Hydroxyzine-induced priapism.

Priapism is a severe urologic condition requiring emergency management. Ischemic priapism is the most common subtype which is characterized by a long-lasting, painful, and rigid erection which can be caused by medications with alpha-adrenergic properties such as hydroxyzine. Typically, medication-induced priapism is reported at therapeutic doses and few case reports exist implicating medication overdose as the cause. We report a case of a patient taking hypercompliant doses of hydroxyzine hydrochloride for worsening insomnia (200-600 mg), including the night before admission. Blood-gas analysis of blood from the right corpora was completed and revealed a pH of 6.736, pCO2 of 147, HCO3 of 18.6 and a base excess of 17.7. The patient required aspiration and 560 µg of intracavernosal phenylephrine to achieve sustained detumescence. Emergency physicians should be aware of this risk as priapism is a medical emergency and this is the first report with hydroxyzine after an intentional overdose to our knowledge.

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.

Second-generation antihistamines: a study of poisoning in children.

Background and objectives: The toxicity of second-generation antihistamines after an overdose by a child is still unknown. The objective of this study is to use data from Poisons Centres in France to describe the toxicity profile of second-generation antihistamines for children and to compare the severity of poisoning observed from these with a first-generation antihistamine.Method: This was a retrospective, multi-centre and observational study focusing on human cases of single-substance exposure to a second-generation antihistamine and to mequitazine, reported between 1 January 2001 and 31 December 2016 in Poisons Centres in France.Results: From a total of 9403 children included, 5980 were exposed to a second-generation antihistamine and 3423 were exposed to mequitazine. The severity of exposure to second-generation antihistamines in children is low: among the children followed until a known outcome, 9% of children were symptomatic and in 97% of cases, the symptoms shown were of a minor-level severity (primarily drowsiness or restlessness). Depending on the substance, children who ingested doses 16 to 69 times the maximum recommended therapeutic dose remained asymptomatic. No deaths or severe symptoms were observed. No cases of lengthening of the QT interval or arrhythmias were identified. Mequitazine led to more symptoms than other substances (14.8% symptomatic children vs. 7.5%, Odd ratio (OR): 2.3 (2.0-2.6), p < 0.0001), more symptoms of moderate intensity (1.4 vs. 0.2%, OR: 8.3 (4.1-18.5), p < 0.0001) and more hospitalisation (19.1 vs. 8.7%, OR: 2.5, 95% CI: (2.2-2.8), p < 0.0001).Conclusion: The severity of poisoning from second-generation antihistamines appears to be low among children and considerably lower than poisoning caused by mequitazine.

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.

[Cyclizine is sold in Denmark as an over-the-counter drug and has serious side effects when overdosed].

Cyclizine is sold in Denmark as an over-the-counter drug and affects not only histaminergic but also muscarinergic, serotonergic and α-adrenergic receptors, with side effects such as respiratory depression and cardiac arrhythmias, leading to fatalities. Due to the numerous side effects, it raises questions concerning the status of cyclizine as an over-the-counter drug. Data of healthcare contacts because of cyclizine intoxication in the 2014-2016 period should be analyzed to further illuminate the health risk of cyclizine poisoning.

Doxylamine succinate overdose: Slurred speech and visual hallucination.

Derinöz-Güleryüz O. Doxylamine succinate overdose: Slurred speech and visual hallucination. Turk J Pediatr 2018; 60: 439-442. Doxylamine succinate is a commonly used antihistamine for respiratory allergies including allergic rhinitis as well as for the management of insomnia. As it is available over-the-counter like other nonprescription antihistamines and sleep aids, there is a risk of overdose. It is believed that doxylamine succinate has both peripheral and central activity with its anticholinergic properties. Delirium, seizures, and coma are among the central adverse effects that are rare. This case was presented since it is the first case in the literature who developed slurred speech and visual hallucination after high dose doxylamine succinate use and received antidotal therapy for anticholinergic side effects.

[Intentional suicide with cyclizine].

