guideline For Treatment of Muti-Drug Resistant Bacterial infections

In 2016 National Centre For Disease Control, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India came out with National Treatment Guidelines for Antimicrobial Use in Infectious Diseases.

Methicillin- Resistant S. aureus (MRSA) 

These organisms are considered resistant to all penicillins, cephalosporins and macrolides.

Though MRSAstrains may be reported as susceptible to Fluoroquinolones, aminogycogides, chloramphenicol and doxycycline in-vitro, these drugs are NOT to be used alone or as initial treatment for serious MRSA infections.

Rifampicin use should be avoided in diseases other than Mycobacterial diseases.

The drug of choice for treatment of infections due to MRSA is the glycopeptides i.e Vancomycin and Teicoplanin.

Linezolid can be used to treat skin and soft tissue infections caused by MRSA.

Mupirocin local application (intranasally bid x 5 days) for eradicating nasal carriage.

Daptomycin: Daptomycin is an intravenous antibiotic approved to be used for the treatment of complicated skin infections and Staphylococcus aureus bacteraemia. Daptomycin should NOT be used for treatment of pneumonia due to its inactivation by surfactant.

Vancomycin Resistant Enterococcus (VRE) 

The treatment for VRE should be based on infection severity and in-vitro susceptibility of the strain to other antibiotics.

Linezolid: Linezolid is the only drug specifically approved for the treatment of VRE-blood stream. Linezolid is effective orally.

Doxycycline: Not a first line therapy. For susceptible isolates, not for bacteremia or endocarditis. It should not be used as monotherapy.

Nitrofurantoin: For uncomplicated UTI

Fosfomycin: For urinary tract infections (cystitis) with isolates susceptible to fosfomycin.

Chloramphenicol: For chloramphenicol-susceptible isolates of E faecium and E. faecalis. Not a first-line therapy and it should not be used as monotherapy.

Gentamicin or streptomycin: To be used in combination with ampicillin for the treatment of enterococcal endocarditis caused by organisms susceptible in vitro to either agent; streptomycin is used when gentamicin cannot be used because of resistance.

Tigecycline: Tigecycline has in vitro activity against a broad spectrum of Gram-positive and -negative bacteria, anaerobes as well as multidrug-resistant pathogens such as MRSA and VRE. However, large scale clinical datar is currently unavailable.

Extended Spectrum Beta-Lactamases (ESBL) Producing Enterobacteriaceae.

ESBLs are plasmid mediated beta—lactamases that confer resistance to broad spectrum beta-lactum antibiotics including third and fourth generation cepahlosporlns, azetronam and extended spectrum penicillins. These plasmids often encode mutations which confere resistance to other broad spectrum agents including aminoglycosides, cortrimoxazole and fluoroquinolones, resulting in organism resistant to most broad spectrum antibiotics. The emergence of ESBL producing enterobacterlaceae is related to indiscriminate use of third generation cephalosporlns.

The carbapenems (Ertapenem, Meropenem and lmipenem) are currently considered the drug of choice for serious infections caused by these pathogens. Piperacillin -Tazobactam and Cefoperazone— Sulbactam may be considered options in mild infections and when ESBL producers are demonstrably susceptible in -vitro.

Carbapenem- Resistant Enterobacteriaceae (CRE)

Most carbapenemase producers are extremely drug resistant: being resistant to β-lactam antibiotics, aminogycosides, and β-lactam–βlactam inhibitor combinations.

Polymyxins, tigecycline & fosfomycin are the agents with most frequent in vitro activity, but all have limitations. Dosage will vary with the patient and infection site, but should be on the principle of ‘highest safe’ rather than ‘minimum potentially effective; durations should be as standard for the infection type.

Colistin – Case reports of successful use in a range of infections due to carbapenemase producers.

Tigecycline: Licensed for complicated skin and soft-tissue Infections and complicated intraabdominal infections. Low blood concentrations; off-label use should be cautious for blood stream infections, unsuitable in urinary infections as only 22% excreted in urine. Excess deaths in some trials, especially ventilator associated pneumonia (not a licensed indication).

Recommended measures to control spread of Multi-drug resistant organisms (MDRO)
Improved laboratory detection and reporting of MDRO.

Enhanced infection surveillance and control in ICUs.

Prevent spread by barrier precautions : Gowns and gloves.

Hand Washing.

Restricted use of 3rd generation cephalosporins.