Losing the race against time in treating snakebites

  • Local case report highlights need for more study to develop specific anti-venom for Lankan snake species

BY Ruwan Laknath Jayakody

Concerning Sri Lankan snake bites, there is a need for more molecular studies and dose-dependent studies, and the preparation of Sri Lankan species-specific anti-venom instead of Indian species-specific anti-venom, academics in the field of forensic medicine noted.

This concern was raised in a case report on “Snake bite: Medico-legal significance”, which was authored by S. Raveendran (postgraduate trainee) and Prof. M. Vidanapathirana (attached to the Sri Jayewardenepura University’s Medical Sciences Faculty’s Forensic Medicine Department) and published in the Medico-Legal Journal of Sri Lanka 4 (1) in December 2016.

Sri Lanka has 93 species of land and marine snakes, and although the majority, as per R. Fernando’s “Management of poisoning”, are non venomous, seven are deadly as they are highly venomous (with highly toxic venom), including kraits, sea snakes, Russell’s viper, and cobra, while the other three – hump-nosed viper, saw scaled viper, and green pit viper – are venomous. Raveendran and Vidanapathirana note that snake bites are a common problem among people living in rural and agricultural areas.

The majority of the related deaths, the duo explain, are due to the delay in giving anti-venom or the non-availability of species-specific anti-venom.

However, when relatives of the deceased allege against that the doctors in treating a particular case of snake bite had not provided immediate and proper care, the forensic pathologist, Raveendran and Vidanapathirana observe, is expected not only to give the cause of death, but to also give an opinion about the role of negligence in such a case.

Case report

A middle-aged woman died while being transported from a local hospital to a tertiary care hospital following a snakebite. The history revealed that the snake had bitten her while she was trying to get onto a bicycle parked in an abandoned house in the evening (at around 6.15 p.m.). She was brought to the hospital with symptoms and signs suggestive of neurotoxin poisoning, such as blurred vision, dysphonia (disorders of the voice where the patient has an abnormal voice or hoarseness), dysphagia (difficulties in swallowing), and confusion with ptosis (a drooping or falling of the upper eyelid). She, however, had no haematemesis (vomiting blood), haematuria (presence of blood in urine), epistaxis (nose bleeds), or anal bleeding.

Anti-snake venom was given at the local hospital based on a clinical diagnosis but without the specimen of the dead snake. The patient developed shortness of breath while snake anti-venom was being infused. Clinicians had then attempted to intubate (insert a tube into a body part, especially the trachea, for ventilation) but failed, and therefore, the patient was then managed with an ambu bag (a bag valve mask, which is a hand held device used to provide positive pressure ventilation to patients who are not breathing or not breathing adequately) and mask ventilation. She was thereafter transferred to a tertiary care hospital for further ventilator support and management but had died before admission, two hours after the snakebite.

Relatives of the deceased had alleged that proper management was not provided even though they had brought the victim early to the hospital. They cited the failed attempt at intubation.

The cobra that was killed with a gunshot was brought to the morgue on the morning of the following day.

At the autopsy/postmortem examination, the original clothes were not available. A bite mark with two fang marks were found on the left upper and inner part of the breast, with a distance of 2.5 cm. Severe inflammatory signs were found around the bite mark with swelling, necrosis, and blister formation. No physical injuries were found to suggest any violence. Internal examination was unremarkable except for pulmonary congestion (accumulation of fluid in the lungs) and oedema (fluid retention). There were no haematological (blood-related) manifestations such as the presence of blood in urine, gastrointestinal bleeding, and mucosal bleeding.

At the end of the examination, the cause of death was given as envenomation (exposure to a poison or toxin resulting from a bite) due to cobra bite. As per M. Fernando’s “Guidelines for the management of snakebites in hospital”, the peculiar symptoms (bite was found on the breast) and signs of a neurotoxic agent, the rapid progression of death, the day biting behaviour of the snake, the place of bite being near to a human dwelling, the morphological (form or structure) features of the killed snake such as the hood between the head and the body and spectacle marking on its dorsal surface, severe local signs of envenomation at the site of the bite, and the absence of natural diseases, confirmed the cause of death as envenomation with neurotoxin due to a cobra bite.

