Faculty Bibliography

Abstract Background. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments (ECTR) in poisoning and the results are presented here for acetaminophen (APAP). Methods. After a systematic review of the literature, a subgroup selected and reviewed the articles and summarized clinical and toxicokinetic data in order to propose structured voting statements following a pre-determined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. Following discussion, a second vote determined the final recommendations. Results. Twenty-four articles (1 randomized controlled trial, 1 observational study, 2 pharmacokinetic studies, and 20 case reports or case series) were identified, yielding an overall very low quality of evidence for all recommendations. Clinical data on 135 patients and toxicokinetic data on 54 patients were analyzed. Twenty-three fatalities were reviewed. The workgroup agreed that N-acetylcysteine (NAC) is the mainstay of treatment, and that ECTR is not warranted in most cases of APAP poisoning. However, given that APAP is dialyzable, the workgroup agreed that ECTR is suggested in patients with excessively large overdoses who display features of mitochondrial dysfunction. This is reflected by early development of altered mental status and severe metabolic acidosis prior to the onset of hepatic failure. Specific recommendations for ECTR include an APAP concentration over 1000 mg/L if NAC is not administered (1D), signs of mitochondrial dysfunction and an APAP concentration over 700 mg/L (4630 mmol/L) if NAC is not administered (1D) and signs of mitochondrial dysfunction and an APAP concentration over 900 mg/L (5960 mmol/L) if NAC is administered (1D). Intermittent hemodialysis (HD) is the preferred ECTR modality in APAP poisoning (1D). Conclusion. APAP is amenable to extracorporeal removal. Due to the efficacy of NAC, ECTR is reserved for rare situations when the efficacy of NAC has not been definitively demonstrated.

The Extracorporeal Treatments In Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, the workgroup presents its results for tricyclic antidepressants (TCAs). After an extensive literature search, using a predefined methodology, the subgroup responsible for this poison reviewed the articles, extracted the data, summarized findings, and proposed structured voting statements following a predetermined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements and RAND/UCLA Appropriateness Method to quantify disagreement. Blinded votes were compiled, returned, and discussed in person at a meeting. A second vote determined the final recommendations. Seventy-seven articles met inclusion criteria. Only case reports, case series, and one poor-quality observational study were identified yielding a very low quality of evidence for all recommendations. Data on 108 patients, including 12 fatalities, were abstracted. The workgroup concluded that TCAs are not dialyzable and made the following recommendation: ECTR is not recommended in severe TCA poisoning (1D). The workgroup considers that poisoned patients with TCAs are not likely to have a clinical benefit from extracorporeal removal and recommends it NOT to be used in TCA poisoning.

Morbidity and mortality from toxic alcohols like ethylene glycol and methanol remain prevalent worldwide. The introduction of fomepizole, a potent blocker of alcohol dehydrogenase, has modified current practice over the last 15 years. The aim of the study was to describe the characteristics of toxic alcohol poisoning reported to US poison centers, the trends in the incidence of antidote use and hemodialysis treatment, as well as the related mortality. A retrospective study of all electronic entries from the AAPCC National Poison Data System database, from the years 2000 to 2013 was reviewed. When considering all exposures, the great majority of patients had a benign outcome. Major effects (e.g., life threatening) occurred in 2.1% and 4.9% of methanol and ethylene glycol cases, respectively. Mortality rates were similar for both toxic alcohols, approximately 0.6%. When only considering ingestions reported to healthcare facilities, a major effect was reported in 9.5% and 20.5%, and the mortality rate was 2.9% and 2.4% for methanol and ethylene glycol exposures, respectively, and remained constant over time. The use of fomepizole increased statistically over the study period while that of ethanol decreased, until it became proportionally negligible by 2012-2013. The use of hemodialysis significantly decreased in "Early" ethylene glycol exposures during the study period. Similar to other reports, it appears that the use of fomepizole has largely supplanted ethanol as the antidote of choice in toxic alcohol exposures and may decrease the requirements for hemodialysis in patients poisoned with ethylene glycol who have no acidosis and normal kidney function.

The use of an extracorporeal treatment (ECTR) in a poisoned patient may be life-saving in a limited number of scenarios. The decision-processes surrounding the use of ECTR in poisoning is complex: most nephrologists are not trained to assess a poisoned patient while clinical toxicologists rarely prescribe ECTRs. Deciding on which ECTR is most appropriate for a poison requires a good understanding of the poison's physicochemical and pharmacokinetic properties. Further, a detailed understanding of the capabilities and limitations of the different ECTRs can be useful to select the most appropriate ECTR for a given clinical situation. This manuscript provides a stepwise approach to assess the usefulness of ECTRs in poisoning.

