Relatively mild symptoms after chronic overdose with a double-dose encorafenib: a case report.

Encorafenib (Braftovi) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi). According to the product label of encorafenib, there are no specific treatment recommendations in case of an overdose. We report on a 63-year-old man who ingested a double dose (900 mg) of encorafenib for 16 days. He developed overall minor chronic overdose symptoms such as nausea and vomiting grade 1 and muscle pain. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured. Kidney function parameters were normal, whereas liver values were slightly increased (grade 1) and QTc slightly prolonged. The plasma concentration 3 h after the last dose was 2110 ng/mL. We describe the course of a case with a chronic overdose during 16 days of the double dose of encorafenib as well as the followed approach, which could be taken into account when observing an encorafenib overdose. Providing information in times of Covid-19 is challenging, but remains necessary for good clinical care.

Paracetamol overdose in the newborn and infant: a life-threatening event.

PURPOSE: Paracetamol is the only drug recommended to treat fever in neonates. At recommended doses, paracetamol has not been associated with liver injury in neonates, while hepatotoxicity may occur after intake of a single high dose or multiple excessive doses. The aim of this narrative review is to critically analyze and summarize the available literature on newborns and infants exposed to supratherapeutic doses of paracetamol, with special focus on their clinical features, outcome, and management. METHODS: The PubMed, SCOPUS, and Google Scholar search engines were used to collect data, without time limitation. The following keywords were used: paracetamol/acetaminophen, overdose, hepatotoxicity, N-acetylcysteine, newborn, infant. RESULTS: The literature search identified a total of 27 case reports, a number of review articles, and few other relevant publications. Neonatal poisoning from paracetamol resulted from transplacental drug transfer after maternal overdose in some published cases, while it was the consequence of medication errors in other cases. Newborns and infants who have received a single overdose and have paracetamol concentrations below the Rumack-Matthew nomogram limits are at low risk of serious hepatic damage, while those who have recently ingested more than one supratherapeutic dose of paracetamol should be managed with caution. The treatment of choice for paracetamol poisoning is N-acetylcysteine, a specific antidote which reduces paracetamol hepatotoxic effects. N-Acetylcysteine should be given according to specific regimens through weight-based dosing tables. CONCLUSIONS: Caution should be used when paracetamol is administered to the newborn. In the event of an overdose, careful patient monitoring and personalization of post-overdose procedures are recommended.

Acute teriflunomide overdose with relatively mild symptoms: A case report.

WHAT IS KNOW AND OBJECTIVE: Teriflunomide is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis. CASE SUMMARY: We present a rare intoxication with a high dose (672 mg) of teriflunomide. According to its product label, the only known treatment is the administration of colestyramine and activated carbon (charcoal). No serious adverse events occurred during the time the patient was admitted (<24 h). No long-term overdose-related symptoms or complaints were reported. WHAT IS NEW AND CONCLUSION: The fact that after the acute overdose both adverse events and laboratory parameters were acceptable, prescribing colestyramine and activated carbon, as well as monitoring of laboratory parameters such as full blood count, liver and kidney values and QTc, seems sufficient during the early stage (<24 h after intake) of teriflunomide overdose.

The conundrum of polysubstance overdose.

WHAT IS KNOWN AND OBJECTIVE: Treating an opioid overdose using an opioid receptor antagonist (such as naloxone) makes mechanistic sense and can be effective. Unfortunately, the majority of current drug overdose deaths involve polysubstance use (i.e., an opioid plus a non-opioid). COMMENT: Respiratory depression induced by opioids results from excessive opioid molecules binding to opioid receptors. This effect can be reversed by an opioid receptor antagonist. However, the respiratory depression induced by non-opioid drugs is not due to action at opioid receptors; thus, an opioid receptor antagonist is ineffective in many of these cases. For respiratory depression induced by non-opioids, receptor antagonists are either not available (e.g., for propofol overdose) or there may be attendant risks with their use (e.g., seizures with flumazenil). This gives rise to a need for more effective ways to treat polysubstance overdose. WHAT IS NEW AND CONCLUSION: A new approach to treating opioid-induced respiratory depression due to drug overdose focuses on agents that stimulate respiratory drive rather than competing for opioid receptors. Such an approach is "agnostic" to the cause of the respiratory depression, so might be a potential way to treat polysubstance overdose.

