Abstract
Objectives
The purpose of this study was to compare patient-reported outcomes regarding tissue injury caused by rattlesnake envenomation for patients treated with Crofab or Anavip.
Methods
We performed a chart review of the Arizona Poison and Drug Information Center’s records from January 2017 through December 2021 for patients who received antivenom for rattlesnake envenomation. We present responses to standardized questions asked on days 7, 14, 90, and 180 regarding the presence of pain, edema, and functional impairment, with full recovery defined as the resolution of all 3.
Results
Patients treated with Crofab (n = 272) and Anavip (n = 241) were similar with regard to age, sex, bite location, and time to treatment. At each time point, the percentage of patients reporting resolution of pain, edema, or function was higher in patients treated with Crofab, when compared with those treated with Anavip. Clinically important differences in the percentage of patients reporting full recovery favoring Crofab were identified at 7 days (15.1% vs 6.6%, difference 8.5%, 95% CI: 3.1%-13.7%), 14 days (34.6% vs 24.9%, difference 9.7%, 95% CI: 1.8%-17.5%), and 90 days (60.3% vs 52.7%, difference 7.6%, 95% CI: −1.0% to 16.2%).
Conclusion
Following rattlesnake envenomation in Arizona, patients treated with Crofab had higher rates of full recovery from tissue injury than patients treated with Anavip at 7, 14, 90, and 180 days.
Keywords: rattlesnake, antivenom, envenomation, recovery, effectiveness
The Bottom Line.
Tissue injury is the predominant clinical effect in US rattlesnake envenomation. There are 2 available antivenoms for treatment, and it is unclear if they differ in their ability to impact recovery. We compared recovery after rattlesnake envenomation in Arizona between patients treated with Crofab versus Anavip and found that 34.6% of Crofab patients reported achieving the full resolution of pain, swelling, and functional impairment within 2 weeks, compared with only 24.9% of Anavip patients. This study may help guide antivenom treatment when tissue injury is the predominant clinical concern in rattlesnake bites.
1. Introduction
1.1. Background
In the United States, there are approximately 5000 to 10,000 venomous snakebites annually.1 Although deaths are rare, morbidity is high due to tissue injury-related pain and physical disability.2,3 Clinical signs and symptoms of envenomation can manifest as systemic toxicity, local tissue injury, or a combination of both.4 The underlying pathophysiology resulting from venom is complex, and persistent tissue injuries manifesting as pain, edema, and functional impairment may last beyond a year.5, 6, 7 The full extent of permanent or temporary disability has not been well characterized, as robust evaluations of recovery are lacking.
The cornerstone of envenomation treatment is antivenom, with 2 products currently available.8 Crotalidae Polyvalent Immune Fab (Ovine) (Crofab) became available in 2000, and Crotalidae Immune F(ab’)2 (Equine) (Anavip) became available in 2018.9 In the pivotal clinical trial for regulatory approval, Crofab and Anavip were compared regarding their effectiveness on subacute coagulopathy, but recovery from tissue injury was not specifically addressed.10 The ability of Crofab antivenom to reduce tissue injury was established in a placebo-controlled trial of mild-to-moderate severity copperhead (Agkistrodon contortrix) envenomations. In this study, Crofab was shown to improve recovery at 14 days, as measured by the patient-specific functional scale, and reduced opioid requirements.3,11, 12, 13 A post-hoc analysis of the Crofab versus Anavip clinical trial data did not find a difference in effectiveness at halting the acute progression of local tissue injury, when comparing the number of antivenom loading doses given to obtain initial control.14 However, this finding was limited by the retrospective nature of the analysis, small sample size, lack of evaluation of recovery from tissue injury, and the lack of power to detect a difference for this outcome measure. More recent evidence among copperhead envenomated patients has suggested differences in antivenom effectiveness regarding tissue injury may exist.15,16
1.2. Importance
For health care professionals, choosing an antivenom should be based on its likely benefit for a given patient. An improved understanding of antivenom effectiveness on tissue injury, as evaluated by time to full recovery, will help determine the most appropriate patient-specific treatment in snake envenomation. To date, no study has compared tissue injury recovery following rattlesnake (Crotalus and Sisturus) envenomation between patients treated with Crofab versus Anavip.
