Corresponding Author Shriprakash Kalantri, Department of Medicine, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha 442102, India. Tel.: +91 07152 284134; Fax: +91 7152 284967; E-mail: email@example.com.
Objective To determine the association between selected admission risk factors and in-hospital mortality in patients admitted with venomous snake bite to a rural tertiary care hospital in central India.
Methods Retrospective cohort study of patients aged 12 years or older admitted to a rural hospital in central India between January 2000 and December 2003 with venomous snake bites. The primary endpoint was in-hospital mortality. We used Cox proportional-hazards regression analysis to evaluate the association between risk factors (home-to-hospital distance, bite-to-hospital time, vomiting, neurotoxicity, urine albumin, serum creatinine concentration and whole-blood clotting time) and in-hospital mortality.
Results Two hundred and seventy-seven patients [mean age 32 (SD 12) years; 188 men (68%)] were admitted with venomous snake bite, 29 patients (11%) died. The probability of survival at day 7 was 83%. Vomiting [hazard ratio 6.51 (95% CI 1.94–21.77), P ≤ 0.002], neurotoxicity [hazard ratio 3.15 (95% CI 1.45–6.83), P = 0.004] and admission serum creatinine concentration [hazard ratio 1.35 (95% CI 1.17–1.56), P ≤ 0.001] were associated with higher risk of death in the adjusted analysis.
Conclusions In our rural hospital setting, the overall mortality rate was 11 per 100 cases of snake bite. Vomiting, neurotoxicity and serum creatinine are significant predictors of mortality among inpatients with snake bite. These predictors can help clinicians assess prognosis of their patients more accurately and parsimoniously and also serve as useful signposts for clinical decision-making.
Objectif Déterminer l'association entre une sélection de facteurs de risque d'admission et la mortalitéà l'hôpital, de patients victimes de morsures de serpent venimeux, admis dans un hôpital de soin tertiaire du centre de l'Inde.
Méthode Une étude rétrospective de cohorte de patients âgés de 12 ans ou plus, victimes de morsures de serpent venimeux, admis dans un hôpital rural du centre de l'Inde, entre janvier 2000 et décembre 2003. L'objectif primaire a été fixé comme étant la mortalitéà l'hôpital. Nous avons utilisé l'analyse de régression de Cox pour évaluer l'association entre les facteurs de risque (distance domicile-hôpital, durée entre le temps de la morsure et l'hôpital, vomissement, neurotoxicité, albumine dans l'urine, concentration de créatinine sérique et temps de coagulation du sang total) et la mortalitéà l'hôpital.
Résultats 277 patients [âge moyen 32 ± 12 ans; 188 hommes (68%)] ont été admis pour morsure de serpent venimeux ; 29 patients (11%) sont décédés. La probabilité de survie au 7eme jour était de 83%. Dans l'analyse après ajustement, le vomissement [risque ratio 6.51 (IC95%: 1.94–21.77), P ≤ 0.002], la neurotoxicité [risque ratio 3.15 (IC95%: 1.45–6.83), P = 0.004] et l'admission pour la concentration sérique de créatine [risque ratio 1.35 (IC95%: 1.17–1.56), P ≤ 0.001) étaient associés à un risque élevé de décès.
Conclusions Dans les dispositions de notre hôpital rural, le taux global de mortalitéétait de 11 pour 100 cas de morsure de serpent. Le vomissement, la neurotoxicité et la créatine sérique sont des prédicteurs significatifs de mortalité chez les patients hospitalisés pour morsures de serpent. Ces prédicteurs peuvent aider les cliniciens àévaluer avec plus de précision et de parcimonie le pronostic de leurs patients. Ils peuvent aussi servir comme indicateurs utiles dans la prise de décision clinique.
Mots clés morsures de serpent, mortalité, prédicteurs, facteurs de risque, venimeux, Inde
Objetivo Determinar la asociación entre factores de riesgo seleccionados en el ingreso y la mortalidad intra-hospitalaria en pacientes hospitalizados con mordedura de serpiente venenosa en un hospital de tercer nivel en India central.
