Retained drugs in the gastrointestinal tracts of deceased victims of oral drug overdose.

CONTEXT: The extent of non-absorbed drug burden in the GI tract following overdose is unknown. Patients who present with clinical signs of toxicity may not undergo decontamination due to assumption that the drug has already been completely absorbed and because of limited scientific evidence of benefit for routine GI decontamination in poisoned patients. OBJECTIVE: The goal of this study was to assess whether people who die of an oral overdose have unabsorbed drug present in the GI tract. The secondary goal was to analyze pharmacologic characteristics of retained drugs when present. MATERIALS AND METHODS: Retrospective review of autopsy reports from 2008 to 2010, whose cause of death was determined as "intoxication" or "overdose, was performed at the Office of Chief Medical Examiner of the City of New York (OCME NYC)." Decedents of all ages were identified via electronic OCME database. Inclusion criteria were as follows: 1) cause of death "intoxication" or "overdose" noted by forensic autopsy, 2) ingestion of a solid drug formulation. RESULTS: 92 out of 1038 autopsies (9%) that met inclusion criteria had documentation of retained pill fragments, granules, paste, sludge, slurry, or whole pills in the GI tract. The most common drugs found were opioids and anticholinergics. Ninety-eight percent (98%) of the retained drugs were either modified-release preparations or drugs known to slow GI transit. Most decedents were dead on arrival; there were twelve in-hospital deaths and eleven patients died in the Emergency Department. Bupropion and venlafaxine were responsible for four deaths in those who received medical care. One person died in the ICU following bupropion ingestion. DISCUSSION AND CONCLUSION: Overdose of an oral drug that either has modified-release properties or slows GI tract motility may result in substantial unabsorbed drug burden remaining in the GI tract.

Prolonged altered mental status and bradycardia following pediatric donepezil ingestion.

CONTEXT: Donepezil is a centrally-acting, reversible acetylcholinesterase inhibitor that is used in the treatment of Alzheimer disease. Altered mental status, nausea, vomiting, and bradycardia have been reported in therapeutic and supratherapeutic ingestions of donepezil, though pediatric exposures have not been well-described. We report a case of prolonged altered mental status and recurrent bradycardia in a child with a single-pill ingestion of donepezil. CASE DETAILS: A 14-month-old boy was brought to the Emergency Department 3 hours after ingesting one of his grandfather's donepezil tablets (10 mg). Upon arrival, he was somnolent and drooling, with multiple episodes of vomiting and diarrhea. Pupils were normal. Initial vitals: temperature, 36.8°C; blood pressure, 103/56 mmHg; heart rate, 140/min; respiratory rate, 36/min; oxygen saturation, 97%. His drooling, vomiting, and diarrhea resolved, but he remained intermittently agitated. Over the course of the following four days, he had intermittent, episodes of asymptomatic bradycardia to a low of 55/min, primarily when sleeping. A transient episode of junctional rhythm was observed. Serum donepezil level 97 hours post-ingestion was 10 ng/ml. He did not require atropine treatment, and was discharged in stable condition on hospital day 5. DISCUSSION: Donepezil has a prolonged elimination of half-life in adults of approximately 70 hours. Despite its relative specificity for central AChEs, peripheral cholinergic symptoms have been described. We report a case of a symptomatic ingestion of donepezil in a child. CONCLUSIONS: Even after a single-tablet ingestion, donepezil may cause prolonged altered mental status and bradycardia in young children.

Inconsistent approach to the treatment of chronic digoxin toxicity in the United States.

