Article

Toxicological identification of diphenhydramine (DPH) in suicide

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Abstract

Diphenhydramine (DPH), an H1-antihistamine, is identified during postmortem toxicological analyses on a relatively rare but still regular basis. This study examines suicidal intoxications with DPH by analyzing blood and gastric content concentration levels. Twenty cases of DPH intoxications within a 10-year period (2000-2010) were discovered by screening the autopsy records of the Institute of Legal Medicine and Forensic Sciences (ILMFS) in Berlin, Germany. In four cases, DPH levels were lower than 1 μg/mL and hence were not considered likely to be responsible for causing death. In 11 cases, DPH played a role in the fatal episode, and five of these cases were monointoxications. Considering that more than 8,000 autopsies were performed by the ILMFS within the time period under examination, there is only one monointoxication case every 2 years, which makes it a rare occurrence. In two of these intoxications, DPH was only measured in toxic but not "lethal" concentrations in blood, with a concentration of 5 μg/mL being generally used as the cut off between categories according to forensic literature. This raises the question as to whether a strict boundary for a "lethal" blood concentration, as suggested in some literature, can be set and applied in any of these cases. This study shows that an individual interpretation of each case is of utmost importance for correct classification. A thorough toxicological analysis of peripheral venous blood and gastric content, as well as a detailed work-up of the death circumstances, are the basis of an exact interpretation of intoxications with DPH.

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... D IPHENHYDRAMINE OVERDOSE CAN be fatal. 1 Peak serum levels of DPH are reached approximately 2-3 h after ingestion, and elimination half-life is approximately 4 h. Because DPH is liposoluble and its volume of distribution is large (3-7 L/kg), 2 its elimination by hemodialysis and hemoperfusion is difficult. ...
... Although DPH is considered as a relatively safe drug with a large therapeutic range, it causes dose-dependent toxicity. Eckes et al. 1 have reported serum DPH concentration of >5 lg/mL as fatal. ...
... It delays depolarization, which results in the prolongation of QRS time and bundle branch block. 3 Eckes et al. 1 reported that pulmonary congestion is frequently seen in autopsies of patients with DPH overdose, which is associated with increased vascular permeability. 4 There is a report of pulmonary edema caused by DPH overdose. ...
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Case A 45‐year‐old man presented to our emergency department with disturbance of consciousness; he had mentioned to his family earlier about a drug overdose. When first responders arrived, he suffered cardiac arrest. Cardiac arrest due to drug overdose was diagnosed.The patient was supported with venoarterial extracorporeal membrane oxygenation. Arterial blood gas showed mixed acidosis, and electrocardiogram showed junctional rhythm and complete right bundle branch block. Outcome The patient's blood pressure gradually decreased, and he died on the third day of hospitalization. After death, his serum diphenhydramine concentration at the time of arrival was found to be 18.7 μg/mL. Conclusion Although diphenhydramine is regarded as a safe medication, it shows dose‐dependent toxicity. High intake is associated with death; therefore, caution should be exercised in cases of drug overdose. Developing a procedure for rapid measurement in the emergency department should be a priority.
... Hingegen waren die ebenfalls lediglich apotheken-, aber nicht verschreibungspfl ichtigen H1-Antihistaminika in unserer Gruppe auff allend stark vertreten, Diphenhydramin zweimal als Einzelsubstanz und zusätzlich einmal in Kombination mit Doxylamin und einmal zusammen mit Doxepin und Melperon. Das ist bemerkenswert, da die therapeutische Breite der H1-Antihistaminika sehr hoch ist und die Substanzen als sicher gelten, Suizide werden selten berichtet (Bockholdt et al., 2001;Eckes et al., 2013;Nine & Rund, 2006). Die Möglichkeit des rezeptfreien Verkaufs an Minderjährige, insbesondere in größeren Abgabemengen, ist kritisch zu hinterfragen. ...
