Use of CytoSorb in cases of acute amitriptyline intoxication.

WHAT IS KNOWN AND OBJECTIVE: Intoxications with the tricyclic antidepressant amitriptyline frequently occur in the clinical setting and require immediate treatment. Although various poisonings can be counteracted with specific remedies, treatment options for amitriptyline intoxication remain sparse. Besides conventional approaches, a new haemoadsorption device might represent an opportunity for therapeutic detoxification. CASE SUMMARY: We report on two patients who were admitted as an emergency case with suspected amitriptyline overdose. Due to potentially life-threatening intoxication, the decision was made to initiate continuous renal replacement therapy (CRRT) together with CytoSorb haemoadsorption. As a result, drug-level measurements showed fast and efficient reduction of amitriptyline levels in the blood (case 1 from 186 µg/l to 54.7 µg/l, case 2 from 844 µg/l to 290 µg/l) and helped to stabilize a critical situation. WHAT IS NEW AND CONCLUSION: We were able to quickly and efficiently reduce amitriptyline to non-toxic serum levels and to stabilize a critical situation using the CytoSorb adsorber. Therefore, in the absence of other proven beneficial treatment regimen, the use of CytoSorb haemoadsorption could represent a potential treatment modality for severe amitriptyline intoxication.

Dexamethasone changes the pharmacokinetics of amitriptyline and reduces its accumulation in rat brain: The roles of P-gp and cyp3a2.

The wide spread use of central nervous system (CNS) drugs has caused thousands of deaths in clinical practice while there are few antidotes or effective treatments to decrease their accumulation in CNS. In this study, we used amitriptyline (AMI) and dexamethasone (DEX) as the corresponding poisoning and pre-protecting drugs, respectively, to study whether DEX has the potential to reduce AMI accumulation in brain. By measuring the pharmacokinetic data of AMI and its main metabolite nortriptyline (NOR), we found that DEX possibly accelerated the metabolism and elimination of AMI with minimal effects on the concentrations of NOR in blood. Nevertheless, the results indicated that DEX reduced the brain/plasma concentration ratio of AMI and NOR, even if the plasma concentration of NOR had an upward trend. Western blot results showed the overexpression of cyp3a2 and P-gp in rat liver and brain capillaries tissues. We propose that cyp3a2 and P-gp could be upregulated in the liver and blood-brain barrier (BBB) when using DEX. Further experiments suggest that DEX may serve as the ligand of PXR to induce P-gp expression.

[Diagnostics and treatment of selected clinically relevant, acute drug intoxications]. / Diagnostik und Behandlung ausgesuchter akuter Arzneimittelvergiftungen mit hoher klinischer Relevanz.

Acute drug poisoning due to accidental or self-damaging overdoses is responsible for 5-10% of emergency medical interventions in Germany. The treatment of asymptomatic to life-threatening courses requires extensive expertise. On the basis of a selective literature search, this article gives an overview of selected clinically relevant, acute drug poisonings with regard to epidemiology, symptomatology, diagnostics, and therapy.Intoxications with psychotropic drugs are the most common drug intoxications. Poisoning with tricyclic antidepressants causes anticholinergic, central nervous, and cardiovascular symptoms. Less toxic are selective serotonin reuptake inhibitors (SSRIs); the intoxication may be characterized by serotonin syndrome. Malignant neuroleptic syndrome is a severe complication of neuroleptic poisoning.Poisoning with analgesics is clinically relevant due to its high availability. For paracetamol poisoning, intravenous acetylcysteine is available as an antidote. Hemodialysis may be indicated for severe salicylate intoxication. Poisoning with nonsteroidal anti-inflammatory drugs is usually only associated with mild signs of intoxication.Poisoning with cardiac drugs (ß-blockers and calcium antagonists) can cause life-threatening cardiovascular events. In addition to symptomatic therapy, insulin glucose therapy also plays an important role.The majority of acute drug poisonings can be treated adequately by symptomatic and partly intensive care therapy - if necessary with the application of primary and secondary toxin elimination. Depending on the severity of the intoxication, pharmacology-specific therapy must be initiated.

A forgotten cause of wide complex tachycardia.

Wide complex tachycardia secondary to an acute overdose from TCA's is a well-documented phenomenon. In this case we present a wide complex tachycardia after clear documentation of no acute overdose, which responded to standard treatment for TCA toxicity. These findings combined with chronic electrocardiographic abnormalities were suggestive of an acute on chronic TCA toxicity.

