Medication errors associated with the use of ethanol and fomepizole as antidotes for methanol and ethylene glycol poisoning.

INTRODUCTION: Little is known about medication errors which occur with the antidotes ethanol and fomepizole, used for treatment of methanol and ethylene glycol poisoning. Study objectives were to describe and compare the frequency, type, outcome and underlying causes of medication errors associated with ethanol and fomepizole. METHODS: Patients aged ≥13 years were included if they were hospitalized in 1996-2005 for methanol or ethylene glycol poisoning and treated with ethanol or fomepizole. Charts from 10 hospitals were separately reviewed by two abstracters who recorded case details. A consensus panel of clinicians used the abstracted data to identify medication errors and classify error outcome. Fisher's exact test determined significant differences in the proportion of ethanol and fomepizole-treated cases with medication error and univariate logistic regression identified risk factors associated with harmful dosage errors. RESULTS: There were 145 ethanol- and 44 fomepizole-treated cases. There was ≥1 medication error in 113/145 (78%) ethanol- and 20/44 (45%) fomepizole-treated cases (p = 0.0001) with more ethanol-related errors involving excessive dose, inadequate monitoring and inappropriate antidote duration. Harmful errors occurred in 19% of ethanol- and 7% of fomepizole-treated cases (p = 0.06) and were largely due to excessive antidote dose or delayed antidote initiation. Occurrence of harmful dosage error was reduced in cases with Poison Control Centre consultation, odds ratio (95% confidence interval) 0.39 (0.17, 0.91), hemodialysis 0.37 (0.16, 0.88), or fomepizole versus ethanol 0.24 (0.06, 1.04). CONCLUSION: Fomepizole was less prone to medication error than ethanol. Error-related harm was most commonly due to excessive antidote dose or delayed antidote initiation.

Fomepizole fails to prevent progression of acidosis in 2-butoxyethanol and ethanol coingestion.

INTRODUCTION: 2-butoxyethanol (2BE) is a solvent commonly incorporated into household and industrial cleaning products. Its ingestion causes rapid central nervous system depression, hypotension, and metabolic acidosis attributable to metabolism of the parent compound to butoxyacetic acid (BAA) by alcohol dehydrogenase. Lactic acidosis is also reported to develop in some cases. Published treatment strategies include the use of ethanol infusion, ethanol with concomitant dialysis, dialysis alone, and fomepizole. CASE REPORT: We present an unusual case of a coingestion of ethanol and 150-250 mL of pure 2BE, which resulted in rapid obtundation, severe airway edema, hypotension, and prolonged acidosis despite the coingestion of ethanol and the administration of a loading dose of fomepizole. Continuous veno-venous hemodialysis was employed to treat the acidosis. Ingestion was confirmed by gas chromatography and mass spectrometric determinaiton of 2BE and BAA. The patient recovered without sequelae. CONCLUSION: Alcohol dehydrogenase inhibitors may not be adequate to prevent acidosis in significant ingestions to 2BE and extracorporeal treatments may be necessary.

Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole.

STUDY OBJECTIVE: We investigate adverse drug events associated with antidotes ethanol and fomepizole in methanol or ethylene glycol poisonings. An "adverse drug event" is harm associated with normal or incorrect drug use. We describe type, frequency, severity, seriousness, and onset time of adverse drug events and test the hypothesis that fomepizole results in fewer adverse drug events than ethanol. METHODS: This cohort study included patients aged 13 years or older, hospitalized between 1996 and 2005 for methanol or ethylene glycol poisoning (identified by International Classification of Diseases, Ninth Revision or 10th Revision codes) and treated with at least 1 dose of ethanol or fomepizole. Two abstractors separately reviewed each chart, identifying new clinical events during antidote treatment. Three toxicologists determined, by consensus, which events were adverse drug events. The primary outcome was at least 1 adverse drug event, expressed as adverse drug event rate per person-day of antidote treatment. Association between time to first adverse drug event and antidote type was modeled by Cox regression, adjusted for confounders. RESULTS: Two hundred twenty-three charts were reviewed and 172 analyzed. Toxicologists identified at least 1 adverse drug event in 74 of 130 (57%) ethanol-treated and 5 of 42 (12%) fomepizole-treated cases. Central nervous system symptoms accounted for most adverse drug events (48% ethanol-treated, 2% fomepizole-treated). Severe adverse drug events occurred in 26 of 130 (20%) ethanol-treated (coma, extreme agitation, cardiovascular) and 2 of 42 (5%) fomepizole-treated (coma, cardiovascular). Serious (life-threatening) adverse drug events occurred in 11 of 130 (8%) ethanol-treated (respiratory depression, hypotension) and 1 of 42 (2%) fomepizole-treated (hypotension, bradycardia) cases. Median adverse drug event onset was within 3 hours after the start of either antidote. Ethanol and fomepizole adverse drug event rates were 0.93 and 0.13 adverse drug events per treatment-day, respectively. Adjusted hazard ratio was 0.16 (95% confidence interval 0.06, 0.40). CONCLUSION: Given observational study limitations, results suggest lower occurrence of adverse drug events with fomepizole than ethanol.