Article
Zusammenfassung. Fragestellung: Suizide tragen stark zur Gesamtmortalität von Adoleszenten bei. Diese Studie untersucht Geschlechts- und Altersdifferenzen in der Methodenwahl. Methodik: Die Untersuchung basiert auf den Todesbescheinigungen der Jahre 1996 bis 2019 der Stadt Leipzig und schließt alle Suizide der unter 25-Jährigen ein. Wir überprüften, ob Methodenwahl und Suizidort mit Geschlecht oder Altersgruppe zusammenhängen. Weiterhin prüften wir einen Zusammenhang zwischen adoleszenten Drogentoten und Suizidtoten. Ergebnisse: Unter den 140 erfassten Suiziden unterschied sich die Suizidmethode zwischen den Altersgruppen ( χ ² = 17,878; p = 0,022). Kinder, Jugendliche und Heranwachsende suizidierten sich fast ausnahmslos durch Erhängen, Sturz, Schienensuizid oder Intoxikation. Im frühen Erwachsenenalter erweiterte sich das Methodenspektrum. Die Suizidmethode war geschlechtsabhängig ( χ ² = 35,166; p < 0,001). Männliche Adoleszente suizidierten sich überwiegend mit harten Methoden, vor allem durch Erhängen. Bei weiblichen Adoleszenten war Intoxikation die häufigste Methode, dabei dominierten Antidepressiva. Es bestand eine Korrelation zwischen den Mortalitätsraten für Suizid und Drogentod (r = 0,571, p = 0,004). Als Trend ( χ ² = 3,125, p = 0,077) konnte eine Vermeidung des eigenen Wohnumfeldes für die Suizidhandlung bei Minderjährigen festgestellt werden. Schlussfolgerungen: Bei der Einschätzung des individuellen Suizidrisikos und der Abwägung sichernder Maßnahmen in der klinischen Tätigkeit sollten die gezeigten Unterschiede in der Methodenwahl Berücksichtigung finden.
... While its strong hypnotic properties lead to its decreased use as an antiallergic agent, these very properties are responsible for its continuous popularity as a FDA-approved overthe-counter sleeping pill. Abuse and overdose with DPH is seen on a regular basis [4]. DPH (hydrochloride) has a molecular weight of 291 D and a 98% protein binding. ...
Article
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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 life-threatening 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.
... 21,22) Diphenhydramine, an antihistamine with sodium channel blockade properties, causes dysrhythmias, seizures, and death with overdose. 23,24) These medications are frequently ingested by SAs worldwide, probably due to their easy availability. Therefore, policies that limit the availability of OTC hypnotics may contribute to the prevention of suicide by overdose. ...
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Objective The availability of suicide methods affects the risk of suicide attempts. This study examined the patterns of substances ingested by suicide attempters (SAs) and the characteristics of SAs using psychotropic overdoses. Methods Data for 384 of the 462 eligible SAs who used self-poisoning were analyzed. Demographic variables, clinical characteristics, and factors related to the suicide attempts were examined. Results There were 256 (66.7%) females and 128 (33.3%) males. Roughly half the SAs ingested psychotropics (n=179, 46.6%). Agricultural chemicals (n=84, 21.9%) were the second most frequently ingested substances, followed by analgesics (n=62, 16.1%), household products (n=27, 7.0%), and other prescribed medications (n=23, 6.0%). Among psychotropics, the most frequently overdosed drugs were sedative-hypnotics, including hypnotics (n=104) and benzodiazepines (n=78). SAs favored Z-drugs and alprazolam. When compared with SAs with non-psychotropic overdoses, significantly more SAs with psychotropic overdoses were female (76% vs. 58.5%, p<0.001) and had a psychiatric history (59.8% vs. 29.8%, p<0.001). They had significantly more previous suicide attempts (0.52±1.02 vs. 0.32±0.80, p<0.05) and lower risk (7.96±1.49 vs. 8.44±1.99, p<0.01) and medical severity (3.06±0.81 vs. 3.37±0.93, p<0.005) scores. Conclusion Psychotropic overdose, especially with sedative-hypnotics, was a major method in suicide attempts. It is important that psychiatric patients are carefully evaluated and monitored for suicidality when prescribing psychotropics.
... While its strong hypnotic properties lead to its decreased use as an antiallergic agent, these very properties are responsible for its continuous popularity as a FDA-approved over-the-counter sleeping pill. Abuse and overdose with DPH is seen on a regular basis [4]. DPH (hydrochloride) has a molecular weight of 291 D and a 98% protein binding. ...
Article
Full-text available
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.
