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Background: Snakebite clinical trials have often used heterogeneous outcome measures and there is an urgent need for standardisation., Method: A globally representative group of key stakeholders came together to reach consensus on a globally relevant set of core outcome measurements. Outcome domains and outcome measurement instruments were identified through searching the literature and a systematic review of snakebite clinical trials. Outcome domains were shortlisted by use of a questionnaire and consensus was reached among stakeholders and the patient group through facilitated discussions and voting., Results: Five universal core outcome measures should be included in all future snakebite clinical trials: mortality, WHO disability assessment scale, patient-specific functional scale, acute allergic reaction by Brown criteria, and serum sickness by formal criteria. Additional syndrome-specific core outcome measures should be used depending on the biting species., Conclusion: This core outcome measurement set provides global standardisation, supports the priorities of patients and clinicians, enables meta-analysis, and is appropriate for use in low-income and middle-income settings., (Copyright © 2023 SFMTSI.)

Snakebite clinical trials have often used heterogeneous outcome measures and there is an urgent need for standardisation. A globally representative group of key stakeholders came together to reach consensus on a globally relevant set of core outcome measurements. Outcome domains and outcome measurement instruments were identified through searching the literature and a systematic review of snakebite clinical trials. Outcome domains were shortlisted by use of a questionnaire and consensus was reached among stakeholders and the patient group through facilitated discussions and voting. Five universal core outcome measures should be included in all future snakebite clinical trials-mortality, WHO disability assessment scale, patient-specific functional scale, acute allergic reaction by Brown criteria, and serum sickness by formal criteria. Additional syndrome-specific core outcome measures should be used depending on the biting species. This core outcome measurement set provides global standardisation, supports the priorities of patients and clinicians, enables meta-analysis, and is appropriate for use in low-income and middle-income settings., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

To categorize the Patient-specific Functional Scale (PSFS) activities in snakebite envenoming (SBE) using the International Classification of Function (ICF) model in order to describe the impact of SBE on patients' activities and daily lives and to develop a theoretical SBE model of functioning, we performed a post-hoc analysis of two multi-center, prospective studies, conducted at 14 clinical sites in the United States with consecutive SBE patients presenting to the emergency department. Qualitative content analysis and natural language processing were used to categorize activities reported in the PSFS using the ICF model. Our sample included 93 patients. The mean age was 43.0 (SD 17.9) years, most had lower extremity injuries (59%). A total of 99 unique activities representing eight domains came within the Activity and Participation component of the ICF model, with the majority in the Mobility and General Tasks and Demands domains. The main concerns of SBE patients are the ability to perform daily activities and to engage within their social environment. Applying the ICF model to SBE can facilitate the creation of a patient-centered treatment approach, moving beyond body-structural impairments towards a function-based treatment approach and facilitate early integration of rehabilitation services.

Introduction: Few data exist to understand the recovery phase of pit viper envenomation. A recently published placebo-controlled clinical trial affords this opportunity. The purpose of this study is to examine the time course of recovery from copperhead snake (Agkistrodon contortrix) envenomation patients managed with and without the use of antivenom, stratified by age, sex, anatomic site of envenomation, initial severity of envenomation, and geographic region., Methods: This is a post-hoc subgroup analysis of data from a multi-center double-blinded clinical trial of Fab antivenom (FabAV) vs. placebo. Outcomes were the Patient-Specific Functional Scale (PSFS) score at 3, 7, 10, and 14 days after envenomation. Least-squares mean PSFS score curves were calculated for each subgroup, and repeated measures ANOVA was used to estimate between-group comparisons., Results: Seventy-two subjects were included, of whom 44 received FabAV. Males demonstrated better overall recovery than females (model predicted PSFS score 6.18 vs 4.99; difference 1.19; 95% CI 0.12 to 2.25; p = 0.029). No sex difference was found in response to FabAV. Overall recovery and effect of FabAV were similar in adult vs adolescent patients, patients with upper vs lower extremity envenomation, and patients with initially mild vs moderate envenomation signs. Analysis by geographic location was not successful due to ANOVA mode instability., Conclusions: Male victims of copperhead snake envenomation demonstrate slightly better recovery than females, but response to Fab antivenom overall is similar across all subgroups studied.

