Toxicity and clinical outcomes of paliperidone exposures reported to U.S. Poison Centers.

CONTEXT: Paliperidone is an atypical antipsychotic that was approved in the U.S. in 2006, and is also available in Canada, Australia, New Zealand, Europe, and Asia. Information regarding paliperidone overdoses is limited to case reports. Serious toxicity has yet to be reported. OBJECTIVE: To evaluate the toxicity of paliperidone exposures using a national poison center database. METHODS: A retrospective, observational case series of single-substance paliperidone cases reported to the National Poison Data System from 2007 to 2012 was conducted. Cases were evaluated for demographics, reason for exposure, clinical effects, treatments, disposition, and coded medical outcomes. For cases with major effects the text fields in poison center charts were evaluated to verify accuracy of coded outcome. The relationship between dose and severity of medical outcome was analyzed for acute exposure cases. RESULTS: There were 801 paliperidone cases that met inclusion criteria that included 592 persons of 13 years or greater, 67 children of 6-12 years, 140 children of less than 6 years, and 2 unknown ages. Most common reasons for exposure included: suicide attempt (39.6%), unintentional general (21.1%), therapeutic error (15.7%), and adverse drug reaction (11.9%). The most commonly observed clinical effects were drowsiness/lethargy (28.7%), tachycardia (23.3%), and dystonia (14.2%). Most patients were managed in the emergency department (40.3%) or were admitted to a health care facility (HCF) (42.7%). In 564 cases treated in a HCF, treatments included activated charcoal (25.7%), antihistamines (21.1%), and benzodiazepines (9.4%). Medical outcomes were no effect (35.0%), minor (30.8%), moderate (33.7%), and major effect (0.5%). There were no deaths. Of 491 acute exposures, dose was coded for 74.3% of exposures. There was a significant difference in the reported median dose between those with no effect (6 mg) and either minor effect (12 mg; p = 0.047) or moderate effect cases (12 mg; p = 0.020) in 91 children less than 6 years. CONCLUSIONS: The majority of patients experienced no or minor toxicity and were not admitted for medical care. Although a higher dose was associated with a more serious outcome in children less than 6 years, the data do not provide clear-cut triage guidelines.

Lack of toxicity from pediatric beta-blocker exposures.

The risk of toxicity in a child who is unintentionally exposed to a beta-blocking drug remains uncertain. The current study further defines this risk, particularly in the common scenario of ingestion of one or two tablets. A prospective cohort of 208 pediatric patients, 6 months to 6 years of age, reported to two regional poison centers serves as the study population. Data were collected with a standardized instrument during the care of each patient and for a minimum of 24 hours after exposure. No instances of serious toxicity typical of beta-blocker intoxication, such as 'shock-like' states, arrhythmias or seizures were observed in this series. Furthermore, there were no reported episodes of hypoglycemia, symptomatic bradycardia or bronchospasm. Nine instances of altered mental status or behavioral changes were reported. All appeared to be minor in nature. The most serious outcome was charcoal aspiration during gastrointestinal decontamination. This study adds to a growing body of evidence suggesting that exposure to one or two beta-blocker tablets places children at very little, if any, risk of toxicity.

Efficacy of the cation exchange resin, sodium polystyrene sulfonate, to decrease iron absorption.

BACKGROUND: Iron is not bound by charcoal; therefore, a method of binding iron in the gastrointestinal tract to prevent absorption in iron overdose is needed. This study investigated the efficacy and safety of sodium polystyrene sulfonate to prevent absorption of iron in human volunteers. METHODS: Six adult volunteers completed this prospective crossover trial. Following an oral dose of elemental iron 10 mg/kg, each subject received sodium polystyrene sulfonate 30 g or water as control. Baseline and serial serum iron samples were drawn to determine pharmacokinetic parameters. RESULTS: A trend toward increased time to peak following sodium polystyrene sulfonate compared to the control arm (5.7 vs 3.6 hours) was observed but was not statistically significant (p = 0.517). A trend toward smaller area-under-the-curve for the sodium polystyrene sulfonate was evident but was not statistically significant (p = 0.77). Iron concentration increased on average 298 mcg/dL and 370 mcg/dL above baseline in the treatment and control arms (p = 0.44). Sodium polystyrene sulfonate is not an effective method of decontamination for iron overdose.

Acute beta blocker overdose: factors associated with the development of cardiovascular morbidity.

