Empirical use of anti-snake venom in the early morning neuroparalysis

Background: Snake bite is a common acute medical emergency, which can present with atypical symptoms in the pediatric age group. Objective: The objective of the present study is to determine the outcome of patients presenting in the early morning with acute onset of atypical symptoms, no history of snake bite or bite marks be considered as a snake bite and treat with anti-snake venom (ASV) and mechanical ventilation. Materials and Methods: The prospective interventional study conducted over a 6 year period between January 2006 and December 2012 at a Rural Health Center in Maharashtra. Results: Out of 41 patients, 28 (68%) were males and 13 (32%) were females with a mean age of 8.59 ± 3.23 and 8.46 ± 2.96 years, respectively. Patients presented between 12 midnight to 7 a.m. with the maximum presentation between 2 a.m. and 4 a.m. (54%). Patients presented with vague complaints such as abdominal pain (60.97%), unconsciousness (17.07%), vomiting (12.19%) and abnormal sensation over body (7.31%) and convulsion (2.43%). All patients were treated with 15 units of ASV and needed mechanical ventilation within 6 h of admission. Duration of ventilation ranged from 36 h to 168 h with and an average of 115 ± 34.753 h. Hospital stay varied from 5 days to 17 days with a mean of 10.892 ± 3.361 days. All patients responded to treatment and there was 1 (2.43%) death owing to the aspiration pneumonitis. Conclusion: Diagnosis of possible snake bite should strongly be considered when patient presents in the early morning with acute onset of atypical symptoms and without any underlying illness, especially krait bite. The study concludes that timely interventions with a bolus dose of ASV and ventilation can definitely save many lives.

Keywords: Anti-snake venom, early morning neuroparalysis, krait, snake bite

Snake bite is common in school age children, adolescent and young adults. It is a significant cause of death in developing countries and a neglected public health problem. There are about 216 species of snakes identifiable in India, of which 52 are known to be poisonous. The major families of poisonous snakes in India are Elapidae, which includes common cobra (Najanaja), king cobra and common krait (B. caerulus), viperidae includes Russell’s viper, saw scaled or carpet viper (Echis carinatus) and pit viper and hydrophidae (sea snakes). ^{[1],[2],[3],[4]}

The common krait (B. caeruleus) is a proteroglyphous elapid snake commonly found in India, Sri Lanka, Bangladesh and Pakistan ^[5] and is regarded as the most dangerous species of venomous snake in the Indian subcontinent. ^[6] The Most elapid venoms are principally neurotoxic, producing a selective neuromuscular block affecting mainly the muscles of the eyes, tongue, throat and chest leading to respiratory paralysis. ^[7] The common krait is a nocturnally active terrestrial snake, which lives close to human dwellings, but it is not vicious by nature. Krait bites occur at night and the paucity or absence of pain and swelling after krait bites may falsely reassure the victim and thus delay treatment. Early morning neuroparalytic syndrome is a rare presentation of the elapid bite. ^[8]

This is a prospective, interventional descriptive study where 41 patients presented in the early morning hours with atypical symptoms and no history or bite marks suggestive of snake bite, after excluding other medical conditions, with the high suspicion of possible snake (krait) bite were treated with anti-snake venom (ASV) and supportive treatment with mechanical ventilation. The clinical profile, response to treatment, time period of ventilatory support, complications and outcome were studied.

This is a prospective, interventional and descriptive study conducted in the Pediatric Department of Krishna Institute of Medical Sciences, Karad, between January 2006 and December 2012 a tertiary rural health-care center in western Maharashtra. Only those children with acute onset of non-specific symptoms progressing to respiratory failure, the cause of which remained undiagnosed after taking a thorough history, clinical examinations and relevant investigations were empirically suspected to be bitten by krait and treated accordingly with ASV and ventilatory assistance were included in this study.

The study is mainly concerned about neuroparalysis, being the potentially lethal manifestation; however, other manifestations with which the patients presented mainly abdominal pain, unconsciousness and vomiting, abnormal sensations over the body and convulsions are also mentioned in this study.

Investigations to establish the diagnosis of acute intermittent porphyria’s viz. urine for urobilinogen, brain tumors and encephalitis viz. magnetic resonance imaging, blood sugar, urine sugar and ketone bodies for diabetic ketoacidosis, serum potassium and electrocardiogram for periodic paralysis and serum cholinesterase for poisoning and drug overdoses were done and the established cases were treated accordingly.

Symptomatic treatment along with tetanus toxoid, antibiotics and adequate hydration was maintained as required. Patients were investigated with complete blood count, renal function tests, electrolytes, urine for hematuria, bleeding and clotting time, whole blood clotting time and chest radiograph.

Anti-venom dosing recommendations are based on the quantity of particular venom (in milligrams, dry weight) that can be neutralized by each milliliter of antivenom. In India, each milliliter of polyvalent antivenom is supposed to neutralize 0.6 mg of Indian cobra venom, 0.6 mg of Russel viper venom, 0.45 mg of common krait venom, 0.45 mg of Saw scaled viper venom. ASV was administered by intravenous route only after taking proper informed consent from the parents. Skin testing was performed prior to ASV administration. ASV was diluted with 200 ml of normal saline and 15 units of ASV were administered as a bolus dose considering respiratory paralysis as a severe envenomation.

