INTRODUCTION
Among the six indigenous venomous snakes of medical importance in Taiwan, Taiwan habu (Protobothrops mucrosquamatus, formerly Trimeresurus mucrosquamatus)1 and green habu (Viridovipera stejnegeri, formerly Trimeresurus stejnegeri)2 are responsible for most cases of envenoming. 3,4 Preclinical laboratory studies in Taiwan had shown that the species–specific monovalent antivenom against P. mucrosquamatus had limited cross-reactivity with the venom of V. stejnegeri, and vice versa5; this phenomenon is different from the cases of other Trimeresurus antivenoms in Thailand and Malaysia, which have broad cross-reactivities. 6,7 Clinically, however, in the absence of specific immunodiagnostic tests, it is still difficult to distinguish between envenoming by P. mucrosquamatus and V. stejnegeri because of the similarities of early local symptoms and signs. Given the previous facts, it becomes practical and safe to prepare bivalent antivenom that covers both P. mucrosquamatus and V. stejnegeri. An equine-derived bivalent F(ab’)2 fragment antivenom has been produced and marketed in Taiwan since 1980.8 Although P. mucrosquamatus and V. stejnegeri are currently classified into different genera, the bivalent antivenom remains the treatment of choice for envenoming by the two pit vipers.
Recent hospital-based studies in Taiwan suggested that the clinical effects and outcomes might be different between envenoming from P. mucrosquamatus and V. stejnegeri,4,9 with the former causing more severe symptoms. In Thailand, Hutton and others 10 showed that there are differences in clinical manifestations between T. albolabris and T. macrops envenoming, with the former resulting in more unfavorable clinical symptoms and outcomes. In Taiwan, no previous study has systematically examined the species–specific clinical manifestations and responses to antivenom therapy after P. mucrosquamatus and V. stejnegeri envenoming in humans. In light of the newly revised taxonomy and the need to better understand the differences in clinical profiles between P. mucrosquamatus and V. stejnegeri envenoming, we conducted a retrospective analysis of patients admitted to a tertiary medical center after envenoming by the two pit vipers in Taiwan.
MATERIALS AND METHODS
The research protocol was approved by the Institutional Review Board at the Taipei Veterans General Hospital. Medical records of patients with snakebite who were admitted to the hospital from 1991 through 2006 were reviewed.
Identification of snakebites.
Culprit snakes were identified and documented by emergency physicians via either: 1) identifying the snake brought in by the patient and/or, 2) having the patient identify the snake by pictures. The two species are easily distinguishable because of their markedly different appearances of color pattern and total length. For V. stejnegeri, the average total length is about 70 cm (ranging from 50 to 90 cm), and the color is bright to dark green over the dorsal side and pale green to whitish on the ventral side. Protobothrops mucrosquamatus is longer, with average total length of about 120 cm (ranging from 100 to 150 cm), and its color is grayish or olive brown on the dorsal part, with dorsal series of continuous large brown, black-edged patches, and with whitish belly heavily powdered with light brown color. There are no other crotalines (pit vipers) with similar appearances in Taiwan. We excluded patients with neurotoxic snakebites (Naja atra and Bungarus multicinctus), bites from hundred-pace snake (Deinagkistrodon acutus), Taiwan Russell’s viper (Daboia siamensis), and bites from unidentifiable snakes.
Classification of complications.
Clinical effects of P. mucrosquamatus and V. stejnegeri envenoming ranged from local signs (e.g., tenderness, edema, and erythema) to systemic complications, including thrombocytopenia, coagulopathy, rhabdomyolysis, acute renal failure, and spontaneous systemic bleeding. 4,9,11 We used World Health Organization (WHO) guidelines for the clinical management of snakebites in the Southeast Asian region in the classification of clinical syndromes and complications of snake envenoming. 12
Systemic complications included thrombocytopenia defined by a platelet count < 150,000/mm3; coagulopathy defined by international normalized ratio (INR) > 1.25, and severe coagulopathy by INR > 1.67 13; rhabdomyolysis defined by creatine kinase (CK) > 1,000 U/L, and severe rhabdomyolysis by CK > 10,000 U/L 14; acute renal impairment defined by creatinine > 1.4 mg/dL, 13 and acute renal failure by creatinine > 3.0 mg/dL and oliguria of less than 400 mL urine in 24 hours. Manifestations of spontaneous systemic bleeding were routinely checked (generally more than or equal to twice daily) in the study hospital by both nurses and attending physicians and were documented in the medical charts.