Objectives: Although more than 1.8 million people survive snakebite envenomation each year, their recovery is understudied. Obtaining long-term follow-up is challenging in both high- and low-resource settings. The Patient-Specific Functional Scale (PSFS) is an easily administered, well-accepted patient-reported outcome that is validated for assessing limb recovery from snakebite envenomation. We studied whether the PSFS is valid and reliable when administered by telephone., Methods: This is a secondary analysis of data from a randomized clinical trial. We analyzed the results of PSFS collected in-person on days 3, 7, 14, 21, and 28 and by telephone on days 10, 17, and 24. We assessed the following scale psychometric properties: (a) content validity (ceiling and floor effects), (b) internal structure and consistency (Cronbach's alpha), and (c) temporal and external validity using Intraclass Correlation Coefficient (ICC). Temporal stability was assessed using Spearman's correlation coefficient and agreement between adjacent in-person and telephonic assessments with Cohen's kappa. Bland Altman analysis was used to assess differential bias in low and high score results., Results: Data from 74 patients were available for analysis. Floor effects were seen in the early post-injury time points (median: 3 (IQR: 0, 5) at 3 days post-enrollment) and ceiling effects in the late time points (median: 9 (IQR: 8, 10). Internal consistency was good to excellent with both in-person (Cronbach α: 0.91 (95%CI 0.88, 0.95)) and telephone administration (0.81 (0.73, 0.89). Temporal stability was also good (ICC: 0.83 (0.72, 0.89) in-person, 0.80 (0.68, 0.88) telephone). A strong linear correlation was found between in-person and telephone administration (Spearman's ρ: 0.83 (CI: 0.78, 0.84), consistency was assessed as excellent (Cohen's κ 0.81 (CI: 0.78, 0.84), and Bland Altman analysis showed no systematic bias., Conclusions: Telephone administration of the PSFS provides valid, reliable, and consistent data for the assessment of recovery from snakebite envenomation., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Rose reports speakers bureau fees from BTG International Inc outside the submitted work. Dr. Greene reports receiving consulting fees and honoraria from BTGInternational Inc outside the submitted work. Drs. Gerardo, Charlton, Mullins, Lavonas and Kleinschmidt and Ms. Anderson report receiving prior study-related grants from BTG International Inc.

Introduction: Copperhead envenomation causes local tissue destruction, leading people to seek treatment for the pain and swelling. First-line treatment for the pain is opioid medications. There is rising concern that an initial opioid prescription from the emergency department (ED) can lead to long-term addiction. This analysis sought to determine whether use of Fab antivenom (FabAV) for copperhead envenomation affected opioid use., Methods: We performed a secondary analysis using data from a randomized clinical trial designed to determine the effect of FabAV on limb injury recovery following mild to moderate copperhead envenomation. Opioid use was a defined secondary outcome in the parent trial. Patients were contacted after discharge, and data were obtained regarding medications used for pain and the patients' functional status. This analysis describes the proportion of patients in each treatment group reporting opioid use at each time point. It also assesses the interaction between functional status and use of opioids., Results: We enrolled 74 patients in the parent trial (45 received FabAV, 29 placebo), of whom 72 were included in this secondary analysis. Thirty-five reported use of any opioids after hospital discharge. A smaller proportion of patients treated with FabAV reported opioid use: 40.9% vs 60.7% of those in the placebo group. The proportion of patients using opioids remained smaller in the FabAV group at each follow-up time point. Controlling for confounders and interactions between variables, the model estimated that the odds ratio of using opioids after hospital discharge among those who received placebo was 5.67 times that of those who received FabAV. Patients who reported higher baseline pain, those with moderate as opposed to mild envenomation, and females were more likely to report opioid use at follow-up. Patients with ongoing limitations to functional status had an increased probability of opioid use, with a stronger association over time. Opioid use corresponded with the trial's predefined criteria for full recovery, with only two patients reporting opioid use in the 24 hours prior to achieving full limb recovery and no patients in either group reporting opioid use after full limb recovery., Conclusion: In this study population, the proportion of patients using opioids for pain related to envenomation was smaller in the FabAV treatment group at all follow-up time points., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The original trial was funded by BTG International Inc. Funding for the statistical analysis for this secondary analysis was also provided by BTG International Inc. Drs Gerardo and Lavonas report receiving grants from BTG during the original trial and outside of the submitted work. Dr. Kleinschmidt and Ms. Anderson report receiving study-related funds from BTG.

