CYP2D6 inhibition by diphenhydramine leading to fatal hydrocodone overdose.

OBJECTIVES: Fatal drug overdoses often involve multiple co-intoxicants, including opioids. Hydrocodone, the most prescribed opioid for pain management, is metabolized to the active metabolite hydromorphone by hepatic CYP2D6. Inhibition of CYP2D6 by other compounds can disrupt the analgesic properties of hydrocodone and extend its half-life. Diphenhydramine is an over-the-counter cold medication and is known to inhibit CYP2D6 activity. CASE PRESENTATION: A woman in her late 50s was prescribed hydrocodone/acetaminophen (Norco® 10/325). Days before her death, she began taking diphenhydramine for cold symptoms. A post-mortem toxicology report detected the following compounds by High Performance Liquid Chromatography/Time of Flight-Mass Spectrometry (LC/TOF-MS) analysis: acetaminophen (14 µg/mL), hydrocodone (410 ng/mL), dihydrocodeine (24 ng/mL), and diphenhydramine (150 ng/mL). Hydromorphone was not detected (<2 ng/mL). All compounds were detected in therapeutic concentrations, except for hydrocodone, which was present at lethal concentrations. CONCLUSIONS: This case highlights a fatal drug-drug interaction between hydrocodone and diphenhydramine. The estimated total body burden of hydrocodone was 6- to 12-fold higher than acetaminophen, which is unexpected, as these two drugs were administered as a single formulation and have similar half-lives. Furthermore, hydromorphone was undetectable. Taken together, these findings are highly suggestive of a fatal opioid overdose precipitated by diphenhydramine.

Impact of social media "challenges" on poison center case volume for intentional ingestions among school-aged children: an observational study.

INTRODUCTION: Mental health problems among youth have escalated over the past decade, with increased rates of self-harm, including suicide attempts by ingestion. Social media use has been linked to youth mental health, including "challenges" urging youth to ingest substances for recreational and other purposes. We hypothesized that social media challenges for particular substances would temporally correspond with increased ingestions of these substances. METHODS: We identified peak Google Trends search times for social media ingestion challenges involving diphenhydramine, laundry pods, nutmeg, and cinnamon, and used data from America's Poison Centers National Poison Data System to plot reported ingestions 3 months before and after peak searches in school-aged children. RESULTS: There were 2,169 individuals in the analysis. Diphenhydramine was the most frequently reported ingestion for misuse/abuse and suicidal purposes (n = 266 and 1,609, respectively). For all ingestions together, 45 percent (n = 979) had a moderate health effect, and 6.35 percent (n = 137) had a major health effect. Time of peak searches corresponded with increased ingestions for each substance. DISCUSSION: We found a temporal relationship between peak Google Trends searches for ingestion challenges and ingestions of that substance reported to United States poison centers. Compared to misuse/abuse ingestions, most suicidal ingestions peaked 1-2 months later, suggesting a public health opportunity for intervention. LIMITATIONS: This retrospective observational study does not establish causal effect. All data are a result of self-reporting of the exposures, which may lead to a reporting bias. Google Trends is not the only search engine and likely underestimates the true incidence of social media posts. CONCLUSIONS: Additional research is needed on the relationship between social media and youth mental health, particularly around "challenges" that place youths' health at risk. There may be opportunities for intervention to decrease medical and mental health sequelae of these challenges.

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.

Clinical and patient characteristics associated with severe outcome in diphenhydramine toxicity.