Evidence-based guidelines do not exist for the treatment of patients with chronic mild-moderate digoxin toxicity. We sought to evaluate differences among specialists in the use of digoxin-specific antibody fragments and the decision to admit these patients. A sample of cardiologists, emergency physicians, and medical toxicologists was surveyed. The survey detailed four hypothetical cases of chronic digoxin toxicity created by consensus among authors. All cases had the same digoxin concentration, but signs and symptoms varied in an attempt to explore four different thresholds. For each scenario, clinicians made decisions about admission and treatment. Survey response varied: cardiologists 17%, emergency physicians 6.7%, and toxicologists 39%. Statistically significant difference was found in the administration of Fab among cardiologists (67%), emergency physicians (82%), or toxicologists (91.5%) and admission rate (cardiologists 34%, emergency physicians 28%, and toxicologists 46%). Differences exist among clinicians of various specialties regarding treatment of chronic digoxin toxicity. These differences may reflect diverse perspectives or knowledge gaps and may translate into excess cost or less than ideal care. Exploring these differences may improve patient care, improve interactions among providers, and set the stage for development of consensus guidelines and research.

A case of levetiracetam (Keppra) poisoning with clinical and toxicokinetic data.

BACKGROUND: Levetiracetam (Keppra) is a new anticonvulsant used to treat partial complex seizures that is also being investigated for its mood-stabilizing properties. Although its precise mechanism of action is unknown, levetiracetam does not appear to directly interact with the GABA system. We report the first intentional overdose with levetiracetam including clinical effects and serial serum concentrations. CASE REPORT: A 38-year-old woman reportedly ingested 60 (500 mg) tablets of levetiracetam that she used as a mood-stabilizing medication for bipolar disorder. She had no other prescription medications available and no other medical history. She vomited 4 hours after ingestion and presented to the ED 2 hours later. In the ED, the patient was obtunded and was intubated secondary to respiratory depression. Her only other significant clinical finding was diminished deep tendon reflexes. Serum ethanol, lithium, carbamazepine, phenytoin, and valproic acid levels were all negative as was a subsequent urine screen for drugs of abuse. Her levetiracetam serum concentration was 400 microg/mL at 6 hours, 72 microg/mL at 18 hours, and 60 microg/mL at 20.5 hours (therapeutic serum concentration is 10-37 microg/mL). The elimination half-life was calculated to be 5.14 hours. She was extubated the next hospital day and recovered without sequelae. CONCLUSION: In overdose, levetiracetam is sedating and causes respiratory depression, however, recovery is rapid with supportive care. This is the first reported case of levetiracetam overdose; serial serum concentrations suggest first-order elimination even at concentrations 10-40 fold higher than therapeutic.

The benefit of houseofficer education on proper medication dose calculation and ordering.

OBJECTIVES: Drug dosing errors commonly cause morbidity and mortality. This prospective controlled study was performed to determine: 1) residents' understanding of drug dose calculations and ordering; and 2) the short-term effect of a brief educational intervention on the skills required to properly calculate dosages and order medications. METHODS: The study was conducted at an urban public hospital with a four-year emergency medicine (EM) residency program. The EM residents served as the study group and were unaware of the study design. A written, eight-question test (T1) with clinical situations and factual questions was administered. Immediately following the test, correct answers were discussed for 30 minutes. Key concepts were emphasized. Six weeks later, a repeat test (T2a) with a similar format was administered to the study group. The same test (T2b) was simultaneously administered to a control group, residents of similar training who did not take T1, in order to determine test equivalency (T1 vs T2). Tests were graded using explicit criteria by a single investigator blinded to the order of administration. RESULTS: Twenty residents completed both tests T1 and T2a. Their mean scores were 48% and 70%, respectively (p < 0.001, paired t-test). The control group of ten residents had a mean score of 49% (T2b), similar to the study group's scores on T1 (T1 vs T2b, p = 0.40, unpaired t-test). CONCLUSION: Emergency medicine residents require specific training in calculating and executing drug ordering. A brief educational intervention significantly improved short-term performance when retested six weeks later. Long-term retention is unknown.

Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing.

