Factors Associated With Difficulty Achieving Initial Control With Crotalidae Polyvalent Immune Fab Antivenom in Snakebite Patients Shan Yin, MD, MPH, Jamie Kokko, MPH, Eric Lavonas, MD, Sara Mlynarchek, MPH, Greg Bogdan, PhD, and Tammi Schaeffer, MD
Abstract Background: The prescribing information for Crotalidae Fab antivenom (FabAV) instructs clinicians to administer FabAV until initial control of the envenomation syndrome is achieved. Risk factors for difficulty achieving initial control are not known. Objectives: The study aim was to identify factors present before administration of antivenom associated with difficulty achieving initial control. Methods: The authors conducted a retrospective study of all patients presenting to any one of 17 centers and receiving FabAV from 2002 to 2004. Demographic and historical information, as well as data about nine specific venom effects, were collected prior to the administration of antivenom. An expert panel used standard criteria to determine if initial control was achieved. The patient group that had difficulty achieving initial control was compared to the group that achieved initial control, and adjusted odds ratios were calculated using stepwise logistic regression. Results: A total of 247 patients were included in the final analysis. The majority of patients were envenomated on the upper extremity and were young males. A total of 203 patients (82.2%) achieved initial control. In univariate analysis, thrombocytopenia, bleeding, neurologic effects, and a severe bite were significantly associated with difficulty achieving initial control. After logistic regression, the presence of neurologic effects and thrombocytopenia remained significantly associated with difficulty achieving initial control. When both factors were present, the patient was 13.8 times more likely to have difficulty achieving initial control. Conclusions: A number of factors were present before the administration of FabAV that were independently associated with difficulty achieving initial control of the envenomation syndrome. Predicting which patients will have difficulty achieving initial control has important ramifications for patient disposition and may provide insight into the mechanisms for lack of antivenom efficacy. ACADEMIC EMERGENCY MEDICINE 2011; 18:46–52 ª 2011 by the Society for Academic Emergency Medicine
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nvenomation by pit viper snakes (family Viperidae, subfamily Crotalinae, genera Crotalus, Agkistrodon, and Sistrurus) is a potentially serious medical condition in the United States. The American Association of Poison Control Centers received more than 2,900 reports of patients who sought emergency care for a crotaline snakebite in 2008.
Approximately 60% of these patients received antivenom as part of their treatment.1 The only specific therapy for crotaline envenomation in the United States is an ovine Fab antivenom product (referred hereafter as FabAV) approved by the U.S. Food and Drug Administration in October 2000 (CroFab, BTG, West Conshohocken, PA). FabAV is a polyclonal antibody mixture that contains
From the Denver Health Hospital Authority, Rocky Mountain Poison and Drug Center, Denver, CO. Received April 6, 2010; revisions received June 1 and June 8, 2010; accepted June 9, 2010. Presented at the 2009 North American Congress of Clinical Toxicology meeting, San Antonio, TX, September 2009. This study was a secondary analysis of data that were originally collected in a study funded by a grant from Fougera (now Nycomed, Zurich, Switzerland). Rocky Mountain Poison and Drug Center also received grant funding to revalidate and reanalyze the data from Protherics (now BTG, West Conshohocken, PA). Rocky Mountain Poison and Drug Center has consultation and call center contracts with Nycomed and BTG. The authors are salaried employees of Rocky Mountain Poison and Drug Center and do not receive any direct funding from Nycomed or BTG. Supervising Editor: Mark Mycyck, MD. Address for correspondence and reprints: Shan Yin, MD, MPH; e-mail:
[email protected].
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ISSN 1069-6563 PII ISSN 1069-6563583
ª 2010 by the Society for Academic Emergency Medicine doi: 10.1111/j.1553-2712.2010.00958.x
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only the antigen-binding fragment of the whole IgG molecule. Envenomation by crotaline snakes is manifested by local, systemic, and ⁄ or hematologic effects. Local venom effects include progressive swelling and pain extending from the bite site. Systemic effects may include hypotension, vomiting, abdominal pain, confusion, dyspnea, and tachycardia. Hematologic effects include thrombocytopenia, hypofibrinogenemia, and coagulopathy. The presence of any one of these effects (local, systemic, or hematologic) is typically considered an indication for antivenom therapy.2 The arrest of these venom effects after administration of antivenom is generally described as ‘‘initial control.’’ The FabAV product insert instructs clinicians to administer four to six vials of antivenom, with additional doses as needed until initial control of the envenomation syndrome is achieved. Once initial control is achieved, the manufacturer recommends administration of maintenance dosing of two vials every 6 hours.3 While most patients achieve initial control with one to two doses (each dose being four to six vials) of FabAV, there are numerous reports of difficulty achieving initial control.4–9 Predicting which patients might have difficulty achieving initial control has important implications on determining whether a hospital has sufficient antivenom stocks to treat a given patient. The objective of this study was to identify factors present before receiving antivenom associated with a subsequent difficulty in achieving initial control.
antivenom doses administered, and an indication of whether or not initial control was believed to have been achieved at the initial time of treatment. The institutional review board at each participating institution approved this study.
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METHODS Study Design This was a secondary analysis of data collected in a multicenter retrospective chart review from 17 U.S. hospitals located throughout the range of geographically indigenous crotaline venomous snakes. Study Setting and Population All patients who received FabAV for treatment of a crotaline snakebite from 2002 to 2004 were eligible. The medical record had to include clinical signs and symptoms before the first dose of antivenom, a record of all
Study Protocol An electronic search of pharmacy records was used to identify all patients treated with FabAV at each study hospital during the study period. The chart for each patient who received FabAV during 2004 was abstracted. Investigators from institutions with fewer than 10 medical records from 2004 abstracted all medical records from 2002 through 2004, to decrease a possible sampling bias. An investigator at each site obtained original medical records and abstracted data to a standardized form. Standardized definitions of key variables were provided. Abstractors received 1 hour of training, followed by practice abstraction of two sample medical records. After practice abstraction, both group and individual feedback were provided to the data abstractors, and the tool was modified to resolve areas of ambiguity. Deidentified forms were sent to the study coordinating center, where the data were entered into a secure database (Access 2003, Microsoft Corp., Redmond, WA). Data were quality checked, and individual feedback with specific queries was sent back to site investigators. Site investigators were blinded to the study hypothesis. Venom effects prior to the receipt of antivenom were recorded and are described in Table 1. Progressive pain and swelling were not defined with uniform criteria, but were determined by each site abstractor. In addition, data on these other variables were also recorded: modified severity score prior to receiving antivenom, number of vials of antivenom given in the first dose, platelet count, international normalized ratio, fibrinogen, and time to treatment with antivenom from envenomation. The modified severity score is a simplified version of the snakebite severity score established and validated by Dart et al.10 The modified severity score (see Table 2) was used because it includes only elements that were likely to be found routinely in medical records documenting an envenomation. Like the
Table 1 Definition of Venom Effects Venom Effect Progressive pain Progressive swelling Coagulopathy Thrombocytopenia Significant or spontaneous bleeding Respiratory Cardiovascular Neurologic Gastrointestinal INR = international normalized ratio.
Definition Increasing pain Increasing swelling Fibrinogen 20 sec, or INR >1.2 Platelet count 20 breaths ⁄ min, dyspnea, apnea, chest tightness, or respiratory distress Heart rate >125 beats ⁄ min or systolic blood pressure 1.2, and ⁄ or platelets 2.0, and ⁄ or platelets
