Medically significant late bleeding after treated crotaline envenomation: a systematic review.

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.

QTc interval screening in an opioid treatment program.

Methadone is highly effective for opioid dependency, but it is associated with Torsade de pointes. Although electrocardiography (ECG) has been proposed, its utility is uncertain, because an ECG-based intervention has not been described. An ECG-based cardiac safety program in methadone maintenance patients was evaluated in a single opioid treatment program from September 1, 2009, to August 31, 2011, in the United States. Time from pretreatment to repeat ECG in new entrants was assessed. The proportion with marked rate-corrected QT (QTc) interval prolongation (>500 ms) and the effect of the intervention on the QTc interval in this group were evaluated. Multivariate predictors of QTc interval change were assessed using a mixed-effects model. Of 531 new entrants, 436 (82%) underwent ≥1 electrocardiographic assessment, and 186 (35%) underwent pretreatment ECG. Median time to follow-up ECG was 43 days but decreased over time (p <0.0001). In 21 patients with QTc intervals >500 ms, the mean QTc interval from peak to final ECG decreased significantly (-55.5 ms, 95% confidence interval -77.0 to -33.9, p = 0.001), and 12 of 21 (57.1%) decreased to lower than the 500-ms threshold. In new entrants with serial ECG, only methadone dose (p = 0.009) and pretreatment QTc interval (p <0.0001) were associated with the magnitude of QTc interval change. In conclusion, this study suggests that the implementation of an ECG-based intervention in methadone maintenance can decrease the QTc interval in high-risk patients; clinical characteristics alone were inadequate to identify patients in need of electrocardiographic screening.

Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011: an analysis of registry data.

BACKGROUND: Long-acting opioids are a leading cause of accidental death in the United States, and methadone is associated with greater mortality rates. Whether this increase is related to the proarrhythmic properties of methadone is unclear. OBJECTIVE: To describe methadone-associated arrhythmia events reported in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). DESIGN: Description of national adverse event registry data before and after publication of a 2002 report describing an association between methadone and arrhythmia. SETTING: FAERS, November 1997 and June 2011. PATIENTS: Adults with QTc prolongation or torsade de pointes and ventricular arrhythmia or cardiac arrest. MEASUREMENTS: FAERS reports before and after the 2002 report. RESULTS: 1646 cases of ventricular arrhythmia or cardiac arrest and 379 cases of QTc prolongation or torsade de pointes were associated with methadone. Monthly reports of QTc prolongation or torsade de pointes increased from a mean of 0.3 (95% CI, 0.1 to 0.5) before the 2002 publication to a mean of 3.5 (CI, 2.5 to 4.8) after it. After 2000, methadone was the second-most common primary suspect in cases of QTc prolongation or torsade de pointes after dofetilide (a known proarrhythmic drug) and was associated with disproportionate reporting similar to that of antiarrhythmic agents known to promote torsade de pointes. Antiretroviral drugs for HIV were the most common coadministered drugs. LIMITATION: Reports to FAERs are voluntary and selective, and incidence rates cannot be determined from spontaneously reported data. CONCLUSION: Since 2002, reports to FAERS of methadone-associated arrhythmia have increased substantially and are disproportionately represented relative to other events with the drug. Coadministration of methadone with antiretrovirals in patients with HIV may pose particular risk. PRIMARY FUNDING SOURCE: Colorado Clinical and Translational Sciences Institute, National Institutes of Health, and Agency for Healthcare Research and Quality.

Incidence of immediate hypersensitivity reaction and serum sickness following administration of Crotalidae polyvalent immune Fab antivenom: a meta-analysis.

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.