Clinical Features and Antivenom Usage in Northern Cottonmouth ( Agkistrodon piscivorus ) Envenomations in Texas

Abstract

Introduction

Cottonmouths, also known as water moccasins, are responsible for <10% of the ∼5000 snakebites reported to America's Poison Centers annually. Envenomations are characterized primarily by local findings. Gastrointestinal signs and hematologic abnormalities have been reported. There are currently 2 antivenoms that are approved by the Food and Drug Administration for the treatment of cottonmouth envenomations. The purpose of this study was to describe the clinical features and antivenom use in the treatment of Northern Cottonmouth envenomations in Texas that were reported to the North American Snakebite Registry.

Methods

We reviewed cottonmouth bites reported between January 1, 2013, and December 31, 2024. Data regarding the circumstances, patient demographics, clinical features, treatment, and outcomes were reviewed.

Results

Sixty patients, with a mean patient age of 26 y, were included. Females accounted for 20 cases (33.3%). Lower extremity bites accounted for 35 cases (58.3%). Swelling was observed in 56 cases (93.3%). Emesis was reported in 10 cases (16.7%). Two patients (3.3%) experienced diarrhea. Hematologic laboratory abnormalities were present in 10 patients (16.7%). Antivenom was administered in 47 cases (78.3%), including 22 pediatric patients (84.6%). Three patients (6.4%) who received antivenom experienced minor acute hypersensitivity reactions.

Conclusions

Cottonmouth envenomations are characterized primarily by local tissue injury. Gastrointestinal signs and hematologic toxicity are observed less commonly. Antivenom is often administered for cottonmouth bites and is associated with a low incidence of acute hypersensitivity reactions. There is a trend toward treating pediatric patients more aggressively.

Keywords

antivenom cottonmouth crotaline envenomation pit viper snakebite water moccasin

Introduction

Of the ∼5000 snakebites reported to America's Poison Centers annually, 98% are due to pit vipers (eg, copperheads, cottonmouths, and rattlesnakes).^1–3 Cottonmouths, also known as water moccasins, are responsible for <10% of these cases. Consequently, many clinicians are unfamiliar with their envenomations.

There are 2 species of cottonmouths. The Florida Cottonmouth, Agkistrodon conanti, is confined to Florida and southern Georgia.⁴ The Northern Cottonmouth, Agkistrodon piscivorus (Figure 1), has a much wider geographic distribution. Although it is located primarily in the Southeast United States, from southern Virginia to Florida, A. piscivorus can be found as far west as eastern Texas and Oklahoma.⁴ There are occasional sightings in southern Illinois, Missouri, and Kansas.⁴

Figure 1.

Northern cottonmouth (Agkistrodon piscivorus). Courtesy of Nathan Wells.

Cottonmouth venom contains a variety of metalloproteinases, serine proteinases, phospholipases A2, and other cytotoxic and hemotoxic compounds. Envenomations are characterized primarily by local findings, which may include swelling, hemorrhagic blebs or bullae, ecchymosis, and necrosis^5–7 (Figure 2). Hematologic abnormalities, including thrombocytopenia, hypofibrinogenemia, and elevated prothrombin time, have been reported. Hypotension may develop. Gastrointestinal signs (eg, emesis and diarrhea), which may indicate systemic toxicity but which also may be attributable to ophidiophobia, may occur. Several deaths also have been attributed to cottonmouths in the past 40 years.⁸

Figure 2.

Cottonmouth envenomation. Courtesy of Bethany Cripanuk.

There are currently 2 antivenoms that are approved by the Food and Drug Administration for the treatment of these pit viper envenomations in pediatric and adult patients. Crotalidae polyvalent immune fab (ovine) (CroFab, BTG International Inc, West Conshohocken, PA, henceforth FabAV) has been available since 2000.⁹ Crotalidae immune F(ab’)₂ (equine) (ANAVIP, Rare Disease Therapeutics, Inc, Franklin, TN, henceforth Fab2AV) became indicated for Agkistrodon (copperhead and cottonmouth) envenomations in 2021.¹⁰

The purpose of this study was to describe the clinical features and evaluate antivenom use in the treatment of Northern Cottonmouth envenomations in Texas that were reported to the North American Snakebite Registry (NASBR).