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.

Electrocardiographic changes in loperamide toxicity: Case report and review of literature.

INTRODUCTION: Loperamide, an antidiarrheal agent, is a µ-opioid receptor agonist increasingly abused to prevent opioid withdrawal or to produce euphoric effects. At supra-therapeutic doses, loperamide can cause cardiac toxicity due to blockade of Na and IKr channels, resulting in wide QRS rhythms, severe bradycardia, prolonged QTc, polymorphic ventricular tachycardia, cardiac arrest, and death. There are limited data on the cardiotoxic effects of high dose loperamide. METHODS AND RESULTS: A case report of loperamide toxicity is presented and then added to a contemporary review of the literature. In total, the presentation and management of 36 cases of loperamide cardiotoxicity are summarized. The overall median daily dose (interquartile range) of loperamide was 200 (134-400) mg. The median QRS duration was 160 (125-170) ms. The median QTc duration was 620 (565-701) ms. Ventricular tachycardia was experienced by 24/36 (67%) of patients, 20 of which were specified to be polymorphic. Treatment was supportive, providing advanced cardiopulmonary life support and aggressive electrolyte repletion. Isoproterenol infusion or overdrive pacing was employed in 19/36 (53%) of cases. The median time to electrocardiogram normalization or hospital discharge, whichever came first, was 5 (3.5-10) days. CONCLUSION: Loperamide overdose is a toxidrome that remains underrecognized, and in patients with unexplained cardiac arrhythmias, loperamide toxicity should be suspected. Prompt recognition is critical due to the delayed recovery and high risk for life-threatening arrhythmias.

Serotonin Toxicity: Associated Agents and Clinical Characteristics.

BACKGROUND: Serotonin toxicity is a common cause of drug-induced altered mental status. However, data on the causes of serotonin toxicity, symptomatology, complications, and rate of antidotal treatment are limited. METHODS: This study evaluated cases of serotonin toxicity in the ToxIC registry, an international database of prospectively collected cases seen by medical toxicologists. Serotonin toxicity was diagnosed by bedside evaluation of medical toxicology specialists and explicit criteria were not used. The database was searched for "serotonin syndrome" between January 1, 2010, and December 31, 2016. RESULTS: There were 1010 cases included. Females made up 608 (60%) cases. Ages are as follows: younger than 2 years (3, 0.3%), 2 to 6 years (8, 0.8%), 7 to 12 years (9, 0.9%), 13 to 18 years (276, 27.3%), 19 to 65 years (675, 67%), older than 66 years (33, 3.4%), unknown (6, 0.6%). Reasons for encounter: intentional (768, 76%), adverse drug event/reaction (127, 12.6%), unintentional (66, 6%), and unknown (55, 5.4%). Signs/symptoms: hyperreflexia/clonus/myoclonus (601, 59.5%), agitation (337, 33.4%), tachycardia (256, 25.3%), rigidity (140, 13.9%), seizures (139, 13.7%), and hyperthermia (29, 2.9%). COMPLICATIONS: rhabdomyolysis (97, 9.7%), dysrhythmias (8, 0.8%), and death (1, 0.1%). TREATMENTS: benzodiazepines 67% (677/1010), cyproheptadine 15.1% (153/1010). There were 192 different xenobiotics reported with 2046 total exposures. Antidepressants were most common (915, 44.7%) with bupropion the most frequent overall (147, 7.2%). Common non-antidepressants were dextromethorphan (95, 6.9%), lamotrigine (64, 3.1%), and tramadol (60, 2.9%). DISCUSSION: Serotonin toxicity most often occurred in adult patients with intentional overdose. Antidepressants were the most common agents of toxicity. Interestingly, bupropion, a norepinephrine/dopamine reuptake inhibitor, was the most frequently mentioned xenobiotic. Though often cited as a potential antidote, only 15% of patients received cyproheptadine. Severe toxicity was rare. A single death was reported.

