Introduction

The world is home to over 3000 snake species, including over 600 venomous and nearly 200 lethal snakes, with their bites causing lethal outcomes1. In 2017, the World Health Organization (WHO) recognized snakebite as one of the most neglected tropical diseases2. It has been observed that each year, about 1.8 to 2.7 million people are attacked by venomous snakes worldwide, resulting in 81,000 to 138,000 fatalities and around 400,000 disability cases3,4. Because of the significant morbidity and mortality associated with snakebites, the WHO has launched a global campaign to reduce 50% of the incidence of snakebites by 20305,6. In China, over 280 snake species are spread across 9 families and 66 genera. In recent years, there has been a rising annual trend in snakebite occurrences across China. Currently, there is a significant gap in comprehensive clinical epidemiological data on snakebites in the country. It has been estimated that in China, over 100,000 people experience snakebite each year, with approximately 5 to 10% mortality rate and 20% cases resulting in disabilities, posing a severe threat to human safety7.

This study conducted a retrospective analysis of Chinese cobra bite patient data collected from the largest general teaching hospital in Guangxi Province, Southwest China, between 2011 and 2023. China faced a notable shortage of Chinese cobra antivenom from 2008 to 2017 due to production issues8. The hospital had last stocked serum in 2010 after production ceased in 2008. After 2018, Chinese cobra antivenom became a routine treatment. Therefore, a number of patients did not receive antivenom due to limitations in its production9,10.

We have carried out this study to summarize the clinical signs, treatment approaches, and outcomes of Chinese cobra bite cases through a retrospective analysis of general data, clinical symptoms, and laboratory findings. The study objective was to provide a clinical reference and guidance for the treatment of cytotoxic snake bites, especially those caused by Chinese cobras. Considering the persistent shortages of antivenom in certain regions, particularly in remote or poverty-stricken areas, the study focused on comparing and analyzing the utilization of antivenom. The findings provide evidence-based support for dealing with Chinese cobra bites in situations where antivenom is not accessible, facilitating appropriate treatment strategies for venomous snake bites.

Methods

All the data of Chinese cobra bite patients hospitalized at the First Affiliated Hospital of Guangxi Medical University from January 2011 to December 2023 were compiled. Relevant medical records were retrieved from the hospital’s electronic information system (HIS), which stores patient information electronically. The inclusion criteria were: ① A definitive patient report of Chinese cobra snakebite, such as by accurately describing the basic snake characteristics (matching those of Chinese cobras) and identifying the snake when shown a standard picture; ② The patient brought the snake to the hospital or took photos of the snake, which the doctor identified as a Chinese cobra. ③ Clinical symptoms consistent with Chinese cobra bite, such as the visible fang marks and local envenoming (swelling, pain, blistering, and necrosis). Each case included in the study was diagnosed as a Chinese cobra bite. Data collected included patient demographics (age and sex), blood biochemical results during hospitalization, body temperature, treatments administered, length of hospital stay, and treatment outcomes (including survival status, wound healing at discharge, etc.), documented on a structured data sheet.

Cases excluded from the study involved venomous snake bites with an unclear diagnosis and patients whose treatment was discontinued before hospital discharge due to various reasons, preventing completion of their treatment.

Due to the retrospective nature of the study, the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University waived the informed consent requirement. All methods were performed in accordance with the guidelines and regulations of the Ethics Committee.

Statistical analysis

All the collected data were analyzed using the SPSS 26.0 statistical software (SPSS Inc, Chicago, Illinois, USA, version26.0. URL link: https://www.ibm.com/products/spss-statistics). Quantitative data that followed a normal distribution were reported as mean ± standard deviation (\(\overline{x}\) ± S), while those not following a normal distribution were described using the median and interquartile range. Categorical data were presented as counts and percentages. The T-test was performed to compare the means of two normally distributed independent samples. The chi-square test (x2-test) was conducted to compare proportions within the contingency table data. Furthermore, the rank sum test was carried out to compare ordinal data between the groups. All the statistical tests were two-tailed, with a significance level set at α = 0.05. p < 0.05 was deemed statistically significant.