Methods

This was a review of patient information reported to the NASBR by medical toxicologists providing bedside care for snakebite patients between January 1, 2013, and December 31, 2024. The NASBR was established by the American College of Medical Toxicology in 2013 as a subregistry of the Toxicology Investigators Consortium (ToxIC) Core Registry, a voluntary nationwide surveillance and research tool that prospectively records deidentified information for patients with toxicologic exposures.¹¹ Physicians from ∼20 sites across the United States evaluate snakebite patients at the bedside and record a variety of demographic information, clinical features, and treatments provided on every bite victim using a standardized data collection form. Specific details on snakebite data collection within the NASBR have been reported previously.¹²

All ToxIC Core Registry and NASBR data were collected and managed by the American College of Medical Toxicology using Research Electronic Data Capture (REDCap) tools hosted at the Vanderbilt University Medical Center Institute for Clinical and Translational Research.¹³ The ToxIC Core Registry and NASBR are compliant with the Health Insurance Portability and Accountability Act and do not collect any protected health information or otherwise identifying fields. Accordingly, patient consent is not obtained, and registry participation is pursuant to the participating institutions’ institutional review board approval and compliance with their policies and procedures. The ToxIC Core Registry and associated subregistries also were reviewed by the Western Copernicus Group Institutional Review Board and determined not to be human subjects research under federal regulation 45 CFR 46 and associated guidance.

Snake identifications were recorded by the treating medical toxicologist and based on patient/family report, photos of the snake, and/or in some cases the specimen at the bedside. Starting in 2017, identifications were further classified as definite or likely. Snake identification was made via multiple gross anatomic features, including the characteristic black band posterior to the eyes, the flower pattern on the dorsum of the head, and the alternating light and dark saddles with pixelated edges, which distinguishes cottonmouths from copperheads, in which the saddles have smooth edges. Identification was considered definite if a snake expert (eg, a herpetologist or a medical toxicologist with specific training in snake identification) directly visualized the snake, whether in person or by photograph. An identification was considered likely if it came from a witness with uncertain expertise in snake identification or if an expert was forced to rely on photograph in which the snake was poorly visualized. For the purposes of this study, we chose to use the term presumed instead of likely because the latter implies greater expertise than many witnesses have.

Interactions were considered intentional if, per the treating toxicologist, the victim could have avoided the bite by not knowingly interacting with the snake. Unintentional interactions were those bites that happened when the patient was unaware of the snake until after the bite occurred.

For this report, all cottonmouth bites reported to the NASBR from Texas sites from January 1, 2013, to December 31, 2024, were reviewed. Bites from other species, cases reported from sites outside of Texas, and bites in which the snake identity was unknown were excluded.

Data regarding the year, state, and circumstances of the snake encounter were reviewed. Patient demographics, antivenom utilization, and clinical outcomes were assessed. Acute hypersensitivity reactions (eg, pruritus, rash, dyspnea, and hypotension) also were recorded.

Local swelling was categorized as mild, moderate, or severe based on the descriptions provided by the treating medical toxicologist. Mild swelling was confined to <7 cm from the bite site. Moderate swelling extended 7 to 50 cm from the bite site or crossed a major joint (eg, wrist or ankle). Swelling was considered severe if it extended >50 cm from the bite or beyond 2 major joints. Hypotension was defined as a systolic blood pressure of <90 mm Hg. Hematologic toxicity was defined as any of the following: platelet count of <150,000/µL, fibrinogen count of <150 mg/dL^–1, or a prothrombin time of >15 s.

Data were entered into an Excel spreadsheet (Microsoft Inc, Redwood, WA) and analyzed by 2 of the authors. Chi-square analyses were performed when appropriate.