US Emergency Department Visits for Acute Harms From Prescription Opioid Use, 2016-2017.

OBJECTIVES: To estimate the number of US emergency department visits for prescription opioid harms by patient characteristics, intent, clinical manifestations, and active ingredient. METHODS: We used data from medical record-based surveillance from a nationally representative 60-hospital sample. RESULTS: Based on 7769 cases, there were 267 020 estimated emergency department visits annually (95% confidence interval [CI] = 209 833, 324 206) for prescription opioid harms from 2016 to 2017. Nearly half of visits (47.6%; 95% CI = 40.8%, 54.4%) were attributable to nonmedical opioid use, 38.9% (95% CI = 32.9%, 44.8%) to therapeutic use, and 13.5% (95% CI = 11.0%, 16.0%) to self-harm. Co-implication with other pharmaceuticals and concurrent illicit drug and alcohol use were common; prescription opioids alone were implicated in 31.5% (95% CI = 27.2%, 35.8%) of nonmedical use visits and 19.7% (95% CI = 15.7%, 23.7%) of self-harm visits. Unresponsiveness or cardiorespiratory failure (30.0%) and altered mental status (35.7%) were common in nonmedical use visits. Gastrointestinal effects (30.4%) were common in therapeutic use visits. Oxycodone was implicated in more than one third of visits across intents. CONCLUSIONS: Morbidity data can help target interventions, such as dispensing naloxone to family and friends of those with serious overdose, and screening and treatment of substance use disorder when opioids are prescribed long-term.

Lacosamide Overdose: A Case of QRS Prolongation and Seizure.

BACKGROUND: Lacosamide is a third-generation antiepileptic drug. Its likely mechanism of action is via neuronal sodium channel blockade, via a unique manner compared with other antiepileptic drugs that block sodium channels. A paucity of information exists regarding lacosamide overdosage. Lacosamide overdosage is thought to cause QRS prolongation and seizures, due to its effect of sodium channel blockade. The potential efficacy of sodium bicarbonate to reverse the effects of lacosamide has not been well studied. Furthermore, prior reports of lacosamide toxicity have occurred in the setting of concomitant polypharmacy. Thus, the isolated toxic effects of the drug have not been well elucidated. CASE REPORT: We report a case of a suspected, single-ingestion overdose on lacosamide. The patient developed signs of cardiotoxicity and seizure. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: After lacosamide overdosage, the emergency physician must be capable of acute management of subsequent lacosamide toxicity. Understanding the mechanisms of action causing toxicity due to this drug can help the clinician to anticipate the interventions that may be needed or useful to treat this potentially toxic ingestion.

Long-term outcome in patients with acute liver failure.

