Adverse Events Related to Accidental Unintentional Ingestions From Cough and Cold Medications in Children.

OBJECTIVES: Previous research has demonstrated that accidental unsupervised ingestions (AUIs) were responsible for the majority of cough and cold medication (CCM) ingestions leading to significant adverse events (AEs) in children. The objective of this analysis was to characterize the role of AUIs in the morbidity associated with CCM exposure in children. METHODS: This surveillance study collected data from 5 United States data sources from 2009 to 2016, in children younger than 6 years with an AE from an AUI involving at least 1 CCM over-the-counter pharmaceutical ingredient. An expert panel reviewed each case to determine causality. RESULTS: From 4756 total cases reviewed, 3134 (65.9%) had an AE from an AUI determined to be at least potentially related to a CCM ingredient. The majority (61.3%) of cases occurred in children aged 2 to younger than 4 years. Most exposures occurred in the child's own residence (94.9%), and 43.8% were admitted to a health care facility (22.0% to a critical care unit). Dextromethorphan and diphenhydramine, when packaged alone or in combination products, contributed to 96.0% of AUIs. The most common specific products involved were single-ingredient pediatric liquid diphenhydramine (30.1%) and single-ingredient pediatric liquid dextromethorphan (21.4%). There were 3 deaths from solid diphenhydramine formulations. CONCLUSIONS: There continues to be opportunities for the implementation of interventions to prevent AUIs of CCM in children. Additional emphasis on engineering controls, such as flow restrictors for liquid formulations targeting diphenhydramine and dextromethorphan products, represent additional opportunities to further reduce AEs from AUIs of CCM.

Evaluation of the quality and value of data sources for postmarket surveillance of the safety of cough and cold medications in children.

BACKGROUND: The purpose of this report is to evaluate the quality of data sources used to study cough and cold medication (CCM) safety in children via the Pediatric Cough and Cold Safety Surveillance System. METHODS: The System utilized the National Poison Data System (NPDS), FDA Adverse Event Reporting System (FAERS), English-language medical literature, manufacturer postmarket safety databases, and news/media reports to identify cases from January 2008 through September 2016. Each data source was evaluated by the proportion of detected cases determined to be eligible (met case criteria) and the proportion determined to be evaluable (able to determine causal relationship between adverse event and exposure). RESULTS: A total of 7184 unique cases were identified from 27,597 detected reports. Of these, 6447 (89.7%) were evaluable. The data source with the highest volume of detected cases was news/media; however, only 0.3% of those cases were eligible for panel review and only 0.2% (24 out of 13,450 cases) were evaluable. The data source with the highest proportion of eligible and evaluable cases was NPDS with 7691 detected cases, 6113 (79.5%) eligible cases, and 5587 (72.6%) evaluable cases. CONCLUSIONS: The data sources utilized to evaluate the safety profile of pediatric CCMs yielded variable detection and evaluation rates, but overall provided a comprehensive look at exposures that otherwise cannot be studied in clinical trials. While this study suggests that each source made a valuable contribution and that evaluable cases are generalizable, improvements are needed in case completeness and accuracy to enhance the quality of postmarket safety evaluations.

Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases.

Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study was to identify and validate reports of liver injury or death in children younger than 6 years who were administered repeated therapeutic doses of acetaminophen. We reviewed US Poison Center data, peer-reviewed literature, US Food and Drug Administration Adverse Event Reports, and US Manufacturer Safety Reports describing adverse effects after acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death after acetaminophen administration to children younger than 6 years were included. The identified reports were double abstracted and then reviewed by an expert panel to determine if the hepatic injury was related to acetaminophen and whether the dose of acetaminophen was therapeutic (≤75 mg/kg) or supratherapeutic. Our search yielded 2531 reports of adverse events associated with acetaminophen use. From these cases, we identified 76 cases of hepatic injury and 26 deaths associated with repeated acetaminophen administration. There were 6 cases of hepatic abnormalities and no deaths associated with what our panel determined to be therapeutic doses. A large proportion of cases could not be fully evaluated due to incomplete case reporting. Although we identified numerous examples of liver injury and death after repeated doses of acetaminophen, all the deaths and all but 6 cases of hepatic abnormalities involved doses more than 75 mg/kg per day. This study suggests that the doses of less than 75 mg/kg per day of acetaminophen are safe for children younger than 6 years.

