1. ENVENOMING CAUSED BY BRAZILIAN SNAKES BENEDITO BARRAVIERA Full Professor of Tropical Diseases Botucatu Medical School - UNESP Research from The Center for the Study of Venoms and Venomous Animals – CEVAP São Paulo State University - UNESP - Brazil 3rd INTERNATIONAL CONFERENCE ON NATURAL TOXINS CAIRO - Police Club Al-Gezera - December, 16 - 18, 2008

2. CONTENTS 1-The São Paulo State University history; 2-The Center for the Study of Venoms and Venomous Animals – CEVAP – facilities; 3-Main Brazilian venomous and nonvenomous snakes; 4-Classification and Epidemiology; 5-Clinical manifestations and physiopathology; 6-Management of snakebite.

6. São Paulo State University campuses

7. São Paulo State University – UNESP Based in São Paulo city Supported by São Paulo State Government Annual Budget – U$ 750,000,000 / year UNESP has 23 University Campuses (32 Colleges, 7 Research Centers and 3 Technical schools) 168 Undergraduate courses – 33,472 students 108 Graduate courses – 13,119 students 3,354 Professors and Researchers 6,837 Employees 30 Libraries, 5 Farms, 2 Medical Hospitals, 3 Veterinary Hospitals and 1,900 Research and Teaching laboratories

9. The Center for the Study of Venoms and Venomous Animals – CEVAP CEVAP was created in 1993. It is based at Lageado Experimental Farm adjoining Botucatu School of Agronomical Sciences. It is a Research Institution focusing Toxinology. The multicampus structure of UNESP allows the interaction among Learning, Research, Continuing education and Extension.

10. The Center for the Study of Venoms and Venomous Animals – CEVAP CEVAP count on the following partners: Botucatu Medical School, Botucatu School of Veterinary Medicine and Animal Husbandry, Botucatu and Rio Claro Institute of Biosciences and Araraquara School of Pharmaceutical Sciences. Total farm area – 2,000 hectares (600 hectares of native forests).

11. The Center for the Study of Venoms and Venomous Animals - CEVAP

13. CEVAP Laboratories and Serpentariums

14. Serpentariums Extension activities

15. MAIN BRAZILIAN SNAKES From Public Health point of view 1-Venomous snakes (about 58 species) Viperidae family – Bothrops sp (28 species) Crotalus sp (6 sub-species) Lachesis sp (2 species) Elapidae family – Micrurus sp (22 species) 2-Nonvenomous snakes (about 250 species) Boidae family - Boa constrictor, Eunectus murinus, Corallus caninus, Epicrates cenchria (11 species) Colubridae family – Clelia clelia, Liophis frenatus, Philodryas olfersii, Dipsas albifrons, Spilotis pullatus, Waglerophis merremii, Mastigodryas bifossatus, etc. (239 species)

16. MAIN BRAZILIAN VENOMOUS SNAKES Viperidae family – Bothrops sp – Bothrops jararaca, B. alternatus, B. moojeni, B. atrox (from Amazon region), B. cotiara, B. erytromelas, etc. -Responsible for 80 to 90% of accidents in Brazil -Crotalus sp – Crotalus durissus terrificus, C. d. collilineatus, C. d. marajoensis, C. d. cascavella, C. d. trigonicus, C. d. ruruima -Responsible for 10 to 20% of accidents in Brazil -Lachesis sp – Lachesis muta muta, Lachesis muta rhombeata -Responsible for 3% of accidents in the Amazon region - Brazil.

17. Bothrops jararaca Bothrops alternatus Bothrops moojeni Bothrops sp distribution

18. Bothrops moojeni

19. Crotalus sp distribution Crotalus durissus terrificus (South American rattlesnake)

20. Crotalus durissus terrificus

21. MAIN BRAZILIAN VENOMOUS SNAKES IN AMAZON REGION

22. MAIN BRAZILIAN VENOMOUS SNAKES IN THE AMAZON REGION Bothrops atrox * Bothrops brazili Bothriopsis bilineata Bothriopsis teniata Lachesis muta muta *

23. MAIN BRAZILIAN VENOMOUS SNAKES IN THE AMAZON REGION Lachesis muta muta Bothriopsis bilineata Bothrops atrox

24. Lachesis muta muta

25. MAIN BRAZILIAN VENOMOUS SNAKES Elapidae family -Micrurus sp – Micrurus frontalis, M. corallinus, M. paraensis, M. spixii, M. filiforms, etc. -Responsible for less than 1% of accidents in Brazil Micrurus corallinus