BACKGROUND & AIMS: Acute liver failure patients who meet poor prognostic criteria have high early mortality without emergency liver transplantation. A recent study however, reported that patients that survive spontaneously have a poorer outcome compared with patients undergoing transplantation. In this single centre study, we aimed to confirm or refute this observation. METHODS: Early survivors (acute liver failure patients who survived 90 days after the ICU admission) were assessed for long-term outcomes in four distinctive cohorts, incorporating aetiology (Acetaminophen overdose or non-Acetaminophen overdose), and management strategy (conservative or liver transplantation). Chi Squared or Fisher test were used to compare outcomes among the four cohorts (P < 0.05) and Kaplan-Meier curve (Log Rank test) to represent cumulative survival. RESULTS: Two hundred consecutive acute liver failure patients between 1990 and 2014 were included; mean age 38.3, ±12.8, male 70, 35%. 124/200 (62%) early survivors were identified; 13/124 (10.5%) acetaminophen patients underwent transplantation and 48/124 (38.7%) survived spontaneously; 36/124 (29.0%) non-acetaminophen underwent transplantation and 27/124 (21.8%) survived spontaneously. A total of 11/124 (8.9%) died subsequently (median survival 5.3± IQR 9.1), three spontaneous survivors and eight transplanted patients (P = 0.025); of the eight transplanted patients, six died of transplant related complications and two of suicide. CONCLUSION: The results of this study suggest that although liver transplantation is a life-saving procedure for acute liver failure patients, they have a worse long-term outcome compared with spontaneous survivors. Novel therapies to increase the percentage of spontaneous survivors are urgently needed.

Delayed hyperthermia from chlorfenapyr overdose.

We describe the hospital course of a 42-year-old patient who presented to the Emergency Department following an ingestion of an unknown quantity of chlorfenapyr, an organochlorine pesticide that acts as a mitochondrial uncoupler (MU). There is limited data on chlorfenapyr toxicity in humans, but reports indicate a 100% mortality rate after a 7-10 day quiescent period.3-6 Our patient was admitted for a 5-day asymptomatic observation period before becoming critically ill. Supportive care, antioxidant therapy, and late hemodialysis (HD) proved futile. The patient expired from complications due to uncontrollable hyperthermia on hospital day 6. This case represents the first reported fatality due to chlorfenapyr in North America, and illustrates: 1) its potency as a human toxin, 2) the futility of extracorporeal decontamination once late toxicity has set in; 3) the potential need for early and aggressive decontamination in the ED; and 4) the need for a better understanding of this unique poison.

Severe beta blocker and calcium channel blocker overdose: Role of high dose insulin.

A 54-year-old female presented after taking an overdose of an unknown amount of hydrochlorothiazide, doxazocin, atenolol and amlodipine. She was initially refractory to treatment with conventional therapy (intravenous fluids, activated charcoal, glucagon 5 mg followed with glucagon drip, calcium gluconate 10%, and atropine). Furthermore, insulin at 4 U/kg was not effective in improving her hemodynamics. Shortly after high dose insulin was achieved with 10 U/kg, there was dramatic improvement in hemodynamics resulting in three of five vasopressors being weaned off in 8 h. She was subsequently off all vasopressors after six additional hours. The role of high dose insulin has been documented in prior cases, however it is generally recommended after other conventional therapies have failed. However, there are other reports that suggest it as initial therapy. Our patient failed conventional therapies and responded well only with maximum dose of insulin. Physicians should consider high dose insulin early in severe beta blocker or calcium channel blocker overdose for improvement in hemodynamics. This leads to early discontinuation of vasopressors. It is important that emergency physicians be aware of the beneficial effects of high dose insulin when initiated early as opposed to waiting for conventional therapy to fail; as these patients often present first to the emergency department. Early initiation in the emergency department can be beneficial in these patients.

Lack of respiratory depression in paracetamol-codeine combination overdoses.

