BITES study: A qualitative analysis among emergency medicine physicians on Snake Envenomation Management practices

Authors: Anna Tupetz1 Loren Barcenas1 Ashley J. Phillips1 Charles J. Gerardo1,2 Joao Ricardo Nickenig Vissoci1,2

1 Division of Emergency Medicine, Department of Surgery, Duke University School of Medicine,

Durham, NC, US. 2Duke Global Health Institute, Duke University, Durham, NC, US;

Funding: This study was funded by BTG Specialty Pharmaceuticals. (PI: Gerardo)

Acknowledgements: We thank all our study participants for offering their insight and expertise with us.

Abstract: Introduction: Antivenom is currently considered standard treatment across the full spectrum of severity for snake envenomation in the United States. Although safe and effective antivenoms exist, their use in clinical practice is not universal. Objective: This study explored physicians’ perceptions of antivenom use and experience with snake envenomation treatment in order to identify factors that influence treatment decisions and willingness to administer. Methods: We conducted a qualitative study based on a grounded theory framework including in- depth interviews via online video conferencing with physicians practicing in emergency departments across the United States. Participants were selected based on purposive sampling methods. Data analysis followed a combination of inductive and deductive strategies, conducted by two researchers. The codebook and findings were discussed within the research team. Findings: Sixteen in-depth interviews with physicians from nine states across the US were conducted. The participants’ specialties include emergency medicine (EM), pediatric EM, and toxicology. The experience of treating snakebites ranged from only didactic education to having treated over 100 cases. Emergent themes for this manuscript from the interview data included perceptions of antivenom, willingness to administer antivenom and influencing factors to antivenom usage. Overall, cost-related concerns were a major barrier to antivenom administration, especially in cases where the indications and effectiveness did not clearly outweigh the potential financial burden on the patient in non-life- or limb-threatening cases. The potential to decrease recovery time and long-term functional impairments was not commonly reported by participants as an indication for antivenom. In addition, level of exposure and perceived competence, based on prior education and clinical experience, further impacted the decision to treat. Resources such as Poison Center Call lines were well received and commonly used to guide the treatment plan. The need for better clinical guidelines and updated treatment algorithms with clinical and measurable indicators was stated to help the decision-making process, especially among those with low exposure to snake envenomation patients. Conclusions: A major barrier to physician use of antivenom is a concern about cost, cost transparency and cost–benefit for the patients. Those concerns, in addition to the varying degrees of awareness of potential long-term benefits, further influence inconsistent clinical treatment practices.

Introduction:

The WHO estimates a global yearly count of 2.7 million snake envenomations that cause up to 138,000 fatalities and approximately 400,000 amputations and permanent disabilities. (1) While endemic venomous snakebites in the US are rarely fatal, with a reported 5 deaths out of 8,000 snake envenomations, the CDC acknowledges the fatality rate is higher with reduced access to high-quality medical care. Medical care is imperative to keeping the mortality rate low and to limit disability and loss of function. In fact, the rate of permanent disabilities in the US following rattlesnake envenomations is estimated to be as high as 44%. (2) Antivenom therapy is used to reduce inflammation, necrosis, hypotension, defibrinogenation, thrombocytopenia and neurotoxicity caused by snake venom. (1–6) Recent studies have found that patients who were treated with Crotalidae polyvalent immune fab [ovine] antivenom (FabAV) had better functional outcomes 14 days after envenomation than those who received placebo. (9) Subgroup analysis showed that those treated earlier had a faster recovery than those who had a delay to care. (10) Associated risks of using FabAV include hypersensitivity and serum sickness, which are both infrequent and tend to be mild, making it a low-risk treatment. (11) The other available US antivenom, Crotalidae immune F(ab’)2 [equine] antivenom (F(ab’)2AV) has similar rates of adverse reactions in the initial comparison trial. (7) Despite this evidence, there remains wide variability in clinicians’ approach to treating snakebite patients, especially among copperhead snakebites. (12) To further improve medical care for patients, we must better understand the factors influencing snakebite treatment and decision-making by physicians to better address disability and loss of function experienced by snakebite patients. Therefore, this qualitative study ‘BITES: Beliefs Influencing Treatment in Snake Envenomation Survivors’ explores physicians’ perceptions of antivenom use and experience with snake envenomation management to identify factors that influence treatment decisions and willingness to administer.

Methods:

Ethics statement This study has been approved by the Duke Health Institutional Review Board, Protocol Number: Pro00103272. Study design We conducted a qualitative study based on a (13) grounded theory framework, using semi- structured in-depth interviews. (14) Recruitment began in January 2020, and interviews took place from January to March 2020. Data analysis continued through June 2020. Research team and reflexivity Personal Characteristics Two research assistants conducted the interviews. Both interviewers have Master of Science degrees and are trained in qualitative research methods. The study team included a physician with extensive snakebite research experience, a licensed physical therapist, PhD and data specialist, as well as a clinical research expert with a Master in Public Health. Relationship with participants The interviewers had no prior relationships with any participants. All participants were first contacted by the interviewers via email with a study-specific email address to invite them to participate and schedule an interview date. The interviewers introduced themselves personally to the participants at the beginning of the interview and provided a short background on their role in this study. Recruitment We aimed to include physicians working in emergency departments (EDs) across the US, regardless of specialty or level of experience treating snakebites. We only included physicians who have completed residency programs. We included physicians working in academic, teaching and community hospitals. We used a snowballing technique to reach a population difficult to contact directly. (15) We first queried current emergency physicians at our institution for contact information of colleagues at other institutions across the US who may be interested in participating. We asked those who participated in our study to recommend any other colleagues who might be willing to be interviewed as well. We enrolled new participants until qualitative data collection reached thematic saturation. Interview procedure Physicians implied consent by scheduling an interview, as communicated to them in the invitation email. Interviews were conducted through video conference and the audio recordings were stored on a secure cloud-based server. Typically, each interview lasted about 30–45 minutes, though some interviews lasted longer depending on participant availability and length of answers. Each interview was guided by a pre-defined, semi-structured interview guide that was piloted with emergency physicians to evaluate the comprehension and adequacy of the questions. All interviews were first machine-transcribed and then edited for accuracy by research assistants. The transcripts were sent back to participants for review and approval. Data analysis Data were analyzed through a mix of inductive content analysis by the two interviewers. The emergent codes were organized into themes based on conceptual similarities, which represent the qualitative information gathered. A codebook was developed and discussed by the two interviewers based on the first four transcripts. Transcripts were independently coded by two investigators using a common codebook in Nvivo 12 software. (16) Then, investigators cross- validated the results by discussing the codes and themes of each interview to reach a consensus. Emergent themes and coding strategies were shared with the rest of the research team, as well as the study participants. All participants received a presentation of the emergent themes and preliminary results to validate the content and ensure accuracy of interpretation.