1.3. Goals of This Investigation
The purpose of this study was to examine the association between the type of antivenom received and full recovery 14 days after envenomation, as reported by patients during outpatient poison center monitoring.
2. Materials and Methods
2.1. Study Design and Setting
We performed a chart review of the Arizona Poison and Drug Information Center’s medical records and abstracted patients’ self-reported symptoms following rattlesnake envenomation. The center serves the state of Arizona, excluding Maricopa County, receiving approximately 200 calls per year regarding rattlesnake bites.17 There are 15 species of rattlesnakes found in Arizona, more than anywhere else in the country. This center and its staff have a long history when it comes to researching and treating rattlesnake envenomations. A prior study found that the center was consulted on 99% of antivenom-receiving patients within its catchment area between 2017 and 2021.18 Incoming calls are answered by Certified Specialists in Poisoning Information, who document pertinent demographic and clinical information into ToxSentry, the poison center’s electronic record system. For certain exposures, including rattlesnake bites, a standardized template is used to guide specialists and ensure consistent documentation.
2.2. Selection of Participants
We searched for all antivenom-receiving patients using the exposure codes “Unknown Types of Snake Envenomation” (0137000), “Rattlesnake Envenomations” (0137103), and “Unknown Crotalid Envenomations” (0137105) among poison center records from January 1, 2017, through December 31, 2021. Charts were excluded if the patient received both types of antivenoms or if the documentation was incomplete, such as when the patient left against medical advice, was transferred to a different poison center, had a significant delay before poison center involvement, or did not participate in follow-up interviews for 14 days.
2.3. Exposure to Antivenom
During this period, the center recommended starting antivenom for all patients with local injury exceeding what would be expected from a needle puncture or the presence of laboratory coagulopathy. Initial control doses of Crofab (4-6 vials) or Anavip (10 vials) were recommended to be repeated hourly until the rate of proximal spreading edema remains less than 1 inch per hour, and laboratory parameters were normal or improving. Once this occurred, patients entered an observation period. If signs or symptoms worsened, additional antivenom was recommended, and the observation period began anew. Patients were considered to have received a sufficient dose of antivenom after no signs or symptoms worsened for a sustained period of 18 hours. From January 1, 2017, through December 31, 2018, Crofab was the only antivenom available. Anavip first became available in 2018 and rapidly became preferentially used for Arizona rattlesnake envenomations due to the absence of late coagulopathy (hypofibrinogenemia) and a perceived lower risk for late bleeding complications.19, 20, 21, 22 Most health systems in Arizona stocked only Anavip by the end of 2019, despite the Arizona Poison and Drug Information Center’s recommendation for hospitals to stock both. Crofab was recommended for select patients when local control was not obtained after 3 loading doses of Anavip, anaphylactic reactions to Anavip developed, and whenever Anavip was unavailable. As patients receiving both antivenoms were excluded from the analysis, there are 2 distinct time periods within this study because only 1 antivenom was ever available for rattlesnake bite patients to receive.
2.4. Poison Center Documentation Practices
The standardized template used for all rattlesnake bites consisted of 3 separate sections, based on distinct time periods after the envenomation. The first section captured the period when the patient was in the hospital receiving antivenom. In addition to documenting the signs and symptoms of envenomation, information was collected regarding the encounter circumstances, patient demographics, medical history, prehospital interventions, medications administered, procedures performed, and laboratory values obtained. Documented findings were routinely confirmed during subsequent calls and by directly reviewing hospital records via remote access.
The next section began after hospital discharge while patients were being monitored for complications. Patients were contacted shortly after hospital discharge to ensure they received the outpatient guidance document, answer any questions, and discuss self-monitoring for infection, serum sickness, bleeding, and thrombosis. Patients were instructed to return to the hospital or contact the poison center if they developed any complications. Subsequent telephone interviews addressed patient-specific needs and followed scripted questions during which specialists confirmed the presence or absence of pain, lymphadenopathy, edema, ecchymosis, erythema, blisters, necrosis, and functional impairment. All symptoms documented as present contained qualitative descriptors and confirmation they were attributable to the envenomation. At a minimum, patients were contacted every 1 or 2 days for at least 14 days from the envenomation. Parents or guardians were interviewed and reported on behalf of children.