Importance: Venomous snakebite severity ranges from an asymptomatic dry bite to severe envenomation and death. The clinical evaluation aids in prognosis and is essential to determine the risks and potential benefits of antivenom treatment., Objectives: To identify historical features, clinical examination findings, basic laboratory testing, and clinical grading scales that will risk-stratify patients with pit viper snake envenomation for severe systemic envenomation, severe tissue injury, and/or severe hematologic venom effects., Data Sources: We conducted a structured search of PubMed (1966-October 3, 2017) and Embase database (1980-October 3, 2017) to identify English-language studies that evaluated clinical features predictive of severe envenomation., Study Selection: We included studies that evaluated the test performance of at least 1 clinical finding with an acceptable reference standard of severe envenomation for venomous snakes of the Western Hemisphere. Only studies involving the most common subfamily, Crotalinae (pit vipers), were evaluated. Seventeen studies with data were available for abstraction., Data Extraction and Synthesis: The clinical features assessed and severity outcome measures were extracted from each original study. We assessed severity in 3 categories: systemic toxicity, tissue injury, and hematologic effects. Differences were resolved by author consensus., Results: The pooled prevalence of severe systemic envenomation was 14% (95% CI, 9%-21%). The pooled prevalence of severe tissue injury and severe hematologic venom effects were 14% (95% CI, 12%-16%) and 18% (95% CI, 8%-27%), respectively. Factors increasing the likelihood of severe systemic envenomation included the time from bite to care of 6 or more hours (likelihood ratio [LR], 3.4 [95% CI, 1.1-6.4]), a patient younger than 12 years (LRs, 3.2 [95% CI, 1.5-7.1] and 2.9 [95% CI, 1.3-6.2]), large snake size (LR, 3.1 [95% CI, 1.5-5.7]), and ptosis (LRs, 1.4 [95% CI, 1.0-2.1] and 3.8 [95% CI, 1.8-8.3]). Envenomation by the genus Agkistrodon (copperhead and cottonmouth), as opposed to rattlesnakes, decreased the likelihood of severe systemic envenomation (LR, 0.28 [95% CI, 0.10-0.78]). Initial hypofibrinogenemia (LR, 5.1 [95% CI, 1.7-15.0]) and thrombocytopenia (LR, 3.7 [95% CI, 1.9-7.3]) increased the likelihood of severe hematologic venom effects. Other clinical features from history, physical examination, or normal laboratory values were not discriminative., Conclusions: Clinical features can identify patients at increased risk of severe systemic envenomation and severe hematologic venom effects, but there are few features that are associated with severe tissue injury or can confidently exclude severe envenomation. Physicians should monitor patients closely and be wary of progression from nonsevere to a severe envenomation and have a low threshold to escalate therapy as needed.

Objective: Valid, reliable, and clinically relevant outcome measures are necessary in clinical studies of snake envenomation. The aim of this study was to evaluate the psychometric (validity and reliability) and clinimetric (minimal clinically important difference [MCID]) properties of the Patient-Specific Functional Scale (PSFS) in snakebite envenomation., Methods: We performed a secondary analysis of two existing snakebite trials that measured clinical outcomes using the PSFS as well as other quality of life and functional assessments. Data were collected at 3, 7, 10, and 17 days. Reliability was determined using Cronbach's alpha for internal consistency and the intraclass correlation coefficient (ICC) for temporal stability at 10 and 17 days. Validity was assessed using concurrent validity correlating with the other assessments. The MCID was evaluated using the following criteria: (1) the distribution of stable patients according to both standard error of measurement (SEM) and responsiveness techniques, and (2) anchor-based methods to compare between individuals and to detect discriminant ability of a positive change with a receiver operator characteristic (ROC) curve and optimal cutoff point., Results: A total of 86 patients were evaluated in this study. The average PSFS scores were 5.37 (SD 3.23), 7.95 (SD 2.22), and 9.12 (SD 1.37) at 3, 7, and 10 days, respectively. Negligible floor effect was observed (maximum of 8% at 3 days); however, a ceiling effect was observed at 17 days (25%). The PSFS showed good reliability with an internal consistency of 0.91 (Cronbach's alpha) (95% CI 0.88, 0.95) and a temporal stability of 0.83 (ICC) (95% CI 0.72, 0.89). The PSFS showed a strong positive correlation with quality of life and functional assessments. The MCID was approximately 1.0 for all methods., Conclusions: With an MCID of approximately 1 point, the PSFS is a valid and reliable tool to assess quality of life and functionality in patients with snake envenomation., Competing Interests: Dr. Rose reports speakers bureau fees from BTG International Inc outside the submitted work. Dr. Greene reports receiving consulting fees and honoraria from BTGInternational Inc outside the submitted work. Drs. Gerardo, Charlton, Mullins, Lavonas and Kleinschmidt and Ms. Anderson report receiving prior study-related grants from BTG International Inc. The parent studies from which data were derived, were funded by BTG International Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: No previous research has studied whether early snake antivenom administration leads to better clinical outcomes than late antivenom administration in North American pit viper envenomation., Methods: A secondary analysis of data from a clinical trial of Fab antivenom (FabAV) versus placebo for copperhead snake envenomation was conducted. Patients treated before the median time to FabAV administration were classified as receiving early treatment and those treated after the median time were defined as the late treatment group. A Cox proportional hazards model was used to compare time to full recovery on the Patient-Specific Functional Scale (PSFS) instrument between groups. Secondary analyses compared estimated mean PSFS scores using a generalized linear model and the estimated proportion of patients with full recovery at each time point using logistic regression. To evaluate for confounding, the main analysis was repeated using data from placebo-treated subjects., Results: Forty-five subjects were treated with FabAV at a median of 5.47 h after envenomation. Patients in the early treatment group had a significantly shorter time to full recovery than those treated late (median time: 17 versus 28 days, p = .025). Model-estimated PSFS scores were numerically higher at each time point in the early group. No difference was found between patients treated early versus late with placebo., Conclusions: In this secondary analysis of trial data, recovery of limb function was faster when Fab antivenom was administered soon after envenomation, as opposed to late administration.