The growing impact of pediatric pharmaceutical poisoning.

OBJECTIVE: To understand which medications, under which circumstances, are responsible for the noted increase in pediatric medication poisonings, resource use, and morbidity. STUDY DESIGN: Patient records from 2001-2008 were obtained from the National Poison Data System of the American Association of Poison Control Centers for children aged ≤5 years evaluated in a health care facility following exposure to a potentially toxic dose of a pharmaceutical agent. Pharmaceutical agents were classified as over-the-counter or prescription and by functional category. Exposures were classified as child self-ingested the medication or as therapeutic error. For the 8-year period, emergency visits, admissions, significant injuries, and trends in these events were calculated for each substance category. RESULTS: We evaluated 453 559 children for ingestion of a single pharmaceutical product. Child self-exposure was responsible for 95% of visits. Child self-exposure to prescription products dominated the health care impact with 248 023 of the visits (55%), 41 847 admissions (76%), and 18 191 significant injuries (71%). The greatest resource use and morbidity followed self-ingestion of prescription products, particularly opioids, sedative-hypnotics, and cardiovascular agents. CONCLUSIONS: Prevention efforts have proved to be inadequate in the face of rising availability of prescription medications, particularly more dangerous medications.

Trends in adverse events and related health-care facility utilization from cough and cold medication exposures in children.

INTRODUCTION: Initial research following regulatory changes addressing the pediatric safety of cough and cold medications (CCMs) demonstrated decreases in adverse events (AEs). Using a national multi-source surveillance system, we studied subsequent CCM-related AE case rate trends and associated health-care facility (HCF) evaluation in children. METHODS: Data were collected from 2009 to 2016. Case eligibility included: age <12 years; exposure to an over-the-counter product containing ≥1 CCM pharmaceutical ingredient; ≥1 significant AE that occurred in the United States. RESULTS: About 4756 (72.6%) cases were determined at least potentially related to an index ingredient. Accidental unsupervised ingestions (AUIs; 3134; 65.9%) were the most common case type. Nearly half of AE cases involved children 2 to <4 years old (2,159; 45.4%). The AE case rate did not change significantly over time (p = 0.22). The proportion of AE cases resulting in HCF admission increased from 32.4% (207) in 2009 to 43.4% (238) in 2016 (p < 0.01). Exposures to diphenhydramine (1,305; 67.3%) and/or dextromethorphan (591; 30.5%) were involved in the majority of HCF admissions. CONCLUSIONS: The proportion of AE cases resulting in HCF admission increased from 2009 to 2016. Efforts to prevent AUIs such as packaging innovation and engineering controls, particularly for diphenhydramine and dextromethorphan-containing products, should be pursued.

Pediatric Fatalities Associated With Over-the-Counter Cough and Cold Medications.

BACKGROUND AND OBJECTIVES: In 2008, over-the-counter cough and cold medications (CCMs) underwent labeling changes in response to safety concerns, including fatalities, reported in children exposed to CCMs. The objective of this study is to describe fatalities associated with exposures to CCMs in children <12 years old that were detected by a safety surveillance system from 2008 to 2016. METHODS: Fatalities in children <12 years old that occurred between 2008 and 2016 associated with oral exposure to one or more CCMs were identified by the Pediatric Cough and Cold Safety Surveillance System. An expert panel reviewed all cases to determine the causal relationship between the exposure and death, if the intent of exposure was therapeutic, and if the dose was supratherapeutic. Other contributing factors related to the child's death were also identified as part of a root cause analysis. RESULTS: Of the 180 eligible fatalities captured during the study period, 40 were judged by the expert panel to be either related or potentially related to the CCM. Of these, the majority (n = 24; 60.0%) occurred in children <2 years old and involved nontherapeutic intent (n = 22; 55.0%). The most frequently involved index ingredient was diphenhydramine (n = 28; 70.0%). In 6 cases (n = 6; 15.0%), the CCM was administered to murder the child. In another 7 cases (n = 7; 17.5%), death followed the intentional use of the CCM to sedate the child. CONCLUSIONS: Pediatric fatalities associated with CCMs occurred primarily in young children after deliberate medication administration with nontherapeutic intent by a caregiver.