Results

Over this 12-year period, 60 cases were reported from 3 sites. Southeast Texas contributed 41 cases (68.3%). North Texas entered 18 cases (30%). A single case (1.7%) was reported from the site in South Texas.

Patient demographics and clinical features are summarized in Table 1. Females accounted for 20 cases (33.3%). The median patient age was 26 y (range 19 mo–76 y). Ten patients (16.7%) had 1 or more chronic illnesses.

Table 1.

Patient Characteristics and Clinical Features.

Characteristic	Detail	Total (N=60)
Median age (y)	—	26
Age (y)	<18	26 (43.3%)
	≥18	34 (56.7%)
Sex	Male	40 (66.7%)
	Female	20 (33.3%)
Bite location	Upper extremity	25 (41.7%)
	Lower extremity	35 (58.3%)
Chronic illnesses	Asthma	2 (3.3%)
	Coronary artery disease	1 (1.7%)
	Diabetes mellitus	1 (1.7%)
	Peripheral vascular disease	1 (1.7%)
	Hypertension	8 (13.3%)
	Hyperlipidemia	2 (3.3%)
Extremity swelling	None	4 (6.7%)
	Mild	14 (23.3%)
	Moderate	33 (55%)
	Severe	7 (11.7%)
	Unspecified swelling	2 (3.3%)
Tissue necrosis	Hemorrhagic bleb	3 (5%)
Hematologic laboratory abnormalities	Thrombocytopenia	3 (5%)
	Elevated prothrombin time	7 (11.7%)
Gastrointestinal signs	Emesis	10 (16.7%)
	Diarrhea	2 (3.3%)

The snake was definitively identified as Northern Cottonmouth in 18 cases (30%). For 19 patients (31.7%), the snake was presumed to be Northern Cottonmouth. Certainty of snake identification was unavailable in 23 cases (38.3%).

Eleven bites (18.3%) resulted from intentional interaction. The exact circumstances were unknown in 5 cases. Three patients were attempting to kill the snake when they incurred the bite. Two intoxicated patients picked up the snake for unclear reasons. One victim picked the snake up believing it was nonvenomous.

Lower extremity bites accounted for 35 cases (58.3%), and 25 patients (41.7%) sustained bites to the upper extremity. Swelling was observed in 56 cases (93.3%). Three patients (5%) developed hemorrhagic blebs prior to hospital discharge, and an additional patient experienced a hemorrhagic bleb after going home. Emesis was reported in 10 cases (16.7%), and 2 patients (3.3%) experienced diarrhea. Neither hypotension nor dyspnea was observed.

Thrombocytopenia was documented in 3 patients (5%). One had nuisance bleeding characterized by oozing from the intravenous site. Elevated prothrombin time was noted in 7 patients (11.7%). There were no reports of hypofibrinogenemia. One patient with mild bleeding from the bite site had normal hematologic laboratory values. There were no differences in hematologic laboratory abnormalities between patients with and without chronic illnesses. There also was no relationship between the degree of local injury and whether the patient had hematologic laboratory abnormalities.

The only significant difference between the patients with definite cottonmouth bites and those with presumed cottonmouth bites was the percentage of pediatric patients (Table 2). There were some notable differences between pediatric and adult patients (Table 3). Bites with mild or no swelling were reported more frequently in pediatric patients than in adult patients (P=0.0423). Elevated prothrombin time was higher in pediatric patients than in adults (P=0.0219), but there was no significant difference in thrombocytopenia. Systemic gastrointestinal signs were comparable in the 2 populations. Definitive snake identification was less common in patients <18 y of age (P=0.0012).

Table 2.

Comparison of Bites from Definite and Presumed Cottonmouths.