OBJECTIVE: To identify factors in exposures to beta blockers (beta-adrenergic receptor antagonists) that are associated with the development of cardiovascular morbidity and contribute to disposition decisions from the emergency department. METHODS: Prospective cohort of 280 beta blocker exposures reported to 2 regional poison centers. Multiple logistic regression was used to determine association of various clinical factors and outcome. RESULTS: In this series of beta blocker exposures, 41 (15%) developed cardiovascular morbidity and 4 (1.4%) died. A history of cardioactive coingestant was the only factor significantly associated with the development of cardiovascular morbidity (p < .05). When cases reporting cardioactive coingestants were excluded, a history of ingesting a beta blocker with membrane stabilizing activity was significantly associated with the development of cardiovascular morbidity (p < .05). All those in whom the timing of symptoms could be determined, developed symptoms within 6 hours of ingestion. CONCLUSIONS: The single most important factor associated with the development of cardiovascular morbidity in beta blocker ingestion is a history of a cardioactive coingestant, primarily calcium channel blockers, cyclic antidepressants, and neuroleptics. In the absence of such coingestion, exposure to a beta blocker with membrane stabilizing activity is associated with an increased risk of cardiovascular morbidity. Beta blocker ingestion is unlikely to result in symptoms if the patient remains asymptomatic for 6 hours after the time of ingestion.

Toxicity of polysaccharide--iron complex exposures reported to poison control centers.

OBJECTIVE: To evaluate the toxicity of polysaccharide-iron complex (PIC) exposures reported to poison centers in the US. DESIGN: A retrospective analysis of potentially toxic exposures to PIC without concomitant substances reported to the American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System from 1990 to 1998 was performed. RESULTS: Of 810 potentially toxic exposures to PIC, 55.9% occurred in females, 43.8% in males; in 0.3%, gender was unknown. The majority of exposures (74.4%) involved children under six years of age. The reasons for exposure were: 86.7% unintentional, 11.6% intentional, and 1.6% adverse reaction. The most frequently reported clinical effects attributed to PIC were vomiting (n = 23), diarrhea (10), nausea (11), abdominal pain (10), and lethargy/drowsiness (7). While the majority of exposures were managed outside a healthcare facility, management site varied depending on age (management in non-healthcare facility in 71.8% of exposures in children under six years of age vs. 44.9% in adolescents and adults). The majority of outcomes (95.6%) were no effect, minor effect, unrelated effect, not followed since nontoxic, or not followed since only minimal toxicity possible. Of two cases coded as moderate effect, it could not be determined whether the symptoms were related to PIC in one, and in the second case inspection of the poison center record revealed that the actual outcome was minor effect. There were no major effects or deaths. CONCLUSIONS: There were no serious adverse events following PIC exposure reported to the AAPCC. Although more data are needed, these findings suggest reduced toxicity for PIC relative to other forms of iron.

Multicenter case series of pediatric metformin ingestion.

OBJECTIVE: There are no large studies, case series, or case reports of metformin ingestion in children. This study summarizes the clinical course and outcomes of metformin ingestion in children reported to the American Association of Poison Control Centers-certified regional poison centers. METHODS: This was a case series of all metformin ingestions in patients <18 years of age reported to eight regional poison centers. Data collection included age, gender, dose ingested, co-ingestants, symptoms, vital signs, laboratory values, length of hospital stay, and medical outcome. Entrance into the study required at least 24 hours of follow-up. RESULTS: Fifty-five cases were collected. Ages ranged from 15 months to 17 years, with a mean (+/- SD) of 42+/-4.4 years. The dose ingested, by history, ranged from 250 mg to 16.5 g, with a mean and median of 1710+/-3391 and 500 mg, respectively. Forty-one children (76%) ingested a maximum of two tablets (< or =1700 mg). In the children younger than six years, dosage ranged from 9 to 196 mg/kg, with a mean and median of 60+/-41.1 and 40 mg/kg, respectively. Thirty-seven children were evaluated in a healthcare facility. Clinical effects were limited to nausea (2), diarrhea (2), and dizziness (1). None of the 38 children who had serial glucose measurements experienced hypoglycemia. Arterial blood gas and electrolyte measurements were performed in three and 19 children, respectively. No evidence of acidosis was demonstrated. Two children had lactate concentrations measured and were determined to be in the normal range. Twenty-nine patients received activated charcoal. Five patients received parenteral glucose and one adolescent with a history of diabetes received insulin for hyperglycemia. CONCLUSIONS: Unintentional ingestion of < or =1700 mg of metformin in the healthy pediatric population does not appear to pose a significant health risk of hypoglycemia or detrimental outcome. In the 21 children who were tested for either blood glucose, electrolyte, or lactate concentrations, no evidence of lactic acidosis was seen.

Multicenter case series of valproic acid ingestion: serum concentrations and toxicity.

