Crotalidae Polyvalent Immune Fab Research Articles

In Reply to Michael Levine, Published December 2022, Pages 525-572

We read the response by Drs. Watkins and Smelski1Watkins S. Smelski G. Epic fail? Try again.Ann Emerg Med. 2023; 81: 765-766Abstract Full Text Full Text PDF Google Scholar and appreciate their interest in our manuscript. Drs. Watkins and Smelski discuss that there is no universal definition of thrombocytopenia. Although we generally agree, we do feel that most clinicians would define platelets of 102,000/μL, and certainly 80,000/μL, as thrombocytopenic. The landmark study comparing Crotalidae polyvalent immune Fab (ovine) [marketed as CroFab®; FabAV] with crotalidae immune F(ab’)2 (equine) [marketed as Anavip®; F(ab’)2AV] defined thrombocytopenia as platelet counts less than 150,000/μL.2Bush S.P. Ruha A.M. Seifert S.A. et al.Comparison of F(ab’)2 versus Fab antivenom for pit viper envenomation: a prospective, blinded, multicenter, randomized clinical trial.Clin Toxicol. 2015; 53: 37-45Crossref PubMed Scopus (70) Google Scholar This was supported by another study by Dr. Smelski.3Dudley S. Smelski G. Massey D.J. et al.Fashionably late: A characterization of late coagulopathies in rattlesnake envenomations between Fab and F(ab’)2 antivenoms.Toxicon. 2022; 212: 49-54Crossref Scopus (0) Google Scholar Drs. Smelski and Watkins also mention that some patients have resolution of thrombocytopenia with a single dose of antivenom and others need multiple doses. Furthermore, they questioned if the inability to achieve control was the result of several smaller doses rather than a few larger doses. One of the advantages of F(ab’)2AV compared with FabAV is the longer half-life. Our patient received 52 vials of F(ab’)2AV in 44 hours. In fact, one reviewer on our original submission commented that the dose was “large (one would suggest excessive) amount of antivenom.” We agree with that statement. Thus, it is highly unlikely that underdosing was the reason for our inability to achieve control. Even with smaller aliquots, at the end of 44 hours, there should have been more than enough circulating antivenom to have achieved a desirable effect given the antivenom’s long half-life. We are concerned that Drs. Smelski and Watson are confusing early and late hematologic toxicity. These are entirely different entities, and achieving control has nothing to do with late hematologic toxicity. We cannot comment on unpublished data but would caution against using unpublished data without knowledge of total antivenom dose to make determinations. As stated, many patients respond to one dose, whereas others may need multiple doses. Thus, it is difficult to comment on unpublished data without knowing total antivenom doses. However, if one-third of patients exhibit inadequate response to an appropriate dose of antivenom, that should be published. In addition, Drs. Watkins and Smelski commented that their unpublished data included 23 years of experience. Most of that 23 years would have nearly certainly involved the use of FabAV, not F(ab’)2AV, as was used in this case. The latter was not available for use until recently. Lastly, drawing any conclusions from Arizona data to this case report should be limited because the southern pacific rattlesnake, C. helleri, is not found in Arizona.

Crotalidae Polyvalent Immune Fab and Cost-Effective Management of Hospital Admissions for Snakebites.

Venomous snakebites are a common clinical scenario in the Southeastern United States. CroFab® (Crotalidae Polyvalent Immune Fab (Ovine), BTG, Wales, UK) antivenom is indicated in cases involving pit vipers and is known to be expensive. The treatment protocol for snakebites is based on clinically subjective measures triggering the application, or escalation of, antivenom administration. The purpose of this study is to characterize the use of CroFab at our institution and to evaluate the impact of its use regarding cost and overall outcomes. We suspect that it is often used but potentially less often needed. We hypothesized that CroFab use was associated with increased length of stay (LOS) without an observed difference in patient outcomes. A retrospective chart review of snakebite patients at our level-1 trauma center from 2000 to 2016 was performed. Snakebite location, snake species, number of vials of CroFab administered, hospital LOS, intensive care unit (ICU) LOS, and complications were identified for each patient. Patients were divided into CroFab (C) and no CroFab (NC) groups. One hundred ninety patients with venomous snakebites were included. 53.7% of patients received CroFab. There was no difference in the complication rate of C versus NC groups, (P = .1118). CroFab use was associated with longer hospital LOS (P < .0001) and ICU LOS (P < .0001). CroFab use was associated with increased LOS in our patient population. There was no difference in observed outcomes between the C and NC groups. These findings imply that CroFab is potentially over-used in our patient population.

