Lotte Christine Groth Hoegberg

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.

Systematic review of the effect of intravenous lipid emulsion therapy for non-local anesthetics toxicity

ABSTRACT Background: The use of intravenous lipid emulsion (ILE) therapy for the treatment of lipophilic drug toxicity is increasing. Despite this, the evidence for its effect in non-local anesthetic toxicity remains sparse. Furthermore, many case reports describe ILE use for substances in which no clear efficacy data exists. The American Academy of Clinical Toxicology established a lipid emulsion workgroup. The aim of this group is to review the available evidence regarding the effect of ILE in non-LA drug poisoning and develop consensus-based recommendations on the use of this therapy. Methods: A systematic review of the literature was performed to capture articles through 15 December 2014. Relevant articles were determined based upon a predefined methodology. Articles involving pre-treatment experiments, pharmacokinetic studies not involving toxicity, and studies not addressing antidotal use of ILE met pre-defined exclusion criteria. Agreement of at least two members of the subgroup was required before an article could be excluded. Results: The final analysis included 203 articles: 141 for humans and 62 for animals. These include 40 animal experiments and 22 case reports involving animal toxicity. There were three human randomized control trials (RCT): one RCT examined ILE in TCA overdose, one RCT examined ILE in various overdoses, and one study examined ILE in reversal of sedation after therapeutic administration of inhaled anesthesia. One observational study examined ILE in glyphosate overdose. In addition, 137 human case reports or case series were identified. Intravenous lipid emulsion therapy was used in the management of overdose with 65 unique substances. Conclusions: Despite the use of ILE for multiple substances in the treatment of patients with poisoning and overdose, the effect of ILE in various non-local anesthetic poisonings is heterogenous, and the quality of evidence remains low to very low.

Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning*

Abstract Background: Although intravenous lipid emulsion (ILE) was first used to treat life-threatening local anesthetic (LA) toxicity, its use has expanded to include both non-local anesthetic (non-LA) poisoning and less severe manifestations of toxicity. A collaborative workgroup appraised the literature and provides evidence-based recommendations for the use of ILE in poisoning. Methods: Following a systematic review of the literature, data were summarized in four publications: LA and non-LA poisoning efficacy, adverse effects, and analytical interferences. Twenty-two toxins or toxin categories and three clinical situations were selected for voting. Voting statements were proposed using a predetermined format. A two-round modified Delphi method was used to reach consensus on the voting statements. Disagreement was quantified using RAND/UCLA Appropriateness Method. Results: For the management of cardiac arrest, we recommend using ILE with bupivacaine toxicity, while our recommendations are neutral regarding its use for all other toxins. For the management of life-threatening toxicity, (1) as first line therapy, we suggest not to use ILE with toxicity from amitriptyline, non-lipid soluble beta receptor antagonists, bupropion, calcium channel blockers, cocaine, diphenhydramine, lamotrigine, malathion but are neutral for other toxins, (2) as part of treatment modalities, we suggest using ILE in bupivacaine toxicity if other therapies fail, but are neutral for other toxins, (3) if other therapies fail, we recommend ILE for bupivacaine toxicity and we suggest using ILE for toxicity due to other LAs, amitriptyline, and bupropion, but our recommendations are neutral for all other toxins. In the treatment of non-life-threatening toxicity, recommendations are variable according to the balance of expected risks and benefits for each toxin. For LA-toxicity we suggest the use of Intralipid® 20% as it is the formulation the most often reported. There is no evidence to support a recommendation for the best formulation of ILE for non-LAs. The voting panel is neutral regarding ILE dosing and infusion duration due to insufficient data for non-LAs. All recommendations were based on very low quality of evidence. Conclusion: Clinical recommendations regarding the use of ILE in poisoning were only possible in a small number of scenarios and were based mainly on very low quality of evidence, balance of expected risks and benefits, adverse effects, laboratory interferences as well as related costs and resources. The workgroup emphasizes that dose-finding and controlled studies reflecting human poisoning scenarios are required to advance knowledge of limitations, indications, adverse effects, effectiveness, and best regimen for ILE treatment.