The final section documented the patient’s recovery. All patients were contacted around 90 days after the envenomation. In addition to repeating previous questions, patients were asked about their involvement with physical or occupational therapy, doctor’s appointments, medication use, abnormal anxiety, sleep disturbances, missed workdays, and financial impact. Patients who reported persistent complications related to their snakebite were contacted again every 90 days thereafter until symptoms resolved. All pertinent materials are available in the Supplementary Appendix 1.
2.5. Data Abstraction
Data abstraction was performed using a standardized case report form by a licensed pharmacist, who was blinded to the study objective and group assignments. Training and a coding guide were provided before beginning data abstraction. A pilot test of the coding guide was performed. Coding of ambiguous circumstances errs on the side of reporting the presence of symptoms. For example, minor symptoms described as “present but not bothersome” by the patient were considered positive for the purposes of this study. Once symptom resolution was reported, it was presumed to persist in the absence of contradictory documentation. Abstractor monitoring was performed by the lead author. Progress meetings were routinely held throughout data collection, during which inaccuracies or inconsistencies would be brought to the abstractor’s attention. The data abstractor then independently reviewed the case and made the final coding determination. Upon concluding the data abstraction portion of the study, the abstractor was interviewed to determine if the study blinding had been effective. In this interview, the abstractor reported feeling as if the blinding had been effective, stating that they were only aware the study had something to do with chronic sequelae following rattlesnake bites, based on the data being collected.
2.6. Outcome Measures
The primary outcome was a comparison of the proportion of Crofab- versus Anavip-treated patients who were fully recovered by 14 days after the envenomation. We defined “full recovery” as a composite outcome measure consisting of the complete resolution of all pain, edema, and functional impairment attributable to the envenomation.6,23, 24, 25 We also defined patients with resolution of 1 or 2 symptoms as “partial recovery,” whereas patients without resolution of any were “poor recovery.”
2.7. Data Analysis
Demographic and descriptive data were stratified by the type of antivenom received. Nominal data were summarized as frequencies with percentages. Ages were summarized as medians with interquartile range (due to the non-normal distribution). We calculated the difference (95% CI) in the proportions of Crofab and Anavip patients meeting each recovery definition (full, partial, and poor) at 7, 14, 90, and 180 days after envenomation. Additionally, we compared the resolution of each symptom (pain, edema, and functional impairment) independently at all time points between the groups. All secondary outcomes were explored to determine if they appeared to influence the overall results and were not intended as primary hypothesis testing. No sample size calculation was conducted because all available data from the study period were used, during which outpatient monitoring practices were standardized and remained unchanged. Analyses were conducted using SAS (v9.4) and R. Figures were created using Microsoft Excel (v16.88).
3. Results
3.1. Characteristics of Study Subjects
We found 652 patients who received antivenom for a rattlesnake envenomation among poison center records between January 1, 2017, and December 31, 2021. A total of 139 patients met the exclusion criteria; the remaining 513 patients were included in the analysis. Crofab was administered to 272 (53.0%) patients, and Anavip to 241 (47.0%) patients (Fig 1). Most patients treated with Crofab were treated in 2017 and 2018, and most patients treated with Anavip were treated in 2020 and 2021, with a mixture of both antivenoms being used in 2019. Patient demographics appear to be similar between the groups (Table 1). Anavip patients were marginally older and more of them were bitten on the lower extremity. No apparent differences were found in the time from envenomation until starting antivenom. More Anavip patients received ≥3 loading doses of antivenom to obtain initial control of the tissue injury.
Figure 1.
Patient flowchart.
Table 1.
