Abstract
Introduction
Despite the widespread use of antivenom for the treatment of snakebite envenoming in the Indian subcontinent, the ideal dose of antivenom has been a point of contention. Low-dose regimens can economize on a scarce resource in low- and middle-income countries. This study assessed the effectiveness of a low-dose (10 vials) antivenom regimen compared to the usual 20 vials in patients with krait bite neuroparalysis requiring mechanical ventilation.
Methods
This study was a prospective controlled pilot study conducted in a tertiary-care hospital in north India. Participants were eligible if they were ≥12 years old, had krait bite neurotoxicity, showed severe paralysis requiring mechanical ventilation, and had access to antivenom therapy within 24 h of the bite. The primary outcome was the duration of mechanical ventilation, and the secondary outcomes were the length of hospital stay and in-hospital survival.
Results
Fifteen patients received 10 vials of antivenom, and 25 received 20 vials. The two treatment groups had similar baseline demographics, clinical and laboratory features, snakebite severity scores, and median time from snakebite to initiation of antivenom therapy. The low-dose regimen was as effective as the standard dose concerning the median duration of mechanical ventilation (41 h vs. 55 h, P = 0.094), the median length of stay (78 h vs. 85.5 h, P = 0.360), and in-hospital deaths (1 vs. 3, P = 1.000). The incidence of ventilator-associated pneumonia was similar between the two groups (1 vs 3, P = 1.000).
Conclusion
A low dose of antivenom effectively treats patients with severe krait bite neuroparalysis.
Keywords: antivenom, Bungarus caeruleus, common krait, envenomation, mechanical ventilation, neuroparalysis
Introduction
Snake envenomation is a common cause of emergency department admission in agricultural-based communities of low- and middle-income countries, such as India, which has the highest snakebite mortality in the world, with >50,000 deaths annually.1,2 Among over 50 venomous species, the Indian cobra (Naja naja), common krait (Bungarus coeruleus), Russell’s viper (Daboia russelii), and saw-scaled viper (Echis carinatus) (also known as “Big Four”) are responsible for the majority of snake envenomation in India.2,3
In north India, B. caeruleus causes about 60%–70% of total envenoming cases and has a 10%–15% mortality rate.3–6 Krait belongs to the family Elapidae and causes progressive descending neuroparalysis. The neurotoxins present in Krait venom act pre-synaptically (β-bungarotoxin) and post-synaptically (α-bungarotoxin and κ-bungarotoxin). Among these, β-bungarotoxins, constituting over 20% of the venom’s composition, are the most potent. These toxins induce neuromuscular failure by depleting the nerve terminal synaptic vesicle content and subsequently causing motor nerve terminal degeneration, resulting in severe neuroparalysis.7–9 The clinical features of neurotoxic envenomation included ptosis, paralysis, dyspnea, diplopia, dysarthria, dysphonia, and/or dysphagia (summarized by the acronym 2P4D).2,3 The treatment includes snake antivenom and intensive supportive care, including mechanical ventilation.
Antivenoms are produced by immunizing a source animal (e.g. horse) with snake venom with subsequently extracting and purifying the animal serum in specific vials. Given that the neutralizing power varies from batch to batch, antivenom is dosed by the vial.2,10 Ideally, antivenom dose for envenomation should be based on the load of total venom or its specific components, but the amount of venom injected is unknown in routine clinical practice. Therefore, the initial antivenom dose is usually empirical and is targeted to reverse the early systemic effects of the venom, with subsequent dosing based on the initial dose response.2,10
Since kits for the rapid detection of venom (and, consequently, identification of the offending species) are generally unavailable for most clinical settings, a polyvalent antivenom is typically used for snake envenomation.2,10 The Indian snakebite treatment guidelines recommend initial dosing with 10 vials of the national polyvalent antivenom (against the “Big Four”) for neuroparalytic snakebite (e.g. krait and cobra), with repeated dosing if the symptoms persist, to a maximum of 20 vials.3 However, these guidelines are not based on well-designed clinical trials of dosing.2
The average venom yield from kraits is 60 mg dry venom, although the amount of venom injected during a bite is often much less, at approximately 20 mg.8,11 This amount may vary depending on the location and depth of the bite, the presence of clothing at the bite site, and the snake’s age, size, and behavior (e.g. aggressivity) during the bite.2,3 Since one vial of polyvalent antivenom neutralizes 4.5 mg of krait venom, it seems reasonable to conclude that administration of the recommended 20 vials for krait bites results in a much higher volume of antivenom being injected in clinical practice than is actually required for venom neutralization.11,12
Since antivenom is expensive and often in short supply, the unnecessary administration of higher doses can worsen this shortage in resource-constrained areas of low- and middle-income countries.2,6 Several reports have shown that a lower dose of antivenom is as equally effective as the recommended normal/standard (or high) dose, although most of these reports have been retrospective studies or small-size trials involving heterogenous populations that have not addressed the specific snake species involved or the severity of envenomation; as a result, these investigations have not generated high-quality evidence.13–16 In this study, we examined the effectiveness of a low-dose antivenom regimen of 10 vials compared to the standard 20 vials used in patients with krait bite neuroparalysis that required mechanical ventilation.
