Diane P. Calello

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.

Utilization and unexpected hospitalization rates of a pediatric emergency department 23-hour observation unit.

Objectives: The 23-hour observation units (OUs) may be used to avoid unnecessary hospital admissions. However, unexpected hospitalizations from the 23-hour OUs involve transfer of care and may decrease the efficiency and safety of care of the patient and the unit itself. The primary objective of this study was to determine the predictors of unexpected hospitalization for admissions to a pediatric 23-hour OU. Methods: This is an observational prospective cohort study of patients admitted to a pediatric 23-hour OU. Bivariate and multivariate regression analyses identify factors associated with unexpected hospitalization. Results: There were 4453 patients admitted to the 23-hour OU during the study. The overall rate of unexpected hospitalization was 20.3%; the mean 23-hour OU stay was 15 hours. Age, sex, race/ethnicity, and insurance status were not associated with increased unexpected hospitalization rates. Multivariate regression modeling revealed that unexpected hospitalization was associated with subgroups of resources used (intravenous medications and fluids, cardiorespiratory monitoring, respiratory therapist use, and supplemental oxygen), of subspecialty consultation, and of diagnosis categories (including asthma, adenitis, cellulitis, bronchiolitis, and esophageal foreign body ingestions). Experience of the health care provider involved in the care of the patient was not associated with increased unexpected hospitalization. Conclusions: Most of the patients (80%) were successfully discharged from the 23-hour OU. Demographics of the patient and practitioner characteristics did not influence the risk of unexpected hospitalizations; however, certain patient diagnoses, use of resources, and subspecialty consultation did increase the risk of unexpected hospitalization and, therefore, may guide future admission criteria for pediatric 23-hour OU.

Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration

Abstract Background: Intravenous lipid emulsions (ILEs) were initially developed to provide parenteral nutrition. In recent years, ILE has emerged as a treatment for poisoning by local anesthetics and various other drugs. The dosing regimen for the clinical toxicology indications differs significantly from those used for parenteral nutrition. The evidence on the efficacy of ILE to reverse acute toxicity of diverse substances consists mainly of case reports and animal experiments. Adverse events to ILE are important to consider when clinicians need to make a risk/benefit analysis for this therapy. Methods: Multiple publication databases were searched to identify reports of adverse effects associated with acute ILE administration for either treatment of acute poisoning or parenteral nutrition. Articles were selected based on pre-defined criteria to reflect acute use of ILE. Experimental studies and reports of adverse effects as a complication of long-term therapy exceeding 14 days were excluded. Results: The search identified 789 full-text articles, of which 114 met the study criteria. 27 were animal studies, and 87 were human studies. The adverse effects associated with acute ILE administration included acute kidney injury, cardiac arrest, ventilation perfusion mismatch, acute lung injury, venous thromboembolism, hypersensitivity, fat embolism, fat overload syndrome, pancreatitis, extracorporeal circulation machine circuit obstruction, allergic reaction, and increased susceptibility to infection. Conclusion: The emerging use of ILE administration in clinical toxicology warrants careful attention to its potential adverse effects. The dosing regimen and context of administration leading to the adverse events documented in this review are not generalizable to all clinical toxicology scenarios. Adverse effects seem to be proportional to the rate of infusion as well as total dose received. Further safety studies in humans and reporting of adverse events associated with ILE administration at the doses advocated in current clinical toxicology literature are needed.

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.

Naloxone in cardiac arrest with suspected opioid overdoses

INTRODUCTION Naloxones use in cardiac arrest has been of recent interest, stimulated by conflicting results in both human case reports and animal studies demonstrating antiarrhythmic and positive ionotropic effects. We hypothesized that naloxone administration during cardiac arrest, in suspected opioid overdosed patients, is associated with a change in cardiac rhythm. METHODS From a database of 32,544 advanced life support (ALS) emergency medical dispatches between January 2003 and December 2007, a retrospective chart review was completed of patients receiving naloxone in cardiac arrest. Forty-two patients in non-traumatic cardiac arrest were identified. Each patient received naloxone because of suspicion by a paramedic of acute opioid use. RESULTS Fifteen of the 36 (42%) (95% confidence interval [CI]: 26-58) patients in cardiac arrest who received naloxone in the pre-hospital setting had an improvement in electrocardiogram (EKG) rhythm. Of the participants who responded to naloxone, 47% (95% CI: 21-72) (19% [95% CI: 7-32] of all study subjects) demonstrated EKG rhythm changes immediately following the administration of naloxone. DISCUSSION Although we cannot support the routine use of naloxone during cardiac arrest, we recommend its administration with any suspicion of opioid use. Due to low rates of return of spontaneous circulation and survival during cardiac arrest, any potential intervention leading to rhythm improvement is a reasonable treatment modality.

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.