Results: For this manuscript, a selection of the available data and emergent codes was analyzed and grouped into the following themes: perceptions of antivenom, willingness to administer and influencing factors to administer antivenom. Supplement A provides a full overview of emergent themes and a codebook with supporting quotes.

Theme Codes

Perceptions of antivenom Indications and effectiveness Risks and side effects

Willingness to administer Treatment hesitancy and perceived confidence antivenom

Influencing factors Availability/accessibility Prior education of EM residents in snakebite management Cost Usage and perceptions on available resources The role of scientific evidence and general suggestions to improve patient care

Table 1: Emergent Themes and Codes

Findings:

Sex, n Male 14

Female 2

Age, Median (IQR) -- 43 (37.3, 51.3)

Residency, n Emergency Medicine 15

Pediatrics 1

Fellowship, n Toxicology 4

Pediatric Emergency Medicine 2

Other* 2 None 8

Years of Experience 0–10 years 6

11–20 years 5

> 20 years 5

Snakebites treated 0 2

1–10 5

11–50 5

51–100 2

> 100 2

Hospital Setting Academic 7

Community 5

Teaching 4

Hospital Region Suburban 8

Urban 6

Rural 2

State, n NC 6

CA 2

MO 2 NY 2

Other*** 4

ED Volume annual, -- 12,000– range 242,000

Table 2: Participant Characteristics * Hyperbaric Medicine, Global Health Emergency Care ** Academic: Medical school and faculty/ academic research institution onsite; Teaching hospital: University-affiliated facility to teach students and residents, but no medical school onsite; Community: no affiliation with academic institution *** FL, MI, NM, TX

This study included a total of 16 physicians working in EDs, the majority identifying as male (n=14 and trained by an emergency medicine residency program (n=15). One quarter of respondents completed a fellowship in clinical toxicology. The years of clinical experience as well as numbers of snakebites treated were fairly evenly distributed. Six participants practiced in North Carolina, followed by California (n=2), Missouri (n=2), New York (n=2), Florida, Michigan, New Mexico and Texas.

Perceptions on antivenom Indications and Effectiveness According to participants, antivenom use would be indicated by laboratory abnormalities, progression of swelling (especially across joint lines), systemic toxicity, coagulopathy, compartment syndrome, widespread ecchymosis, signs of tissue damage, changes in hematologic status and if symptoms severely impacted mobility. Antivenom was reported to always be indicated if there was a perceived risk of losing life or limb. Generally, the greater the number of bites and level of perceived dysfunction based on the bite location, the more likely antivenom is to be administered. One participant said, “Correct. Um, I mean I think, I think it has the potential to be beneficial, [INT: Uh huh] in the right case, but it’s not something that I would give to every copperhead [bite patient] just because they got bit by a snake, because I don’t think that the indication is there for every copperhead without the right symptoms.” P13

Participants explained that antivenom would not be indicated for dry bites or patients with no signs of envenomation. In less severe cases with mild swelling or a minimal envenomation syndrome, most physicians agreed that observation and routine supportive care would be sufficient. While one participant specifically pointed out that, in her opinion, pain alone was not a sufficient indication for administering antivenom, others mentioned that antivenom is effective in controlling pain. One participant mentioned that antivenom use in snakebite patients could limit opioid prescriptions. Effectiveness of antivenom treatment was believed to vary between patients, depending on their underlying health conditions, the time to treatment and complicating factors that would cause their envenomation to be more severe. Antivenom was perceived as being very effective for decreasing swelling and swelling-related pain and tissue damage. Those more familiar with the snakebite treatment literature mentioned decreased morbidity and faster return to function with antivenom; however, there was no overall consensus among participants if those potential benefits would be significant enough to indicate antivenom use for milder envenomations. One participant mentions: “So, I typically claim that if, you're having extensive, significant tissue damage or, tissue damage that seems to be progressive, we typically would recommend [fab antivenom] to kind of help decrease, disability down the road, disability and pain later on. So that’s kind of how we discuss this I guess, would be our recommendation.” P15

Several participants were uncertain of the potential benefits or effectiveness of antivenom due to lack of personal experience and were unaware of any potential improvement in long-term outcomes: “[M]y impression is that [antivenom] is just for […] halt[ing] the progression of the disease […] preventing it from getting worse and stuff. But I, I don't know what effects some of the stuff [has] later down the line.” P16

Risks and side effects The vast majority of participants mentioned allergic reactions, including hives and itching, as the main side effect of antivenom; however, they perceived the administration of antivenom to be safe and low risk. Other potential risks included serum sickness and hypersensitivity.

Willingness to administer antivenom Treatment hesitancy by the providers While risks and side effects did not seem to be strong barriers to antivenom treatment, the majority of physicians reported being generally hesitant to administer antivenom to their patients. The threshold at which physicians decided to treat with antivenom seemed to be influenced by personal practice and individual risk tolerance. However, potential risks or side effects did not contribute to treatment hesitancy: “Maybe it is that I've spent a little more time reading about it and stuff, and so I try not to over-treat. So maybe that's part of it: the toxicology training and the extra reading. Maybe another part of it is I'm aware of the price to some extent. I think that's much lesser of a reason. Yeah. […] And then, you know, lastly, it's more of a personal question on practice and stuff like that. I mean my risk tolerance is different than someone else's risk tolerance.” P16

Rather, lack of experience in treating snakebite patients may either lead to hesitancy to treat to avoid unknown risks associated with the treatment or to early treatment with fewer indications to reduce the risk of progression of symptoms. Some participants expressed that increasing confidence and perceived competence in snakebite management required personal and practical experience through, for example, being trained in high-prevalence areas, while reading the available literature alone would not be sufficient. Among our interviewees, those with more clinical and snakebite treatment experience generally felt more comfortable withholding antivenom to avoid what they saw as unnecessary treatment. More experienced physicians trained with fewer resources would rely more heavily on clinical judgement. “But I think the more experience you have with it, probably the more comfortable you are withholding antivenom than if someone has minimal symptoms. Because if people see any symptoms, they… it's a strong word, but they kind of panic and they shoot for the antivenom. A lot of times that that's appropriate. Right? Because that patient would have gotten sicker. But you never know because they've gotten antivenom. So would they have gotten better on their own? You know, some people aren't willing to wait and watch.” P9

Those with experience using unfractionated antibody antivenoms, which are no longer in use, usually tried to refrain from antivenom use in general. Unfractionated antibody antivenoms had much worse side effects and the majority of their patients eventually recovered. Even with the newer forms available that are safe and low-risk, such practitioners do not view antivenom as vital for the care of mild cases. When it comes to venomous exotic snakes or severe copperhead bites, there was no hesitancy to treat in order to save life or limb. Institutions without an institutional treatment protocol generally had physicians with differing opinions on treatment plans and more treatment hesitancy. Even those that did have institutional guidelines mentioned room for personal interpretation of the guidelines, as the language was typically not precise enough with clearly defined terms and thresholds (for example, what the medical definition of ‘mild’ swelling is). One physician, however, mentioned that, based on available data, his institution tends to treat snakebites more aggressively with antivenom than other medical professionals might:

“But we've always, […] based on the data, the decreasing morbidity and […] improving functional outcomes, improving pain long term, I think we tend to be more aggressive than some.” P15

Other factors contributing to treatment hesitancy included skepticism of scientific data supporting antivenom for non-life-threatening conditions based on funding sources of studies, and the belief that financial costs to the patient would potentially outweigh the clinical benefit of receiving antivenom treatment. Emergency physicians typically did not have the opportunity to follow up with their patients to gather anecdotal evidence, so they reported the absence of an intuitive sense for how well or poorly patients recover and their long-term outcomes. The perceived value of anecdotal experience was demonstrated by one participant who did not recommend antivenom to a neighbor, who later said that his chronic pain after the bite was so bad that he wished to have been treated with antivenom if insurance covered it. Seeing how the prolonged symptoms impacted his social and work life gave the physician a new perspective on treating snake envenomation patients. After that experience, he saw the value in receiving follow-up data, saying that this information could help physicians gain more confidence in their treatment decisions and shared decision-making:

“I think [feedback on recovery from discharged snakebite patients] would [help.] And it would be part of my shared decision-making speech with the patient. [INT: OK] And I think that it could potentially cut, you know, as with all shared decision-making - It's never completely neutral. And so, I think […] it would potentially push me to encourage the patient to use the treatment if there was something where cost was a satisfactory part of the consideration.” P3

Influencing factors in the choice for or against antivenom Availability and accessibility The availability and accessibility of antivenom was not cited as a major concern for treating snakebite patients within our study sample. One participant states:

“[fab antivenom] was the only available antivenom and is still the only available antivenom here in our institution.” P10

Other potential barriers for optimal treatment were identified. In some cases, antivenom was not kept in stock at the facility, requiring transfer of either the patient or the antivenom. In such cases, distance, mode of available transportation, and road or weather conditions could impact timely access to care. Access to institutions with available antivenom and experts to treat snakebite patients may be limited due to small clinics, which are not part of larger networks, not being aware of any nearby expert centers, and lack of awareness where to search for referral centers. Accessing antivenom for exotic snakebites could be a challenge depending on the snake type if a local institution or zoo does not have any in stock, and it might have to be delivered from distant locations for very rare bites.

Prior education of EM residents in snakebite management The level of didactic training received during EM residency did not seem to shape the general acceptance of antivenom, but more so the clinical approaches of local experts and mentors during residency. In areas with little to no snakebite patients, the education mainly consisted of didactic training, as well as how to use available resources like the Poison Center Call line and under what circumstances to refer patients.

“Well, you know, it's one of those things that all emergency physicians need to know about. I think you're going to find it a very variable fund of knowledge. And it's just because with rare exception, they just don't see that many of them. […] one of the wonderful things about emergency medicine is you have this diversity of things that you get to do. The curse is that you can't be the world's expert on everything.”P9

Cost All interviewees agreed that if administering antivenom would be a lifesaving treatment, cost would not be an influencing factor in their decision-making. However, cost would become an influencing factor when antivenom was used to prevent tissue damage in non-life-threatening conditions. Physicians typically informally weighed the costs and benefits of antivenom in these situations, with the caveat that those who primarily only treat severely toxic bites usually do not consider the cost of antivenom. One physician explicitly named the cost of the antivenom to be a risk factor to take into account. When it comes to the transparency of the cost of antivenom itself, most were not aware of the exact costs per vial for the hospital to acquire it, as well as for the patient to receive it. Those who were more acutely aware of the pricing had made a deliberate effort to find the information, and sometimes those who did still could not obtain a clear answer. There was uncertainty regarding national standard pricing, a lack of transparency within hospitals, and further uncertainty when it comes to how much insurance may cover. “The other consideration for maintenance vials is that they're super expensive. So a single vial of [fab antivenom] can cost the hospital between three and four thousand dollars. And depending on the charge master and what the hospital wants to charge [a] patient with or without insurance, that could go up, you know, seven times upwards to twenty thousand dollars per vial. So, if you’re giving 6 additional vials, for somebody, you're looking at about one hundred twenty thousand dollars in cost to patients.” P10

Despite this uncertainty, physicians were aware that the financial cost was high, and patients may be partly or fully responsible for covering it. In one case, however, the physician doubted that patients would actually be charged by the hospital if uninsured, stating: “I just, I highly doubt that any of the ER patients I see are actually receiving bills, like, I don’t know.” P 16

Cost emerged as the biggest barrier to antivenom treatment. Some participants expressed that, if costs were minimal, they would be more likely to treat more aggressively in mild cases to decrease chronic morbidity. However, some maintained that they still did not see mild cases as being an indication for antivenom, no matter the cost:

“I think having greater availability of antivenom at lower cost can take the question of whether or not to give antivenom to patients, in the equation that anyone with minimal symptoms may be able to get the antivenom without just thinking about how it will affect them financially. I think it's going to be huge.“ P10

Usage and perceptions on available resources Box 1 provides an overview of the available resources and influencing factors that impacted their utilization. While resources seemed to be readily available, some physicians pointed out that clinical judgement and personal experience may take precedence over general guidelines. The Poison Center Call line generally was thought to be a valuable and high-quality resource for physicians at bedside. However, if experts were available within their own institution, the physicians would consult them prior to using Poison Center Call lines. The benefits of Poison Center Call lines were that they were always available over the phone and potentially on bedside, yet one physician who worked for Poison Center Call lines raised the concern that over the phone consultations may result in hesitancy to follow their recommendations by the treating physicians. None of the other study participants who used Poison Center Call lines as a resource shared that concern. However, small nuances in their recommendations could occur based on the individual consultant. Overall, the available information on toxicology and pathology in the United States was thought to be of high quality and the physicians generally trusted the guidelines, recommendations as well as the safety of antivenom. In terms of antivenom though, some physicians voiced concerns about the trustworthiness of the data behind maintenance vial recommendations in regards of quality and the limited available evidence of its necessity:

“...the question is, do we have a good enough study that a perfectly defined mild, moderate, severe bite that shows a definition that they should actually benefit in the time that they got back to function. I don’t know that […] we’ve shown enough evidence to show that giving someone body [Fab2] will get you back to function faster.” P13

In addition, some felt that most of the evidence and available guidelines were snake-specific and non-transferrable. In terms of the quality of the available resources, the validity of online resources was questioned by a few participants, and one physician suggests increasing efforts in distributing better information to reach the physicians at bedside.