BACKGROUND: Diphenhydramine is frequently misused and ingested recreationally for its antihistaminergic and antimuscarinic effects and is often involved in both serious and fatal poisonings, either in isolation or in combination with other xenobiotics. OBJECTIVE: This analysis sought to determine which patient and encounter characteristics were associated with severe outcome after diphenhydramine overdose. METHODS: This is an analysis of the multi-center ToxIC registry (2010-2016). Descriptive analysis of all cases with diphenhydramine listed as the "primary agent" contributing to toxicity were included. Analysis sought to determine which patient and encounter characteristics were associated with severe outcome, defined as occurrence of seizure, ventricular dysrhythmia, or intubation. To determine which patient and encounter characteristics were individually associated with severe outcome, we performed chi-square tests. Fisher's exact tests were used in the case of sparse data. We also performed multivariable logistic regression to further determine independent risk factors for severe outcome in diphenhydramine overdose. RESULTS: Eight hundred and sixty-three cases remained after exclusion with 15.6% (n = 135) of all patients having one or more severe outcome. The most common severe outcome was seizures which occurred in 98 (11.6%) of all ingestions. Females comprised 59.1% (n = 510) of all ingestions. Most ingestions were intentional (86.0%, n = 742) with the most common known reason for an intentional ingestion being self-harm, accounting for 37.5% (n = 324) of all ingestions. Self-harm ingestions and ingestions in males were more commonly associated with intubation. When examining outcomes by age, there were no significant differences overall or in any individual outcome except intubation in which children 0-12 were less likely to be intubated as compared to teens and adults. Signs and symptoms most strongly associated with a severe outcome included acidemia (pH < 7.2), QRS prolongation (QRS > 120 ms), and elevated anion gap (AG > 20). DISCUSSION: Acidemia, QRS prolongation, and elevated anion gap are associated with severe outcomes in diphenhydramine toxicity. Further research is warranted to determine their predictive characteristics.

Increased rates of diphenhydramine overdose, abuse, and misuse in the United States, 2005-2016.

OBJECTIVES: To describe trends in abuse, misuse, and suicide attempts involving diphenhydramine (DPH). METHODS: We analyzed intentional DPH exposures of individuals ≥10 years old reported to U.S. Poison Control Centers using data from the National Poison Data System, 2005-2016. RESULTS: There were 158,774 intentional DPH exposures in our dataset. The rate of intentional exposures increased 63% over the 12-year study period for all ages combined. Suicide attempts involving DPH showed a bimodal distribution-increasing 263% among children 10-14 years of age, and 126 and 143% among those 55-64 and ≥65 years of age, respectively. Older adults in both the 55-64 and ≥65-year-old age groups had about a 230% increase in rates of misuse. Major adverse clinical effects increased by 91%. There were 745 total reported deaths with a 3.6% increase across all age groups. CONCLUSIONS: Intentional DPH exposures among individuals ≥10 years old have been increasing since 2005. Increasing rates of suicide attempts among children ages 10-14 and increasing misuse among individuals ≥65, coupled with a trend toward greater severity of overdoses, highlight the significant public health impact of this commonly available over-the-counter drug.

Donepezil: an unusual therapy for acute diphenhydramine overdose.

An elderly man presented with the history of diphenhydramine hydrochloride overdose as a suicidal attempt. At presentation, he was in an acute confusional state with several anticholinergic features and had to be managed in intensive care unit. As an antidote for diphenhydramine hydrochloride, donepezil was used instead of physostigmine due to the unavailability of physostigmine in Bangladesh. The patient improved within the next 24 hours; his level of consciousness improved and the anticholinergic features regressed.

Persistent Vegetative State after Diabetic Ketoacidosis Triggered by an Overdose of Psychotropic Agents.

A 28-year-old man with type 1 diabetes mellitus was admitted for shock and coma due to diabetic ketoacidosis. Despite aggressive treatment and management of the patient's underlying clinical issues, the patient remained in a comatose state. Further investigations revealed an excess consumption of psychotropic agents; however, there was no evidence of an insulin overdose. Physicians should be aware that, in patients who are highly dependent upon insulin, an overdose of psychotropic agents can lead to hypoxic-ischemic brain injury.

Extracorporeal Cardiopulmonary Resuscitation After Diphenhydramine Ingestion.

INTRODUCTION: Diphenhydramine is a widely used first-generation histamine (H1) antagonist that can be obtained without prescription in many countries. Massive ingestions can result in severe toxicity and even death. We describe a case of diphenhydramine overdose leading to cardiac arrest, cardiopulmonary resuscitation (CPR), and extracorporeal membrane oxygenation (ECMO) cannulation for refractory ventricular fibrillation, a process we refer to as extracorporeal cardiopulmonary resuscitation (ECPR). CASE REPORT: Responding to a call for altered mental status, emergency medical service (EMS) personnel found an unconscious and seizing 17-year-old male. He had reportedly developed generalized tonic-clonic seizures and dysrhythmias after ingesting approximately 800 25-mg diphenhydramine tablets. He was transferred to our pediatric intensive care unit (PICU) after stabilization at a local emergency center. After approximately 7 hours of clinical stability and normalization of cardiac rhythm, electrolytes, and acidosis, he developed renewed seizure activity and accelerated ventricular rhythm leading to hemodynamic collapse and cardiac arrest. He was cannulated for veno-arterial extracorporeal membrane oxygenation (VAECMO) with CPR in progress. A pharmacobezoar located in his stomach was presumed to be the cause of his biphasic clinical deterioration. After 5 days, the patient was successfully weaned from ECMO support. Ten days later, his convalescence continued in the step-down unit and was discharged with good functional outcome. DISCUSSION: Significant ingestion of anticholinergic substances is often fatal. This case describes a favorable outcome after ECPR and aggressive supportive management following a large intentional overdose of diphenhydramine.

