Faculty Bibliography

CONTEXT/BACKGROUND:Early onset acidosis from mitochondrial toxicity can be observed in massive acetaminophen poisoning prior to the development of hepatotoxicity. In this context, the efficacy of acetylcysteine to reverse mitochondrial toxicity remains unclear and hemodialysis may offer prompt correction of acidosis. Unfortunately, toxicokinetics of acetaminophen and acetylcysteine during extracorporeal treatments hemodialysis have seldom been described. CASE DETAILS/METHODS:An 18-year-old woman presented to the emergency department 60 minutes after ingestion of 100 g of acetaminophen, and unknown amounts of ibuprofen and ethanol. Initial assessment revealed an agitated patient. Her mental status worsened and she required intubation for airway protection. Investigations showed metabolic acidosis with lactate peaking at 8.6 mmol/L. Liver and coagulation profiles remained normal. Acetaminophen concentration peaked at 981 μg/ml (6496 μmol/L). Pending hemodialysis, the patient received 100 g of activated charcoal and an acetylcysteine infusion at 150 mg/kg over 1 hour, followed by 12.5 mg/kg/h for 4 hours. During hemodialysis, the infusion was maintained at 12.5 mg/kg/h to compensate for expected removal before it was decreased to 6.25 mg/kg for 20 hours after hemodialysis. The patient rapidly improved during hemodialysis and was discharged 48 hours post-admission. TOXICOKINETICS/METHODS:The acetaminophen elimination half-life was 5.2 hours prior to hemodialysis, 1.9-hours during hemodialysis and 3.6 hours post hemodialysis. The acetaminophen and acetylcysteine clearances by A-V gradient during hemodialysis were 160.4 ml/min and 190.3 ml/min, respectively. Hemodialysis removed a total of 20.6 g of acetaminophen and 17.9 g of acetylcysteine. CONCLUSION/CONCLUSIONS:This study confirms the high dialyzability of both acetaminophen and acetylcysteine. Hemodialysis appears to be a beneficial therapeutic option in cases of massive acetaminophen ingestion with coma and lactic acidosis. Additionally, these results suggest that the infusion rate of acetylcysteine must be more than double during hemodialysis to compensate for its ongoing removal and provide similar plasma concentrations to the usual acetylcysteine regimen.

The treatment of dermatophytoses, including onychomycosis, has come a long way over the past few decades with the introduction of oral antifungals (e.g., terbinafine and itraconazole). However, with these advancements in oral therapies come several undesirable effects, such as kidney and liver toxicity, along with drug-drug interactions. Consequently, there is a need for new topical agents that are effective against dermatophytosis. ME1111 is a topical antifungal under development. In this study, thein vivoefficacy of ME1111 was compared to that of ciclopirox in the topical treatment of dermatophytosis caused byTrichophyton mentagrophytesusing a guinea pig model. Animals were treated with the topical antifungals starting at 3 days postinfection, with each agent being applied once daily for seven consecutive days. After the treatment period, the clinical and mycological efficacies were evaluated. The data showed that both antifungals demonstrated significant clinical and mycological efficacies; however, ME1111 showed clinical efficacy superior to that of ciclopirox (46.9% and 25.0%, respectively, with aPvalue of <0.001). The potent efficacy of ME1111 could be attributed to its properties, such as low keratin binding.

The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup conducted a systematic literature review using a standardized process to develop evidence-based recommendations on the use of extracorporeal treatment (ECTR) in patients with phenytoin poisoning. The authors reviewed all articles, extracted data, summarized findings, and proposed structured voting statements following a predetermined format. A 2-round modified Delphi method was used to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. 51 articles met the inclusion criteria. Only case reports, case series, and pharmacokinetic studies were identified, yielding a very low quality of evidence. Clinical data from 31 patients and toxicokinetic grading from 46 patients were abstracted. The workgroup concluded that phenytoin is moderately dialyzable (level of evidence = C) despite its high protein binding and made the following recommendations. ECTR would be reasonable in select cases of severe phenytoin poisoning (neutral recommendation, 3D). ECTR is suggested if prolonged coma is present or expected (graded 2D) and it would be reasonable if prolonged incapacitating ataxia is present or expected (graded 3D). If ECTR is used, it should be discontinued when clinical improvement is apparent (graded 1D). The preferred ECTR modality in phenytoin poisoning is intermittent hemodialysis (graded 1D), but hemoperfusion is an acceptable alternative if hemodialysis is not available (graded 1D). In summary, phenytoin appears to be amenable to extracorporeal removal. However, because of the low incidence of irreversible tissue injury or death related to phenytoin poisoning and the relatively limited effect of ECTR on phenytoin removal, the workgroup proposed the use of ECTR only in very select patients with severe phenytoin poisoning.

