A retrospective study of use of polyvalent anti-snake venom and risk factors for mortality from snake bite in a tertiary care setting,Shraddha M Pore1, Sunita J Ramanand1, Praveenkumar T Patil1, Alka D Gore2, Mayur P Pawar1, Smita L Gaidhankar1, Ravi R Ghanghas1, : Indian Journal of Pharmacology

Home

RESEARCH ARTICLE	[Download PDF]

Year : 2015 \| Volume : 47 \| Issue : 3 \| Page : 270--274

A retrospective study of use of polyvalent anti-snake venom and risk factors for mortality from snake bite in a tertiary care setting

Shraddha M Pore¹, Sunita J Ramanand¹, Praveenkumar T Patil¹, Alka D Gore², Mayur P Pawar¹, Smita L Gaidhankar¹, Ravi R Ghanghas¹,
¹ Department of Pharmacology, Government Medical College, Miraj, Maharashtra, India
² Department of Preventive and Social Medicine, BVDU Medical College, Sangli, Maharashtra, India

Correspondence Address:
Dr. Smita L Gaidhankar
Department of Pharmacology, Government Medical College, Miraj, Maharashtra
India

Abstract

Aims: Envenomation with poisonous snakes is associated with considerable morbidity and mortality. The present study was undertaken with the objectives of assessing anti-snake venom (ASV) use, early adverse reactions to ASV, premedication and clinical outcomes in snake bite patients. Association of various risk factors (age, gender, dose of ASV, time gap between snake bite and ASV administration, use of mechanical ventilation and type of snake bite) with mortality was also assessed. Settings and Design: This retrospective study was conducted at two Tertiary Care Teaching Hospitals. Subjects and Methods: The medical records of 176 patients of snake bite with documented use of ASV were retrospectively analyzed to retrieve relevant data. Statistical Analysis: Descriptive statistics was used to express results about ASV use, early adverse reactions to ASV, premedication and clinical outcomes. Univariate and multivariate analysis was performed to find out significant risk factors associated with mortality. Results: The main indication for ASV was vasculotoxic snake bite (75%) followed by neurotoxic snake bite (16%). Mean dose of ASV was 18.63 ± 14.52 vials. Prophylactic premedication with corticosteroids alone or in combination with antihistaminic was used in more than 70% patients. Early adverse reactions to ASV were seen in 4% patients. Neurotoxic snake bite was a significant risk factor associated with mortality in multivariate analysis. Conclusions: Neurotoxic snake bite is an independent predictor of mortality in snake bite patients. Currently used polyvalent ASV may be less effective in treating neurotoxic snake bite.

How to cite this article:
Pore SM, Ramanand SJ, Patil PT, Gore AD, Pawar MP, Gaidhankar SL, Ghanghas RR. A retrospective study of use of polyvalent anti-snake venom and risk factors for mortality from snake bite in a tertiary care setting.Indian J Pharmacol 2015;47:270-274

How to cite this URL:
Pore SM, Ramanand SJ, Patil PT, Gore AD, Pawar MP, Gaidhankar SL, Ghanghas RR. A retrospective study of use of polyvalent anti-snake venom and risk factors for mortality from snake bite in a tertiary care setting. Indian J Pharmacol [serial online] 2015 [cited 2023 Oct 1 ];47:270-274
Available from: https://www.ijp-online.com/text.asp?2015/47/3/270/157117

Full Text

Introduction

Envenomation with poisonous snakes is a major problem in India especially in rural areas among the farming community. The true burden of morbidity and mortality from snake bites is not known. The Registrar General of India's "Million Death Study" indicated that in 2005 snake bites caused 45,900 deaths (99% CI: 40,900-50,900) in India. [1] Assuming that there are 100 nonfatal bites for each fatal bite, there could be as many 4.6 million snake bites in India each year. [2]

The only effective measure to prevent or reverse most of the manifestations of venomous snake bite is the timely administration of snake antivenom. In India, polyvalent anti-snake venom (ASV) raised in horses using venoms of four important venomous snakes in India viz. Indian cobra (Naja naja), Indian krait (Bangarus caeruleus), Russell's viper (Daboia russelii) and saw scaled viper (Echis carinatus) is widely used in the management of snake bites.

