The role of fresh frozen plasma in reducing the volume of anti-snake venom in snakebite envenomation

Introduction

Snakebite, a neglected global public health problem,^1,2 predominantly affects the rural population in many tropical and subtropical countries around the world. It is an occupational risk for farmers and agricultural labourers leading to significant mortality and morbidity.^1,3,4 Snakebites and their related mortality are most common in India, but have a varied distribution across the country. There were 76,948 bites and 1359 deaths in 2007 according to the data released by the government of India. ¹ Poisonous snakes producing venom-induced consumption coagulopathy (VICC) may be treated satisfactorily with specific antivenom, but the dose has to be repeated several times, at 6-h intervals, to restore the blood coagulability permanently. Lack of availability, cost and risk of allergic reactions are some of the important considerations related to the use of anti-snake venom (ASV).^4,5 Any treatment strategy, therefore, which decreases antivenom requirement has obvious benefits. Since re-synthesis of clotting factors takes time despite successful antivenom therapy, factor replacement using fresh frozen plasma (FFP) is suggested to restore clotting factor levels rapidly and consequently reduce complications.^5,6 However, controversies exist suggesting that FFP may provide a substrate which actually worsens coagulopathy. ⁷

Materials and methods

Our multicentre hospital-based observational study was conducted in the hospitals attached to Kasturba Medical College, Mangalore between July 2014 and July 2016. Patients aged >18 years with snakebite and whole blood clotting time (WBCT) >20 min without history of allergy or objections to blood products were included. Patients with fluid overload state owing to renal dysfunction, cardiac failure, history of bleeding diathesis and coagulopathy from underlying liver disease were excluded from the study. At admission, all snakebite victims with WBCT >20 min received ten vials of ASV according to World Health Organization (WHO) criteria. ² Then, after 6 h, patients with WBCT >20 min were divided into two groups at the discretion of the treating physician. One (control) group received only five ASV vials and a second (test) group received both five ASV vials and four units of FFP (Figure 1). OPEN IN VIEWER

Ethical clearance was obtained from the institutional Ethics Committee of Kasturba Medical College, Mangalore. Permission was obtained from the hospital authority for data collection. Informed consent from the patients was obtained.

Statistical analysis

Data were entered into a Microsoft Excel (Microsoft, Redmond, WA, USA) worksheet and analysed using statistical software SPSS (IBM, New York, NY, USA) version 17.0. Descriptive statistics were presented and differences in the findings between the two groups were examined by using χ ² and Fisher’s exact tests for comparison of categorical variables in small sample sizes. A P value <0.05 was considered statistically significant.

Results

A total of 62 snakebite victims who were eligible and consented were included. The test and control groups were well matched (Table 1). At 12 h, 29.4% in the test group had a prolonged 20-minute whole blood clotting test (20WBCT) compared to 100% in the control group. At 18 h, 14.7% in the test group and 96.8% in the control group still had prolonged 20WBCT. The percentage of patients with 20WBCT at various time intervals after starting treatment is shown in Figure 2. After 12 h, ten patients in the test group, but 30 in the control group, required ASV. This decreased, at 18 h, to only two patients in the test group requiring ASV, compared to 20 patients in the control group. At the end of 24 h, none of the patients in the test group required ASV, while 12 in the control group did. The total number of ASV vials used in test cases was 17 and 31 vials in the control group (median dose vials = 30, interquartile range [IQR] = 25–35 vials) (Figure 3).

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Table 1.

Demographic features and base line characteristics among the test and control groups.

Characteristics	Test group (n = 31)	Control group (n = 31)
Sex (n (%))
Male	25 (80.6)	19 (61.3)
Female	6 (19.4)	12 (38.7)
Age (years), median (IQR)	35 (24–44)	36 (24–53)
Time since bite to admission (h) (median (IQR))	6 (4–8)	5 (4–7)

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Figure 2.

Bar diagram depicting percentage of prolonged WBCT in test and controls at various time intervals after treatment initiation. At 12 h, 29.4% in the test group had prolonged WBCT, compared to 100% in the control group. At 18 h, 14.7% in the test group and 96.8% in the control group had prolonged WBCT. The percentage of patients with WBCT at various time intervals after starting treatment is shown in the figure. Among the test group, WBCT normalized at 24 h compared to 74. 2% of the control group who had prolonged WBCT which normalized only after 42 h. WBCT, whole blood clotting time.

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Figure 3.