Método Estudio de corte retrospectivo de pacientes con 12 o mas años de edad, ingresados en un hospital rural de la India central con mordedura de serpiente venenosa entre enero del 2000 y diciembre del 2003. El resultado primario fue la mortalidad intra-hospitalaria. Utilizamos el análisis de regresión de Cox de peligros proporcionales (hazards) para evaluar la asociación entre los factores de riesgo (distancia entre el hogar y el hospital, tiempo entre mordedura y llegada al hospital, vómitos, neurotoxicidad, albúmina urinaria, concentración sérica de creatinina y tiempo total de coagulación) y la mortalidad intra-hospitalaria.
Resultados Se ingresaron 277 pacientes [edad media 21 (DS 12) años, 188 hombres (68%)] con mordedura de serpiente venenosa. La probabilidad de supervivencia al día 7 fue de 83%. Vómitos [razón de riesgo instantáneo (hazard ratio) 3.15 (95% CI 1.45–6.83), P = 0.004), neurotoxicidad [razón de riesgos instantáneo 6.51 (95% IC 1.94–21.77, P < 0.002] y la concentración sérica de creatinina al ingreso [razón de riesgo instantáneo 1–35 (95% CI 1.17–1.56), P ≤ 0.001)] se asociaron con un mayor riesgo de muerte en el análisis ajustado.
Conclusión En las condiciones de nuestro hospital rural, la tasa general de mortalidad fue de 11 por cada 100 casos de mordedura de serpiente. Los vómitos, la neurotoxicidad y la creatinina sérica son predictores de muerte entre pacientes con mordedura de serpiente. Estos predictores pueden ayudar a los clínicos a evaluar con mayor exactitud el pronóstico de sus pacientes, además de ser señales útiles en el proceso de toma de decisión clínico.
Palabras clave mordedura de serpiente, mortalidad, supervivencia, predictores, factores de riesgo, envenenamiento, India
Snake bite, an important cause of death in rural patients in developing countries, is a neglected public health problem. Worldwide, of the estimated 5 million people bitten by snakes each year, about 125 000 die (Murray & Lopez 1996). More than 200 000 cases of snake bite are reported in India each year and 35 000–50 000 of them are fatal. In Maharashtra, a state in India, an estimated 10 000 annual venomous snake bites account for 2000 deaths (Warrell 1999). However, these data are derived from hospital-based sources, which are likely to grossly underestimate the incidence and mortality of snake bites.
About 75% of the Indian population is rural. Most snake bite victims live in villages, seek traditional treatment and many die at home or during transport to hospital (Sharma et al. 2004a). In India, victims of snake bite run a high risk of dying even if they reach hospital. This is because snake venom contains a variety of enzymes and non-enzymatic toxic polypeptides, which affect multiple organs such as kidneys, the coagulation system and respiratory muscles. Most rural hospitals lack the intensive care facilities required for care of patients with multi-organ dysfunction. Also, inappropriate use of antivenom in rural hospitals is common (Warrell 2003).
To make more meaningful use of resources such as antivenom, ventilator therapy and renal support systems in patients with snake bite, it is important that the healthcare providers should be able to identify patients with snake bites at high risk of potentially fatal complications. Simple demographic and clinical characteristics could be used to help doctors distinguish between high-risk and low-risk patients. To be useful, the predictors should be simple, accurate and clinically credible. We conducted this retrospective study to evaluate predictors of in-hospital mortality in a rural hospital setting in India.
Materials and methods
Setting and study design
The Mahatma Gandhi Institute of Medical Sciences (MGIMS), Sevagram is a 648-bed teaching institution in rural central India with 325 000 patient visits and about 5500 patient admissions to medicine wards per year. The hospital, located in a small town in Maharashtra state, serves a predominantly rural population and admits about 100 patients with snake bite each year. All patients with snake bite aged 12 years and older are admitted to the medicine wards of the hospital. They are monitored for at least 24 h and receive lyopholized polyvalent antivenom (Haffkine Bio-pharmaceutical Company Ltd., Bombay, India) if they show progressive venom injury such as local swelling, a clinically important coagulation abnormality [incoaguable blood on 20-minute whole-blood clotting test (20WBCT)] or systemic effects such as ptosis or respiratory weakness. The intensive care unit of the hospital is equipped with a ventilator and has facilities for peritoneal dialysis. Residents and nurses record hospital data on a structured monitoring sheet. Ethical approval for the study was granted by the hospital ethical committee.
