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Case Report

Jesús del Carmen Madrigal Anayaa; Andrea Cruz Ibarraa; Nancy Cristal Rodríguez Uvallea; Guillermo Gil Alarcónb; Alejandro Alagónc; Gabriela Rodríguez Floresa; Leslie Boyerd; Edgar Neri-Castro (0000-0003-1551-4584)c.
aToxicología Clínica, Hospital Juárez de México, Ciudad de México, México; bSecretaría Ejecutiva de la Reserva Ecológica del Pedregal de San Ángel, Coordinación de la Investigación Científica, Universidad Nacional Autónoma de México, Ciudad de México, México; cDepartamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México; dVenom Immunochemistry, Pharmacology, and Emergency Response (VIPER) Institute, University of Arizona, Tucson, EE. UU..
Corresponding Author: , . Tel: ; e-mail: edgar.neri@ibt.unam.mx

Citation: Madrigal Anaya JC, Cruz Ibarra A, Rodríguez Uvalle NC, Alarcón GG, Alagón A, Rodríguez Flores G, et al. A case of exotic envenomation by Naja kaouthia in Mexico.
Lat Am J Clin Sci Med Technol. 2022 Jan; 4: 1-8.
Received: October 21st, 2021.
Accepted: January 4th, 2022.
Published: January 4th, 2022.
Views: 1273
Downloads: 18
ABSTRACT

In Mexico, an average of 3,893 venomous snakebites is registered annually. Since not all bites are informed, that figure is likely an underestimation. Most bites involve snakes native to Mexico, but reports do not distinguish among the species involved, so the percentage of bites caused by exotic (non-native) snakes is unknown. However, numerous exotic species of venomous snakes are kept in the country, both legally and illegally. Commonly, owners of these snakes do not acquire appropriate antivenoms, leaving themselves vulnerable to severe envenomation. In this article we present the clinical case of a 25-year-old man bitten on the right index finger by a monocled cobra (Naja kaouthia). He developed severe neurotoxicity 15 minutes after the bite and required ventilator support for 16 hours. He recovered after the intravenous administration of eight vials of antivenom specific to N. kaouthia. He had necrosis at the site of the bite, which covered two thirds of the finger but resolved satisfactorily without surgical intervention. Quantitative ELISA assays on seven serum samples confirmed the envenomation and illustrated a secondary rise and fall in systemic venom levels during antivenom treatment.

Keywords: snakebite, exotic snake, Naja kaouthia, antivenom, venom serum levels
RESUMEN

En México se registra un promedio anual de 3,893 envenenamientos por mordeduras de serpiente. Dado que no todas las mordeduras se reportan, es posible que esa cifra no sea correcta. La mayoría de las mordeduras se relaciona con serpientes endémicas en México, pero los reportes no distinguen entre las especies involucradas; de modo que se desconoce el porcentaje de mordeduras causadas por serpientes (no endémicas) exóticas. A numerosas especies exóticas de serpientes venenosas se les mantiene en el país, tanto legal como ilegalmente. Es común que los dueños de dichas serpientes no adquieran los antivenenos correctos, lo cual los hace vulnerables a envenenamientos graves. En este artículo presentamos el caso de un paciente masculino de 25 años que fue mordido por una cobra monócula (Naja kaouthia). El paciente presentó neurotoxicidad grave 15 minutos después de la mordedura y requirió ventilador durante 16 horas. Se recuperó después de la administración de ocho viales de un antiveneno específico para N. kaouthia. Tuvo necrosis en el sitio de la mordedura, la cual cubría dos tercios del dedo, pero se resolvió satisfactoriamente sin intervención quirúrgica. Los ensayos cualitativos de ELISA de siete muestras de suero confirmaron envenenamiento e ilustraron un segundo aumento y disminución de los niveles de veneno durante el curso del tratamiento con antiveneno.

Palabras clave: mordedura de serpiente, serpiente exótica, Naja kaouthia, antivenenos, niveles séricos de veneno

INTRODUCTION

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 hospitals 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 2nd, 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.

CASE PRESENTATION

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.