[How I treat a poisoning with tricyclic antidepressants : potential role of a treatment with lipid emulsion]. / Comment je traite l'intoxication aux antidépresseurs tricycliques : efficacité potentielle d'un traitement par émulsion lipidique.

Poisoning with tricyclic antidepressants is common and can be life-threatening. The classic management is well known (chelating gastrointestinal, sodium bicarbonate, benzodiazepine, norepinephrine). A few years ago, a treatment with lipid emulsion, previously used in local anesthetics poisoning, has been successfully tested in tricyclic poisoning with cardiac arrest. We are currently unable to explain the exact mechanism of this treatment but it could have a place in the treatment of severe tricyclic poisoning with hemodynamic instability in addition to the conventional treatment.

L'intoxication aux antidépresseurs tricycliques n'est pas rare et peut engager le pronostic vital du patient. La prise en charge classique est bien connue (chélateurs gastrointestinaux, bicarbonate de sodium, benzodiazépines, amines vasoactives). Il y a quelques années, un traitement par émulsion lipidique, jusque-là utilisé dans les intoxications aux anesthésiques locaux, a été testé avec succès dans les intoxications aux tricycliques en arrêt cardio-respiratoire. Nous sommes, actuellement, incapables d'expliquer le fonctionnement exact de ce traitement, mais il pourrait avoir une place dans la prise en charge des intoxications aux tricycliques avec instabilité hémodynamique échappant au traitement conventionnel.

Comparison of High-Fidelity Medical Simulation to Short-Answer Written Examination in the Assessment of Emergency Medicine Residents in Medical Toxicology.

We compared high-fidelity medical simulation to short-answer written examination in the assessment of emergency medicine residents (EMR) on a month-long medical toxicology rotation. Knowledge-based assessment tools using cases of an aspirin overdose and a tricyclic antidepressant overdose were used to assess all consecutive rotating EMR (n=53). Assessment by simulation had similar accuracy and precision but higher satisfaction rates when compared to written examination. Incorporating simulation into the ABEM certifying examination warrants further study.

Case Report: Hemodynamic Instability Following Severe Metoprolol and Imipramine Intoxication Successfully Treated With Intravenous Fat Emulsion.

We present the case of a 22-year-old patient who was successfully treated with intravenous fat emulsion for severe and refractory cardiac depression after an overdose with a tricyclic antidepressant and beta-blocker.

Why are we Still Dialyzing Overdoses to Tricyclic Antidepressants? A subanalysis of the NPDS database.

A recent analysis of the American Association of Poison Control Centers database, showed that poisonings from toxins not usually considered amenable to extracorporeal purification ("non-classic toxins" such as ethanol and tricyclic antidepressants) continue to be reported. This publication investigates factors that may explain these findings. Our results suggest that: 1) the relatively high absolute number of ECTR performed for non-classic toxins may simply reflect the large number of exposures to these toxins, 2) poisoning from another toxin may have been the reason for ECTR initiation in some exposures to non-classic toxins, 3) poisoning from non-classic toxins may receive ECTR for purposes other than toxin removal, and 4) the decisional threshold to initiate ECTR may be lower for non-classic toxins because of heightened toxicity.

ECG Of the Month: Suicide.

Apparently depression ran in this man's family, and when he took an overdose of his tricyclic antidepressant, he also took the tricyclics of his mother and his sister. Most patients who die of an overdose of a tricyclic antidepressant are pronounced dead without reaching a hospital, and those who die after arriving in the emergency room do so within a few hours.2 Central nervous system toxicity of tricyclic antidepressants may manifest as confusion, agitation, hallucinations, coma, myoclonus, or seizures. Generalized seizures often presage cardiopulmonary arrest,2 and within 20 seconds of the ECG with evidence of generalized seizure activity shown here, the QRS duration increased from 188 ms to 212 ms, and the patient died soon thereafter.

Effect of lipid emulsion during resuscitation of a patient with cardiac arrest after overdose of chlorpromazine and mirtazapine.

