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.

Toxicological detection of pholcodine in blood, urine and hair in three cases of fatal intoxication.

Pholcodine is an opioid antitussive reputed for its low toxicity and absence of addictive effect. We report three cases of pholcodine intoxication with fatal outcome. Large concentrations of pholcodine were quantified by gas chromatography coupled to mass spectrometry (GC/MS) in peripheral postmortem blood (respectively 2890 ng/mL, 979 ng/mL and 12,280 ng/mL). Segmental hair analyses by GC/MS and detected pholcodine in three 1.5-2 cm segments (38-161 ng/mg, 8.54-41.6 ng/mg, and 0.26-2.66 ng/mg, respectively). These findings underline that pholcodine can be involved in fatal poisoning and raise the question of misuse or abuse and of taking account of this drug in opioid overdose prevention policies.

A description of the clinical course of severe benzonatate poisonings reported in the literature and to NPDS: A systematic review supplemented with NPDS cases.

BACKGROUND: Benzonatate is a commonly prescribed medication that can be lethal in acute overdose of a small number of capsules. OBJECTIVE: This was a systematic review to describe the course of severe poisoning and deaths from benzonatate supplemented with the National Poison Data System (NPDS) fatalities module. METHODS: The NPDS was queried from 2000 to 2018 for benzonatate fatalities. Pubmed, Cochrane, Embase, and Google Scholar were searched for combinations of benzonatate and "poisoning," "overdose," and "toxicity." References of relevant articles were searched for additional publications. Articles were included if they described the clinical course of at least one patient suffering from benzonatate poisoning and available in English. Dual independent review and extraction were performed. RESULTS: Seventeen cases from NPDS and 19 published reports met the inclusion criteria resulting in 36 cases, mostly (28/36) self-harm ingestions. Most patients were young [17 (11-29), median (IQR)] and female (22). Onset of toxicity was rapid at <5 min (9). Most common symptoms included cardiac arrest (29), seizures (24), and dysrhythmias (24). Treatments included intubation (26), cardiopulmonary resuscitation (28), vasopressors (20) and others. Return of spontaneous circulation was achieved in 23/28 patients, but most had significant neurologic deficits or other end organ damage and 5 survived with a good neurologic outcome. CONCLUSION AND RELEVANCE: Overdose ingestions of benzonatate can cause significant toxicity with a rapid onset. Interventions performed were generally supportive in nature. Duration of directly toxic effects is short, but dramatic with neurologic devastation and resuscitated patients often still have a poor outcome.

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.

Inhalant Abuse and Dextromethorphan.

Inhalant abuse is the intentional inhalation of a volatile substance for the purpose of achieving an altered mental state. As an important, yet underrecognized form of substance abuse, inhalant abuse crosses all demographic, ethnic, and socioeconomic boundaries, causing significant morbidity and mortality in school-aged and older children. This review presents current perspectives on epidemiology, detection, and clinical challenges of inhalant abuse and offers advice regarding the medical and mental health providers' roles in the prevention and management of this substance abuse problem. Also discussed is the misuse of a specific "over-the-counter" dissociative, dextromethorphan.

A pseudoencephalitis presentation of a pediatric non-intentional intoxication.

UNLABELLED: We report a case of a pseudo encephalitis presentation of pediatric intoxication - Case report - a 7 year-old girl was admitted to our pediatric emergency unit after she developed sudden agitation, visual and tactile hallucinations. She was febrile (38.3 °C). She had not experienced any recent head trauma, infection or toxic ingestion; she did not take any medication for ADD. Her physical exam revealed tachycardia, normal pupils, reflexes and normal plantar responses. Laboratory investigations (complete blood count, basic metabolic panel, plasma lactate level, ammonia level) produced normal results. Lumbar puncture and computed tomography of the brain were normal. A serum and urine drug screening (benzodiazepines, barbiturates, cocaine, cannabis, amphetamines, methadone, ethanol) was negative. An electroencephalogram, performed during an episode of hallucinations, was compatible with benzodiazepine intoxication. A larger toxic detection by liquid chromatography/diode array detector (LC-DAD) detected promethazine and its metabolites. Symptoms lasted 20 h and she finally said she drank syrup from an over-the-counter cough suppressant medication. Comments - Anticholinergic syndrome is not well recognized or evoked in children presenting hallucinations. Promethazine is still present in several over-the-counter medications, alone or in combination with acetaminophen, carbocisteine or opiates. CONCLUSION: Medications containing promethazine should not be prescribed in children. Such intoxication can mimic encephalitis.

Short-term UROD treatment on cerebral function in codeine-containing cough syrups dependent male individuals.