BACKGROUND: Valproic acid exposures reported to poison centers have increased more than 4-fold over the last 5 years. There are no large case series published on valproic acid ingestion. METHODS: A prospective multicenter case series of all patients reporting an ingestion of valproic acid. Data collected included: age, gender, dose ingested, concomitant medications, symptoms and vital signs, laboratory values, length of hospital stay, and medical outcome. Entrance into the study required a serum valproic acid concentration above the therapeutic threshold of 100 microg/mL. Statistical analysis was by Fisher's exact test. RESULTS: A total of 335 patients were reported to participating centers of which 186 (55%) had serum valproic acid concentrations greater than 100 microg/mL. Of the 186 cases, 53 were multiple drug exposures leaving 133 cases of sole valproic acid ingestion for evaluation. Age ranged from 2 to 66 years with a mean of 30.1 years +/- 12. Peak serum valproic acid concentrations ranged from 110 microg/mL to 1840 microg/mL with a mean of 378.3 microg/mL +/- 310.2 microg/mL. Time from postingestion to the peak measured valproic acid concentration ranged from 1 to 18 hours, with a mean of 7.4 hours +/- 3.9. Symptoms included lethargy (n = 94), coma (n = 19), tachycardia (n = 24), aspiration (n = 8), metabolic acidosis (n = 8), and hypotension (n = 4). A peak concentration of > 450 microg/mL was more likely to be associated with a moderate or major adverse outcome (p < 0.005). A peak concentration > 850 microg/mL was more likely to be associated with coma (p < 0.005) and acidosis (p < 0.005). Eleven patients experienced transient thrombocytopenia (platelets < 150,000) and all had peak valproic acid concentrations >450 microg/mL. Four patients experienced transient leukopenia (WBC < 3,500). The mean hospital stay for all patients was 42 +/- 33.1 hours. A hospital stay > 48 hours was more likely to be associated with a peak valproic acid concentration > 450 microg/mL (p < 0.05). There were 2 fatalities. CONCLUSIONS: In this case series, patients with peak valproic acid concentrations above 450 microg/mL were more likely to develop significant clinical effects and have longer hospital stays. A peak valproic acid concentration above 850 microg/mL was more likely to be associated with coma, respiratory depression, aspiration, or metabolic acidosis.

Donepezil overdose: a tenfold dosing error.

OBJECTIVE: To report toxicity resulting from donepezil administration following a tenfold dosing error. CASE SUMMARY: A 79-year-old white nursing home patient with a history of Alzheimer disease and hypertension was inadvertently given 50 mg of donepezil instead of her usual 5-mg dose. She presented to the emergency department with nausea, vomiting, and persistent bradycardia (HR in the 40s). Routine laboratory studies were all within normal limits. Basilar rales were noted five hours after arrival. She was treated with atropine 0.2 mg as needed for bradycardia (HR <50 beats/min); a total of 3.0 mg was administered over 18 hours. Each bolus kept her HR >60 beats/min for one-half to two hours. No further vomiting or evidence of pulmonary edema occurred after her initial episodes. She returned to baseline by day 2 (HR in the 70s) and was returned to the nursing home. DISCUSSION: Donepezil is a centrally acting, reversible cholinesterase inhibitor that is used in the treatment of Alzheimer disease. Donepezil is highly specific for neural acetylcholinesterases, preferentially binding acetylcholinesterase by greater than three orders of magnitude over butyrylcholinesterases. This specificity minimizes peripheral adverse effects at therapeutic doses. Our patient mainly experienced bradycardia and had minimal secretory effects compared with what is usually seen with nonspecific cholinesterase inhibition. Medication errors like the one that produced this overdose are a common but preventable cause of morbidity in healthcare facilities. CONCLUSIONS: A tenfold dosing error caused donepezil toxicity. The main effect of this overdose was bradycardia, which responded to atropine therapy.

Accidental and suicidal adolescent poisoning deaths in the United States, 1979-1994.

OBJECTIVE: To describe the epidemiological features of poisoning deaths in adolescents in the United States. DESIGN: Descriptive analysis of poisoning deaths in persons aged 10 to 19 years in the United States from January 1, 1979, to December 31, 1994, based on national mortality data. STUDY POPULATION: Adolescents whose cause of death was identified as poisoning using International Classification of Diseases, Ninth Revision codes. MAIN OUTCOME MEASURE: Nature of injury (accident vs suicide). RESULTS: There were 4129 suicides and 3807 accidental deaths due to poisoning. Victims were most frequently male and white. However, poisoning was more often the method of suicide in adolescent girls than in boys (28.0% vs 8.7%). The number of deaths (7138 vs 798) and death rate (2.36 vs 0.28 per 100,000 population) were higher in 15- to 19-year-olds vs 10- to 14-year-olds. The distribution of substances involved was different for 10- to 14-year-olds compared with 15- to 19-year-olds and for suicides compared with accidents. Among 10- to 14-year-olds, drugs other than alcohol accounted for 232 (85.3%) of 272 suicides but only 118 (22.4%) of 526 accidental deaths. Gases and vapors played an important role in accidental deaths and suicides in 15- to 19-year-olds and in accidents in 10- to 14-year-olds. CONCLUSIONS: The rates of suicides and accidental poisoning deaths were lower in 10- to 14-year-olds compared with 15- to 19-year-olds. Areas where injury-prevention efforts might have an influence on adolescent fatalities include management of depression, substance abuse education, and use of carbon monoxide detectors or shutoff switches.

