Worldwide, snakebite is a serious public health issue, with an estimated 2.7 million bites each year.^1,2 In Mexico, from 2003 to 2019, an average of 3,893 envenomations and 34 deaths per year were registered.³ There are no national statistics on the percentage of snakebites caused by native vipers and elapids or the number involving exotic (non-native) snakes. Based on some hospital reports⁴ and our own experiences, 98 to 99% are caused by vipers, and the rest by elapids.⁵

In Mexico, exotic snake species are legally kept in scientific, zoological, and herpetarium collections. Nevertheless, the illegal trade explains their presence in private collections. These exotic species have caused envenomation, but the country does not have a centralized bank of antivenoms to treat envenomation by exotic species. Therefore, the importation and stocking of appropriate antivenom is the responsibility of the owners of the animals, but this only happens in very few cases. The lack of handy antivenom leads to a delay in snakebite treatment, which complicates the course of the envenomation.

Naja kaouthia, commonly known as the monocled cobra, is one of the most common exotic snake species in Mexico and perhaps the one leading to the highest number of exotic envenomations.

In the last five years, at least five people have been bitten by monocled cobras in Mexico City alone (according to Alarcón’s personal communication [Online talk: 14 años de la red de ayuda para el accidente ofídico UNAM: Dilemas éticos del ofidismo. Event organized by Herpetario “X-Plora Reptilia” for a general audience on July 2^nd, 2021]).

In most cases, the geographic origin of the specimens is unknown. Naja kaouthia is found in the Indochina subcontinent, the northern Malayan Peninsula, north-eastern India, and southern China.

Studies on the venom composition have shown that all contain cytotoxins⁶, but the dominant components are neurotoxins. In one study comparing venom from three populations —Malaysia, Thailand, and Vietnam— the median lethal doses (LD₅₀) were 0.9, 0.18, and 0.9 µg/g, respectively. The venoms of all three populations comprise three-finger toxins (63-77%), but there are essential differences in the proportions of component toxins. The population with the lowest LD₅₀, native to Thailand, is comprised 50% of long neurotoxins, while those of Vietnam contains 29%, and Malaysia 18%.⁶

The most lethal toxins are the postsynaptic neurotoxins that bind to the nicotinic cholinergic receptor sites at the neuromuscular junction. N. kaouthia envenomation causes a markedly neurotoxic clinical syndrome involving dysphagia, ptosis, diplopia, and flaccid paralysis.

In addition to neurotoxicity, inflammation and necrosis also occur at the bite site, caused by the cytotoxins in the venom.⁷ Generally, tissue damage occurs at the skin and subcutaneous tissue level, possibly due to the depth reached by the fangs. Postmortem examination may also demonstrate neutrophilic extravasation from regional lymph nodes, with focal necrosis of adjacent fatty tissue.⁸

In a 45-patient study in Thailand, 41 (91.1%) had necrosis at the bite site, generally confined to the immediate region of the bite site, and 31% had respiratory failure. Patients received antivenom (manufactured by Queen Saovabha Memorial Institute, the Thai Red Cross Society, Bangkok, Thailand) with an average range of 4.4 to 6.2 vials and an average of 5.6 days in hospital.⁹

This case report aimed to describe the clinical syndrome and the treatment of a patient bitten by an adult specimen of Naja kaouthia and to describe and correlate clinical findings with the levels of venom in the blood.

A previously-well-known-25-year-old man was bitten on the right index finger by his pet cobra (N. kaouthia) while feeding the animal in Cuautitlán Izcalli, Estado de México, Mexico. Fifteen minutes after the bite, he developed nausea, vomiting, general weakness, and blurred vision.

A relative of his contacted the toxicology center at Hospital Juárez de México for medical attention, then, the patient was transported there by a private vehicle. He arrived at the medical center 30 minutes following the bite, presenting with rapidly progressive paralysis and respiratory failure.

Vital signs immediately after arrival included blood pressure (BP) 209/134 mmHg, heart rate (HR) of 111, respiratory rate (RR) 7, and axillary temperature of 32.5 ºC.

He became utterly unresponsive and did not show any reflex two minutes later. He also had flaccid paralysis, absence of corneal responses, and unreactive 3-mm pupils. Doll’s eyes response was observed, and there were fasciculations involving muscles of the left leg.

Respiratory sounds were absent and the heart rate was irregular, but distal pulses were present and capillary refill was immediate. The abdomen was non-tender, and there were decreased bowel sounds. Fang puncture marks were present on the lateral aspect of the right index finger. Overall, the classification of envenomation was assessed as severe.

Due to ventilatory failure from paralysis, advanced airway management was immediately established using a modified rapid intubation sequence (etomidate 20 mg and propofol 20 mg, without a neuromuscular paralytic agent). Intubation was accomplished without incidents or complications, ten minutes after the hospital arrival, with immediate correction of oxygen saturation. Laboratory findings are summarized in Table 1.