Results

A total of 804 patients were treated for snakebite in this hospital between 2011 and 2023. Of these 804 patients, 282 (35.1%) were bitten by Chinese cobras and were selected for this study (Table 1). Of the included 282 patients, 210 (74.5%) were males, 72 (25.5%) were females, spanning all age groups, with the majority aged between 20 and 60 years (83.7%). The oldest patient was 78 years old, and the youngest was 9 years old (Fig. 1). In China, cobras are often raised for use in traditional medicine; it was observed that 69 (24.5%) cases occurred while handling these snakes. Furthermore, 106 (37.6%) cases occurred because the bites were from captive snakes, while the remaining 107 (37.9%) cases resulted from accidental bites or after actively chasing the snakes to dislodge them.

Table 1 The general information of enrolled patients.
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Fig. 1
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Gender and age composition.

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From January 2011 to July 2017, due to limitations in antivenom production, no patient (184 of 282,65.2%) received Chinese cobra antivenom. However, after July 2017, 98 patients (34.8%) were treated with Chinese cobra antivenom. Comprehensive blood tests were conducted for all admitted patients, including routine blood work and creatine kinase tests. Blood samples were collected from all patients before administering antivenom. Among all venomous Chinese cobra bite cases, 41 (14.5%) indicated normal creatine kinase levels at admission, while 241 (85.5%) had significantly elevated levels. White blood cell (WBC) counts were normal in 35 (12.4%) patients and elevated in 247 (87.4%). In terms of recovery, 172 (60.9%) patients fully recovered, 84 (29.8%) experienced functional healing with outcomes like residual scars, 12 (4.3%) suffered permanent disabilities such as amputations, and the prognosis for 14 (5%) patients could not be confirmed due to incomplete discharge records and lack of follow-up. Moreover, there were no reported deaths directly attributable to cobra bites, regardless of antivenom use (Table 1).

Snakebite cases were reported throughout the year, with the highest frequency from April to November, which significantly declined from December to March. Furthermore, there were notable snakebite cases reported in February (Fig. 2).

Fig. 2
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Frequency of snake bites by month.

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Among the 282 snakebite patients, 67 (23.8%) reported symptoms of dizziness, chest tightness, or shortness of breath, which later resolved spontaneously, and there was no evidence linking these symptoms to organic lesions. Gastrointestinal reactions like nausea, vomiting, abdominal pain, and diarrhea were experienced by 16 out of 184 (8.7%) patients shortly after being bitten by a Chinese cobra. Anaphylaxis was observed in 6 out of 98 (6%) patients treated with antivenom, with recovery following treatment. Hyperthermia is defined as a body temperature of ≥ 37.3℃, which was recorded in 125 (44.3%) patients throughout the treatment period. Secondary organ damage was noted in 44 (15.6%) patients, primarily affecting the kidneys. This damage was more chronic in the case of pre-existing conditions and was more common in patients who had prolonged hospital stays, severe illnesses, and repeated secondary infections. The symptoms include fever, local redness, pain, and even pus, with examinations indicating increased WBCs and neutrophil percentage. The patients were graded according to the Snakebite Severity Scale11. Overall, 15 (5.3%) patients were asymptomatic, with only bite marks and no obvious local necrosis, presumed to have been caused by a dry bite. Furthermore, 182 (64.5%) patients showed mild symptoms, with swelling at the bite site without spreading and no obvious necrosis, while 67 (23.8%) patients had symptoms of moderate envenomation (observed in the spread of swelling to the periphery), necrosis, and systemic envenomation (including fever or organ damage), but with stable hemodynamics and no respiratory failure. In addition, 18 (6.4%) patients were severely poisoned, with a large necrotic area, swelling in the affected limb, osteofascial compartment syndrome, damage to multiple organs, hemodynamic instability, and even respiratory failure (Table 2).

Table 2 Patient symptoms.
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In China, snakes are bred on a large number scale. Some patients were bitten while handling farmed snakes. It was observed that the severity of symptoms and the likelihood of developing sequelae were lower in these patients than those bitten by wild snakes, and the differences were statistically significant (p < 0.01, Table 3).