No specific treatment exists for poisoning with most fat-soluble drugs. Intravenous lipid emulsion (ILE) may be effective therapy against such drugs, but effects of ILE treatment are unclear. A 24-year-old woman with depression seen sleeping in the morning was found comatose in the evening, and an emerging lifesaving technologies service was called. After emerging lifesaving technologies departure to hospital, she stopped breathing, became pulseless, and cardiopulmonary life support was started immediately. Electrocardiographic monitoring showed asystole during resuscitation even after arrival at hospital. Empty packaging sheets of 60-tablet chlorpromazine (CPZ) (50 mg/tablet) and 66-tablet mirtazapine (MZP) (15 mg/tablet) found at the scene suggested drug-related cardiopulmonary arrest. Along with conventional administration of adrenaline (total dose, 5 mg), 20% Intralipid 100 mLwas given intravenously 8 minutes after hospital arrival and readministered 27 minutes after hospital arrival because of continued asystole. Return of spontaneous circulation occurred 29 minutes after arrival (70 minutes after cardiac arrest). The patient recovered without any major complications and was transferred to another hospital for psychiatric treatment 70 days after admission. Concentrations of CPZ and MZP were still high when return of spontaneous circulation was achieved with ILE. This case suggested the possible benefit of ILE in treating life threatening cardiotoxicity from CPZ and MZP overdose.

Intravenous lipid emulsion in the emergency department: a systematic review of recent literature.

BACKGROUND: Intravenous lipid emulsion (ILE) has been broadly attempted in the resuscitation of neurologic and cardiac toxic drug overdoses, however, the role of ILE in the emergency department is poorly defined. OBJECTIVE: This review aims to identify recent literature on the use of ILE in humans as an antidote and to familiarize emergency providers with the indications, availability, dosing recommendations, and adverse reactions associated with ILE use. METHODS: A systemic literature search of MEDLINE, EMBASE, and major toxicology conference abstracts was performed for human cases using ILE as an antidote with documented clinical outcomes through January 2014. RESULTS: Ninety-four published articles and 40 conference abstracts were identified, 85% of which had positive outcomes. The most common indication for ILE was for local anesthetic systemic toxicity (LAST). The most common nonlocal anesthetic xenobiotics were tricyclic-antidepressants and verapamil. DISCUSSION: No standard of care is defined for the use of ILE, although the American Heart Association recommends use in LAST, and the American College of Medical Toxicology recommends consideration for circumstances of hemodynamic instability resultant from lipid-soluble xenobiotics. ILE should be administered per American Society of Regional Anesthesia and Pain Medicine dosing recommendations. Laboratory interference, pancreatitis, respiratory distress syndrome, and interference with vasopressors should be considered as risks but are uncommon. CONCLUSIONS: In the setting of severe hemodynamic compromise by lipid-soluble xenobiotics, ILE may be considered for resuscitation by emergency physicians. As such, ILE may be stocked in emergency departments in close proximity to resuscitation rooms and areas where local nerve blocks are performed.

[The determination of amitriptyline and its metabolite, nortriptyline, in the biological objects of the corpse by the high-performance liquid chromatography technique].

Tricyclic antidepressants are among the preparations that most frequently cause intoxication in adults and children; moreover, poisoning with these substances not infrequently has a fatal outcome. Medications belonging to this group, such as amitriptyline, are extensively used to manage manifestations of depression, anxiety, migraine, neuropathic pain, and hyperactivity syndrome. Amitriptyline overdosage causes non-specific symptoms of intoxication, and its clinical picture does not allow to identify the nature of a psychotropic xenobiotic. Of primary importance in connection with this is to establish the cause of intoxication or death by the clinical toxicological and forensic medical methods based on the results of the fast identification and quantitation of amitriptyline in biological materials including blood, urine, hepatic tissues, etc. The authors describe the method for the determination of amitriptyline and its principal physiological metabolite nortriptyline in biological objects with the help of high performance liquid chromatography (HPLC).

Extracorporeal treatment for tricyclic antidepressant poisoning: recommendations from the EXTRIP Workgroup.

The Extracorporeal Treatments In Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, the workgroup presents its results for tricyclic antidepressants (TCAs). After an extensive literature search, using a predefined methodology, the subgroup responsible for this poison reviewed the articles, extracted the data, summarized findings, and proposed structured voting statements following a predetermined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements and RAND/UCLA Appropriateness Method to quantify disagreement. Blinded votes were compiled, returned, and discussed in person at a meeting. A second vote determined the final recommendations. Seventy-seven articles met inclusion criteria. Only case reports, case series, and one poor-quality observational study were identified yielding a very low quality of evidence for all recommendations. Data on 108 patients, including 12 fatalities, were abstracted. The workgroup concluded that TCAs are not dialyzable and made the following recommendation: ECTR is not recommended in severe TCA poisoning (1D). The workgroup considers that poisoned patients with TCAs are not likely to have a clinical benefit from extracorporeal removal and recommends it NOT to be used in TCA poisoning.