Local complications included 1) cellulitis – diagnosis as documented in medical charts, including local manifestations plus signs of infection such as fever, increased C-reactive protein, and/or painful lymphadenopathy; 2) necrosis – clinical symptoms and signs as documented in medical chart and operative notes; and 3) compartment syndrome – clinical symptoms with intra-compartmental pressure documentation > 30 mmHg and operative note confirmation. Surgical treatments consisted of debridement, dermatomy, fasciotomy, and skin graft, whereas permanent sequela was defined as digit or limb amputation.
Outcome measures.
The main outcomes were systemic complications, especially life-threatening complications that were defined as severe rhabdomyolysis and acute renal failure. Other outcome measures included local complications, surgical treatments, permanent sequela, and length of hospital stay. We tabulated all outcome measures by counting the occurrence of each individual event.
Analysis plan and statistical methods.
The information on major comorbidities (e.g., diabetes mellitus), sites of snake-bite, severity of envenoming, timing of initial administration of antivenom, and use of antibiotics was abstracted from medical records. Severity of envenoming was classified into mild, moderate, severe, and very severe according to the number of swollen limb segments (1 to 3) and whether systemic effects were present. 15
We analyzed the data by the Statistical Product and Service Solutions (SPSS for Windows, version 11.0, Chicago, IL). Continuous variables were expressed as mean ± standard deviation, and categoric variables were expressed as proportion in percentage (%). We used student’s t test to compare inter-group difference in continuous variables, and used Fisher’s exact test to evaluate categoric variables. Because of a relatively small number of patients and rare occurrence of certain outcome measures in the V. stejnegeri group, we used univariate analysis with Peto method to estimate the odds ratio (OR) of developing categoric outcomes by using patients bitten by V. stejnegeri as the reference group. 16 Peto OR were expressed as point estimate and relevant 95% confidence intervals (CI). A P value less than 0.05 was considered statistically significant.
RESULTS
Demographic data and manifestations of envenoming.
There were initially 270 inpatients whose medical records were available for review. After the application of various exclusion criteria (N. atra and B. multicinctus 44 patients, D. acutus 3 patients, D. siamensis 2 patients, unidentifiable snakes 21 patients), a total of 200 patients, including 149 patients with P. mucrosquamatus envenoming and 51 patients with V. stejnegeri envenoming, were eligible for final analysis. Of the 200 patients, 102 patients brought the culprit snakes to the emergency department (ED), and 98 patients identified the snakes by picture recognition in ED. Patients with P. mucrosquamatus envenoming were younger and were bitten more frequently in lower limbs, developed bruising more easily, received more antivenom, and had a longer hospital stay (Table 1) as compared with those patients bitten by V. stejnegeri . The baseline characteristics of the 200 patients are summarized in Table 1.
Main outcomes.
Systemic and life-threatening complications.
The depvelopment of systemic complications, especially life-threatening complications (severe rhabdomyolysis and acute renal failure) was markedly different between the two groups of patients. All of the eight patients (5%) who developed life-threatening complications were envenomed by P. mucrosquamatus (Table 2). All of the 9 patients (6%) who developed coagulopathy (including one with severe coagulopathy) were envenomed by P. mucrosquamatus. None of the patients had spontaneous systemic bleeding, such as gingival bleeding, hemoptysis, hematemesis, or gross hematuria. Rhabdomyolysis (including four with severe rhabdomyolysis) was detected in 11% of patients (17 out of 149) envenomed by P. mucrosquamatus and 2% of patients (1 out of 51) envenomed by V. stejnegeri. Eight patients (5%) envenomed by P. mucrosquamatus had acute renal impairment (including five with acute renal failure), as compared with two (4%) acute renal impairments by V. stejnegeri. All renal impairment and renal failure developed within 3 days after envenoming, despite antivenom therapy. Two patients with acute renal failure required temporary hemodialysis and returned to normal renal function within 6 months.