Table 3 Therapeutic effects following bites by captive and wild cobras.
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Most patients admitted to the hospital did not show any increase in WBCs (normal range 3.5–9.5*109/L, neutrophil percentage range 40–75%). This initial count was measured before administering antivenom, and the results revealed that whether or not antivenom was used, it did not affect the initial WBC count in patients bitten by Chinese cobras; there was no statistically significant difference (p > 0.05, Table 4). Considering 37.3℃ as the temperature threshold for fever, the patients had no symptoms of fever despite elevated WBCs (> 9.5*109/L). A reexamination between 4 and 7 days revealed normalization of WBC counts and neutrophil ratios, with no fever. However, if patients had not fully recovered after a week, their WBC counts increased again, and fever developed regardless of antivenom use. Moreover, although antibiotics could temporarily reduce the fever, this condition recurred and persisted throughout the follow-up treatment period.

Table 4 Association of antivenoms with infection.
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After the Chinese cobra bite, the increase in WBCs within the first three days did not correlate with the presence of fever, regardless of whether antivenom was used. However, a correlation was observed between elevated WBCs and neutrophils and varying body temperatures after four days. Furthermore, patients with increased WBC counts were more likely to develop fever (Table 5).

Table 5 Relationship between WBCs and fever.
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The toxin of the Chinese cobra is predominantly cytotoxic, causing local necrosis in most cases, along with muscle cell damage and necrosis. This results in elevated levels of creatine kinase in the blood (normal range 50–175 U/L), which is positively correlated with the severity of the disease (p < 0.01). An early, pronounced rise in creatine kinase levels indicated more severe local damage and a longer treatment duration (Fig. 3).

Fig. 3
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Relationship between creatine kinase and hospital stays.

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The average length of hospital stays of patients after antivenom application was significantly reduced compared with those who did not receive it (6.71:11.76, p < 0.01). Moreover, antivenom use was associated with a significantly reduced need for surgical interventions and the severity of sequelae (p < 0.01). Regardless of antivenom application, under the current treatment protocols and with proactive medical care, there were no deaths directly attributable to snake venom following Chinese cobra bites (Table 6).

Table 6 Effect of antivenom on prognosis.
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Discussion

Most snake bites are globally associated with poverty or agriculture3,12,13. However, in China, some snakes are bred for use in traditional Chinese medicine; therefore, the cases of snake bites differ from the typical causes in other countries. In this study, the patients were between 9 and 78 years old, with the majority between 20 and 60 years old. Furthermore, the observed predominance of male patients over females may be attributed to the higher likelihood of men engaging in activities such as catching or raising snakes due to a generally lower fear of snakes than women. As snake protection measures improve and snake farming expands, bites from trapping are decreasing while those from breeding are on the rise. Children and the elderly are similarly prone to accidental bites. It has been found that the peak bite season is from April to November, which coincides with the activity season of snakes. Since snakes are cold-blooded and tend to hibernate, the cooler climate from December to March in Guangxi marks their hibernation period, and the sporadic bite incidents during these months are usually associated with snake farming. February is associated with the Spring Festival, the most significant festival in China, during which people return to their hometowns to celebrate the festival and thus activities such as snake farming are reduced. Consequently, the incidence of snake bites was lower14.

Here, approximately 23.8% (67 out of 282) of snakebite patients experienced symptoms like dizziness, chest tightness, or dyspnea, which later alleviated on their own. There is no direct evidence linking these symptoms to organic lesions, which were considered subjective and a result of fear or panic. The Chinese cobra primarily releases cytotoxins, and symptoms like dyspnea are not typically seen after a bite15,16,17, suggesting these reactions could be psychological. The inherent fear of snakes in humans might lead to psychological distress following a bite from a venomous snake18,19. In this study, some patients indicated pronounced gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea. These gastrointestinal reactions cannot be explained by psychological factors and have been specifically reported following cobra bites20,21, indicating that cobra venom may contain toxins that irritate the gastrointestinal system, though the exact components remain undetermined. Most patients did not show direct organ damage; however, those who did suffer organ damage had it as a secondary complication to pre-existing conditions. Severe infections or significant necrosis of muscle tissue following the bite allowed toxins to enter the bloodstream, leading primarily to kidney damage. Unlike in animal models where direct liver and indirect kidney damage are observed, such phenomena are less apparent in humans. This might be because of the differences in the target organs affected by snake venom between humans and animals22,23,24.

