Review of toxicity and trends in the use of tiagabine as reported to US poison centers from 2000 to 2012.

BACKGROUND: Tiagabine is a novel antiepileptic that acts by increasing synaptic and extracellular gamma-aminobutyric acid concentrations. Information concerning overdose of tiagabine is limited. After introduction, an increasing number of off-label uses suggested that tiagabine use would increase. However in 2005 and 2008, warnings from the Food and Drug Administration (FDA) were issued on the risk of seizures in non-epileptic and increased suicide ideation. We evaluated the temporal trends associated with these two warnings as well as clinical outcomes from tiagabine overdose. METHOD: A retrospective review of all single substance tiagabine exposures in National Poison Data System (NPDS) from 2000 to 2012. RESULTS: A total of 2147 patients had ingested tiagabine, with a mean of 165 year(-1). This was disproportionally distributed, with a steep rise leading up to 2004 (max 559 year(-1)) and then a significant decline (p < 0.05) between 2005 and 2006. The number of cases reported to NPDS mirrored the sales of tiagabine. Clinical effects were predominantly neurological, with the most commonly reported effects being drowsiness (27%), agitation (19%), confusion (12%), seizures (11%), and tachycardia (10%). In all, 758 patients (35%) showed a major or moderate medical outcome, with no deaths reported. A disproportionate share of the major outcomes was in the suicide attempt group (73%). The majority of patients (75%) were treated in a health-care facility (HCF). CONCLUSIONS: The HCF usage is likely due to high rate of symptomatic patients (59%) and the large proportion of suicide attempt cases. The frequency of tiagabine cases in NPDS mirrored pharmaceutical sales, with steep declines temporally related to the 2005 FDA warning.

Identification of N-Hydroxy-para-aminobenzoic acid in a cyanotic child after benzocaine exposure.

CONTEXT: Methemoglobinemia (MetHb) after exposure to benzocaine (BZC) has been reported for more than 50 years, however the pathophysiologic mechanism has not been previously established. Direct administration of BZC to blood does not produce MetHb. After topical use, due to the lipophilicity and rapid acetylation in the tissue, little BZC reaches the liver for hepatic biotransformation. However, isolated human livers have been shown to produce MetHb forming N-hydroxyl metabolites from BZC. We report a case of BZC-induced MetHb with the first identification and quantification of the reactive metabolite responsible for the oxidative stress: N-Hydroxy-Para-amino benzoic acid (N-OH-PABA). CASE DETAILS: An 8 year old male was admitted to a hospital for an appendectomy. Several applications of BZC spray were used during multiple attempts at nasogastric tube placement. In various attempts to achieve local anesthesia, benzocaine spray was used in both nares and through the mouth aimed at the posterior oropharynx. The patient subsequently became cyanotic with an initial MetHb level of 32.9 %. Methylene blue was administered and the patient promptly responded with resolution of cyanosis. Blood taken within 20 min of the initial symptoms contained benzocaine (5.2ug/mL), bupivacaine (740ng/mL), lidocaine (530ng/mL), acetaminophen (12ug/mL), midazolam (60ng/mL), PABA and N-OH-PABA (35ng/mL). Serum was analyzed using Liquid Chromatography- Quadrupole Time-of-Flight Mass Spectrometry. Mass spectrometry was done using an electrospray ionization source run in negative and positive polarities. A reference standard for N-OH-PABA was synthesized for confirmation and quantification. DISCUSSION: The rare and idiopathic nature of methemoglobinemia after benzocaine use has made study of the pathophysiologic mechanism in humans difficult. Lack of understanding has brought calls for restriction of use of the widely used medication that may not be based on evidence. Our case presents several unique features: 1) benzocaine absorption after topical administration was documented with serum concentrations 2) confirmation of an in vivo formation of MetHb-forming n-hydroxyl-metabolite after benzocaine use and 3) the documentation of N-OH-PABA in humans within 20 min of MetHb post-benzocaine administration.

Medication errors reported to U.S. Poison Control Centers, 2000-2012.

CONTEXT: Previous studies of medication errors have largely focused on healthcare facilities and have not reported generalizable national trends among out-of-hospital medication errors. OBJECTIVE: We sought to understand U.S. trends in medication errors, including the age-related risks, the involved medications, and the medical outcomes. MATERIALS AND METHODS: We performed a retrospective analysis of National Poison Data System (NPDS) data from the American Association of Poison Control Centers for years 2000-2012. Medication error cases were analyzed by age, gender, pharmaceutical involved, substance rank, dosing error type, management site, level of healthcare received, and medical outcome. Trends in medication error rates were analyzed using Poisson regression. RESULTS: From 2000 to 2012, the NPDS recorded 2,913,924 calls reporting unintentional pharmaceutical-related errors that met inclusion criteria. Non-healthcare facility calls comprised 99.2% calls related to unintentional therapeutic errors. Eighty-seven percent of medication errors were managed on site. The annual medication error rate for all callers per 10,000 U.S. population increased significantly (p < 0.0001) by 69.8% from 2000 (4.98 calls per 10,000 population) to 2012 (8.46 calls per 10,000 population). Among adults aged 20 years and older, age was positively correlating (r = 0.96) with the rate of medication error. Analgesics were the most frequent pharmaceutical class involved in medication errors for ages 6-49 (N = 221,061). Among ages 20-49 years, opioid-related medication errors decreased by 7.9% from 2010 to 2012. Cardiovascular drugs were the leading source of injury among all ages (N = 14,440) and also the leading pharmaceutical class involved in medication errors among adults 50 years and older (N = 187,760). CONCLUSION: Medication errors continue to be a source of preventable injury with increasing incidence across the out-of-hospital population.