Although viper bites are the common cause of death among snakebites in Sri Lanka, and there are local signs predominant in the bite (similar to the cobra bite as per S.K. Jindal, P.S. Shankar, S. Raoof, and D. Gupta’s “Textbook of pulmonary and critical care medicine: Volumes one and two”), it was excluded in this case owing to the absence of haematological manifestations. The krait (Indian and Ceylon) bite was also excluded due to the fact that it usually bites at night when the victim sleeps on the floor of a small hut or a house in a cultivated area, and the bite usually not producing visible fang marks or local reaction, and the presence of severe local signs and rapid progression to death not being seen, as per A. Silva, D. Gamlaksha, and D. Waidyaratne’s “Medico-legal significance of the identification of the offending snake in a fatal snakebite: A case report”.

Features of neurotoxin are dominant in the cobra and krait, while P. Mohankumar, C. Sivagurunathan and R. Umadevi’s “Study on the clinico-epidemiological profile and the outcome of snakebite victims in a rural health centre in the Kancheepuram District, Tamil Nadu” noted that features of coagulopathy (derangement of haemostasis [mechanism that leads to the cessation of bleeding from a blood vessel] resulting in either excessive bleeding or clotting) are dominant in Russell’s viper, saw scaled viper, and hump-nosed viper.

Explaining further, M.R. Kumar, M. Veeraprasad, P.R. Babu, S.S. Kumar, B.V. Subrahmanyam, P. Rammohan, M. Srinivas, and A. Agrawal note in “A retrospective review of snakebite victims admitted in a tertiary level teaching institute” that the peculiar feature observed in this case was that the bite was found on a breast in contrast to the usual site of a lower limb and not so commonly on the upper limb. Raveendran and Vidanapathirana opine that this may be the reason for the quick death as the absorption of venom, Kumar et al. note, is very quick in the chest when compared with the upper or lower limbs. Further, Raveendran and Vidanapathirana add that though the original clothes were not available, thin and tight clothes are not protective in the case of a snakebite.

For Raveendran and Vidanapathirana, the allegation made by the relatives regarding negligence in the management of respiratory failure cannot be proven with confidence as the clinicians had exercised a reasonable degree of skills by starting anti-snake venom and making all efforts to transfer the patient to a tertiary care hospital as early as possible, while the failed intubation may have been overcome by the accepted ambu and mask ventilation methods prescribed by Fernando. Further, the allegation can be challenged as death could occur rapidly within 30 minutes to two hours in cobra bites, and in this regard, they note that any delay in transporting the victim may also have played a crucial role, especially considering that this is a rural area.

Moreover, Raveendran and Vidanapathirana point out that snake anti-venom is ineffective in neutralising local envenomation in the post synaptic cleft (the postsynaptic cell is a cell which has places for the neurotransmitters to land, or receive information while the synaptic cleft is the space located between the presynaptic and postsynaptic endings [the neuron transmitting or generating a spike and incident onto a synapse is the presynaptic neuron while the neuron receiving the spike from the synapse is the postsynaptic neuron]) of the neuromuscular junction in the chest muscle, adding that this might, therefore, have played a key role in causing an early death. Raveendran and Vidanapathirana explain that snake anti-venom usually neutralises the systemic envenomation but not local envenomation.

Anti-venom therapies available in Sri Lanka, as per I.D. Simpson and R.L. Norris’ “Snake anti-venom product guidelines in India: The devil is in the details”, are Haffkine from the Haffkine Bio-Pharmaceutical Corporation Ltd. (Mumbai, India) and Vins Anti-Venom from Vins Bio Products Ltd. (Hyderabad, India). It has polyvalent (having a valency [the combining power of an element] of three or more) antibodies prepared by injecting the venom of these snakes into a horse. This is, however, prepared for Indian species-specific snakes and not for Sri Lankan snakes.