Patients bitten by farmed snakes experienced milder symptoms and fewer sequelae than those bitten by wild snakes25. Possible reasons include: ① Most farmers possess basic knowledge and tools for initial snakebite treatment; for instance, they are equipped with first-aid devices like negative pressure suction for detoxification26 and usually can quickly reach a hospital for optimal treatment after a bite; ② Breeding snakes are fed regularly, which often results in the venom being depleted from their venom sacs; therefore, the amount of venom injected during a bite is reduced; ③ The venom of farmed snakes may differ significantly from that of wild snakes. Previous research has indicated that macroscopic factors such as the type of prey (whether ectothermic or endothermic) can influence changes in snake venom composition during a species’ development27,28. Farmed cobras are typically fed dead chicks that have been culled from farms and stored in cold conditions, whereas wild cobras consume raw prey at ambient temperatures. This dietary difference could significantly change the composition and potentially reduce the toxicity of the venom in farmed snakes compared to that of wild snakes. ④ In addition, snake handlers who are repeatedly bitten by snakes might develop antibodies against snake venom, which provides them with certain immunity29,30,31,32. A crucial issue arises because of the significant differences in venom composition between farmed and wild cobras33, as most currently produced antivenoms use venom from farmed cobras. This raises the question of whether these antivenoms are sufficiently effective in treating bites from wild snakes.

Antivenom is recognized as an effective treatment for snake bite; however, it is unable to prevent soft tissue infection. It has been reported that 27.17% of patients with cobra bites develop a secondary wound infection34. In addition, the prophylactic use of antibiotics for treating cobra bites is controversial35. The majority of patients (247 out of 282; 87.6%) indicated elevated WBC counts, primarily neutrophil, but no sign of fever (Table 5). This phenomenon could be attributed to the cytotoxic nature of Chinese cobra venom, which leads to local cell necrosis and non-bacterial inflammation following a bite. Furthermore, conditions such as local osteofascial compartment syndrome may arise, contributing to increased WBCs36. Moreover, the stress response triggered by the bite might also increase WBC counts37. However, since the early local necrosis caused by a cobra bite does not generally involve the entire body, the systemic inflammatory response is not severe, and fever does not occur. Here, no correlation was observed between the early increase in WBCs and the incidence of fever (p < 0.01), and WBC counts returned to normal without using antibiotics in the early stages after a bite.

In the intermediate and later stages following a snakebite, simultaneous occurrences of increased WBCs and fever are common. This is typically due to soft tissue necrosis caused by the cobra bite, which can cause secondary bacterial infections38,39. The likelihood of infection has been associated with the severity of the bite, and patients with moderately severe disease or venomous snake bite envenomation often experience recurrent wound infections40,41,42. For Chinese cobra bites, the more extensive the soft tissue necrosis, the higher the chance of secondary infection and the more challenging it becomes to manage the infection. This can be attributed to two main factors: First, the bacteria found in an infected snakebite wound often reflect the microbial flora present in the snake’s mouth, as pathogens are directly transferred from the snake’s mouth into the wound; Second, the tissue damage caused by the venom provides an opportunity for bacteria from the snake’s mouth, the skin’s symbiotic flora, or environmental bacteria to colonize the wound34. In the early stage of a cobra bite, leukocyte elevation is not typically indicative of secondary bacterial infection and thus does not justify the preemptive use of antibiotics. However, during the middle and late stages, in case of increased WBCs accompanied by fever, secondary infection at the bite site should be suspected. Managing the wound carefully by removing necrotic tissue and administering effective antibiotic treatment is crucial43.

