Sophie Gosselin

Recommendations for the role of extracorporeal treatments in the management of acute methanol poisoning: a systematic review and consensus statement.

Objective: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. Design and Methods: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. Results: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 adequate supportive measures and antidotes, serum anion gap higher than 24 mmol/L; or, serum methanol concentration 1) greater than 700 mg/L (21.8 mmol/L) in the context of fomepizole therapy, 2) greater than 600 mg/L or 18.7 mmol/L in the context of ethanol treatment, 3) greater than 500 mg/L or 15.6 mmol/L in the absence of an alcohol dehydrogenase blocker; in the absence of a methanol concentration, the osmolal/osmolar gap may be informative; or, in the context of impaired kidney function. Intermittent hemodialysis is the modality of choice and continuous modalities are acceptable alternatives. Extracorporeal treatment can be terminated when the methanol concentration is <200 mg/L or 6.2 mmol/L and a clinical improvement is observed. Extracorporeal Treatments in Poisoning inhibitors and folic/folinic acid should be continued during extracorporeal treatment. General considerations: Antidotes and extracorporeal treatment should be initiated urgently in the context of severe poisoning. The duration of extracorporeal treatment extracorporeal treatment depends on the type of extracorporeal treatment used and the methanol exposure. Indications for extracorporeal treatment are based on risk factors for poor outcomes. The relative importance of individual indications for the triaging of patients for extracorporeal treatment, in the context of an epidemic when need exceeds resources, is unknown. In the absence of severe poisoning but if the methanol concentration is elevated and there is adequate alcohol dehydrogenase blockade, extracorporeal treatment is not immediately required. Systemic anticoagulation should be avoided during extracorporeal treatment because it may increase the development or severity of intracerebral hemorrhage. Conclusion:Extracorporeal treatment has a valuable role in the treatment of patients with methanol poisoning. A range of clinical indications for extracorporeal treatment is provided and duration of therapy can be guided through the careful monitoring of biomarkers of exposure and toxicity. In the absence of severe poisoning, the decision to use extracorporeal treatment is determined by balancing the cost and complications of extracorporeal treatment to that of fomepizole or ethanol. Given regional differences in cost and availability of fomepizole and extracorporeal treatment, these decisions must be made at a local level.

Treatment for calcium channel blocker poisoning: A systematic review

Abstract Context. Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. Objective. To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations. Methods. Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in the initial search, 216 were selected for analysis, including 117 case reports. The kappa on the quality analysis tools was greater than 0.80 for all study types. Results. The only observational study in humans examined high-dose insulin and extracorporeal life support. The risk of bias across studies was high for all interventions and moderate to high for extracorporeal life support. High-dose insulin. High-dose insulin (bolus of 1 unit/kg followed by an infusion of 0.5–2.0 units/kg/h) was associated with improved hemodynamic parameters and lower mortality, at the risks of hypoglycemia and hypokalemia (low quality of evidence). Extracorporeal life support. Extracorporeal life support was associated with improved survival in patients with severe shock or cardiac arrest at the cost of limb ischemia, thrombosis, and bleeding (low quality of evidence). Calcium, dopamine, and norepinephrine. These agents improved hemodynamic parameters and survival without documented severe side effects (very low quality of evidence). 4-Aminopyridine. Use of 4-aminopyridine was associated with improved hemodynamic parameters and survival in animal studies, at the risk of seizures. Lipid emulsion therapy. Lipid emulsion was associated with improved hemodynamic parameters and survival in animal models of intravenous verapamil poisoning, but not in models of oral verapamil poisoning. Other studies. Studies on decontamination, atropine, glucagon, pacemakers, levosimendan, and plasma exchange reported variable results, and the methodologies used limit their interpretation. No trial was documented in humans poisoned with calcium channel blockers for Bay K8644, CGP 28932, digoxin, cyclodextrin, liposomes, bicarbonate, carnitine, fructose 1,6-diphosphate, PK 11195, or triiodothyronine. Case reports were only found for charcoal hemoperfusion, dialysis, intra-aortic balloon pump, Impella device and methylene blue. Conclusions. The treatment for calcium channel blocker poisoning is supported by low-quality evidence drawn from a heterogeneous and heavily biased literature. High-dose insulin and extracorporeal life support were the interventions supported by the strongest evidence, although the evidence is of low quality.

The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: Guideline methodology

Abstract Extracorporeal treatments (ECTRs), such as hemodialysis and hemoperfusion, are used in poisoning despite a lack of controlled human trials demonstrating efficacy. To provide uniform recommendations, the EXTRIP group was formed as an international collaboration among recognized experts from nephrology, clinical toxicology, critical care, or pharmacology and supported by over 30 professional societies. For every poison, the clinical benefit of ECTR is weighed against associated complications, alternative therapies, and costs. Rigorous methodology, using the AGREE instrument, was developed and ratified. Methods rely on evidence appraisal and, in the absence of robust studies, on a thorough and transparent process of consensus statements. Twenty-four poisons were chosen according to their frequency, available evidence, and relevance. A systematic literature search was performed in order to retrieve all original publications regardless of language. Data were extracted on a standardized instrument. Quality of the evidence was assessed by GRADE as: High = A, Moderate = B, Low = C, Very Low = D. For every poison, dialyzability was assessed and clinical effect of ECTR summarized. All pertinent documents were submitted to the workgroup with a list of statements for vote (general statement, indications, timing, ECTR choice). A modified Delphi method with two voting rounds was used, between which deliberation was required. Each statement was voted on a Likert scale (1–9) to establish the strength of recommendation. This approach will permit the production of the first important practice guidelines on this topic.