Other outcomes.
Local complications, surgical treatments, doses of antivenom, and length of hospital stay.
In addition to systemic complications, local complications also occurred much more frequently among patients with P. mucrosquamatus envenoming (Table 2). Furthermore, patients envenomed by P. mucrosquamatus received more surgical treatments, including debridement, dermatomy, fasciotomy, skin graft, and digit amputation (Table 2). Despite the higher severity of P. mucrosquamatus envenoming, no mortality was noted during the study period. There were two patients with digit amputations. One of them received right thumb amputation and toe-to-hand transplantation. The function of the right hand was compromised. The other patient received right third toe amputation without residual dysfunction in terms of walking or working.
With regard to antivenom therapy, 1 vial of antivenom was routinely administered to all symptomatic patients on initial presentation. Antivenom was then given in increments of 1 vial every 2 hours (up to 4 vials) by clinical toxicologists and 2 vials every 2 hours (no upper limit) by surgeons until symptoms of envenoming ceased to progress.4 For patients envenomed by P. mucrosquamatus, the mean number of antivenom dose was 4.4 ± 3.6 vials, and 98 (66%) patients needed at least 3 vials during the course of treatment (Table 1). Patients bitten by P. mucrosquamatus also stayed longer in the hospital (7.5 ± 7.1 versus 3.8 ± 2.2 days, P < 0.001).
DISCUSSION
We found that P. mucrosquamatus caused more unfavorable and severe clinical events compared with V. stejnegeri, as evidenced by the occurrence of systemic complications, particularly life-threatening complications of severe rhabdomyolysis and acute renal failure. In addition, patients envenomed by P. mucrosquamatus suffered more local complications, and the necessity for surgical treatments was found only among patients with P. mucrosquamatus envenoming. The previous results might be due to the fact that the average amount of venom of P. mucrosquamatus (33.4 ± 15.5 mg) is much higher than that of V. stejnegeri (6.9 ± 3.1 mg),5 and the potency and constituents in the venoms are different, which could lead to discrepant toxicities in clinical settings. As a result of the differential toxicities, P. mucrosquamatus envenoming required higher doses of antivenom and longer hospitalization in our study.
Protobothrops mucrosquamatus snake bite also differed from V. stejnegeri snakebite in terms of their envenoming scenario. Protobothrops mucrosquamatus bit patients on lower limbs more frequently, and the accidents generally occurred nearby the house and/or footpath (Table 1). This is likely explained by the fact that P. mucrosquamatus favors eating mice and crawls on the ground around human dwellings, whereas V. stejnegeri inhabits bushes or trees during the daytime. 17
In this study, we found that P. mucrosquamatus envenoming caused a greater bleeding tendency (thrombocytopenia and coagulopathy) as compared with V. stejnegeri, which was consistent with prior observations.9 The venoms of P. mucrosquamatus and V. stejnegeri contain various components, including phospholipase A2 isoenzymes, prothrombin activation inhibitors, platelet aggregation inhibitors, and fibrinogenases, all of which have complex effects on blood coagulation and platelet aggregation. 18 Data from previous animal and in vitro studies indicated that the basic phospholipase A2 isoenzymes in P. mucrosquamatus venom exhibited a stronger anticoagulant action than the acidic phospholipase A2 isoenzymes in V. stejnegeri venom,18 and the average envenoming dose of P. mucrosquamatus is higher than that of V. stejnegeri.5 In this study, we found that the INR values in eight out of the nine patients with coagulopathy returned to normal within one day, and the one remaining within two days after antivenom treatment, which suggested that coagulopathy may be effectively reversed by prompt administration of antivenom.