Patient demographic and treatment characteristics.
| Demographics | Total treated patients (N = 513) | Anavip-treated patients (N = 241) | Crofab-treated patients (N = 272) |
|---|---|---|---|
| Age, y | |||
| Median (IQR) | 54 (35) | 54 (31) | 52 (36) |
| Range | 1-93 | 2-93 | 1-89 |
| Age strata, no. (%) | |||
| Older adult (≥65 y) | 142 (27.7) | 75 (31.1) | 67 (24.6) |
| Adult (18-64 y) | 299 (58.3) | 139 (57.7) | 160 (58.8) |
| Adolescent (12-17 y) | 21 (4.1) | 6 (2.5) | 15 (5.5) |
| Children (<12 y) | 51 (9.9) | 21 (8.7) | 30 (11.0) |
| Sex, no. (%) | |||
| Male | 306 (59.6) | 135 (56.0) | 171 (62.9) |
| Comorbidities, no. (%) | |||
| Diabetesa | 30 (5.8) | 15 (6.2) | 15 (5.5) |
| Anatomic location, no. (%) | |||
| Upper extremity | 219 (42.7) | 93 (38.6) | 126 (46.3) |
| Lower extremity | 294 (57.3) | 148 (61.4) | 146 (53.7) |
| Time to antivenom, no. (%) | |||
| Start < 4 h | 426 (83.0) | 200 (83.0) | 226 (83.1) |
| Start > 4 h | 87 (17.0) | 41 (17.0) | 46 (16.9) |
| Antivenom for local control, no. (%) | |||
| Loading dose × 1 | 390 (76.0) | 176 (73.0) | 214 (78.7) |
| Loading dose × 2 | 68 (13.3) | 31 (12.9) | 37 (13.6) |
| Loading dose ≥ 3 | 55 (10.7) | 34 (14.1) | 21 (7.7) |
| PT/OT consult, no. (%) | |||
| Patient evaluated | 383 (74.7) | 189 (78.4) | 194 (71.3) |
IQR, interquartile range; OT, occupational therapy; PT, physical therapy.
Sex is defined as male or female designated at birth.
Diabetes: based on available past medical history, patients were not routinely screened.
3.2. Main Results
We found that 34.6% of Crofab-treated patients met our definition of full recovery at 14 days, compared with 24.9% of Anavip-treated patients (difference: 9.7%, 95% CI: 1.8%, 17.5%). In support of this primary analysis, secondary analyses showed that more Crofab patients also reported full recovery at 7, 90, and 180 days, with more Anavip patients reporting poor recovery at all 4 time points after envenomation (Table 2). When considering each symptom independently, no single symptom appeared to be disproportionately influencing the results, further supporting the primary outcome (Fig 2).
Table 2.
Resolution of tissue injury following rattlesnake envenomation.
| Patient-reported recovery | Crofab-treated patients (N = 272) | Anavip-treated patients (N = 241) | Crofab vs Anavip difference, % (95% CI) |
|---|---|---|---|
| D 7, no. (%) | |||
| Full | 41 (15.1) | 16 (6.6) | 8.5 (3.1, 13.7) |
| Partial | 102 (37.5) | 74 (30.7) | 6.8 (−1.4, 15.0) |
| Poor | 129 (47.4) | 151 (62.7) | −15.3 (−6.7, -23.7) |
| Day 14, no. (%) | |||
| Full | 94 (34.6) | 60 (24.9) | 9.7 (1.8, 17.5) |
| Partial | 113 (41.5) | 84 (34.9) | 6.6 (−1.7, 15.1) |
| Poor | 65 (23.9) | 97 (40.2) | −16.3 (−8.4, −24.4) |
| Day 90, no. (%) | |||
| Full | 164 (60.3) | 127 (52.7) | 7.6 (−1.0, 16.2) |
| Partial | 63 (23.2) | 55 (22.8) | 0.4 (−7.0, 7.6) |
| Poor | 6 (2.2) | 19 (7.9) | −5.7 (−1.9, −9.5) |
| Lost to follow-up | 39 (14.3) | 40 (16.6) | - |
| Day 180, no. (%) | |||
| Full | 177 (65.1) | 145 (60.2) | 4.9 (−3.5, 13.3) |
| Partial | 24 (8.8) | 16 (6.6) | 2.2 (−2.4, 6.8) |
| Poor | 0 (0.0) | 6 (2.5) | −2.5 (−0.5, −4.5) |
| Lost to follow-up | 71 (26.1) | 74 (30.7) | - |
Full: resolution of all 3 symptoms (pain, edema, and functional impairment); partial: resolution of 1 or 2 symptoms; poor: patient is still experiencing pain, edema, and functional impairment. The primary outcome is bolded for ease of recognition.
Figure 2.
Resolution of pain, edema, and functional impairment following rattlesnake envenomation.