α-Gal on Crotalidae-polyvalent Fab antivenom (CroFab): Investigating the relevance to immediate hypersensitivity reactions

Crotalidae-polyvalent immune Fab [ovine] (FabAV) is a polyvalent Fab fragment antivenom that is generated by papain digestion of Crotalidae-specific antibodies derived from hyperimmunized sheep. FabAV is approved for administration in patients being treated for snake envenomation of the Crotalidae subfamily, which includes rattlesnakes, copperheads, and cottonmouths/water moccasins.1,2 The frequency of acute adverse reactions is lower with FabAV than with whole immunoglobulin IgG antivenom products, but nonetheless immediate reactions (ie, occurring within 3 hours) do occur and can be severe.

Prevalence of Acute Hypersensitivity Reactions in Pediatric Patients Receiving Crotalidae Polyvalent Immune Fab.

Studies of acute hypersensitivity reactions in pediatric populations receiving Crotalidae Polyvalent Immune Fab (CPIF) are complicated by small size, wide age ranges, and diverse definitions of such reactions. This is a retrospective chart review of patients aged 13years or younger treated with CPIF for Crotalid envenomation from November 2006 to 2016. The primary outcome was the presence of an acute hypersensitivity reaction to CPIF and was defined as the development of any of the following symptoms within 3hours of initiation of CPIF infusion: urticaria, wheezing or respiratory distress, angioedema, hypotension, nausea, and/or vomiting. Demographics, CPIF dose to control and total dose, bite location, level of care, and length of stay were also recorded. Thirty-four patients were ultimately treated with CPIF. Ages ranged from 10months to 13years. Twenty-one patients (60%) were male, 24 (70.6%) were admitted to the ICU, and the median length of stay was 2days with a range of 1-11days. Zero patients developed an acute hypersensitivity reaction to CPIF. Acute hypersensitivity reactions to CPIF did not occur in this cohort. Such reactions are rare with the use of CPIF in pediatric patients.

Unpredicted late-, new-onset thrombocytopenia and hypofibrinogenemia in Fab antivenom-treated rattlesnake envenomation

The use of Fab antivenom (Crotalidae Polyvalent Immune Fab (Ovine) (CroFab); Boston Scientific) against North American Crotalidae envenomation is associated with the development of late- (≥4 days post-envenomation), new-onset of hematological abnormalities. Although attempts have been made to identify predictive indicators during the acute phase of an envenomation, of patients who are not at-risk of late-, new-onset of hematological abnormalities, there has been at least one prior report of a patient who developed thrombocytopenia that was unpredicted by current indicators. We add three cases of unpredicted, late-, new-onset of hematological abnormalities in patients with Fab-treated rattlesnake bite.

Acute adverse events associated with the administration of Crotalidae polyvalent immune Fab antivenom within the North American Snakebite Registry

Background: Crotalidae Polyvalent Immune Fab (Fab Antivenom) is the primary Viperid antivenom used in the United States since 2000. Adverse event data associated with its use are limited. The purpose of this study is to describe the prevalence of acute adverse events associated with the use of Fab antivenom.Methods: The American College of Medical Toxicology’s Toxicology Investigators Consortium maintains a prospective case registry of poisoned and envenomated patients managed by medical toxicologists at the bedside. This registry includes the North American Snakebite sub-registry. We performed a review of 438 cases entered into the Snakebite sub-registry.Results: A total of 373 (85.2%) received at least one vial of Fab Antivenom. Forty percent were children. Adverse events occurred in 10 patients (2.7%) of whom six were adults. Rash was the most common adverse event. More severe adverse events (hypotension, bronchospasm, and/or angioedema) occurred in four (1.1%) patients. Prophylaxis was administered prior to Fab antivenom in 4.0%. Eight patients received various treatments for their adverse events. Neither the initial number of Fab antivenom vials, atopic history, nor prior envenomation correlated with the prevalence of adverse events.Discussion: This prevalence of adverse events was lower than in previous studies and in a meta-analysis of 11 studies. The types of adverse events and treatments used are consistent with those in previous reports. There were no prior reports of prophylaxis use with which to compare.Conclusion: The prevalence of Fab antivenom adverse events in the North American Snakebite Registry was 2.7%.

