Bryan D. Hayes

Frequency of Medication Errors with Intravenous Acetylcysteine for Acetaminophen Overdose

Background: Acetadote, an intravenous preparation of acetylcysteine, became commercially available in the US in June 2004 for the treatment of acetaminophen poisoning. The dosing regimen is complex, consisting of a loading dose followed by 2 maintenance doses, each with different infusion rates. Objective: To analyze the frequency of medication errors related to the complex dosing regimen for intravenous acetylcysteine. Methods: A retrospective chart review of a regional poison centers records was performed for all patients treated with intravenous acetylcysteine from August 1, 2006, to August 31, 2007. Data collected included acetylcysteine dose, infusion rate, interruptions in therapy, unnecessary administration, and medical outcome. Records that revealed medication errors were further examined for the time and location of the errors. Results: There were 221 acetaminophen overdose cases treated with intravenous acetylcysteine that met inclusion criteria. Of these, 84 medication errors occurred in 74 (33%) patients. The frequency and types of errors were 1.4% incorrect dose, 5% incorrect infusion rate, 18.6% more than 1 hour of interruption in therapy, and 13.1% unnecessary administration. The frequency and types of medication errors in pediatric patients were similar to those in the total patient population. Errors occurred most frequently in the emergency department compared with Intensive care units or general medical floors. In addition, errors occurred most frequently on third shift, compared with first or second shift. Evaluation of medical outcomes in cases involving acetaminophen only found that medication errors did not have an impact on coded outcomes. Conclusions: Medication administration errors occur frequently with intravenous acetylcysteine. Awareness of this problem, coupled with increased vigilance in identifying factors associated with errors, should decrease medication errors with intravenous acetylcysteine therapy for acetaminophen poisoning.

COMPARISON OF TOXICITY OF ACUTE OVERDOSES WITH CITALOPRAM AND ESCITALOPRAM

BACKGROUND Seizures and QTc prolongation are associated with citalopram poisoning; however, overdose experience with escitalopram is more limited. OBJECTIVES The goals of this study were to compare citaloprams vs. escitaloprams clinical effects in overdose, including the incidence of seizures. METHODS A retrospective review was conducted for single-substance acute overdoses with citalopram and escitalopram, managed in hospitals, that were reported to six U.S. poison centers from 2002-2005. RESULTS There were 374 citalopram and 421 escitalopram overdose cases. Gender and ages were similar between the two, with 68-70% females and a median age of 20 years for citalopram and 18 years for escitalopram. Median dose by history was 310 mg for citalopram and 130 mg for escitalopram. More serious outcomes were associated with citalopram overdoses (p < 0.001). Most frequently reported clinical effects with citalopram and escitalopram were tachycardia, drowsiness, hypertension, and vomiting. Seizures (30 vs. 1, respectively, p < 0.001) and tremor (32 vs. 13, respectively, p = 0.001) were more common with citalopram. QTc prolongation occurred in 14 citalopram cases and 7 escitalopram cases (p = 0.109). There was an association between increasing dose and severity of outcome for citalopram (p < 0.001) and escitalopram (p = 0.011). In children < 6 years old, 12 of 66 citalopram and 5 of 57 escitalopram cases experienced toxicity, such as drowsiness, nausea/vomiting, and tachycardia. There were no seizures in this age group. CONCLUSIONS Escitalopram seems to be less toxic than citalopram after an acute overdose; seizures and tremors were more common with citalopram. Initial management of overdoses should include seizure precautions for citalopram and cardiac monitoring for both drugs.