Characteristic	Detail	Definite cottonmouth (n=18)	Presumed cottonmouth (n=19)	Total (n=37)
Sex	Male	12 (66.7%)	13 (68.4%)	25 (67.6%)
	Female	6 (33.3%)	6 (31.6%)	12 (32.4%)
Patient age (y)	<18	1 (5.6%)	9 (47.4%)	10 (27%)
	≥18	17 (94.4%)	10 (52.6%)	27 (73%)
Bite location	Upper extremity	10 (55.6%)	7 (36.8%)	17 (45.9%)
	Lower extremity	8 (44.4%)	12 (63.2%)	20 (54.1%)
Extremity swelling	None	1 (5.6%)	3 (15.8%)	4 (10.8%)
	Mild	3 (16.7%)	5 (26.3%)	8 (21.6%)
	Moderate	12 (66.7%)	7 (36.8%)	19 (51.4%)
	Severe	1 (5.6%)	3 (15.8%)	4 (10.8%)
	Not specified	1 (5.6%)	1 (5.3%)	2 (5.4%)
Tissue injury	Hemorrhagic bleb	3 (16.7%)	0	3 (8.1%)
Hematologic laboratory abnormalities	Thrombocytopenia	0	2 (10.5%)	2 (5.4%)
	Elevated prothrombin time	1 (5.6%)	1 (5.3%)	2 (5.4%)
Gastrointestinal signs	Emesis	5 (27.8%)	1 (5.3%)	6 (31.6%)
	Diarrhea	1 (5.6%)	0	1 (2.7%)
Treatment	Antivenom	15 (83.3%)	12 (63.2%)	27 (73%)

Certainty of snake identification was not collected until 2017

Table 3.

Comparison of Pediatric and Adult Patients.

Characteristic	Detail	Pediatric (<18 y old, n=26)	Adult (≥18 y old, n=34)	Total (n=60)
Sex	Male	15 (57.7%)	25 (73.5%)	40 (66.7%)
	Female	11 (42.3%)	9 (26.5%)	20 (33.3%)
Bite location	Upper extremity	6 (23.1%)	19 (55.9%)	25 (41.7%)
	Lower extremity	20 (76.9%)	15 (44.1%)	35 (58.3%)
Extremity swelling	None	2 (7.7%)	0	2 (3.3%)
	Mild	17 (65.4%)	12 (35.3%)	29 (48.3%)
	Moderate	4 (25.4%)	16 (47.1%)	20 (33.3%)
	Severe	0	3 (8.8%)	3 (5%)
	Unavailable	3 (11.5%)	1 (2.9%)	4 (6.7%)
Tissue injury	Hemorrhagic bleb	0	3 (8/8%)	3 (5%)
Hematologic laboratory abnormalities	Thrombocytopenia	1 (3.8%)	2 (5.9%)	3 (5%)
	Elevated prothrombin time	6 (23.1%)	1 (2.9%)	7 (11.7%)
Gastrointestinal signs	Emesis	3 (11.5%)	7 (20.6%)	10 (16.7%)
	Diarrhea	1 (3.8%)	1 (2.9%)	2 (3.3%)

Antivenom was administered to 47 patients (78.3%), including 39 of 40 patients (97.5%) with moderate or severe local swelling; only 7 of 18 patients (38.9%) with mild or no swelling were treated (P=0.02; Table 4). The 1 patient with moderate extremity swelling who did not receive antivenom refused treatment and left the emergency department after he was informed that he was unlikely to die from the envenomation.

Table 4.

Antivenom Use by Site.

Factor	Detail	North Texas (n=18)	Southeast and South Texas (n=42)	Total (n=60)
Bite location	Upper extremity	6/7 (85.7%)	16/18 (88.9%)	22/25 (88%)
	Lower extremity	7/11 (63.6%)	18/24 (75%)	25/35 (71.4%)
Extremity swelling	None	0/2 (0%)	0/2 (0%)	0/4 (0%)
	Mild	2/3 (66.7%)	5/11 (45.5%)	7/14 (50%)
	Moderate	7/8 (87.5%)	25/25 (100%)	32/33 (97%)
	Severe	3/3 (100%)	4/4 (100%)	7/7 (100%)
	Not specified	1/2 (50%)	N/A	1/2 (50%)
Hematologic toxicity	Thrombocytopenia	2/3 (66.7%)	N/A	2/3 (66.7%)
	Elevated prothrombin time	1/1 (100%)	6/6 (100%)	7/7 (100%)
Gastrointestinal signs	Vomiting	2/3 (66.7%)	7/7 (100%)	9/10 (90%)
	Diarrhea	N/A	2/2 (100%)	2/2 (100%)
Patient age (y)	<18	9/11 (81.8%)	13/15 (86.7%)	22/26 (84.6%)
	≥18	4/7 (57.1%)	21/27 (77.8%)	25/34 (73.5%)