Methodology
Study design
This study was a prospective, open-label, clinician-initiated, controlled trial conducted at the medical emergency department (Department of Internal Medicine), Postgraduate Institute of Medical Education and Research, Chandigarh, India, from January 2022 to December 2022. The study was approved by the institutional ethics committee at the Postgraduate Institute of Medical Education and Research, Chandigarh (Protocol No.: INT/IEC/2022/SPL-748). The study was done within the guidelines for the Indian Council of Medical Research’s National Ethical Guidelines for Biomedical and Health Research (2017) and the Declaration of Helsinki.
Participants
Participants were eligible if they were ≥12 years of age; had krait bite neurotoxicity; had access to antivenom therapy within 24 h of the bite, and showed severe paralysis requiring mechanical ventilation (before or during antivenom therapy). The diagnosis of krait bite neuroparalysis was made according to the national and World Health Organization guidelines.2,3 The clinical features of neuroparalysis included ptosis, paralysis, dyspnea, diplopia, dysarthria, dysphonia, and/or dysphagia (“2P4D”). The diagnosis of krait bite was made based on the description by the victim or witness along with an analysis of photographs of the offending snake species, identification of the dead snake if it was brought to the hospital, absent or minimal local signs (e.g. local swelling, necrosis, blistering, bleeding), and absence of coagulopathy. Persons were ineligible for participation if they had dry or incomplete bite without neurotoxicity. Written informed consent was obtained by all participants or their representatives, and for patients <18 years old, parental approval was obtained.
Study groups and regimen
Lyophilised polyvalent antivenom, an equine F(Ab’)2 antivenom, manufactured by Bharat Serums and Vaccines Limited (Ambernath, India) was used. The amount of venom neutralized by one vial (10 mL) of antivenom was 4.5 mg for krait and E carinatus and 6 mg for cobra and Russell’s viper, as stated by the manufacturer. Participants were assigned to receive 10 vials (low dose) or 20 vials (standard or usual dose) of antivenom based on their condition at admission. For the low dose regimen, the 10 vials of antivenom were administered as an intravenous infusion in normal saline over 30–60 min. For the standard dose protocol, antivenom therapy was initiated with 10 vials (as above), followed by a further 10 vials if neuroparalysis persisted after 1 h, to a maximum dose of 20 vials.3 Antibiotics were administered if misguided first-aid efforts (e.g. incision or mouth suction of the bite site) had been used before hospitalization. All participants received tetanus immunization as appropriate.
Data collection
All enrolled patients underwent a comprehensive anamnesis and physical examination, with particular emphasis on neurotoxicity features (“2P4D”) and vital signs. Baseline laboratory investigations included a complete blood count, serum electrolytes, renal function tests, coagulation profile, blood gas analysis, electrocardiogram, and chest radiograph. The Snakebite Severity Score was calculated for all patients, and assessed the respiratory, cardiovascular, hematological, gastrointestinal, central nervous system, and local wound conditions, to assign scores to each parameter.17 The score ranges from 0 to 23, with higher scores indicating more severe envenomation.
After admission and assignment to the treatment groups in the emergency room, the participants were shifted to an Emergency Department Observation Unit or an Intensive Care Unit, depending on bed availability. All participants were under regular observation for their entire hospital stay. All clinical features and complications (e.g. hospital-acquired infections) were recorded.
Outcomes
The primary outcome measure was the duration of mechanical ventilation in the two treatment groups. Secondary outcome measures included the total duration of hospital stay and the in-hospital mortality.