... In four of these cases DA was ingested in combination with diphenhydramine (DPH), also a first-generation H1-antihistamine with similar adverse effects and intoxication profile to DA [25][26][27]. Their anticholinergic and sedative effects can amplify each other while acting simultaneously in the body [5,12]. An example of a combined intoxication with DA and DPH is Case 22. ...
Article
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 90 years). Maximum blood concentration was measured at 77.5 μg/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.
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Antihistamines are a class of drugs that inhibits the action of histamine and are used to alleviate symptoms associated with allergic reactions, but some of them can cause side effects, the most unpleasant and dangerous of which are the sedative effects that may hinder important psychological functions and impair skilled performance. These side effects could decrease safety in certain common and critical tasks, such as driving or operating machinery leading to accidents. Antihistamines can also cause intoxications, sometimes lethal, especially when co-administered with alcohol or other sedative drugs. Thus, the development of analytical methods for their determination in biological fluids is considered to be useful for the investigation of clinical and forensic cases. These methodologies could also be used for pharmacokinetic studies. Several liquid and a few gas chromatographic methods have been developed for the determination of antihistamines in biological matrices after proper pretreatment procedures. This article reviews the published analytical methodologies that were gathered through the search in PubMed database and the recent developments on isolation or determination of antihistamines in biological materials. Current trends and future perspectives on bioanalysis of antihistamines are also discussed. This article is protected by copyright. All rights reserved.
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Diphenhydramine is a moderately lipophilic antihistamine with sodium channel blockade properties. It is consumed recreationally for mild hallucinogenic and hypnotic effects and causes dysrhythmias, seizures, and death with overdose. Intravenous lipid emulsion is a novel agent used to treat lipophilic drug overdose. Two case reports describe clinical improvement with intravenous lipid emulsion after diphenhydramine toxicity, but no prospective studies have been reported. Our objective is to determine whether intravenous lipid emulsion improved hypotension compared with sodium bicarbonate for severe diphenhydramine toxicity in a model of critically ill swine. Twenty-four swine weighing 45 to 55 kg were infused with diphenhydramine at 1 mg/kg per minute until the mean arterial pressure reached 60% of baseline. Subjects were randomized to receive intravenous lipid emulsion (bolus of 7 mL/kg and then 0.25 mL/kg per minute) or sodium bicarbonate (2 mEq/kg plus an equal volume of normal saline solution). We measured pulse rate, systolic blood pressure, mean arterial pressure, cardiac output, QRS interval, and serum diphenhydramine level. Twelve animals per group provided a power of 0.8 and α of .05 to detect a 50% difference in mean arterial pressure. We assessed differences between groups with a repeated-measures linear model (MIXED) and Kaplan-Meier estimation methods. We compared systolic blood pressure, mean arterial pressure, and cardiac output with repeated measures ANOVA. Baseline weight, hemodynamic parameters, QRS interval, time to hypotension, and diphenhydramine dose required to achieve hypotension were similar between groups. After hypotension was reached, there was no overall difference between intravenous lipid emulsion and sodium bicarbonate groups for cardiac output or QRS intervals; however, there were transient differences in mean arterial pressure and systolic blood pressure, favoring intravenous lipid emulsion (difference: mean arterial pressure, sodium bicarbonate versus intravenous lipid emulsion -20.7 [95% confidence interval -31.6 to -9.8]; systolic blood pressure, sodium bicarbonate versus intravenous lipid emulsion -24.8 [95% confidence interval -37.6 to -12.1]). Time to death was similar. One intravenous lipid emulsion and 2 sodium bicarbonate pigs survived. End-of-study mean total serum diphenhydramine levels were similar. The mean lipid layer diphenhydramine level was 6.8 μg/mL (SD 3.1 μg/mL) and mean aqueous layer level 8.6 μg/mL (SD 5.5 μg/mL). In our study of diphenhydramine-induced hypotensive swine, we found no difference in hypotension, QRS widening, or diphenhydramine levels in aqueous layers between intravenous lipid emulsion and sodium bicarbonate. Copyright © 2015 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.