26. Micrurus sp distribution Micrurus frontalis

27. Boa constrictor Corallus caninus Eunectus murinus Boidae family Nonvenomous snakes

28. Colubridae family Nonvenomous snakes Spilotes pullatus Liophis miliaris Philodryas olfersii

29. Accidents caused by venomous animals in Brazil Snakes – 30,000/year Scorpions – 35,000/year Spiders – 19,500/year Bees and wasps – 1,500/year Catterpilars – 500/year São Paulo State – 2,000/year Botucatu – 100/year EPIDEMIOLOGY

30. Main season Summer – from December to March Patient´s characteristics Rural workers, Male (74.84%), 15 to 49 years old, lower limbs (62.75%) Snakes characteristics 87.33% Bothrops sp envenoming 7.43% Crotalus sp envenoming 1.37% Lachesis sp envenoming 0.41% Micrurus sp envenoming The Amazon region – 3,000 cases/year 90% Bothrops sp envenoming 10% Lachesis sp and others EPIDEMIOLOGY

31. Bothropic envenoming Clinical aspects Venom activity – Bothrops sp 1-Coagulative activity – cause bleeding and clotting disturbances Patient with severe gingival bleeding Bothrops alternatus

32. Mild bothropic envenomings Bothrops alternatus Bothropic envenoming Clinical aspects Venom activity – Bothrops sp 2-Citotoxic venom activity – citotoxicity - capacity to destroy tissues

33. Venom activity – Bothrops sp 2-Citotoxic venom activity – citotoxicity - capacity to destroy tissues Bothrops alternatus Moderate bothropic envenomings Bothropic envenoming Clinical aspects

34. Severe bothropic envenomings Bothrops alternatus Bothropic envenoming Clinical aspects Venom activity – Bothrops sp 2-Citotoxic venom activity – citotoxicity - capacity to destroy tissues

35. Venom activity – Bothrops sp 3-Hemorrhaging activity – spontaneous hemorrhage by damaging vascular endothelium Patients develop local or distant hemorrhage Bothrops alternatus Bothropic envenoming Clinical aspects

36. Venom activity – Crotalus sp 1-Neurotoxic activity – neurotoxic symptoms Crotalic envenoming Clinical aspects Crotalus durissus terrificus Midriasis Local bite Ptosis, Diplopia and blurred vision

37. Crotalic envenoming Clinical aspects Crotalus durissus terrificus Rhabdomyolysis Increase of CPK, DHL, AST and ALT enzymes Myoglobinuria Venom activity – Crotalus sp 2-Systemic rhabdomyolyses – skeletal muscle

38. Crotalic envenoming Clinical aspects Crotalus durissus terrificus Tubular necrosis causing renal failure Venom activity – Crotalus sp 3-Renal failure

39. Crotalic envenoming Clinical aspects Crotalus durissus terrificus Liver cells with mitochondrial edema Increase of Alanine aminotransferase enzyme Liver necrosis Venom activity – Crotalus sp 4-Liver toxicity Liver with edema

40. Lachetic envenoming Clinical aspects Venom activities – like Bothrops sp 1-Coagulative – cause bleeding and clotting disturbances 2-Citotoxic – citotoxicity - capacity to destroy tissues 3-Hemorrhaging – spontaneous hemorrhage by damaging vascular endothelium 4-Neurotoxic – bradicardia, diarrhea and arterial hipotension including shock

41. Elapidic envenoming Clinical aspects This venom - low molecular weight neurotoxins - neurotoxic facial expression (bilateral ptosis) - respiratory muscle paralysis. The most severe Brazilian ophidic accident! Micrurus corallinus Neurotoxic facial expression

42. MANAGEMENT OF THE SNAKEBITE “The early specialized medical assistance is essential to the evolution and prognosis of the patient” “All victims should be hospitalized and observed for at least 24 hours”

43. Tetanus immunoprophylaxis is recommended. Make the patient rest. If possible, wash the bite area with soap and water; Go to nearest hospital or medical facility as soon as possible where there is antivenom to be applied; Keep the bitten extremity above the level of the heart ; If possible, try to identify the snake and take it to the hospital; Tetanus immunoprophylaxis is recommended. What to DO immediately ?