Several factors justify region specific surveillance of ASV use. Polyvalent ASV cannot be assumed to be uniformly effective in all poisonous snake bites. With the recognition of other snake species occurring in localized areas of the country, the concept of "Big Four" is being increasingly challenged. [3],[4] Moreover, the phenomenon of intraspecies variation in venom composition and varying antigenicity is also well-documented [5],[6],[7] and may have a major effect on the efficacy of antivenoms especially in regions away from the source of immunizing venoms. [8] Besides, other problems associated with ASV use are the occurrence of hypersensitivity reactions, lack of evidence for optimal dosing schedule, high cost, limited availability and possibility of inappropriate use. [9]

With this background, we undertook the present study with the objective of examining ASV use, premedication, early adverse reactions to ASV and clinical outcomes in snake bite patients in our setting. Identification of risk factors associated with mortality obviously has important implications for physicians and policy makers. Hence, we have assessed risk factors associated with mortality from snake bite.

Subjects and Methods

This retrospective observational study was conducted at two tertiary care teaching hospitals affiliated to the same institute. The study was approved by Institutional Ethics Committee. All indoor patients of snake bite with documented use of ASV during the period of July 2010 to June 2013 were included in the study. The patients whose hospital records were missing or grossly inadequate were excluded.

The protocol for the management of patients with snake bite in these centers is as follows. All patients with suspected snake bite are admitted to Intensive Care Unit. They are monitored for at least 24 h. ASV is administered to patients showing signs of systemic envenomation like clinically important coagulation abnormality or systemic effects such as ptosis or respiratory weakness. The initial and repeat doses of ASV are administered as clinically indicated. The Intensive Care Unit of these centers is equipped with ventilators and has facilities for hemodialysis.

The medical records of enrolled patients were reviewed to extract information regarding demographics, type of snake bite and its severity, details of ASV administration, premedication, occurrence of early adverse reactions to ASV, clinical outcomes etc. This information was then entered in a structured proforma. Early reactions were defined as reactions occurring within 24 h of ASV administration.

Statistics

Data were entered in Microsoft excel sheets. Descriptive statistics was used to express results about ASV use, early adverse reactions to ASV, premedication and clinical outcomes. For assessment of risk factors, statistical analysis was done using statistical software SPSS for windows, version 22.0. U.S.A. Proportions and percentages were obtained. Chi-square test and Fischer's exact test were applied to check the association of different factors like age, gender, time gap, type of snake bite, total dose of ASV and mechanical ventilation with mortality. Binary logistic regression analysis was done to find out the significant and best predictor for mortality. The factors, which were significant (i.e. P < 0.05) in univariate analysis, were used for multivariate analysis. "Enter method" was applied for the binary logistic regression.

Results

After application of inclusion and exclusion criteria, data of 176 patients were available for analysis. Three patients were excluded due to grossly inadequate or missing information in medical records. Information regarding time gap between snake bite and ASV administration was not available for 30 patients, and one patient of neurotoxic snake bite died on arrival before administration of ASV. Univariate and multivariate analysis were performed for six factors viz. age, gender, time gap between snake bite and ASV administration, type of snake bite, total dose of ASV and use of mechanical ventilation. Thirty patients for whom information about time gap was lacking (this included four patients with no apparent indication for ASV) were not included in univariate and multivariate analysis.

Snake bite predominantly affected young males. The most common site was lower limb [Table 1]. Approximately, 70% of patients received ASV within 6 h of bite (results not shown). The main indication for ASV was vasculotoxic snake bite in 75% of cases followed by neurotoxic snake bite in 16% of cases [Table 2]. Four patients received ASV without clinical signs of systemic toxicity. These patients were referred from the periphery and received one vial of ASV before admission to study site. There were eight incidences of early adverse reactions to ASV in seven patients (4%). Mortality was seen in nine patients. Eight of these suffered from neurotoxic snake bite.{Table 1}{Table 2}

In univariate analysis, age <18 years, neurotoxic type of snake bite, use of mechanical ventilation, and time gap of more than 24 h between snake bite and administration of ASV were significantly associated with mortality [Table 3]. Of these, neurotoxic snake bite showed a statistically highly significant association with mortality. ASV requirement of more than 30 vials showed marginally higher mortality, but it was not statistically significant. Mortality was also higher in males than in females (6.8% vs. 3.4%) but it was not statistically significant. In binary logistic regression [Table 4] only neurotoxic type of snake bite was found to be significant predictor of mortality.{Table 3}{Table 4}

Discussion

Snake bite remains an important occupational hazard in South-East Asia region. The use of polyvalent ASV greatly reduces morbidity and mortality from poisonous snake bite.

