Antivenom effect on lymphatic absorption and pharmacokinetics of coral snake venom using a large animal model.

Context: Historically, administration and dosing of antivenom (AV) have been guided primarily by physician judgment because of incomplete understanding of the envenomation process. As demonstrated previously, lymphatic absorption plays a major role in the availability and pharmacokinetics (PK) of coral snake venom injected subcutaneously, which suggests that absorption from subcutaneous tissue is the limiting step for venom bioavailability, supporting the notion that the bite site is an ongoing venom depot. This feature may underlie the recurrence phenomena reported in viperid envenomation that appear to result from a mismatch between venom and AV PK. The role of lymphatic absorption in neutralization of venom by AV administered intravenously remains unclear. Methods: The effect of AV on systemic bioavailability and neutralization of Micrurus fulvius venom was assessed using a central lymph-cannulated sheep model. Venom was administered by subcutaneous injection in eight sheep, four with and four without thoracic duct cannulation and drainage. Two hours after venom injection, AV was administered intravenously. Venom and AV concentrations in serum and lymph were determined by ELISA assay from samples collected over a 6-h period and in tissues harvested post-mortem. Results: After AV injection, venom levels in serum fell immediately to undetectable with a subsequent increase in concentration attributable to non-toxic venom proteins. In lymph, AV became detectable 6 min after treatment; venom levels dropped concurrently but remained detectable 4 h later. Post-mortem samples from the venom injection site confirmed the presence of venom near the point of injection. Neither venom nor AV was detected at significant concentrations in major organs or contralateral skin. Conclusions: Intravenous AV immediately neutralizes venom in the bloodstream and can extravasate to neutralize venom absorbed by lymph but this neutralization seems to be slow and incomplete. Residual venom in the inoculation site demonstrates that this site functions as a depot where it is not neutralized by AV, which allows the venom to remain active with slow delivery to the bloodstream for ongoing systemic distribution.

Effectiveness of Centruroides scorpion antivenom compared to historical controls.

BACKGROUND: Envenomation by North American scorpions of genus Centruroides is associated with a syndrome of neurotoxicity and respiratory compromise that disproportionately affects rural children. Severe scorpion envenomation is rare, which makes treatment difficult to study using conventional controlled clinical trials; and small-scale placebo-controlled trials conducted in tertiary centers are of limited generalizability to the community setting. Open label studies, although safer and easier to conduct, are of limited value unless a suitable comparator group is used. Historical controls may be appropriate when concurrent controls are not feasible or ethical. METHODS: A successful placebo-controlled, double-blind clinical trial design was adapted for community use in Arizona and Mexico. A comparator population was established by replacement of the placebo group with a retrospective cohort and preservation of criteria for inclusion, exclusion, dosing and endpoint assessment. Study endpoints were selected to demonstrate the clearest possible difference between treatment groups, while minimizing confounders. Results were summarized and endpoints were directly compared between groups and with the prior double-blind study. RESULTS: The clinical syndrome remained evident in 95.9% of the historical cohort (93/97) 4 h after admission, and their cumulative dose of midazolam given between baseline and discharge was 5.29 ± 8.68 mg/kg (range 0-62.8). Among 78 prospectively treated cases, none received midazolam and only 2 (2.8%) remained symptomatic at 4 h. Venom was detectable in the plasma of all antivenom recipients tested, and it dropped by 90% of baseline in 95% of cases studied. CONCLUSIONS: The results of this pragmatic study strongly support the findings of the double-blind, placebo controlled clinical trial of the same antivenom. Recipients of antivenom at rural sites improved at a rate similar to that in the intensive care (ICU) setting, and historical cases resolved at a rate similar to that for untreated ICU controls. Use of antivenom in the primary care setting appeared to be safe and effective and to eliminate the need for intensive care or for transport to a tertiary care center, in all subjects prospectively studied.

A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States.