Box 1: Overview of available and utilized resources

The role of scientific evidence and general suggestions to improve patient care While scientific literature was, in a few cases, used as a tool to discuss treatment indications with the patients, the physicians also stated that personal experiences and beliefs might take precedence in choosing and recommending treatment options. Very few physicians were aware of studies investigating the effect of antivenom on pain or other long-term functional outcomes. In fact, several physicians reported a lack of awareness of ongoing scientific efforts and advancements in snakebite research and were unaware of available high-quality studies to guide their treatment decisions. In addition, skepticism of the available data was raised when funded by pharmaceutical companies, voicing the need for different funding sources, as well as skepticism surrounding the quality of available research data supporting antivenom for non-life- threatening conditions. Box 2 provides an overview of recommendations the physicians provided specifically to enhance the scientific research and literature surrounding snakebite management. Box 2: Recommendations to improve scientific evidence base on snakebite management practices

One physician pointed out that, while there were many suggestions on new evidence-based guidelines, we should also seek to understand what keeps treating physicians from following the already existing guidelines and then move forward promoting a socially and fiscally responsible practice:

“In those cases, where the diagnosis is not in question, nor the treatment in question, but at which time and at which patient this treatment would be appropriate for... Those are when I feel that we need to have more guidance and more standards, and then develop and fine tune those standards over a period of experience.” P5

Generally, the physicians agreed that to improve patient care, focus should be on high-quality evidence and guidelines, continuing education, patient-friendly information, increased transparency of long-term outcomes for EM physicians, and reassessing the cost for patients. Box 3 provides an overview of the suggestions provided by the study participants.

“[F]irst of all, education, and trying to find a platform to disseminate it. And that is so that EM-RAP [Emergency Medicine Reviews and Perspectives] is a great way of doing it, number 1. And number 2: I think if there was a very easy website that someone could just [find] snakebite guidelines and […] anybody from anywhere could easily [access], and then it goes through these different tabs so you know, indications, diagnostics, evaluations, patient education, what to notify a patient, and […] that you could easily print out […] and give it to a patient and go over information.” P12 Box 3: Suggestions to improve patient centered clinical best practices in snakebite management

Discussion: This study details the barriers to antivenom treatment and physicians’ needs in order to improve patient care by utilizing widely accepted best practices. Treatment approaches and perceptions of antivenom usage were influenced by a wide variety of factors in snake envenomation. Barriers to using antivenom were rooted in a wide variability in experience, awareness, and trust in available resources and evidence to inform physician decision-making. Some participants primarily relied on textbooks, raising questions on the timeliness and inclusion of current advancements in snakebite management. Aside from the Poison Control Center call line, there was little overlap of widely used and accepted resources by our participants. Having such a variability in resources including local expert opinions, on-site toxicologists, websites, apps and blogs increases the challenges to ensure consistent evidence-based recommendations. Participants echoed this notion and called for a systematic and high-quality national guideline, with precise and applicable clinical treatment recommendations. Our sample did not appear to be broadly aware of the detailed national guidelines already exist. (17)(18) Available scientific data, when funded by pharmaceutical companies, was often met with skepticism by our participants, especially when the findings recommended antivenom for milder cases. The fact that the majority of clinical trials in medicine are funded by industry did not seem to influence this belief. (19,20) Another consideration the majority of study participants brought up was the potential financial burden for patients, lack of transparency surrounding cost, and the need for cost–benefit analyses regarding initial doses and maintenance vials of antivenom. The potential detrimental financial burden for patients, in other studies referred to as ‘financial toxicity’ (21–23), is a known factor among medical practitioners in the United States. However, current research on cost transparency focuses on the hesitancy of seeking care from the patient’s perspectives (24,25), but not on how cost transparency and deeming financial toxicity for the patients can influence the provider’s treatment approaches. Our study demonstrates how cost is an important factor that providers consider when advising patients on snakebite envenomation treatment options. In addition to the possible financial burden influencing decision-making processes, some physicians based their clinical decision-making on their clinical experiences and conversations with colleagues and mentors, instead of current scientific evidence. Potential reasoning behind the experience-based medicine approach, instead of evidence-based (26), was the lack of trust in the data, as well the perceived superior value of clinical experience and competence. Providers, as well as patients, tend to be hesitant in accepting treatment suggestions based on poorly designed studies, increasing the value of expert opinions in the decision-making process. (27) Clinical judgment is a cornerstone of clinical practice to interpret clinical data. However, “like any judgment, these perceptions are not always reliable. It is known that physicians are highly variable in their interpretation of clinical data. [...] Further, they disagree with themselves when presented with the same information at two points in time.” (28) Other influencing factors in clinical decision-making may also include autonomy, education, understanding the patient status and awareness of the situation. Another challenge is the successful translation from research findings into clinical practice. Grimshaw et al. emphasize the importance of synthesizing research findings of specific topics to facilitate the integration in clinical practice. An assessment of barriers and facilities among different groups and settings is deemed critical to identify opportunities for successful knowledge translation into clinical practice patterns. (29) Lastly, we have found perceived safety and accessibility of antivenom were not considered barriers to treating snakebite patients with antivenom. Given the history of antivenom and strong side effects of the early forms of treatment, it would have not been surprising if some participants, especially those who were trained when the older antivenom was available, to base their reservations on antivenom usage on the perceived high risks for patients. While there is still a debate on “whether antivenom manufacturers are producing high quality and efficacious antivenoms” (30), especially in rural tropical areas with the highest burden of venomous snake bites (31), our US study sample perceived the quality and safety of the available antivenoms as high. Copperhead snakebites were generally not considered a life-threatening condition requiring immediate antivenom treatment. This was felt to provide additional time to determine if antivenom is necessary, despite evidence that copperhead snakebite is likely a time-dependent disease. (10) Limitations: Some limitations to the current study exist, though measures were taken to minimize their effect on the quality of the study. The Principal Investigator was known to some of our study participants, which could have influenced their participation in this study. In order to control for that, we informed the participants that the interviews will be de-identified and sent out for their approval before the PI would have access to the data. In addition to that, the majority of our study sample practiced in North Carolina and academic or teaching hospitals, limiting the representation across the US and community hospital providers.

Conclusion: The lack of awareness and trust in available scientific evidence regarding the benefits and indications for antivenom especially in non-life-threatening conditions, in addition to the lack of cost transparency, led to a wide variability in treatment approaches by practicing physicians. Our study emphasized the need for a widely accepted best practice guideline that is evidence based, includes concise clinical indicators developed by topic experts, and is implemented by practicing physicians.

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Supplement A: Full Coding overview and selected quotes Themes Codes Selected supporting Quotes

Snakebite treatment, Snakebite P1: Yeah. I think maybe once during residency, we had somebody who clinical decision management was bitten by a snake. Uhm… But the rest of the time, it was just all… making education of academic education in preparation for my E.M. boards. trainees INT: So you mentioned that you were a resident at Z. But now that you work elsewhere, how would you say that the education about snakebite treatment is at your current facility? P2: Well, I work at a resident, you know resident learning institution. So I think we're a little bit more involved with teaching residents and other attendings about, you know, kind of the oddities like snake bites. But I think our surrounding institutions where they don't have residents and there isn´t ongoing education, I would imagine it's a little bit behind on the data for the educational side. Even at our institution, though, we're still behind. I think just because of the limited amount of snake bites we receive, being that we're kind of in a city that's not very not very good compared to an institution like Z was.