Clinical data about age, sex, clinical manifestations, time period of ventilatory support, complications and outcome were analyzed.

A total of 63 patients presented to us in the early morning hours with symptoms suggestive of krait poisoning. Out of which 22 patients were diagnosed with some other disease and hence were excluded from the study and treated accordingly. A total of 41 patients were enrolled for the study and their profile is given in [Table 1]. All patients were admitted late night or in early hours of dawn [Figure 1].

Patients presented with various symptoms, neurological or non-neurological without a history of snake bite at the time of admission. The various modes of presentation were abdominal pain in 25 (60.97%), unconsciousness 7 (17.07%), vomiting 5 (12.19%), abnormal senzation over body 3 (7.31%) and convulsion 1 (2.43%) [Figure 2]. As the most common mode of the presentation was abdominal pain, patients were initially admitted in surgery ward and referred to us after a normal ultrasound or computed tomography of the abdomen. Retrospectively 16 patients gave the history of some bite, but were not revealed to the parents due to fear of being scolded. The majority of our patients were admitted between June and October [Figure 3].

After admission, the patients were investigated and with the high index of suspicion in cases where all reports were normal and there was an acute history of onset of symptoms were labeled as snake (krait) bite. Most of these patients deteriorate with development of respiratory paralysis and had to be intubated and ventilated. The time lag to initiation of ventilation was 30 min to 6 h with a mean of 2 h. 29 (70.73%) patients needed ventilation within 30 min of admission. 12 (29.26%) patients developed respiratory arrest within 6 h of admission and thus all our 41 patients needed ventilatory care. Diverse views about the use of ASV in krait poisoning can be observed in literature, some authors are of the view that ASV does not help in krait poisoning, ^[9] but studies conducted on patients have shown ASV to be effective in krait envenomation. ^{[1],[6],[7],[10]} Thus, all patients were given 150 ml of ASV diluted in 200 ml of normal saline in spite of their weight and age considering it to be severe envenomation. ^[11]

The complications encountered in our patients are given in [Table 2]. Only two patients developed mild allergic reactions to ASV, who were treated with pheniramine maleate and dexamethasone after stopping the ASV infusion. The infusion was again started after 20 min at a lower rate and this was well-tolerated by both patients. All patients were continuously monitored and were treated symptomatically later. None of our patients were given atropine, antihistamines or neostigmine. The criteria for weaning of the ventilator was the patient condition and early signs of recovery were movements of eyeball, watering from eyes, which was later followed by improvement in neck muscles and intercostal muscles and last to gain power were muscles of upper limb followed by muscles of lower limb. Recovery of neck flexion to power grade 2-3 had significant correlation to the onset of stable recovery of respiration; this was used as a parameter to wean patients off ventilation. Patients showed improvement with a minimum of 36 h and a maximum 168 h with and an average of 115 ± 34.754 h where most of our patients were weaned off. The duration of hospital stay ranged from 5 days to 17 days with a mean of 10.83 ± 3.36 days.

All our patients responded to the above mentioned treatment. The mortality rate of the study was 2.43% i.e., there was death of a 10-year-old girl child who had recovered from the envenomation and collapsed due to aspiration after extubation. No other long-term complication was seen in any patient.

Snake bite is a frequently encountered the problem in rural India. Common neurotoxic snakes in India include Cobra (Naja naja) and Krait (B. caeruelus). ^[12] In Maharashtra, snake bite cases have shot up sharply due to long periods of electric load shedding in villages leaving these villages in darkness. Kraits are generally secretive, unaggressive nocturnal animals that frequently enter rural dwellings in search of their prey. ^[13] Their bites are commonly reported between 2 a.m. and 3 a.m. and those sleeping on the floor are at a greater risk and typically occur when the snakes are disturbed by the sleeping occupant. ^[10]

Children are at risk of sustaining snake bite mainly because of their curiosity about the unknown creature, innocent act of invading unused areas and crevices, playing until dusk and post dinner in bushes around the house, habit of bare foot walking in the dark and sleeping on the floor when parents are busy winding up for the day and thus making them a common prey to kraits.