OBJECTIVE: To investigate alterations of resting brain function in codeine-containing cough syrups (CCS) dependent individuals before and after ultra-rapid opioid detoxification under general anaesthesia (UROD) combined with naltrexone treatment (NMT). METHODS: Fourteen CCS-dependent individuals were scanned using resting-state fMRI. After UROD and 2 weeks of NMT, CCS-dependent individuals were rescanned. Fourteen matched controls were studied at baseline and compared. The amplitude of low frequency fluctuations (ALFF) and seed-based functional connectivity (FC) were used to characterize resting-state cerebral function. RESULTS: After UROD and 2 weeks of NMT, CCS-dependent individuals had increased ALFF in the bilateral parahippocampal gyrus and right medial orbitofrontal cortex (mOFC), decreased ALFF in the left post-central gyrus (PoCG), left middle occipital cortex (MOC) and left dorsal lateral prefrontal cortex (DLPFC), and reduced FC between right mOFC and right DLPFC, and between left DLPFC and left inferior parietal lobe relative to pretreatment. Decreased ALFFs in the left PoCG and left MOC were associated with decreased withdrawal syndrome severity in CCS-dependent individuals. CONCLUSIONS: We offer the first report describing how regional and integral synchronous neural activity occurs after UROD and short-term NMT, accompanied by decreased withdrawal syndrome severity. These findings contribute to the understanding of complex systems involved in UROD-NMT effects. KEY POINTS: • CCS-dependent individuals had reduced ALFF and increased FC at baseline. • UROD treatment can change the regional and integral brain function of CCS-dependent individuals. • Attenuated ALFFs are correlated with the withdrawal syndrome after treatment.

Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: Paediatric deaths associated with over the counter cough and cold medicines.

A short cut review was carried out to establish whether over the counter cough and cold medicines were associated with unexpected deaths in childhood. 115 papers were found using the reported searches, of which three presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of those best papers are tabulated. It is concluded that while over the counter cough and cold medications may be associated with unexpected paediatric deaths, the degree of risk is not clear.

Effect of cough and cold medication restriction and label changes on pediatric ingestions reported to United States poison centers.

OBJECTIVE: To determine the impact of industry and Food and Drug Administration initiatives implemented to limit the use of over-the-counter (OTC) cough and cold medications in children younger than 6 years of age. STUDY DESIGN: This is a retrospective database study of OTC cough and cold medication ingestions reported to US poison centers between 2000 and 2010. Data analyzed from the National Poison Data System included the month and year of ingestion, reason for ingestion, health care utilization, and medical outcome. Ingestion frequencies were stratified by age and reason. Data were divided into pre- and postintervention periods for comparative analysis. RESULTS: Unintentional ingestions of OTC cough and cold medications decreased 33.4% and therapeutic errors by 46.0%. Health care facility referral declined for unintentional ingestions (28.9% <2 years of age, 19.9% 2-5 years of age, P < .0001) and therapeutic errors in children younger than 2 years of age (59.2%, P < .0001). Moderate and severe adverse outcomes decreased for unintentional ingestions in children younger than 2 years of age by 32.4% and by 21.3% in 2- to 5-year olds, P < .0001. CONCLUSIONS: The restriction of OTC cough and cold medications has led to a decline in unintentional ingestions, therapeutic errors, health care facility referral, and serious medical outcomes in children younger than 2 years of age. There has also been a decline in ingestions in 2- to 5-year-old children.

Codeine-associated pediatric deaths despite using recommended dosing guidelines: three case reports.

This report describes the deaths of three children ages 4-10 years due to codeine toxicity at home. All three children were overweight or obese; however, the codeine doses were within recommended dose ranges for adjusted lean weight. Codeine's analgesic effect depends on its metabolic conversion to morphine in the liver via the drug-metabolizing enzyme CYP2D6. Genetic variation may result in poor analgesia, opioid toxicity, or oversedation. Caregivers must be warned about risks associated with comorbidities including obesity and polypharmacy. Codeine should no longer be prescribed to children due to its poor analgesic effect and risk of opioid toxicity and oversedation.

Clinical characteristics of cough mixture abusers referred to three substance abuse clinics in Hong Kong: a retrospective study.