Use an As-Needed Antivenom Dosing Strategy for Rattlesnake Bites

CroFab antivenom is the treatment for rattlesnake envenomation, but it is expensive (~$2,300 per vial). After initial control of the envenomation,

The Epidemiology, Clinical Course, and Management of Snakebites in the North American Snakebite Registry.

The American College of Medical Toxicology established the North American Snakebite Registry (NASBR), a national database of detailed, prospectively collected information regarding snake envenomation in the United States, in 2013. This report describes the epidemiology, clinical course, and management of snakebites in the NASBR. All cases entered into the NASBR between January 1, 2013 and December 31, 2015 were identified. Descriptive statistics are used to report results. Fourteen sites in 10 states entered 450 snakebites. Native species comprised 99% of cases, almost all of which were pit viper bites. 56.3% were identified as rattlesnakes and 29.4% as copperheads. 69.3% were male and 28.2% were children age 12 and under. Fifty-four percent of bites were on the lower extremity. Twenty-seven percent of patients with lower extremity bites were not wearing shoes. Common tissue findings associated with envenomation were swelling, ecchymosis, and erythema. Systemic effects and hematologic toxicity were more common in rattlesnake than copperhead or cottonmouth envenomations. Crotalidae Polyvalent Immune Fab antivenom was given to 84% of patients. Twelve patients (4.3%) were re-admitted to the hospital after completion of treatment. Eight were re-treated with antivenom. The NASBR gathers detailed data on venomous snakebites across the US. In its initial years, useful information has already been gained. Data regarding footwear will inform public health interventions and education, and information regarding the clinical presentation may help physicians better anticipate effects and manage snakebite. As the number of cases in the NASBR grows, associations between patient-related factors and outcomes may be studied.

Thromboelastography Utilization in Delayed Recurrent Coagulopathy after Severe Eastern Diamondback Rattlesnake Envenomation

Venomous snakebites are fairly common in the United States and can present with a wide range of symptoms. A 48-year-old man presented after Eastern Diamondback rattlesnake envenomation. His hospital course was complicated by right leg compartment syndrome and delayed recurrent coagulopathy, requiring multiple doses of Crotalidae Polyvalent Immune Fab (CroFab) antivenom and transfusions. Thromboelastography was used as an adjunct to standard coagulation studies in monitoring his delayed recurrent coagulopathy.

Use of polyvalent equine anti-viper serum to treat delayed coagulopathy due to suspected Sistrurus miliarius streckeri envenomation in two children

Background: Western Pygmy Rattlesnake (WPR) envenomation reportedly causes refractory and persistent coagulopathy when treated with CroFab® (Crotalidae Polyvalent Immune Fab). We report two cases where polyvalent equine anti-viper serum (AntivipmynTRI®) was used to treat recurrent coagulopathy in children.Case details: The first patient was a 16-month-old male who was bitten by a confirmed WPR. The patient received a total of 18 vials of CroFab®. His labs normalized, swelling gradually improved, and the child was discharged to home. On day 5, the child returned to the emergency department with a great deal of inguinal tenderness. Labs were obtained and the child’s INR was >13.1, while the fibrinogen was <60 mg/dL and the d-dimer was 11.72 mg/L. A decision was made to administer Antivipmyn TRI®, and the child received a total of 10 vials. Lab values significantly improved: INR 1.2, fibrinogen 93 mg/dL, and d-dimer 4.21 mg/L. The second patient was a 20-month-old male who presented following snake envenomation. The child was administered a total of 22 vials of CroFab® over approximately 70 h following envenomation. Physical exam continued to improve, however, lab results showed an increasing INR 1.98, decreasing platelet count 124 × 103 per μL, fibrinogen <60 mg/dL, and d-dimer >20 ug/mL. A total of 15 vials of Antivipmyn TRI® were administered to this patient. Following this administration, labs and clinical exam both significantly improved. Labs revealed INR 1.16, fibrinogen 110 mg/dL, d-dimer 3.2 mg/L and platelet count 215 × 103/μL.Discussion: CroFab® is still the first-line treatment for children bitten by a WPR, but in some cases patients develop a recurrent coagulopathy. The rapid response demonstrated by Antivipmyn TRI® leads us to conclude that this is a potential therapy for this clinical situation.

