Marc Ghannoum

We disagree with the statement of Paland1 summarizing the clinical course of two patients that these “findings encourage the use of CytoSorb therapy in amitriptyline intoxications as a detoxification approach.” In 2014, the Extracorporeal Treatments In Poisoning (EXTRIP) workgroup recommended against extracorporeal treatments in severe poisoning to tricyclic antidepressants.2 The lack of a clinical benefit from extracorporeal removal was based on the structured analysis of 108 patients. Moreover, tricyclic antidepressants like amitriptyline are lipophilic and exhibit high protein binding (>90%) and a large volume of distribution (14– 17 L/kg).3 Paland reports two cases of amitriptyline poisoning where CytoSorb adsorbers were used to accelerate amitriptyline poisoning.1 The device is aimed to adsorb hydrophobic substances of a molecular weight up to 55 kD and is mainly used in the context of cytokine storm. Treatments were performed in conjunction with continuous venovenous haemodialysis. The author showed a decrease in blood amitriptyline concentration during the procedure. Moreover, in one patient, blood amitriptyline concentration into the Cytosorb was markedly higher than that leaving the Cytosorb.1 These data should not be mistaken for adequate removal. In the guideline methodology, EXTRIP recommends specific methods to quantify “dialyzability”, a term applicable for all extracorporeal procedures from dialysis, haemoperfusion to apheresis technologies. The gold standard is the measurement of the % of the poison (either ingested or in the body) that is removed by the procedure during a specified treatment period.4 This primary criterion is the preferred one for poisons having a large (> 5 L/kg) volume of distribution such as amitriptyline. Alternative criteria are the comparison of the total body clearance to the clearance of the extracorporeal procedure or the halflife with and without the extracorporeal procedure. None of those data were presented in the two reported cases. However, a recent paper reported that, despite a decline in plasma concentration and a measurable dialyzer plasma clearance of amitriptyline using a highcutoff membrane (58 ml/min and 33 ml/min), removal of amitriptyline was negligible (<0.1% of the ingested dose).5 In essence, the data and conclusions presented by Paland are potentially misleading and do not show that the CytoSorb “contributed directly and significantly” to the reduction in amitriptyline plasma levels as stated by the author. However, we do agree with the statement that “more studies are ideally needed to better understand amitriptyline pharmacokinetics in the overdose setting.”

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 108min in women, significantly different from the 129min in men. In a training set of 28 patients with MP, using the 90th percentile of gender-specific elimination T1/2 (147min in men and 141min in women) and a target methanol concentration ...

We disagree with the statement of Paland1 summarizing the clinical course of two patients that these “findings encourage the use of CytoSorb therapy in amitriptyline intoxications as a detoxification approach.” In 2014, the Extracorporeal Treatments In Poisoning (EXTRIP) workgroup recommended against extracorporeal treatments in severe poisoning to tricyclic antidepressants.2 The lack of a clinical benefit from extracorporeal removal was based on the structured analysis of 108 patients. Moreover, tricyclic antidepressants like amitriptyline are lipophilic and exhibit high protein binding (>90%) and a large volume of distribution (14– 17 L/kg).3 Paland reports two cases of amitriptyline poisoning where CytoSorb adsorbers were used to accelerate amitriptyline poisoning.1 The device is aimed to adsorb hydrophobic substances of a molecular weight up to 55 kD and is mainly used in the context of cytokine storm. Treatments were performed in conjunction with continuous venovenous haemodialysis. The author showed a decrease in blood amitriptyline concentration during the procedure. Moreover, in one patient, blood amitriptyline concentration into the Cytosorb was markedly higher than that leaving the Cytosorb.1 These data should not be mistaken for adequate removal. In the guideline methodology, EXTRIP recommends specific methods to quantify “dialyzability”, a term applicable for all extracorporeal procedures from dialysis, haemoperfusion to apheresis technologies. The gold standard is the measurement of the % of the poison (either ingested or in the body) that is removed by the procedure during a specified treatment period.4 This primary criterion is the preferred one for poisons having a large (> 5 L/kg) volume of distribution such as amitriptyline. Alternative criteria are the comparison of the total body clearance to the clearance of the extracorporeal procedure or the halflife with and without the extracorporeal procedure. None of those data were presented in the two reported cases. However, a recent paper reported that, despite a decline in plasma concentration and a measurable dialyzer plasma clearance of amitriptyline using a highcutoff membrane (58 ml/min and 33 ml/min), removal of amitriptyline was negligible (<0.1% of the ingested dose).5 In essence, the data and conclusions presented by Paland are potentially misleading and do not show that the CytoSorb “contributed directly and significantly” to the reduction in amitriptyline plasma levels as stated by the author. However, we do agree with the statement that “more studies are ideally needed to better understand amitriptyline pharmacokinetics in the overdose setting.”