In our study, 17 patients (11%) envenomed by P. mucrosquamatus (including four with severe rhabdomyolysis) and one patient (2%) envenomed by V. stejnegeri developed rhabdomyolysis. None of them had ever received intramuscular injections. Laboratory studies suggested that myotoxic phospholipases A2 in snake venoms can lead to local and systemic skeletal muscle damage through influx of calcium into the sarcoplasma. 19 Furthermore, as mentioned previously, P. mucrosquamatus envenoming involves a higher amount of venom dose,5 and such envenoming might produce systemic myonecrosis because of the effects of high contents of asparagine-6 and lysine-49 phospholipases A2 in the venom. 20,21 However, some basic phospholipiase A2 homologues found in the venom of V. stejnegeri were less potent and caused only local myonecrosis and edema in animals. 22 Our finding of the more common and severe rhabdomyolysis from P. mucrosquamatus envenoming as compared with V. stejnegeri corroborates previous laboratory research results on these two pit vipers. 20–22
Despite the administration of antivenom within two hours after snakebite, five patients (3%) with P. mucrosquamatus envenoming developed acute renal failure, with two patients requiring hemodialysis. The exact underlying pathogenesis for snake venom related nephropathy has not been well elucidated; however, several mechanisms have been proposed from previous studies: direct nephrotoxicity, hemodynamic alterations leading to renal ischemia, pigment nephropathy (e.g., myoglobinuria), and immunologic mechanisms (e.g., immune complex in situ).23 Rhabdomyolysis and hemolysis are usually the suggestive clinical features for pigment nephropathy. In this study, none of the five patients with acute renal failure developed rhabdomyolysis or hemolysis. Therefore, these patients’ clinical pictures do not suggest a strong correlation between pigment nephropathy and acute renal failure. Prior reports of P. mucrosquamatus envenoming in Taiwan have shown that regardless of the dose and timing of antivenom administration, the development of acute renal failure requiring hemodialysis seems inevitable in some cases, 9,24 a phenomenon similar to other hemorrhagic snakebites. 25 Renal biopsy in a Taiwanese patient with acute renal failure from P. mucrosquamatus envenoming showed tubular necrosis and interstitial nephritis, which suggested the roles of hemodynamic alteration and direct nephrotoxicity in causing P. mucrosquamatus venom-related nephropathy. 23,24
In our study, P. mucrosquamatus envenoming resulted in more severe local manifestations (limb necrosis and compartment syndrome), which might be explained by the snake’s larger amount of venom as discussed earlier, and a higher magnitude of myotoxicity. In animal studies, P. mucrosquamatus envenoming produced myonecrosis and limb edema resulting from phospholipase A2 isoenzymes, proteases, and esterases in conjunction with degranulation of mast cells. 26,27 However, the phospholipase A2 isoenzymes from V. stejnegeri resulted in tissue damage of a milder degree. 22
Identification of the culprit snakes in this study was likely to be accurate because the two species are easily distinguishable by their appearances. However, immunodiagnosis (if available) and preservation and proper documentation of the dead snakes brought in by the patients should always be considered in future studies for species identification. Furthermore, this study was retrospective in design; the identification of minor study outcomes might thus be incomplete and could result in under- or overestimation of certain effects. In particular, the outcome measure of cellulitis was based on the diagnoses as documented in medical charts and was dependent mostly on the accuracy of physician’s clinical judgment at the time of admission. However, because local envenoming effects could be difficult to distinguish from true cellulitis in the absence of definitive microbiology culture, the true incidence of cellulitis in our study could have been overestimated. In contrast, the findings on the major outcomes were unlikely to be biased, but the rare occurrence of certain outcome measures would jeopardize effective comparisons between patients bitten by P. mucrosquamatus and V. stejnegeri.