FabAV antivenin use after copperhead snakebite: clinically indicated or knee-jerk reaction?

BackgroundCrotalidae Polyvalent Immune Fab (Ovine) (FabAV) antivenin is commonly recommended after pit viper snakebites. Because copperhead envenomations are usually self-limited, some physicians are reluctant to use this costly treatment routinely, while others follow a more liberal approach. We hypothesized that, in practice, only patients with evidence of significant (moderate or severe) copperhead envenomation [those with snakebite severity score (SSS) > 3] receive FabAV and examined a large cohort to determine the relationship between clinical findings and FabAV administration.MethodsAll data from patients evaluated for copperhead snakebite at a rural tertiary referral center from 5/2002 to 10/2013 were compiled. Demographics, transfer status, antivenin use, and clinical findings were collected; SSS was calculated. The relationships among FabAV use, clinical findings, and SSS were analyzed using t-test, chi-square, and Pearson’s coefficient (p < 0.05 was significant).ResultsDuring the study period, 318 patients were treated for copperhead snakebite; 44 (13.8 %) received antivenin. Median dose was four vials (range: 1–10; IQR: 4,6). There were no deaths. Most patients receiving FabAV (63.6 %) were admitted. With regard to demographics and symptoms, only the degree of swelling (moderate vs. none/mild; p < 0.01) and bite location (hand/arm vs. leg: p < 0.0001) were associated with FabAV use. A SSS > 3, indicating moderate or severe envenomation, was only very weakly correlated with antivenin use (r = 0.217; p < 0.0001). The majority of patients with SSS > 3 (65.8 %) did not receive antivenin while most patients who did receive antivenin (70.5 %) had SSS ≤ 3 (indicating mild envenomation).ConclusionsConsiderable variation occurs in antivenin administration after copperhead snakebite. Use of FabAV appears poorly correlated with patients’ symptoms. This practice may expose patients to the risks of antivenin and increasing costs of medical care without improving outcomes. Guidelines used for treating other pit viper strikes, such as rattlesnake or cottonmouth snakebite may be too liberal for copperhead envenomations. Our data suggests that most patients with mild or moderate envenomation appear to do well independent of FabAV use. We suggest, for patients with copperhead snakebite, that consideration be given to withholding FabAV for those without clinical evidence of severe envenomation until prospective randomized data are available.

Comparison of F(ab’)2 versus Fab antivenom for pit viper envenomation: A prospective, blinded, multicenter, randomized clinical trial

Background. Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab’)2 immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab’)2 antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation. Methods. We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab’)2 with maintenance doses [F(ab’)2/F(ab’)2], or F(ab’)2 with placebo maintenance doses [F(ab’)2/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count < 150 K/mm3, fibrinogen level < 150 mg/dL) between end of maintenance dosing and day 8. Results. 121 patients were randomized at 18 clinical sites and received at least one dose of study drug. 114 completed the study. Of these, 11/37 (29.7%) in the Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3%, p < 0.05) in the F(ab’)2/F(ab’)2 cohort and 2/38 (5.3%, p < 0.05) in the F(ab’)2/placebo cohort. The lowest heterologous protein exposure was with F(ab’)2/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness. Conclusions. In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab’)2 antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation.

Ethical considerations in design of a study to evaluate a US Food and Drug Administration-approved indication: antivenom versus placebo for copperhead envenomation.

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. 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. 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.