We describe the case of a 42-year-old female who presented to our care 1 hour after ingesting 3.6 g of phenytoin. She was stuporous 48 hours after admission despite supportive therapy. She was treated with hemodialysis (HD) for nearly 6 hours in order to remove phenytoin. Her level of consciousness improved markedly during the procedure. During HD, phenytoin levels decreased by 47% and measured half-life was 6.8 hours as compared to 116 hours when not on HD. Finally, we were able to remove 547 mg of phenytoin (directly measured from the dialysate), representing approximately a third of estimated body stores. The use of extracorporeal therapy in phenytoin overdose is reviewed here. We believe that in severe cases of phenytoin intoxication, hemodialysis can be used to accelerate total body burden of the drug, even if protein binding is significant.

Poisoning occurs after exposure to any of a number of substances, including medicines, which can result in severe toxicity including death. The nephrologist may be involved in poisonings that cause kidney disease and for targeted treatments. The overall approach to the poisoned patient involves the initial acute resuscitation and performing a risk assessment, whereby the exposure is considered in terms of the anticipated severity and in the context of the patient's status and treatments that may be required. Time-critical interventions such as gastrointestinal decontamination (e.g., activated charcoal) and antidotes are administered when indicated. The nephrologist is usually involved when elimination enhancement techniques are required, such as urine alkalinization or extracorporeal treatments. There is increasing data to guide decision making for the use of extracorporeal treatments in the poisoned patient. Principles to consider are clinical indications such as whether severe...

Baclofen toxicity results from intentional self-poisoning ("acute baclofen poisoning") or accumulation of therapeutic dose in the setting of impaired kidney function. Standard care includes baclofen discontinuation, respiratory support and seizure treatment. Use of extracorporeal treatments (ECTRs) is controversial. To clarify this, a comprehensive review of the literature on the effect of ECTRs in baclofen toxicity was performed and recommendations following EXTRIP methods were formulated based on 43 studies. (1 comparative cohort, 1 aggregate results cohort, 1 pharmacokinetic modeling, and 40 patient reports or series). Toxicokinetic data were available for 20 patients. Baclofen's dialyzability is limited by a high endogenous clearance and a short half-life in patients with normal kidney function. The workgroup assessed baclofen as "Moderately dialyzable" by intermittent hemodialysis for patients with normal kidney function (quality of evidence C) and "Dialyzable" for patients with impaired kidney function (quality of evidence C). Clinical data were available for 25 patients with acute baclofen poisoning and 46 patients with toxicity from therapeutic baclofen in kidney impairment. No deaths or sequelae were reported. Mortality in historical controls was rare. No benefit of ECTR was identified in patients with acute baclofen poisoning. Indirect evidence suggests a benefit of ECTR in reducing the duration of toxic encephalopathy from therapeutic baclofen in kidney impairment. These potential benefits were balanced against added costs and harms related to the insertion of a catheter, the procedure itself, and the potential of baclofen withdrawal. Thus, the EXTRIP workgroup suggests against performing ECTR in addition to standard care for acute baclofen poisoning and suggests performing ECTR in toxicity from therapeutic baclofen in kidney impairment, especially in the presence of coma requiring mechanical ventilation.