Bradycardia and hypotension associated with fomepizole infusion during hemodialysis.

UNLABELLED: We report a case of hypotension and bradycardia associated with intravenous fomepizole infusion. CASE REPORT: A 59-year-old man presented to hospital 10 hours after ethylene glycol ingestion with ataxia, slurred speech, metabolic acidosis, heart rate 70/min, blood pressure 160/100 mmHg. Treatment with hemodialysis and fomepizole began 7.5 hours after admission. Severe bradycardia (29/min) and hypotension (69 mmHg systolic) occurred immediately following a 30 minute intravenous infusion of the first (19 mg/kg) fomepizole dose, but rapidly corrected with 1 mg atropine. Transient bradycardia (48/min) and hypotension (89/57 mmHg) recurred immediately after the second (10 mg/kg) fomepizole dose, also given during dialysis. DISCUSSION: Hemodialysis may cause a drop in blood pressure and heart rate; however, the close temporal relationship with fomepizole infusions, dose-related symptom intensity and recurrence with rechallenge suggest a causal relationship with fomepizole. Hemodialysis, acidosis and high initial fomepizole dose may have enhanced patient susceptibility, as a post-dialysis fomepizole dose was well tolerated. CONCLUSION: Fomepizole may precipitate bradycardia and/or hypotension during hemodialysis. Monitor vital signs closely during and immediately after infusion.

Insulin & C-peptide levels in sulfonylurea-induced hypoglycemia: a systematic review.

OBJECTIVES: We will describe insulin and C-peptide levels observed in sulfonylurea-induced hypoglycemia and determine whether these levels differed if obtained before or after hypoglycemic therapy. METHODS: We performed a systematic review of the English literature to identify Medline articles containing "sets" (glucose <60 mg/dL with insulin and C-peptide levels). These "sets" were categorized as being obtained BEFORE, AFTER, or UNKNOWN with respect to hypoglycemic therapy. RESULTS: 22 articles, 76 patients, and 97 "sets" were included. Mean glucose (mg/dL), insulin (muIU/mL), and C-peptide (ng/mL) for all "sets' were 28.6 (+/-12.6; 26.1 to 31.2), 54.4 (+/-126.3; 28.3 to 80.5), 7.2 (+/-6.2; 5.9 to 8.5). The BEFORE measures were 24.3 (+/-7.3; 18.7 to 30.0), 36.6 (+/-26.2; 16.5 to 56.7), 5.4 (+/-4.6; 1.5 to 9.2). The AFTER measures were 33.1 (+/-9.8; 28.2 to 38.0), 126.7 (+/-278.1; 0 to 265.0), 10.3 (+/-10.5; 5.1 to 15.4). The UNKNOWN measures were 28.0 (+/-13.5; 24.7 to 31.3), 37.1 (+/-21.8; 31.7 to 42.5), 6.5 (+/-4.3; 5.4 to 7.6). Only one "set" (glucose 49 mg/dL) had insulin <3.9 muIU/mL and C-peptide <1.4 ng/mL. CONCLUSIONS: Insulin > or =3.9 muIU/mL, C-peptide > or =1.4 ng/mL, and glucose <49 mg/dl are consistent with sulfonylurea-induced hypoglycemia. BEFORE levels were lower, but they were consistent with sulfonylurea-induced hypoglycemia.

The effect of amiodarone pretreatment on survival of mice with cocaine toxicity.