Extracorporeal Treatment for Metformin Poisoning: Systematic Review and Recommendations From the Extracorporeal Treatments in Poisoning Workgroup.

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.

Extracorporeal treatment for digoxin poisoning: systematic review and recommendations from the EXTRIP Workgroup

Abstract 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.

Extracorporeal Treatment for Lithium Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup

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 evidence=A) and made the following recommendations: Extracorporeal treatment is recommended in severe lithium poisoning (1D). Extracorporeal treatment is recommended if kidney function is impaired and the [Li(+)] is >4.0 mEq/L, or in the presence of a decreased level of consciousness, seizures, or life-threatening dysrhythmias irrespective of the [Li(+)] (1D). Extracorporeal treatment is suggested if the [Li(+)] is >5.0 mEq/L, significant confusion is present, or the expected time to reduce the [Li(+)] to <1.0 mEq/L is >36 hours (2D). Extracorporeal treatment should be continued until clinical improvement is apparent or [Li(+)] is <1.0 mEq/L (1D). Extracorporeal treatments should be continued for a minimum of 6 hours if the [Li(+)] is not readily measurable (1D). Hemodialysis is the preferred extracorporeal treatment (1D), but continuous RRT is an acceptable alternative (1D). The workgroup supported the use of extracorporeal treatment in severe lithium poisoning. Clinical decisions on when to use extracorporeal treatment should take into account the [Li(+)], kidney function, pattern of lithium toxicity, patients clinical status, and availability of extracorporeal treatments.

Extracorporeal treatment for acetaminophen poisoning: Recommendations from the EXTRIP workgroup

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.

Analytical interferences resulting from intravenous lipid emulsion

Context. Lipid resuscitation therapy using intravenous lipid emulsion (IVLE) for drug overdoses has gained widespread use. However, there is little information regarding its adverse effects. Objectives. We performed lipemic interference studies on typical automated platforms to investigate the potential of lipid resuscitation therapy to interfere with the reliability and turnaround time of analytes that would be of interest in acute intoxications. We also tested methods to minimize interferences. Materials and methods. Serum pools were supplemented with increasing concentrations of Intralipid-20%® (0–30%). Analyses were performed on Beckman-Coulter DXC800 and DXI and Roche Modular-P. Analytes demonstrating significant interference were re-measured after centrifugation (14 000 × g for 10 minutes). Results. Triglyceride and glycerol-blanked triglyceride concentrations were similar in IVLE-free samples. However, with addition of IVLE, concentrations were markedly different (139 vs. 76 mmol/L). There was no appreciable interference on the troponin-I, sodium, potassium, chloride, calcium, bicarbonate or urea assays. Albumin and magnesium assays demonstrated significant interference. Amylase, lipase, phosphate, creatinine, total protein, ALT, CK and bilirubin became unmeasurable in IVLE-supplemented samples. Whereas glucose measurement by potentiometry was free of interference, colorimetric methodology was error prone. Centrifugation removed > 90% of glycerol-blanked triglyceride (max = 5.8 mmol/L), dramatically reducing lipid interferences. Discussion. IVLE results in appreciable analytical interferences at concentrations demonstrated in lipid resuscitation therapy. Of particular concern is the marked interference on glucose and magnesium, which may result in unsuccessful and potentially harmful interventions. Major implications for patient care include reporting of incorrect results and delays in the reporting of time-sensitive results. Whenever possible, blood samples should be collected prior to initiating lipid therapy. Interferences can be minimized by brief centrifugation at relatively low speeds on equipment readily available in most core labs.

Extracorporeal Treatment for Tricyclic Antidepressant Poisoning: Recommendations from the EXTRIP Workgroup

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.

Treating acetaminophen overdose: thresholds, costs and uncertainties

The United Kingdoms Medicines and Healthcare Products Regulatory Agency (MHRA) modified the indications for N-acetylcysteine therapy of acetaminophen (paracetamol) overdose in September 2012. The new treatment threshold line was lowered to 100 mg/L (662 μmol/L) for a 4 hours acetaminophen concentration from the previous 200 mg/L (1325 μmol/L). This decision has the potential to substantially increase overall costs associated with acetaminophen overdose with unclear benefits from a marginal increase in patients protected from hepatotoxicity, fulminant hepatic failure, death, or transplant. Changing the treatment threshold for acetaminophen overdose also implies that ingestion amounts previously thought not to require acetaminophen concentration measurements would need to be revised. As a result, more individuals will be sent to hospitals in order that everyone with a predicted 4 hours concentration above the 100 mg/L line will have concentrations measured and potentially be treated with N-acetylcysteine. Before others consider adopting this new treatment guideline, formal cost-effectiveness analyses need to be performed to define the appropriate thresholds for referral and treatment.