Variability of Polyvalent ASV efficacy Clinical experience of Christian Medical College, Vellore & Government Vellore Medical College 1

Introduction Variability of ASV efficacy Batch to batch variability Inadequate antibody titre Quality control Species variability Lack of Ab to specific proteins - Geographical intra-species venom variation Adequate Antibody - ineffective - Ab cannot neutralise tissue bound venom protein - Irreversible tissue damage 2

Objectives Variability of anti-snake venom efficacy 1. Specific snake species/clinical syndromes 2.Batch to Batch variability 3

Profile of snake bites in Vellore Government Vellore Medical College Free treatment Liquid ASV Christian Medical College Advanced ICU and Dialysis Lyophilised ASV 4 9 monthsGVMCCMC Number27375 Venomous46.5%93.3%

5 What is the variability of ASV efficacy between clinical envenomation syndromes? Big 4 species Clinical syndromes Saw Scaled ViperLocal signs and Bleeding Russell’s viper Russells’ viper Local signs and Bleeding +/- Paralysis & Renal Failure Indian Cobra Local signs and Paralysis Common Krait No Local signs and Paralysis Study of 31 dead snakes confirmed the specificity of syndromes

Comparison of effectiveness of ASV between the four clinical syndromes Indices of variability of efficacy of ASV 1.Death rate 2.ASV requirement 3.Rates of mechanical ventilation 4.Rates of dialysis 5.Rate of blood transfusion Increase in these indices suggests relative ineffectiveness of ASV 6

Venomous bites-Syndrome distribution SyndromeGVMC (%)CMC (%)Total (%) Cobra34 (26.8)5 (7.5)39 (20.1) Krait12 (9.4)4 (6)16 (8.2) RV39 (30.7)39 (58.2)78 (40.2) Haem42 (33.1)19 (28.3)61 (31.4) Total % 30% 70% Viperidae 30% Elapidae

Deaths according to clinical syndrome Syndr GVMC Death CMC Death Total Cobr 202 Krait 404 RV Haem Number of deaths GVMC & CMC Krait and Russell’s viper syndrome Had highest mortality rate

Average ASV dose - Envenomation syndrome 9 Highest ASV dose GVMC - Cobra, Russell’s viper and Krait CMC - Russell’s viper

Rate of ventilation according to syndrome 10 Proportion ventilated greater in Krait syndrome compared to Cobra syndrome

Viperidae syndrome Rate of dialysis and blood transfusion 11 Russell’s viper syndrome greater requirement for dialysis and transfusion compared to pure haemotoxic syndrome

Conclusion ViperidaeElapidae MORE EFFECTIVESAW SCALED VIPERINDIAN COBRA LESS EFFECTIVERUSSELL’S VIPERCOMMON KRAIT Increased Death rate Requirement of transfusion & dialysis Increased death rate Requirement of mechanical ventilation Relative ineffectiveness of ASV for Russell’s viper bite and Common Krait bite 12

13 Anti-snake venom efficacy Batch to batch variation

GVMC- Deaths No. Venom. Bites 14 No. Of Deaths

GVMC- Deaths BATCH 1-6 BATCH 7-9 BATCH 2- 4,6 BATCH 1, 4, 8, 11 ASV Batch 15 No. Of Deaths No. Venom. Bites

ASV Batch specific deaths ASV batchNo. Ven. bitesNo. Deaths (%) (13%) (15%) 754 (80%) 8314 (13%) 9142 (14%)

Categories of ASV inefficacy 1.High efficacy - 6 batches 2. Intermediate efficacy - 4 batches 3. Low efficacy - 1 batch No mortality Mortality 10-15% High mortality 80% 17 MORE EFFICACY LESS EFFICACY More efficacy ASV Batch 1-3, 5, Less efficacy ASV Batch 4,6-9

ASV batch efficacy Syndrome distribution and mortality Syndrome More efficacy ASV (n) Less efficacy ASV Deaths (%) Cobra5252 (8%) Krait1104 (40%) RV (36%) Haemo8253 (12%) Total Distribution of syndromes similar in more & less efficacy ASV Patients given less efficacy ASV died of all syndromes Inefficacy to Krait & Russell’s viper syndrome demonstrated only with less efficacy ASV

ASV batch efficacy-Complication rate Syndrome More efficacy ASV N= 24 Less efficacy ASV N= 88 Ventilation n (%) Cobra01 (4%) Krait04 (40%) Dialysis n (%) RV02 (7%) Haem02 (8%) Transfusion n (%) RV2 (20%)6 (21%) Haem07 (28%) 19 More efficacy ASV protected against syndrome complications

Treatment variables According to ASV batches- deaths and no deaths Treatment variables More efficacy ASV (24) Less efficacy ASV (88) Prior treatment (%) 18 (75%)66 (75%) ASV allergy n (%)7 (29%)15 (17%) ASV requirement (no. vials/patient) Death in 48 hours n (%) 013 (68%) 20 Greater deaths in less efficacy ASV was not due to delayed treatment, ASV allergy, inadequate ASV or late complications

Batch to batch efficacy Conclusions Different batches demonstrated clinical efficacy ranging from high efficacy to low efficacy Deaths occurred due to all syndromes in low efficacy ASV Inefficacy to Russell’s viper and Krait syndrome (deaths and complications) was shown with low efficacy ASV High efficacy ASV protected against death and complications The withdrawal of specific ASV batches was associated with fall in mortality 21

Variability of ASV efficacy Interactions BATCH TO BATCH VARIABILITY HIGH EFFICACY ASV LOW EFFICACY ASV SYNDROME RELATED VARIAIBLITY PROTECTION AGAINST ALL SYNDROMES MORE EFFECTIVE COBRA & PURE HAEMOTOXIC LESS EFFECTIVE RV & KRAIT SYNDROME DEATH RATE & COMPLICATION LOWHIGH 22

Further studies Need for laboratory tests to evaluate the quality of ASV in hospitals managing snake bites Need to study the biological basis of variable ASV efficacy - Venom protein profiles in the serum - Adequacy of specific antibodies to toxin venom proteins These studies may provide a basis for an improved anti-venom and dose finding treatment 23

CMC Team Department of Medicine Neurochemistry lab Cochrane centre Dept of Forensic Medicine Government Vellore Medical College Department of Medicine