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Diphenhydramine is an H1 histamine antagonist that is commonly used for allergic reactions, colds and cough, and as a sleep aid. In addition to anticholinergic and antihistaminergic effects, sodium channel blockade becomes evident following diphenhydramine overdose. While seizures may occur following overdose of a diphenhydramine, status epilepticus is distinctly uncommon. We report a case with both status epilepticus and wide-complex dysrhythmias following an intentional diphenhydramine overdose. A 36-year-old woman with a medical history of hypothyroidism on levothyroxine was brought to the emergency department with active seizures by emergency medical services after what was later determined to be a diphenhydramine overdose. One hour after an argument with her husband he found her lethargic in a locked room. Initial vital signs were: blood pressure, 90/55 mmHg; heart rate, 160 beats/min; respiratory rate 18 breaths/min; room air oxygen saturation, 99%; temperature, 99.8°F; rapid point-of-care glucose, 130 mg/dL. The generalized seizures continued for duration of 30 min, despite the intravenous administration of 8 mg of lorazepam. The patient underwent endotracheal intubation and a propofol infusion terminated her seizures. An electrocardiogram after the status was terminated which revealed a wide-complex tachycardia with QRS duration of 127 ms. The QRS narrowed after 200 mEq of intravenous sodium bicarbonate was administrated. The patient was neurologically intact upon extubation on hospital day 2. The serum diphenhydramine concentration drawn on arrival to the ED was 1200 ng/mL (9-120 ng/mL); a tricyclic screen was negative. While seizures and sodium channel blockade are recognized complications of diphenhydramine toxicity, reported cases of status epilepticus from diphenhydramine overdose are rare. Elements of the patient's presentation were similar to a tricyclic overdose and management required aggressive control of her seizures, sodium bicarbonate therapy, and recognizing that physostigmine was contraindicated due to wide complex tachycardia. Diphenhydramine overdose may cause status epilepticus and wide-complex tachycardia. Management should focus on antidotal therapy with sodium bicarbonate and supportive neurological management with appropriate anticonvulsants and airway protection if clinically indicated.
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The histamine I receptor antagonist diphenhydramine is a freely available, over the counter medication for sleep and the most frequently used antihistamine drug. It inhibits the fast sodium channels and, at higher concentrations, the repolarising potassium channels, particularly Ikr which leads to prolongation of the action potential and the QT interval. The toxicity of diphenhydramine is dose-dependent, with a critical dose limit of 1.0 g. We report a case of a young woman who consumed more than 3 g of diphenhydramine in the setting of alcohol intoxication and developed QTc prolongation with nonsustained polymorphic ventricular tachycardia. These changes reverted to normal with supportive treatment. An overdose of diphenhydramine with concomitant alcohol use can induce torsade de pointes in an otherwise normal heart.
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First-generation H(1)-antihistamines obtained without prescription are the most frequent form of self-medication for allergic diseases, coughs and colds and insomnia even though they have potentially dangerous unwanted effects which are not recognized by the general public. To increase consumer protection by bringing to the attention of regulatory authorities, physicians and the general public the potential dangers of the indiscriminate use first-generation H(1)-antihistamines purchased over-the counter in the absence of appropriate medical supervision. A GA(2)LEN (Global Allergy and Asthma European Network) task force assessed the unwanted side-effects and potential dangers of first-generation H1-antihistamines by reviewing the literature (Medline and Embase) and performing a media audit of US coverage from 1996 to 2008 of accidents and fatal adverse events in which these drugs were implicated. First-generation H(1)-antihistamines, all of which are sedating, are generally regarded as safe by laypersons and healthcare professionals because of their long-standing use. However, they reduce rapid eye movement (REM)-sleep, impair learning and reduce work efficiency. They are implicated in civil aviation, motor vehicle and boating accidents, deaths as a result of accidental or intentional overdosing in infants and young children and suicide in teenagers and adults. Some exhibit cardiotoxicity in overdose. This review raises the issue of better consumer protection by recommending that older first-generation H(1)-antihistamines should no longer be available over-the-counter as prescription- free drugs for self-medication of allergic and other diseases now that newer second- generation nonsedating H(1)-antihistamines with superior risk/benefit ratios are widely available at competitive prices.