Successful reversal of life threatening cardiac effect following dosulepin overdose using intravenous lipid emulsion

Context. We report a successful acute reversal of potential life threatening QRS complex widening and prolonged QT interval following dosulepin overdose using intravenous lipid emulsion 20% in an unstable patient. Case details. A 36-year-old female following the ingestion of 5.25 g of dosulepin. On submission the QRS complex was 120 ms and the QT interval was 348 ms (BP 129/71 mmHg, HR 113 beats/min). Her level of consciousness deteriorated and the patient had episodes of seizures. The patient received bicarbonate, 200 mmol, and assisted ventilation. Ninety minutes following submission, the QRS complex was 158 ms and the QT interval was 422 ms (BP 118/55 mmHg, HR 91 beats/min), and to treat the intoxication intravenous lipid emulsion 20% was dosed as 1.5 ml/kg (100 ml) in 5 min followed by 400 ml in 20 min. Blood pressure was immediately stabilised and the monitored QRS complex narrowed and QT interval became shorter. Discussion. Cyclic antidepressants affect the cardiac conduction system and the myocardium. The exact mechanism of action from intravenous lipid emulsions may not be determined from the data presented, and the obtained effect does not rule out the supposed effects of alkalinisation and supported ventilation. However, the effects of the treatment of the severe dosulepin intoxication support the theory of intravenous lipid emulsions creating an intravenous lipid sink for drugs with high lipid solubility.

Methodology for AACT evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning

Abstract Intravenous lipid emulsion (ILE) therapy is a novel treatment that was discovered in the last decade. Despite unclear understanding of its mechanisms of action, numerous and diverse publications attested to its clinical use. However, current evidence supporting its use is unclear and recommendations are inconsistent. To assist clinicians in decision-making, the American Academy of Clinical Toxicology created a workgroup composed of international experts from various clinical specialties, which includes representatives of major clinical toxicology associations. Rigorous methodology using the Appraisal of Guidelines for Research and Evaluation or AGREE II instrument was developed to provide a framework for the systematic reviews for this project and to formulate evidence-based recommendations on the use of ILE in poisoning. Systematic reviews on the efficacy of ILE in local anesthetic toxicity and non-local anesthetic poisonings as well as adverse effects of ILE are planned. A comprehensive review of lipid analytical interferences and a survey of ILE costs will be developed. The evidence will be appraised using the GRADE system. A thorough and transparent process for consensus statements will be performed to provide recommendations, using a modified Delphi method with two rounds of voting. This process will allow for the production of useful practice recommendations for this therapy.

A Nationwide Register-Based Survey of Baclofen Toxicity

To study the use and misuse (poisonings) of baclofen in the time period of 2007–2012 and to evaluate the severity and clinical symptoms of poisonings including ingested baclofen. The National Patient Register (NPR) was searched for admissions due to baclofen poisonings from 2007 to 2012. The search was conducted with ICD‐10 codes for poisoning, self‐harm and suicide, and coupled with the baclofen ATC code. All enquiries about baclofen to the Danish Poison Information Centre (DPIC) in the same period were evaluated. Demographic and clinical data were extracted, and the poisonings were classified according to the Poison Severity Score. The number of baclofen poisonings did not increase from 2007 to 2012. Thirty‐eight admissions with baclofen poisoning were registered at the NPR; however, only one‐third of the reviewed DPIC cases were registered at the NPR with the correct coding. In the group of severely poisoned patients (PSS 3), three patients had only ingested baclofen (mean 2000 mg; SD 500 mg) and eight patients had ingested baclofen together with alcohol or psychotropic drugs (mean 900 mg; SD 641 mg). All patients presented with deep coma and respiratory depression. Additionally, seizures and cardiovascular events (mild hypo‐ or hypertension and bradycardia) occurred. There is a substantial degree of underreporting of baclofen poisonings in Denmark. Symptoms of baclofen poisoning progress very fast, and toxicity was observed even with doses as low as 150 mg. We therefore recommend that observation and treatment of these patients should be carried out in an intermediate‐ or intensive care unit. The most important treatment is the maintenance of a protected airway and respiration.

Practice Trends in the Use of Extracorporeal Treatments for Poisoning in Four Countries.

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.

Electrocardiographic study in Ghanaian children with uncomplicated malaria, treated with artesunate-amodiaquine or artemether-lumefantrine

