Introduction

Treatment for the bites by the many-banded krait (Bungarus multicinctus) is common at the Poison Control Center at Bach Mai Hospital (BMPCC). According to the BMPCC information unit, in 5 years (2010-2014) they accounted for 208 of the total of 1342 (15.5%) snakebite cases over that time period, with an annual average of 41.6 cases (17-61).

In Vietnam, there are two main species of Bungarus: Bungarus multicinctus(Northern Vietnam only) and Bungarus candidus (Malayan or blue krait, mainly in Southern Vienam) (1, 2). The most consequential effect of envenomation, paralysis, typically appears about 3 hours (0.5-24 hours) following B. multicinctus bite. The clinical effects progress over time to jaw weakness (90%), pharyngeal pain (83%), palatal palsy (90%), neck muscle paralysis (85%), limb paralysis (85%) and paralysis of the respiratory muscles (87%). Local effects are very mild, and there is typically no pain or swelling, despite the presence of two fang marks at the bite site (3). Hyponatremia, due to urine loss of sodium, is common (79%), and appears between 2 to 10 days after the bite, being most severe on day 2-4 (minimum 104 mmol/L) with average 128.4 ± 2.81 mEq/L, and could last up to 20 days (4, 2). Respiratory paralysis requiring mechanical ventilation, lasting for a mean of 8 days, is associated with complications such as hospital acquired pneumonia and pneumothorax, and carries a hospital mortality of up to 7% (3).

Antivenom administration is the mainstay of therapy in the majority of medically significant cases of envenoming. Such specific therapy may dramatically reduce the consequences of the envenomation (5, 6-8). Supportive care, including mechanical ventilation and 2% sodium infusion, is an important part of the management of Bungarus multicinctus snakebite, especially for situations in which no antivenom is available (4).

An antivenom for B. multicinctus demonstrated impressive effectiveness by shortening mechanical ventilation time from 8.6 ± 8.1 to 2.3 ± 2.5 days, decreasing the number of patients who developed ventilator-associated pneumonia, and shortening the length of ICU stay from 11.6 ± 9.7 to 6.1 ± 3.2 days. Rapid initiation of antivenom therapy is associated with improved outcomes (5).

However, Bungarus antivenom is not immediately available. As a horse-derived product, it carries a high risk of potential adverse events such as anaphylaxis, anaphylactoid reaction and delayed serum sickness. These have been reported to occur in 18% of the receiving North American Coral Snake Antivenin, a related antivenom (9).

Trypsin is a serine protease digestive enzyme that has demonstrated efficacy in some of Elapidae envenomations. After their experiments with dogs and mice, Hsiung Yu-Liang et al. concluded the local injection of trypsin can be used in clinical practice as a new and effective therapy for snakebite (10). Furthermore, Parker-Cote et al. concluded that in an animal model local injection of trypsin at the site of envenomation decreased the toxicity of eastern coral snake venom and increased survival significantly (9, 11).

We report a case of successful application of alphachymotrypsin, a related enzyme, in the treatment of severe paralysis due to B. multicinctus snakebite. There are no previous reports about the use of trypsin or alphachymotrypsin in the treatment of patients with B. multicinctus snakebite.

Case Presentation

A 38-year-old man was bitten on his left hand by B. multicinctus(This kind of species was recognized by the patient after successful treatment and epidemic distribution of the snake) (1-3, 5). Two hours after the bite, the patient developed a sore throat, diffuse myalgia, and progressive paralysis. He was transferred to Thai Binh provincial hospital, where he required endotracheal intubation due to complete

flaccid paralysis. He was at Bach Mai PCC 17hours after the bite.

On admission to the referral hospital, the patient was awake, oriented with the following vital signs: BP, 140/90 mmHg; HR, 100 BPM; RR depended on ventilation; SpO2 95% on 35% oxygen. Two fang puncture marks like pins were noticed at finger III of his left hand, but there was no local swelling and other changes. Neurological examination showed he had totally bilateral ptosis, dilated pupil 5 mm, ophthalmoplegia, jaw paralysis with inability to open his mouth, severe limb paralysis and total paralysis.

Routine laboratory tests:

Whole blood count: RBC 5.27 T/L; Hb 165 g/L; PLT 299 G/L; WBC 24 (Neutrophils 95,4%).

Coagulation test: PT 100 %; INR 1; APTTs 26; APTTbc 0.86; Fibrinogen 2.661g/L; Ethanol test: negative; Von-Kaulla tesst  > 60 phút.