The venom of kraits contains three major types of neurotoxin. α-bungarotoxins cause a failure of neuromuscular transmission by binding to post-synaptic n-acetylcholine receptors at the neuromuscular junction. ^[14] κ-Bungarotoxins are found exclusively in the venom of kraits. They are structurally similar to α-bungarotoxins, bind to neuronal n-acetylcholine receptors but are minor components of the venom. The β-bungarotoxins constitute >20% of the protein content of the venom and are the most toxic components of the venom. They are presynaptically active neurotoxic phospholipases A2. Exposure to these toxins causes the failure of neuromuscular transmission for 2-3 h and the depletion of synaptic vesicles from nerve terminal boutons is a primary pathological feature of toxicity. ^[15] Structural damage to the motor nerve terminal and terminal components of the motor axon follows rapidly and destruction of the nerve terminal is complete by 12-24 h. ^{[15],[16],[17]} It has been suggested that β-bungarotoxin (alone or in combination with α-bungarotoxin) is primarily responsible for the severe paralysis associated with envenoming bites by kraits. The underlying hypothesis is that the onset of paralysis is caused by the depletion of synaptic vesicles from the nerve terminal, the destruction of the terminal boutons explains the phase of profound treatment-resistant paralysis and the slow recovery of neuromuscular function reflects the regeneration of nerve terminals and the re-innervation of the denervated muscle fibers. ^[9] The mechanism of action of the toxin, the explains the type of symptoms experienced in our patients, the type of onset of paralysis and the slow recovery of the patients ranging from 36 h to 7 days on the ventilator.

Studies have been conducted all over the world where authors have studied about the clinical profile of different types of snake bites, their response to ASV and outcome of these patients. The studies conducted on krait bite did have an aspect where few patients were treated on high suspicion of the patients being snake bite in spite of no available history of bite marks could be appreciated. Theakston et al. described four cases of Krait bite where the bite had occurred when the patient was asleep, no local signs were seen, but all four patients developed features of systemic envenomation including paralysis, muscle pain, tenderness and abdominal pain. ^[18] In a study by Kularatne from Srilanka where the clinical profile of 210 patients with krait bite were studied. A significant number of patients 65 (31%) had not been aware of the bite, but had woken up with colicky abdominal pain. In 35 (17%) patients, the site of the bite was undetectable and they presented with abdominal pain, dyspnea, dysphagia and signs of neuromuscular paralysis. ^[5] Punde have studied 633 cases of snake bite where 42 (9.8%) were due to krait of which three patients did not give a history of snake bite and one patient was referred with chest pain and sweating who subsequently developed neuroparesis and was treated as krait bite. ^[10] Monteiro et al. described a study of 46 female patients where signs of envenomation (neurological symptoms) were observed in 50% of the cases and bite marks were seen only in 50% of patients. ^[7] Various case reports have been published over the years where different manifestations of krait envenomation have been shed light on. ^{[12],[13],[18]}

Common neurological symptoms in decreasing order of frequency include ptosis (85.7%), ophthalmoplegia (75%), limb weakness (26.8%), respiratory failure (17.9%), palatal weakness (10.7%) and neck muscle weakness (7.1%). Pain abdomen, the cardinal symptom of krait bite, can precede neurological symptoms by several hours. ^[5] Similar observation was made in our study where the majority of 60.75% patients presented with abdominal pain as the chief complaint. Patients then subsequently developed neuroparalysis. Bites by kraits produce very fine puncture marks similar to that made by injection needle. Paucity of local tissue reaction, as seen in all of our patients, is a typical feature of krait bites. ^[19] The intercostal muscles are paralyzed before the limbs, diaphragm and superficial muscles of the digits. At any time during respiratory paralysis, obstruction by inhaled vomitus or secretion can result in sudden death, similar to what we observed in our study. In krait bites, pre-paralytic stage is more marked than the paralytic stage. The victim usually succumbs to death due to respiratory failure. Convulsions are usually intense in krait bites. On an average death ensues within 6-24 h. ^{[20],[21],[22]}

The limitations of this study was there was no definitive clinical or laboratory diagnosis of krait bite, the diagnosis and the therapeutic trails mainly being on empirical basis after ruling out other conditions of acute onset neuroparalysis. The study is not a controlled study as such a study is not ethically possible or desirable and patient cannot be kept away from life-saving treatment with established efficacy.

ASV is the most effective when administered within a few hours of krait bite; hence, a high degree of suspicion is required as the bite is frequently not witnessed and initial symptoms can be non-neurological. Following administration of antivenom, the signs of recovery became evident within a few hours to several days and the duration for complete recovery ranges from 4 h to 2 weeks. ^[23] Ventilatory support forms a corner-stone of krait envenomation therapy. There are reports that describe complete recovery from snake bite, over a period of time, with mechanical ventilation, in the absence of ASV therapy. ^[24] Current evidence does not indicate a strong role of anti-cholinesterase drugs (Neostigmine) in patients with common krait envenomation. ^[5] As seen in our study, all patients responded to ASV and mechanical ventilation; which forms the main modalities of treatment. All patients except one were discharged in previous health state and no long-term complications were observed.

In the present study, we found that all the patients presenting with early morning non-specific symptoms suggestive of snake (krait) bite responded well to ASV and mechanical ventilation. ASV was given as a bolus and the dose was not repeated again. Thus, the main aim of this study is to stress a fact that in cases of undiagnosed acute paralysis every clinician should suspect krait bite as a possible diagnosis and treat accordingly on empirical basis in rural as well as urban set-up.

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1755-6783.140224

[Figure 1], [Figure 2], [Figure 3]

[Table 1], [Table 2]