Cyclizine is an antihistamine with a sedative effect. In Denmark it is an over-the-counter drug, whereas it is a prescription drug in many other countries. It possesses anticholinergic and antiemetic properties, although the exact mechanism of action is unknown. At doses greater than 5 mg/kg potent side effects of anticholinergic character can be expected. This case report is a description of an intentional suicide with a dose greater than 70 mg/kg.

A Danish Survey of Antihistamine Use and Poisoning Patterns.

The first-generation antihistamine, promethazine, became a prescription-only drug in Denmark as of December 2014. First-generation antihistamines are known to have a higher toxic potential than second-generation antihistamines. The aim of this study was to provide a nationwide description of the antihistamine use and poisoning pattern from 2007 to 2013 in Denmark based on two independent databases. There were 1049 antihistamine exposures in the national, advisory telephone service specialized in poisonings, the Danish Poison and Information Centre (DPIC), and 456 exposures in the three registers used within the State Serum Institute of Denmark (SSI), a department under the Danish Ministry of Health dealing with research-based health surveillance in Denmark. First-generation antihistamines constitute 61% and 73% of antihistamine registrations in DPIC and SSI, respectively. Antihistamine exposures increased by 7 exposures/10,000 enquiries per year in DPIC and six admissions per year in SSI - this increase is not significant due to a sudden decrease in 2012. Intentional exposures constituted 65% in DPIC of which 82% was due to suicide attempts, and 78% of the involved antihistamines were first-generation antihistamines. Accidental exposures constituted 33% of which 61% were due to play and 29% involved first-generation antihistamines. Single antihistamine exposures constituted 65% of DPIC exposures of which 98% involved only one brand of antihistamine. Multidrug exposures constituted 35% of DPIC exposures with equally distributed coingestants. Hospitalization was recommended in 78% of DPIC exposures. Admissions required only 1-day of treatment in 91% of the SSI exposures. One of the 14 identified deaths in the SSI study population was directly related to antihistamine poisoning. Results support the limited disclosure of promethazine in Denmark and illustrate a generation-specific pattern indicating a suspected replacement of promethazine with other first-generation antihistamines.

Retrospective review of unintentional pediatric ingestions of doxylamine.

BACKGROUND: Doxylamine is a first-generation antihistamine similar in structure to diphenhydramine. Unlike diphenhydramine, however, there is a paucity of data regarding the risk of toxicity following unintentional exposures in pediatric patients. METHODS: We performed an observational case series with data collected retrospectively from a poison system database for all single-substance pediatric (5 years-old and younger) doxylamine ingestions for the period of 1997-2012. Data collected included age, gender, weight, reason for exposure, exact or estimated maximum dose, clinical effects and medical interventions. RESULTS: A total of 140 cases were identified; 74 (53%) involved males. Ages ranged 6 months to 5 years. In 30 cases (21%), the exact amount ingested was documented and ranged from 6.25-50 mg with a maximum weight-based dose of 6.2 mg/kg. In 76 cases, the estimated maximum dose ranged from 12.5 to 375 mg with a maximum weight-based dose of 37 mg/kg. All symptoms were mild and self-limiting. The only documented intervention was the administration of activated charcoal in 13 cases. CONCLUSION: Unintentional isolated pediatric doxylamine ingestions did not result in significant toxicity in our 140 cases. Reported doses of up to 6.2 mg/kg resulted in only transient drowsiness and tachycardia.

Diphenhydramine overdose with intraventricular conduction delay treated with hypertonic sodium bicarbonate and i.v. lipid emulsion.

Diphenhydramine toxicity commonly manifests with antimuscarinic features, including dry mucous membranes, tachycardia, urinary retention, mydriasis, tachycardia, and encephalopathy. Severe toxicity can include seizures and intraventricular conduction delay. We present here a case of a 23-year-old male presenting with recurrent seizures, hypotension and wide complex tachycardia who had worsening toxicity despite treatment with sodium bicarbonate. The patient was ultimately treated with intravenous lipid emulsion therapy that was temporally associated with improvement in the QRS duration. We also review the current literature that supports lipid use in refractory diphenhydramine toxicity.