Objective: To compare the incidence of hypersensitivity reactions following copperhead envenomation treated with Fab antivenom (FabAV) or placebo., Methods: Patients with copperhead snakebites received treatment and follow-up in a prospective, randomized, double-blind, placebo-controlled trial of FabAV or placebo. The treatment allocation ratio was 2:1 (FabAV:placebo). All of the included patients received at least one dose of study treatment. We reviewed all treatment-emergent adverse events (AEs) using a previously published scale to classify likely hypersensitivity reactions as mild, moderate, or severe., Results: We enrolled 74 patients at 13 sites. Forty-five patients received FabAV, and 29 patients received placebo. Five FabAV patients and 4 placebo patients had moderate envenomations; the rest were mild. Twenty-five FabAV patients and 8 placebo patients had at least 1 AE. Mild skin reactions occurred in 11 (24%) FabAV patients (pruritis, urticaria, rash, ecchymosis, erythema) and 1 (3%) placebo patient (pruritis). Moderate gastrointestinal AEs occurred in 7 (16%) FabAV patients (nausea, vomiting, constipation, diarrhea, oral paresthesia) and in 2 (7%) placebo patients (nausea). Respiratory AEs occurred in 3 (7%) FabAV patients (dyspnea, pulmonary embolism, nasal congestion, sneezing) and no placebo patients. Hypotension occurred in 1 patient in each group., Conclusions: In a randomized controlled trial of FabAV for copperhead bites, the incidence of hypersensitivity reactions was low. Most reactions were mild skin reactions.

Study Objective: Copperhead snake (Agkistrodon contortrix) envenomation causes limb injury resulting in pain and disability. It is not known whether antivenom administration improves limb function. We determine whether administration of antivenom improves recovery from limb injury in patients envenomated by copperhead snakes., Methods: From August 2013 through November 2015, we performed a multicenter, randomized, double-blind, placebo-controlled, clinical trial to evaluate the effect of ovine Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) antivenom therapy on recovery of limb function in patients with copperhead snake envenomation at 14 days postenvenomation. The study setting was 18 emergency departments in regions of the United States where copperhead snakes are endemic. Consecutive patients aged 12 years or older with mild- to moderate-severity envenomation received either FabAV or placebo. The primary outcome was limb function 14 days after envenomation, measured by the Patient-Specific Functional Scale. Additional outcomes included the Patient-Specific Functional Scale at other points; the Disorders of the Arm, Shoulder, and Hand, Lower Extremity Functional Scale, and Patient's Global Impression of Change instruments; grip strength; walking speed; quality of life (Patient-Reported Outcomes Measurement Information System Physical Fucntion-10); pain; and analgesic use., Results: Seventy-four patients received study drug (45 FabAV, 29 placebo). Mean age was 43 years (range 12 to 86 years). Fifty-three percent were men, 62% had lower extremity envenomation, and 88% had mild initial severity. The primary outcome, the least square mean Patient-Specific Functional Scale score at 14 days postenvenomation, was 8.6 for FabAV-treated subjects and 7.4 for placebo recipients (difference 1.2; 95% confidence interval 0.1 to 2.3; P=.04). Additional outcome assessments generally favored FabAV. More FabAV-treated subjects experienced treatment-emergent adverse events (56% versus 28%), but few were serious (1 in each group)., Conclusion: Treatment with FabAV reduces limb disability measured by the Patient-Specific Functional Scale 14 days after copperhead envenomation., (Copyright © 2017 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Although much is known about signs, symptoms, and management in the acute phase of crotaline snake envenomation, little is known about signs, symptoms, function, and quality of life during the recovery phase. The purpose of this observational pilot investigation is to evaluate the utility of several clinical outcome instruments in the setting of copperhead snakebite, and to characterize the clinical course of recovery., Methods: This is a multi-center prospective, open-label, observational study of patients envenomated by copperhead snakes. We administered the Disabilities of the Arm, Shoulder, and Hand (DASH), Lower Extremity Functional Scale (LEFS), Patient-Specific Functional Scale (PSFS), Work Productivity and Ability Impairment: Special Health Problem (WPAI: SHP), Patients' Global Impression of Change (PGIC), Patient's Global Assessment of Recovery (PGAR), and SF-36 instruments, obtained numeric pain rating scales, and measured grip strength, walking speed, and swelling prior to hospital discharge and 3, 7, 14, 21, and 28 days after envenomation., Results: 20 subjects were enrolled; none were lost to follow-up. Most (80%) had moderate severity swelling, and most (75%) received antivenom. Across the broad range of measures, abnormalities of pain, swelling, impairments of physical and role function, and quality of life persisted for 7-14 days in most subjects. Validated self-reported outcome measures, such as the DASH, LEFS, PSFS, PGIC, SF-36, and the daily activities impairment portion of the WPAI: SHP were more responsive than measurements of swelling or walking speed. Data quality issues limited the utility of the work impairment portion of the WPAI: SHP. Residual signs, symptoms, and impairment in some subjects lasted through the 28-day study period. The study design precluded any assessment of the effectiveness of antivenom., Conclusions: Signs, symptoms, impaired function, and decreased quality of life typically last 7 - 14 days after copperhead envenomation. Several tools appear responsive and useful in studying recovery from pit viper envenomation., Trial Registration: ClinicalTrials.gov NCT01651299.