Statistical analysis
All statistical analyses were done using SPSS 25.0 (IBM, Trialware, USA). Categorical variables were described in numbers and percentages. Continuous variables were expressed as mean ± standard deviation (SD) or median with interquartile range (IQR), depending on whether data distribution was normal. The Kolmogorov-Smirnov test and visual inspection of quantile-quantile plots were used to check the normalcy of data. A Chi-square or Fisher’s exact test was used to compare categorical variables. Analysis of variance (ANOVA) or the Mann-Whitney U-test was used to compare continuous variables. Kaplan-Meier survival curves were constructed for the duration of mechanical ventilation and length of hospital stay in the two treatment groups. The log-rank test was used to compare the survival times or time to event between the groups. The P value for significance was set at <0.05 for all statistical tests.
Results
Study participants and baseline characteristics
A total of 77 patients with krait bite neuroparalysis were assessed for eligibility. Thirty-two patients did not receive mechanical ventilation and were excluded. Of the remaining 45 patients, 20 were assigned to the 10-vial group, and 25 were assigned to the 20-vial group. Five patients who were initially allocated to the 10-vial group were given 20 vials of antivenom at the discretion of the attending clinician, and were excluded, thus yielding 15 patients in the 10-vial and 25 in the 20-vial group for final analysis (Fig. 1).
Fig. 1.
Flow chart showing the enrollment process and flow of the patients.
The median age of the study population was 25 years (IQR, 17.5–35), and there was a slight male predominance (n = 22, 55.0%). All patients were admitted from 1 July 2022 to 18 September 2022. Thirty-eight snakebites (95%) snakebite occurred between 10 PM. to 6 AM (during the night and early morning), with the remaining two cases (5%) occurring at about 5 PM and about 7 AM, respectively. The study population came from adjoining geographical regions of north India, including Punjab (n = 19, 47.5%), Himachal Pradesh (n = 14, 35.0%), Haryana (n = 4, 10.0%), Chandigarh (n = 2, 5.0%), and Uttar Pradesh (n = 1, 2.5%). The median baseline snakebite severity score was 6 (IQR 4.25–8) across all participants.
The baseline characteristics of the patients were similar between the two groups (Table 1). Out of 40 patients, 26 first received treatment in a previous local hospital, five went to a local traditional healer, and only 9 came directly to our institute. Six patients who initiated antivenom therapy at another health center and completed 20 vials before enrollment were assigned to the 20-vial group. The median time from snakebite to initiation of antivenom therapy was similar in the two treatment groups, i.e. 7 h (IQR 4–14) in the 10-vial group and 8 h (IQR 5–14) in the 20-vial group.
Table 1.
Baseline characteristics of the study patients.
| Parameter | 10-vial group (n = 15) | 20-vial group (n = 30) |
|---|---|---|
| Age (years), median (IQR) | 25 (18–39) | 25 (17–33) |
| Males, n (%) | 9 (60%) | 13 (52.0%) |
| Snake bite mark, n (%) | 7 (46.7%) | 17 (68.0%) |
| Ptosis, n (%) | 14 (93.3%) | 24 (96.0%) |
| Dysarthria, n (%) | 13 (86.7%) | 23 (92.0%) |
| Dysphagia, n (%) | 11(73.3%) | 22 (88.0%) |
| Abdominal pain, n (%) | 10 (66.7%) | 19 (76.0%) |
| Chest pain, n (%) | 10 (66.7%) | 15 (60.0%) |
| Shortness of breath, n (%) | 7 (46.7%) | 14 (56.0%) |
| Altered mental status, n (%) | 6 (40.0%) | 6 (24.0%) |
| Systolic blood pressure (mmHg), median (IQR) | 120 (100–138) | 120 (104–130) |
| Diastolic blood pressure (mmHg), median (IQR) | 70 (68–80) | 70 (68–89) |
| Pulse rate (per min), mean ± SD | 101.6 ± 21.7 | 102.5 ± 22.6 |
| Glasgow coma scale score, median (IQR) | 8 (3–13) | 10 (6–11) |
| Hemoglobin (g/dL), mean ± SD | 13.8 ± 1.5 | 12.9 ± 2.1 |
| Platelet count (per μL), median (IQR) | 207,000 (166,000–291,000) | 189,000 (136,500–272,500) |
| Total leucocyte count (per μL), median (IQR) | 16,000 (9,000–18,700) | 11,700 (10,300–17,550) |
| Sodium (mEq/L), mean ± SD | 138.5 ± 3.4 | 137.8 ± 3.3 |
| Potassium (mEq/L), mean ± SD | 3.8 ± 0.4 | 3.8 ± 0.5 |
| Chloride (mEq/L), mean ± SD | 104.5 ± 4.3 | 104.8 ± 4.0 |
| Blood urea (mg/dL), mean ± SD | 29.9 ± 10.7 | 25.2 ± 11.9 |
| Creatinine (mg/dL), mean ± SD | 0.7 ± 0.2 | 0.6 ± 0.2 |
| Prothrombin time (sec), mean ± SD | 14.6 ± 1.3 | 14.7 ± 1.1 |
| Activated partial thromboplastin time (sec), mean ± SD | 27.7 ± 5.1 | 28.6 ± 7.1 |
| International normalized ratio, mean ± SD | 1.1 ± 0.1 | 1.1 ± 0.1 |
| Arterial blood pH, mean ± SD | 7.34 ± 0.15 | 7.35 ± 0.10 |
| Arterial PCO2 (mmHg), mean ± SD | 40.3 ± 15.8 | 37.1 ± 11.0 |
| Snakebite severity score, median (IQR) | 6 (4–9) | 6 (4.5–8) |
| Time interval between snakebite and anti-snake venom initiation (hr), median (IQR) | 7 (4–14) | 8 (5–14) |
| Time interval between snakebite and initiation of mechanical ventilation (hr), median (IQR) | 7.5 (4.5–16) | 9.0 (4.75–16.75) |
Abbreviation: PCO2- Partial pressure of carbon dioxide.