BackgroundSeveral anti-malarial drugs are associated with adverse cardiovascular effects. These effects may be exacerbated when different anti-malarials are used in combination. There has been no report yet on the potential cardiac effects of the combination artesunate-amodiaquine.MethodsElectrocardiographic (ECG) intervals in Ghanaian children with uncomplicated malaria treated with artesunate-amodiaquine (n=47), were compared with that of children treated with artemether-lumefantrine (n=30). The ECG measurements were repeated one, two, three, seven and 28 days after treatment. The ECG intervals of artesunate-amodiaquine treated subjects were correlated with plasma concentrations of desethylamodiaquine (DEAQ), the main metabolite of amodiaquine.ResultsThe mean ECG intervals were similar in both groups before treatment. After treatment (day 3), ECG intervals changed significantly from baseline in all subjects, but there were no differences between the two treatment groups. A significantly higher proportion of children treated with artesunate-amodiaquine developed sinus bradycardia compared with artemether-lumefantrine treated subjects (7/47 vs 0/30; χ2 p=0.03). Subjects who developed bradycardia were significantly older, and had higher DEAQ concentrations than those who did not develop bradycardia. The proportion of subjects with QTc interval prolongations did not differ significantly between the groups, and no relationship between prolonged QTc intervals and DEAQ levels were observed. No clinically significant rhythm disturbances were observed in any of the subjects.ConclusionArtesunate-amodiaquine treatment resulted in a higher incidence of sinus bradycardia than artemether-lumefantrine treatment in children with uncomplicated malaria, but no clinically significant rhythm disturbances were induced by combining artesunate with amodiaquine. These findings, although reassuring, may imply that non-amodiaquine based artemisinin combination therapy may be preferable for malaria treatment in patients who are otherwise at risk of cardiac effects.

Combined paracetamol and amitriptyline adsorption to activated charcoal.

Objectives. High-gram drug doses seen in multiple-drug poisonings might be close to the adsorption capacity of activated charcoal (AC). The aim was to determine the maximum adsorption capacities (Qm) of amitriptyline and paracetamol, separately and in combination, to AC. Methods. ACs (Carbomix® and Norit Ready-To-Use) were tested in vitro. At pH 1.2 and pH 7.2, 0.250 g AC and paracetamol and/or amitriptyline were mixed and incubated. The AC : drug ratios were 10 : 1, 5 : 1, 3 : 1, 2 : 1, and 1 : 1. The mixed-drug adsorption vials contained the same AC : paracetamol ratios, but amitriptyline was added as fixed dose (0.080 g) to all samples. Drug concentrations in the liquid phase were analyzed using high-performance liquid chromatography (HPLC)/UV-detection. Results. Qm, amitriptyline, were 0.49 g/g Carbomix® and 0.70 g/g Norit Ready-To-Use, and Qm, paracetamol, were 0.63 g/g Carbomix® and 0.72 g/g Norit Ready-To-Use. The tested pH differences had minor effect on the adsorption. The mixed-drug adsorption showed about 40% Qm reduction of each drug with increasing amounts of drug/g AC, but the total gram of drug adsorbed to AC was increased compared to one-drug conditions. Conclusion. The adsorption of the two compounds to AC seems to compete resulting in lower maximum adsorption capacity for both drugs when mixed. However, a great adsorptive capacity was noted and might be explained by adsorption of the drugs to different AC surface sites. Furthermore, the Norit Ready-To-Use preparation, with less volume and total weight for the same AC dose as Carbomix®, showed a higher Qm. This might be clinically significant in terms of preventing nausea, vomiting, and subsequent aspiration.

Adherence to international recommendations for gastric lavage in medical drug poisonings in Denmark 2007-2010.

Abstract Objective. Recent reviews strongly discourage the routine use of gastric lavage in oral poisonings, but the authors suspected that gastric lavage might still be in widespread use in Denmark. We wished to estimate the extent to which gastric lavage in cases of medical drug poisoning, reported in inquiries to the Danish Poison Information Centre (DPIC) from 2007 to 2010, was performed according to international recommendations and whether adherence to recommendations improved over the period. Methods and materials. Inquiries from hospital and emergency departments (EDs) concerning medical drug poisonings were identified in the DPIC database. Patients receiving gastric lavage prior to inquiry were identified, and demographic and poisoning characteristics were retrieved. Indication for gastric lavage was determined from a predefined set of criteria. Results. 10 740 inquiries from hospitals and EDs were identified, of which 1091 cases received gastric lavage. In logistic regression, the frequency of lavage fell significantly from 13.5% in 2007 to 7.9% in 2010 (odds ratio (OR) 0.547, confidence interval (CI) 0.455–0.659). All criteria for gastric lavage were fulfilled in 60 lavaged cases (5.5%), and the fraction did not improve significantly over the period (OR 1.717, CI 0.791–3.724). No individual criterion for lavage showed consistent improvement over the period. Conclusion. Gastric lavage is still widely used in Denmark, mostly on questionable grounds where the procedure is unlikely to be beneficial. Recommendations for gastrointestinal decontamination may need to be promoted more actively, and clinicians should be encouraged to seek toxicological advice before performing gastric lavage.