Sean P. Bush

Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop

BackgroundEnvenomation 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.MethodsA 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.ResultsA 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.ConclusionsClinical 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.

Effects of a negative pressure venom extraction device (Extractor) on local tissue injury after artificial rattlesnake envenomation in a porcine model

OBJECTIVES To determine if a commercially available negative-pressure venom extraction device (Extractor) reduces local tissue injury after artificial rattlesnake envenomation in a porcine model. METHODS We prospectively studied 10 pigs using a crossover design. After the pigs were anesthetized, 25 mg Crotalus atrox venom was injected obliquely with a 22-gauge needle 7 mm deep into subcutaneous tissues proximal to the ventral hind hoof. Pigs were randomized to receive either the Extractor (applied 3 minutes following envenomation and left in place for 30 minutes) or no Extractor. The protocol was repeated 14 days later by using the alternate treatment group and opposite hind leg for each animal. We measured leg circumference at standardized locations on the hoof, foreleg, and thigh at baseline and then 1, 2, 3, 4, 5, 6, 24, 48, 72, and 96 hours following venom injection. Maximal changes in circumference at 6 hours were compared using the paired t test. Minimum residual swelling at up to 96 hours was similarly compared. RESULTS Maximal 6-hour swelling was similar with and without the Extractor: the hoof difference with the Extractor was -0.1% (95% CI = -3.4% to 3.2%, P = .95), foreleg difference was 0.3% (95% CI = -4.1% to 4.7%, P = .88), and thigh difference was -2.8% (95% CI = -10.0% to 4.4%, P = .40). Minimum residual swelling at up to 96 hours was also similar with and without the Extractor: hoof difference with the Extractor was 1.2% (95% CI = -5.6% to 8.0%, P = .70), foreleg difference was 0.6% (95% CI = -3.7% to 4.9%, P = .76), and thigh difference was 0.3% (95% CI = -2.4% to 3.0%, P = .81). A circular lesion identical in size and shape to the Extractor suction cup, which later necrosed and resulted in tissue loss, developed where the device had been applied in 2 animals. No such lesions occurred in legs not treated with the Extractor. CONCLUSION No benefit was demonstrated from Extractor use for artificial rattlesnake envenomation in our animal study. The skin necrosis noted in 2 Extractor-treated extremities suggests that an injury pattern may be associated with the device.

Neurotoxicity associated with suspected Southern Pacific rattlesnake (Crotalus viridis helleri) envenomation

An 18-year-old man was bitten on the hand by a snake he believed to be a Southern Pacific rattlesnake (Crotalus viridis helleri). Within minutes he developed generalized weakness, difficulty breathing, diplopia, dysphagia, and dysphonia. Neurological examination revealed ptosis and decreased motor strength. These symptoms partially improved after administration of Antivenin (Crotalidae) Polyvalent, but the patient continued to have difficulty walking for several days due to weakness. In addition to neurological symptoms, the patient also experienced pain immediately after the bite occurred and rapid swelling of the entire extremity, which extended beyond the shoulder. He complained of a metallic taste in his mouth and developed intense muscle fasciculations of the face, tongue, and upper extremities, which lasted for 2 days and did not improve with antivenin treatment. He exhibited laboratory evidence of coagulopathy and rhabdomyolysis. Although neurotoxins are known to occur in the venom of certain populations of rattlesnakes, only a few clinical reports describing severe neurological symptoms appear in the literature. To our knowledge, this is the first reported case of neurotoxicity associated with a suspected Southern Pacific rattlesnake envenomation.

Severe rattlesnake envenomation with anaphylaxis and rhabdomyolysis.

A 7-year-old boy presented to the emergency department with severe hypotension and lethargy after a rattlesnake bite. He developed anaphylaxis to antivenom and required intubation, epinephrine, antihistamines, and steroids. Severe rhabdomyolysis and myoglobinuric kidney failure developed over 24 hours, with a peak creatine phosphokinase level of 214,500 units/L. Severe hypocalcemic tetany was treated with replacement therapy. Local wound swelling was never severe and the patient had no coagulopathies. Marked motor weakness improved with antivenom administration. Because of the myotoxic and neurologic effects in the absence of fibrinogenolysis/thrombocytopenia and minimal tissue signs, as well as the similarity to a previously reported case from our area, the envenomation was most likely caused by a Mojave rattlesnake.

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

Abstract 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.

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

BACKGROUND In 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. METHODS This 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. RESULTS Five 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. DISCUSSION The 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. CONCLUSIONS A 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.