Analysis of the primary outcomes
The median duration of mechanical ventilation was 41 h (IQR 30.5–55) in the 10-vial group and 55 h (IQR 38–78.5) in the 20-vial group, and was not statistically different in the two groups (P = 0.108). Figure 2 shows the Kaplan-Meier curves for the duration of mechanical ventilation in the two groups. The difference between the survival curves was not significant (log-rank test; P = 0.204).
Fig. 2.
Kaplan-Meier survival curves showing the duration of mechanical ventilation for patients in the 10-vial and 20-vial groups. Deaths are indicated by vertical ticks on the survival curves.
Analysis of the secondary outcomes
The median length of hospital stay was 78 h (IQR 57–101) in the 10-vial group and 85 h (IQR 62.5–114.5) in the 20-vial group, and was not statistically different in the two groups (P = 0.476). Figure 3 shows the Kaplan-Meier curves for the length of stay in the two groups. The difference between the survival curves was not significant (log-rank test; P = 0.577). In-hospital mortality was 4 (10.0%), including 1 (6.7%) in the 10-vial group and 3 (12.0%) in the 20-vial group, but with no statistical difference between them (P = 1.000).
Fig. 3.
Kaplan-Meier survival curves showing the length of stay for patients in the 10-vial and 20-vial groups. Deaths are indicated by vertical ticks on the survival curves.
Adverse events
Three patients developed hospital-acquired infections, and all had ventilator-associated pneumonia. The causative organisms were Acinetobacter baumannii (n = 2) and Pseudomonas species (n = 1). The incidence of hospital-acquired infections was not significantly different between the two groups, i.e. 1 (6.67%) in the 10 vials group and 2 (8.0%) in the 20 vials group (P = 1.000). No study participant developed anaphylaxis-related cutaneous or cardiovascular features in response to the antivenom. Nevertheless, several symptoms, particularly respiratory and gastrointestinal, could not be documented as the participants were receiving mechanical ventilation.
Discussion
Despite the widespread use of antivenom for the treatment of snakebite envenoming in the Indian subcontinent, the ideal dose of antivenom has been a point of contention, primarily because of the lack of well-designed clinical studies. In this prospective controlled trial involving patients with krait bite neurotoxicity requiring mechanical ventilation, we found that a low-dose (10-vial) antivenom regimen was as effective as the standard 20-vial dose with respect to the duration of mechanical ventilation, length of hospital stay, and in-hospital survival. The incidence of adverse events (including ventilator-associated pneumonia) was similar between the two treatment groups.
Krait bite is a common cause of severe envenomation in Southeast Asia and has a high mortality.2,3,6 The timely administration of antivenom remains the mainstay of treatment and should be initiated at the earliest sign of neurotoxicity (including mild ptosis), since antivenom interrupts and reverses the paralysis.2,3,10 A delay in antivenom therapy is strongly associated with complications of envenomation. In agreement with previous data from tertiary care centers, about 60% of our cases developed respiratory paralysis that required mechanical ventilation at presentation, with antivenom administration being initiated about 6 h after the bite.5,13,14 This lag in starting antivenom therapy could be attributed to initial visits to local traditional healers or to health centers with little or no antivenom, a delay in recognizing krait envenomation because of the lack of fang marks and the presence of a painless bite, the presence of abdominal or chest pain that mimicked other medical disorders, and the nocturnal habits of kraits, with persons bitten at night only seeking medical attention the next day.