Ingestion of long-acting anticoagulant rodenticides such as brodifacoum can lead to prolonged and life-threatening coagulopathy. A paucity of conflicting information is available on brodifacoum's half-life and elimination pharmacokinetics. In addition, the optimal dose, duration, and route of administration of vitamin K(1) therapy are unknown. We report the case of a 52-year-old man who ingested eight 43-g boxes of a rodenticide (d-Con Mouse-Prufe II; 0.005% brodifacoum; Reckitt & Colman, Wayne, NJ). This case demonstrates that after stabilization with fresh frozen plasma, high-dose oral vitamin K(1) therapy ( congruent with 7 mg/kg per 24 hours divided every 6 hours) was effective in treating brodifacoum-induced coagulopathy. The concentration of vitamin K(1) required for normal coagulation in this case was less than the accepted value of 1 microg/mL, which is derived from a rabbit model. In this case, brodifacoum appears to follow zero-order elimination pharmacokinetics. In future cases of patients with ingestions of long-acting anticoagulants who present with coagulopathy, it may be useful to obtain serial brodifacoum concentrations to determine elimination curves to help predict the duration of oral vitamin K(1) therapy.

Feasibility and pharmacokinetics of carbamazepine oral loading doses.

The pharmacokinetics and adverse effects of an oral loading dose of carbamazepine administered in tablet or suspension form were studied. Patients on a hospital epilepsy unit who were to receive carbamazepine as a discharge medication were randomly assigned to receive either an oral 8-mg/kg loading dose of the tablet formulation or the same dose of the suspension on an empty stomach. Blood samples were drawn before and at intervals up to 12 hours after the loading dose. Adverse effects were evaluated subjectively and objectively. Total and free serum carbamazepine and carbamazepine-10, 11-epoxide (CBZE) concentrations were determined by high-performance liquid chromatography. Six adult patients were enrolled in and completed the study. All the patients achieved therapeutic total carbamazepine levels; the suspension group did so within two hours and the tablet group within five hours. Maximum serum carbamazepine concentrations ranged from 7.10 to 9.92 mg/L, area under the concentration-versus-time curve from 54.85 to 82.23 micrograms.hr/L, and terminal elimination half-life from 14.05 to 15.71 hours. Adverse effects were mild, few, and short-lived; none of the patients developed gastrointestinal toxicity. Adverse effects were not associated with total or free carbamazepine and CBZE concentrations or with total or free CBZE:carbamazepine ratios. An oral loading dose of carbamazepine 8 mg/kg achieved therapeutic levels within two hours when given as a suspension and within five hours when given as tablets and was well tolerated in all patients.

Pharmacokinetics following a loading plus a continuous infusion of pralidoxime compared with the traditional short infusion regimen in human volunteers.

BACKGROUND: Many authors currently recommend infusing the adult dose (1 g) of pralidoxime over a 15-30 minute period. When administered in this manner, computer simulations predict that plasma pralidoxime concentrations will fall below 4 mg/L as early as one and one half hours after administration. The objective of this study was to assess whether a loading dose followed by a continuous infusion would maintain therapeutic levels longer than the traditional short infusion regimen of pralidoxime if the same total dose was administered. METHODS: Utilizing a randomized, crossover design, healthy volunteers were administered either 16 mg/kg of pralidoxime intravenous over 30 minutes or 4 mg/kg of pralidoxime intravenous over 15 minutes followed by 3.2 mg/kg/h for 3.75 h (for a total dose of 16 mg/kg). Pralidoxime levels were obtained at 0, 10, 20, 30, 60, 120, 180, 240, 300, and 390 minutes and patients were observed for vital sign changes and adverse effects. RESULTS: Seven subjects completed both arms of the study. One subject's data were excluded from pharmacokinetic analysis due to aberrant plasma pralidoxime analysis. The loading dose followed by the continuous infusion maintained therapeutic levels for 257.3 +/- 50.5 minutes whereas the short infusion maintained therapeutic levels for 118.1 +/- 52.1 (p < 0.001). Adverse effects were encountered during the short infusion regimen which did not occur during the continuous infusion. Dizziness or blurred vision occurred in all subjects during the short infusion regimen. Additionally, statistically significant increases in diastolic blood pressure occurred during the short infusion regimen. CONCLUSIONS: The results of this study indicate that a loading dose followed by a continuous infusion of pralidoxime maintains therapeutic concentrations for a longer period of time than the currently recommended short infusion regimen in healthy volunteers.