Fatal diphenhydramine poisoning in a dog.

We report a fatal diphenhydramine poisoning of a 10-year-old, male poodle-cross dog with pre-existing conditions and suspected co-ingestion of ethanol. This case illustrates that diphenhydramine overdose can be fatal in certain circumstances and that analytical toxicology may play an important role in animal death investigations.

Empoisonnement mortel à la diphenhydramine chez un chien. Nous signalons un empoisonnement mortel à la diphenhydramine chez un caniche croisé mâle âgé de 10 ans ayant des conditions préexistantes et une co-ingestion soupçonnée d'éthanol. Ce cas illustre qu'une surdose de diphenhydramine peut être mortelle dans certaines circonstances et qu'une toxicologie analytique peut jouer un rôle important dans les enquêtes sur la mort d'animaux.(Traduit par Isabelle Vallières).

Diphenhydramine's role in death investigations: an examination of diphenhydramine prevalence in 2 US geographical areas.

PURPOSE: Diphenhydramine (DPH), an over-the-counter first-generation H1 receptor antagonist, is not a common drug of abuse; however, it is encountered in cases of overdose both in the clinical setting and in death investigations. The toxicology laboratories in the Tarrant County Medical Examiner's Office and the District of Columbia Office of The Chief Medical Examiner analyze antemortem and postmortem specimens. Presented are the findings of this evaluation and detailed histories of cases involving DPH. METHODS: Toxicology reports, autopsy reports, and death investigator narratives were obtained in cases involving DPH at toxic and lethal levels in which this compound was the primary cause or a contributing factor in the death. RESULTS: Blood concentrations were quantified at a range of 2870 to 21,263 ng/mL. A rare occurrence of DPH abuse via documented intravenous administration leading to death is presented. The cases presented here generally involved much higher concentrations of DPH and an older population than those in previous published data regarding DPH's role in death investigation and abuse. CONCLUSIONS: As people seek legal alternative drugs to abuse and with the ease of obtaining information via online forums, there is a potential to see an increase in the number of cases involving excessive use of DPH.

Post-mortem evidence of doxylamine in toxicological analyses.

BACKGROUND: Doxylamine (DA) is widely available in pharmacies without prescription and can be used in suicidal intention because of its sedative and anticholinergic properties. Research of literature shows that only a few publications deal with post-mortem evidence of DA and its interpretation during toxicological examination. MATERIAL AND METHODS: In this study, all cases with a positive detection of DA during toxicological analyses with high-performance liquid chromatography in the time period 2000 to 2010 at the Institute of Legal Medicine and Forensic Sciences in Berlin, Germany were retrospectively analysed and interpreted, taking into account police investigations, autopsy results and toxicological analyses. RESULTS: In total, 22 cases with DA intoxications were discovered (♂=16/♀=6, age-at-death range 17 to 90years). Maximum blood concentration was measured at 77.5µg/mL. Cause of death was due to DA intoxication in eight suicide cases; seven of those were combined intoxications (DA and other substances, particularly diphenhydramine). During the evaluated time period no monointoxications with DA were discovered. CONCLUSION: Benchmarks published in past literature are meant as orientation during evaluation of post-mortem DA evidence. These should not be used as absolute values and need to be interpreted individually in each case. Post-mortem redistribution needs to be considered as a main factor in alteration of DA concentration measurement. Furthermore, proof of DA ingestion found in gastric content should only be interpreted quantitatively due to unreliable calculation of the ingested amount. In conclusion, a variety of factors, such as the time period between time of death and the time of the first toxicological analysis, the condition of the body and the findings at autopsy, must also be critically considered.

Suicide due to cyclizine overdose.

