Snakebite is an important preventable health hazard.

Transcription

1 Original Article Rational Use of Anti-snake Venom (ASV) : Trial of Various Regimens in Hemotoxic Snake Envenomation J Srimannarayana*, TK Dutta*, A Sahai**, S Badrinath*** Abstract Background : Viperine snake bites cause hemotoxicity in the form of coagulation dysfunction. Optimal dose requirement of anti-snake venom (ASV) and duration of therapy in such situation have not yet been fully explored. Our aim in this study was to compare two low-dose continuous infusion regimes with the standard high dose intermittent bolus regime in treating systemic envenomation and preventing its recurrence. Methods : A prospective interventional study was conducted on 90 adult patients with snake bite with hemotoxicity. Patents were allocated into three treatment regimes, each regime being tried on 30 patients. Regimen I (standard high dose regimen) consisted of conventional, intermittent bolus dosage of 100 ml of ASV as a loading dose followed by 50 ml every six hours till whole blood coagulation time (CT) became normal. Regimen II consisted of 30 ml of ASV as a loading dose followed by 30 ml continuous infusion every six hours till two CTs at an interval of six hours were normal and a further dose of 30ml over 24 hours. Regimen III was similar to Regimen II in all aspects except that loading dose was 70 ml (instead of 30 ml). Results : In patients with mild envenomation, even though the average requirement of ASV was only marginally lower in Regimen II (128.6 ml) as compared to in Regimen I (137.5 ml), one patient on Regimen I had relapse of coagulation dysfunction. In patients with moderate envenomation, average requirement of ASV was ml and 179 ml in Regimens II and III respectively, which was much less than in Regimen I (343.8 ml) (p values 0.05 and 0.01 respectively). Further, no patient receiving Regimen III had relapse of coagulation dysfunction. In severe envenomation, average dose of ASV required was almost similar in Regimens II and III, i.e., ml and ml respectively, as compared to ml required in Regimen I (p values 0.02 and respectively). However, time lapse for CT normalization was only 18 hours in Regimen III as compared to 23.6 hours and 24 hours in Regimens I and II respectively. Conclusion : Regimens consisting of continuous intravenous infusion of ASV i.e., Regimen II in mild envenomation and Regimen III in moderate and severe envenomation are likely to make significant saving of ASV and reduction of recurrence of coagulation dysfunction. INTRODUCTION Snakebite is an important preventable health hazard. Patients with snake envenomation present as emergencies with significant morbidity and mortality. Viperine bites with Echis carinatus species particularly are extremely common in areas in and around Pondicherry and they present with hemotoxicity, in form of various degrees of coagulation *Department of Medicine; **Department of Preventive and Social Medicine; ***Ex-Medical Superintendent, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry. Received : ; Revised : ; Accepted : dysfunction (ranging from mild prolongation of whole blood clotting time [CT] to incoagulable blood with severe bleeding manifestations) following systemic envenomation. 1 Russell s viper bite is also encountered from time to time. The mortality in such cases may be, importantly, due to uncontrolled bleeding because of primary fibrinolysis (PF) or disseminated intravascular coagulopathy (DIC), 2 or renal failure resulting from DIC or direct nephrotoxicity. 1 The issue which confronts the physician when attending to a patient with snakebite is assessment of degree of systemic envenomation and decision on dose of anti-snake venom (ASV). The presently available polyvalent anti-snake venom JAPI VOL. 52 OCTOBER 2004