Table 1. Tests performed
Test/time (h)0481216202428Reference values

SBP (mmHg)20912712413914012512710791-129

DBP (mmHg)1347975757068627061-84

HR (bpm)111104103767073748660-89

arterial pH7.27.39ND7.38NDNDNDND7.35-7.45

HCO3 (mEq/L)14.616.9ND21.8NDNDNDND18-21

LAC (mmol/ L)70.7ND0.8NDNDNDND0.5-1.6

BE (mmol/L)-12.8-6.3ND-2.2NDNDNDND2+4

PCO2 (mmHg)3828.6ND36.9NDNDNDND35-48

Proximal perimeter (cm)2426.52625.524.52423.824.221.5*

Medial perimeter (cm)18.522222120.820.920.92118.3*

Distal perimeter (cm)283029.729.430.730.530.43128*

Leucocytes (mm3)9.74NDND8.81NDNDNDND5.20-12.40

Hgb (g/dL)15.4NDND15.7NDNDNDND12.00-18.00

Hct (%)46.6NDND47.2NDNDNDND37.00-52.00

Plt (10 ^3/IU)207NDND201NDNDNDND130.00-400.00

TP (sec)15.1NDNDNDNDNDNDND9.30-11.50

TPT (sec)24.5NDNDNDNDNDNDND20.60-38.60

INR1.37NDNDNDNDNDNDND0.80-1.20

*Measurement taken from contralateral limb. SBP: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate; ND: non-determined; HCO3: bicarbonate; LAC: lactate; BE: base excess; PCO2: partial pressure of carbon dioxide; Hgb: hemoglobin; Hct: hematocrit; Plt: platelets; TP: prothrombin time; IU: international units;TPT: partial thromboplastin time; sec: second; INR: international normalized ratio.

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).

7 hours
14 hours
48 hours
4 days
Picture 1. Swelling evolution
8 hours
12 hours
48 hours
72 hours
5 days
7 days
10 days
18 days
5 months
Picture 2. Bite site damage evolution. Pictures are shown from the first minutes after the bite. The patient did not have surgery at any time.

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).

A shows the interpolation of samples 0 to 4 (S0 to S4). B shows data from samples 5 to 7 (S5-S7). The minimum limit of detection and minimum limit of quantification were 0.31 and 0.89 ng/mL, respectively. C shows the venom concentrations: zero represents the time of the bite; the purple arrow is the time at which Coralmyn™ was administered; the orange arrows represent the times at which the specific antivenom was administered. The blue dots represent the average antivenom concentration with the line indicating the standard deviation (n=3). S0 refers to the baseline sample collected before administration of antivenom.
DISCUSSION

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 others12,13, 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 described12,13, 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 Micrurus17,18 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.

CONCLUSIONS

Lack of experience and awareness of exotic envenomation in Mexico and worldwide may complicate emergency snakebite management. Clinicians should be aware of specific antivenom products and their importance in envenomation treatment, even when there is a delay in their acquisition or when a product is outdated. Consultation with regional experts and collaboration with academic centers may result in more timely application of specific treatment and better patient outcomes.

Venom quantification in the blood is a method that should be considered whenever practical to refine our understanding of dosing and timing of antivenom administration. That will improve the future exotic animal stocking of foreign products and the research and collection. Complete reporting of such cases and the antivenom impact may also inform better public policy for this neglected tropical disease.

ACKNOWLEDGMENTS

The authors thank the following herpetariums: UMA TS AB KAAN (SEMARNAT, registration number UMA-IN-0183-YUC-10) and Deval Animal (DGVS-CR-IN-0957-D.F./07) for the assistance in the venoms extraction.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

FUNDING

This case report was financially supported by DGAPA-PAPIIT (project IN- 211621), CONACYT (project 264255); FORDECYT PRONACE (project 1715618/2020), and FORDECYT (project 303045).

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Latin American Journal of Clinical Sciences and Medical Technology,
Año 1, No. 1, octubre, 2019 es una publicación contínua editada por Vesalio S.C.; http://www.lajclinsci.com/    Editor responsable: Gilberto Castañeda Hernández.    Reserva de Derechos al Uso Exclusivo: 04-2019-062013242000-203; ISSN: 2683-2291; ambos otorgados por el Instituto Nacional del Derecho de Autor.    Responsable de la última actualización de este número, Web Master Hunahpú Velázquez Martínez,
Calle San Luis Potosí #182-1, Col. Roma, Alcaldía Cuauhtémoc, C.P. 06700, Ciudad de México; teléfono: 55 64 40 41    Fecha de última modificación, 30 de marzo de 2020.
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Latin American Journal of Clinical Sciences and Medical Technology,
Año 1, No. 1, octubre, 2019 es una publicación contínua editada por Vesalio S.C.; http://www.lajclinsci.com/    Editor responsable: Gilberto Castañeda Hernández.    Reserva de Derechos al Uso Exclusivo: 04-2019-062013242000-203; ISSN: 2683-2291; ambos otorgados por el Instituto Nacional del Derecho de Autor.    Responsable de la última actualización de este número, Web Master Hunahpú Velázquez Martínez,
Calle San Luis Potosí #182-1, Col. Roma, Alcaldía Cuauhtémoc, C.P. 06700, Ciudad de México; teléfono: 55 64 40 41    Fecha de última modificación, 30 de marzo de 2020.