Extracorporeal treatments (ECTRs) such as hemodialysis (HD), enhance the elimination of a small number of toxins. Changes in overdose trends, prescribing practices, antidotes, and dialysis techniques may alter the indications and rates of ECTR use over time. This study analyzed trends in ECTR for poisonings in four countries. A retrospective study of national poison center databases from the United States, Denmark, United Kingdom, and five regional databases within Canada was performed. All cases of patients receiving an ECTR were included. ECTR cases were totalled annually and reported as annual rates per 100,000 exposures with stratification per types of ECTR and toxins. The data collection varied by countries. United States, 1985-2014; United Kingdom, 2011-2013; Denmark, 2005-2014, and regions of Canada as follows: Alberta, 1991-2015; Saskatchewan, 2001-2015; Nova Scotia-PEI, 2006-2015; Quebec, 2008-2014; Ontario-Manitoba, 2009-2015; British Columbia, 2012-2015. During the study period, the total number of ECTRs and rates per 100,000 exposures, respectively, were: United States, 40,258 and 65.7; United Kingdom, 343 and 232.6; Denmark, 616 and 305.5; Canada, 2709 and 177.5; case rates increased over time for the United States, Denmark, and Canada, but decreased in the United Kingdom. Across the United States and Denmark, HD was the preferred modality used. Toxins for which ECTR was most often used were: United States, ethylene glycol; Canada, methanol; United Kingdom, ethylene glycol; Denmark, salicylates. A high number of ECTRs were performed for atypical toxins such as acetaminophen and benzodiazepines. These data demonstrate a growing use of HD for poisoning with significant regional variations in the overall rates and indications.

BACKGROUND: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, we present our results for digoxin. METHODS: After a systematic literature search, clinical and toxicokinetic data were extracted and summarized following a predetermined format. The entire workgroup voted through a two-round modified Delphi method to reach a consensus on voting statements. A RAND/UCLA Appropriateness Method was used to quantify disagreement, and anonymous votes were compiled and discussed in person. A second vote was conducted to determine the final workgroup recommendations. RESULTS: Out of 435 articles screened, 77 met inclusion criteria. Only in-vitro, animal studies, case reports and case series were identified yielding a very low quality of evidence for all recommendations. Based on data from 84 patients, including six fatalities, it was concluded that digoxin is slightly dialyzable (level of evidence = B), and that ECTR is unlikely to improve the outcome of digoxin-toxic patients whether or not digoxin immune Fab (Fab) is administered. Despite the lack of robust clinical evidence, the workgroup recommended against the use of ECTR in cases of severe digoxin poisoning when Fab was available (1D) and also suggested against the use of ECTR when Fab was unavailable (2D). CONCLUSION: ECTR, in any form, is not indicated for either suspected or proven digoxin toxicity, regardless of the clinical context, and is not indicated for removal of digoxin-Fab complex.

The duration of hemodialysis (HD) in methanol poisoning (MP) is dependent on the methanol concentration, the operational parameters used during HD, and the presence and severity of metabolic acidosis. However, methanol assays are not easily available, potentially leading to undue extension or premature termination of treatment. Here we provide a prediction model for the duration of high-efficiency HD in MP. In a retrospective cohort study, we identified 71 episodes of MP in 55 individuals who were treated with alcohol dehydrogenase inhibition and HD. Four patients had residual visual abnormality at discharge and only one patient died. In 46 unique episodes of MP with high-efficiency HD the mean methanol elimination half-life (T1/2) during HD was 108 min in women, significantly different from the 129 min in men. In a training set of 28 patients with MP, using the 90th percentile of gender-specific elimination T1/2 (147 min in men and 141 min in women) and a target methanol concentration of 4 mmol/l allowed all cases to reach a safe methanol of under 6 mmol/l. The prediction model was confirmed in a validation set of 18 patients with MP. High-efficiency HD time in hours can be estimated using 3.390 × (Ln (MCi/4)) for women and 3.534 × (Ln (MCi/4)) for men, where MCi is the initial methanol concentration in mmol/l, provided that metabolic acidosis is corrected.