We identified all cases of suspected snake bite admitted to the medicine wards of our hospital between January 2000 and December 2003 on the basis of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for venomous snakes and lizards (E 905.0) and venom (E 989.5). We excluded patients who did not show features of envenoming from the analyses. We used pilot-tested data abstraction forms to collect data on patient demographics and admission clinical variables. The data were checked for consistency and completeness. In the univariate analysis, we regarded the following variables as potential prognostic factors: age, sex, bite-to-hospital time (time taken by the patient to be brought to the hospital after the bite), home-to-hospital distance (distance from the patient's home to hospital, recorded in km and derived by measuring the radial distance of the patients’ residence from the hospital), diurnal variation (day or night), the site of snake bite, use of tourniquet, local swelling, symptoms (vomiting and neurotoxicity), urine albumin, 20WBCT and serum creatinine concentration. Neurotoxicity was defined as documented ptosis, external ophthalmoloplegia, weakness of neck or bulbar muscles, use of neostigmine or ventilatory support (endotracheal intubation, Ambu bag or a mechanical ventilator). All patients underwent a whole-blood clotting test similar to that described by Warrell et al. (1999). Age, bite-to-hospital interval, home-to-hospital distance and serum creatinine concentration were continuous variables; the rest were binary variables (coded as 0= absent and 1= present).
All analyses were performed using Stata software (Version 8, Stata Corporation, College Station, TX, USA) and R Version 2.01 (R Foundation for Statistical Computing, Vienna, Austria). To compare demographic and clinical characteristics between survivors and non-survivors, we used the t-test for continuous, normally distributed variables; chi-square or Fisher's exact test, as appropriate for categorical variables and Wilcoxon's Mann–Whitney U-test for non-parametric variables. All tests were two-sided, with a P value of 0.05 or less considered statistically significant.
We explicitly considered the time to event for each individual in the study, and analysed the data with ‘survival analysis’ methods. The Kaplan–Meier product-limit estimator was used to estimate survival and for the time-to-event plot. Time to discharge and time to death were investigated with follow-up for all patients starting at hospital admission and ending on day 7. Patients were censored if they were still alive and did not have a poor outcome at the end of follow-up. Event-free subjects were right censored on day 7 after admission to the hospital, because no patient died in the hospital after day 7. The primary end point in this analysis was in-hospital mortality. Mortality was defined as death during the index hospitalization. To identify those predictors with the most significant independent influence on prognosis, we used the log rank test for simple comparisons. Crude hazard ratios were computed to assess the strength of association between risk factors (covariates) and outcome (in-hospital mortality). We used the Cox proportional-hazards regression model for analyses of multiple predictor variables (Cox 1972). This model measures the hazard ratio – the relative effect of a predictive factor on an outcome – by assuming that this relation is constant over time. The assumption of proportional hazards was validated graphically by the log–log time plot. Because many of the risk factors were correlated, collinearity was evaluated by generating correlation matrices and handled by eliminating one of the two collinear variables. Only three variables with a significant unadjusted association with death were included in our final regression model. Since we had only 29 outcome events, this approach accords with accepted statistical practice (Katz 1999). A forward stepwise technique was used in the selection of covariates. For a variable to enter in the model, the P value had to be <0.1 and for it to exit, the P value had to be >0.1. No interactions were entered into the final model because they did not improve fit of the model. Both the crude and the adjusted hazard ratio estimates were computed along with 95% confidence intervals (CI).
Between January 1, 2000, and December 31, 2003, a total of 370 snake bite patients, aged 12 years and older, consisting of 242 men and 128 women [mean (SD) age 32 (12) years] were admitted to the hospital. Of these, 93 patients (25%) were excluded from the analysis because they had a non-venomous bite (n = 47), or a dry bite (bite without envenoming; n = 16) or were stung by scorpion and not bitten by a snake (n = 30) (Figure 1). The final dataset comprised records of 277 patients [mean (SD) age 32 (12) years]; [188 (68%) men and 89 (32%) women]. Eighty-four per cent were from rural areas and most patients were bitten engaged in farming activities. Most bites (56%) occurred between June and September, a period of rains and intense farming activity in rural India. Of the 277 patients with venomous snake bites, 81 (29%) patients or bystanders claimed that they could identify the species of the snake on the basis of size, shape, colour or pattern of marking [vipers, 68 (24%), cobras, 11 (4%) and kraits, 2 (1%)].