Creatine kinase, found in muscle tissue, is released into the bloodstream when muscle cells are damaged, increasing its levels in the blood. Therefore, creatine kinase is a useful marker for indirectly assessing the extent of muscle damage. In cases of Chinese cobra bite injuries, 85.5% (141 out of 282) of the patients had elevated creatine kinase levels. This was associated with the cytotoxin in Chinese cobra venom, which can directly cause cell hydrolysis, leading to cell necrosis and rupture, thereby releasing creatine kinase into the bloodstream22. In some cases, patients did not show a significant increase in creatine kinase levels following a Chinese cobra bite, which might be attributed to the location of the bite and the amount of venom injected. Occasionally, a bite might not penetrate deep into the tissue but merely scratch the surface with the snake’s teeth, preventing venom from being effectively released into the body. Furthermore, there are instances known as “dry bites,” where, despite clear bite marks, the cobra does not inject any venom. The “dry bite” phenomenon was first recognized in the early 1980s, defined as a venomous snake bite where no or only a negligible amount of venom is injected, resulting in no clinical signs of envenomation post-bite44. “Dry bite” rates vary between snake species, with about 50% of snake species exhibiting dry bite45,46. Possible causes of dry bite include: ① Snakes may evaluate their interaction with a target and choose not to activate the muscles that control their venom glands, thereby releasing no venom; ② The ability of the snake to activate these muscles might be limited, which is common in juvenile snakes. However, some juvenile snakes may release more venom after a bite than adult snakes47. Moreover, some patients were bitten after feeding the snake, resulting in less apparent local necrosis. It is suspected that the venom glands are depleted of toxins post-feeding, which results in reduced venom release. It is difficult to determine whether the bite is a “dry bite” or not in the early stage. It can be typically assessed based on clinical signs, inflammation markers, and other auxiliary indicators48. The creatine kinase level is directly correlated with the extent of muscle cell damage and can be used as one of the criteria to determine if a bite was a “dry bite.” The present retrospective analysis revealed that an increase in creatine kinase levels after a Chinese cobra bite is directly correlated with longer treatment recovery periods (p < 0.01), indicating a more severe bite and serving as a marker for bite severity (Fig. 3).

Antivenom is the preferred snakebite treatment and can significantly reduce patient mortality and expedite recovery. Antivenoms are available in monovalent or multivalent forms, which are effective against specific snakes but do not cross-protect against other snakes, whereas polyvalent antivenoms cross-protect against bites from multiple snakes. Monovalent or polyvalent antivenoms have their advantages and disadvantages. Monovalent antivenoms have high antibody titers and strong effects, but the culprit snake needs to be identified before use, while polyvalent antivenoms require higher production technology and production costs48. The risk of hypersensitivity reactions to antivenoms ranges from very low to high (type 1 or acute), depending on the source animal, whether an IgG, F(ab′)2, or Fab fragment is produced, further purification techniques, and host factors49,50,51. Moreover, there is no evidence that monovalent antivenoms are associated with significantly fewer adverse effects compared with polyvalent antivenoms50.

Soft tissue necrosis is a common complication following Chinese cobra bites, and wound necrosis can occur despite the early administration of large amounts of antivenom16,38,52. This might be because the antibodies in Chinese cobra antivenom do not effectively target the cytotoxins in the venom, which are low molecular weight proteins (< 10 k Da) with low immunogenicity53,54. In addition, after intravenous administration, the local concentration of antivenom might be insufficient to completely neutralize the venom remaining at the bite site55,56. After a Chinese cobra bite, significant local necrosis has been observed, affecting the skin, muscles, blood vessels, and even the bone fascia, and often does not heal on its own. Furthermore, many patients develop secondary bacterial infections at the necrotic site, which further exacerbates the necrosis. Some patients may require one or more reconstructive surgeries, such as skin grafting, to aid wound healing57,58. In severe cases, when the treatment is delayed or the venom dose is high, extensive necrosis can lead to amputation. Recently, vacuum sealing drainage (VSD) technology has proven effective in reducing the extent of necrosis and accelerating healing after cobra bite injuries59.