Risks of parenteral deferoxamine for acute iron poisoning.

OBJECTIVE: To review the adverse effects and risks of deferoxamine for the treatment of iron poisoning. METHODS: A literature search of deferoxamine induced adverse effects was used to identify pertinent articles. The references of these articles served as the source of other references not previously identified. RESULTS: Deferoxamine is a relatively safe antidote for iron intoxication, but adverse effects have been recognized with increased usage, particularly with prolonged intravenous dosing. This paper focuses on deferoxamine induced cardiovascular, pulmonary, ocular and auditory toxicity as well as its potential to increase the risk of infection. Information on iron's toxicology and toxicokinetics and deferoxamine's pharmacology and pharmacokinetics are reviewed. With this background information a hypothesis is generated to maximize deferoxamine benefit while minimizing deferoxamine induced pulmonary toxicity. The hypothesis is based upon a stoichiometric approach to maximal chelation during the first 24 h following iron ingestion. CONCLUSION: Deferoxamine is a relatively safe antidote for iron poisoning but the potential for pulmonary and cardiovascular toxicity should be respected. Studies defining maximum regimens over defined periods of time will allow a more logical utilization of deferoxamine, optimizing benefit and minimizing risk.

Pharmacokinetics of extended relief vs regular release Tylenol in simulated human overdose.

BACKGROUND: The purpose of this trial was to compare the pharmacokinetics of the two available acetaminophen dosage forms in simulated human overdose. METHODS: Ten healthy volunteers received acetaminophen, 75 mg/kg orally, either as the regular release or extended relief formulation in a random, crossover fashion. Blood samples were analyzed using a TDx assay and a best fit correlation of data points was determined by PCNONLIN. RESULTS: The area under the curves for extended relief acetaminophen and regular release acetaminophen were 426 mg h/L and 432 mg h/L, respectively (p = 0.768). The mean half times for extended relief acetaminophen and regular release acetaminophen were 4.02 h and 2.56 h, respectively (p < 0.001). The mean maximum serum acetaminophen concentrations were 62.6 mg/L (414.4 mmol/L:) and 94.3 mg/L (624.3 mmol/L) for extended relief acetaminophen and regular release acetaminophen, respectively (p < 0.001) and the mean time to maximum serum acetaminophen concentrations were 0.87 h and 0.75 h for extended relief acetaminophen and regular release acetaminophen, respectively (p = 0.508). CONCLUSIONS: Although the formulations appear to have equal bioavailability, their half-lives and peak concentrations were significantly different. Further study is required to determine whether these differences affect the assessment and management of poisoned patients.

Concepts and controversies of bronchodilator overdose.

Beta-adrenergic agonists and theophylline are both capable of producing tremor, agitation, tachycardia, metabolic acidosis, hypokalemia, hyperglycemia, cardiac arrhythmias, and seizures. However, theophylline preparations, especially in the sustained-release formulations, are associated with a much higher incidence of morbidity and mortality secondary to status epilepticus and cardiovascular collapse. Overdoses of sustained-release preparations place patients at exceedingly high risk. This article describes the differentiation of the patient with acute and chronic theophylline overdoses and the implications for management of both clinical states.

Prevalence of sorbitol in multiple-dose activated charcoal regimens in emergency departments.