Adolescent with prolonged toxidrome.

A 13-year-old female was presented to the emergency department following an intentional ingestion. The patient developed significant toxicity including multiple, discreet tonic-clonic seizures. Despite appropriate resuscitation and antidotal management, the patient's symptoms persisted for more than 36 hours post-ingestion. An upright abdominal radiograph was performed revealing a radiopacity suggesting a pharmacobezoar. An esophagogastroduodenoscopy was performed with successful removal of a tennis ball-sized pharmacobezoar. The patient's symptoms subsequently subsided and she recovered fully with no neurologic deficits. Diphenhydramine has not been previously identified as a medication likely to form a pharmacobezoar and has not been shown to be radiopaque. Though bezoar formation is a rare clinical scenario, it is one that toxicologists must consider in patients with clinical courses that persist far beyond expected based on known toxicokinetic principles.

Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning.

BACKGROUND: Although intravenous lipid emulsion (ILE) was first used to treat life-threatening local anesthetic (LA) toxicity, its use has expanded to include both non-local anesthetic (non-LA) poisoning and less severe manifestations of toxicity. A collaborative workgroup appraised the literature and provides evidence-based recommendations for the use of ILE in poisoning. METHODS: Following a systematic review of the literature, data were summarized in four publications: LA and non-LA poisoning efficacy, adverse effects, and analytical interferences. Twenty-two toxins or toxin categories and three clinical situations were selected for voting. Voting statements were proposed using a predetermined format. A two-round modified Delphi method was used to reach consensus on the voting statements. Disagreement was quantified using RAND/UCLA Appropriateness Method. RESULTS: For the management of cardiac arrest, we recommend using ILE with bupivacaine toxicity, while our recommendations are neutral regarding its use for all other toxins. For the management of life-threatening toxicity, (1) as first line therapy, we suggest not to use ILE with toxicity from amitriptyline, non-lipid soluble beta receptor antagonists, bupropion, calcium channel blockers, cocaine, diphenhydramine, lamotrigine, malathion but are neutral for other toxins, (2) as part of treatment modalities, we suggest using ILE in bupivacaine toxicity if other therapies fail, but are neutral for other toxins, (3) if other therapies fail, we recommend ILE for bupivacaine toxicity and we suggest using ILE for toxicity due to other LAs, amitriptyline, and bupropion, but our recommendations are neutral for all other toxins. In the treatment of non-life-threatening toxicity, recommendations are variable according to the balance of expected risks and benefits for each toxin. For LA-toxicity we suggest the use of Intralipid® 20% as it is the formulation the most often reported. There is no evidence to support a recommendation for the best formulation of ILE for non-LAs. The voting panel is neutral regarding ILE dosing and infusion duration due to insufficient data for non-LAs. All recommendations were based on very low quality of evidence. CONCLUSION: Clinical recommendations regarding the use of ILE in poisoning were only possible in a small number of scenarios and were based mainly on very low quality of evidence, balance of expected risks and benefits, adverse effects, laboratory interferences as well as related costs and resources. The workgroup emphasizes that dose-finding and controlled studies reflecting human poisoning scenarios are required to advance knowledge of limitations, indications, adverse effects, effectiveness, and best regimen for ILE treatment.

Analysis of Gastric Lavage Reported to a Statewide Poison Control System.