Prolonged formation of methemoglobin following nitroethane ingestion.

BACKGROUND: Artificial nail removers containing nitroethane pose a serious risk of toxicity when ingested. CASE REPORTS: We report 3 cases of children under 3 years of age who developed prolonged methemoglobinemia following ingestions of small quantities of these nitroethane-containing products. Methylene blue therapy reduced the methemoglobin level in all 3 children; however, in 2 of these children methemoglobin levels increased again several hours later and required additional methylene blue. Accurate substance identification is essential for appropriate management of ingestions of fingernail products. The availability of nitroethane products for home use should be questioned.

Agricultural and horticultural chemical poisonings: mortality and morbidity in the United States.

STUDY OBJECTIVE: To provide a comprehensive analysis of morbidity and mortality from poisoning by agricultural and horticultural chemicals in the United States. METHODS: Descriptive analysis of national mortality data, National Hospital Discharge Survey data, and American Association of Poison Control Centers national data for 1985 through 1990. RESULTS: There were 341 fatalities from agricultural and horticultural chemicals over the 6-year period, of which 64% were suicides, 28% were unintentional, and 8% were of undetermined intent. There were 25,418 hospitalizations; 78% were reported to be unintentional. Both deaths and hospitalizations occurred more frequently in males, and rates were higher in nonwhites than in whites. There were 338,170 poison exposures reported to poison centers for fungicides, herbicides, pesticides/insecticides, and rodenticides. Life-threatening manifestations or long-term sequelae occurred in 782 cases, and 97 deaths were reported. Pesticides and insecticides accounted for 72% of the poison center cases and 63% of the fatalities. Although they accounted for only 8% of poison exposures, herbicide deaths were disproportionately high (25%). CONCLUSION: Poisonings with agricultural and horticultural chemicals are an important public health problem. Prevention efforts need to incorporate the fact that many serious cases, such as paraquat poisonings, are suicidal in nature.

Analysis of sertraline-only overdoses.

Sertraline is an antidepressant for which preliminary data suggest a low inherent toxicity. Previously reported case series have included coingestants or had small numbers of patients. This study was undertaken to determine the toxicity of overdoses of sertraline alone. A 2-year retrospective and 6-month prospective study was conducted at a regional poison center. There were 52 patients with a mean age of 19.3 +/- 13.8 years and a mean dose of 727 +/- 686 mg. There were no symptoms in 34 cases. Symptomatic patients experienced mild central nervous system, cardiovascular, and gastrointestinal effects. Two patients developed bradycardia which resolved without therapy. While all but 3 of 38 adolescents and adults were treated in a health care facility, 10 of 14 children were managed at home. Gastrointestinal decontamination was performed in 37 cases. No other specific therapy was required. Serious toxicity would not be expected following sertraline-only overdoses.

Use of activated charcoal in a simulated poisoning with acetaminophen: a new loading dose for N-acetylcysteine?

STUDY OBJECTIVES: To investigate the ability of a supranormal dose of N-acetylcysteine to overcome the effects of activated charcoal on N-acetylcysteine bioavailability and to determine the effects of activated charcoal on serum acetaminophen levels. DESIGN, SETTING, AND PARTICIPANTS: Ten healthy adult volunteers participated in a controlled cross-over experiment. During phase I (control), subjects ingested 3 g acetaminophen, followed one hour later by the normal loading dose of N-acetylcysteine (140 mg/kg). During phase II (charcoal), subjects ingested 3 g acetaminophen, followed one hour later by 60 g activated charcoal and a supranormal loading dose of N-acetylcysteine (235 mg/kg). MAIN OUTCOME MEASURES: Serum levels of N-acetylcysteine were measured every 30 minutes for six hours. A serum acetaminophen level was measured at four hours. RESULTS: The area under the curve for N-acetylcysteine was significantly higher for phase II than phase I (P < .05, two-tailed paired t-test). Peak N-acetylcysteine and time to peak were not significantly different. The four-hour serum acetaminophen level was significantly lower for phase II than phase I (P < .05, two-tailed paired t-test). Diarrhea occurred during both phases, but N-acetylcysteine was otherwise well tolerated. CONCLUSION: These results suggest that activated charcoal can be used safely for victims of acetaminophen overdose. A beneficial effect in preventing acetaminophen absorption can be expected if it is given within one hour after ingestion. If N-acetylcysteine is needed because of a toxic serum acetaminophen level, bioavailability can be ensured by increasing the N-acetylcysteine loading dose from 140 mg/kg to 235 mg/kg.