BACKGROUND: Current therapy for crotaline snakebite includes antivenin (Crotalidae) polyvalent, an antivenom with numerous adverse effects. We compared the efficacy and safety of 2 dosing regimens with a new antivenom, Crotalinae polyvalent immune Fab (Fab AV). METHODS: A single dose of Fab AV alone (as-needed [PRN] group) was compared with an initial dose plus repeated treatments during 18 hours (scheduled group) in a multicenter randomized trial. The study included patients with minimal or moderate envenomation by a crotaline snake within the preceding 6 hours, aged 10 years or older, in whom worsening of the envenomation syndrome was observed before Fab AV treatment. After treatment with Fab AV to achieve initial control, patients were randomized to the scheduled or PRN treatment group. Scheduled group patients received additional doses of Fab AV every 6 hours for 3 doses. The PRN group received no planned additional doses of antivenom. RESULTS: The mean severity score of the 31 patients decreased from 4.35 to 2.39 points (P<.001); there was no difference between scheduled and PRN groups. No patient in the scheduled group received unplanned Fab AV doses, but 8 of 16 patients in the PRN group received unplanned doses (P =.002). Acute reactions occurred in 6 patients (19%), and serum sickness occurred in 6 (23%) of 26 patients who returned for follow-up. CONCLUSIONS: In the first randomized trial of antivenom in the United States, Fab AV effectively terminated venom effects. Since the unplanned use of Fab AV in the PRN group was common, the treatment regimen may require more than 1 initial dose.

Recurrence phenomena after immunoglobulin therapy for snake envenomations: Part 1. Pharmacokinetics and pharmacodynamics of immunoglobulin antivenoms and related antibodies.

The production of immunoglobulin antivenoms has evolved over the past 50 years, resulting in a choice of source animals and highly purified, target-specific immunoglobulin fragments (IgG, Fab2, and Fab). Differences in pharmacokinetic and pharmacodynamic properties of these fragments may affect clinical efficacy. For example, both local and systemic recurrences (worsening after initial improvement) with intact or fragmented immunoglobulin antivenoms have been observed. Local recurrence may result in greater tissue injury, and coagulopathic recurrence may result in the risk of hemorrhage. The latter is of particular concern because coagulopathic recurrence usually occurs after patient discharge. Similar phenomena of symptom recurrence have been observed with ovine, digoxin-specific Fab, and with Fab2 and IgG antivenoms from a variety of source animals as well. Recurrence of venom effects in Fab-treated patients appears to be the result of a pharmacokinetic and pharmacodynamic mismatch between the antivenom and target venom components. That is, tissue penetration and venom neutralization is incomplete, and clearance of unbound antivenom (antivenom that has not bound its venom target) is significantly faster than the clearance of some venom components, allowing signs and symptoms of envenomation to recur. Understanding the relative kinetics and dynamics of immunoglobulins and their targets may allow the physician to anticipate their clinical implications and may suggest modifications of the drug or dose to produce better clinical results.

Recurrence phenomena after immunoglobulin therapy for snake envenomations: Part 2. Guidelines for clinical management with crotaline Fab antivenom.

Recurrent local and coagulopathic effects (worsening after clinical improvement) have been described after treatment with Fab antivenom for envenomation by North American crotaline snakes. Although similar phenomena have been described previously in snakebite, few studies have examined recurrence or its management. Recurrence is consistent with known venom and antivenom kinetics and dynamics. The clinical significance of late coagulopathy after snakebite is uncertain, but clinically significant bleeding is a possibility. Prevention and treatment of recurrence with Fab antivenom require repeated dosing for at least 18 hours, with close monitoring of at-risk patients in the follow-up period. Duration of therapy depends on individual risk factors and coagulation response.

Mercury toxicity due to use of a cosmetic cream.

The Arizona Department of Health Services performed an investigation to determine the health effects associated with the use of a mercury-containing beauty cream. A urine test for mercury was offered to cream users who contacted the Arizona Department of Health Services. Those with urine mercury levels > 20 micrograms/L were offered clinical evaluation. Eighty-nine urine specimens were submitted for testing. Of these, 66 showed an elevated urine mercury level (> 20 micrograms/L), and 55 people were evaluated in clinic. There were no major abnormalities found through physical examination or laboratory testing. Urine mercury levels declined from an initial mean of 170 micrograms/L to 32 micrograms/L at the final test (mean, 139 days later). The high urine mercury levels indicate that the use of this cosmetic cream constitutes a significant exposure. Neuropsychiatric symptoms were frequently reported, but few objective signs were noted.

Recurrent and persistent coagulopathy following pit viper envenomation.