Serial blood samples, 3 ml each, were collected in red-topped vacutainer tubes. The first blood sample was taken 0.5 h after the bite (S0), the second sample (S1) at 7.2 h, the third (S3) at 11.2 h after the bite, and the following ones every 4 h (S4, S5, S6 and S7). In each case, the cell pack was separated by centrifugation at 1500 x g for 7 min, and the serum was stored at -70 ºC pending venom quantification by ELISA.

The protocol and solutions used for the ELISA were described in previous works.^10,11 The purification of the capture antibody has also been described.⁸ Lyophilized N. kaouthia venom was obtained from the Herpetarium “Deval Animal”; 96-well plates (Nunc MaxiSorp®) were sensitized with 100 μL of polyclonal rabbit anti-Naja kaouthia at 5 µg/mL; then the entire plate was blocked with gelatin. Subsequently, a standard curve was placed, starting with 2 µg/mL followed by 1:3 consecutive dilutions.

The blood samples were initially placed in a 1:10 dilution followed by 1:3 consecutive dilutions. Next, we added 100 μL of 75 μg/mL monovalent antivenom anti-N. kaouthia; then 100 µL of a commercial horse anti-IgG antibody coupled to HRP was added at a 1:4000 dilution. Finally, the colorimetric reaction was obtained using ABTS, as before.

Absorbances were quantified in an ELISA reader (Magellan R) at 405 nm.

Since there was no antivenom specific to N. kaouthia, four vials of locally-sourced elapid antivenom (Coralmyn^®, a product targeted against venom of Micrurus species) were administered, intravenously, 1.8 hours after the snakebite. A bleb formed on the ulnar aspect of the second digit 2.5 hours after the bite and the edema (Pictures 1 and 2).

Blister fluid was collected for culture (later negative), and ceftriaxone was administered.

Four hours after the bite, the patient did not show clinical improvement, so he received two vials of specific antivenom, anti-Naja kaouthia (manufactured by Queen Saovabha Memorial Institute, Thai Red Cross Society, Bangkok, Thailand, Lot: NK 00514, expiration date: 10/10/2019). It was reconstituted in 10 mL saline, diluted to 250 mL in normal saline, and infused intravenously over 30 minutes. Then, two-vial doses of this product were applied at 10, 15, and 19 hours after the snakebite, for a total of eight vials (antivenom was infused following blood sampling for all analyses listed in Table 1).

Between the second and third doses of cobra-specific antivenom, propofol dosing was reduced, ventilatory parameters were weaned to CPAP (continuous positive airway pressure), and spontaneous movements of the fingers were observed.

Sixteen hours after the bite, one hour following the third dose of specific antivenom, spontaneous respiratory efforts were sufficient to allow extubation, and spontaneous movements of the hands were observed. However, strength remained ⅕ in the upper extremities generally.

The first motor activity involving lower extremities was noted 24 hours after the bite. After 36 hours, upper and lower extremities strength were ⅘ and ⅖, respectively; then, the patient was finally able to ambulate 65 hours following envenomation. He was discharged home on day four. Wound care was limited during this time to simple debridement and the use of purified hemoglobin (Granulox), with no extension of necrosis beyond the immediate bite site.

ELISA analysis of serum showed a venom concentration of 1810 ng/mL, 30 minutes after the bite, before administration of any antivenom. The level dropped to 12.9 ng/mL following the first dose of specific antivenom, then rebounded to 418 ng/mL. After all antivenom dosing was complete, the level reached a low of 9.3 ng/mL, followed by a slow rise to 24 ng/mL, 27 hours after the bite. (Graphic 1).

In Mexico, the species and number of exotic venomous snakes are unknown, and in most cases, specific antivenoms are not readily available for emergency use. That is a severe problem because the delay before definitive envenomation treatment may be many hours, enabling the development of neurotoxicity and tissue damage.

Clinical manifestations in our patient were consistent with published reports of envenomation by N. kaouthia. Similar to cases described by others^12,13, our patient had a rapid onset of symptoms following the bite, progressing by 40 minutes to respiratory failure, and paralysis, accompanied by a local injury that turned into necrosis.

The delay in onset of paralysis and respiratory failure has been reported to range from 15 minutes to 12 h.^7,13 Neurotoxicity presents as cranial nerve palsies, including ptosis, ophthalmoplegia, dysphagia, and dysarthria. Increased somnolence, confusion, flaccid paralysis, compromised respiratory function, and coma often follow.

Cardiovascular symptoms are not typically described^12,13, but they are consistent with our patient, who only presented tachycardia and hypertension, which resolved together with supportive care and antivenom.

Inflammatory response to N. kaouthia venom has been reported in a third of treated patients, including leukocytosis and neutrophilia¹⁴, which was not apparent in our patient.

Local findings include swelling, blistering, and necrosis, with 80% of wound cultures growing E. faecalis, M. morganii, S. aureus, or E. coli¹⁴; but there was no evidence of infection in our patient.