Intravenous lipid emulsion for the treatment of drug toxicity.

Intravenous lipid emulsion (ILE) has emerged as a powerful antidote for the treatment of drug toxicity in the past decade. Initial efficacy of ILE was shown in the setting of local anesthetic systemic toxicity (LAST), but recent case reports suggest its consideration in a variety of other drug toxicities. In this review, we will summarize the experimental evidence as well as the clinical experience in using ILE as an antidote. Specifically, we will look at the evidence for using ILE in LAST as well as toxicity due to beta-blockers, calcium-channel blockers, and tricyclic antidepressants. We will also review the current dosing recommendations as well as potential side effects of ILE as an antidote.

Extracorporeal life support and plasmapheresis in a case of severe polyintoxication.

BACKGROUND: Resuscitation without return to spontaneous circulation in patients with suicidal ingestion of cardiotoxic drugs necessitates alternative bridging therapies for drug removal. OBJECTIVES: To show the effectiveness of emergency extracorporeal membrane oxygenation (ECMO) and plasmaspheresis in severe polyintoxication. CASE REPORT: A 21-year-old woman developed asystole after suicidal polyintoxication with 1.75 g carvedilol, 300 mg amlodipine, 6 g amitriptyline, 500 mg torsemide, 1.5 g ketoprofen, 28 g nicotinic acid, and 16 g gabapentin. After 3 h of cardiopulmonary resuscitation without return to spontaneous circulation, ECMO was used as a bridging therapy and a temporary pacemaker was inserted. Plasma peak levels were measured for amlodipine (29.3 µg/L), amitriptyline (1456 µg/L), carvedilol (585 µg/L), and gabapentin (126.8 mg/L). To facilitate drug removal, therapeutic plasma exchange was performed. The patient could be weaned from ECMO at day 4 and extubated on day 8 after admission without neurologic sequelae. CONCLUSION: ECMO and plasma exchange should be considered as a therapeutic option in selected patients under resuscitation without return to spontaneous circulation after severe intoxication.

Patterns of toxicity and factors influencing severity in acute adult trimipramine poisoning.

AIMS: To analyze the clinical features of trimipramine poisoning, identify a minimal toxic dose, and the dose bearing a 50% risk of developing a moderate, severe or fatal outcome. METHODS: All acute adult trimipramine monointoxications reported by physicians to the Swiss Toxicological Information Centre between January 1992 and December 2009 were identified. RESULTS: Two hundred and thirty cases (26 confirmed and 204 probable) were analyzed, the mean age was 35.7 years and 74% were females. One hundred and thirty-seven patients showed mild, 54 moderate and 21 severe symptoms. Three cases were fatal due to refractory cardiovascular collapse. Ninety-three per cent of the events were attempted or completed suicides. The most common symptoms were central nervous system depression (79.2%), tachycardia (19.1%) and QT(c) prolongation (13.9%). The severity of poisoning depended significantly on the ingested dose (P < 0.001). The minimal dose for moderate symptoms was 250 mg (median dose 1.2 g) and 850 mg for severe symptoms (median dose 2.7 g). The dose for a 50% risk of developing a moderate, severe or fatal outcome was 5.11 g. In 38 patients early gastrointestinal decontamination was performed. Overall, these patients ingested higher trimipramine doses than the late- or not-decontaminated patients (P = 0.113). The median doses were also higher in the decontaminated group within each severity category except in the fatal cases. CONCLUSIONS: We demonstrated that moderate trimipramine poisoning can already occur after ingestion of doses in the high therapeutic range. Poisoned patients have to be monitored for central nervous system depression, dysrhythmias and QT(c) prolongation. Early decontamination might be beneficial.

Cerebellitis developing after tricyclic antidepressant poisoning.

Acute cerebellitis is a rare inflammatory disease involving the cerebellum and is characterized by acute compromise of cerebellar functions. It most frequently originates from infectious causes, although cases of cerebellitis associated with other causes have also been reported. This report discusses a case of cerebellitis developing in a 4-year-old girl who had to be intubated after accidental ingestion of tricyclic antidepressant. There are no previous reports of cerebellitis after tricyclic antidepressant. This case shows that cerebellitis can develop in patients with poisoning of this kind.