BACKGROUND: Metformin toxicity, a challenging clinical entity, is associated with a mortality of 30%. The role of extracorporeal treatments such as hemodialysis is poorly defined at present. Here, the Extracorporeal Treatments In Poisoning workgroup, comprising international experts representing diverse professions, presents its systematic review and clinical recommendations for extracorporeal treatment in metformin poisoning. METHODS: A systematic literature search was performed, data extracted, findings summarized, and structured voting statements developed. A two-round modified Delphi method was used to achieve consensus on voting statements and RAND/UCLA Appropriateness Method to quantify disagreement. Anonymized votes and opinions were compiled and discussed. A second vote determined the final recommendations. RESULTS: One hundred seventy-five articles were identified, including 63 deaths: one observational study, 160 case reports or series, 11 studies of descriptive cohorts, and three pharmacokinetic studies in end-stage renal disease, yielding a very low quality of evidence for all recommendations. The workgroup concluded that metformin is moderately dialyzable (level of evidence C) and made the following recommendations: extracorporeal treatment is recommended in severe metformin poisoning (1D). Indications for extracorporeal treatment include lactate concentration greater than 20 mmol/L (1D), pH less than or equal to 7.0 (1D), shock (1D), failure of standard supportive measures (1D), and decreased level of consciousness (2D). Extracorporeal treatment should be continued until the lactate concentration is less than 3 mmol/L (1D) and pH greater than 7.35 (1D), at which time close monitoring is warranted to determine the need for additional courses of extracorporeal treatment. Intermittent hemodialysis is preferred initially (1D), but continuous renal replacement therapies may be considered if hemodialysis is unavailable (2D). Repeat extracorporeal treatment sessions may use hemodialysis (1D) or continuous renal replacement therapy (1D). CONCLUSION: Metformin poisoning with lactic acidosis appears to be amenable to extracorporeal treatments. Despite clinical evidence comprised mostly of case reports and suboptimal toxicokinetic data, the workgroup recommended extracorporeal removal in the case of severe metformin poisoning.

STUDY OBJECTIVE: Salicylate poisoning is a challenging clinical entity associated with substantial morbidity and mortality. The indications for extracorporeal treatments such as hemodialysis are poorly defined. We present a systematic review of the literature along with evidence- and consensus-based recommendations on the use of extracorporeal treatment in salicylate poisoning. METHODS: The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup is a multidisciplinary group with international representation whose aim is to provide evidence-based recommendations on the use of extracorporeal treatments in poisoning. We conducted a systematic literature review followed by data extraction and summarized findings, following a predetermined format. The entire work group voted by a 2-round modified Delphi method to reach consensus on voting statements, using a RAND/UCLA Appropriateness Method to quantify disagreement. Anonymous votes were compiled, returned, and discussed in person. A second vote determined the final recommendations. RESULTS: Eighty-four articles met inclusion criteria, including 1 controlled clinical trial, 3 animal studies, and 80 case reports or case series, yielding an overall very low quality of evidence for all recommendations. Clinical data on 143 patients (130 sets of which could be analyzed for patient-level entry data), including 14 fatalities, were reviewed. Toxicokinetic data on 87 patients were also included. After the second round of voting, the workgroup concluded that salicylates are dialyzable by hemodialysis and hemoperfusion (level of evidence=B) and recommended extracorporeal treatment in patients with severe salicylate poisoning (1D), including any patient with altered mental status (1D), with acute respiratory distress syndrome requiring supplemental oxygen (1D), and for those in whom standard therapy is deemed to be failing (1D) regardless of the salicylate concentration. High salicylate concentrations warrant extracorporeal treatment regardless of signs and symptoms (>7.2 mmol/L [100 mg/dL] [1D]; and >6.5 mmol/L [90 mg/dL] [2D]), with lower thresholds applied for patients with impaired kidney function (>6.5 mmol/L [90 mg/dL] [1D]; >5.8 mmol/L [80 mg/dL] [2D]). Extracorporeal treatment is also suggested for patients with severe acidemia (pH