A literature review performed by the EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup highlighted deficiencies in the existing literature, especially the reporting of case studies. Although general reporting guidelines exist for case studies, there are none in the specific field of extracorporeal treatments in toxicology. Our goal was to construct and propose a checklist that systematically outlines the minimum essential items to be reported in a case study of poisoned patients undergoing extracorporeal treatments. Through a modified two-round Delphi technique, panelists (mostly chosen from the EXTRIP workgroup) were asked to vote on the pertinence of a set of items to identify those considered minimally essential for reporting complete and accurate case reports. Furthermore, independent raters validated the clarity of each selected items between each round of voting. All case reports containing data on extracorporeal treatments in poisoning published in Medline in 2011 were reviewed during the external validation rounds. Twenty-one panelists (20 from the EXTRIP workgroup and an invited expert on pharmacology reporting guidelines) participated in the modified Delphi technique. This group included journal editors and experts in nephrology, clinical toxicology, critical care medicine, emergency medicine, and clinical pharmacology. Three independent raters participated in the validation rounds. Panelists voted on a total of 144 items in the first round and 137 items in the second round, with response rates of 96.3% and 98.3%, respectively. Twenty case reports were evaluated at each validation round and the independent raters' response rate was 99.6% and 98.8% per validation round. The final checklist consists of 114 items considered essential for case study reporting. This methodology of alternate voting and external validation rounds was useful in developing the first reporting guideline for case studies in the field of extracorporeal treatments in poisoning. We believe that this guideline will improve the completeness and transparency of published case reports and that the systematic aggregation of information from case reports may provide early signals of effectiveness and/or harm, thereby improving healthcare decision-making.

Atropine is the mainstay of therapy in organophosphate (OP) toxicity, though research and consensus on dosing is lacking. In 2004, as reported by Eddleston et al. (J Toxicol Clin Toxicol 42(6):865-75, 2004), they noted variation in recommended regimens. We assessed revisions of original references, additional citations, and electronic sources to determine the current variability in atropine dosing recommendations. Updated editions of references from Eddleston et al.'s work, texts of Internal and Emergency Medicine, and electronic resources were reviewed for atropine dosing recommendations. For comparison, recommendations were assessed using the same mean dose (23.4 mg) and the highest dose (75 mg) of atropine as used in the original paper. Recommendations were also compared with the dosing regimen from the World Health Organization (WHO). Thirteen of the original recommendations were updated and 15 additional references were added giving a convenience sample of 28. Sufficient information to calculate time to targeted dose was provided by 24 of these samples. Compared to 2004, current recommendations have greatly increased the speed of atropinization with 13/24 able to reach the mean and high atropine dose within 30 min compared to 1/36 in 2004. In 2004, there were 13 regimens where the maximum time to reach 75 mg was over 18 h, whereas now, there are 2. While only one recommendation called for doubling the dose for faster escalation in 2004, 15 of the 24 current works include dose doubling. In 2004, Eddleston et al. called for an evidence-based guideline for the treatment of OP poisoning that could be disseminated worldwide. Many current recommendations can adequately treat patients within 1 h. While the WHO recommendations remain slow to treat patients with OP poisoning, other authorities are close to a consensus on rapid atropinization.

Background: ED patients with acute drug overdose have been shown to suffer adverse cardiovascular events, but prediction of these events is difficult. Objectives: To validate previously derived features of the initial ECG associated with adverse cardiovascular events in this population. Methods: We performed a prospective validation cohort study to evaluate adult ED patients with acute drug overdose at two urban university hospitals over 5 years in whom ED admission ECGs were performed. Excluded were patients with alternate diagnoses, anaphylaxis, chronic drug toxicity, and missing outcome data. Adverse cardiovascular events were defined as any of the following: shock (vasopressor requirement), myocardial injury (MI, elevated troponin), ventricular dysrythmia, or cardiac arrest (pulseless). Blinded cardiologists interpreted ECGs for rhythm, intervals, QT dispersion, ischemia (T wave inversion, ST depression), and infarction (ST elevation, Q waves). Diagnostic test characteristics of the previously derived ECG rule (ectopy, non-sinus rhythm, QTc), as well as univariate statistics, odds ratios (OR), and 95% confidence intervals (CI) were calculated. Assuming 10% prevalence of predictor variables and baseline 8% adverse cardiovascular event rate in the population, we calculated the need to enroll 552 patients to show three-fold increased risk per factor with 80% power and 5% alpha. Results: Of 589 acute drug overdose patients who met inclusion criteria (48% male, mean age 42), there were 95 adverse cardiovascular events (39 shock, 64 MI, 26 dysrhythmia, 16 cardiac arrest). The most common drug exposures were benzodiazepines, opioids, and acetaminophen. All previously derived criteria were highly predictive of adverse events, with QTc >500 ms the highest risk feature associated with over 10-fold increased adverse cardiovascular event risk (OR 11.2, CI 4.6-27). All high-risk ECG features as well as diagnostic test characteristics of the ECG rule are presented in Table 217. Conclusion: This study val!