Bar diagram depicting number of patients requiring ASV in test and controls at various time intervals. Until 6 h, all patients in the test and control groups required ASV. After 12 h, only ten patients in the test group and 30 patients in the control group still required ASV. At 18 h, only two patients in the test group required ASV compared to 20 patients in the control group. At the end of 24 h, none of the patients in the test group required ASV, while 12 patients in the control group required ASV. x-axis, hours; y-axis, ASV vials.

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Table 2.

Poisonous snakes of India and geographical distribution.

Family	Snake species	Common name	Geographical distribution in India
Elapidae	Najanaja	Common spectacled Indian	Throughout
	Najasagittifera	cobra	Andaman
	Ophiophagushannah	Andaman cobra	South, Northeast,
	Bungaruscaeruleus	King cobra	Andaman
	Bungarusniger	Common krait	Northeast
		Black krait	Northwest
Viperidae	Daboiarusselli	Russell’s viper	Southwest
	Echiscarinatus	Saw-scaled viper	Southwest
	Hypnalehypnale	Hump-nosed pit viper	Western Ghats
	Trimeresurusgramineus	Indian bamboo viper	South, Andaman

There was a mild reaction to ASV in 15 patients (48.4%) in the test group and 14 (45.2%) in the control group. None had a severe or life-threatening reaction. An average number of 5 FFP units were used per patient in the test group. Six patients in this group had a reaction to FFP in the form of chills, pain at infusion site and fever which were managed symptomatically. There was no serious adverse event (Table 3).

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Table 3.

Treatment outcome in the test and control groups.

	Case (n = 31)	Control (n = 31)
Time for WBCT to be normal (<20 min) (h)	24	42
Reaction to ASV (n (%))
Minor	15 (48.4)	14 (45.2)
Major	0	0
Reaction to FFP (n (%))	6 (19.4)	0
Deaths	0	0
Mean duration of hospital stay (days)	∼3.5	∼6.8

Discussion

The coagulation defect seen in VICC is due to consumption of fibrinogen, factor V, factor VIII and prothrombin. Coagulopathy may be reversed by ASV administration, but for complete neutralisation of venom, a large quantity of ASV is required. Though ASV neutralises venom, re-synthesis of coagulation factors takes 24–48 h which again places the patient at high risk of bleeding. ¹³ This provides the official basis for the use of FFP. The current advice of the Association of Physicians of India, based on the WHO guidelines, recommends an initial administration of ten vials of ASV for in patients with WBCT >20 followed by repeat doses every 6 h based on the WBCT result. ¹⁴

The 20WBCT is very easy to perform and useful where coagulation tests are not readily available: 2 mL blood is taken into a glass tube and left undisturbed at room temperature for 20 min. Plastic syringes or detergent-washed bottles are not used. Time to clotting is measured. The test is repeated every 30 min for 3 h and then every hour if normal. If deranged, it is repeated every 6 h to determine the dosage of ASV required. ² The 20WBCT is 100% specific but not sensitive. If it is negative, it does not rule out envenomation. However, a positive WBCT is a reasonable indication for antivenom administration.

ASV in India is polyvalent, i.e. effective against all four common species: Russell’s viper; common cobra; common krait; and saw-scaled viper (Table 2). Monovalent ASV is not available in India. Liquid ASV needs cold chain maintenance and remains efficacious for two years. Lyophilised ASV does not need refrigeration. The half-life of Indian ASV is 90 h and hence a prophylactic dose to prevent re-envenomation is not essential. ¹⁰

FFP does not appear in official recommendations, although its use is known to speed the normalisation of coagulopathy. Indeed, FFP alone (without ASV) has been administered to snakebite victims with coagulopathy with desirable outcomes.^13,15,16 FFP alone, however, does nothing to inactivate or prevent the VICC process and the patient is then at the mercy of the half-life of the venom itself for resolution. The major concern with the use of FFP is that it adds more substrate for the pro-coagulant toxins present in the venom to activate and thus may worsen the coagulopathy by activating the venom. ⁷ The use of FFP is, of course, not without risks, one of the most significant being the transmission of HIV disease as one unit of FFP is produced from several donors.

A study done in Australia showed administration of FFP hastens recovery but is less effective when administered in <4 h. ¹³ Two small observational studies suggest that the administration of FFP after a course of ASV reduces the number of vials of ASV required for treatment of snakebite.^5,6

Small sample size, non-randomisation, single centre and lack of correlation with severity of envenomation are limitations of our study.

Nonetheless, we clearly showed a more rapid reversal of coagulation defect where FFP was used. FFP is easily available throughout the world, even in many resource-poor countries such as India, at a price lower than ASV. Therefore, if supplies of ASV are conserved and faster recovery is achieved, its use should be considered and suitable protocols introduced.