The value of acute toxicity studies to support the clinical management of overdose and poisoning: a cross-discipline consensus.

Acute toxicity studies are no longer required to support first clinical trials of pharmaceuticals in man. However, it is unclear in the wording of the revised ICH M3 whether acute toxicity studies are required later in drug development (e.g., phase 3) in order to support the management of overdose. The NC3Rs held a workshop in January 2010 with representatives from international poison centres, the pharmaceutical and chemical industries, and regulatory and government bodies to explore further whether acute toxicity studies are used to support the clinical management of overdose of pharmaceuticals and whether this work can be translated to other sectors such as the chemical industry. The consensus formed at the workshop was that acute toxicity studies are not used for managing overdose of pharmaceuticals and are of little value in treating human poisoning from chemicals. In this paper, the authors describe the key considerations in treating human overdose and poisoning, challenge the value of the classification and labelling process of chemicals for this purpose and discuss how acute toxicity studies can be improved to better inform risk assessment.

Medication Errors From Over-the-Counter Cough and Cold Medications in Children.

OBJECTIVE: Out of hospital medication-related adverse events (AEs) from cough and cold medications (CCMs) can have significant public health impact. The objective of this study was to characterize pediatric medication error AEs involving over-the-counter (OTC) CCMs to identify preventable factors. METHODS: Multisource national data surveillance system study using an expert panel evaluating CCM AEs related to medication errors. INCLUSION CRITERIA: age <12 years, and at least 1 significant AE from at least 1 index ingredient from a CCM OTC product. RESULTS: From 2009 through 2016, 4756 cases were determined to have a significant AE related to an OTC CCM ingredient and 513 (10.8%) cases were due to a medication error. Nearly half of medication errors involved children 2 to <6 years old (n = 235; 45.8%). Many involved administration by a parent (n = 231; 45.0%) or alternative caregiver (n = 148; 28.8%). In nearly all cases (93.2%), the medication error involved the wrong dose of the medication. Health care facility evaluation occurred in 381 (74.3%) cases. Diphenhydramine and dextromethorphan were responsible for most medication errors and medication errors involving health care facility evaluation. There were no deaths from medication errors. CONCLUSION: In this multiyear surveillance study, medication errors most commonly occurred in children <6 years old who received the wrong volume of a liquid product. Diphenhydramine and dextromethorphan dosing errors were the most common cause of medication errors resulting from CCM use. Continued standardization of measuring devices, concentrations, and units of measure along with consumer education are needed to further decrease medication errors from CCMs.

Adverse events associated with diphenhydramine in children, 2008-2015.

Introduction: Diphenhydramine (DPH) exposures in children may be the result of accidental unsupervised ingestions, caregiver error, and intentional misuse of DPH-containing cough and cold medications (CCM). We sought to understand the nature of pediatric ingestions of DPH, particularly the toxicity and outcome of a single product, single ingredient DPH (DPH-only) exposures, in order to derive ingredient-specific information about the clinical effects and course of such cases.Methods: As part of a U.S. multi-year safety surveillance program to assess the safety of over-the-counter (OTC) medications used in cough and cold preparations in children <12 years of age, an expert panel reviewed cases involving symptomatic adverse events potentially related to oral exposures to these medications. After individual review, the cases were categorized by causal relationship of the reported ingredients to the adverse event, exposure intent (therapeutic, non-therapeutic, unknown intent), and dose (therapeutic, supratherapeutic, or unknown). Following panel review, any disagreement on classification was discussed until a consensus was reached. The data were then analyzed with respect to descriptive findings.Results: The panel reviewed 6618 eligible cases and determined 2802 were at least potentially related to oral exposure to DPH. Of these, 2028 were DPH-only cases (39.1% of all cases judged at least potentially related to a cough and cold medication). The majority (79.5%) of DPH-only cases occurred in children 2 to <4 years of age and involved accidental unsupervised ingestions (74.7%). Liquid pediatric formulations were the most common (51.7%) products reported followed by solid pediatric formulations (24.0%). The most common adverse events were tachycardia (53.4%), hallucinations (46.5%), somnolence (34.7%), agitation (33.9%), and mydriasis (26.3%). Seizures occurred in only 5.5% of cases. Five (0.2%) deaths were reported; in the death cases, the DPH dose was judged supratherapeutic in one and unknown in the other four. Child abuse was reported in four of the five death cases and three of the five deaths were homicides.Conclusions: Exposures to DPH-only products were the most common type of exposure detected in our study of adverse events associated with CCM in children. The majority of the DPH-only cases were the result of accidental unsupervised ingestions. Most adverse events were relatively mild self-limited anticholinergic effects and few deaths occurred. Deaths involving DPH were often associated with child abuse or homicide. Interventions targeting the prevention of accidental unsupervised are likely to be impactful in preventing morbidity associated with DPH-only exposure.