As noted by S.A. Kularatne, B.D. Budagoda, I.B. Gawarammana, and W.K. Kularatne in “Epidemiology, clinical profile, and management issues of cobra (Naja naja) bites in Sri Lanka: First authenticated case series”, there are hardly any studies on cobra venom performed in Sri Lanka to characterise its constituents. Studies in India (M.K. Bhat and T.V. Gowada’s “Purification and characterisation of myotoxic [small, basic peptides – a short chain of amino acids – found in snake venom], phospholipase [enzyme that hydrolyses – chemical reaction in which a molecule of water breaks one or more chemical bonds], phospholipids [group of polar lipids that consist of two fatty acids, a glycerol unit, and a phosphate group which is esterified – combined with an alcohol or an alcohol combined with an acid to form an ester – to an organic molecule] into fatty acids and other lipophilic – combined with or dissolves in lipids or fats – substances] A2 from the Indian cobra [Naja naja] venom” and L.M. Rudrammaji and T.V. Gowada’s “Purification and characterisation of three acidic, cytotoxic [a substance or process which results in cell damage or cell death] phospholipases A2 from Indian cobra venom”) have isolated from the Indian cobra venom, a low molecular weight isoform (a protein that has the same function as another protein but which is encoded by a different gene and may have small differences in its sequence) of hyaluronidase (family of enzymes that catalyse the degradation of hyaluronic acid), which has hydrolysed hyaluronan in human skin sections, while cytotoxic and myotoxic phospholipases A2 have also been found as characteristics in the Indian cobra.

Therefore, Raveendran and Vidanapathirana emphasise that this knowledge could be extrapolated to the Sri Lankan context to explain the extensive local damage and its varying degree of severity from patient to patient. Furthermore, Kularatne et al. too have documented similar extensive skin necrosis in the cobra bite.

As per A. De Silva’s “Venomous snakes, their bites, and treatment in Sri Lanka”, krait venom damages presynaptic nerve endings, thus making recovery take a longer time, whereas cobra venom is postsynaptic and its effect reverses fast, with contrasting behaviour of neurotoxins of two Elapids (a family of venomous snakes characterised by their permanently erect fangs at the front of the mouth) in the same geographical location being seen.

While local doctors have managed to produce a Sri Lankan monovalent anti-venom called Polonga Tab (a suboptimal dose of 1 g costing Rs. 43,000 per patient, as per H.J. De Silva, M.M.D. Fonseka, S.B. Gunathilake, S.A.M. Kularatne, and K.H. Sellahewa’s “Anti-venom for snakebite in Sri Lanka: We need an effective, low-reactogenic, affordable, and polyvalent anti-venom serum”) which has been tested on patients in Anuradhapura and has been found to be “very much better” than the Indian anti-venom, it is, Raveendran and Vidanapathirana elaborate, extremely expensive as it is produced in the UK with sheep.

The duo add that even though anti-venom serum should not be used inappropriately, as per S.L. Seneviratne, C.J. Opanayaka, N.S. Ratnayake, K.E. Kumara, A.M. Sugathadasa, N. Weerasuriya, W.A. Wickrama, S.B. Gunatilake, and H.J. de Silva’s “Use of anti-venom serum in snakebite: A prospective study of hospital practice in the Gampaha District”, practices such as administering the Haffkine polyvalent anti-venom serum (an average dose of 10 g costs Rs. 8,000 per patient) for hump-nosed viper bites still continues.

De Silva et al. also found that the currently available polyvalent Haffkine anti-venom serum was more effective than the monovalent Polonga Tab anti-venom serum, the latter of which is specifically prepared against the Sri Lankan Russell’s viper venom.

Moreover, De Silva et al. further add that the reported rates of adverse reactions to the polyvalent anti-venom serum used in Sri Lanka vary from about 30-68% with only a small proportion of 5-10% of such reactions appearing to be severe, while in the case of the monovalent anti-venom Polonga Tab, the overall rate of adverse reactions reported is 34% for suboptimal doses of the anti-venom serum. Therefore, they note that there are also concerns about the possibility of more frequent adverse reactions owing to the use of a more effective higher initial dose of the Polonga Tab.

Explaining further, Raveendran and Vidanapathirana elaborate that proper molecular studies on Sri Lankan snake venom and dose-dependent studies were not done in Sri Lanka owing to practical reasons.

In conclusion, they add that assuming that the molecules of Indian snakes are the same as Sri Lankan ones is questionable, and may, according to the duo, also have contributed to the death in this case.

“What doctors treating snakebite envenoming in Sri Lanka require is an effective, low-reactogenic, cheap, and polyvalent anti-venom serum. Until that becomes available, the currently available anti-sera imported from India seems good enough. However, the role played by the non-availability of species-specific anti-venom and the efficacy of common anti-snake venom should be further studied prior to giving opinions regarding medical negligence,” it was noted.