STUDY OBJECTIVES: To determine the availability and use of premixed activated charcoal in sorbitol preparations during multiple-dose activated charcoal therapy in the emergency department. DESIGN AND SETTING: A prospective telephone survey of all 911 receiving hospitals within the catchment area of one poison center. TYPE OF PARTICIPANTS: Hospital pharmacy supervisors and ED charge nurses. INTERVENTION: Hospital pharmacy supervisors were surveyed about the available preparations of activated charcoal on their hospital's formulary, and ED charge nurses in these same hospitals were surveyed about the prevalence of sorbitol use in multiple-dose activated charcoal regimens. MEASUREMENTS AND MAIN RESULTS: Eleven hospitals (16%) stocked only activated charcoal in sorbitol preparations. Twenty-one hospitals (31%) had both activated charcoal in sorbitol preparations and activated charcoal without sorbitol preparations, and 35 hospitals (52%) had only activated charcoal without sorbitol preparations. Repeat dosing of sorbitol during multiple-dose activated charcoal therapy occurred in 33 of 67 (49%) of the EDs surveyed. CONCLUSION: Sorbitol dosing is often repeated with activated charcoal during multiple-dose activated charcoal therapy in the ED because of the ready availability (and sometimes exclusive availability) of premixed activated charcoal in sorbitol preparations.

Theophylline toxicity in a premature neonate--elimination kinetics of exchange transfusion.

Exchange transfusion was utilized in the treatment of a 1871 gram female, 32 weeks gestational age, who received an IV bolus of aminophylline at 11 h for the treatment of apnea, with subsequent tachycardia and hypotension. At 22 h, plasma theophylline was 369.29 mumol/L (67 mg/L). During a single volume exchange transfusion at 33 h, the plasma theophylline decreased 19% and the estimated removal of theophylline was 13.5% of the whole body theophylline. The theophylline apparent half-times before, during, and after the exchange were 52.5, 6.6, and 53.3 h respectively.

An in vitro evaluation of cocaine hydrochloride adsorption by activated charcoal and desorption upon addition of polyethylene glycol electrolyte lavage solution.

Cocaine body-packers and body-stuffers have become a common medical problem. Significant morbidity and mortality result when cocaine is absorbed from the gastrointestinal tract due to cocaine package compromise. The clinical prevention of gastrointestinal absorption of cocaine includes oral activated charcoal and/or whole bowel irrigation with polyethylene glycol--electrolyte lavage solution. This in vitro study investigates the maximal adsorptive capacity of activated charcoal for cocaine at varying activated charcoal:cocaine ratios, at pH 1.2 and pH 7.0, and the effect of polyethylene glycol--electrolyte lavage solution upon this binding. The percent adsorption of cocaine to activated charcoal was significantly better at pH 7.0 for all ratios of activated charcoal:cocaine tested and the maximal adsorptive capacity was 29% greater at pH 7.0 (273 micrograms/mg) than at pH 1.2 (212 micrograms/mg) (p < 0.05). Addition of polyethylene glycol--electrolyte lavage solution to the cocaine-activated charcoal slurry caused significant desorption of cocaine from activated charcoal at all pHs and ratios tested (except the 1:1 ratio at pH 7.0) and was most pronounced at pH 1.2. The addition of polyethylene glycol--electrolyte lavage solution to activated charcoal prior to adding cocaine solution further decreased the adsorption of cocaine to activated charcoal. This difference was significant at both pHs and all ratios tested except the 1:1 ratio at pH 1.2. The maximal adsorptive capacity of activated charcoal for cocaine at pH 1.2 was reduced 75% by pretreatment with polyethylene glycol--electrolyte lavage solution from 212 to 54.2 micrograms/mg, while at pH 7.0 the maximal adsorptive capacity was reduced by 11%, from 273 to 243 micrograms/mg. Polyethylene glycol--electrolyte lavage solution significantly reduces the adsorption of cocaine to activated charcoal particularly if the two are combined at a low pH prior to the addition of cocaine. The in vitro effects suggest that activated charcoal mixed in water should be administered first, followed by the polyethylene glycol--electrolyte lavage solution.