OBJECTIVES. Cough mixture is the third most commonly abused substance in patients attending the Prince of Wales Hospital Substance Abuse Clinic. The content of the local cough mixture is not well researched. Paranoid psychosis manifesting as persecutory delusions and derogatory hallucination, as well as mood symptoms, is common in these patients. The natural history and outcome of such psychoses associated with cough mixture abuse are not well known. This study aimed to address these questions. METHODS. This was a retrospective study of cough mixture abuse in Hong Kong. Case records of cough mixture abusers currently receiving treatment at the 3 substance abuse clinics at the Prince of Wales Hospital, Alice Ho Miu Ling Nethersole Hospital, and the North District Hospital were retrieved for data collection. The patients' demographic data, duration and intake pattern of cough mixture, and use of any other drugs were documented. The presenting psychopathology, first urine toxicology results, diagnosis, treatment, number of hospitalizations, and course of the illness were also recorded. RESULTS. A total of 63 patients with the diagnosis of cough mixture abuse were identified in the database; 89% were male. The mean +/- SD age of the patients was 34.4 +/- 6.2 years; 67% were single and 83% were unemployed. The mean +/- SD age of onset of cough mixture abuse was 20 +/- 5 years. Psychiatric symptoms developed a mean +/- SD of 7.6 +/- 6.0 years after onset of abuse. According to the ICD-10 Mental and Behavioural Disorders criteria, the top psychiatric diagnoses were substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%), and dysthymia (10%). The most common ingredients in the urine sample at first presentation were promethazine (75%), pseudoephedrine (67%), codeine (60%), ephedrine (57%), zopiclone (17%), and hydrocodone (16%). Additionally, 16% of patients were in the priority follow-up group. The mean +/- SD follow-up period was 6.2 +/- 7.1 years during which there were 3.2 +/- 3.7 episodes of hospitalizations, with a mean +/- SD length of stay in each admission of 25.0 +/- 40.9 days. CONCLUSIONS. Promethazine, ephedrine, pseudoephedrine, codeine, and hydrocodone are the most common ingredients of cough mixture abused in this locality. Psychotic disorders are the most frequent psychiatric diagnosis associated with cough mixture abuse.

A fatal case due to cough syrup abuse.

UNLABELLED: We describe here a fatal abused case of cough syrup, containing chlorpheniramine and dihydrocodeine. Postmortem blood concentration of chlorpheniramine was above fatal levels, but dihydrocodeine concentration was within a therapeutic ranges, and those drug levels in blood were discussed from the viewpoint of forensic pharmacokinetics. We concluded that the cause death was due to the chlorpheniramine poisoning. KEYWORDS: cough syrup abuse - chlorpheniramine - dihydrocodeine.

Effects of the antitussive drug cloperastine on ventricular repolarization in halothane-anesthetized guinea pigs.

Cloperastine is an antitussive drug, which can be received as an over-the-counter cold medicine. The chemical structure of cloperastine is quite similar to that of the antihistamine drug diphenhydramine, which is reported to inhibit hERG K⁺ channels and clinically induce long QT syndrome after overdose. To analyze its proarrhythmic potential, we compared effects of cloperastine and diphenhydramine on the hERG K⁺ channels expressed in HEK293 cells. We further assessed their effects on the halothane-anesthetized guinea-pig heart under the monitoring of monophasic action potential (MAP) of the ventricle. Cloperastine inhibited the hERG K⁺ currents in a concentration-dependent manner with an IC50 value of 0.027 µM, whose potency was 100 times greater than that of diphenhydramine (IC50; 2.7 µM). In the anesthetized guinea pigs, cloperastine at a therapeutic dose of 1 mg/kg prolonged the QT interval and MAP duration without affecting PR interval or QRS width. Diphenhydramine at a therapeutic dose of 10 mg/kg prolonged the QT interval and MAP duration together with increase in PR interval and QRS width. The present results suggest that cloperastine may be categorized as a QT-prolonging drug that possibly induces arrhythmia at overdoses like diphenhydramine does.

Dextromethorphan abuse leading to assault, suicide, or homicide.

Dextromethorphan is a commonly encountered antitussive medication which has found additional therapeutic use in the treatment of pseudobulbar disorder and as an adjunct to opiate use in pain management. Dextromethorphan at high doses has phencyclidine-like effects on the NMDA receptor system; recreational use of high doses has been found to cause mania and hallucinations. The toxicology and pharmacology of the drug in abuse are reviewed, and the historical literature of adverse psychiatric outcomes is assessed. Five new cases of dextromethorphan intoxication that resulted in assault, suicide, and homicide are reported, together with the corresponding toxicology results. Blood concentrations ranged from 300 to 19,000 µg/L. These results are compared with typical concentrations reported in therapeutic use and impaired driving cases. Based on these findings, dextromethorphan should be considered as a potential causative agent in subjects presenting with mania, psychosis, or hallucinations, and abusers are at risk for violent and self-destructive acts.