Biochemistry test: Ure 3.4 mmol/L, Creatinine 65µmol/L; Glucose 8.2 mmol/L; GOT 23 U/L; GPT 19 U/L; CK 329 U/L; Na 140 mmol/L, K 4.09 mmol/L, Cl 99.9 mmol/L; Protein 77.9 g/L; Albumin 44,7 g/L; Procalcitonin 0.034 ng/mL.

Urine test: RBC 0 /µL; WBC 0; Protein 0 g/L.

Blood gas: pH 7.33; pCO2 35 mmHg, PO2 231 mmHg; HCO3 18.5 mmol/L (BE -7.4 mmol/L); Lactate 6.3 mmol/L (table 1).

Since antivenom was not available, we decided to administer alphachymotrypsin after the risks and benefits were carefully discussed. A dose of 5000 IU alphachymotrypsin was administered by the IM route at 24 and 31 hours after bite. At the time of the first dose of alphachymotrypsin, muscle power was 0/5. The muscle power improved rapidly, from 0/5 (24 hours) to 2/5 (at 44 hours). After that, additional doses of 10.000 IU of alphachymotrypsin were administered at 45, 55, 69, 75, 94 and 100 hour after the bite; the muscle power increased gradually then to 3/5 (66 hours), 4/5 (75 hours), and 5/5 (97 hours) (figure 1). The decision of pulling out the tracheal tube was at the 101th after the bite. The total mechanical ventilation time was 86 hours (~ 3.6 days). The total dose of alphachymotrypsin administered was 60.000 IU.

(Alphachymotrypsin: Empty arrow: 5000 UI, thick arrow: 10.000 UI; Muscle power scale: Point 0: total paralysis, Point 1: movement of some of a muscle group, Point 2: muscle power weaker than contradiction power, Point 3: muscle power stronger than contradiction power, Point 4: muscle power well, Point 5: normal muscle power; NKQ = tracheal tube).

Comment: Total time of tracheal tube and mechanical ventilation was 86 hours (~3.6 days); total dose of alphachymotrypsin was 60.000 UI.

Discussion

Diagnosis of Bungarus snakebite is simple if the patient sees and catches the snake. In case the snake has not been seen, diagnosis is usually due to triage: history of a bite, local symptom with two fang marks like pins, clinical symptoms with varying levels of paralysis even die by respiratory paralysis with dilated pupil, and laboratory test showed hyponatremia due to urine sodium loss.

The severity of the patient can be estimated through some factors as following: the heavier and longer the snake, the more severe the threat, time from bite to symptoms: the sooner the more severe, the level of paralysis, and the level of hyponatremia. According to these signs, the patient was classified under the severe group because the snake was long and heavy (1.5 m and 300 gr), symptoms appeared right after 2 hours after the bite, and level of paralysis was 0/5 17 hours after the bite. Based on our experience, he could be in mechanical ventilation from two weeks to months, or about 8 days according to Hung et al. in their study with a lot of complications and risk of mortality being 7% (3).

Prior research in pigs, dogs, and mice showed the beneficial effects on both clinical effects and mortality of trypsin for treatment of Bungarus envenomation (9-11).

Moreover, no side effects with a higher dose of alphatrypmochysin – 200 times of usual dose – were reported (12).

The effect of alphachymotrypsin rapidly helped muscle power improvement. The duration of mechanical ventilation in this patient was much shorter in comparison to the typical patient (8 days per Hung et al., and 14-30 days based on our experience) (3).

The hyponatremia in this case was not severe, although the urinary sodium concentration is high, especially in light of the falling serum sodium. The death resulted by severe hyponatremia being reported in a case report of B. multicinctus before could be in relation with cerebral edema (2).

The mild hyponatremia could be related to either a minor B. multicinctus envenomation, which is unlikely given the severity of the other clinical findings, or the effectiveness of alphachymotrysin. This hypothesis requires further investigation, both mechanistically and clinically.

Conclusion

The use of alphachymotrypsin was associated with a shortening of the need for mechanical ventilation, length of ICU stay, and a reduced extent of hyponatremia in a patient with severe B. multicinctus envenomation. In evaluating the effect of alphachymotrypsin in the treatment of Bungarus snakebite both in mechanistic and clinical toxicology, more study should be carried out in the future.

Figure 1. Evolution of muscle power condition and the use of  alphachymotrypsin