Table 1 shows the demographic and clinical characteristics of the patients according to their outcome status: survival (n = 248) and death (n = 29). The median bite-to-hospital time was 3 h (range: 1–72 h). One-third of patients lived within 10 km of the hospital and 190 patients (69%) had the snake bite between 0600 and 1800 h. All bites were on extremities; legs were three times more often involved than hands. About 18% received antivenom at the village-based primary health centre before they were referred to our hospital and 37% of patients used at least one of the following first-aid measures: incision of wound, application of tourniquet or both. However, no data were available to quantify the width and pressure of the circumferential ligature or its duration. No patient used a pressure immobilization bandage over the bitten extremity. The common presenting symptoms were pain and swelling at the bite site, vomiting, drooping of eyelids and difficulty breathing. All deaths occurred within 7 days of admission.
Table 1. Demographic and clinical characteristics of the patients with venomous snake bites
All patients (n = 277)
Survivors (n = 248)
Non-survivors (n = 29)
SD, standard deviation; AV, IQR, interquartile range.
* P value (two sided) for t-test (means), Wilcoxon's Mann–Whitney U-test or Fisher's exact test (medians) or chi-square test (proportions) comparing characteristics of survivors and non-survivors.
† To convert values of serum creatinine to micromoles per litre, multiply by 88.4.
Mean age, years (SD)
Mean bite-to- hospital time, hours (SD)
Bite-to-hospital distance >15 km (%)
Bite during day (%)
Bite on leg (%)
Tourniquet use (%)
Local swelling (%)
Urine albumin (%)
Abnormal whole-blood clotting test (%)
Median serum creatinine (mg/dl)† (IQR)
Determinants of fatal outcome
In the univariate analysis the following risk factors were significantly associated with mortality: home-to-hospital distance, vomiting, neurotoxicity, urine albumin and serum creatinine (Table 2). Age and sex differentials were not significant. In the final model, vomiting [hazard ratio 6.51 (95% CI 1.94–21.77) χ2 = 15.34, P = 0.002); neurotoxicity [hazard ratio 3.15 (95% CI 1.45–6.83); χ2 = 6.79, P = 0.004) and serum creatinine [hazard ratio 1.35 (95% CI 1.17–1.56); P < 0.001) were independent predictors of mortality. The risk of death was six times higher for those with a history of vomiting and three times higher for those with neurotoxicity compared to patients who did not have these risk factors. After adjustment for other risk factors, for every 1 mg increase in serum creatinine, the likelihood of death increased by a factor of 1.35 (95% CI 1.21–1.55).
Table 2. Factors associated with mortality in inpatients with venomous snake bite
‡ To convert values of serum creatinine to micromoles per litre, multiply by 88.4.
Bite-to-hospital time, hours†
Home-to-hospital distance, kms†
Serum creatinine (mg/dl)†‡
The Kaplan–Meier estimates showed that patients who did not vomit after snake bite were more likely to survive during the 7-day-study period than those who did [0.98 (95% CI 0.95–1.00) vs. 0.72 (95% CI 0.61–0.84)]. Similarly, compared to those with neurotoxicity, patients without neurotoxicity had better chances of survival [0.89 [95% CI 0.81–0.96) vs. 0.75 (95% CI 0.64–0.87)] (Figure 2).
Common venomous snakes in central India are cobras (Naja naja), Russell's viper (Daboia russelii), the saw scaled viper (Echis carinatus) and kraits (Bungarus caeruleus) (Bambery et al. 1993). Vipers, the most abundant snake species in our study area, cause rapid progressive swelling and coagulopathy. Renal failure, unusual after Echis bite, is a classical feature of Russell's viper envenoming. By contrast, krait and cobra bites are characteristically associated with neurotoxicity. Half the patients in our study presented with local swelling and systemic bleeding and a third presented with neurotoxicity. Clinical syndromes of snake bite are relatively species-specific, but only a quarter of victims in our study were able to accurately identify the species of the snake.