Overall mortality in this study was 5%. But it was disproportionately higher for neurotoxic snake bite. Neurotoxic snake bite accounted for about 16% of total snake bite but about 90% of deaths. Multivariate logistic regression analysis indicated neurotoxic snake bite as an independent predictor of mortality. Higher mortality for neurotoxic snake bites has been reported previously in Maharashtra [10],[11] and elsewhere. [12] Neurotoxicity and respiratory paralysis were found to be important risk factors for mortality in patients with snake bite. [13],[14]

Several factors may be responsible for the inadequate efficacy of ASV in treating neurotoxic snake bite. [15] Firstly snake venom is not a homogenous toxin but a complex combination of multiple toxins with different neurotoxic properties. Though the effect of some post synaptically active neurotoxins can be antagonized by ASV or anticholinesterases, the action of other postsynaptically active neurotoxins that bind almost irreversibly with nicotinic acetylcholine receptor is not readily reversible. Moreover, presynaptically active neurotoxins with phospholipase activity cause degeneration of the motor nerve terminal. Clinical recovery is slow and depends on the regeneration of motor nerve terminal. Hence, treatment with ASV or anticholinesterases is unlikely to be effective in presynaptic toxicity and incomplete recovery, and delayed effects are more likely. Pharmacokinetic properties of venom and antivenom also have important pharmacodynamic implications. Antivenom which is largely confined to vascular compartment may not effectively neutralize the effect of highly diffusible low molecular weight toxins such as neurotoxins with a high volume of distribution. [16] Thus early administration of antivenom, before toxins bind to target sites could be crucial in neurotoxic snake bites. Secondly polyvalent ASV may be less effective or noneffective in snake bite caused by other venomous species, besides "Big Four" and even in case of "Big-Four" due to geographical variation in venom composition. [2] And lastly it is noteworthy that availability of ASV in Government Hospitals is largely dependent on supply by manufactures. A recent study indicates that ASV produced by different manufactures using the same source of venom may not be identical in their therapeutic potential. [17]

More than one-fourth (28%) patients in our study required 30 or more vials of ASV. Almost half of the patients with neurotoxic snake bite required 30 or more vials. Use of high dose ASV has been reported previously by various authors. [18],[19] Higher requirements of ASV are suggestive of low potency. In addition, there may be increased risk of dose-related adverse effects including anaphylaxis. [2]

Low frequency (about 4%) and mostly mild to moderate severity of early adverse reactions to ASV in our study suggest that this should not be an important concern in the treatment of snake bite. Prophylactic premedication with hydrocortisone and pheniramine or hydrocortisone alone in more than two-thirds of patients and use of neostigmine in almost all patients with neurotoxic features without prior "edrophonium test" in our study are not concordant with standard guidelines. [20] It points to the need for continuing medical education of physicians on all aspects of treatment of snake bite.

The strength of our study is consideration of three years data from two Tertiary Care Centers affiliated to the same institute. The important limitation is the retrospective nature of the study. As patients with grossly inadequate data or missing information were excluded, results may have been underestimated. It was also not possible to know the exact species of snake or ASV preparation used in an individual patient.

Given the problems associated with currently used polyvalent ASV, a brief account of important recent developments in this area would not be out of context here.

Venomics is a relatively new science. It involves techniques and strategies for assessing the toxin composition of snake venoms directly through proteomics-centered approaches or indirectly via high-throughput venom gland transcriptomics and bioinformatic analysis. Venomics analyses have revealed that snake venoms are mixtures of pharmacologically active proteins and peptides synthesized from several tens to a few hundred of unique gene products, which, however, belong to only a handful (<13) of toxin families. The usefulness and validity of antivenomics-the translational venomics has been extensively demonstrated in in vivo standard preclinical assays. Developments in venomics and antivenomics are likely to revolutionize the design and preclinical assessment of antivenoms by bringing to bear technologies that enable us to evaluate imprecision that exist in current methodologies, and get to heart of the problem by being able to design and test new antivenom preparations developed using these dynamic platforms. [2],[21]

Oral administration of ASV may also become possible in near future. Entrapping multiple components of antivenom in alginate, an economic, biodegradable polymer have been shown to retain the functional property of the antivenom even after intestinal absorption and suggest possibility of the development of an orally effective first aid against snake envenomation, thereby increasing chances of survival of the victim. [22]

Conclusion

Important findings of our study are higher mortality in neurotoxic snake bite, high ASV dose (>30 vials) requirement in one-fourth of patients and excess use of prophylactic premedication and neostigmine. In future, development of region specific, highly potent antivenom, and prospective evaluation of its safety and efficacy is needed. Development of appropriate local guidelines and training of physicians involved in the treatment of snake bite is equally important.

