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- Materials and methods
- Determinants of fatal outcome
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
- Top of page
- Materials and methods
- Determinants of fatal outcome
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.
Determinants of fatal outcome
- Top of page
- Materials and methods
- 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
|Characteristics||Univariate analysis||Multivariate analysis|
|No. of events||Incidence of mortality % (95% CI)||Hazard ratio (95% CI)|| P value||Adjusted hazard ratio (95% CI)|| P value*|
|Age, years†|| || ||0.98 (0.95–1.0)||0.441|| || |
| Men||23/188||12.0 (7.3–16.6)||Reference||0.153|| || |
| Women||6/89||6.7 (1.5–11.9)||0.50 (0.21–1.27)|| || || |
|Bite-to-hospital time, hours†|| || ||0.37 (0.05–2.73)||0.332|| || |
|Home-to-hospital distance, kms†|| || ||2.62 (0.91–7.54)||0.073|| || |
| Day||23/291||12.0 (7.4–16.6)||Reference||0.196|| || |
| Night||6/57||10.5 (2.5–11.3)||0.55 (0.22–1.36)|| || || |
| Leg||22/200||11.6 (6.7–15.3)||Reference||0.658|| || |
| Arm||7/77||10.0 (3.3–16.7)||0.82 (0.35–1.93)|| || || |
| Absent||3/124||2.4 (0.1–4.9)||Reference||0.001||6.51 (1.94–21.77)||0.002|
| Present||26/153||17.0 (11.0–22.9)||7.40 (2.23–23.45)|| || || |
| Absent||12/189||6.3 (2.83–9.76)||Reference||0.013||3.15 (1.45–6.58)||0.004|
| Present||17/88||19.3 (11.1–27.5)||2.56 (1.21–5.38)|| || || |
| Absent||13/93||13.8 (6.8–20.8)||Reference||0.052|| || |
| Present||16/84||19.0 (10.6–27.3)||2.09 (0.99–4.40)|| || || |
| Abnormal||26/227||11.4 (7.3–15.5)||Reference||0.281|| || |
| Normal||3/50||6.0 (0.5–12.6)||1.83 (0.55–6.06)|| || || |
|Serum creatinine (mg/dl)†‡|| || ||1.37 (1.21–1.55)||<0.001||1.35 (1.17–1.56)||<0.001|
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).
Figure 2. Kaplan–Meier survival probability estimates for time from hospital admission to mortality in 277 patients with venomous snake bites. (Panel A) vomiting and (Panel B) neurotoxicity. Neuro indicates neurotoxicity.
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- Top of page
- Materials and methods
- Determinants of fatal outcome
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.