BACKGROUND: Coagulation abnormalities following crotaline (pit viper) snakebite have traditionally been considered short-lived, but laboratory studies have rarely been reported beyond the first few days of treatment for envenomation. During the course of an antivenom clinical trial, we observed coagulation defects as late as 2 weeks following envenomation. OBJECTIVES: To document and characterize the recurrence or persistence of coagulopathy among patients envenomed by pit vipers and treated with a Fab antivenom. METHODS: Patients with moderate pit viper envenomation were enrolled in a multicenter, prospective clinical trial. A Fab-based antivenom preparation, antivenom polyvalent crotalid (ovine) Fab, was administered in all cases. Platelet count, fibrinogen level, presence of fibrin split products, prothrombin time, and partial thromboplastin time were determined before treatment and at standard intervals during the following 2 weeks. RESULTS: Of 38 patients completing the study, 20 (53%) had recurrent, persistent, or late coagulopathy 2 to 14 days after envenomation. Thrombocytopenia occurred in patients with prior thrombocytopenia; hypofibrinogenemia occurred only in those with prior hypofibrinogenemia or positive fibrin split products. No patient experienced significant spontaneous bleeding. One patient with coagulopathy developed minor bleeding following minor surgery 12 days after envenomation. CONCLUSIONS: Prolonged or recurrent coagulopathy may occur after envenomation by North American pit vipers. Patients treated with Fab-based antivenom may benefit from periodic rather than single-bolus dosing. Patients with coagulopathy should undergo close monitoring during the first 2 weeks after snakebite.

Exotic snakebite: envenomation by an African puff adder (Bitis arietans).

We report an envenomation by the African puff adder (Bitis arietans), an exotic snake in the United States. The patient developed swelling and ecchymoses in the affected extremity, and cutaneous necrosis of the envenomated fingertip. There was no significant coagulopathy. He received 20 vials of specific antivenin (Schlangengift-Immunserum Behring Zentralafrika, Behringwerke, Marburg, Germany) and debridement of devitalized finger tissue. The only permanent sequelae were cutaneous scarring and permanent loss of the fingernail on the envenomated finger. Exotic snakebite is a rare presenting problem in emergency departments. The initial approach to a patient envenomated by an exotic venomous snake is discussed. Use of antivenin and supportive care are emphasized.

Relationship of venom effects to venom antigen and antivenom serum concentrations in a patient with Crotalus atrox envenomation treated with a Fab antivenom.

STUDY OBJECTIVE: To describe the association among venom antigenemia, serum antivenom concentrations, and venom effects in a 53-year-old woman who was bitten by a Western Diamondback rattlesnake (Crotalus atrox). METHODS: The patient was enrolled in a multicenter trial of an investigational Fab antivenom. Her clinical condition and coagulation parameters were monitored for 2 weeks after the bite. RESULTS: After antivenom administration, the progression of the venom's effects was arrested. The antivenom reversed some local venom effects, caused venom antigens to disappear from the blood, and resolved the patient's profound thrombocytopenia (before antivenom, 12,000/mm3; 1 hour after antivenom, 227,000/mm3). Local venom effects recurred twice in the 24 hours after antivenom administration but were easily managed with additional Fab antivenom. Venom antigenemia was detected on days 5 and 8 after the initial treatment and was accompanied in one instance by the new onset of hypofibrinogenemia (119 mg/L) that resolved spontaneously and in both instances by renewed profound thrombocytopenia. Repeat Fab antivenom does no days 6 and 9 were followed by increases in platelet count (from 16,000 to 40,000/mm3 and from 11,000 to 20,000/mm3, respectively) and by the reduction or disappearance of venom antigenemia. The patient sustained no significant bleeding complications, and all laboratory values had returned to normal 2 weeks after the bite. CONCLUSION: Initial control of local symptoms and coagulopathy was prompt after the administration of Fab antivenom. Repeat doses during the 24 to 36 hours after a bite may be necessary for local control. Recrudescence of coagulopathy was likely due in part to renewed venom antigenemia after clearance of Fab antivenom. The role of Fab antivenom in the treatment of recurrent coagulopathy requires further study.

Cerebral infarction immediately after ingestion of hydrogen peroxide solution.

BACKGROUND: We report the clinical and neuroimaging findings of a patient who sustained multiple cerebral infarcts after the ingestion of concentrated hydrogen peroxide solution sold as a "health food" product. CASE DESCRIPTION: An 84-year-old man sustained focal neurological deficits immediately after ingesting 30 mL of 35% hydrogen peroxide solution. Physical examination disclosed a left hemiparesis, frontal release signs, and cerebellar dysfunctions. Magnetic resonance imaging revealed multiple cerebral and cerebellar infarctions in the anterior, middle, and posterior vascular territories. CONCLUSIONS: The likely mechanism of pathogenesis involves cerebral oxygen gas embolization. The use of hyperbaric therapy should be considered in treating hydrogen peroxide poisoning.