There was a trend toward more antivenom usage in pediatric patients, in bites to the upper extremity, and when emesis or diarrhea were present, but these findings were not significant. The presence of thrombocytopenia was not associated with increased antivenom administration. Antivenom usage rates were similar in patients who intentionally interacted with the snake and those who did not.

FabAV was used in 37 patients (78.7%), and Fab2AV was used in 10 patients (21.3%). Acute hypersensitivity reactions were observed in 3 patients (8.1%) treated with FabAV. All 3 developed a rash. One also had one episode of emesis.

One patient was admitted to the intensive care unit for <24 h. He did not require mechanical ventilation or treatment with vasopressors. The indication for intensive care unit admission was not provided in the registry data. The median hospital length of stay was <24 h, and the longest hospitalization was <72 h.

Follow-up data were available for 22 cases (36.7%). There were no new cases of hematologic toxicity. None of the patients who had hematologic laboratory abnormalities while in the hospital had repeat bloodwork performed. There were no reports of abnormal bleeding. One patient was readmitted for worsening local swelling and following the development of a new hemorrhagic bulla.

Ten patients (16.7%) had multiple follow-up encounters, including 2 directly and 8 via phone call or email. In each case, the local findings had improved. One patient developed serum sickness characterized by rash and myalgias 10 d after receiving Fab2AV.

Discussion

In this study of cottonmouth envenomations in Texas, swelling of the affected limb was the most common manifestation of envenomation. Gastrointestinal signs and hematologic abnormalities were observed less often. No patients became hypotensive or experienced respiratory distress.

Most patients were treated with antivenom. Unsurprisingly, there was a significant correlation between the severity of the local findings and the likelihood of receiving antivenom. Patients with emesis or diarrhea also were more likely to be treated. It was surprising that patients with elevated prothrombin times received antivenom more often than patients with thrombocytopenia. This was likely random chance because of the few cases.

Pediatric patients received antivenom more frequently than adults despite having a lower percentage of bites with moderate and severe local findings. There are several potential explanations for this. It is possible that clinicians fear that children are at risk for more severe envenomations than adults. A study by Gerardo et al suggested that age <12 y was associated with a worse outcome than older victims.¹⁴ Parents may request more aggressive treatment for their children. It is plausible that the financial concerns that may dissuade some clinicians and snakebite victims from choosing antivenom may not exist in pediatric patients likely to be covered by private or state-sponsored insurance.

Antivenom was administered more frequently at the Southeast Texas site than at the North Texas site. This may be due to different toxicologists having different thresholds to treat. It is also possible that despite the objective criteria used to stratify bite severity, a typical mild or moderate bite at 1 site was more severe than a bite in another region. Regional variation in snake envenomation has been documented in multiple species.^15–18 It is plausible that there are similar geographic differences seen in A. piscivorus, although this has not been documented in the literature to our knowledge.

In this study, the incidence of acute hypersensitivity reactions was similar to that in previous reports. In several studies that looked solely at FabAV, the incidence ranged from 0 to 8%.^19–21 In 2 studies comparing FabAV with Fab2AV, the incidence of acute hypersensitivity reactions to FabAV ranged from 0 to 3.8%, whereas the incidence of acute hypersensitivity reactions to Fab2AV ranged from 6.6 to 14.7%.^22,23

Several conclusions can be reached from this study. Most cottonmouth bites follow unintentional interaction with the snake and frequently affect the lower extremity. Cottonmouth envenomations are characterized primarily by local tissue injury. Gastrointestinal signs and hematologic toxicity are observed less commonly. Antivenom is associated with a low incidence of acute hypersensitivity reactions. We hope that these findings will minimize unnecessary intensive care unit admissions and help clinicians who treat envenomation patients feel more comfortable administering antivenom.

