Giant T waves and QT interval prolongation associated with guanfacine toxicity.

INTRODUCTION: Guanfacine is a central α2-adrenergic receptor agonist that produces drowsiness, bradycardia, hypotension, and occasionally QT interval prolongation. We discuss giant T waves associated with guanfacine toxicity. CASE SUMMARIES: Three patients presented to the hospital with histories and physical findings compatible with guanfacine toxicity. Supratherapeutic concentrations were confirmed in two of them. All three developed QT interval prolongation and giant T waves on the electrocardiogram. Giant T waves occur commonly in patients with acute myocardial infarct and hyperkalemia, as well as rarely with a number of other cardiac and non-cardiac causes. CONCLUSION: Guanfacine toxicity may cause the novel electrocardiographic finding of 'giant T wave with QT interval prolongation'. Further studies are warranted to investigate the association between the novel electrocardiographic finding and guanfacine toxicity, as well as its diagnostic utility in such cases.

Guanfacine toxic ingestion with subsequent cardiogenic pulmonary edema.

Guanfacine is a central alpha-2 agonist often prescribed for Attention-deficit hyperactive disorder as well as tic disorder, with a usual dose of 1-4 mg per day. Due to its sympatholytic mechanism of action, Guanfacine can cause autonomic instability and hypotension. It can additionally cause cardiac dysfunction to include symptomatic bradycardias and contractility suppression. The authors present a case of a 17 year-old male with an ingestion of 80 mg of extended release Guanfacine with delayed onset cardiogenic pulmonary edema requiring mechanical ventilation. Previous pediatric ingestions have generated bradycardia, hypotension, and decreased level of consciousness, responsive to intravenous fluids, vasopressors, and occasionally naloxone. However, cardiogenic pulmonary edema from reduced cardiac contractility is a novel consequence of extended release Guanfacine ingestion. With Guanfacine's extended half-life, this unique case underscores the importance of emergency providers' familiarity with this toxidrome as well the necessity for prolonged, close observation following Guanfacine ingestion.

A 4-Year-Old With Altered Mental Status and Bradycardia After Clonidine Overdose.

This case presentation describes the clinical management of a pediatric patient during transport after a single-drug overdose of clonidine. Clonidine overdose closely resembles opiate intoxication, and treatment is largely supportive; however, the patient in this case presentation had a declining altered mental status with evidence of airway compromise within 1 to 2 hours after ingestion, which warranted protective airway management. The patient was extubated the following day with a successful outcome.

Amitraz: A Perpetual Silent Menace Among Children in Developing Countries-A Case Report.

Amitraz is an acaricide and insecticide used to treat ticks, which infest domestic animals in developing countries. Because of its widespread use, it is one of the common poisons unintentionally consumed by infants and children when left unsupervised. A 3-year-old boy was brought with unintentional consumption of Amitraz. On examination, he was found to be progressively drowsy, with an irregular pulse, bradycardia, and hypotension. He was treated with atropine, intravenous fluids, and dopamine infusion; hemodynamic stability was achieved within 36 hours after ingestion. Amitraz is an unusual but deadly poison unintentionally consumed by children. It can be suspected in the setting of rural households in developing countries having pets. There is no antidote available, and treatment is mainly supportive.

Clonidine exposures in children under 6 (2004-2017): a retrospective study.

OBJECTIVE: To describe trends in clonidine exposures in children under 6. Clonidine has become increasingly popular for management of paediatric behavioural disorders. Clonidine has a narrow therapeutic index, and toxicity can occur with inadvertent double dosing. Clonidine is not recommended for use in children under 6 years. DESIGN AND SETTING: A retrospective review of clonidine exposures in children under 6 reported to the New South Wales Poisons Information Centre (NSWPIC, Australia's largest poison centre), 2004-2017. This was compared with community clonidine utilisation using dispensing data from Australian Statistics on Medicines, 2004-2015. Australian trends were compared with clonidine exposure calls to US poison centres, 2006-2016. MAIN OUTCOME MEASURES: Trends in poisonings and dispensing; demographics, dose, exposure type, clonidine source, symptoms, disposition. RESULTS: There were 802 clonidine exposures in the NSWPIC database, increasing 4.9% per year, 2004-2017 (95% CI 3.1% to 6.7%, p<0.001), correlated with increased dispensing, r=0.846 (95% CI 0.529 to 0.956, p<0.001). 78.6% were hospitalised and medical toxicologists were consulted in 7.2%, indicating high risk and/or morbidity. Clonidine was prescribed for the patient in at least 27.8%, providing evidence for prescribing outside of recommendations. US data reveals 19 056 clonidine exposures, with 3.7% increase per year, 2006-2016 (95% CI 2.2% to 5.3%, p<0.001). CONCLUSIONS: Clonidine exposures in children under 6 are increasing, and this trend is not isolated to Australia. Exposures have a high hospital referral rate and high morbidity. Caution should be exercised when prescribing clonidine, and parent/carer education is important for safe storage and increased vigilance when dosing.