β-bungarotoxins in krait venom are the leading cause of neuroparalysis.7–10,18–21 These toxins are presynaptically active neurotoxins that enter motor nerve terminals where they impair neurotransmitter release.7,18–21 This process can be completed within a few minutes after a snake bite.20 Thus, the internalized toxin would not be available for neutralization by antivenom after this time frame. In contrast, postsynaptic neurotoxins (e.g. principal neurotoxins in cobra venom) bind to and block membrane receptors but remain extracellular.21 Hence, the progressive paralysis caused by postsynaptically active neurotoxins would be more effectively antagonized by antivenom. The severity of neuroparalysis from presynaptic venom depends on the degree of the depletion of the synaptic vesicles before antivenom administration.7,8,19,21 Thus, the recovery depends on the regeneration of synaptic vesicles, which may take a significant time, about seven days, to normalize neuromuscular functions completely.7,8 Clinical studies demonstrate the onset of neuroparalysis after a krait bite ranges from 0.5 to 50 h (mode 6 h), the duration of severe paralysis (i.e. requiring ventilation) is 0.5 to 29 days (mode two days), and complete recovery occurs in 8–9 days.8 The median duration of mechanical ventilation in our patients was about two days and was not different in the two antivenom dose groups.
Several randomized trials have demonstrated the efficacy of a low dose of antivenom compared to the usual (high) dose. However, these studies had small sample sizes and included all cases of snakebite envenomation, regardless of the snake species (predominantly viper bites) or the severity of the bite.13,22–26 A few retrospective studies have reported that low-dose regimens are adequate for treating venom-induced neuroparalysis but did not differentiate among elapid species, e.g. krait vs. cobra.14–16 The present pilot study specifically evaluated severe neuroparalysis after bites by the common krait that required mechanical ventilation and investigated the duration of mechanical ventilation as the primary outcome measure. The 10-vial dose was as effective as the 20-vial dose in reverting the neuromuscular blockade. Although the duration of mechanical ventilation and hospital stay were less with the low-dose regimen, these differences did not reach statistical significance. A few previous studies have also observed the advantage of low doses; however, several limitations exist.23 The exact reason remains unknown, but one hypothesis is that because antivenom is derived from animal proteins, it could potentially cause toxic effects in patients who already have severe systemic envenomation.
Limitations of the study
This study has a few limitations. First, although the sample size was reasonable, the monocentric nature of this work and the fact that it was done in a tertiary referral care center may have introduced some bias in patient selection and enrollment. Second, a few patients had already received varying amounts of antivenom at other health centers before being referred to our center, which precluded us from doing a blind randomized trial. Given the open-label nature of this investigation, our trial was liable to ascertainment bias. Moreover, five patients had to be shifted from the 10-vial to the 20-vial group at the attending clinician’s discretion. Third, no venom-specific enzyme immunoassay was done to confirm the snake species involved in the envenomation, particularly for cases where the patient did not photograph or bring the offending snake for identification.
Conclusions
A low-dose antivenom regimen (10 vials) was effective in treating patients with severe krait envenoming who developed neuroparalysis and required mechanical ventilation. Confirmation of this finding through rigorous clinical trials should prove helpful in reducing the excessive use of antivenom in regions where this commodity is scarce.
Supplementary Material
Acknowledgments
The authors thank Mrs Sunaina Verma for help in statistics.
Contributor Information
Ashok Kumar Pannu, Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, 4th Floor, F Block, Nehru Hospital, Chandigarh 160012, India.
Duni Chand, Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, 4th Floor, F Block, Nehru Hospital, Chandigarh 160012, India.
Ashish Bhalla, Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, 4th Floor, F Block, Nehru Hospital, Chandigarh 160012, India.
Deba Prasad Dhibar, Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, 4th Floor, F Block, Nehru Hospital, Chandigarh 160012, India.
Author contributions
Ashok Kumar Pannu (Conceptualization [supporting], Methodology [supporting], Data curation [supporting], Formal analysis [lead], Writing—original draft [lead], Writing—review & editing [lead]), Duni Chand (Data curation [lead], Writing—original draft [supporting]), Ashish Bhalla (Conceptualization [lead], Methodology [lead]), and Deba Prasad Dhibar (Data curation [supporting].
Funding
None.
Conflict of interest statement
There are no conflicts of interest to declare.
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