Limitations

There are some notable limitations to this study. Two sites were responsible for all but 1 case. The small sample size precluded more robust statistical analyses. The snake was definitively identified as a cottonmouth in only 18 cases (30%), including 1 pediatric patient. A previous study demonstrated that copperheads and cottonmouths are often misidentified; some of the snakes responsible for the bites may have been copperheads.²⁴ Lastly, the study does not address the relative merits of the 2 antivenoms. A recent study has suggested that FabAV is more effective than Fab2AV in Agkistrodon envenomations in Louisiana.²⁵ Additional studies may be warranted.

Footnotes

Acknowledgments

The ToxIC North American Snakebite Study Group includes Salman Ahsan, Peter Akpunonu, Adam Algren, Jacob Altholz, Alexandra Amaducci, Sukhshant Atti, Kevin Baumgartner, Gillian Beauchamp, Sarah Berg, Michael Beuhler, Patricia Beuhler, Joshua Bloom, Erica Brandy, Kimberly Brayer, Jeffrey Brent, Dazhe Cao, Kathleen Chen, Michael Christian, Matthew Cook, Colleen Cowdery, Lee Crawley, Jenna Davis, Jazmin Davison, Sara Delatte, Aaron Deutsch, Rita Farah, Hank Farrar, Andrew Ferdock, Derek Fikse, Ari Filip, Caleb Fredrickson, Samantha Gaetani, Kira Galeano, Austin Gay, Hayley Gartner, Timlin Glaser, Kimberlie Graeme, Spencer Greene, Veronica Groff, Eniola Gros, Stacey Hail, LaTambria Hampton, Carleigh Hebbard, Robert Hendrickson, Robert Hoffman, Christopher Holstege, Zane Horowitiz, Keahi Horowitz, Adrienne Hughes, Laura James, Kenneth Katz, Chris Kennedy, Abigail Kerns, Kurt Kleinschmidt, Andrew Koons, Anita Kurt, Shana Kusin, Mary Claire Lark, Becky Latch, Michael Levine, Carl Levy, Erica Liebelt, David Liss, Chin-Yu Lo, Michael Marlin, Danae Massengill, Serah Mbugua, Conner McDonald, Kevan Meadors, Andrea Nillas, Michael Mullins, Kim-Long Nguyen, Sandra Nixon, Angela Padilla-Jones, Tammy Phan, Ravikar Ralph, Shahanaz Rashid, Tony Rianprakaisang, Lynn Rosenberg, Brett Roth, Michelle Ruha, William Rushton, Emmelyn Samones, Scott Schmarlzried, Evan Schwarz, Anthony Scoccimarro, Stephanie Shara, Kapil Sharma, Andrew Sheen, Sophia Sheikh, Alexander Sidlak, Reeves Simmons, Miya Smith, Hannah Spungen, Meghan Spyres, Fermin Suarez, Ryan Surmaitis, Sammy Taha, Courtney Temple, Stephen Thornton, Daniel Tirado, Herbert Wan, George Warpinski, Tyler Willing, Jessica Winkels, Brian Wolk, Amy Young, Anna Zmuda, Josue Zozaya.

ORCID iD

Chelsea R Caplan

Author Contribution(s)

Spencer Greene: Conceptualization; Data curation; Formal analysis; Methodology; Project administration; Writing – original draft; Writing – review & editing.

Chelsea R Caplan: Data curation; Investigation; Writing – review & editing.

George Warpinski: Data curation; Investigation; Writing – review & editing.

Rachel Culbreth: Data curation; Formal analysis; Methodology; Project administration; Writing – review & editing.

Sharan Campleman: Conceptualization; Data curation; Investigation; Methodology; Project administration; Writing – review & editing.

Financial/Material Support

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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