Continuous IV Crotalidae Polyvalent Immune Fab (Ovine) (FabAV) for selected North American Rattlesnake bite patients

BackgroundIn patients bitten by North American rattlesnakes and treated with Crotalidae Polyvalent Immune Fab (Ovine) (FabAV), late hematologic abnormalities—persistent, recurrent, or late, new onset of hypofibrinogenemia, prolonged PT/INR, prolonged PTT, and/or thrombocytopenia beyond 48 h post-envenomation—are common, difficult to manage, and may result in morbidity and mortality are common, difficult to manage, and may result in morbidity and mortality. The optimal management of late hematologic abnormalities, particularly the use of further treatment with antivenom, has not been well defined. The current FabAV treatment regimen is to give antivenom as a bolus dose over a one-hour period. We describe our experience using a continuous intravenous infusion of FabAV for late hematologic effects and/or associated bleeding complications in rattlesnake envenomation. MethodsThis is a retrospective, observational case series of patients envenomated by North American rattlesnakes at three medical centers managed with a continuous intravenous infusion of FabAV for late hematologic abnormalities and/or associated bleeding complications. Indications, dilution and infusion protocols, and duration of therapy were individualized. ResultsFive cases were identified between July 2010 and September 2011. All patients had profound late hematologic abnormalities and/or were associated with bleeding complications. Several patients had received repeat bolus infusions of FabAV, with or without human blood products, with either inadequate or only transient beneficial response. All patients were then managed with a continuous intravenous infusion of FabAV and all appeared to respond to the continuous intravenous infusion of FabAV, titrated to effect, with cessation of progression and, in most cases, improvement in hematologic abnormalities. Rates of infusion varied from 2 to 4 vials per 24 h (mean = 3.1 ± 0.4 vials/day). The termination of FabAV infusion was between day 6 and day 14 from the time of envenomation (mean = 10 ± 3 days), after which hematologic values were normalized or were normalizing in all patients and continued to do so. DiscussionThe use of FabAV as a continuous intravenous infusion, particularly after the acute phase of envenomation has passed, provides a continuous source of circulating antibodies to neutralize venom components reaching circulation from tissue stores and allows natural replenishment of hematologic factors such as platelets and/or fibrinogen. This method is an efficient use of FabAV, avoiding the wasteful excess of a bolus dose, may be more effective, eliminating the potential for destruction of hematologic factors when protective antivenom levels are lost between bolus FabAV doses, and appears to be safe. Further assessments of the stability and sterility of the product during infusion are needed. The need to continue hospitalization is the major drawback, but continued observation and inpatient care may be needed for other indications (e.g. bleeding) in this subset of patients. ConclusionsA continuous intravenous infusion of FabAV between 2 and 4 vials per day, titrated to effect, and continued for 6–14 days post-envenomation appeared to be associated with reversal of late hematologic effects of rattlesnake envenomation and, when combined with indicated human blood products, control of significant bleeding. Continuous intravenous infusion of FabAV may be safer, more efficacious, and more cost-effective than observation without FabAV treatment or as-needed bolus dosing in selected patients with late hematologic abnormalities.

Validating a faster method for reconstitution of Crotalidae Polyvalent Immune Fab (ovine)

BackgroundReconstitution of CroFab® (Crotalidae Polyvalent Immune Fab [ovine]) lyophilized drug product was previously performed using 10 mL sterile water for injection followed by up to 36 min of gentle swirling of the vial. CroFab has been clinically demonstrated to be most effective when administered within 6 h of snake envenomation, and improved clinical outcomes are correlated with quicker timing of administration. An alternate reconstitution method was devised, using 18 mL 0.9% saline with manual inversion, with the goal of shortening reconstitution time while maintaining a high quality, efficacious product. MethodsAn analytical study was designed to compare the physicochemical properties of 3 separate batches of CroFab when reconstituted using the standard procedure (10 mL WFI with gentle swirling) and a modified rapid procedure using 18 mL 0.9% saline and manual inversion. The physical and chemical characteristics of the same 3 batches were assessed using various analytic methodologies associated with routine quality control release testing. In addition further analytical methodologies were applied in order to elucidate possible structural changes that may be induced by the changed reconstitution procedure. ResultsBatches A, B, and C required mean reconstitution times of 25 min 51 s using the label method and 3 min 07 s (a 88.0% mean decrease) using the modified method. Physicochemical characteristics (color and clarity, pH, purity, protein content, potency) were found to be highly comparable. Characterization assays (dynamic light scattering, analytical ultracentrifugation, LC–MS, SDS-PAGE and circular dichroism spectroscopy were also all found to be comparable between methods. DiscussionWhen comparing CroFab batches that were reconstituted using the labeled and modified methods, the physicochemical and biological (potency) characteristics of CroFab were not significantly changed when challenged by the various standard analytical methodologies applied in routine quality control analysis. Additionally, no changes in the CroFab molecule regarding degradation, aggregation, purity, structure, or mass were observed. ConclusionThe analyses performed validated the use of the more rapid reconstitution method using 18 mL 0.9% saline in order to allow a significantly reduced time to administration of CroFab to patients in need.