INT: Um alright. So, how much have you been educated on snake bites um through med school, residency, and then I guess on the job training? How – [P5: Gosh] Where did you get your information from? P5: Uh… I would say that probably all together, maybe five hours worth of CME, my math on snake bites. If you had to put together studying that I had to do for the boards, a talk maybe at a residents conference because there was something neat that somebody said they were travelling somewhere else.

INT: Great, so within your facility uhm, your already said it is a university hospital, so how does the, the training of the residents look like in terms of snake bites? P13: Um, well all of our ER residents spend a month on toxicology during their residency [INT: Uh huh] So, you know they have that, exposure to us and the Poison Center. And then, you know they all work on the adults and peds side of the ED so they, they get to see snakebites throughout their training [INT: Mhmm], you know.

Snake P1: Well, if we were to see a victim of a snake bite, first thing we would do identification is try and identify the snake. [INT: Mm hmm. Right.] Is it poisonous or not poisonous? [INT: Yeah] I think that's sort of critical to the… ah future path that we take in, in terms of care. [INT: mhmm] And If it's not poisonous then we manage the wound and go on our day. [INT: Right]. If it's poisonous, then we have to identify what type to facilitate the antivenom [INT: mhmm] administration at the receiving facility, at at XY.

P2: He was pretty sure it was a black snake and we're pretty sure the black racer based on his description. And we have a snake identifier app on our phone. Most of us do on our phones.

INT: And does that influence your, um, your clinical approach at all - whether the patient knows a) whether it was a snake, definitely that bit them? And b)what type of snake it was? P3: Um… So I guess, um… um… I guess technically it should. I - I think that, um…. I don't really think it does that much at the end of the day because, you know, I'm – I’m looking at a snake bite in general, like how sick, you know, how bad the wound is, how sick the patient looks. So if it's a significant looking swelling, you know, like that, there is some type of venom - [INT: mhm] I'm presuming based on our epidemiology, or our geography that it did - it would be - if it is a venomous, poisonous snake, it would be a copperhead. So not really. Like it doesn't really influence what we do I think.

P9: Well um, I try and be a good doctor. Um. I try and get the best history I possibly can. Um. You know, there's some key features. Number one is, if you can get a positive I.D. on the snake, that helps a lot. [INT: Mhm] And so if there's an opportunity to… if there's an opportunity to do that, uh either directly with a photograph or by virtue of a description and a location, do that, then, you know, do a good history um and find out what the course of the patient's um…

Assessment P15: Um, I think that, I mean, probably somewhere in the middle of that. [INT: OK] I mean I don't know that I personally use a lot of envenomation scores…but certainly if they just have a little mild swelling at the site, I don't think we necessarily would do it then. [INT: OK] If the swelling seems deep or ecchymosis seems to be progressive or passes over a joint, um, so I mean like for example, if the entire foot is edematous and ecchymotic, even if it doesn't cross the ankle, we might still be more likely to, to give [fab antivenom], [INT: mhm] if it’s just a simple bite wound with minimal swelling, we may just watch those and see.

INT: Mhm. And so you mentioned that you also spent some time in a children's hospital. Do you think that the way you approach treating a snakebite patient would be different for a pediatric patient versus an adult patient? P14: I do, only in the way that if they're really young, you know, having them use crutches is really hard. So, a 3 year old using crutches, um, is probably not going to be realistic [INT: mhm] um versus, you know, if it's a 10, a 12 year old, that's someone probably that we can probably train to use crutches. So, if it's really going to be for two weeks that, you know, mom or dad has to carry the kid everywhere they go, they can't walk and they can't use crutches, um, then that kind of changes, you know, the algorithm. With that said, um with copperheads I've had, I have had some families who still just didn't want to give antivenom and were OK, kind of carrying around their kid for [INT: mhm] a week or two until they were able to start bearing weight.

P14: Um, and for them, it was kind of pain and swelling going up their leg. Um, and generally, you know, we’re able to identify that was a copperhead [INT: mhm], so I'm not really worried about systemic toxicity, at least any significant systemic toxicity. So really, it's a matter of getting their pain and swelling under control [INT: mhm], um, which we do with a combination of, NSAIDS, opioids, foot elevation, um, and then depending on how that goes, and I guess just how significant the swelling is, then you could discuss antivenom with them.

Alternative or INT: Mm hmm. So you mentioned if it's available, how would you proceed if supplemental it was not available? care to P4:I guess it depends on the envenomation, and that's mostly supportive antivenom care at that point, depending on if it's a respiratory failure or cardiac failure, kind of a cobra managing symptoms, kind of sympathomimetic access, you know with blood pressure control, heart rate control and ventilatory support and pain management, plus or minus surgical debridement or if there was a significant necrotic area that would require a surgery.

INT: My last question for you is just if you had a patient, what are some of the alternative treatment options if they didn't want to go through with antivenom? P10: Certainly, pain control monitoring and outpatient follow up, and physical therapy, occupational therapy. Those are all helpful.

INT: Right. OK. So, are there, if you had a snake bite patient and you thought that their symptoms weren't severe enough to warrant using antivenom, then what are some of the alternative treatment options you would do for them? P15: Usually just observation is the main thing. You know, we watch them for, you know, eh, four hours or so and they won’t have any progression or any signs of significant envenomation, we usually let them go home and come back if that materializes.

Antivenom Treatment Effectiveness INT: OK, great, perfect. And what what are the indications for [fab and antivenom]? So, you already mentioned, you know, when you would decide indications to to administer it. Um, is it pain, swelling, recovery time? What is the expected outcome of using antivenom? P16: Mm hmm. Um, it’s, uh, increased swelling [INT: Mhm] I think is something that I can objectively quantify. Um, and then, uh, I don't think that pain is, uh, is enough. You know, I think I've had some patients that, hmm, have had pain, uh, increased pain. But I don't think that's pushed me to treat just simply increased pain, [INT: Mhm] Swelling, and, uh, you know, if if there are, um, signs of necrosis, that kind of stuff, those kinds of local effects. Symptoms, I really haven't treated on that much, signs or so. Um, and then certainly we talked about any, uh, signs of like a coagulopathy on on their vascular panels. Again, um, INRs and platelets probably being the biggest thing. Um, and then like I said, I’ve treated one patient with what I thought was a systemic effect; nausea and vomiting. [INT: Yeah, OK, great] Um, so tho those will be my indications for treatment.

P15: But we've always, I think, kind of been, um, you know, based on the data, the decreasing morbidity and decreasing, you know, improving functional outcomes, improving pain long term, I think we tend to be more aggressive than some.