Both population and hospital-based studies show considerable variation in mortality rates in snake bites. For example, previous population-based studies reported a mortality incidence of 34–162 per thousand per year in patients with snake bite (Pugh & Theakston 1980; Sharma et al. 2004a). In hospital-based studies, mortality rates ranged from 3% in northern India (Sharma et al. 2005) to 20% in Nepal (Hansdak et al. 1998; Sharma et al. 2003). The case-fatality rate in our study was 11%. Clearly the rates of death in resource-limited settings are three to six times higher than those reported from rich countries.
What factors might account for discrepancy in mortality rates? Although no study has compared patient characteristics and outcomes between rural and urban hospitals, hospital setting might be an important determinant of survival. Sharma et al. (2005) show that the rate of death in a specialty hospital – equipped with enough antivenom, ventilators and dialysis machines – is much lower than rural hospitals. Several other factors can explain poor outcome in rural areas. Severe envenoming can kill quickly: within 8 h after cobra bite, 18 h after krait bites, 3 days after D. russelii bite, and 5 days after Echis bite (Warrell 2003). Half of the victims seek treatment by traditional healers before they present to the hospital and many die before they can find transport to reach the nearest hospital (Sharma et al. 2004b). Although antivenom has proven benefits (Warrell et al. 1986; Otero-Patino et al. 1998), it is expensive and poorly stocked in rural hospitals in developing countries. Working with scarce resources and fearful of early anaphylactoid allergic reactions to the antivenom, rural doctors tend to under-use antivenom even in patients with severe envenoming. Victims of snake bite die because they do not receive antivenom, receive it too late or receive too little (Gold et al. 2002).
We found that levels of serum creatinine concentration on admission, vomiting, and neurotoxicity after the snake bite were strong predictors of mortality among in-hospital patients. A common cause of death in viper envenomation is acute renal failure resulting from hypovolemia, intravascular haemolysis, a syndrome resembling disseminated intravascular coagulation or venom-induced nephrotoxicity (Gold et al. 2002). In our study, of the 16 patients with an admission creatinine concentration of more than 2 mg/dl, eight died. Six of them underwent peritoneal dialysis, eight received low-dose dopamine or loop diuretics and two received mannitol. In a clinical trial (ANZICS Clinical Trials Group 2001) low-dose dopamine did not confer a clinically significant degree of renal protection in critically ill patients at risk of renal failure and was associated with an increase in adverse events. A recent meta-analysis (Friedrich et al. 2005) supports the view that low-dose dopamine has no clinically meaningful benefits but failed to find a connection between dopamine use and adverse effects. We did not have adequate data to assess what led to renal failure in our patients and whether renal failure was aggravated by pharmacological interventions.
Abdominal pain, thought to be caused by submucosal haemorrhages in the stomach, has long been recognized as an important and early symptom of venomous snake bite (Theakston et al. 1990; Kularatane 2002). Vomiting, also an important feature of severe systemic envenomation (Warrell 1999), by contrast, has not received as much attention in clinical practice. Our study shows that vomiting after snake bite is strongly associated with mortality. Severe envenoming is associated with several autonomic symptoms such as vomiting, nausea, sweating, abdominal colic and diarrhoea (Jorge et al. 1997). However, vomiting is not a specific sign of severe envenoming, and may be induced by fear (Gold & Barish 1992) or use of herbal medicines or alcohol after a snake bite. An important feature of early anaphylactoid reaction to the antivenom, vomiting could also be associated with uremia. The question of whether vomiting is a surrogate marker of severity of snake bite requires more research.