2 (ASV), one effective against bites due to common neurotoxic and hematotoxic snakes of India, is expensive (present cost of one vial of 10 ml of ASV of Serum Institute of India is Rs. 375/-), scarce - especially in high-risk areas, and may be associated with allergic reaction to serum. 3 However, it is the cornerstone in management of snakebite, even though the optimal dose, frequency and mode of administration and duration of therapy remain unclear. 4-9 There are only a few trials from India which address these questions Accurate optimization of therapy, we believe, may lead to a reduction in the dose. Delivery of ASV by continuous intravenous infusion is the best way to exactly titrate the dose of ASV and is likely to reduce the total dose of ASV vis-à-vis the presently practiced method of intermittent delivery of bolus doses. After correction of coagulopathy (blood CT), extra dose of ASV is given to prevent relapse of coagulation dysfunction due to late envenoming. 11,12 We felt continuous intravenous infusion method of ASV requires further evaluation with regard to its dosage in various degrees of coagulation dysfunction. Ho observed recurrence of bleeding in 26% of their cases. 13 Duration of such relapse in their studies varied from 12 to 72 hours. However, relapse can occur as long as 130 hours after initial correction. 14 Authors of this work also felt, relapses could be prevented by giving extra dose of ASV after full correction of CT. Keeping all the above-mentioned issues in mind, this study was conducted. MATERIAL AND METHODS This was a prospective interventional study on 90 patients, and involved three groups of patients, each of thirty. The study was conducted in a large teaching hospital of South India. The period of study was two years. Adult patients aged 13 years with snakebite with systemic signs of coagulation dysfunction, as evidenced by whole blood clotting time (CT) of 11 minutes (with or without bleeding manifestation) were only included in the study. 1,2 Severity of coagulation dysfunction due to systemic envenomation (mild, moderate and severe) was graded according to the degree of CT prolongation, 15 i.e. mild: minutes, moderate: minutes and severe: incoagulable blood, respectively. Coagulation dysfunction was graded to see the relative requirement of ASV. Patient allocation (Table 1) : There are four medical units in this hospital. Two of the authors were directly in charge of one of the units i.e. Unit III. Other units were under the charge of other consultants. Thus, Unit III was chosen for trial of new low-dose regimes. Conventional regime was followed in other units. Three study groups, as follows, were formed. Thirty consecutive patients from other units formed Group I (Conventional high dose regime group). Sixty consecutive adult snakebite patients with hemotoxicity from Medicine Unit III (parent unit where two of the authors were directly incharge of the patients) were randomized into groups II and III using a randomization table. ASV was administered as mentioned in Table 1. Groups I, II and III received regimens I, II and III respectively. Two extra doses of 30 ml of ASV in Regimens II and III were given to prevent recurrence of coagulation dysfunction/ bleeding. Authors earlier experience had shown one extra dose was often not enough. Acute renal failure (ARF) was diagnosed when there was acute rise in serum creatinine to >2.0 mg/dl. 1 Patients with ARF were managed with fluid challenge and hemodialysis, wherever indicated. The study was approved by the Institute Ethics Committee and informed consent was obtained from each patient. Continuous variables were expressed as mean ± standard deviation and the discrete variables as percentage. One-way ANOVA was used to test the overall significance. The chisquare test with appropriate modifications (Yates correction or Fisher s exact test) was used to examine the significance of difference between the proportions (nominal data). The Student s t test was employed to find out the significance of difference between the means (numerical data). OBSERVATIONS The mean age of the studied patients was 33.9, 32.8 and 32.4 years in groups I, II and III respectively. Most of the patients were males and were agricultural labourers. All our patients were from in and around Pondicherry. Approximately four of five patients had the bite on one of the lower limbs. The mean bite to needle time (time taken from bite to the first dose of ASV received) was 18.3 hours; only one-third of patients presented within six hours of bite. The mean bite to needle time was 18.1 hours, 19.6 hours and 17.4 hours in groups I, II and III respectively. 