4. Limitations
This is an observational study using data retrospectively abstracted from poison center records and is subject to the potential biases of this study design. However, we attempted to mitigate these limitations by using the widely accepted methodology for conducting this type of study. This included ensuring chart review was appropriate for this research question, using a representative patient sample, a systematic process for chart abstraction, a consistent manner of dealing with data missingness, as well as abstractor training, blinding, and monitoring.26 As an observational study, we determine associations of the specific antivenom with full recovery and do not make a causal inference. It is possible that the 2 populations were systematically different. We report the proportion of diabetic patients in each group due to the disease’s established association with poor wound healing, and because the information had been systematically collected, yet other patient-specific factors such as smoking history are likely important but were not clearly available for all patients. Details regarding the patient’s ethnicity were not available. In a before-and-after type study, bias may result from secular trends in the disease, the host, or other aspects of treatment. We do not see evidence of significant change in measured variables. Furthermore, we do not think it is likely that any changes that may have occurred between 2017 and 2021 in patient demographics, access to treatment, or use of nonantivenom therapies would explain the degree of difference in outcomes reported by the 2 treatment groups. This study was not designed to determine the cost-effectiveness of any specific treatment.
Another limitation is the generalizability of these findings. From a clinical standpoint, crotaline envenomation is currently treated as a single disease. However, venom consists of several different toxins, with significant inter- and intra-species variation in composition and clinical effects known to occur regionally.27,28 Also, antivenom binding to venom toxins (efficacy) and subsequent neutralization of toxicity (effectiveness) are known to be incomplete because binding relies on cross-reactivity of similar structures.29 Variability in venom composition, in combination with differing extents of individual toxin neutralization, limit the generalizability of these findings because antivenom effectiveness may be region-specific. We believe these findings should be validated in a similar manner using other databases.
Finally, the outcome used in this study may not fully capture the patient’s tissue injury and recovery experience. We presumed that some degree of pain, edema, and functional impairment existed for all patients and categorized symptoms dichotomously because of concerns for potential missingness in qualitative descriptor documentation. These assumptions are an oversimplification, which limits the clinical significance of our findings. However, we incorporated both patient-reported symptoms and functional recovery into our composite scoring. These surrogates for recovery have been previously used in snakebite research.14,30, 31, 32, 33, 34
5. Discussion
We found a difference in day 14 full recovery after rattlesnake envenomation between Crofab- and Anavip-treated patients. This finding was augmented by concordant findings among patients who reported recovery at 7, 90, and 180 days. Pain, edema, and functional impairment represent 3 distinct sequelae, which are important to patients. An earlier recovery after a traumatic event, such as a rattlesnake envenomation, affords patients the ability to quickly return to their occupations, hobbies, social interactions, and other activities and therefore may improve their quality of life.3
There are several differences in the properties of the 2 antivenoms, which may explain our findings. The products are manufactured using venom from different snake species and inoculated animals, either of which may result in differences in the ability to neutralize venom toxins.35,36 Crofab is produced using the venom of 4 snakes (Crotalus atrox, Crotalus adamanteus, Crotalus scutulatus, and Agkistrodon piscivorus) found within the United States, including the Western Diamondback Rattlesnake (C. atrox), which is believed to be responsible for the majority of Arizona envenomations.37 By contrast, Anavip is produced using the venom from 2 pit vipers (Bothrops asper and Crotalus simus) found in Central America. There may be better matches of the venom toxins that cause tissue injury in the rattlesnakes of this geographic region and the neutralizing antibody profiles of Crofab that result in improved recovery.
