SNAKEBITE ENVENOMATION AND DEATH IN THE DEVELOPING WORLD The purpose of this review is to address the Luzia S. Cruz, MD; Roberto Vargas, MD, MPH; global incidence and management of snake- Antoˆnio Alberto Lopes, MD, MPH, PhD bite envenomation and to describe the clinical characteristics and pathogenesis of envenom- ation by species of the family Viperidae, genera Bothrops and Crotalus, the most INTRODUCTION bite envenomation are reported each common venomous snakes in Brazil. We focus year, with an estimated 35,000–50,000 15,24 on the pathogenesis of the acute renal failure Envenoming from poisonous ani- deaths. In Pakistan, there are 24 induced by these snakes. Envenomation after mals, particularly terrestrial venomous <20,000 snakebite deaths annually. snakebite is an underestimated and neglected In Nepal, there are an estimated 20,000 public health issue responsible for substantial snakes, causes substantial illness and illness and death as well as socioeconomic death and represents an economic snakebites and <200 deaths in hospitals hardship to impoverished populations living in hardship on poor, rural populations annually, predominantly in the eastern 4,24 rural and tropical Africa, Asia, Oceania, and and healthcare systems of tropical and Terai. In Vietnam, from 1992 to Latin America. In developed nations, snake subtropical Africa, Asia, Oceania, and 1998, there were an estimated 300,000 bite typically occurs during recreational activ- 1–25 ities, whereas in developing countries it is an Latin America. Although mortality bites per year, and a case fatality ratio of occupational disease more likely to affect from snakebite is estimated to be one- 22% was reported among plantation young agricultural workers, predominantly tenth that of malaria, no equivalent workers bitten by Malayan pit vipers.24 men. Scarcity and delay of administration of global snakebite control program exists. In Mynamar, there were 14,000 bites antivenom, poor health services, and difficul- 24 An international effort is necessary to and 1,000 deaths in 1991. Papua New ties with transportation from rural areas to health centers are major factors that contribute focus global attention on this neglected Guinea has one of the world’s highest 17 17 to the high case-fatality ratio of snakebite and treatable condition. incidence rates of snake bites. In envenomation. (Ethn Dis. 2009;19[Suppl The World Health Organization Africa, the annual incidence rate of 1]:S1-42–S1-46) (WHO) estimates that <2,500,000 snake bites in the Benue Valley of northeastern Nigeria is 497 per Key Words: Snakebite Envenomation, Epi- venomous snakebites per year result in demiology, Pathogenesis, Acute Renal Failure, 125,000 deaths worldwide, 100,000 of 100,000 population, with a case-fatality 4 Clinical Characteristics, Bothrops, Crotalus, which are in Asia and approximately ratio of 12.2%. In northern Africa, the Treatment 20,000 in Africa.5,6 The true global species that causes most bites and deaths incidence of envenomation and its belongs to the family Viperidae, Echis sp severity remain largely misunderstood. (saw-scaled vipers), whereas in Asia Hospital-based data are likely to under- most frequent envenomations result estimate the incidence, the case-fatality from bites by species of the Elapidae ratio, and the overall contribution family, represented by the Naja sp snakebites make to worldwide morbid- (cobras) and Bungarus sp (kraits). In ity and mortality because most victims Central and South America, bites by seek traditional treatment; these victims Bothrops asper and Bothrops atrox (lance- may die at home and their deaths headed pit vipers) predominate.4 In remain unrecorded.4,21 Brazil, the most severe cases of snakebite The objectives of this review are to result from envenomation inflicted by describe the worldwide incidence and species of the family Viperidae, genera treatment of snakebite envenomation, as Bothrops and Crotalus (South American well as clinical characteristics and the rattlesnake). From 1990 to 1993, the From the CLINIRIM, Clı´nica do Rim e pathogenesis of common venomous Brazilian Ministry of Health reported Hipertensa˜o Arterial Ltda (LSC), Medicine snakebites in Brazil. 65,911 snakebites.1 Bites by snakes of Department, Nephrology Service and Epi- genus Bothrops were responsible for demiology Unit, Federal University of Bahia 90.5%, and bites by Crotalus rattle- (AAL), Salvador, Bahia, Brazil; Department of Medicine, Geffen School of Medicine, EPIDEMIOLOGY snakes accounted for 7.7% of these. 