Pediatric fatalities associated with over the counter (nonprescription) cough and cold medications.

STUDY OBJECTIVE: The use of nonprescription cough and cold medicines is widespread, but their use has been sporadically associated with severe toxicity and death. We evaluate the role of these medications in pediatric fatalities and identified factors that contributed to the death. METHODS: Fatalities that involved a child younger than 12 years and mentioned a cough and cold ingredient were obtained from 5 sources. An independent panel of 8 experts (pediatrics, pediatric critical care, pediatric toxicology, clinical toxicology, forensic toxicology, forensic pathology) used explicit definitions to assess the causal relationship between medication ingestion and death. Contributing factors were identified. RESULTS: Of 189 cases included, 118 were judged possibly, likely, or definitely related to a cough and cold ingredient. Of these 118 cases, 103 involved a nonprescription drug, whereas 15 cases involved a prescription medication alone. Of 103 cases associated with nonprescription drugs, the evidence indicated that 88 involved an overdosage. A dosage could not be assessed in the remaining 15 cases. Several contributing factors were identified: age younger than 2 years, use of the medication for sedation, use in a daycare setting, use of 2 medicines with the same ingredient, failure to use a measuring device, product misidentification, and use of a nonprescription product intended for adult use. All cases that occurred in a daycare setting involved a child younger than 2 years. CONCLUSION: In our sample, pediatric fatalities caused by nonprescription cough and cold medications were uncommon, involved overdose, and primarily affected children younger than 2 years. The intent of caregivers appears to be therapeutic to relieve symptoms in some cases and nontherapeutic to induce sedation or to facilitate child maltreatment in other cases.

A clinical decision aid for triage of children younger than 5 years and with organophosphate or carbamate insecticide exposure in developing countries.

STUDY OBJECTIVE: Unintentional pediatric exposure to insecticides is common in developing countries. A clinical decision aid could guide early triage decisionmaking. METHODS: Study design was prospective observational data collection in a specialty poisoning hospital in Cairo, Egypt. Patients were children 2 months to 59 months of age, without pretreatment, presenting within 2 hours of an exposure to an organophosphate or carbamate insecticide. A resource-requiring course was defined as any occurrence of hypoxia, use of atropine or obidoxime, use of ICU care, or death. The goal of analysis was derivation of a clinical decision aid to predict a resource-requiring course with 100% sensitivity. RESULTS: During the 21-month study, 197 children 2 months to 59 months of age exposed to an organophosphate or carbamate insecticide were treated at the center. One hundred two of these children met the study inclusion criteria: 95 had parental consent and completed the study observation period of which 65 used resources (4 died). All patients who ultimately met resource-requiring criteria initially did so at arrival. Pinpoint pupil alone identified 63 of 65 of these patients yet wrongly identified only 5 of 30 minimally ill patients. Pinpoint pupil or diarrhea identified 65 of 65 patients with a resource-requiring course while identifying 7 of 30 patients with a non-resource-requiring course (sensitivity 1.00; 95% confidence interval 0.95 to 1.00; specificity 0.77; 95% confidence interval 0.58 to 0.90). CONCLUSION: Using 2 features, pinpoint pupils and diarrhea, we identified at presentation all patients who ultimately had a course using medications or advanced resources. According to this preliminary study, symptoms occur rapidly, so using an early triage aid may be feasible. A validation study is necessary.