INTRODUCTION: Cocaine is a common drug of abuse and use has been associated with ventricular dysrhythmias. Published guidelines suggest that amiodarone is the first line antidysrhythmic for ventricular tachycardia and fibrillation. However, the effects amiodarone in the setting of cocaine toxicity are unknown and unstudied. The purpose of this study was to evaluate the safety and efficacy of amiodarone pretreatment in a murine model of acute cocaine toxicity. METHODS: This was a randomized, blinded, placebo controlled investigation using male CF-1 mice weighing 29-37 g. First, the safety of an intraperitoneal dose of amiodarone (40 mg/kg) was confirmed in 5 mice. Second, based on preliminary investigations, an approximate intraperitoneal LD50 dose of cocaine (110 mg/kg) was identified and used as the cocaine dose in this study. Animals were then randomized to 2 groups. The control group received 0.5 mL of intraperitoneal 0.9% saline 30 minutes before cocaine. The study group received 40 mg/kg of intraperitoneal amiodarone (40 mg/kg) 30 minutes before cocaine. A blinded observer monitored mice for 2 hours after cocaine administration. RESULTS: No mice in the amiodarone-only group developed any signs of toxicity or died. In the saline + cocaine group 31/32 (96.9%; 95% CI 83.8 to 99.9) mice seized with a median time to seizure of 2.5 minutes, and 23/32 (71.9%; 95% CI 52.3 to 86.3) died with a median time to death of 5.5 minutes. In the amiodarone + cocaine group 31/33 (93.9%; 95% CI 79.0 to 99.3) mice seized with a median time to seizure of 2.0 minutes, and 24/33 (72.7%; 95% CI 54.5 to 86.7) died with a median time to death of 6.0 minutes. All animals that died did so within 9 minutes. The difference in the proportion of animals dying in the amiodarone + cocaine group compared to the saline + cocaine group was 0.008 (-21 to 22%). CONCLUSIONS: In this study, pretreatment with amiodarone in cocaine poisoned mice resulted in no change in seizure incidenceor mortality. However, definite conclusions about the reason for these findings cannot be drawn from this model.

Pharmacology, pathophysiology and management of calcium channel blocker and beta-blocker toxicity.

Calcium channel blockers (CCB) and beta-blockers (BB) account for approximately 40% of cardiovascular drug exposures reported to the American Association of Poison Centers. However, these drugs represent >65% of deaths from cardiovascular medications. Yet, caring for patients poisoned with these medications can be extremely difficult. Severely poisoned patients may have profound bradycardia and hypotension that is refractory to standard medications used for circulatory support.Calcium plays a pivotal role in cardiovascular function. The flow of calcium across cell membranes is necessary for cardiac automaticity, conduction and contraction, as well as maintenance of vascular tone. Through differing mechanisms, CCB and BB interfere with calcium fluxes across cell membranes. CCB directly block calcium flow through L-type calcium channels found in the heart, vasculature and pancreas, whereas BB decrease calcium flow by modifying the channels via second messenger systems. Interruption of calcium fluxes leads to decreased intracellular calcium producing cardiovascular dysfunction that, in the most severe situations, results in cardiovascular collapse.Although, CCB and BB have different mechanisms of action, their physiological and toxic effects are similar. However, differences exist between these drug classes and between drugs in each class. Diltiazem and especially verapamil tend to produce the most hypotension, bradycardia, conduction disturbances and deaths of the CCB. Nifedipine and other dihydropyridines are generally less lethal and tend to produce sinus tachycardia instead of bradycardia with fewer conduction disturbances.BB have a wider array of properties influencing their toxicity compared with CCB. BB possessing membrane stabilising activity are associated with the largest proportion of fatalities from BB overdose. Sotalol overdoses, in addition to bradycardia and hypotension, can cause torsade de pointes. Although BB and CCB poisoning can present in a similar fashion with hypotension and bradycardia, CCB toxicity is often associated with significant hyperglycaemia and acidosis because of complex metabolic derangements related to these medications. Despite differences, treatment of poisoning is nearly identical for BB and CCB, with some additional considerations given to specific BB. Initial management of critically ill patients consists of supporting airway, breathing and circulation. However, maintenance of adequate circulation in poisoned patients often requires a multitude of simultaneous therapies including intravenous fluids, vasopressors, calcium, glucagon, phosphodiesterase inhibitors, high-dose insulin, a relatively new therapy, and mechanical devices. This article provides a detailed review of the pharmacology, pathophysiology, clinical presentation and treatment strategies for CCB and BB overdoses.