26 University of California at Los Angeles and Bucaretchi et al analyzed hospital RAND Institute, Los Angeles, California (RV). Approximately 3000 species of records of 73 children aged ,15 years snakes exist worldwide, and 410 are who were bitten by Bothrops sp snakes in Address correspondence and reprint 18 Sa˜o Paulo, Brazil, from January 1984 requests to: Luzia S. Cruz, MD; 1845 considered venomous. The reported Mallard Dr; Panama City, FL 32404; 850- rate of bites from these snakes is high. In through March 1999. Most bites oc- 871-2684; [email protected] India alone, .200,000 cases of snake- curred from October to March, which S1-42 Ethnicity & Disease, Volume 19, Spring 2009 SNAKE BITE ENVENOMATION - Cruz et al reflects the influence of seasonal factors, consequence, consumption coagulopa- nephrotoxic, leading to acute tubular such as an increase in temperature and thy and partial or complete blood necrosis, the primary and most serious humidity associated with the rainy incoagulability may develop. Envenom- complication of human crotalid enven- season, and also in human agricultural ing by Bothrops sp inflicts severe tissue omation.5,10,13,37–39 Tissue damage at activities, such as planting and harvest- damage, such as swelling, blistering, the site of the bite has been reported to ing. Bothrops jararaca, the most com- hemorrhage, and necrosis of skeletal be minimal or absent, a feature that mon species of Bothrops in southeast muscle. Systemic effects include spon- differentiates the South American rat- Brazil, which was responsible for most taneous hemorrhage (of which cerebral tlesnake from other species of Crotalus. snake bites in this study, is more active hemorrhage is the most serious mani- Spontaneous bleeding has only been during this season and in the evening. festation), disseminated intravascular rarely observed in human patients.1,10,18 The rise in river levels due to tropical coagulation, and cardiovascular shock A prospective survey of 100 cases of rains may cause an inland migration of secondary to hypovolemia and vasodi- C. durissus bites followed from hospi- these snakes.3 lation,1–3,7,16,26,29,34 Bothrops jararaca talization to death or discharge in Sa˜o In developed countries, venomous venom is a potent inhibitor of angio- Paulo, Brazil, revealed a high prevalence snakebites frequently occur during rec- tensin-converting enzyme (ACE) and of acute renal failure (ARF) (29%), reational activities, whereas in the potentiates the hypotensive effect of defined as a creatinine clearance developing world, snakebite is an occu- circulating bradykinin. Murayama et al ,60 mL/min/1.73 m2 in the first pational disease more likely to affect cloned and sequenced cDNA isolated 72 hours after the bite.5 Most cases of young agricultural workers, predomi- from the Bothrops jararaca venom ARF were nonoliguric, and the frac- nantly men.3,8,18,20 The high case- gland; it encodes 2 distinct classes of tional excretion of sodium was signifi- fatality ratio of snakebites in tropical bioactive peptides, bradykinin-potenti- cantly higher in ARF patients. Age developing countries is the result of a ating oligopeptides and a C-type natri- ,12 years was an independent risk combination of factors, including the uretic peptide, which display synergistic factor for ARF, which may be related scarcity of antivenom, poor health effects on blood pressure and most to an increased concentration of the services, and problems with transporta- likely contribute to the cardiovascular venom and a more severe clinical tion from rural areas to health cen- effects caused by Bothrops jararaca picture as a result of a lower blood ters.4,17,19–23,27,28 envenomation.35,36 volume and smaller body surface in children. The case fatality ratio was Crotalus (South 10%. The most important finding in CLINICAL American Rattlesnake) the study was that delay in administer- CHARACTERISTICS Among the species of Crotalus, ing an adequate dose of the crotalid AND PATHOGENESIS Crotalus durissus terrificus is the most antivenom increased the risk of ARF by frequently implicated in envenomation more than 10 times. Therefore, Burd- This section primarily focuses on the in Brazil. The venom of C d terrificus mann et al suggest that antivenom major clinical characteristics and the contains a variety of toxic peptides, should be available in health centers pathogenesis of envenomation by select- including crotoxin, crotamine, giroxin, and emergency services of small com- ed species of snakes that are highly convulxin, and a thrombin-like enzyme. munities rather than concentrated in prevalent in Brazil. Crotoxin is responsible for the high urban reference hospitals. toxicity of the venom and has neuro- Bothrops sp (Lance-headed toxic, myotoxic, and nephrotoxic activ- Pit Vipers) ity. It is a powerful presynaptic neuro- PATHOGENESIS OF Bothrops venom contains various toxin that targets neuromuscular SNAKEBITE-INDUCED ARF biologically active peptides, such as junctions and inhibits the release