BACKGROUND: As decontamination trends have evolved, gastric lavage (GL) has become a rare procedure. The current information regarding use, outcomes, and complications of GL could help refine indications for this invasive procedure. OBJECTIVES: We sought to determine case type, location, and complications of GL cases reported to a statewide poison control system. METHODS: This is a retrospective review of the California Poison Control System (CPCS) records from 2009 to 2012. Specific substances ingested, results and complications of GL, referring hospital ZIP codes, and outcomes were examined. RESULTS: Nine hundred twenty-three patients who underwent GL were included in the final analysis, ranging in age from 9 months to 88 years. There were 381 single and 540 multiple substance ingestions, with pill fragment return in 27%. Five hundred thirty-six GLs were performed with CPCS recommendation, while 387 were performed without. Complications were reported for 20 cases. There were 5 deaths, all after multiple ingestions. Among survivors, 37% were released from the emergency department, 13% were admitted to hospital wards, and 48% were admitted to intensive care units. The most commonly ingested substances were nontricyclic antidepressant psychotropics (n = 313), benzodiazepines (n = 233), acetaminophen (n = 191), nonsteroidal anti-inflammatory drugs (n = 107), diphenhydramine (n = 70), tricyclic antidepressants (n = 45), aspirin (n = 45), lithium (n = 36), and antifreeze (n = 10). The geographic distribution was clustered near regions of high population density, with a few exceptions. CONCLUSIONS: Toxic agents for which GL was performed reflected a broad spectrum of potential hazards, some of which are not life-threatening or have effective treatments. Continuing emergency physician and poison center staff education is required to assist in patient selection.

Postmortem computed tomography and magnetic resonance imaging facilitates forensic autopsy in a fatal case of poisoning with formic acid, diphenhydramine, and ethanol.

A case of fatal poisoning by ingesting formic acid, diphenhydramine, and ethanol by a 25-year-old woman who committed suicide is presented. Prior to autopsy, postmortem computed tomography and postmortem magnetic resonance tomography were performed and revealed severe damage to the stomach, the left thoracic wall, and parts of the liver. Imaging detected acid-induced fluid-fluid level within the thoracic cavity (fat-equivalent fluid and necrotic pleural effusion). This case report illustrates that postmortem cross-sectional imaging may facilitate dissection of severely damaged or complex regions, and may provide additional information compared to autopsy and toxicological examinations alone.

Diphenhydramine exposure in dogs: 621 cases (2008-2013).

OBJECTIVE To characterize the signalment, dose response, and clinical signs of diphenhydramine toxicosis in dogs. DESIGN Retrospective case series. ANIMALS 621 dogs with diphenhydramine exposure. PROCEDURES The electronic medical record database for an animal poison control center was reviewed from January 2008 through December 2013 to identify dogs that had ingested or been injected with diphenhydramine. Information extracted from the records and evaluated included the signalment, clinical signs observed, and estimated exposure dose of diphenhydramine. Clinical signs were categorized as none, mild, moderate, and severe. RESULTS The mean ± SEM age of dogs was 3.6 ± 0.1 years (range, 0.1 to 16 years). Diphenhydramine exposure was by ingestion for 581 (93.6%) dogs and injection for 40 (6.4%) dogs. Only 146 (23.5%) dogs developed ≥ 1 clinical signs of toxicosis, the most common of which were associated with the nervous (lethargy, hyperactivity, agitation, hyperthermia, ataxia, tremors, and fasciculations) or cardiovascular (tachycardia) systems, and 3 dogs died. Although the presence and extent of clinical signs varied greatly among dogs, the exposure dose of diphenhydramine was positively associated with the severity of clinical signs in a dose-dependent manner regardless of the route of exposure (ingestion or injection). CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that dogs exposed to diphenhydramine developed clinical signs of toxicosis fairly infrequently, and those clinical signs were generally mild and primarily affected the neurologic and cardiovascular systems. Supportive treatment for diphenhydramine toxicosis should be administered on the basis of the clinical signs observed.

Saving two lives with one dialysis treatment.

Hemodialysis is the extracorporeal treatment of choice for various life-threatening intoxications, with the exception of highly protein-bound substances, which are preferably removed by charcoal hemoperfusion. This technique, however, is limited by its availability and its significant side effects. We present a potentially lifethreatening diphenhydramine (DPH) overdose in a stuporous female patient in which high cut-off hemodialysis was used. Timely detoxification resulted in rapid gain of consciousness, allowing the patient to state the existence and location of another poison victim.