Clonidine Overdose in a Toddler Due to Accidental Ingestion of a Compounding Cream.

A 22-month-old girl without any significant medical history accidentally consumed a small amount of a therapeutic compounding cream that contained camphor, gabapentin, clonidine, ketoprofen, and lidocaine. Upon presentation to the emergency department, the child exhibited immediate onset of altered mental status with wide fluctuation in her vital signs, which included intermittent apnea requiring bag-valve mask assistance and endotracheal intubation. Serum laboratory analysis measured a clonidine level of 2.6 ng/mL and undetectable camphor, gabapentin, and ketoprofen levels. While on mechanical ventilation, the patient exhibited hypothermia, bradycardia, and hypotension; all of which responded to supportive care. After approximately 12 hours in the intensive care unit, the patient was successfully extubated and remained asymptomatic. This unique case of a patient with brief, unintentional oral exposure to a compounding cream, who demonstrated severe toxicity despite only a measured, supratherapeutic clonidine concentration, is discussed. Emergency physicians and pediatricians should be alert to the potential for exposure of pediatric patients to these medicinal compounds. Furthermore, parents must be made aware of the potential dangers of compounded medications and ensure their proper usage and storage.

Amitraz poisoning: A case report of an unusual pesticide poisoning in Sri Lanka and literature review.

BACKGROUND: Amitraz is a pesticide used worldwide on animals and in agriculture. It contains triazapentadiene, which is a centrally acting alpha-2 adrenergic agonist. Amitraz poisoning is fairly uncommon in humans and occurs via oral, dermal or inhalational routes. Only a limited number of case reports of human intoxication have been published and most of them are of accidental ingestion by children. CASE PRESENTATION: A twenty-year-old Sri Lankan female presented following self-ingestion of 20 ml of amitraz resulting in 37.8 mg/ kg of amitraz poisoning. She lost consciousness after 20 min of ingestion, developed bradycardia and hypotension, which needed intravenous fluid resuscitation and dobutamine. Gastric lavage was performed. Her bradycardia persisted for 36 h and she was drowsy for 48 h. She did not develop respiratory depression, convulsions or hypothermia and the urine output was normal. Arterial blood gas revealed mild respiratory alkalosis. She recovered fully within 48 h and was discharged on day 3. CONCLUSION: The clinical manifestations of amitraz (impaired consciousness, drowsiness, vomiting, disorientation, miosis, mydriasis, hypotension, bradycardia, respiratory depression, hypothermia, generalized seizures, hyperglycemia and glycosuria) can be explained by the agonist action of amitraz on α1 and α2 receptors. Management of amitraz poisoning is still considered to be supportive and symptomatic with monitoring of nervous system, cardiovascular and respiratory systems. Activated charcoal may still be considered for treatment and the place for gastric lavage is controversial. Atropine is effective for symptomatic bradycardia and inotropic support is needed for hypotension that does not respond to fluid resuscitation. Diazepam or Lorazepam is used for convulsions and some patients may require intubation and ICU care. Several α2 adrenergic antagonists like yohimbine have been tried on animals, which have successfully reversed the effects of amitraz. Since the majority of amitraz poisoning cases are due to accidental ingestion, manufactures, regulatory authorities and national poisons control centers have a significant role to play in minimizing its occurrence.

Endotracheal Intubation for Toxicologic Exposures: A Retrospective Review of Toxicology Investigators Consortium (ToxIC) Cases.

BACKGROUND: Endotracheal intubation remains a cornerstone of early resuscitation of the poisoned patient, but little is known about which substances are associated with intubation. OBJECTIVES: Our objective was to describe patient exposures to substances reported to the American College of Medical Toxicology (ACMT) Toxicology Investigators Consortium (ToxIC) that were managed with intubation between 2010 and 2014. METHODS: We performed a retrospective review of cases managed with endotracheal intubation in the ACMT ToxIC Registry from January 1, 2010 through December 31, 2014. Descriptive statistics were used to describe patient exposures. RESULTS: A total of 2724 exposures to substances were managed with endotracheal intubation. Intubated patients were 52% male and 82% adults. For all ages taken together, the most common known single-substance exposures managed with intubation were sedative hypnotics (9.8%), antidepressants (8.7%), and opioids (8.0%). The most common single ingestions associated with intubation in various age groups were: opioids (<2 years old), alpha-2 agonists (2-6 years old), antidepressants (7-18 years old), sedative-hypnotics (19-65 years old), and cardiac medications (>65 years old). Multiple substances were involved in 29.0% of exposures. Decontamination and elimination processes were used in 12.8% of patients. CONCLUSIONS: The most common substances involved in single- and multiple-substance exposures managed with intubation varied by age group. Most patients were managed with supportive care. Knowledge of substances commonly involved in exposures managed with intubation may inform triage and resource planning in the emergency department resuscitation of critically ill poisoned patients.