Pygmy rattlesnake envenomation treated with Crotalidae Polyvalent Immune Fab Antivenom

Documented envenomations by the pygmy rattlesnake (Sistrurus miliarius barbouri) are rare. While there have been no documented fatalities, several older case reports describe significant morbidity. We describe the first known case of pygmy rattlesnake envenomation that was treated with Crotalidae Polyvalent Immune Fab Antivenom (CroFab®). CaseA 28-year-old man with no significant past medical history presented after being envenomated on the right hand by his friend's pet pygmy rattlesnake. He developed swelling and pain in his hand and forearm. He responded well to a ten vial loading dose and a 18 h maintenance protocol of CroFab and was discharged the following day without developing any hematological or electrolyte derangements. ConclusionThis is the first documented use of CroFab for S. m. barbouri envenomation. The outcome of this case suggests that CroFab is a safe treatment modality in this setting.

Crotalidae Polyvalent Immune Fab: A Guide to Its Use in North American Crotaline Envenomation

Intravenous crotalidae polyvalent immune Fab (CroFab(®)) is effective in patients with minimal, moderate or severe crotaline envenomation, halting the progression of local venom effects and ameliorating haematological and other systemic abnormalities of envenomation. Despite treatment, patients may experience delayed-onset or recurrent venom effects (e.g. coagulopathy). Intravenous crotalidae polyvalent immune Fab is generally well tolerated, with acute hypersensitivity reactions being the most commonly occurring adverse event.

Retrospective evaluation of neurotoxic rattlesnake envenomation in dogs and cats: 34 cases (2005–2010)

To describe common physical examination findings, clinicopathologic changes, treatment, and outcome in patients with evidence of neurotoxicity secondary to rattlesnake envenomation. Retrospective multicenter study (2005-2010). Three private veterinary referral centers. Thirty-four client-owned cats and dogs with evidence of neurotoxicity secondary to rattlesnake envenomation. None. Patient signalment, approximate time between envenomation and presentation for veterinary evaluation, physical examination and clinicopathologic findings, treatments, serial neurologic assessment, duration of hospitalization, and outcome were recorded. Signs of neurotoxicity such as ataxia, postural deficits, muscle fasciculations, paresis, paralysis, or seizures were required for inclusion into the study. The incidence of neurotoxicity amongst the general population treated with antivenin for rattlesnake envenomation in this study was 5.4%. Crotalidae Polyvalent Immune Fab(b) and veterinary approved Antivenin (Crotalidae) Polyvalent(a) were both used in this study. There was no statistically significant difference between type of antivenin or number of vials of antivenin administered and neurologic status, length of hospitalization (LOH), or survival. Hypokalemia was a frequently identified complication, but the presence of hypokalemia did not have a statistically significant association with LOH or survival. Four of the 34 patients (11.8%) required positive pressure ventilation for signs consistent with respiratory paralysis; 2 of these patients survived to discharge. Overall mortality rate was 17.6%. Survival was not significantly different between dogs and cats. However, cats had a significantly longer LOH when compared with dogs (median LOH 3.5 d for cats, 2 d for dogs). Cats appear to be overrepresented in the subset of envenomated patients with neurotoxicity. Although the incidence of neurotoxicity secondary to rattlesnake envenomation may be relatively low, patients can have rapid progression of their clinical signs and a higher mortality rate, necessitating timely and appropriate treatment. Patients treated for neurotoxicity secondary to envenomation appear to have a fair to good prognosis.