44. No ice or any other type of cooling on the bite. Research has shown this to be potentially harmful; No tourniquets. This cuts blood flow completely and may result in loss of the affected limb; No electric shock. This method is under study and has yet to be proven effective. It could harm the victim; No incisions, no suction in the wound. Such measures have not been proven useful and may cause infection and persistent bleeding; Do not give beverages (alcohol or any other drink). What NOT to do

45. SPECIFIC ANTIVENOM TREATMENT Viperidae family Bothrops sp -Mild accident - 4 (100 mg) antibotropic venom ampules by intravenous route without allergic test; -Moderate accident - 8 (200 mg) antibotropic venom ampules by intravenous route without allergic test; -Severe accident - 12 (300 mg) antibotropic venom ampules by intravenous route without allergic test.

46. immunoprophylaxis. 1-Hospitalize the patient for at least 24 hours; 2-Make the Clotting Test after 12 hours to evaluate the clotting disturbance and indicate, if necessary, more antivenom; 3-Clean and wash the bite region; 4-Hydrate by intravenous route; 5-Give antibiotic prophylaxis with cefuroxime 125 to 250 mg twice a day; 6-Recommend tetanus immunoprophylaxis. SUPPORTIVE TREATMENT

47. SPECIFIC ANTIVENOM TREATMENT Viperidae family Crotalus sp -Mild accident - 10 (100 mg) anticrotalic venom ampules by intravenous route without allergic test; -Moderate accident - 20 (200 mg) anticrotalic venom ampules by intravenous route without allergic test; -Severe accident - 30 (300 mg) anticrotalic venom ampules by intravenous route without allergic test.

48. immunoprophylaxis; 7-If renal failure occurs hemodyalisis. 1-Hospitalize the patient for at least 24 hours; 2-Make Clotting Test after 12 hours to evaluate clotting disturbance and indicate, if necessary, more antivenom; 3-Clean and wash the bite region; 4-Hidrate to prevent renal failure with Manitol 20%, four times a day for at least 5 days. 5-Increase pH with Sodium bicarbonate 5%, 50 ml by oral route, four times a day. 5-Give antibiotic prophylaxis – cefuroxime 125 to 250 mg twice a day, for 5 to 7 days; 6-Indicate tetanus immunoprophylaxis; 7-If renal failure occurs hemodyalisis. SUPPORTIVE TREATMENT

49. SPECIFIC ANTIVENOM TREATMENT Viperidae family Lachesis sp Apply 10 to 20 antilachetic or antibotropic/lachetic venom ampules by intravenous route without allergic test; Supportive treatment = Bothrops sp; These accidents the Amazon region.

50. SPECIFIC ANTIVENOM TREATMENT Elapidade family Micrurus sp Apply 10 (150 mg) antielapidic venom ampules by intravenous route without allergic test; Supportive treatment to prevent neurotoxic effects Respiratory paralysis Atropine, neostigmine and edrophonium chloride are indicated. Less than 1% of accidents occur in Brazil every year.

51. Prevention of Antivenom Reactions according to Health Ministry -Pre-medication - 10 to 15 minutes before antivenom treatment; -Dextroclorfeniramine (Polaramine®) – 0.08 or Prometazine (Fenergan®) – 0.6 mg/Kg mg/Kg by intramuscular route; -Hidrocortisone (Solu-cortef®) – 10 mg/Kg by intravenous route;

52. Prevention of Antivenom Reactions according to Health Ministry - Cimetidine (Tagamet®) – 10 mg/Kg or Ranitidine (Antak®) – 2 mg/Kg by intravenous route -Antivenom, without dilution, for 15 to 30 minutes, by intravenous route without allergic test; “Medical supervision must be continuous during antivenom administration”

53. NONVENOMOUS SNAKE ACCIDENTS Boidae family No envenomation Wash the bite area with soap and water; Inform the patient that antivenom treatment is not necessary. Accident with Boa constrictor

54. NONVENOMOUS SNAKE ACCIDENTS Colubridae family -Rare envenomation; -Rare pain and local swelling; -Rare partial defibrination; -Controversial antibotropic treatment. Envenomation by Philodryas olfersii

55. December

58. Our thankful homage to all of you!

59. This lecture is available at: http://www.barraviera.med.br Email bbviera@jvat.org.br bbviera@gnosis.com.br Thank you very much!