Dyskinesias associated with atomoxetine in combination with other psychoactive drugs.

Toxicity experience with atomoxetine, a selective norepinephrine reuptake inhibitor approved for Attention Deficit Hyperactivity Disorder (ADHD), is limited. We report two cases of neurologic complications requiring hospitalization in patients when atomoxetine was added to other psychoactive drugs. A 9-year-old taking clonidine and dextroamphetamine developed psychosis, abnormal involuntary movements, and insomnia. An 18-year-old also initiating venlafaxine developed facial tics, tremors, and speech disturbance. Acute symptoms did not respond to diphenhydramine in either case, but resolved after atomoxetine and other medications were discontinued. Possible explanations include atypical atomoxetine effect, excess atomoxetine or metabolites due to poor metabolizer status (CYP 2D6 polymorphism/deficiency), a drug-drug interaction leading to elevated drug levels or to excess synaptic norepinephrine or dopamine. Serotonin syndrome is a possibility in the second case, but not the first. Clinicians should be aware of emergent dyskinesias when combining atomoxetine with dopaminergic, noradrenergic, or serotonergic medications.

Adverse events associated with pediatric exposures to dextromethorphan.

STUDY OBJECTIVE: Dextromethorphan is the most common over-the-counter (OTC) antitussive medication. We sought to characterize adverse events associated with dextromethorphan in children <12 years old from a surveillance program of OTC cough/cold medication exposures. METHODS: This is a retrospective case series of oral exposures to dextromethorphan with ≥1 adverse event from multiple U.S. sources (National Poison Data System, FDA Adverse Event Reporting System, manufacturer safety reports, news/media, medical literature) reported between 2008 and 2014. An expert panel determined the relationship between exposure and adverse events, estimated dose ingested, intent of exposure, and identified contributing factors to exposure. RESULTS: 1716 cases contained ≥1 adverse event deemed at least potentially related to dextromethorphan; 1417 were single product exposures. 773/1417 (55%) involved only one single-ingredient dextromethorphan product (dextromethorphan-only). Among dextromethorphan-only cases, 3% followed ingestion of a therapeutic dose; 78% followed an overdose. 69% involved unsupervised self-administration and 60% occurred in children <4 years old. No deaths or pathologic dysrhythmias occurred. Central nervous system [e.g., ataxia (N = 420)] and autonomic symptoms [e.g., tachycardia (N = 224)] were the most common adverse events. Flushing and/or urticarial rash occurred in 18.1% of patients. Dystonia occurred in 5.4%. CONCLUSIONS: No fatalities were identified in this multifaceted surveillance program following a dextromethorphan-only ingestion. Adverse events were predominantly associated with overdose, most commonly affecting the central nervous and autonomic systems.

Safety Profile of Cough and Cold Medication Use in Pediatrics.

BACKGROUND AND OBJECTIVES: The safety of cough and cold medication (CCM) use in children has been questioned. We describe the safety profile of CCMs in children <12 years of age from a multisystem surveillance program. METHODS: Cases with adverse events (AEs) after ingestion of at least 1 index CCM ingredient (brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, and pseudoephedrine) in children <12 years of age were collected from 5 data sources. An expert panel determined relatedness, dose, intent, and risk factors. Case characteristics and AEs are described. RESULTS: Of the 4202 cases reviewed, 3251 (77.4%) were determined to be at least potentially related to a CCM, with accidental unsupervised ingestions (67.1%) and medication errors (13.0%) the most common exposure types. Liquid (67.3%), pediatric (75.5%), and single-ingredient (77.5%) formulations were most commonly involved. AEs occurring in >20% of all cases included tachycardia, somnolence, hallucinations, ataxia, mydriasis, and agitation. Twenty cases (0.6%) resulted in death; most were in children <2 years of age (70.0%) and none involved a therapeutic dose. The overall reported AE rate was 0.573 cases per 1 million units (ie, tablets, gelatin capsules, or liquid equivalent) sold (95% confidence interval, 0.553-0.593) or 1 case per 1.75 million units. CONCLUSIONS: The rate of AEs associated with CCMs in children was low. Fatalities occurred even less frequently. No fatality involved a therapeutic dose. Accidental unsupervised ingestions were the most common exposure types and single-ingredient, pediatric liquid formulations were the most commonly reported products. These characteristics present an opportunity for targeted prevention efforts.