Objectives: To prevent unnecessary antivenom administration in crotaline snakebite, observation for progression is recommended for the patient with minor envenomation whose condition is stable and not progressing. The objective of this study was to determine the association between the time from bite to initial antivenom administration (Time(AV)) and the total amount of antivenom administered (Total(AV)) and to determine what proportion of patients did not have progression of the envenomation syndrome and did not receive antivenom., Methods: This was a retrospective chart review of patients presenting with crotaline snakebite within 24 hours from 2009 through 2012. Blinded dual-chart abstraction and strict data point definitions were used. Spearman correlation was used to determine the association between Time(AV) and Total(AV). A general linear model was used to examine this association using Time(AV) categorized to early and late administration, adjusted for likely confounders. Confounders included age, extremity involved, initial severity, and year of envenomation., Results: Ninety-five eligible patients were analyzed with 45 (47%) males and a mean (±SD) age of 36.5 (±21.1) years. Eighty-five (89%) received antivenom, with a median Time(AV) of 3.3 hours (interquartile range [IQR] = 2.5 to 5.2 hours). The median Total(AV) was 10 vials (IQR = 6 to 14 vials). The univariate analysis showed a small but statistically significant decrease in Total(AV) given to patients treated greater than 6 hours from bite (r = -0.26, p = 0.015). The multivariate analysis resulted in no significant relation between early or late Time(AV) and Total(AV) (p = 0.10) after adjustment for confounders. Most minimal envenomation syndromes (80%, or 41 of 51) progressed to moderate grade envenomations., Conclusions: Time(AV) was not associated with Total(AV) when adjusted for likely confounders and supports current recommendations to observe for progression in minor envenomation. The majority of envenomations progressed, resulting in only a small proportion of patients not eventually receiving antivenom. The authors recommend observation in an environment where the patient can be adequately reassessed for progression of the envenomation., (© 2015 by the Society for Academic Emergency Medicine.)

Background: In 2000, the US Food and Drug Administration approved CroFab(®) Crotalidae Polyvalent Immune Fab, ovine (FabAV), which had received orphan drug designation, for use in patients with minimal to moderate North American crotaline envenomations including copperhead snakes. As existing evidence on the effectiveness of FabAV for this indication is limited, wide practice variation in its use exists. In order to provide more definitive clinical evidence as to the role of this treatment, a new randomized, placebo-controlled trial of FabAV specifically for copperhead bites was initiated., Purpose: In light of the existing US Food and Drug Administration approval, ethical considerations of participation in this trial have been raised. We discuss the ethical principles pertinent to this randomized, placebo-controlled trial with placebo arm. We apply an accepted framework for ethical research to this trial. Due to the evidence gap in the literature, wide-ranging treatment recommendations by medical experts, and broad practice variation, clinical equipoise exists in the treatment of copperhead envenomation with FabAV. The impact of this clinical equipoise on the value and scientific validity of the trial is discussed. The trial's risk-benefit ratio is also considered. Potential risks to the patients are minimized as the protocol includes a plan for rescue therapy in the event that patients progress to severe envenomation symptoms. Overall, risks are further minimized by the inclusion of an interim analysis with stopping rules based on demonstrated efficacy should the therapy clearly prove to be beneficial., Conclusion: Although a post-marketing clinical study of this nature is unusual for an approved indication, this trial adheres to all ethical preconditions found in existing guidelines for clinical research involving human subjects., (© The Author(s) 2014.)