In conclusion, we found that the general clinical manifestations of P. mucrosquamatus and V. stejnegeri envenoming in Taiwan were largely similar to those of other pit vipers in Southeast Asia. 12 Nevertheless, P. mucrosquamatus envenoming caused more severe clinical manifestations than V. stejnegeri, reflecting the differences in the amount, potency, and constituents of the venoms between the two pit vipers. Because of the higher toxicity, patients with P. mucrosquamatus envenoming seemed more likely to develop life-threatening complications and needed higher antivenom doses and longer hospitalization. On the basis of the results of this study, the authors recommend that in the case of P. mucrosquamatus envenoming, the initial antivenom dosage should be higher than the dose regimen currently recommended by the Taiwan Poison Control Center.4 In addition, special precautions in monitoring potential major complications, especially acute renal failure, should be exercised in patients with P. mucrosquamatus envenoming, even after administration of antivenom therapy. In accordance with the new taxonomy, which reclassified P. mucrosquamatus and V. stejnegeri into different genera, our study also showed that envenoming by these two pit vipers in Taiwan manifested in different clinical profiles. Further studies are needed to support our findings and to develop a more specific model associating the clinical manifestations and treatment recommendations.
Distribution of demographic and clinical characteristics of 200 patients with pit viper bite in Taiwan
| Characteristics | P. mucrosquamatus N = 149 (%)* | V. stejnegeri N = 51 (%)* | P value† |
|---|---|---|---|
| * P. mucrosquamatus denotes Protobothrops mucrosquamatus envenoming, whereas V. steinegeri denotes Viridovipera stejnegeri envenoming. | |||
| † All P values were derived from Fisher’s exact test except for mean age, mean antivenom dose, and hospital stay. | |||
| ‡SD = standard deviation. | |||
| Age, mean ± SD years‡ | 43.5 ± 18.5 | 52.7 ± 19.1 | 0.003 |
| Age ≥ 65 | 24 (16) | 19 (37) | 0.003 |
| Male | 101 (68) | 32 (63) | 0.6 |
| Major comorbidities | 4 (3) | 0 (0) | 0.6 |
| Sites of snakebite | < 0.001 | ||
| Upper limb | 55 (37) | 41 (80) | – |
| Lower limb | 94 (63) | 10 (20) | – |
| Acute symptoms/signs | |||
| Local pain | 149 (100) | 51 (100) | 1.0 |
| Inflammation | 149 (100) | 51 (100) | 1.0 |
| Bleeding from fang marks | 45 (30) | 11 (22) | 0.3 |
| Bruising | 112 (75) | 26 (51) | 0.003 |
| Blistering | 26 (17) | 4 (8) | 0.1 |
| Severity of envenoming | |||
| Mild | 13 (9) | 4 (8) | 1.0 |
| Moderate | 67 (45) | 28 (55) | 0.3 |
| Severe | 61 (41) | 19 (37) | 0.7 |
| Very severe | 8 (5) | 0 (0) | 0.2 |
| Initiation of antivenom ≤ 8 hours | 131 (88) | 44 (86) | 1.0 |
| Treatment team | |||
| Clinical toxicologists | 81 (54) | 29 (57) | 0.9 |
| Surgeons | 68 (46) | 22 (43) | 0.9 |
| Antivenom dose, mean ± SD vials‡ | 4.4 ± 3.6 | 3.4 ± 2.9 | 0.06 |
| Antivenom dose ≥ 3 vials | 98 (66) | 21 (41) | 0.003 |
| Use of antibiotics | 113 (76) | 32 (63) | 0.1 |
| Hospital stay, mean ± SD days‡ | 7.5 ± 7.1 | 3.8 ± 2.2 | < 0.001 |
Comparison of clinical outcomes between 149 patients with Protobothrops mucrosquamatus envenoming and 51 patients with Viridovipera stejnegeri envenoming in Taiwan