Poisonings Associated with Intubation: US National Poison Data System Exposures 2000-2013.

Patients may be intubated after exposure to a variety of substances because of respiratory failure, CNS sedation, pulmonary pathology, or cardiovascular instability. However, there is little data describing the types of substances that are associated with endotracheal intubation or the rates of intubation after these exposures. Evaluation of this association may inform future research on intubation after exposures to specific substances and guide poison prevention education. Our objective was to determine which exposures were commonly associated with intubation using the data from National Poison Data System (NPDS). The NPDS tracks data from potential exposures to substances reported to all American Association of Poison Control Centers. We performed a retrospective analysis of NPDS data from January 1st, 2000 to December 31st, 2013 to identify human exposures to substances that were associated with endotracheal intubation. Descriptive statistics were used to analyze the data. There were 93,474 single substance exposures and 228,507 multiple substance exposures that were associated with intubation. The most common exposures to substances that were associated with intubation were atypical antipsychotics (7.4 %) for single exposures and benzodiazepines (27.4 %) for multiple exposures. Within each age group, the most common known exposures to substances were for patients under 6 years, clonidine for single and multiple exposures; for patients aged 6-12 years, clonidine for single exposures and atypical antipsychotics for multiple exposures; for patients aged 13-19 years, atypical antipsychotics for single and multiple exposures; and for patients over 19 years, atypical antipsychotics for single exposures and benzodiazepines for multiple exposures. From 2000-2013, the exposures to substances most commonly associated with intubation varied by single versus multiple exposures and by age. This study helps clarify the exposures to substances that are associated with intubation reported to poison centers in the USA.

[Clonidine poisoning in a child: a case report]. / Intoxication pédiatrique sévère avec une faible dose de clonidine : à propos d'un cas.

Clonidine poisoning's clinical feature is well documented in the medical literature, but the minimal toxic dose has not yet been established. The effectiveness of naloxone is also controversial. The authors describe a clonidine overdose in a 9-year-old boy (25 kg) during a growth hormone test: he received tenfold the prescribed clonidine dose (0.23 mg instead of 0.023 mg) with 6.2 mg betaxolol. About 40 min later, he became drowsy and then complained of low blood pressure, bradycardia, and myosis. By maintaining the Trendelenburg position, administering fluids as well as salbutamol and naloxone (three doses of 0.2 mg were required), he recovered and was discharged from the hospital on day 2. The minimal clonidine toxic dose, the clinical picture, and the effectiveness of naloxone administration are discussed in this paper.

Significance of the imidazoline receptors in toxicology.

INTRODUCTION: The alpha-2 adrenergic (AA-2) receptor agonists and imidazolines are common exposures in the American Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS). Although the interaction between the AA-2 receptor and imidazoline receptors has been extensively studied, it largely remains unknown to health-care professionals. This review describes these interactions and mechanisms by which agonists affect physiologic responses binding to these receptors. METHODS: Papers published in English from 1960 to 2013 were retrieved from PubMed. A total of 323 original articles were identified and 173 were included. Background. The toxicity associated with clonidine (e.g., bradycardia, miosis, and hypotension) is largely assumed to be secondary to the functional overlap of the AA-2 receptors and the mu receptors. However, the effects at the AA-2 receptor could not fully account for these symptoms. Subsequently, clonidine was found to produce its pharmacologic effect in the central nervous system (CNS) by interaction not only with the AA-2 receptor but also on selective imidazoline receptors. IMIDAZOLINE RECEPTORS: Since their discovery, three distinct classes of imidazoline receptors, also known as imidazoline binding sites or imidazoline/guanidinium receptive sites, have been characterized. Imidazoline-1 (I-1) receptors are involved in the hypotensive activity of clonidine and related compounds supporting the idea that the I-1 receptors are upstream from the AA-2 receptor and work in tandem for its effect on blood pressure. Additionally, stimulation of N-type Calcium-2 channels, G-protein inwardly rectifying potassium channel, adenosine receptors, phosphatidyl-choline-specific phospholipase C, and nicotinic receptors have been implicated to be involved. Previous studies have shown that I-1 receptors may also be involved in other physiologic responses beyond cardiac function. Imidazoline-2 (I-2) receptors interact with monoamine oxidase A and monoamine oxidase B leading to research that has focused on the effect of I-2 receptors and depression and the suggestion of a possible antidepressant action of the imidazolines. I-2 receptor ligands may have substantial antinociceptive activity and work synergistically with opioids in acute pain. Imidazoline-3 (I-3) receptors are located on the pancreatic ß-cells and modulate glucose homeostasis. IMIDAZOLINE LIGANDS: Four endogenous compounds have been found to bind and include clonidine-displacing substance, agmatine, harmane, and imidazole acetic acid. Significant interest in developing new agents with higher selectivity and affinity for I-1 receptors has resulted. Toxicology. Alpha-2 adrenoceptor and imidazoline receptor agonists such as clonidine and tetrahydrozoline are common ingestions reported to poison control centers. The most common toxic effects of clonidine are similar to those of the over-the-counter imidazolines and include CNS depression, bradycardia, hypotension, respiratory depression, miosis, hypothermia, and hypertension (early and transient). Based on their structure and subsequent studies, imidazoline receptors seem to be the primary binding site for these chemicals. Case reports typically illustrate rapid onset of action with serious side effects following ingestion of relatively small amounts. These agents have been reportedly used in drug-assisted sexual assaults. CONCLUSION: Much of the toxicity associated with drugs such as clonidine, guanfacine, and tetrahydrozoline are due to their binding to imidazoline receptors. Knowledge of the imidazoline receptors may lead to new therapeutic agents and inform management of patients with imidazoline overdose.