INT: Okay. Great. So how long, how long do you usually give the the patient to kind of observe the bite before you have to make a decision whether antivenom would be indicated or not. Is there a certain time frame [P13: Uhm] that you can.. P13: I think it depends on a little bit where the bite is [INT: Uh huh] Right so. Uhm, you know, a young child that’s like a, a finger bite, I’m going to be more cautious with and and, if it starts to spread faster, more pain that control them I might give them antivenom faster than I would an ankle bite that has more area for swelling and more, uhm, kind of flexibility and that. But [INT: Mhmm] usually if you have significant progression, you know past, past more than one joint uhm, from the bite sight, within like, within an hour [INT: Mhmm] then you know then you start to think, you know, do I need to add antivenom, versus, you know, I think it really depends on the situations because if they had their ankle down to gravity for the past hour of course it’s going to be more painful [INT: Right] so I want to get them in the right positions, get them some pain medicine and you know give them an hour probably to kind of see where we’re going.

Treatment INT: And when it comes to the dosage of antivenom treatment, how do you regimen determine that? Is that something that there's a strong protocol for or something that you would have to consult someone else to find out the proper way to do it? P4: I'd have to, I guess it depends on the antivenom (INT: right) and then I ´d have to look it up. I don't have it memorized, so we would probably, at that point, we'd be working with our toxicologists and our emergency pharmacists with the dosing.

P13: Most of the Copperheads here do not get maintenance vials. And they don’t need them. And so I do not think that it is wise to throw a [inaudible] that doesn’t have indication for why you need 12 vials on somebody [INT: Uh huh] up front on somebody. If you think that they need it, then I think giving them the 4 to 6 bolus dose as previously documented in the literature as being beneficial then, um you know, it can be, can be fine. But most of them don’t even need their maintenance doses so I think that- I think that they are some places that probably, in my opinion, give too much [fab antivenom].

Availability INT: Yeah. You said, though, that the antivenom usually is – uh is stored at and the facility? Or would that also be with the transportation or getting the accessibility antivenom also be another, another factor to consider? P5: At most of the facilities, it's it's not going to be stored and it would um be one or two things. Um and I would guess which would be the quicker. Could you courier or reverse courier the antivenom to your facility if the patient was able to stay there? But I'm guessing if they were in shock and looking like sepsis and with coagulopathy, the patient probably would be transported almost immediately. And thankfully, we do have a lot of air transport that can help out. [INT: OK] Um. So air transport to a, another facility at least where I'm at is anywhere between a half hour to 90 minute flight time. [INT: Mhm] Um. And then you have to, you know, add in the 15 minutes to warm up to helicopter and a 15 minutes to package a patient. So at best, if from the door I had identified a snakebite concern for an envenomation and shock with coagulopathy and um and called the flight crew right away, I could get somebody packaged up within 20 minutes and then flown to the nearest facility if they had a bed in 30 minutes. [INT: Mhm] So an hour transport time to get somebody the medication if it was available. [INT: Ok. Ok, great.] Well, like I said, I haven't called it up before, nor have I given it.

P4: And I think in our facility there is a limitation because we treat so few toxic snake envenomation, that you know, our hospital doesn't stock it per se, so we're acquiring it anytime there's a toxic envenomation from an outside source, it happens fairly rapidly. But it's not as, you know it happens so infrequently in our institution that, (cuts out for 4 seconds) that´s kind of where we´re at. We just don't treat very many of those.

INT: Okay, got you. Great. And I assume you have, you have the antivenom in stock at your facility? P13: Yeah. Yes, we do.

Risk and side INT: Are there any adverse effects of using it? effects P8: Well, I mean the patients can develop allergies because this was made out of serum [INT: Mhm] and the new ones are less allergic. But uh I think there’s a big cost issue with [fab antivenom] as well. [INT: mhm]. But that doesn’t really factor that much into your decision to use.

INT: Mhm, yea that's very interesting. So, you mentioned that you think anyone, ideally anyone with minimal symptoms should get antivenom. Is there any concern for any adverse effects or any unintended consequences from an unnecessary treatment? P10: Yea mostly just the pocketbook consequences, right? The financial cost of it. I think that [fab antvenom] and [fab2 antivenom] are clean enough products that the, um the allergic reaction, the anaphylactic reaction, derm thickness reaction, are relatively minimal compared with the past type of antivenom.

Cost P1: ... to give somebody a lifesaving medication - It doesn't matter what the cost is, [INT: mhm] it's to save their life. [INT: mhm] So that's why we do what we do. [INT: Right.] So the answer is, I don't care what the cost is, I'm gonna get them to try and get their therapy. [INT: mhm] Luckily, we're not socialized health care where the cost is the limiting factor sometimes. [INT: Right] Here in America, we don't have that. We have, just get the person to care and work out - work out the money later.

INT: Okay. And when you are talking about this treatment with the patient, do you ever bring up the cost of the treatment? P2: I did, yes. I had a pharmacist look it up. INT: Ok, and do you think that ever plays into a patient's decision of going forward with the treatment or not? P2: I think so, yes. It depends on how serious the snake bite is. And if there is an obvious, you know, a risk to limb or life, then the patient's probably less likely to worry about costs. But if it's, you know, kind of one of these questionable snake bites and questionable envenomation, someone's gonna give it to be careful, that may come into factor if it's a couple thousand dollar medicine.

INT: OK, and are you aware of if you get the antivenom from the zoo, does the hospital pay for that or does insurance or where does that come from? P4:I have no idea, honestly.

INT: That's great, thank you. So you mentioned that you would talk about the evidence and some of the benefits and harms. Do you think that anything like cost would come into the conversation? P6: Yea, I think that if it cost a million dollars for a dose, then probably that's something the healthcare system and the patient will want to know and the insurance company. I think there is probably a threshold above which costs would become an issue. And it's solely would depend on if the patient has to pay out of pocket for that, you can put them into debt for the rest of your life, I don't know what that threshold would be. I would hope that there would be a cost-effectiveness analysis somewhere in the antivenom literature that would help to inform that.

P9: Well, I don't think we can dodge the cost issue. INT:Uh huh. Can you talk a little more about that? P9: Well, it's expensive. So, you know, all things being equal, um, it depends who's paying for it. It's not that in a life-threatening situation, you wouldn't make decisions independent of cost. But, you know, given how expensive it is [INT: Mhm] that factors, I mean, that comes up frequently. Like you realize how many vials of antivenom this person has gotten. Do you know how much this cost? [INT: Mhm] You know, people look at their hospital bills and go, oh, my God. [INT: Yeah] You know? And so I think it's it's a cost benefit analysis. [INT: Mhm] And so that's that's a factor. [INT: Yeah] Those are the two biggies. INT: OK. So who, who usually is paying for the antivenom in your own experience? P9: It really is, it's like anything else in health care. [OK] Just depends what the patient's insurance coverage is. [INT: Yeah] So, if they have insurance coverage, then hopefully the insurance covers it. But if they don't um and if it's the right thing to do to give it, the hospital has to eat it. I don't think we can hand people uh bills for hundreds of thousands of dollars. Um. And I just don't think we can do that. We’re, you know, [INT: Yeah] That’s across the whole spectrum of health care. [INT: OK] Right. [INT: Right] Well, you know, if you're if you're the company making this stuff, [INT: Mhm] there's a certain profit margin that they I'm sure they expect or would like. Um… But they, you know, compassionate use programs are very important. INT: Right. Yeah, okay. So do you know how much how much a vial actually is? P9: I don't know what the cost of that. You know, I don't know what the cost is. [INT: Uh huh] I know that I've seen prices that are in high thousands of dollars per vial. [INT: OK] And I also don't know if there's standard pricing across the country, you know, whether the retail price is the same in northern California as it is in Arkansas. INT: I see. OK. Great. And then how do you educate the patients um on the cost factor? P9: You know, um, if I… um if I think the patient is on the bubble about getting antivenom or not – [INT: Mhm] And if I think they're going to get the bill, um, and I think that they should have input into the decision - And this is not just for antivenom, this is for any form of care for which I think the patient should be allowed to have input into whether they get it or not.