The venom quantification in the blood is a very useful tool that cannot always be performed due to the complexity of analysis and the lack of systematically collected samples. In this case, however, we were able to collect blood samples for laboratory analysis in the days following the envenomation. The venom quantified at baseline was 1800 ng/mL, higher than previously published reports of baseline levels of 725 ng/mL in a Daboia russelii bite, 387 ng/mL in a Naja haje case¹⁵, and of a postmortem level of 519 ng/mL reported in an N. kaouthia envenomation that had not received antivenom prior to death.⁸

In our laboratory, we have analyzed several samples from patients bitten by M. tener (18 ng/mL) and Crotalus atrox (42 ng/mL).⁵ An improved understanding of the venom concentration in serum is of great importance to guide future antivenom dosing. It is clear from the large amount of venom detected at baseline that this patient had a substantial envenomation.

In the absence of rapidly available venom levels, observation of the clinical syndrome determines the need for additional doses, as in this case, where the paralysis and respiratory arrest occurred and improved following the application of specific antivenom.

Based on the lack of prospective human envenomation studies, which would be ethically unfeasible, cases such as this one serve to inform future patient care. Formal toxicokinetic and compartmental analysis of venom levels has not been conducted in humans. Still, reports from large animal models of envenomation by Crotalus¹⁶ and by Micrurus^17,18 snakes suggest that ongoing absorption from the bite site (combined with slow passage through the lymphatic collecting system) may account for the secondary rise in venom levels, which is sometimes seen following initial antivenom treatment.^19,20

Since there was no specific antivenom, four vials of Micrurus-specific antivenom were administered. However, the administration was not followed by any discernible clinical improvement. That is not surprising given the significant difference between North American and Asian elapid venoms. As this was the case here, we have previously challenged mice with high dose Coralmyn (Lot: B-2H-12; expiration: October 2020; protein concentration: 16.2 mg) against 2.7 µg/g of N. kaouthia venom (three times the reported median lethal dose of 0.9 µg/g)⁶, but it did not show any effect, not even delaying death (Neri et al., unreported data). ELISA recognition of Coralmyn lot against the venom of N. kaouthia is low, with a titer of 0.014 against Micrurus diastema. We do not recommend the use of this antivenom for N. kaouthia snakebite.

Given the severity of the envenomation and the lack of an in-date alternative, our patient received an expired antivenom (October 2019), that is to say, thirteen months prior to the envenomation. This decision was made with authorization from the patient’s family in consultation with the treating physician. Properly stored, expired antivenoms have been shown to maintain potency for years after their expiration date.^21-24

Evidence for the continuing potency of the product used in this case includes the dramatic reduction in serum venom level that followed infusion of the first two vials of antivenom. The rebound in venom level observed at 8 hours is similar to that described in patients bitten by rattlesnakes, and it is likely the result of a functional venom depot at the site of the bite itself.^16,19

Although only eight vials of antivenom were available for this case, we believe that two additional vials would have helped reduce the blood venom level further. Though a residual concentration of 15 ng/mL was detected, it was fortunately not associated with further clinical complications, and the patient remained stable following the eight vials provided. Previous studies have reported that patients bitten by the same species receive 4 to 6 vials with an average of 5.5 days of hospitalization⁹, which is very similar to the results presented here.

Supportive care and mechanical ventilation were necessary for this patient before acquiring and administering specific antivenom. Because of flaccid paralysis caused by the venom, the rapid sequence intubation was modified to exclude the use of a neuromuscular blocking agent. This modification was expected, considering the blockade in the neuromuscular junction described with N. kaouthia venom.²⁵ Intubation is not always necessary following N. kaouthia envenomation, but when it is required, it is common to observe a response to antivenom administration.⁹

In cases of N. kaouthia envenomation, symptoms vary, but the use of specific antivenom is directed particularly toward prevention or correction of neurotoxicity. General supportive care is vital in managing severe paralysis. It should not be delayed while waiting for the administration of antivenom or cholinesterase inhibitors, such as neostigmine or edrophonium. Administering a specific antivenom as soon as possible is essential. In cases where antivenom is unavailable, supportive care will be the most critical intervention. The subsequent reduction in ventilatory support should be guided by the return of muscular tone and spontaneous respiratory effort.

Exotic species snakebite is a severe problem that could occur more frequently in the coming years as more and more people keep these kind of snakes in captivity. Therefore, it is necessary that our country has an antivenom bank for exotic species and that the laws are applied to those who do not have the required permits.

A medical expert must evaluate the use of expired antivenoms because the conditions in which the product has been stored can affect its quality. Thus, a macroscopic evaluation of the product and its efficacy must be assessed in detail.

Treatment by exotic venomous snakes rarely occurs in Mexico. Therefore, all cases should be reported in scientific journals in order to generate handy expertise for other health professionals.