Case files of the medical toxicology fellowship training program at the children’s hospital of Philadelphia: A pediatric exploratory sulfonylurea ingestion

A 26-month-old boy was taken to the Emergency Department (ED) with the concern that he had ingested his mother’s oral hypoglycemic medication. He and his 4-year-old sister had been caught playing with their mother’s pill bottles, and the girl admitted to giving him one pill to eat. Although the implicated pills could be positively identified as extended-release glipizide (10 mg), a pill count was deemed unreliable because the medicine had been transferred from its original childproof container. In addition, too many pills were present had the mother been compliant with her prescribed dosing. The boy was developmentally normal, in good health and had no medication allergies. Additional medications reportedly available within the home included several over-the-counter preparations, prescription pain medications, and a different bottle of anti-diabetic agents. Several months earlier he had received care in another ED for an exploratory cold-medication ingestion. The boy arrived at the ED approximately 80 minutes after the presumed exposure. He was alert, playful, and interactive, with a heart rate of 102 beats/minute and a blood pressure of 100/62 mmHg, and was not diaphoretic. His physical examination was unremarkable, and he was given 25 g of activated charcoal, in an aqueous solution flavored with cherry syrup, to drink. He was estimated to have cooperated in drinking a little more than half of his charcoal.

Prednisone for Emergency Department Low Back Pain: A Randomized Controlled Trial

BACKGROUND Although oral corticosteroids are commonly given to emergency department (ED) patients with musculoskeletal low back pain (LBP), there is little evidence of benefit. OBJECTIVE To determine if a short course of oral corticosteroids benefits LBP ED patients. METHODS DESIGN Randomized, double-blind, placebo-controlled trial. SETTING Suburban New Jersey ED with 80,000 annual visits. PARTICIPANTS 18-55-year-olds with moderately severe musculoskeletal LBP from a bending or twisting injury ≤ 2 days prior to presentation. Exclusion criteria were suspected nonmusculoskeletal etiology, direct trauma, motor deficits, and local occupational medicine program visits. PROTOCOL At ED discharge, patients were randomized to either 50 mg prednisone daily for 5 days or identical-appearing placebo. Patients were contacted after 5 days to assess pain on a 0-3 scale (none, mild, moderate, severe) as well as functional status. RESULTS The prednisone and placebo groups had similar demographics and initial and discharge ED pain scales. Of the 79 patients enrolled, 12 (15%) were lost to follow-up, leaving 32 and 35 patients in the prednisone and placebo arms, respectively. At follow-up, the two arms had similar pain on the 0-3 scale (absolute difference 0.2, 95% confidence interval [CI] -0.2, 0.6) and no statistically significant differences in resuming normal activities, returning to work, or days lost from work. More patients in the prednisone than in the placebo group sought additional medical treatment (40% vs. 18%, respectively, difference 22%, 95% CI 0, 43%). CONCLUSION We detected no benefit from oral corticosteroids in our ED patients with musculoskeletal LBP.

Characteristics and Treatment of Patients with Clinical Illness Due to Synthetic Cannabinoid Inhalation Reported by Medical Toxicologists: A ToxIC Database Study

IntroductionSynthetic cannabinoid (SC) abuse has resulted in numerous outbreaks of severe clinical illness across the United States over the past decade. The primary objective of this study was to determine the clinical characteristics of patients abusing SC requiring bedside consultation by medical toxicologists.MethodsThis was a multicenter analysis from a prospectively collected cohort of patients presenting to medical care after synthetic cannabinoid exposure, utilizing the ToxIC Registry. Management of cases by medical toxicologists in this cohort occurred in emergency departments, inpatient medical floors, and intensive care units. Cases were identified from January 5, 2010 – July 31, 2015. We characterized the clinical presentations, treatments, outcomes, and sociologic factors associated with SC use in these patients.ResultsMedical toxicologists participating in the ToxIC Registry cared for 39,925 cases between 2010 and 2015. Three hundred fifty three of these cases were determined to be SC toxicity. The median age of patients was 25 (IQR: 18, 36) and the majority were males (84%). The most common symptoms were agitation, delirium and toxic psychosis, n=146 (41%). Forty-four (12.5%) had heart rates above 140 beats per minute. Bradycardia was the second most commonly reported severe vital sign abnormality with 20 (5.7%) having heart rates of less than 50 beats per minute. Fifteen (4.2%) patients had hypotension. Fifty-nine (17%) had seizures. The most common pharmacologic treatment provided was benzodiazepines (n=131, 37%) followed by antipsychotics (n=36, 10%).Disposition was available for 276; of these 167 (61%) were managed in the emergency department, 42 (15%) were admitted to the hospital floor, and 67 (24%) were admitted to the ICU.ConclusionsSynthetic cannabinoids are associated with severe central nervous system and cardiovascular effects.