Dermal exposure to a compounded pain cream resulting in severely elevated clonidine concentration.

INTRODUCTION: Clonidine is an imidazoline derivative antihypertensive medication that is also used as adjunctive therapy for neuropathic pain disorders via topical administration. Clonidine overdose can manifest both central and peripheral alpha-adrenergic agonist effects. CASE REPORT: A 23-year-old man presented to an emergency department with altered mental status, bradycardia, and hypertension after suspected overdose. He had rubbed a specially compounded medicinal cream over his entire body containing clonidine 0.2 % (w/w), gabapentin 6 %, imipramine 3 %, ketamine 10 %, lidocaine 2 %, and mefenamic acid 1 %. The patient presented with severe hypertension, bradycardia, and altered mental status. He was found to have a subarachnoid hemorrhage and was treated for hypertensive emergency. Toxicological analysis of initial blood samples revealed a serum clonidine concentration of 5,200 ng/ml. At 6-month follow-up, the patient had made a full recovery. DISCUSSION: There are limited reports of topical clonidine toxicity, and to our knowledge, this case involves the highest concentration yet reported following clonidine overdose by any route of exposure. The severely elevated serum clonidine concentration found in our patient demonstrates the possibility of toxicity resulting from inappropriate use of such a product. At high serum concentrations, the pharmacodynamic effects of clonidine appear to cause significant peripheral alpha-1 adrenergic stimulation. Toxicologists should be aware of the increasing use of topical clonidine preparations for the treatment of neuropathic pain and the potential for toxicity.

Unintentional pediatric exposures to central alpha-2 agonists reported to the National Poison Data System.

OBJECTIVE: To investigate national trends in unintentional pediatric exposures to 3 common alpha-2 agonists: clonidine, guanfacine, and tizanidine. Secondary objectives were to describe outcomes, symptoms, treatments, and death. STUDY DESIGN: Retrospective chart review from the American Association of Poison Control Centers National Poison Data System from January 2000 to December 2011 for unintentional exposure to clonidine, guanfacine, and tizanidine in children ≤ 12 years of age. RESULTS: From 2000-2011, there was a significant increase (5.9% per year, CI 3.6, 8.2) in unintentional pediatric exposures to National Poison Data System for central alpha-2 agonists. There were 27,825 clonidine exposures (67.3% male, median age: 4 years), 6143 guanfacine exposures (69.8% male, median age: 6 years), and 856 tizanidine exposures (51.9% male, median age: 2 years). Guanfacine had the greatest proportional increase among the medications. Clonidine was associated with the most respiratory (799, 2.9%) and central nervous system symptoms (12,612, 45.3%), as well as the most episodes of bradycardia (2847, 10.2%) and hypotension (2365, 8.5%). Seven-hundred twenty-eight (2.0%) patients were intubated, and 141 patients (0.5%) were administered vasopressors. There were 7 cardiac arrests and 3 deaths from clonidine. CONCLUSIONS: The number of unintentional pediatric exposures to alpha-2 agonists increased from 2000-2011. Clonidine exposures were the most commonly reported, more symptomatic, and associated with 3 deaths. Despite central nervous system depression, bradycardia, and hypotension being common, the need for intubation and vasopressors was rare.