26.7%, 30% and 30% of patients in groups I, II and III respectively reached the hospital after 24 hours of snakebite. Hematuria and hematemesis were the common systemic clinical manifestations of hemotoxicity observed in 31(34.4%) and 34 (37.7%) patients respectively. Other important clinical Table 1 : Different regimens of ASV used in the study Regimens Loading Dose Followed By End-Point Regimen I (Conventional High Dose Regimen) 100 ml 50 ml Q 6 Hours Till CT normalizes n=30 Regimen II (Low Dose Regimen) 30 ml 30 ml infusion over 6 hours, every 6 Till 24 hours after n=30 hours till CT normal twice at an the CT Regimen III (Low Dose Regimen) interval of 6 hours, followed by normalizes n=30 70 ml 30 ml of ASV infusion over 24 hours twice Note: Same regimen was repeated in case of relapse. JAPI VOL. 52 OCTOBER

3 ASV Therapy 90 Patients Regime I Regime II Regime III (30 patients) (30 patients) (30 patients) 100 ml bolus 30ml bolus 70ml bolus ml 6hrly 30 ml cont. infusn. 6hrl 30 ml cont. infusn. 6hrly Average CT (at presentation) 26.2 ± 5.64mins ± 6.51mins. 25 ± 5.88 mins. ASV dose 376 ± ml ± 76.4 ml ± 43.6 ml required* (95% CI: ml ml) (95% CI: ml ml) (95% CI: ml ml ) Adverse reaction 8 (26.67%) 3 (10%) 5 (16.67%) Time lapse for CT ± 9.61 hrs ± 9.84 hrs 13.4 ± 7.16 hrs normalization** (95% CI: hrs hrs) (95% CI: hrs hrs) (95% CI: hrs hrs) Recurrence 8 (26.67%) 5 (16.67%) 4 (13.33%) Outcome Cured Death Cured Death Cured Death 21 (70%) 9 (30%) 25 (83.3%) 5 (16.7%) 24 (80%) 6 (20%) *p value between Regimen I and Regimen II < ; *p value between Regimen I and Regimen III < ; **p value between Regimen I and Regimen III < Fig. 1 : Flowchart.. observation was oliguria due to ARF in approximately 50% of cases (47 patients). All patients had local swelling (swelling at the site of bite). Fifteen (16.7%) and 34 (37.7%) patients had presented with signs of mild and moderate envenomation respectively, whereas forty one (45.6%) patients presented with signs of severe envenomation (incoagulable blood). The average requirement of ASV, time lapse for CT normalization, incidence of adverse reaction and recurrence of coagulation dysfunction in various groups are shown in flow chart (Fig. 1). Adverse ASV reactions were mainly in form of itching, urticaria, and erythema; and responded to antihistaminics and hydrocortisone. Three patients, however, developed hypotension and required adrenaline. Characteristics of patients with mild, moderate and severe envenomation are shown elaborately in Tables 2, 3 and 4 respectively. About half of the total patients developed acute renal failure [17 (56.7%), 15 (50%) and 15 (50%) patients in groups I, II and III respectively]. While only 10 (35.7%) of 28 patients who arrived within six hours of bite developed ARF, the incidence of ARF among the patients who arrived after 24 hours was 80.7% (21/26 patients) (p value <0.001). Later the arrival to hospital more was the incidence of ARF. Table 2 : Characteristics of patients with mild envenomation (clotting time min) (n=15) Parameter Regimen I Regimen II Regimen III No. of patients Bite to needle 17 ± ± ± 9.6 time (hours) Average CT (min) ± ± ± 0.0 Average dose ± ± ± 0.0 of ASV (ml)* (95% CI: (95% CI: (95% CI: ) ) ) Time lapse to CT 10.5 ± ± ± 0.0 normalization (95% CI: 5.73 (95% CI: 5.01 (95% CI: 6.00 (hours)** ) ) ) Relapse after CT normalization No. with ARF No. with DIC Duration of stay (days) 5 ± ± ± 0.81 Mortality * p value between Regimen II and Regimen III = ** p value between Regimen I and Regimen III = Of the total of 90 patients enrolled in the study, 20 (22.2%) patients succumbed to various complications. ARF was the main contributor in 85% (17/20 patients) of cases. Other JAPI VOL. 52 OCTOBER 2004