Cyclizine is an antihistamine with sedative effect used to treat motion sickness. A few studies have reported on cyclizine abuse among teenagers, and cyclizine abuse has been reported among opioid dependants receiving methadone, with the combination having been reported to produce strong psychoactive effects. Few reports exist on the possible toxic effects of cyclizine, and it is regarded as a safe drug most often sold as a non-prescription/over-the-counter drug. Very few cases of fatalities resulting from cyclizine overdose can be found in the literature. We present a case where a 22-year-old female was found unconscious and intoxication with drugs and alcohol was suspected. Whole blood from the femoral vein, urine and stomach content were collected during autopsy and screened for drugs of abuse and medicinal drugs. GC-MS screening of the stomach contents revealed presence of cyclizine and meclozine. Cyclizine and meclozine concentrations in blood were determined using a UPLC-MS-MS method. Quantification of femoral blood revealed a high concentration of cyclizine (16 mg/L), a low concentration of meclozine (0.2 mg/L) and ethanol 0.16 g/dL. No other medicinal drugs or drugs of abuse were detected. We report on a case of suicide where cyclizine was found to be the principal drug and question the safety of this drug.

Hydroxyzine distribution in postmortem cases and potential for redistribution.

Hydroxyzine is an antihistaminic with sedative properties used in the control of anxiety and emesis. Peripheral blood hydroxyzine concentrations are compared to central blood and liver concentrations in 10 medical examiner cases. Specimens were initially screened for alcohol and simple volatiles by GC-FID headspace analysis, ELISA for drugs of abuse, and alkaline drugs by GC/MS. Hydroxyzine, when detected by the alkaline drug screen, was subsequently confirmed and quantified by a specific GC-NPD procedure. Data suggest that postmortem peripheral blood hydroxyzine concentrations may be considered therapeutic to at least 0.24 mg/L and corresponding liver concentrations to at least 4.9 mg/kg. Hydroxyzine concentrations ranged 0.07-3.0mg/L in peripheral blood, 0.04-3.8 mg/L in central blood, and 0.88-55 mg/kg in liver. Hydroxyzine central blood to peripheral blood ratios averaged 0.92±0.25 (±standard deviation; N=6). Liver to peripheral blood ratios, on the other hand, were higher and averaged 13.8±6.2 (±standard deviation; N=10). Given that a liver to peripheral blood ratio less than 5 is consistent with little to no postmortem redistribution while exceeding 20-30 is indicative of propensity for significant postmortem redistribution, these data suggest that hydroxyzine is prone to a moderate degree of postmortem redistribution.

Accidental death of elderly persons under the influence of chlorpheniramine.

Older individuals are susceptible to accident, such as falls, some of which are fatal. In such cases, autopsies and toxicological analysis may be deemed unnecessary, especially if the critical injuries and manner of death can be determined conclusively based on information at the scene and an external investigation. Here, we report the results of two autopsies performed on elderly individuals who died accidentally under the influence of chlorpheniramine. These autopsies revealed valuable additional information. Case 1: A woman in her 70s, who was living alone, was found dead under the stairs in her house. She had no history of a condition that could have led to sudden death. The autopsy revealed a neck fracture, multiple rib fractures, and a coccyx fracture. The histopathological findings showed fat embolisms in numerous small vessels of the interalveolar septum. Toxicological analysis of blood samples revealed the presence of chlorpheniramine (0.41µg/ml). Case 2: A woman in her 70s, who was living alone, was found dead in the bathtub in her house. There was no past medical history other than diabetes mellitus and vertigo. The autopsy revealed hyper-inflated lungs and brown-red fluids in the trachea, but there was no evidence of a pathology or injury that could have induced a loss of consciousness. Toxicological analysis of the fluids in the right thoracic cavity revealed the presence of chlorpheniramine (0.57µg/ml). In both cases, re-examination of the scene after the autopsy revealed the presence of common cold medicine containing chlorpheniramine. The victim may have accidentally overdosed on common cold medicine. This overdose would have been compounded by anti-histamine-induced drowsiness. The present cases suggest that forensic pathologists should always notify physicians/pharmacists of findings pertaining to unexpected drug side effects. Such intervention would prevent many accidental deaths. In addition, each autopsy must be performed in conjunction with a detailed postmortem investigation. Such efforts would also increase the accuracy of the public health record's mortality statistics.