Mitigation of pennyroyal oil hepatotoxicity in the mouse.

OBJECTIVES: Pennyroyal oil ingestion has been associated with severe hepatotoxicity and death. The primary constituent, R-(+)-pulegone, is metabolized via hepatic cytochrome P450 to toxic intermediates. The purpose of this study was to assess the ability of the specific cytochrome P450 inhibitors disulfiram and cimetidine to mitigate hepatotoxicity in mice exposed to toxic levels of R-(+)-pulegone. METHODS: 20-g female BALB/c mice were pretreated with either 150 mg/kg of cimetidine intraperitoneal (IP), 100 mg/kg of disulfiram IP, or both. After one hour, mice were administered 300 mg/kg of pulegone IP and were killed 24 hours later. Data were analyzed using ANOVA. Post-hoc t-tests used Bonferroni correction. RESULTS: There was a tendency for lower serum glutamate pyruvate transaminase in the disulfiram and cimetidine groups compared with the R-(+)-pulegone group. The differences were significant for both the cimetidine and the combined disulfram and cimetidine groups compared with the R-(+)-pulegone group. Pretreatment with the combination of disulfiram and cimetidine most effectively mitigated R-(+)-pulegone-induced hepatotoxicity. CONCLUSIONS: Within the limitations of a pretreatment animal model, the combination of cimetidine and disulfiram significantly mitigates the effects of pennyroyal toxicity and does so more effectively than either agent alone. These data suggest that R-(+)-pulegone metabolism through CYP1A2 appears to be more important in the development of a hepatotoxic metabolite than does metabolism via CYP2E1.

Use of vasopressin in a canine model of severe verapamil poisoning: a preliminary descriptive study.

OBJECTIVES: The purpose of this preliminary study was to evaluate the effect of arginine vasopressin (AVP) administration in a model of shock induced by calcium channel antagonist overdose and to determine endogenous serum AVP concentrations in calcium channel antagonist-induced shock. METHODS: This was a controlled, randomized laboratory investigation based on a previously described canine model of verapamil toxicity. After induction of verapamil toxicity, animals in both the control and the experimental groups (n = 6 each) received a continuous infusion of verapamil. Experimental animals received an escalating dose of AVP, while control animals received an equal volume of 0.9% saline infusion. The hemodynamic end point was return of mean arterial pressure (MAP) to within 20% of baseline. Surviving animals were killed after 60 minutes. RESULTS: In the treatment group, administration of low-dose AVP (4 mU/kg/min) resulted in further declines in cardiac index and heart rate. No significant change was noted in MAP with low-dose AVP. A slight increase in MAP was noted with both escalating doses of AVP and equivalent volumes of normal saline. By the end of the 60-minute antidote/saline phase, the MAPs of the saline control group and the AVP experimental group were similar. The primary hemodynamic end point was not achieved in either the AVP or the saline control arm. Mean baseline serum AVP concentration in control animals was 5.8 pg/mL, increasing to 225 pg/mL during the toxicity phase. CONCLUSIONS: In an animal model of verapamil-induced shock, endogenous AVP levels increased nearly 40-fold compared with baseline levels. Escalating doses of exogenous AVP worsened cardiac index and failed to return MAP to within 20% of baseline.

Trends in hepatic injury associated with unintentional overdose of paracetamol (Acetaminophen) in products with and without opioid: an analysis using the National Poison Data System of the American Association of Poison Control Centers, 2000-7.