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The hybrid chemical structure of trimipramine incorporates an imipramine nucleus and levomepromazine side chain. This structure predicts much of the clinical profile of trimipramine. The initial studies on trimipramine date back nearly 30 years. It now has a well-recognised clinical profile with some characteristics akin to other tricyclic antidepressants (TCA) and others which are quite distinct. It is well established as a highly effective antidepressant with an efficacy profile similar to the other TCAs. Clinically, its anxiolytic and sedative properties distinguish it from most other TCAs. Its effects on sleep architecture are unique and explain some of its unique properties. The side effect profile of trimipramine is in some ways similar to those of the tertiary amine TCAs with a preponderance of anticholinergic and sedative effects. Its cardiotoxic properties are minimal, with some findings suggesting a very favourable profile. Interactions with other drugs, psychotropic or non-psychotropic, are compatible with its pharmacological profile. These are reviewed with its clinical applications in mind. The pharmacokinetic characteristics of trimipramine differ from those of many of the other TCAs. The application of this to clinical situations is addressed. Based on experience using trimipramine, a profile of 'ideal' patient characteristics has been built up. Finally, the use of trimipramine in selected patient populations is reviewed.
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In West Germany, the antihistaminic diphenhydramine is marketed as a non-prescription hypnotic. Results of toxicological screening in cases of drug overdose indicate that poisoning with diphenhydramine represents a substantial part (4.5%) of the total number of intoxications. A total of 136 cases of diphenhydramine poisoning in 1982-1985 were evaluated with respect to age, ingested dose, plasma level, and clinical symptomatology. All patients had taken diphenhydramine with suicidal intent. Two-thirds of the patients were aged 14-30 years. In about 50% of the cases, between 6 and 40 times a therapeutic dose was ingested. Diphenhydramine plasma levels showed a wide range (0.1-4.7/micrograms/ml) due to differences in ingested dose and time between ingestion and admission to hospital. Impaired consciousness was the most common symptom. Psychotic behavior similar to catatonic stupor--often combined with anxiety--was highly specific for diphenhydramine poisoning. Further symptoms included hallucinations, mydriasis, tachycardia, and less frequently diplopia, respiratory insufficiency, and seizures. Primary treatment included gastric lavage, administration of activated charcoal and sodium sulfate. In one case, hemodialysis and ultrafiltration were performed which had only limited effect on diphenhydramine plasma elimination kinetics. This patient died of diphenhydramine overdose and extreme hypothermia. All intoxications except the one mentioned before had an uncomplicated clinical course. In vitro experiments indicate that diphenhydramine may be almost completely removed from the plasma compartment by hemoperfusion. Routine analysis of urine samples in diphenhydramine overdose led to the identification of 4 previously unknown metabolites and artifacts of diphenhydramine.
Article
A 25-year-old female died from a suicidal overdose of imipramine, acetaminophen, codeine, diphenhydramine, and ethanol. Blood samples from ten segregated arterial and venous sites, twenty-four tissue samples, cerebrospinal fluid, vitreous humor, and bile were analyzed. Imipramine and desipramine, which were highly concentrated in the liver and lungs, each showed marked site dependent differences in blood concentrations. The highest concentrations were in pulmonary venous blood and the lowest in peripheral venous blood. Imipramine concentrations in the ten blood samples differed by as much as 760% (range 2.1 to 16.0 mg/L). Blood desipramine concentrations ranged from 1.4 to 10.6 mg/L. In contrast, blood concentrations of acetaminophen differed by less than 20% (55 to 65 mg/L) and blood ethanol concentrations ranged from 151 to 175 mg/100 mL. Blood concentrations of diphenhydramine ranged from 0.34 to 2.07 mg/L and codeine from 0.33 to 0.89 mg/L. The data illustrates that a marked site dependent variability in postmortem blood concentrations exists for some drugs but not others.
Article
A fatal monointoxication with diphenhydramine in a male 28 year old is reported. The patient went into hyperpyrexia and tachycardia and died from sudden cardiac arrest. Hemorrhagic pulmonary edema and renal shock were the most prominent pathomorphological findings. At the time of death, the concentration of diphenhydramine was 5 mg/l plasma and was particularly high in the lungs (55 mg/kg) and kidneys (50 mg/kg).