4 Table 3 : Characteristics of patients with moderate envenomation (clotting time min) (n=34) Table 4 : Characteristics of patients with severe envenomation (incoagulable) (n=41) Parameter Regimen I Regimen II Regimen III No. of patients Bite to needle ± ± ± 15.1 time (hours) Average CT (min)* ± ± ± 3.43 Average dose ± ± ± 30.8 of ASV (ml)** (95% CI: (95% CI: (95% CI: ) ) ) Time lapse to CT ± ± ± 6.1 normalization (95% CI: (95% CI: (95% CI: 5.70 (hours)**** ) ) ) 3 (37.5%) 4 (26.67%) 0 Relapse after CT (95% CI : 8.52 (95% Cl : 7.78 (95% CI : 0.00 normalization*** ) ) ) No. with ARF 5 (62.5%) 9 (60%) 6 (54.54%) No. with DIC 4 (50%) 5 (33.33%) 2 (18.18%) Duration of stay (days) ± ± ± 1.7 Mortality 2 (25%) 3 (20%) 2 (18.18) * p - value between Regimen I and Regimen II = **p - value between Regimen I and Regimen II = p - value between Regimen I and Regimen III = ***p - value between Regimen I and Regimen III = ****p-value between Regimen I and Regimen III = p-value between Regimen II and Regimen III = causes contributing to death were DIC, primary fibrinolysis and septicemia. The mortality among various groups is shown in flowchart (Fig. 1). DISCUSSION None of the continuous IV infusion studies 11,12 conducted Table 5 : Average dose of ASV and modes of administration in various studies Study Protocol ASV Required Parameter Regimen I Regimen II Regimen III No. of patients* Bite to needle ± ± ± 20.8 time (hours) Average dose ± ± ± 32.8 of ASV (ml)* (95% CI: (95% CI: (95% CI: ) ) ) Time lapse to CT normalization 23.6 ± ± ± 5.75 (hours)** Relapse after CT normalization 4 (22.22%) 1 (12.5%) 4 (26.67%) No. with ARF 12 (66.67%) 5 (62.5%) 9 (60%) No. with DIC 9 (50%) 4 (50%) 7 (46.67%) Duration of stay (days) 6.47 ± ± ± 2.4 Mortality 7 (38.89%) 2 (25%) 4 (26.67%) * p - value between Regimen I and Regimen II = ** p - value between Regimen I and Regimen II = p - value between Regimen I and Regimen III = in India so far have tried to address the dosage requirement in various degrees of coagulation dysfunction i.e. in mild, moderate and severe dysfunctions; instead they formulated generalised protocol for all degrees of coagulation dysfunction. Thus, we conducted this trial. The mean bite to needle time of our patients was 18.3 hours; only one-third of patients presented within six hours after bite. This was in contrast to the studies by Thomas et al, 11 and Tariang et al 12 where majority of patients reached Vijeth et al (2000), Intermittent bolus doses: Pondicherry 2 Initial ml ml Repeat - 50 ml q 6 h till CT corrects to normal Bhat (1974), Intermittent bolus doses: Mild envenomation - 80 ml ( ml) Jammu 10 Initial - 20 ml Moderate ml ( ml) Repeat - 20 ml q 4-6 h till CT corrects to normal Severe ml Continuous iv infusion: Thomas and Jacob Traditional schedule: 153 ml (1985), 40 ml in 1st hour, 40 ml in next 2 hrs, Kerala ml in next 3 hrs, 30 ml every 3 hours. Modified Schedule: 20 ml in 1st hour, 20 ml over 2 hrs, 20 ml every 3 hrs till CT normalizes. (After CT normalizes, 20 ml in 5% dextrose over 24 hours). 79 ml Tariang et al Continuous iv infusion: (1999), High dose: Vellore ml in 100 ml 5% dextrose over 1 hr, followed by 20 ml in 100 ml 5% dextrose over 4 hrs, till CT normalizes, and then, 89 ml 2 vials over 24 hours Low dose: 20 ml over 1 hour, followed by 10 ml in 100 ml of 5% dextrose over 4 hours till CT normalizes, then 10 ml in 100 ml 5% dextrose over 24 hours. 47 ml JAPI VOL. 52 OCTOBER