Study Objective: We estimate the proportion of patients with crotaline snake envenomation who are treated with Crotalidae polyvalent immune Fab (ovine) antivenom and who develop medically significant late bleeding., Methods: We performed a systematic review of all published cohort studies of North American crotaline snake envenomation patients treated with Fab antivenom. We searched PubMed, Ovid MEDLINE, and EMBASE from January 1, 1997, to April 30, 2012. Data were extracted by 2 trained researchers. Late bleeding was defined as bleeding that began or recurred after initial control of the envenomation syndrome. Medically significant late bleeding was defined a priori as late bleeding treated with RBC transfusion, vasoactive drug infusion, surgery, or rehospitalization or associated with a hemoglobin decrease of greater than or equal to 3 g/dL, hematocrit decrease of greater than or equal to 8%, disability, or death. Summary incidence and 95% confidence intervals (CIs) were calculated with a random-effects Poisson regression model., Results: Nineteen unique cohort studies were identified. Four studies collected data prospectively, and in 9 studies, patients were followed actively after hospital discharge. A total of 1,017 subjects were enrolled in these cohort studies. Late bleeding was reported in 9 subjects (0.9%; 95% CI 0.4% to 2.2%), of whom 5 subjects (0.5%; 95% CI 0.1% to 1.7%) had medically significant late bleeding. Three patients received RBC transfusion; no deaths or permanent sequelae were reported. Estimates of risk may be affected by underreporting., Conclusion: Medically significant late bleeding appears to be uncommon in snakebite victims treated with Fab antivenom., (Copyright © 2013 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.)

Background: Animal-derived antivenoms have been used to treat snake envenomation for more than 100 years. Major technological advantages in the past 30 years have produced antivenoms that are highly purified and chemically modified to reduce the risk of acute hypersensitivity reactions. Like all pharmaceutical manufacture, commercial-scale antivenom production requires making trade-offs between cost, purity, pharmacokinetic profile, and production yield., Scope: This article reviews the current state of the art for antivenom production and development. Particular attention is paid to controversies and trade-offs used to achieve a balance between improved safety and pharmacokinetic performance.

Objectives:   Crotalidae polyvalent immune Fab (ovine) (FabAV) is commonly used in the treatment of symptomatic North American crotaline snake envenomation. When approved by the U.S. Food and Drug Administration in 2000, the incidences of immediate hypersensitivity reactions and serum sickness were reported as 0.14 and 0.18, respectively. The objective of this meta-analysis was to evaluate the incidence of immediate hypersensitivity reactions and serum sickness reported in studies of patients treated with FabAV therapy after North American crotaline envenomation., Methods:   The authors searched PubMed, Ovid MEDLINE, and EMBASE from January 1, 1997, to September 20, 2010, for English-language medical literature and cross-referenced bibliographies of reviewed articles. The published abstracts of the major toxicology conferences were also searched. All prospective and retrospective cohort studies with patients receiving FabAV therapy for North American crotaline envenomations were eligible for data abstraction. Two content experts reviewed full-text articles and extracted relevant study design and outcome data. Proportions of immediate hypersensitivity and serum sickness for each study were analyzed in a random-effects model to produce an overall estimate of immediate hypersensitivity and serum sickness incidence associated with FabAV administration., Results:   The literature search revealed 11 unique studies of patients who received FabAV that contained information on immediate hypersensitivity reactions and serum sickness. The meta-analysis produced a combined estimate of the incidence of immediate hypersensitivity of 0.08 (95% confidence interval [CI] = 0.05 to 0.11) and a combined estimate of the incidence of serum sickness of 0.13 (95% CI = 0.07 to 0.21)., Conclusions:   In this systematic literature review and meta-analysis, the combined estimates of the incidence of immediate hypersensitivity reactions and serum sickness from FabAV in the treatment of symptomatic North American crotaline envenomations appear to be lower than previously reported, at 0.08 and 0.13, respectively., (© 2012 by the Society for Academic Emergency Medicine.)