Article
Several poisonings by diphenhydramine were reported shortly after it had been introduced as an antihistamine in 1945. In the Federal Republic of Germany its combination with 8-chlorotheophylline (dimenhydrinate) is available as a hypnotic without prescription. Replacing the dangerous diethylpentenamide diphenhydramine is a drug which is also often abused. Fatal poisonings, suicide attempts, and traffic accidents were increasingly observed. In seven cases drug-influenced road users caused traffic accidents. We observed blood concentrations of diphenhydramine as high as in four cases of clinically treated patients after ingestion of large doses. This indicates a serious drug abuse. The measurement of the concentration of diphenhydramine and its major metabolite (diphenmethoxy acetic acid) in blood and urine is a means of recognizing chronic use and misuse of diphenhydramine. As the metabolite accumulates in blood one may find an elevated level after multiple dosing. Shortly after taking a single dose no or only low metabolite concentration is found. The concentration of diphenhydramine and its metabolite was measured in several fatal cases. In one of these cases the concentration in body fluids and tissues was in a range not observed until now.
Article
A 19-year-old woman presented with status epilepticus and ventricular dysrhythmias less than one hour after ingesting 5,000 mg dimenhydrinate (Dramamine). Aggressive resuscitation including the use of physostigmine stabilized the cardiac rhythm; however, she suffered a severe neurologic deficit. Development of ischemic and infarcted bowel necessitated colonic resection. After surgery, her condition worsened, and after demonstration of minimal cerebral activity, supportive measures were withdrawn, and she died. Overdose with dimenhydrinate and diphenhydramine, both of which are over-the-counter drugs, can result in rapid central nervous system stimulation, including status epilepticus. Death can occur within two hours. To our knowledge, this is the first reported fatality resulting from ingestion of dimenhydrinate.
Article
QT interval prolongation and torsades de pointes ventricular tachycardia have been reported after therapeutic doses and overdosage of second generation antihistamines, such terfenadine and astemizol. Diphenhydramine (DPHM), a first generation H1 antagonist, is the most frequently used antihistaminic drug. Despite its widespread use, there are no data about cardiac action and electrocardiographic consequences of DPHM overdose. The 12-lead electrocardiograms of 126 patients (mean age 26 +/- 11 years) who had DPHM overdose were evaluated. The ingestion of large doses of DPHM (in majority of cases the dose was >500 mg) was primarily suicidal. Repolarization duration, dispersion, and morphology were evaluated in DPHM overdose patients and compared with those of healthy subjects. Mean heart rate of DPHM overdose patients was 103 +/- 25 beats/min. The QTc duration was significantly longer (453 +/- 43 vs 416 +/- 35 ms, respectively, p <0.001) and mean T-wave amplitude significantly lower (0.20 +/- 0.10 vs 0.33 +/- 0.15 mV, respectively, p <0.001) in DPHM-overdose patients than in control subjects. Dispersion of repolarization was significantly lower in DPHM-overdose patients than in control subjects (42 +/- 25 vs 52 +/- 21 ms, respectively; p = 0.003). None of the DPHM-overdose patients experienced torsades de pointes. In conclusion, DPHM overdose is associated with a significant increase in heart rate and a significant but moderate QTc prolongation. None of the studied patients, including those who had apparent QTc prolongation, experienced torsades de pointes ventricular tachycardia.
Article
Diphenhydramine (DPH)-related deaths in adults are extremely rare, and detailed autopsy studies are rarer still. Toxicologic and anatomic findings in 4 cases of suicidal DPH overdose are described and compared with findings in a database of cocaine- and heroin-related deaths. Blood DPH levels were many times higher than those considered therapeutic (5000-35,000 ng/ml versus 50-100 ng/ml). Marked pulmonary edema with visceral congestion was a constant finding. Mean lung-body weight ratios for DPH, cocaine, heroin, and trauma controls were 0.015, 0.015, 0.019, and 0.013, respectively. When normalized for body weight in this fashion, edema in DPH-related deaths was comparable to that in cocaine-related deaths. Cardiac enlargement was apparent in 3 of the 4 DPH cases, 1 with marked myocardial fibrosis. The finding of increased heart size suggests that preexisting heart disease may provide the necessary substrate for lethal cases of DPH toxicity. Pulmonary edema in these cases remains unexplained, with edema in cases of heroin-related toxicity significantly worse than that produced by cocaine or DPH (p < .0001). Because DPH and cocaine can exert similar effects on the heart, a common mechanism may produce pulmonary edema in both. A different mechanism may account for heroin-related edema.