Large Snake Size Suggests Increased Snakebite Severity in Patients Bitten by Rattlesnakes in Southern California

OBJECTIVE To correlate rattlesnake size and other characteristics of envenomation with the severity of envenomation. METHODS We retrospectively reviewed 145 charts of patients bitten by rattlesnakes in Southern California between 1995 and 2004, measuring Snakebite Severity Scores (SSS) and characteristics of envenomation that might be correlated with snakebite severity, including rattlesnake size, rattlesnake species, patient size, and anatomic location of the bite. Outcomes measured included SSS, complications of envenomation, number of vials of antivenom used, and length of hospital stay. RESULTS Of the patients bitten by rattlesnakes, 81% were men, and 79% of bites were on the upper extremities. Fifty-five percent of bites were provoked by the patient, and 44% were unprovoked. Neither location of snakebite nor provocation of snakebite affected the SSS. Only 1 patient had a snakebite without envenomation, and only 1 patient died from envenomation. Rattlesnake size was positively correlated with SSS, and SSS was positively correlated with the number of vials of antivenom used and with the length of hospital stay. Rattlesnake species and patient mass did not affect SSS. CONCLUSIONS Larger rattlesnakes cause more severe envenomations, which contradicts popular belief.

Mojave rattlesnake envenomation in southern California: A review of suspected cases

To clarify whether Mojave rattlesnake (Crotalus scutulatus scutulatus) envenomations occurring in California cause typical crotalid tissue effects, pain, edema, and ecchymosis, we reviewed charts of snakebite victims at a tertiary care teaching hospital and a moderate-size community hospital. Forty-two patients were bitten within the range of Mojave rattlesnakes. Eight snakes were identified as Mojave rattlesnakes (group 1); of these, four were confirmed by experts in snake identification (group 1a). Fifteen patients were reported bitten by other rattlesnake species (group 2), and in 19 envenomations the species was unknown (group 3). Seventy-five percent of patients in group 1 were reported to have local edema at the envenomation site compared with all of the patients in group 2. Ecchymosis was found in 25% of group 1 patients and 73% of group 2 patients. Pain was documented in only 12% of group 1 and 67% of group 2 victims. Neurotropic events, many severe, were found in 75% of group 1 patients compared with 7% of those in group 2. Although this study does not have the power to justify statistical evaluation, C. scutulatus envenomations do appear inclined to less tissue reaction. A disturbing trend toward severe neurotropic manifestations was also suggested in presumed Mojave rattlesnake envenomations.

The Efficacy of Crotalidae Polyvalent Immune Fab (Ovine) Antivenom Versus Placebo Plus Optional Rescue Therapy on Recovery From Copperhead Snake Envenomation: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial

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.

A Randomized, Double-Blind, Placebo-Controlled Trial of a Highly Purified Equine F(ab)2 Antibody Black Widow Spider Antivenom

STUDY OBJECTIVE Black widow spider antivenom has never been tested in a randomized clinical trial, to our knowledge. We explore various efficacy measures for a novel F(ab)2 antivenom in patients with moderate to severe pain caused by black widow spider envenomation. METHODS A randomized, placebo-controlled, double-blind, clinical trial was conducted in 12 academic emergency departments. We included patients at least 10 years old with moderate to severe latrodectism. Subjects received either a single intravenous infusion of antivenom or placebo. Pain was assessed with the visual analog scale. The primary efficacy outcome was the difference in pre- and posttreatment visual analog scale score. Prospectively defined secondary outcomes included treatment failures and time to clinically important decrease in pain. RESULTS Twenty-four subjects were enrolled between October 2005 and October 2006; 13 were randomized to antivenom and 11 to placebo. The median change in visual analog scale at 150 minutes posttreatment was -50.0 mm (Interquartile Range [IQR] -67, -41 mm) in the antivenom treatment group and -46.0 mm (IQR -51, 0 mm) in the placebo treatment group (P=.14). There were 7 treatment failures (64%; 95% confidence interval 35% to 92%) in the placebo group and 3 (23%; 95% confidence interval 0.2% to 46%) in the antivenom group (P=.06). The median time to a clinically important decrease in pain after treatment was shorter in the antivenom group compared with the placebo group (30 minutes [IQR 30, 60 minutes] versus 90 minutes [IQR 30, 90 minutes]; P=.03). No serious adverse events or deaths were reported. CONCLUSION Although the overall reduction in pain was similar for antivenom- and placebo-treated subjects, antivenom reduced pain more rapidly than placebo. No significant adverse events occurred in either group.