Prashek and colleagues present a patient who underwent continuous kidney replacement therapy (CKRT) for removal of ethylene glycol [1]. We commend the authors for publishing such cases due to the scarcity of reports with CKRT, but express caution about the interpretation of many of their observations, calculations, and conclusions. The authors claim that “CVVHDF can effectively remove ethylene glycol with an extraction that is comparable to IHD”. This assumption is based on their calculation of an ethylene glycol half-life of 2.81 h during CVVHDF being comparable to other published cases in which intermittent hemodialysis was used. This ssertion is erroneous as the first ethylene glycol measurement used in their calculation was performed prior to the initiation of both CVVHDF and fomepizole therapy. Using the last 2 data points, we calculated the ethylene glycol half-life as 5.8 h which is in keeping with other cases in which CKRT was performed [2– 4]. This is double the ethylene glycol half-life achieved during high-efficiency intermittent hemodialysis (<3 h) [5]. Further evidence of the inferior performance of CKRT compared to intermittent hemodialysis is the maximum achievable clearance: clearance of solutes is limited by the lesser of either blood or effluent flow. In the present case, CVVHDF was performed with a blood flow = 200 mL/min and an effluent flow = 84 mL/min. Ethylene glycol clearance could therefore not exceed 84 mL/min which again is well under what can be achieved by intermittent hemodialysis (>200 mL/min). Finally, since the patient did not require net ultrafiltration for volume overload, it is unclear why the patient would tolerate CKRT better than intermittent hemodialysis. We agree that if CKRT is the only option available onsite, then it is preferable to use it instead of transferring the patient to a center that offers intermittent hemodialysis. However, when both options are available, we advocate for using the one that can maximize clearance, especially when a patient has evidence of extensive end-organ damage and accumulation of toxic metabolites. We encourage authors and journals to promote increased reliability of cases reporting poison removal during extracorporeal treatment, including more than 2 time points for half-life calculations and regular sampling of effluent and outflow blood concentration [6].

Methanol poisoning can induce death and disability. Treatment includes the administration of antidotes (ethanol or fomepizole and folic/folinic acid) and consideration of extracorporeal treatment for correction of acidemia and/or enhanced elimination. The Extracorporeal Treatments in Poisoning workgroup aimed to develop evidence-based consensus recommendations for extracorporeal treatment in methanol poisoning. Utilizing predetermined methods, we conducted a systematic review of the literature. Two hundred seventy-two relevant publications were identified but publication and selection biases were noted. Data on clinical outcomes and dialyzability were collated and a two-round modified Delphi process was used to reach a consensus. Recommended indications for extracorporeal treatment: Severe methanol poisoning including any of the following being attributed to methanol: coma, seizures, new vision deficits, metabolic acidosis with blood pH ≤7.15, persistent metabolic acidosis despite a...

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 concentrat...

The EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup presents its systematic review and clinical recommendations on the use of extracorporeal treatment (ECTR) in valproic acid (VPA) poisoning. The lead authors reviewed all of the articles from a systematic literature search, extracted the data, summarized the key 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 the RAND/UCLA Appropriateness Method was used to quantify disagreement. Anonymous votes were compiled, returned, and discussed in person. A second vote was conducted to determine the final workgroup recommendations. The latest literature search conducted in November 2014 retrieved a total of 79 articles for final qualitative analysis, including one observational study, one uncontrolled cohort study with aggregate analysis, 70 case reports and case series, and 7 pharmacokinetic studies, yiel...

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. 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. 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 studi...

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). 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. 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 w...

Platelet indices, including mean platelet volume (MPV), are readily available blood tests, although their prognostic value in patients with septic shock has not been fully explored. Current evidence has found contradictory results. This study aims to explore the behavior of platelet indices in septic shock and their clinical prognostic value. Charts of septic shock patients from January to December 2012 in a tertiary medical center in Northern China were reviewed retrospectively. Platelet indices were recorded during the first five consecutive days after admission, as well as the penultimate and the last day of hospital stay. The data were compared between surviving and non-surviving patients. A total of 124 septic shock patients were enrolled. Thirty-six of the patients survived and 88 of them expired. MPV in the non-survivor group was higher than that of the survivor group, especially on the last day. PDW and PLCR showed increased trends, while PCT and PLT decreased in the non-sur...