Background: Envenomation by crotaline snakes (rattlesnake, cottonmouth, copperhead) is a complex, potentially lethal condition affecting thousands of people in the United States each year. Treatment of crotaline envenomation is not standardized, and significant variation in practice exists., Methods: A geographically diverse panel of experts was convened for the purpose of deriving an evidence-informed unified treatment algorithm. Research staff analyzed the extant medical literature and performed targeted analyses of existing databases to inform specific clinical decisions. A trained external facilitator used modified Delphi and structured consensus methodology to achieve consensus on the final treatment algorithm., Results: A unified treatment algorithm was produced and endorsed by all nine expert panel members. This algorithm provides guidance about clinical and laboratory observations, indications for and dosing of antivenom, adjunctive therapies, post-stabilization care, and management of complications from envenomation and therapy., Conclusions: Clinical manifestations and ideal treatment of crotaline snakebite differ greatly, and can result in severe complications. Using a modified Delphi method, we provide evidence-informed treatment guidelines in an attempt to reduce variation in care and possibly improve clinical outcomes.

Study Objectives: We seek to determine the short-term outcomes associated with the use of Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) therapy for severe crotaline snake envenomation and to better define the incidence of hypersensitivity reactions associated with FabAV use., Methods: We conducted a multicenter observational case series study of patients who received FabAV at 17 US hospitals in 2002 to 2004. A 7-point score incorporating local, systemic, and hematologic venom effects was used to grade envenomation severity before and after FabAV therapy. The primary outcome for response to therapy was the change in overall envenomation severity after FabAV administration. The primary safety outcomes were the rates of immediate hypersensitivity reactions and serum sickness., Results: The outcome-evaluable population included 209 patients, of whom 28 had severe envenomation. All severely envenomated patients improved after receiving FabAV. The median severity scores of severely envenomated patients were 5 (interquartile range [IQR] 5 to 5) before FabAV, 1 (IQR 1 to 2) at the last FabAV loading dose, and 1 (IQR 0 to 1) at the last clinical observation. The proportion of patients with progressive pain, progressive swelling, cardiovascular effects, respiratory effects, neurologic effects, gastrointestinal effects, coagulopathy, and thrombocytopenia all improved after FabAV therapy. The safety population included 247 patients. Immediate hypersensitivity reactions were reported in 6.1% (95% confidence interval 3.4% to 9.8%) of patients. Serum sickness was reported in 5% (95% confidence interval 0.6% to 17%) of patients with a minimum of 6 days of follow-up after the last dose of FabAV., Conclusion: FabAV therapy is associated with clinical improvement in severe crotaline snake envenomation. Immediate hypersensitivity and serum sickness rates may be less than described in the FabAV prescribing information., (Copyright © 2010. Published by Mosby, Inc.)

Background: In 2000, the United States Food and Drug Administration approved Crotalidae Polyvalent Immune Fab (Ovine) (hereafter, FabAV), "for the management of patients with minimal to moderate North American Crotalid envenomation." Because whole-IgG pit viper antivenom is no longer available in the United States, FabAV is currently the only specific treatment option available to United States clinicians treating snakebite victims of any severity. No clinical trial data are available concerning the effectiveness of FabAV for treatment of severe snakebite, but several published articles describe its use in this setting., Methods: We performed a comprehensive review of the English-language medical literature to identify all publications (1996 to July, 2008) containing data about the administration of FabAV. Two trained reviewers separately extracted case-level data concerning the administration of FabAV to patients with severe envenomation by North American crotaline snakes to a standardized form. Descriptive statistics were used. In addition, we hand-searched the US National Poison Data System reports for the years 2000-2006 to identify and describe any reports of death that occurred after FabAV administration., Results: The literature review found 147 unique publications regarding FabAV. Twenty-four evaluable cases of severe human envenomation treated with FabAV were identified in 19 publications. Seven cases were described in five cohort studies, and 17 cases were described in 14 single patient case reports or non-cohort case series. Sixty-five specific severe venom effects were reported in these 24 patients, of which 50 effects (77%) improved or resolved after FabAV therapy. Initial control of all severe venom effects was achieved in 12 patients (50%). The rate at which initial control was achieved was significantly higher among patients reported in the cohort series than in the case series and non-cohort reports (100% vs. 29%, P = 0.005). The median dose of FabAV used to obtain initial control was 6 vials (range: 4 - 18 vials). Nine patients had severe venom effects that persisted despite FabAV therapy. Recurrent and/or delayed-onset severe defibrination syndrome occurred in 12 patients, most of whom did not receive recommended maintenance FabAV dosing. No patient developed systemic bleeding., Conclusion: In this structured literature review, FabAV appears to be effective in the management of severe crotaline snake envenomation. Incomplete response to therapy, recurrence of venom effects, and delayed-onset venom effects were reported in case reports, but not reported in cohort studies.