Crofab antibody fragments are formed by digestion with papain producing a single Fab fragment with a single antigen-binding site. As a result, Crofab antibodies are smaller in size (50 kDa), potentially increasing tissue penetration in the setting of significant inflammation.38,39 The smaller size of Crofab also results in a more rapid elimination (half-life 15 hours), and this relatively short half-life is thought to allow for venom recrudescence and recurrent toxicity.40 Anavip is formed by digestion with pepsin, producing 2 Fab regions linked by a disulfide bond. Although the larger size (100 kDa) of Anavip molecules results in a slower elimination rate (half-life 133 hours) and has been credited with preventing recurrent toxicity, this characteristic may also diminish tissue penetration.10,20,21
The amount of time from envenomation until starting antivenom is a major factor determining the outcome.41 In our study, the time until antivenom was similar between the groups. However, we found that Anavip-treated patients were more likely to require multiple doses of antivenom before initial control of the tissue injury was obtained. A sufficient dose of antivenom is necessary to ensure adequate venom neutralization and only considering the time until the start of antivenom does not account for potential underdosing. We speculate that patients who received numerous doses of antivenom before initial control of the envenomation was obtained may represent a group of patients with a delay in receiving the fully neutralizing dose and a subsequent delay in recovery. Although some experts have recommended that time to antivenom should be reported in all snake envenomation studies, the amount of time from envenomation until the patient receives a sufficient dose of antivenom to halt envenomation progression may also be an important measure in future studies.31,42
Outcome measures for snakebite envenomation have historically focused on mortality or significant events such as major bleeding, but these events are rare and limit our ability to compare treatment effectiveness.43 Future research is needed to develop envenomation outcome measures using a model that incorporates risk factors and predictors of a rapid full recovery versus the development of chronic sequelae. We need to establish standardized objective measures for characterizing the extent of local tissue injury and the degree of disability resulting from this injury, allowing for improved generalizability between studies.
The next steps include collecting more data regarding the acute period of progressive tissue injury, and more frequent evaluations during the subacute period to identify potential factors influencing recovery. We believe that a decrease in symptom severity, even without complete resolution, was still meaningful for many patients. Additionally, alternative measures of recovery with more granular details to report alongside our composite scoring will allow for a more robust understanding of the patient’s experience after a rattlesnake bite.
In summary, these results support prior findings that these 2 antivenoms do not perform identically.10,15,16,20,21,44 Each rattlesnake-envenomated patient may have a predominant local tissue injury, coagulopathy, systemic toxicity, or a combination of these. Prior studies have demonstrated the advantage of Anavip in cases of coagulopathy. It may be appropriate to select which antivenom to use based on factors, such as geographic regions and the patient’s toxicity profiles. Although further study is needed to verify these results, this study demonstrates a potential advantage of Crofab antivenom regarding recovery from local tissue injury.
Author Contributions
GTS, FS, FW, and CJG conceived and designed the study. GTS created the standardized data template and coding guide as well as supervised data collection and performed quality control. DRA and CJG analyzed the data. GTS and AMG generated the tables. DRA confirmed the accuracy of all data reported and generated the figures. GTS, AMG, and FS drafted the manuscript, and all authors contributed substantially to its revision. GTS takes responsibility for the paper as a whole.
Funding and Support
The Arizona Poison and Drug Information Center routinely receives funding and conducts rattlesnake envenomation research with multiple antivenom manufacturers: SERB (Société d’Études et de Recherches Biologiques) Pharmaceuticals, Rare Disease Therapeutics, Ophirex, and Trinity Antivenom. This research project was partially funded by an investigator-initiated grant through SERB Pharmaceuticals, as well as a research grant from Rare Disease Therapeutics, the manufacturers of Crofab® and Anavip®, respectively. CJG receives research funding from Ophirex, Inc. DRA reports grant funding from the American Association of Colleges of Pharmacy, Arizona Department of Health, Merck & Co., National Council for Prescription Drug Programs Foundation, Pharmacy Quality Alliance, and Tabula Rasa HealthCare Group, outside of this study. None of the authors were compensated directly or indirectly for their role in conducting this study. All the findings and content within this manuscript are expressly the interpretation and opinions of the authors. This study was approved by the Institutional Review Board at the University of Arizona, IRB#2108137685.
Conflict of Interest
All authors have affirmed they have no conflicts of interest to declare.
Acknowledgments
We thank Jennifer Ramirez for performing the data abstraction; as well as William F. Rushton and Anna Tupetz for contributing contextual information critical for developing the definitions of tissue injury and recovery used in this study. Finally, we also thank Timothy F. Platts-Mills and Richard C. Dart for their time and insight during the writing process, providing the authors with a valuable outside perspective.
Footnotes
Supervising Editor: Sing-Yi Feng, MD
Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j.acepjo.2025.100157
Supplementary Materials
References
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