| Outcomes | P. mucrosquamatus* N = 149 (%) | V. stejnegeri* N = 51 (%) | Peto odds ratio | 95% confidence interval | P value† |
|---|---|---|---|---|---|
| * P. mucrosquamatus denotes Protobothrops mucrosquamatus envenoming, whereas V. steinegeri denotes Viridovipera stejnegeri envenoming (reference group). | |||||
| †Fisher’s exact test. | |||||
| ‡Including severe rhabdomyolysis (creatine kinase ≥ 10,000 U/L) and acute renal failure (creatinine ≥ 3 mg/dL). | |||||
| Systemic complications | |||||
| Life-threatening complications‡ | 8 (5) | 0 (0) | 4.02 | 0.80–20.28 | 0.207 |
| Thrombocytopenia | 18 (12) | 5 (10) | 1.25 | 0.46–3.37 | 0.802 |
| Coagulopathy | 9 (6) | 0 (0) | 4.05 | 0.88–18.70 | 0.115 |
| Rhabdomyolysis | 17 (11) | 1 (2) | 3.15 | 1.04–9.55 | 0.047 |
| Acute renal impairment | 8 (5) | 2 (4) | 1.35 | 0.32–5.80 | 1.000 |
| Local complications | |||||
| Cellulitis | 38 (26) | 3 (6) | 3.31 | 1.51–7.29 | 0.002 |
| Necrosis | 17 (11) | 0 (0) | 4.30 | 1.38–13.42 | 0.008 |
| Compartment syndrome | 9 (6) | 1 (2) | 2.35 | 0.55–10.07 | 0.457 |
| Surgical treatments | |||||
| Dermatomy/fasciotomy | 7 (5) | 0 (0) | 3.99 | 0.71–22.4 | 0.194 |
| Skin graft | 13 (9) | 0 (0) | 4.17 | 1.15–15.10 | 0.042 |
| Digit amputation | 2 (1) | 0 (0) | 3.85 | 0.16–93.39 | 1.000 |
Address correspondence to Chen-Chang Yang, Division of Clinical Toxicology, Department of Medicine, Taipei Veterans General Hospital, 201, Shih-Pai Road Sec. 2, Taipei 112, Taiwan. E-mail: ccyang@vghtpe.gov.tw
Authors’ addresses: Yen-Wen Chen, Department of Respiratory Therapy, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan, Republic of China, Tel: 886-933-241-960, E-mail: albert6369@gmail.com. Min-Hui Chen, Center for Drug Evaluation, Taiwan, 1F, No. 15-1, Section 1, Hang-Jou Southern Road, Taipei, Taiwan 100, Republic of China, Tel: 886-2-2322-4567, Fax: 886-2-2327-9135, E-mail: chen.minhui@gmail.com. Yen-Chia Chen, David Hung-Tsang Yen, Chun-I Huang, and Chen-Hsen Lee, Department of Emergency Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan, Republic of China, Tel: 886-2-2875-7628, Fax: 886-2-2873-8013, E-mail: ycchen4@gmail.com, hjyen@vghtpe.gov.tw, cihuang@vghtpe.gov.tw, and chlee@vghtpe.gov.tw. Dong-Zong Hung, Toxicology Center of China Medical University Hospital, 2 Yuh-Der Road, Taichung, Taiwan, 404, Republic of China, Tel: 886-4-2205-2121, Fax: 886-4-2233-1584, E-mail: dzhung@mail.cmu.edu.tw. Chien-Kuang Chen, Department of Surgery, Taoyuan Veterans Hospital, No. 100, Section 3, Cheng-Kung Road, Tao-Yuan 330, Taiwan, Republic of China, Tel: 886-932-364-872. Lee-Min Wang, Department of Emergency Medicine, Taichung Veterans General Hospital, No. 160, Section 3, Chung-Kang Road, Taichung, Taiwan, Republic of China, Tel: 886-4-2359-2525, E-mail: lmwang@vghtc.gov.tw. Chen-Chang Yang, Division of Clinical Toxicology, Department of Medicine, Taipei Veterans General Hospital, 201, Shih-Pai Road Sec. 2, Taipei 112, Taiwan, Tel: 886-2-28757525, Fax: 886-2-28739193, E-mail: ccyang@vghtpe.gov.tw.
Acknowledgment: We thank Susan S. Sheu for her critical review and editing of the manuscript.
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