BACKGROUND: Unintended hepatic injury associated with the use of paracetamol (acetaminophen)-containing products has been growing. OBJECTIVE: The aim of the study was to seek a better understanding of the causes of this observation in order to evaluate the potential impact of proposed preventive measures. STUDY DESIGN: Retrospective analysis of a large database containing prospectively collected patient exposure data, clinical symptomatology and outcome. SETTING: The National Poison Data System database for 2000-7 involving exposures to paracetamol and an opioid was obtained and analysed. This dataset was limited to non-suicidal cases in patients 13 years of age and older. For comparison, the parallel, mutually exclusive dataset involving exposures to one or more non-opioid containing paracetamol products was analysed. OUTCOME MEASURE: Trends in the numbers of patients exposed, treated, and mildly and severely injured were obtained and compared with each other and with trends calculated from publicly available data on sales and population. The association of injury with the number of paracetamol-containing products and the reason for taking them were also assessed. RESULTS: Comparators: During the study period, the US population of those 15 years of age and over rose 8.5%; all pharmaceutical-related calls to all US poison centres rose 25%. For the 8-year period from 2001 to 2008, sales of over-the-counter paracetamol products rose 5% (single-ingredient products fell 3%; paracetamol-containing combination cough and cold products rose 11%) and prescription paracetamol combination products rose 67%. Opioids with paracetamol: A total of 119 731 cases were identified, increasing 70% over the period. The exposure merited acetylcysteine treatment in 8995 cases (252% increase). In total, 2729 patients (2.3%) experienced some hepatic injury (500% increase). Minor injuries rose faster than severe injuries (833% vs 280%) and most injuries (73.0%) were from overuse of a single combination product only, but the injury rate increased with use of more than one paracetamol-containing product. Abuse and misuse accounted for 34% of cases but 58% of the severe injuries. Paracetamol without opioid: A total of 126 830 cases were identified, increasing 44%, and 15 706 cases merited acetylcysteine (70% increase). A total of 4674 patients (3.7%) experienced some hepatic injury (134% increase). [corrected] Use of more than one non-opioid paracetamol product occurred in 7.3% of patients and was associated with a lower injury rate. CONCLUSIONS: Hepatic injury associated with paracetamol use is increasing significantly faster than population, paracetamol product sales and poison centre use. This suggests a growing portion of consumers is self-dosing paracetamol beyond the toxic threshold. This is true for paracetamol with and without opioids, but the increase in hepatic injury is greater when paracetamol is taken with an opioid. This disproportionate rise is greatest with misuse and abuse of paracetamol products in combination with opioids. Increasing self-dosage of the opioid combination products for the opioid effect is likely to result in more cases of toxic exposure to paracetamol. In contrast, cases of exposure to paracetamol-containing cough and cold products are underrepresented among those injured. In the absence of opioid-containing products, consumption of more than one paracetamol-containing product did not contribute to injury. Efforts to modulate unintentional paracetamol-related hepatic injury should consider these associations.

Emergency department use after pediatric pharmaceutical ingestion: comparison of two national databases.

BACKGROUND: As no "gold standard" measure exists for the number of children evaluated in emergency departments (EDs) for medication-related injuries, the public health impact is based on estimates. In January 2006 the Morbidity and Mortality Weekly Report published a National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP) estimate on unintentional pediatric medication exposure to children < or =4 years of age that resulted in an ED visit: 53,517 per year for the period 2001-2003. We sought to generate a parallel estimate using American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS) to see how these estimates compare. METHODS: To match data reported from the NEISS-AIP, NPDS was searched for the electronic medical records of children < or =4 years of age whose call type was an unintentional exposure to a pharmaceutical that involved presenting to a health care facility (HCF) in 2001-2003. RESULTS: 178,513 met all of the criteria: 57,100 in 2001; 60,098 in 2002; and 61,315 in 2003. Comparing NEISS-AIP to NPDS: 10% versus 13% were hospitalized; 72% versus 68% were either 1 or 2 years of age; and the substance distribution was acetaminophen (8.1%, 6.8%), cough/cold (7.5%, 9.6%), cardiovascular (7.8%, 11.0%), anticonvulsant (3.6%, 3.2%), and vitamins (4.5%, 3.4%). CONCLUSION: These results are close suggesting that the actual number is near these numbers. The NPDS number is greater than NEISS-AIP point estimate but within the 95% confidence interval. As NPDS is an actual count and NEISS-AIP is an extrapolation from a sample, to the extent that every child presenting to an ED following a medication exposure is not reported to a poison center, both databases may underestimate the problem. The NEISS-AIP extrapolation tool may need to be reassessed.