A comparison between patients treated with Chinese cobra antivenom and those who were not indicated that those receiving antivenom had shorter average hospital stays and were less likely to require subsequent surgical interventions (Table 6). Furthermore, the incidence of adverse sequelae and amputations was lower among patients treated with antivenom compared to non-treated patients (Table 6). Under the current medical regimen, no fatalities have been reported after adequate treatment for Chinese cobra bites, regardless of the use of antivenom. The Chinese cobra, belonging to the cobra family, does not cause direct fatalities60,61. Moreover, it shares many characteristics with other cobras but also displays some distinct differences. For instance, the Indian cobra has a higher content of neurotoxins, which can cause nerve blockage, respiratory muscle weakness, and potentially fatal outcomes for the patient62,63. In contrast, the Chinese cobra venom primarily consists of cytotoxins, with fewer neurotoxins and other components. A bite from a Chinese cobra does not cause immediate respiratory or cardiac arrest but death can still occur due to MODS triggered by soft tissue necrosis and secondary infections64. However, advancements in medical care have significantly mitigated these complications, virtually eliminating fatalities, though the rate of local necrosis remains high60. After a Chinese cobra bite, most cytotoxins initially accumulate at the bite site and then spread through the surrounding soft tissue65. These cytotoxins do not enter the bloodstream66; therefore, distant cell necrosis is rare. When Chinese cobra antivenom is administered, it travels through the bloodstream to the bite area, where it binds to and neutralizes the venom, thereby inhibiting subsequent soft tissue necrosis. It has been established that early and sufficient use of antivenom is beneficial for wound healing16,67,68. Since snake venom is a heterologous protein, it was inferred that it would stimulate antibody production after entering the human body, thereby clearing the venom. Thus, snake venom in the human body will be cleared even if the antivenom is not administered. However, it takes time for antibodies to develop, suggesting why patients who do not receive antivenom take longer to recover. This can also be because the snake venom may degrade or metabolize in vivo69. However, further research is warranted. Although bites from Chinese cobras are generally nonfatal, studies have indicated that the early administration of antivenom is nevertheless beneficial18,26. Therefore, currently, the principal clinical outcome of Chinese cobra antivenom is not to reduce mortality but to decrease the incidence of local necrosis.

Limitations

We conducted a retrospective analysis of data on Chinese cobra bites treated at our hospital over the past decade, and summarized the clinical manifestations, treatment protocols, and prognostic outcomes associated with these envenomations. Additionally, the efficacy of antivenom therapy versus non-antivenom interventions was compared. The findings provide valuable insights for the management of cobra bites. However, the study was conducted at a single hospital, potentially limiting the generalizability of the findings to broader populations or geographical regions. As a retrospective analysis, the study relied on existing medical records, which may be incomplete or contain errors, leading to potential biases in data collection and analysis. Despite data collection over a significant period, the sample size of 282 patients is relatively small, potentially limiting the statistical power and generalizability of the study findings. Furthermore, the patients included in the study may not have been representative of all snakebite cases, as those who sought treatment at the hospital may have differed in the severity of their condition or other characteristics compared to those who did not seek medical care. In addition, the study period spanned a decade, during which changes in treatment protocols or medical practices may have occurred, potentially influencing patient outcomes and complicating the interpretation of results.

Conclusion

This study revealed that after a Chinese cobra bite, local necrosis typically dominates, accompanied by transient non-bacterial inflammation in the initial stages. Prophylactic antibiotics are ineffective during this phase, as they cannot prevent local infection, which tends to recur and worsen later. Effective treatment involves removing necrotic tissue and facilitating wound healing with anti-infection measures. Furthermore, creatine kinase levels correlate with the extent of local damage post-bite, indicating severity. In addition, early administration of Chinese cobra antivenom has benefits, such as effective alleviation of local necrosis and reduced adverse healing outcomes. However, under current treatment protocols, the use or nonuse of Chinese cobra antivenom does not significantly impact survival outcomes.

As the study was retrospective in nature with a relatively small sample size, further confirmation of the findings is needed using prospective studies with larger samples.