Interferon-gamma release assays (IGRAs) are newly approved for diagnosing latent tuberculosis infection (LTBI). An internal audit was conducted to review the use of a newly implemented IGRA at the Hôpital du Sacré-Coeur de Montréal (Montréal, Québec) to evaluate its concordance with Canadian recommendations and its implication on diagnosis. From April 2007 to January 2009, all Quantiferon TB Gold In-Tube (QFT, Cellestis inc, USA) tests performed in at the Hôpital du Sacré-Coeur de Montréal were retrieved. Strategies used to investigate LTBI and clinical interpretation of test results were compared with the local algorithm, which is derived from the current national guidelines. A total of 200 patients tested with QFT were included in the analysis. LTBI investigation and QFT testing were considered to be appropriate in 87.5% and 66.5% of patients, respectively. Overall, 67 QFT tests were performed inappropriately; 25 were performed when a LTBI investigation was not indicated and 42 we...

The Extracorporeal Treatments in Poisoning Workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments in poisoning. Here, the EXTRIP workgroup presents its recommendations for lithium poisoning. 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. In total, 166 articles met inclusion criteria, which were mostly case reports, yielding a very low quality of evidence for all recommendations. A total of 418 patients were reviewed, 228 of which allowed extraction of patient-level data. The workgroup concluded that lithium is dialyzable (Level of evid...

Despite the risk of aluminum (Al) toxicity in dialysis patients, little is known about its toxicokinetics (TK) in this population. A national contamination of dialysate solutions with Al provided the opportunity to study Al TK in peritoneal dialysis (PD) patients and to better understand the influence of covariates on its disposition. Al levels in serum and dialysate as well as other laboratory values were collected prospectively from 83 PD patients after correction of Al contamination. Population TK analyses were conducted with NONMEM VI using standard model discrimination criteria. Covariate analyses were also performed using stepwise forward regression followed by backward deletion. After correction of Al exposure, serum levels declined in a biphasic manner, which was captured by the TK model. The TK of Al were best described by a 2-compartment model with linear elimination. Total creatinine clearance was a significant covariate for total clearance (CL). Mean parameter estimates for volume of central compartment (V1), CL, volume of peripheral compartment (V2), volume of distribution at steady-state (Vss), and intercompartmental clearance (Q) were 168 L, 8.99 L/day, 12 000 L, 12 168 L, and 4.93 L/day, respectively. Inter-individual variability for CL and V2 were 22.6 and 51.1%, respectively. Al distributional half-life was 8.5 days, while the terminal elimination half-life was 7.2 years. This model confirms that the large Vss reflects the widespread distribution of Al in bone, lungs, liver, and other tissues. This study describes the first population Al TK model in a large group of PD patients, which includes a covariate effect. The model confirms the extensive half-life and tissue distribution of Al in a dialysis-dependent population.

BackgroundAlthough chloroquine, hydroxychloroquine, and quinine are used for a range of medical conditions, recent research suggested a potential role in treating COVID-19. The resultant increase in prescribing was accompanied by an increase in adverse events, including severe toxicity and death. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup sought to determine the effect of and indications for extracorporeal treatments in cases of poisoning with these drugs.MethodsWe conducted systematic reviews of the literature, screened studies, extracted data, and summarized findings following published EXTRIP methods.ResultsA total of 44 studies (threein vitrostudies, two animal studies, 28 patient reports or patient series, and 11 pharmacokinetic studies) met inclusion criteria regarding the effect of extracorporeal treatments. Toxicokinetic or pharmacokinetic analysis was available for 61 patients (13 chloroquine, three hydroxychloroquine, and 45 quinine). Clinical data were ...