Patient INT: Okay, great. So in the, in the two cases that you treated, it sounded education, like antivenom wasn't even um up for discussion. In, in those two cases. shared Um. Did you, did you inform the patients at all that, you know, there is decision antivenom available, and if so, how do you, how do you educate patients making on their treatment options? P5: Interesting. So um when talking about that, I usually phrase it as this looks like this is going to be a more local reaction. And the most important thing I either say they have already done by doing wound care and presenting to the emergency department so they can get checked up because there can be serious complications. So I do that with most of my patients to be like, thank you. You've done 50 percent of the work by just showing- showing up. [INT: Right] And then we'll figure out the rest from here [INT: Mhm] and then inform them about we're going to do some labs. And I want to observe you and I want to let you know- And in case you didn't know, there is a treatment that we give in envenomation in very specific cases when people get really, really sick. [INT: Mhm] Um, your labs and the way you look and feel will tell us how to do that. And then I'm like and I also talk to the poison control people um who are experts in this particular medication. Um. That's sort of how I approach, approach most of the subjects when I talk to them.

P14: Um, I think think for the most part uh, you know, we try I try to cater it based on, you know what I think you know, I don't want to have a conversation I don't think that they they they can understand or truly truly understand what I'm trying to say. So if, you know, if it, so I do try to cater the language and everything to them [INT: mhm], but I think for the most part they do and we're watching them and I, you know, if they want to go ahead with the antivenom, um, and that’s one thing or they're like, well, we'll hold, they understand like if things change, we can always give it then.

INT: And when you're talking to the patient, do you ever bring up the cost into the conversation? P15: Um, you know, not typically, unless they ask.

INT: OK, great. And how how do you how do you educate or inform the patients about the the possible cost factor, um, when you discuss treatment with them? Does that come up at all? P16: I don't bring it up. [INT: OK] I don't bring it up because, um, uh, I guess I'm afraid that that it might change their opinion, um, either way and stuff on it, you know. I'm not sure if that's a wise approach, um, because, you know, maybe patients should know the prices of stuff when they choose. [INT: Hmm] Um, but I don't, I guess I, I don’t know, I just get a little bit uncomfortable, I don't know how to approach that. And I haven’t figured out the best way to approach, um, like the pharmacoeconomic talk of stuff. So, um, so I haven't. [INT: Yeah, OK], I can’t remember that I've ever brought up the cost.

Patient P4: I haven't really recommended anti-venom to somebody that has behavior and refused it at that point, and I haven't had anybody that insisted upon it that seeking care hasn't needed it and then administered it, like there hasn't been that I demand this treatment, but there's no indication for it that we went ahead with, so.

INT: I see. OK. Alright. But from, from your experience, patients are usually pretty um, when they get the recommendation from you they, they usually aren't too too worried about the cost? Or how, how do they usually react to that? P7: Yeah, so I’ve had people worried about it, but I think that that issue is more just that people realize that like if we've gotten to the point where, ya know, they may really have serious consequences from the snakebite, people seem to be pretty willing to kind of sort it out.

Treatment P9: Other people who are more comfortable with clinical judgment, which I hesitancy and think, frankly, tend to be older doctors, because we didn’t have all that stuff perceived [laughs] in those days. So we're used to watching patients. confidence INT: Yeah. Yeah. P9: Um… You know, I think so. There's a whole – that, that could be an area of study that you might drive out of this. [INT: Yeah] Which is, you know, depending on what questions you can ask people as are, are older people or people who have been around, more clinically experienced, [INT: Mmm] less likely to give you antivenom.

P12: I would probably have the ED pharmacist or a pharmacist kinda go over with them uhm, that uhm, or I would you know, really have to review the package insert before I talk to the patient, or an article that is update [INT: mmmh] as a reference and review it. Just because again, for something that is so so so infrequent, [INT: yeah] uhh, I think it would be important to take a reference or just to be sure I am uh, providing them all the accurate best information.

INT: OK. And do you think that, you know, you mentioned that you stay current with the literature, do you think that besides reading journals, there's a way to, you know, get this information out if people aren't aware of the current literature? Or do you think that just, you know, relying on calling the poison center is how physicians typically get their information if they're not an expert in this area? P14: Yeah, I mean, I think there's ways to get out, uh, what they're webinars or other types of educational opportunities to get things out. Um, with that said, I think for someone who's only going to deal with maybe a couple a year, um, I think they're always going to call for help to make sure they're doing the right thing [INT: right]. And, even if they're reading something , there is a difference between reading about something and and truly seeing it enough that you feel comfortable

INT: OK. So you can't think of any reason why they wouldn't [administer antivenom]? P2: I mean, maybe just like I said, maybe uncomfortableness with delivering [fab antivenom] and treating snake bites because of the limited amount that we have here in Orlando.

INT: Do you feel that there's any hesitation among physicians to use antivenom? P4: Not that I've experienced, no.

P8: And uhm, so you know everyone gets excited, everybody wants to give [fab antivenom] because the rep was there a couple of months ago and [fab antivenom] was introduced, and I said, let’s just wash the wound off and swab the area, look at it, mark it, elevate his arm and I wasn’t too convinced of using any [fab antivenom]. Because I think when you want to use [fab antivenom], you have to be very cautious before you make that decision now.

P9: Well, you only get confident by practicing. [INT: Uh huh] So, yeah, you know, that part's gonna be a little tougher. [INT: Right]

Resources Usage and INT: Do you know of any other information resources that you can tap in, perceptions tap into ? on available P1: Yes , we have uh -- I have -- We have online resources. The X health resources system is very robust with information [INT: mhmm] and data. We can tap into an online toxicology…. online… wilderness medicine just so we can identify the bite marks. [INT: OK .] There's a huge library of data that we could access. whatever, whatever you think you want to look for [INT: Yeah], we just log in and look for it.