Comparison of US population and live birth rates with poison exposures reported to the National Poison Data System (NPDS): children ages 0-5 years from 2000 to 2012.

BACKGROUND: Monitoring of poison control center data has provided an important public health surveillance tool. Previous work has identified the population with the greatest risk of poisoning as children of < 6 years. It follows that the size of the population at highest risk should be an important driver/factor of poison center volume. Therefore, one would expect population changes to be reflected in corresponding National Poison Data system (NPDS) call volume changes. We examined this relationship. METHOD: This was a retrospective comparison of young children's poison exposures reported to NPDS with changes in US population as reported by the US Census Bureau and by live birth counts in the United States. We examined the relation of population and live birth counts to NPDS exposures in children of 0-5 years and for the total (children of 0-5 years). RESULTS: There was a statistically significant relation between exposures and population for the three of the seven age groups (1-3 years old) and between exposures and live birth counts for the five of the seven age groups (1-4 years old and total (0-5)). The highest correlation was seen with the age groups of 2-year olds (r = 0.815; slope, 4.7373; 95% CI, 2.36-7.11) and 1-year olds (r = 0.785; slope, 4.878; 95% CI, 2.163-7.592). Live birth count was more closely related than population for all but the 1-year-old age groups. DISCUSSION: Our study reports a number of interesting findings including 1) live birth counts and population are closely associated with each other, 2) poison exposures in NPDS were more strongly associated with live birth counts than with population, 3) the population at greatest risk is the 1- and 2-year-old age groups and the strongest associations between exposures and population and exposures and live birth counts occurred in these two age groups, and 4) changes occurring in the live birth counts, both positive and negative, were reflected in annual changes reported in NPDS human exposures in children < 6 years. These results mean that population changes underlie 37%-66% of the changes in poison exposures and suggests that the population at risk should be considered in monitoring poisoning injuries in the future. CONCLUSION: These results provide a quantitative assessment of the age-based risk rates and changes over time for NPDS exposure in children who are 0-5 years old. With the decrease in live births noted over the last 4 years (2008, 2009, 2010, and estimated 2011), US poison centers may expect a similar decline in human exposures in children of 0-5 years. Our analysis adds additional support to the validity of this data set as a public health surveillance tool.

Age-specific and age-adjusted penetrance as poison center outcome measures.

BACKGROUND: The American Association of Poison Control Centers defines penetrance as the number of exposures per 1000 residents of a population during one year. This metric fails to account for confounding by age group variability. We demonstrate the error caused by using raw penetrance and present two alternate methods of calculation, age-specific penetrance and age-adjusted penetrance. METHODS: Data from the toxic exposure surveillance system were collected from calls to our 41 county regional poison centers in 1998. Age-specific penetrance (ASP) was calculated by dividing the number of exposures (E) in age interval "i" in county "A" by 1000 population in age interval "Pi" in county "A" or ASP = Ei/Pi. AAP is the summation of the weighted age-specific penetrance. Weights (w(si)) represent the relative age distribution of a standard population, in this case the 1998 US population. AAP = sigma(i) w(si) * Ei/Pi. RESULTS: [table: see text] County C has low raw penetrance and is known to have relatively fewer toddlers and presumably a lower incidence of poisoning. This demonstrates that raw penetrance misrepresents populations with small proportions of children and should not be used to compare promotion or prevention activities between populations. CONCLUSION: We recommend poison centers and the American Association of Poison Control Centers replace raw penetrance with age-adjusted penetrance as one measure of the effectiveness of a poison center's awareness efforts.

Does fluorescent urine indicate antifreeze ingestion by children?

OBJECTIVE: Fluorescent urine has been reported to indicate antifreeze ingestion. Recently, we evaluated a child who was suspected of ethylene glycol ingestion. Although she had fluorescent urine, subsequent studies showed that she had not ingested antifreeze. We tested whether fluorescent urine indicates antifreeze ingestion by children. METHODS: A convenience sample of urine specimens from 30 hospitalized children was obtained. All of the patients had been hospitalized for reasons unrelated to poisoning. The specimens were viewed with a Wood's lamp, and the samples were identified as fluorescent or not fluorescent. A second convenience sample of urine specimens from a group of 16 healthy children was obtained, and these specimens were identified as fluorescent or not fluorescent in a similar manner. RESULTS: The majority of urine specimens obtained from children are fluorescent. There is variation in the interpretation of urine fluorescence among observers. The type of container used may influence the finding of fluorescence. CONCLUSIONS: Fluorescent urine is not an indicator of ethylene glycol antifreeze ingestion by children.