Ethylene glycol (EG) is metabolized into glycolate and oxalate and may cause metabolic acidemia, neurotoxicity, acute kidney injury (AKI), and death. Historically, treatment of EG toxicity included supportive care, correction of acid–base disturbances and antidotes (ethanol or fomepizole), and extracorporeal treatments (ECTRs), such as hemodialysis. With the wider availability of fomepizole, the indications for ECTRs in EG poisoning are debated. We conducted systematic reviews of the literature following published EXTRIP methods to determine the utility of ECTRs in the management of EG toxicity. The quality of the evidence and the strength of recommendations, either strong (“we recommend”) or weak/conditional (“we suggest”), were graded according to the GRADE approach. A total of 226 articles met inclusion criteria. EG was assessed as dialyzable by intermittent hemodialysis (level of evidence = B) as was glycolate (Level of evidence = C). Clinical data were available for analysis on...

CONTEXT Ethylene glycol poisoning manifests as metabolic acidemia, acute kidney injury and death. The diagnosis and treatment depend on history and biochemical tests. Glycolate is a key toxic metabolite that impacts prognosis, but assay results are not widely available in a clinically useful timeframe. We quantitated the impact of serum glycolate concentration for prognostication and evaluated whether more readily available biochemical tests are acceptable surrogates for the glycolate concentration. OBJECTIVES The objectives of this study are to 1) assess the prognostic value of the initial glycolate concentration on the occurrence of AKI or mortality in patients with ethylene glycol exposure (prognostic study); 2) identify surrogate markers that correlate best with glycolate concentrations (surrogate study). METHODS A systematic review of the literature was performed using Medline/PubMed, EMBASE, Cochrane library, conference proceedings and reference lists. Human studies reporting measured glycolate concentrations were eligible. Glycolate concentrations were related to categorical clinical outcomes (acute kidney injury, mortality), and correlated with continuous surrogate biochemical measurements (anion gap, base excess, bicarbonate concentration and pH). Receiver operating characteristic curves were constructed to calculate the positive predictive values and the negative predictive values of the threshold glycolate concentrations that predict acute kidney injury and mortality. Further, glycolate concentrations corresponding to 100% negative predictive value for mortality and 95% negative predictive value for acute kidney injury were determined. RESULTS Of 1,531 articles identified, 655 were potentially eligible and 32 were included, reflecting 137 cases from 133 patients for the prognostic study and 154 cases from 150 patients for the surrogate study. The median glycolate concentration was 11.2 mmol/L (85.1 mg/dL, range 0-38.0 mmol/L, 0-288.8 mg/dL), 93% of patients were treated with antidotes, 80% received extracorporeal treatments, 49% developed acute kidney injury and 13% died. The glycolate concentration best predicting acute kidney injury was 12.9 mmol/L (98.0 mg/dL, sensitivity 78.5%, specificity 88.1%, positive predictive value 86.4%, negative predictive value 80.9%). The glycolate concentration threshold for a 95% negative predictive value for acute kidney injury was 6.6 mmol/L (50.2 mg/dL, sensitivity 96.9%, specificity 62.7%). The glycolate concentration best predicting mortality was 19.6 mmol/L (149.0 mg/dL, sensitivity 61.1%, specificity 81.4%, positive predictive value 33.3%, negative predictive value 93.2%). The glycolate concentration threshold for a 100% negative predictive value for mortality was 8.3 mmol/L (63.1 mg/dL, sensitivity 100.0%, specificity 35.6%). The glycolate concentration correlated best with the anion gap (R2 = 0.73), followed by bicarbonate (R2 = 0.57), pH (R2 = 0.50) and then base excess (R2 = 0.25), while there was no correlation between the glycolate and ethylene glycol concentration (R2 = 0.00). These data can assist clinicians in planning treatments such as extracorporeal treatments and prognostication. Potentially, they may also provide some reassurance regarding when extracorporeal treatments can be delayed while awaiting the results of further testing in patients in whom ethylene glycol poisoning is suspected but not yet confirmed. CONCLUSIONS This systematic review demonstrates that the glycolate concentration predicts mortality (unlikely if <8 mmol/L [61 mg/dL]). The anion gap is a reasonable surrogate measurement for glycolate concentration in the context of ethylene glycol poisoning. The findings are mainly based on published retrospective data which have various limitations. Further prospective validation studies are of interest.