Study Objective: Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) effectively treats patients bitten by rattlesnakes. The copperhead snake (Agkistrodon contortrix) caused 37% of venomous snakebites reported to US poison centers in 2001 and is the major envenomating reptile in the southeastern United States. FabAV has not been tested in human beings envenomated by copperhead snakes., Methods: In this preliminary study, we performed a retrospective chart review of all copperhead snake envenomations reported to the Carolinas Poison Center that were treated with FabAV. Progression of limb swelling, coagulopathy, and hemodynamic status before and after FabAV administration, adverse effects of FabAV therapy, and recurrence phenomena were recorded., Results: Of approximately 400 copperhead envenomation cases reported to the poison center during the study period, 32 received FabAV and were included. Most patients had moderate envenomation. The median time to FabAV administration was 4.0 hours. The median time to achieve initial control was 1.0 hour, with a median dose of 4 vials of FabAV. A rapid initial response, defined as cessation of the progression of local tissue injury within 4 hours of FabAV administration, occurred in 28 cases (88%; 95% confidence interval [CI] 76% to 99%). Four cases (13%; 95% CI 1% to 24%) were considered treatment failures. Recurrent swelling occurred in 6 cases (19%; 95% CI 5% to 32%). The incidence of recurrent swelling was not reduced by administration of repeated doses of antivenom on a planned schedule. One patient developed late-onset coagulopathy. One minor allergic reaction was observed., Conclusion: In this select group of patients bitten by copperhead snakes, local tissue effects of envenomation halted promptly after FabAV treatment in most cases. Treatment failures occurred, and recurrence of swelling and defibrination syndrome was sometimes problematic. Time to return to work and long-term limb function were not assessed. A controlled trial with long-term follow-up is needed to define the role of FabAV treatment for copperhead envenomation.

Introduction: Although the copperhead (Akistrodon contortrix) is responsible for most Crotaline envenomations in the Carolinas, manifestations and treatment are poorly characterized., Objective: We sought to describe the clinical course after copperhead bites., Method: Structured review of copperhead exposures reported to a regional poison center from 1997-2000. Hospital records were reviewed when available. Phone followup was attempted., Results: A total of 178 cases were identified. Of these 75% were males. The median age was 31 yr (range 2-93). The bite site included hand (52%), foot (36%), leg (7%), and arm (5%). Classification included dry (7%), mild (48%), moderate (39%), and severe (6%). The most common symptom was pain (93%). Local findings included swelling (94%), fang marks (93%), ecchymosis (53%), erythema (37%), bullae (13%), and tissue necrosis (8%). Eleven of 37 patients developed abnormal PT and/or PTT. Two patients bled. Patients were treated at a healthcare facility in 160 cases, with 79 patients admitted. Opioid analgesics were the most common therapy (81%). Equine-derived antivenin was given in 14 cases (range 2-30 vials). Antivenin reactions developed in three. Two patients received blood products. Surgical treatment included debridement (6), grafting (2), digit amputation (1), digit dermotomy (1), and fasciotomy (1). No patients died. In followup, 18 patients reported limb dysfunction ranging from 5-365 days., Conclusion: Copperhead bites typically result in mild to moderate envenomation due to local tissue effects. Significant systemic manifestations are rare. Limb dysfunction can be prolonged.

Background: The puff adder (Bitis arietans) is a highly toxic venomous snake that is responsible for a large proportion of the venomous snakebites in sub-Saharan Africa, where it is indigenous. Puff adder bites in North America result from snakes in captivity. Although thrombolytic enzymes are present in puff adder venom, significant coagulopathy has not been previously reported with a confirmed puff adder envenomation., Results: We report a serious puff adder envenomation to the finger, characterized by severe swelling, local tissue necrosis, hypotension, thrombocytopenia, severe coagulopathy, and hemorrhage. Fifteen vials of South Africa polyvalent antivenom were administered, beginning 4.5 hours post-envenomation, with step-wise improvement in hematological abnormalities. Other treatments included vasopressors, ventilatory support, leeches, transfusion, and eventual digit amputation. After a prolonged hospital course, the patient had a good outcome., Conclusions: Puff adder envenomation causes tissue necrosis, hypotension, coagulopathy, thrombocytopenia, and spontaneous bleeding. Severe coagulopathy may occur. Physicians treating severe cases should be prepared to administer at least 15 vials of antivenom if needed.