Article
Mixed drug reactions are frequently encountered in emergency department overdose cases and also in fatal intoxications. Assessment of the relative contribution of each drug in producing adverse effects is often compounded by lack of case history and the paucity of cases reported in the literature. This report describes a fatal intoxication with three common over-the-counter medications: guaifenesin, diphenhydramine, and chlorpheniramine. A 48-year-old woman was found dead in the attic bedroom of her residence. Specimens obtained at autopsy for toxicologic analysis included heart blood, urine, bile, gastric contents, vitreous humor, and cerebrospinal fluid. The over-the-counter drugs were identified and quantitated by acid/neutral or basic liquid-liquid extraction followed by gas chromatographic analysis with nitrogen phosphorus detection. Concentrations of guaifenesin, diphenhydramine, and chlorpheniramine detected in the heart blood were 27.4, 8.8, and 0.2 mg/L, respectively. The cause of death was determined to be acute intoxication by the combined effects of guaifenesin, diphenhydramine, and chlorpheniramine, and the manner of death was determined to be suicide. To our knowledge, the blood guaifenesin concentration in this case is the highest reported concentration to date associated with an acute intoxication.
Article
Histamine is an important neurotransmitter. Old (first-generation) H1-receptor antagonists such as chlorpheniramine, diphenhydramine, or triprolidine produce histamine blockade at H1-receptors in the central nervous system (CNS) and frequently cause somnolence or other CNS adverse effects. New (second generation) H1-antagonists such as cetirizine, fexofenadine, and loratadine represent an advance in therapeutics; in manufacturers' recommended doses, they enter the CNS in smaller amounts, produce relatively little somnolence or other CNS adverse effects, and do not exacerbate the adverse CNS effects of alcohol or other CNS-active chemicals. Two H1-antagonists, astemizole and terfenadine, have been found to prolong the QTc interval and, rarely, to cause cardiac dysrhythmias after overdose or under other specific conditions. This has led to withdrawal of regulatory approval for them. An H1-antagonist absolutely free from adverse effects under all circumstances is not yet available for use.
Article
Histamine has an important role as a chemical messenger in physiologic responses, neurotransmission, allergic inflammation, and immunomodulation by way of the H1-receptor. Most H1-antihistamines, which are useful in treating these effects, possess similar efficacy in allergic rhinoconjunctivitis and chronic urticaria. However, there are clinically relevant differences among them in their pharmacology and safety profiles.
Article
Diphenhydramine overdose in one of the frequent reported causes of acute poisoning. Patients with diphenhydramine overdose can present with central nervous system manifestations, anticholinergic manifestations and cardiovascular symptoms. The cardiovascular symptoms of diphenhydramine overdose include myocardial depression and refractory hypotension. Massive ingestions have been reported to cause myocardial depressant effect with widening of QRS complex and prolonged QT interval on electrocardiogram. We report an adolescent male with moderate diphenhydramine ingestion, who was found unresponsive with seizure like activity. Electrocardiogram on presentation showed wide complex tachycardia with right bundle branch block pattern and QT interval prolongation. These changes reverted to normal with treatment. Diphenhydramine overdose may occasionally result in prolongation of QT interval.
Article
As an antihistamine, diphenhydramine (DPH) is well known for its use in allergy treatment. Since its introduction in 1946, it has been marketed under various trade names, the most popular being Benadryl. Three years after its introduction, the first fatality due to DPH toxicity was reported in 1949. To better understand the incidence of fatalities due to DPH monointoxication, we reviewed deaths that were reported from 2 data sources: (1) the English-language literature using PubMed, from 1946 through 2003; and (2) the Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System (ARAAPCCTESS), from 1983 through 2002. The results were then tabulated using age, gender, clinicopathologic findings, and toxicology results. Combined results from both data sets show the following mean (and range) for age and DPH levels: Adult, 35.6 years (18-84) and 19.53 mg/L (0.087-48.5); pediatric, 8.6 years (1.25-17) and 7.4 mg/L (1.3-13.7); infant, 31 weeks (6 weeks-11 months) and 1.53 mg/L (1.1-2.2), respectively. Most deaths were certified as accident or suicide; however, 6 infant homicides were reported. The most common symptoms for all cases were cardiac dysrhythmias, seizure activity, and/or sympathetic pupil responses. The most common autopsy finding was pulmonary congestion.