CONTEXT Ethylene glycol is metabolized to toxic metabolites that cause acute kidney injury, metabolic acidemia, and death. The treatment of patients with ethylene glycol poisoning includes competitively inhibiting alcohol dehydrogenase with ethanol or fomepizole to prevent the formation of toxic metabolites, and extracorporeal treatments such as hemodialysis to remove ethylene glycol and its metabolites. In the absence of significant metabolic acidemia or kidney injury, it is hypothesized that extracorporeal treatments may be obviated without adverse outcomes to the patient if alcohol dehydrogenase inhibitors are used. OBJECTIVES The objectives of this study are to: (1) identify indicators predicting ADH inhibitor failure in patients with ethylene glycol poisoning treated with either ethanol or fomepizole for whom extracorporeal treatment was not performed (aside from rescue therapy, see below) (prognostic study), and (2) validate if the anion gap, shown in a previous study to be the best surrogate for the glycolate concentration, is associated with acute kidney injury and mortality (anion gap study). METHODS We conducted a systematic review to identify all reported patients with ethylene glycol poisoning treated without extracorporeal treatments but with either fomepizole (fomepizole monotherapy) or ethanol (ethanol monotherapy). Analyses were performed using both one case per patient and all cases (if multiple events were reported for a single patient). Data were compiled regarding poisoning, biochemistry, and outcomes. Treatment failure was defined as mortality, worsening of acid-base status, extracorporeal treatments used as rescue, or a worsening of kidney or neurological function after alcohol dehydrogenase inhibition was initiated. Also, we performed an analysis of previously described anion gap thresholds to determine if they were associated with outcomes such as acute kidney injury and mortality. RESULTS Of 115 publications identified, 96 contained case-level data. A total of 180 cases were identified with ethanol monotherapy, and 231 with fomepizole monotherapy. Therapy failure was noted mostly when marked acidemia and/or acute kidney injury were present prior to therapy, although there were cases of failed ethanol monotherapy with minimal acidemia (suggesting that ethanol dosing and/or monitoring may not have been optimal). Ethylene glycol dose and ethylene glycol concentration were predictive of monotherapy failure for ethanol, but not for fomepizole. In the anion gap study (207 cases), death and progression of acute kidney injury were almost nonexistent when the anion gap was less than 24 mmol/L and mostly observed when the anion gap was greater than 28 mmol/L. CONCLUSION This review suggests that in patients with minimal metabolic acidemia (anion gap <28 mmol/L), fomepizole monotherapy without extracorporeal treatments is safe and effective regardless of the ethylene glycol concentration. Treatment failures were observed with ethanol monotherapy which may relate to transient subtherapeutic ethanol concentrations or very high ethylene glycol concentrations. The results are limited by the retrospective nature of the case reports and series reviewed in this study and require prospective validation.

Methotrexate is used in the treatment of many malignancies, rheumatological diseases, and inflammatory bowel disease. Toxicity from use is associated with severe morbidity and mortality. Rescue treatments include intravenous hydration, folinic acid, and, in some centers, glucarpidase. We conducted systematic reviews of the literature following published EXtracorporeal TReatments In Poisoning (EXTRIP) methods to determine the utility of extracorporeal treatments in the management of methotrexate toxicity. The quality of the evidence and the strength of recommendations (either “strong” or “weak/conditional”) were graded according to the GRADE approach. A formal voting process using a modified Delphi method assessed the level of agreement between panelists on the final recommendations. A total of 92 articles met inclusion criteria. Toxicokinetic data were available on 90 patients (89 with impaired kidney function). Methotrexate was considered to be moderately dialyzable by intermittent...