AIMS: Codeine containing analgesics are commonly taken in overdose, but the frequency of respiratory depression is unknown. We investigated whether paracetamol-codeine combination overdoses caused respiratory depression more than paracetamol alone. METHODS: We reviewed deliberate self-poisoning admissions with paracetamol (>2 g) and paracetamol-codeine combinations presenting to a tertiary toxicology unit (1987-2013). Demographic information, clinical effects, treatment (naloxone, length of stay [LOS], mechanical ventilation) were extracted from a prospective database. Primary outcome was naloxone requirement or ventilation for respiratory depression. RESULTS: From 4488 presentations, 1376 admissions were included with paracetamol alone (929), paracetamol-codeine combinations (346) or paracetamol-codeine-doxylamine combinations (101) without co-ingestants. Median age was 23 years (12-89 years); 1002 (73%) were female. Median dose was 12 g (interquartile range [IQR]: 7.5-20 g). Median LOS was 16 h (IQR: 6.5-27 h) and 564 (41%) were given acetylcysteine. Significantly larger paracetamol doses were ingested and more acetylcysteine given in paracetamol alone versus paracetamol combination overdoses. Seven out of 1376 patients were intubated or received naloxone (0.5%; 95% CI: 0.2-1.1%), three intubated, three given naloxone and one both. Three out of 929 patients ingesting paracetamol alone (0.3%; 95% CI: 0.1-1%) required intubation or naloxone, compared to two out of 346 ingesting paracetamol-codeine combinations (0.6%; 95% CI: 0.1-2.3%; absolute difference, 0.26%; 95% CI: -0.7-1.2%; P = 0.62). Two out of 101 patients ingesting paracetamol-codeine-doxylamine combinations (2%; 95% CI: 0.3-8%) required intubation or naloxone. Four patients were intubated for reasons other than respiratory depression: hepatotoxicity (2), retrieval (1), no data (1). Two out of 929 (0.2%) paracetamol alone overdoses had a Glasgow coma score < 9 compared to three out of 346 (0.9%) in the paracetamol-codeine group. CONCLUSIONS: Paracetamol-codeine combination overdoses are rarely associated with severe respiratory depression, with only two given naloxone and none intubated for respiratory depression.

Effect of benzocaine and propranolol on phospholipid-based bilayers.

Cell membranes play a fundamental role in protecting the cell from its surroundings, in addition to hosting many proteins with fundamental biological tasks. A study of drug/lipid interactions is a necessary and important step in fully clarifying the role and action mechanism of active ingredients, and shedding light on possible complications caused by drug overdosage. In this paper, the influence of benzocaine and propranolol drugs on the structure of l-α-phosphatidylcholine-based membranes has been investigated by means of neutron reflectivity, grazing incidence small angle neutron scattering, and small/ultra-small angle neutron scattering. Investigations allowed discovering a stiffening of the membranes and the formation of stalks, caused by the presence of benzocaine. On the other hand, disordered bilayers (lamellar powders) and highly curved structures were found in the presence of propranolol. The results obtained may be rationalized in terms of the molecular structures of drugs and may serve as a starting point for explaining the toxic behavior in long-term and overdosage scenarios.

Successful treatment of propafenone-induced cardiac arrest by calcium gluconate.

Propafenone is prescribed for the control of cardiac ventricular arrhythmias. Poisoning from propafenone intoxication is rare, but the survival rate of patients is low. We present a case of a 37-year-old man who developed cardiac arrest due to propafenone intoxication. Cardiopulmonary resuscitation, plasmapheresis, and other medical treatments had no effect on cardiac arrest. After repeated administrations of calcium gluconate, the patient achieved a full recovery. To the best of our knowledge, this is the first case report in which a full recovery from cardiac arrest was achieved by administration of calcium gluconate. We recommend that for patients poisoned by propafenone, close monitoring for decreased blood calcium is important.

Emergency department approach to QTc prolongation.

QTc prolongation has been associated with increased risk of developing ventricular tachydysrhythmias, particularly Torsades de Pointes (TdP). QTc prolongation is influenced by many factors including congenital causes, heart rate, metabolic imbalances, and pharmacotherapy. Several commonly used medications in the emergency department (ED), such as antipsychotics and antiemetics, are known to prolong the QT interval. In addition, ED patients may present with conditions that may predispose them to QTc prolongation, such as drug overdose or hypokalemia, which can further complicate management. ED providers should not only be aware of which medications have these effects, but must also thoroughly investigate any pertinent patient history that may contribute to QTc prolongation. This review discusses commonly encountered medications that are associated with QTc prolongation, the mechanisms by which they prolong the QTc interval, and other factors that may influence ED medication administration and management.