The frequency of neurotoxic envenoming varies from 10% to 60% (Sharma et al. 2004a,2005). A study from Nepal (Sharma et al. 2004b) and another from Sri Lanka (Theakston et al. 1990) reported mortality of 2% among patients with neurotoxicity. Snakes cause acute reversible muscular paralysis by inhibiting neuromuscular transmission. Post-synaptic (α) neurotoxins such as α-bungarotoxin and cobrotoxin bind to acetylcholine receptors at the motor endplate and do not allow the receptor to get acetylcholine released from the nerve terminal. Pre-synaptic (β) neurotoxins such as β-bungarotoxins prevent release of acetylcholine from the motor endplate. Because optimal treatment differs, it is important to distinguish neurotoxic envenoming of krait from cobra: the former blocks both pre-synaptic and post-synaptic receptors (Singh et al. 1999) and needs prolonged mechanical ventilation until their receptors are generated (Bawaskar & Bawaskar 2002); the later blocks post-synaptic receptors (Watt et al. 1986) and needs more antivenom and neostigmine. Bawaskar and Bawaskar (2004) report that of the 30 individuals with krait and cobra bite who presented to their rural hospital in Maharashtra, two died during transport and another seven died in the hospital. Our experience is similar: one-third of our patients presented with neurotoxicity; one-fifth of them died. The mortality rates among our patients with neurotoxic envenoming were higher because cobras and kraits, species of snakes known to result in severe neurotoxicity, presumably bit a third of patients in our study. We could institute mechanical ventilation in only 11 of 59 patients (19%) with neurotoxicity severe enough to necessitate ventilatory support. By contrast, in a recent study from North India (Sharma et al. 2005) 65 of 86 patients (75%) with neurotoxicity underwent mechanical ventilation. Fewer patients received ventilatory support in our study because several critically ill patients with diseases as diverse as organo-phosphate poisoning and tetanus competed with the single ventilator available in our hospital during the study period.
Our study has several limitations. First, a retrospective chart review design has inherent problems of missing values. For example, a previous study has shown that the 20WBCT is a simple, accurate and reliable marker for identifying low levels of fibrinogen and assessing the effectiveness of antivenom therapy (Sano-Martins et al. 1994). We could not use the 20WBCT as a time-dependent covariate in our study because a number of records were missing data on this variable. Second, antivenom is a key determinant of survival after snake bite (Warrell 2003). Injected early and in adequate quantities, it neutralizes the snakevenom and reduces in-hospital mortality. We evaluated risk factors related to envenoming (vomiting, clotting test, neurotoxicity and serum creatinine concentration) but did not adjust for antivenom administration to assess its association with mortality. Our preliminary analyses showed that individuals who received large amounts of antivenom had higher mortality rates. The amount of antivenom administered, therefore, was an indicator of underlying severity of disease. Given this potential for confounding by indication (severity), we did not include antivenom in our final multivariate model. Identifying snake species by using enzyme immunoassay (Smalligan et al. 2004) and stratifying severity of snake bite by using the severity score (Dart et al. 2001) could have helped us evaluate severity and progression of envenoming in our patients more objectively. However, we lacked such data to assess influence of disease severity on mortality. Third, we evaluated survival of snake bite patients aged 12 years and older, who received in-hospital treatment. We therefore missed those who died before reaching our hospital or those with mild envenoming who did not present to the hospital. Doctors caring for snake bite patients in nearby villages refer patients with severe envenoming to our hospital. Our study population, therefore, may represent patients with more complex disease (referral filter bias). Also, our patient group was heterogeneous – envenoming was caused by several undefined species of snakes. Finally, severely envenomed patients need such support measures as dialysis, ventilator therapy or fresh frozen plasma. Our hospital is a typical rural hospital in India where many patients with significant neurotoxicity could not be offered ventilatory support using a mechanical ventilator, and had to be manually ventilated using Ambu bags. Our results should not be generalized to those settings in which patients have access to sophisticated life support systems.
In conclusion, our study shows that in-hospital mortality after snake bite can be predicted by simple variables. These prognostic variables can help clinicians predict outcomes more accurately and parsimoniously, may influence treatment decisions (such as rational use of antivenom) and may reduce in-hospital mortality of snake bite. More research is needed to validate these findings in other populations and to evaluate whether early identification of prognostic indicators and aggressive management can reduce the risk of death in patients following snake bite, particularly in resource-limited settings.
We thank Dr AP Jain and Dr NK Tyagi for letting us use the hospital records. We are grateful to Prashant Raut and Santosh Chavhan for helping us collect the data. Shriprakash Kalantri, Samuel Malamba and Joseph Ezoua are funded by the Fogarty AIDS International Training and Research Program (AITRP), National Institutes of Health, USA [Grant 1-D43-TW00003-16].