5 hospital within six hours. This explains higher requirement of ASV in the current study; experimentally delay in administering antivenom results in steep increase of median effective neutralizing dose. 9 Further, none of the patients in Tariang s study groups had incoagulable blood; 12 whereas almost half of our patients had incoagulable blood at presentation, thus requiring more of ASV. In a study by Paul V et al, authors found no additional advantage of giving fixed 12 vials (120 ml) of ASV over six vials (60 ml) of ASV. 16 However all the cases included in that study were those who arrived within 24 hours of bite, whereas 26 (28.9%) of our patients arrived after 24 hours of bite. Further none of their patients had incoagulable blood. We feel epidemiologically there may not be much difference between our place of study i.e. Pondicherry and Kerala, their place of study. However, ours being a tertiary referral center, we had a higher load of sicker cases and thus had higher mean requirement of ASV. However, the average dose of ASV required in Regimens II and III in our study was significantly lower than that required in Regimen I. The lower requirement in regimens II and III was probably due to the delivery of ASV by continuous infusion and thus more accurate titration of dose, as opposed to delivery by multiple bolus doses in Regimen I. Continuous intravenous infusion may be the best method to exactly titrate the dose of ASV, and at the same time it does not necessarily cause slower correction of CT, as evidenced in this study. A bolus dose of 70 ml in Regime III caused further quicker correction of CT compared to that in Regime II. Recurrence after clotting time (CT) normalization was observed in as high as 35.7% of cases of Echis carinatus (saw-scaled viper) bite with hemotoxicity in an earlier study by Vijeth et al from this hospital. 2 No extra dose of ASV was given to patients in that series. A significant observation in the present study was that no recurrence was observed in any patient having mild and moderate severity of coagulation dysfunction treated with Regime III. This was due to extra dose of ASV administered. In patients with mild envenomation, Regimen II was found as effective as the other regimens and at the same time it had comparatively lesser requirement of ASV at ml on an average. In patients with moderate envenomation, the average requirement of ASV at 179 ml in Regimen III was much less as compared to that required in other regimens. In patients with severe envenomation, Regimen III, with average requirement of ASV at ml, offered quicker correction of CT than observed in Regime II, without having any significant increase in requirement of ASV. It is thus concluded, Regimen II is ideal for mild envenomation and Regimen III for moderate and severe envenomation. Regimen II and III appear to be significantly economical regimens as compared to Regimen I (standard regimen), currently practised in our hospital as well as in other hospitals of India. 2,17 Following these new regimens, the amount of ASV saved with Regimen III in our study was as much as 160 ml and 200 ml in moderate and severe envenomation respectively. Further, giving extra dose of ASV after CT normalization reduced recurrence of coagulation dysfunction. Subgroup analysis according to severity of coagulation has been hitherto done only in one study 10 and ours is only one, which has further extended its scope to study the effect of continuous low dose (IV) infusion on various degrees of coagulation dysfunction. Following the prescribed regimes suggested in this study, the requirement of ASV will become automatically low in mild and moderate envenomation, even though the mean requirement of ASV (in a series) may be high due to more number of severe envenomation cases, as in this study. This factor was eliminated, once we did the subgroup analysis of requirement of ASV. The mean dose requirement in mild, moderate and severe cases with the prescribed regimes concluded from this study (128.6, 179, ml respectively) was found to be not much different from that required by Bhat RN in the study from Jammu, only other study from India where subgroup analysis has been done 10 (Table 5). Slightly higher mean dose requirement in mild and moderate envenomation in our study was due to extra dose of ASV given after correction of CT. However, we vigorously recommend this to prevent relapse of