Toxicity of Buprenorphine Overdoses in Children

OBJECTIVE. There are few reports in children of overdoses of buprenorphine, a partial opioid agonist used in the treatment of opioid dependence and pain. The purpose of this study was to analyze buprenorphine overdoses in young children reported by US poison centers to the Researched Abuse, Diversion, and Addiction-Related Surveillance System. METHODS. A retrospective review of buprenorphine overdoses in children <6 years of age reported to the Researched Abuse, Diversion, and Addiction-Related Surveillance System from November 2002 through December 2005 was performed. Patients lost to follow-up and those ingesting multiple substances were excluded. RESULTS. Eighty-six cases met inclusion criteria. In the 54 children who developed toxicity, the clinical effects included drowsiness or lethargy (55%), vomiting (21%), miosis (21%), respiratory depression (7%), agitation or irritability (5%), pallor (3%), and coma (2%). There were no fatalities. The mean time to onset of effects was 64.2 minutes, with a range of 20 minutes to 3 hours. Duration of clinical effects was under 2 hours in 11%, 2 to 8 hours in 59%, 8 to 24 hours in 26%, and >24 hours in 4%. Children who ingested ≥2 mg of buprenorphine were more likely to experience clinical effects, and all of the children who ingested >4 mg experienced some effect. No child ingesting <4 mg experienced a severe effect. Of the 22 children administered naloxone, 67% had at least a partial response. CONCLUSIONS. Buprenorphine overdoses are generally well tolerated in children, with significant central nervous system and respiratory depression occurring in only 7%. Any child ingesting >2 mg and children <2 years of age ingesting more than a lick or taste should be referred to the emergency department for a minimum of 6 hours of observation. Naloxone can be used to reverse respiratory depression.

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.

Development of Hepatic Failure Despite Use of Intravenous Acetylcysteine After a Massive Ingestion of Acetaminophen and Diphenhydramine

Acetylcysteine is an antidote used to prevent liver failure after acetaminophen overdose. We report the development of liver failure despite administration of intravenous acetylcysteine in a patient with massive ingestion of an acetaminophen and diphenhydramine combination product. An atypical, delayed, bimodal peak in the serum acetaminophen concentration was observed. This case suggests that individualized dosing of antidotal therapy may be needed for preparations of acetaminophen that result in delayed absorption or after massive overdose.

Causes of Therapeutic Errors in Older Adults: Evaluation of National Poison Center Data

OBJECTIVES: To evaluate the reasons for unintentional therapeutic errors in older adults, the types of medications most frequently involved, and the medical outcomes related to these adverse drug events.

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.

Intravenous lipid emulsion in the management of amlodipine overdose.

Objective To report a case of amlodipine overdose successfully treated with intravenous lipid emulsion (ILE). Case Summary A 47-year-old, 110 kg female ingested at least 350 mg of amlodipine with an unknown amount of ethanol. Initial blood pressure was 103/57 mm Hg, mean arterial pressure (MAP) 72 mm Hg, and heart rate 113 beats per minute. In the early clinical course, activated charcoal, intravenous fluid, and calcium boluses were administered. Worsening hypotension prompted a 100 mL bolus of 20% ILE. Stable hemodynamics were maintained for 2 hours. Subsequently, profound hypotension and shock developed (MAP 38 mm Hg), which failed to fully respond to 3 vasopressor agents, calcium, and glucagon. With continuing shock despite optimized vasopressors, an infusion of 2,300 mL 20% ILE was administered over 4.5 hours (20.9 mL/kg infusion total). By completion of the infusion, 2 vasopressors were tapered off and MAP remained above 70 mm Hg; within 12 hours, no further interventions were required. Possible adverse events of ILE, lipemia and hypoxia, were experienced but quickly resolved. The patient survived to hospital discharge within 8 days. Discussion Toxicity of amlodipine presents similar to distributive shock as both are due to marked peripheral vasodilation. There are numerous interventions in the management of amlodipine overdose, despite which many patients continue to suffer life-threatening shock as observed with this patient. ILE has been used with promising preliminary results as salvage therapy in case reports of other lipophilic molecules. This is the first report of lone amlodipine overdose treated with ILE. Conclusion ILE is a novel antidote for overdoses of lipophilic substances and demonstrated efficacy in this case of amlodipine overdose without the use of hyperinsulinemic euglycemia.

Drug-Induced Hyperthermic Syndromes: Part I. Hyperthermia in Overdose

Drugs and natural compounds that affect the thermoregulatory system can induce or contribute to hyperthermia when used in excess. Hyperthermia associated with drug overdose is dangerous and potentially lethal. This article reviews the bodys process of maintaining thermodynamic equilibrium, and describes the mechanisms by which it is influenced by sympathomimetic and anticholinergic drugs, salicylates, and thyroid replacement medications. Appropriate treatment strategies such as cooling and the administration of counteractive medications are discussed.