Article
The antihistaminic drug diphenhydramine (DPH) is mainly used as a sedative, hypnotic and antiemetic. In many countries it is over-the-counter available, very common, and generally regarded as a harmless drug. Sixty-eight non-fatal and 55 fatal poisonings with DPH alone or in combination with other drugs were investigated in the Institute of Legal Medicine of the University Hospital Charité between 1992 and 2004. The analytical investigations were performed by HPLC with photodiode array detector (HPLC-DAD). The DPH concentrations ranged from 0.5 to 8.9 microg/mL in the non-fatal cases and from 0.3 to 119 microg/mL in fatal cases. The intoxication symptoms stated during emergency admission were inconsistent, with somnolence, sedation and retardation on one hand and tachycardia, anticholinergic syndrome, agitation, hallucinations, confusion, tremor, convulsions, delirium and coma on the other. In three cases rhabdomyolysis occurred. A concentration above 5 microg/mL can be regarded as potentially lethal. In many of the survivors the time course of the concentrations of DPH and the metabolites desmethyldiphenhydramine (DM-DPH) and diphenylmethoxyacetic acid (DPMA) were investigated. Whereas DM-DPH is present in blood from the very beginning because of the high first pass metabolism, DPMA is slowly formed over several metabolic steps. For this reason, the concentration ratio DPMA/DPH can be used for an approximate estimation of the time between drug intake and sampling in clinical cases or of the survival time after drug ingestion in death cases. In some of the deaths the concentrations in heart blood were much higher than in venous blood. This is explained mainly by agonal aspiration of the vomited gastric content. Besides the majority of suicidal cases also a case of child maltreatment and a case, in which the drug was forcibly administrated in a drug facilitated crime, were investigated. From the results it follows that diphenhydramine is not less poisonous than other prescribed hypnotics. However, despite the hallucinogenic effects, an abuse for recreational purposes was not observed until now.
Article
Anticholinergic syndrome has been widely documented in the literature but is uncommon in paediatric medicine. Teenage boys are most at risk of self-induced anticholinergic syndrome through intentional ingestion of plants. We report on a 14 year old boy who presented to our hospital with clinical signs of anticholinergic toxicity and who was discharged 36 hours after admission with no major residual effects. Classical anticholinergic syndrome should be readily diagnosed by the experienced clinician ('hot as a hare, red as a beet, dry as a bone, blind as a bat and mad as a hatter'). Acute presentations should be treated with benzodiazepines and supportive care. Treatment of the delirium with haloperidol may be harmful. Lack of familiarity with anticholinergic syndrome may also delay the diagnosis or result in potentially harmful treatments. A high index of suspicion is often required in the paediatric setting due to infrequent acute hospital presentation.
Article
Fatal adult cases of acute diphenhydramine poisoning are extremely rare. Transiently awakened by a roommate, a 39-year-old man admitted to massive ingestion of an over-the-counter drug containing diphenhydramine salicylate. On admission the patient was semicomatose and developed circulatory collapse with severe dehydration and metabolic acidosis, followed by status epilepticus. Despite extensive life support measures including percutaneous cardiopulmonary support, vascular permeability progressively increased, with pulmonary congestion as well as peripheral vasodilation evident as rubedo. The patient died without improvement of cardiac function. Subsequent diphenhydramine assays in serum specimens obtained at the time of delayed congestive symptoms indicated decreases in drug concentration to a sublethal amount. We suspect that metabolites of diphenhydramine with histamine-agonist actions contributed to the development of fatal delayed symptoms.
Global allergy and asthma European network. Risk of first-generation H(1)-antihistamines: a GA(2)LEN position paper
  • M K Church
  • M Maurer
  • Fer Simons
  • C Bindslev-Jensen
  • P Van Cauwenberge
  • J Bousquet
  • S T Holgate
  • T Zubier
  • MK Church
Church MK, Maurer M, Simons FER, Bindslev-Jensen C, van Cauwenberge P, Bousquet J, Holgate ST, Zubier T. Global allergy and asthma European network. Risk of first-generation H(1)-antihistamines: a GA(2)LEN position paper. Allergy. 2010; 65(4):459-66.