coagulation dysfunction. Bhat RN did not find any return of coagulation defect, once it got corrected with ASV. This is surprising, since there are several studies reporting the recurrence of 2, 13, 14 coagulation defect as a significant problem. Approach suggested in this study can be considered more rational and scientific. REFERENCES 1. Vijeth SR, Dutta TK, Shahapurkar J. Correlation of renal status with hematologic profile in viperine bite. Am J Trop Med Hyg 1997;56: Vijeth SR, Dutta TK, Shahapurkar J, Sahai A. Dose and frequency of antisnake venom injection in the treatment of Echis carinatus (saw-scaled viper) bite. J Assoc Phys India 2000;48: Hanvivatvong O, Mahasandana S, Karnchanachetanee C. Kinetic study of Russell s viper venom in envenomed patients. Am J Trop Med Hygiene 1997;57: Davidson TM, Schafer SF. Rattle snake bites. Guidelines for aggressive treatment. Postgrad Med J 1994;96: Seiler JG, Sagerman SD, Geller RJ, Eldridge JC, Fleming LL. Venomous snake bite: Current concepts of treatment. Orthopaedics 1994;17: Gold BS, Winger WA. Snake venom poisoning in the United States: A review of therapeutic practice. South Med J 1994;87: Smith MA. The Fauna of British India, Ceylon. Reptilia and Amphibia: Volume III. Serpents. London: Taylor and Francis Reid HA, Theakston RD. The management of snakebite. Bulletin WHO 1983;61: JAPI VOL. 52 OCTOBER 2004

6 9. Progress in the characterization of venoms and standardization of antivenoms. WHO Offset Publication. 1981: Bhat RN. Viperine snakebite poisoning in Jammu. J Indian Med Assoc 1974;63: Thomas PP, Jacob J. Randomized trial of antivenom in snake envenomation with prolonged clotting time. Brit Med J 1985;291: Tariang DD, Philip PJ, Alexander G, Macaden S, Jeyaseelan L, Peter JV, Cherian AM. Randomized controlled trial on the effective dose of antisnake venom in cases of snakebite with systemic envenomation. J Assoc Phys India 1999;47: Ho M. Clinical significance of venom antigen levels in patients envenomed by the Malayan pit viper (Calloselosma rhodostoma). Am J Trop Med Hyg 1986;35: Reid HA, Chan KE, Thean PC. Prolonged coagulation defect (defibrination syndrome) in Malayan pit viper bite. Lancet 1963;1: Dutta TK, Ghotekar LH. Rational use of antisnake venom (ASV). In Das AK (Ed), APICON. Med Update 1998;8: Paul V, Pratibha S, Prahlad KA, Earali J, Francis S, Lewis F. High-dose anti-snake venom versus low-dose anti-snake venom in the treatment of poisonous snake bites - a critical study. J Assoc Phy India 2004;52: Seth AK, Varma PP, Pakhetra R. Randomized control trial on the effective dose of anti-snake venom in cases of snake bite with systemic envenomation (correspondence). J Assoc Phys India 2000;48:756. Book Review National Series Practical Clinical Neurology Second Edition Farokh Jamshed Master Foreword Writing a book from one's own experience or compiling information from various sources so that it is available in one volume is no easy matter. Those who have writen a chapter in a book can realize it only too well when they come to imaging what effort it would take to write a dozen or more such chapters to bring out a worthwhile book. Dr. Farokh J Master is a young homoeopath whose energy, enthusiasm and drive have made him bring out a book which though not of his own experience is a reasonable compilation of facts and information culled from various sources. It is a book principally written for undergraduates ut may be profitably used by postgraduates in their early whilst getting down to studying for their postgraduate examination. The book has some ups and down and some occasional flews, but then there is practically no book which is written which does not have its strong and weak points and its flaws. Dr. Master's effort as young person to become an author is commendable. NH Wadia MD., F.R.C.P (London), F.A.M.S., F.A.SC., F.N.A. Published by The National Book Depot Opp. Wadia Children's Hospital, Parel, Mumbai Tel / / Fax : prachint@bom7.vsnl.net.in Indian Price : Rs. 300/- JAPI VOL. 52 OCTOBER