P2: Yeah, I mean I think it would be based on, in our facility it is based on the physicians. I mean, obviously the patients have to agree to do it with some side effects that can attract with allergic reactions. But yeah, we don't have a protocol for it. We would probably use Poison Control's input as well. Most physicians I think would, but it's still the physician's decision, yea. INT: OK, so you talked a little bit about the policies include calling poison control if you need consultation. Are there any other policies at your current workplace in terms of snake bite treatments? P2: I wouldn´t say it´s a policy to call poison control, I think it is a thing most physicians would do, due to you know due to the limited amount of snakebites that we receive. But we actually don’t have any policy written. So, it would be individually based on the physician. INT: OK. And do you think that there's a common uhm, Physicians would tend to treat snake bite patients in the same way at your facility or there might be…are there any different opinions on how to treat them? P2: I would imagine there is different opinions. Without a protocol, there´s always different opinions.

INT: Where do those resources come from that guide your decision making? P3: Yeah. Umm… our um management. Yes, we do- we do have a champion. And that would be where bias in the sense that Dr.A is co- investigator on all these snakebite studies. [INT: Mhm] But our current document literally is a cut and paste, comes from the article by Lavonas et al, 2011, currently “Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop”. And we have their- their, uh, flow chart. [INT: OK] And that's why I'm looking at and that's that's what I would pull from – and I think is similar to what the poison center has. They may have some updated stuff, but [INT: Mhm] but this is 2011, so.

P05: And and uh. Yeah, and then just looking it up when seeing those two patients [INT: OK] going to Up-To-Date or some other E.M. reference guide, Rebel EM, EMcrit, EMrap are some of the specific sites that I use, um then uh then I would have to say that would be it in total.

The role of P6: So I'd be looking for I think reasonable levels of evidence showing scientific benefits outweigh harms in the forms of systematic reviews of observational evidence studies, again using the Bradford Hill criteria (INT: Mhm) and then single observation studies would be below that. I would not accept a single patient case report. INT: OK, thank you, that's very informative. OK. So you'd be looking for evidence to show that it is supported that the benefits outweigh the harms. So if there was no evidence that antivenom, no strong evidence, maybe there is questionable evidence- how do you think that would play into your decision making? P6: I think that if the toxicology team was recommending an antivenom therapy and there wasn't any evidence to support it or very weak evidence or contradictory evidence where some evidence suggest benefits, some evidence suggests harms, and some evidence suggest both, I would, with the toxicologist want to go into patient's room and discuss what we know about the antivenom therapy, the potential benefits, potential harms and then in a shared decision making way come to a decision. The toxicology, myself and the patient about the best option for that patient.

INT: Okay. I got you. Great. So, what do you think would need to, what do you-think we would have to do, and, and, research to get to that point? What would you suggest? What kind of date would - P13: Um, I think you would. Um, I think you would have to have a very a very standardized dosing regimen, timing regiment, and um, specific criteria for what you’re using as mild, moderate, serve, um, to show benefit and then I think that on top of that, you’d have to argue what does one person consider “back to function”, right? That’s where the subjectivity of it comes in right like? [INT: Yeah] Like I’m two weeks out on a patient or like, you know, do they feel like they have 90 percent of their hand back or 75 percent of their hand back? Like, that’s going to be a very hard depiction, you know [INT: hmm] unless you find some objective criteria like grip strength or, um, you know some, some specific objective criteria they can do in the ED- it’s not a, it’s not a ‘I feel this way’ it’s a ‘I could do this activity’ or ‘I could do this activity’ which would make me therefore seem like I’m back to my function.

INT: Yeah, OK, great. And how how do you yourself stay up to date with recent literature or best practices when it comes to snake bite treatment? [P16: Ummm] Where do you get your information? P16: I think I do end up reading all the paper, all the snake related papers in the, um, in the emergency medicine literature. [INT: Mm hmm]. Umm, yeah, I think I would be pretty familiar with most of those, um, recently went to umm, a venom week [INT: Mhm] conference, that was, uhh, I don’t know, last-weekish maybe? Umm, yeah, so I’ve been to those a few times.

Suggestions Information INT: So is there any suggestions that you have on how you think snake by dissemination, patient treatment can improve locally or globally? Guidelines, P10: So definitely two very different questions. [INT: OK] So, you know, I Feedback think locally it has to do with more so with the whole health care system. Right. So if you're going to charge me twenty thousand dollars per vial of antivenom, that is very beneficial to them um, that’s a big problem, right. [INT: Mhm] Um. Globally, the use of antivenom potentially costs, you know, 20, 30 dollars, a hundred dollars per vial. I understand that there's need for innovation, and drug development costs that goes into it. So I think it's a huge systemwide problem that this orphan drug costs so much money. I think having greater availability of antivenom at lower cost can take the question of whether or not to give antivenom to patients, in the equation that anyone with minimal symptoms may be able to get the antivenom without just thinking about how it will affect them financially.

INT: So if you know if there were literature, basically with similar set up that was done for adults, in terms of length of hospital stay, recovery time, all that stuff, would you expect it to be different for the pediatric population? P11: Uh I don’t know uh it’s a good question, I don’t know, I would uh I would expect uh probably not uh you know and again, like I guess the question is like what markers are you looking for, like return to function, uh like because obviously kids aren’t going back to work, but like going back to school and you know participating in their activities and sports, [INT: Yeah] so maybe the markers would be a little different, I don’t know that I would expect a tremendous difference, but I mean again that another reason to study it because maybe there is. INT: Yeah right. P11: Again, I don’t know that people are going to do it, because it a lot of times stuff like this it’s not, it’s harder to study stuff like this for kids for various reasons.

INT: OK, or maybe any suggestions for how physicians can be better informed about this or anything that would be helpful if you did have a snakebite patient that would help you in treating the patient better? P6: No, I think my lack of exposure to these patients limits my ability to answer that question.

P5: My thought at this point in time that if there is a… if it comes back and from the manuscripts, a conclusion that could be made, that there is quite a variable at this, because this is sort of a low frequency but potentially highly acute event um that that tells me there needs to be more education, but not only in, not only education, but also as you're mentioning, and I hope we can get to at some point in time, a standard or a guideline that we can all appreciate. [INT: Mhm] And then following that, the only thing that if I ask for, if I ask for a guideline, the important part is how would it be disseminated and implemented? [INT: Mhm] And finally how would it how would it be tracked to make sure that people can follow this guideline in their practice areas and then act? And then the last part of that being, if people aren't following practice guidelines, um, what are the barriers um to prevent them from doing that? And hopefully doing that in a very non- confrontational way, which seems to be nearly impossible in the world of quality assurance and [INT laughs] and risk management in our current practice. Um… Meaning that this is about this is about education and elevating everybody's standard of care, um, making it about the patients and our communities to make sure they're doing the right thing. [INT: Mhm] Um. But so we're sort of being socially and fiscally responsible with which I'm guessing is a pretty expensive medication. I'll venture to guess, is it like five thousand per dose that we give?