Venomous Snakebites

More than 5 million people are bitten by venomous snakes annually and more than 100 000 of them die. In Europe, one person dies due to envenomation every 3 years. There is only one venomous snake species in Lithuania – the common adder (Vipera berus) – which belongs to the Viperidae family; however, there are some exotic poisonous snakes in the zoos and private collections, such as those belonging to the Elapidae family (cobras, mambas, coral snakes, etc.) and the Crotalidae subfamily of the Viperidae family (pit vipers, such as rattlesnakes). Snake venom can be classified into hemotoxic, neurotoxic, necrotoxic, cardiotoxic, and nephrotoxic according to the different predominant effects depending on the family (i.e., venom of Crotalidae and Viperidae snakes is more hemotoxic and necrotoxic, whereas venom of Elapidae family is mainly neurotoxic). The intoxication degree is estimated according to the appearance of these symptoms: 1) no intoxication (“dry” bite); 2) mild intoxication (local edema and pain); 3) moderate intoxication (pain, edema spreading out of the bite zone, and systemic signs); 4) severe intoxication (shock, severe coagulopathy, and massive edemas). This topic is relevant because people tend to make major mistakes providing first aid (e.g., mouth suction, wound incision, and application of ice or heat). Therefore, this article presents the essential tips on how first aid should be performed properly according to the “Guidelines for the Management of Snake-Bites” by the World Health Organization (2010). Firstly, the victim should be reassured. Rings or other things must be removed preventing constriction of the swelling limb. Airway/breathing must be maintained. The bitten limb should be immobilized and kept below heart level to prevent venom absorption and systemic spread. Usage of pressure bandage is controversial since people usually apply it improperly. Incision, mouth suction, or excision should not be performed; neither a tourniquet nor ice or heat should be applied. A doctor must monitor respiratory rate, blood pressure, heart rate, renal function, fluid balance, and coagulation status. The only specific treatment method is antivenin – serum with antibodies against antigens of snake venom. Antivenins against pit vipers used in the United States are Antivenin Crotalidae Polyvalent (ACP) and a more purified and hence causing less adverse reactions – Crotalidae Polyvalent Immune Fab (CroFab). In Europe, a polyvalent antiserum against Viperidae family snakes (including the common adder) can be used. Antivenins often may cause severe hypersensitivity reactions because of their protein nature. The bite of the common adder (the only poisonous snake in such countries as Lithuania and Great Britain) relatively rarely results in death; thus, considering the risk of dangerous reactions the antivenin causes itself, the usage of it is recommended to be limited only to life-threatening conditions.

Crotalidae Polyvalent Immune Fab

Crotalidae polyvalent immune Fab is an antivenom comprising purified, sheep-derived, Fab IgG fragments and is indicated for use in patients with North American crotaline envenomation. Crotalidae polyvalent immune Fab is produced using four North American snake venoms: Crotalus atrox, Crotalus adamanteus, Crotalus scutulatus, and Agkistrodon piscivorus. Intravenous crotalidae polyvalent immune Fab was effective in patients aged ≥10 years who had minimal or moderate envenomation by a North American crotaline, who presented within 6 hours of the snakebite, and who had progression of the envenomation syndrome, according to the results of two prospective trials. One trial was a noncomparative, multicenter pilot study and the other trial was a randomized, open-label, multicenter trial in which patients received scheduled or 'as needed' administration of crotalidae polyvalent immune Fab after initial control had been achieved. A prospective, postmarketing trial demonstrated the efficacy of crotalidae polyvalent immune Fab in confirmed Crotalus viridis helleri envenomation (indicating cross-protection against a venom not used in its production). Results of these prospective trials are supported by the findings of additional (mainly retrospective) studies demonstrating the efficacy of crotalidae polyvalent immune Fab in patients with crotaline envenomation, including patients with severe envenomation, pediatric patients, and patients with symptoms of neurotoxicity. Despite treatment with crotalidae polyvalent immune Fab, patients may experience delayed-onset or recurrent venom effects (e.g. coagulopathy). Intravenous crotalidae polyvalent immune Fab was generally well tolerated; acute hypersensitivity reactions (e.g. urticaria, rash, pruritus) were the most commonly occurring adverse event.