References

1	Mohapatra B, Warrell DA, Suraweera W, Bhatia P, Dhingra N, Jotkar RM, et al. Snakebite mortality in India: A nationally representative mortality survey. PLoS Negl Trop Dis 2011;5:e1018.
2	Warrell DA, Gutiérrez JM, Calvete JJ, Williams D. New approaches and technologies of venomics to meet the challenge of human envenoming by snakebites in India. Indian J Med Res 2013;138:38-59.
3	Kumar V, Sabitha P. Inadequacy of present polyspecific anti snakevenom-A study from central Kerala. Indian J Pediatr 2011;78:1225-8.
4	Pillai LV, Ambike D, Husainy S, Khaire A, Captain A, Kuch U. Severe neurotoxic envenoming and cardiac complications after the bite of a ′Sind Krait′ (Bungarus cf. sindanus) in Maharashtra, India. Trop Med Health 2012;40:103-8.
5	Venkatesh M, Prasad N, Sing T, Gowda V. Purification, characterization, and chemical modification of neurotoxic peptide from Daboia russelii snake venom of India. J Biochem Mol Toxicol 2013;27:295-304.
6	Kumar AV, Gowda TV. Novel non-enzymatic toxic peptide of Daboia russelii (Eastern Region) venom renders commercial polyvalent antivenom ineffective. Toxicon 2006;47:398-408.
7	Shashidharamurthy R, Kemparaju K. Region-specific neutralization of Indian cobra (Naja naja) venom by polyclonal antibody raised against the eastern regional venom: A comparative study of the venoms from three different geographical distributions. Int Immunopharmacol 2007;7:61-9.
8	Ali SA, Yang DC, Jackson TN, Undheim EA, Koludarov I, Wood K, et al. Venom proteomic characterization and relative antivenom neutralization of two medically important Pakistani elapid snakes (Bungarus sindanus and Naja naja). J Proteomics 2013;89:15-23.
9	Patil TB. Snake bite envenomation: A neglected public health problem in India. Med J DY Patil Univ 2013;6:123-5.
10	Inamdar IF, Aswar NR, Ubaidulla M, Dalvi SD. Snakebite: Admissions at a tertiary health care centre in Maharashtra, India. S Afr Med J 2010;100:456-8.
11	Bawaskar HS, Bawaskar PH. Envenoming by the common krait (Bungarus caeruleus) and Asian cobra (Naja naja): Clinical manifestations and their management in a rural setting. Wilderness Environ Med 2004;15:257-66.
12	Saravu K, Somavarapu V, Shastry AB, Kumar R. Clinical profile, species-specific severity grading, and outcome determinants of snake envenomation: An Indian tertiary care hospital-based prospective study. Indian J Crit Care Med 2012;16:187-92.
13	Kalantri S, Singh A, Joshi R, Malamba S, Ho C, Ezoua J, et al. Clinical predictors of in-hospital mortality in patients with snake bite: A retrospective study from a rural hospital in central India. Trop Med Int Health 2006;11:22-30.
14	Suchithra N, Pappachan JM, Sujathan P. Snakebite envenoming in Kerala, South India: Clinical profile and factors involved in adverse outcomes. Emerg Med J 2008;25:200-4.
15	Ranawaka UK, Lalloo DG, de Silva HJ. Neurotoxicity in snakebite - the limits of our knowledge. PLoS Negl Trop Dis 2013;7:e2302.
16	Gutiérrez JM, León G, Lomonte B. Pharmacokinetic-pharmacodynamic relationships of immunoglobulin therapy for envenomation. Clin Pharmacokinet 2003;42:721-41.
17	Leong PK, Tan NH, Fung SY, Sim SM. Cross neutralisation of Southeast Asian cobra and krait venoms by Indian polyvalent antivenoms. Trans R Soc Trop Med Hyg 2012;106:731-7.
18	Agrawal PN, Aggarwal AN, Gupta D, Behera D, Prabhakar S, Jindal SK. Management of respiratory failure in severe neuroparalytic snake envenomation. Neurol India 2001;49:25-8.
19	Sharma N, Chauhan S, Faruqi S, Bhat P, Varma S. Snake envenomation in a north Indian hospital. Emerg Med J 2005;22:118-20.
20	Warrell D. Guidelines for the management of snake-bites. New Delhi: WHO Regional Office for Southeast Asia; 2010. Available from: http://www.toxinology.org. [Last accessed on 2013 Aug 19].
21	Calvete JJ. Snake venomics: From the inventory of toxins to biology. Toxicon 2013;75:44-62.
22	Bhattacharya S, Chakraborty M, Mukhopadhyay P, Kundu PP, Mishra R. Viper and cobra venom neutralization by alginate coated multicomponent polyvalent antivenom administered by the oral route. PLoS Negl Trop Dis 2014;8:e3039.