Valproic Acid Overdose Review of a Case With Electrocardiographic Changes.

BACKGROUND: Valproic acid (VPA) is increasingly used to treat a variety of medical disorders, such as seizures, psychiatric disorders, and headaches. Therefore, accidental and intentional ingestions with valproic acid are increasing. OBJECTIVES: A case is presented in an adolescent with ischemic electrocardiographic changes after an acute overdose with VPA. DISCUSSION: Major features of a valproic acid overdose include respiratory depression, progressive coma, hepatotoxicity, thrombocytopenia, and hemodynamic instability. Electrocardiographic abnormalities usually consist of tachycardia and nonspecific changes. Supportive care is indicated in most overdoses and involves the monitoring and correction of electrolyte abnormalities, coagulopathies, and acid-base imbalances. Treatment may include activated charcoal, naloxone, l-carnitine, and extracorporeal detoxification. CONCLUSIONS: Valproic acid overdose is a relatively rare and electrocardiographic changes usually consist of tachycardia and nonspecific changes, but ischemic changes may occur and usually transient and require only recognition.

Attempted suicide by Flécainide overdose: A case report.

Class Ic antiarrythmic overdose is associated with a relatively high mortality. We presenta case report regarding a suicidal intoxication of an 18-year old female with a medical history of Wolff-Parkinson-White syndrome. The preliminary examination highlighted a profound cardiovascular collapse. The electrocardiogram showed a PR interval extended to 360 ms. The QRS complexes were enlarged to 360 ms with a right bundle brunch block appearance associated with left posterior hemibloc. There were repolarization abnormalities such as elevation of the J-point, convex ST segment and biphasic T wave in the right precordial leads ("Brugada-Like ECG pattern"). Sodium bicarbonate was administered. A rapid decrease in the duration of the QRS complexes was noted as well as a slowing of the heart rate. The electrocardiogram aspect on the 4th day showed the reappearance of the ventricular pre-excitation. The severity and lethal potential of Flecainide poisoning are linked to the cardiotoxic effects of these molecules. The prognosis remains poor despite progress in intensive care procedures.

Noninvasive End Tidal CO2 Is Unhelpful in the Prediction of Complications in Deliberate Drug Poisoning.

STUDY OBJECTIVE: We study the performance of capnometry in the detection of early complications after deliberate drug poisoning. METHODS: This was a prospective cohort study of self-poisoned adult patients who presented at an emergency department (ED) between April 20, 2012, and May 6, 2014. Patients who ingested at least 1 neurologic or respiratory depressant drug were included. The primary outcome was the predictive value of an end tidal CO2 (etco2) measurement greater than or equal to 50 mm Hg for the detection of early complications defined a priori by hypoxia requiring oxygen greater than or equal to 3 L/min, bradypnea less than or equal to 10 breaths/min, or ICU admission after intubation or antidote administration because of unresponsiveness to pain or respiratory arrest. Consciousness scales and clinical data were recorded at admission and every 30 minutes. Noninvasive etco2 was continuously measured for 2 hours after inclusion unless the patient was admitted to the ICU. Patients and physicians were blinded to etco2 values. RESULTS: Two hundred one patients were included, 35 of whom exhibited at least 1 complication. An etco2 measurement greater than or equal to 50 mm Hg predicted the onset of a complication, with a sensitivity of 46% (95% confidence interval [CI] 29% to 63%) and a specificity of 80% (95% CI 73% to 86%), leading to a positive predictive value of 33% (95% CI 20% to 48%) and a negative predictive value of 88% (95% CI 81% to 92%). etco2 was less able to predict complications than the Glasgow Coma Scale score at inclusion. CONCLUSION: Capnometry in isolation does not provide adequate prediction of early complications in self-poisoned patients referred to the ED. A dynamic minute-by-minute assessment of etco2 could be more predictive.