Newly initiated cardiovascular medication and short-term risk of unintentional poisoning among Swedish middle-aged and older adults: A national register-based case-crossover study.

BACKGROUND: Although some studies have shown the average side effects of cardiovascular medication, the short-term effect after newly initiated cardiovascular medications has not been studied in any detail. We aim to determine the effect of newly initiated cardiovascular medications resulting in unintentional poisoning and to identify those at high risk. METHODS: A case-crossover design was used. From the Swedish National Patient Register, a total of 9,354 persons aged ≥ 50 and hospitalized with a first event of unintentional poisoning between July 2006 and September 2018 were identified. Through linkage to the Prescribed Drug Register, exposure to newly initiated cardiovascular medication during the case period (1-28 days prior to the onset date of unintentional poisoning) was compared with that in a corresponding control period (113-140 days prior to the onset date). Conditional logistic regression was used to determine the associations in total, for different time periods as well as by age, sex, underlying comorbidity, and use of other medications. RESULTS: Newly initiated cardiovascular medications were associated with a higher risk of unintentional poisoning, especially during the first week after initiation (odds ratio [OR]=1.39), (95% confidence interval [CI]=1.08-1.79). The risk of unintentional poisoning was comparable across age groups, sex, underlying comorbidities, and medications with OR (95% CI) ranging from 1.15 (0.75-1.74) to 2.00 (1.15-3.47). CONCLUSION: This large population-based case-crossover study showed that newly initiated cardiovascular medication is associated with an increased risk of unintentional poisoning, particularly during the first week after initiation. The risk is comparable across age, sex, underlying comorbidity, and medications.

Fatal intoxication with ivabradine: First case report.

Ivabradine is a bradycardic drug used worldwide in the treatment of chronic stable angina and chronic heart failure. We presented here a case of a 61-year-old woman who was admitted to emergency department for overdose. She presented with drowsiness, bradycardia (45bpm) and a low blood pressure (116/21mmHg). She died ten hours after admission from multiple organ failure. Ivabradine was quantified in different matrices sampled during autopsy using a method on LC-MS/MS (TSQ Vantage Thermo Fisher Scientific®), after a double liquid-liquid extraction with a mixture of hexane/ethyl acetate (1/1; v/v) and then chloroform/isopropanol (80/20; v/v). Chromatographic separation was achieved using a Hypersyl gold PFP column (200×2.1mm, 1.9µm) and an acetonitrile/formiate 2mM, 0.1% formic acid buffer gradient. Method was fully validated on whole blood. The mean overall recovery was 90%. Linearity was validated in the 5-500ng/mL range, with intra and inter-day precision lower than 14.3%. The ivabradine concentration found in patient post-mortem blood was 1210ng/mL. Ivabradine was also quantified in different viscera like lung (2910ng/g), kidney (1510ng/g), liver (1050ng/g), heart (900ng/g), and brain (110ng/g). The vitreous humor concentration was 760ng/mL. Pregabalin and zopiclone were also found in blood at 50µg/mL and 206ng/mL, respectively. This case seems to be the first report of a fatal intoxication involving ivabradine and the first published concentrations in organs.

Sex Differences in Poisonings Among Older Adults: An Analysis of the Toxicology Investigators Consortium (ToxIC) Registry, 2010 to 2016.

PURPOSE: Adults aged >65 years are susceptible to intentional and unintentional poisoning, with contributing factors that include polypharmacy, comorbidity, susceptibility to medication error, and gaps in research. Although toxicologists are often tasked with managing and preventing poisoning among older adults, little is known about sex differences in these poisonings. The aim of this study was to review sex differences in poisonings among older adults managed at the bedside by medical toxicologists. METHODS: All case subjects aged >65 years in the Toxicology Investigators Consortium (ToxIC) registry between January 2010 and December 2016 were reviewed. Data included reasons for exposure and consultation, exposure agents and routes, presenting clinical findings, and treatment provided. Cases missing age, sex, or primary reason for toxicology consultation data were excluded. We used χ2 tests to assess differences in distribution of study variables according to participant sex. FINDINGS: Among 51,441 total registry cases, 542 (1.05%) were excluded because of missing data. Among the remaining 50,899 cases, 2930 (5.8%) were included for age >65 years; 52.3% of older adults were female. Race was missing or unknown for 49.2% of cases. Adverse drug reactions were more commonly encountered in female subjects than in their male counterparts (9.6% vs 6.4%; P = 0.001). No statistically significant sex differences were observed for total numbers of intentional, unintentional pharmaceutical, and nonpharmaceutical exposures. The most common medications involved were cardiovascular (16.8%) and analgesics/opioids (14.8%). Female subjects were more likely than male subjects to be evaluated by a toxicologist for cardiovascular medications (18.7% vs 14.7%; P = 0.004) and analgesics/opioids (17.6% vs 11.8%; P < 0.001). Male subjects were more likely than female subjects to be evaluated for ethanol toxicity (7.4% vs 1%; P < 0.001) and for envenomations (4.2% vs 1.8%; P < 0.001). The most common route of exposure was oral ingestion (81.3%). Signs/symptoms were noted in 54.8% of cases, with the most common abnormal vital sign being bradycardia (17.2%). Pharmacologic support was the most common intervention and was more common in male subjects than in female subjects (17.7% vs 12.3%; P < 0.001). Deaths were reported in 38 female subjects (2.45%) and 46 male subjects (3.34%); there was no statistically significant difference in death rate according to sex (P = 0.148). IMPLICATIONS: Older female adults were more commonly evaluated by a medical toxicologist for an adverse drug reaction than older male adults. Female patients were more likely than male patients to be evaluated for poisoning related to analgesic/opioids and cardiovascular medications, and older male patients more frequently received pharmacologic support than older female patients. No significant sex differences were observed in numbers of toxicology consultations for intentional, unintentional pharmaceutical, and nonpharmaceutical exposures.

Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1).

CONTEXT: We hypothesized that in chronic digoxin toxicity, anti-digoxin antibodies (Fab) would be efficacious in binding digoxin, but this may not translate into improved clinical outcomes. OBJECTIVE: This study aims to investigate changes in free digoxin concentrations and clinical effects on heart rate and potassium concentrations in chronic digoxin poisoning when anti-digoxin Fab are given. MATERIALS AND METHODS: This is a prospective observational study. Patients were recruited if they have been treated with anti-digoxin Fab for chronic digoxin poisoning. Data was entered into a standardised prospective form, supplemented with medical records. Their serum or plasma was collected, analysed for free and bound digoxin and free anti-digoxin Fab concentrations. RESULTS: From September 2013 to February 2015, 36 patients (median age, 78 years; 22 females) were recruited from 18 hospitals. Median heart rate (HR) was 49 beats/min. Initial median digoxin and potassium concentrations were 4.7 nmol/L (3.6 µg/L) (range: 2.3-11.2 nmol/L) and 5.3 mmol/L (range: 2.9-9.2 mmol/L) respectively. Beta-blockers (n = 18), calcium antagonists (n = 6), spironolactone and/or angiotensin blocking agents (n = 24) were also used concomitantly. Renal impairment and gastrointestinal symptoms were present in 31 (86%) and 22 (63%) patients respectively. Five patients died from conditions unrelated to digoxin toxicity. Median change in HR was 8 beats/min post-Fab with no effect on blood pressure; they were 4, 10 and 17 beats/min for the 1, 2 and ≥3 vials of anti-digoxin Fab groups respectively. Concomitant treatments with potassium lowering agents (12/36) and inotropic drugs (7/36) were used. Gastrointestinal effects resolved in all 22 patients. The median decrease for potassium was 0.3 mmol/L. Digoxin concentration reduced from 3.8 to 0 nmol/L post-Fab. There was a rebound observed in the free digoxin concentration in 25 patients but none had associated clinical deterioration. CONCLUSIONS: One to two vials of anti-digoxin Fab initially bound all free digoxin confirming Fab efficacy. However, this was associated with only a moderate improvement in HR and potassium, suggesting bradyarrhythmia and hyperkalaemia may be from other co-morbidities.

Ranolazine overdose-induced seizures.

Ranolazine is a new anti-anginal medication that was approved by the US Food and Drug Administration (FDA) in 2006 for patients with symptomatic chronic angina despite optimized therapy. This paper presents a case report of a fifteen year old male patient admitted to the pediatric intensive care unit after ranolazine overdose ingestion. He had recurrent new onset seizures that are most likely due to ranolazine overdose. Seizures have never been reported with ranolazine use or abuse.

Massive Atenolol, Lisinopril, and Chlorthalidone Overdose Treated with Endoscopic Decontamination, Hemodialysis, Impella Percutaneous Left Ventricular Assist Device, and ECMO.

BACKGROUND: Overdose of cardiovascular medications is increasingly associated with morbidity and mortality. We present a case of substantial atenolol, chlorthalidone, and lisinopril overdose treated by multiple modalities with an excellent outcome. CONCLUSION: Aggressive medical intervention did not provide sufficient hemodynamic stability in this patient with refractory cardiogenic and distributive shock. Impella® percutaneous left ventricular assist device and extracorporeal membrane oxygenation provided support while the effects of the overdose subsided. We present concentrations demonstrating removal of atenolol with continuous venovenous hemodiafiltration. This is the first report of esophagogastroduo denoscopy decontamination of this overdose with a large pill fragment burden.

Toxicology in the ICU: Part 2: specific toxins.

This is the second of a three-part series that reviews the generalized care of poisoned patients in the ICU. This article focuses on specific agents grouped into categories, including analgesics, anticoagulants, cardiovascular drugs, dissociative agents, carbon monoxide, cyanide, methemoglobinemia, cholinergic agents, psychoactive medications, sedative-hypnotics, amphetamine-like drugs, toxic alcohols, and withdrawal states. The first article discussed the general approach to the toxicology patient, including laboratory testing; the third article will cover natural toxins.

Cardiovascular medication exposures and poisonings in Izmir, Turkey: a 14-year experience.

Cardiovascular medications (CVMs) are frequently prescribed for cardiovascular diseases. The unconscious use of cardiovascular drugs may lead to severe clinical manifestations, even to death, especially when in overdose. The objective of this study is to clarify the profile of CVM exposures admitted to Department of Emergency Medicine in Dokuz Eylul University Hospital (EMDEU) between 1993 and 2006. Case demographics, type of the medication, route and reason for exposure, clinical effects and outcome were recorded. Related to the CVM exposures, 105 poisoning cases were admitted. Mean age of children and adults were 12.8 ± 1.0 and 30.1 ± 1.8, respectively. Females were dominating (77.1%). Poisoning by accident occurred mainly among children in the 0-6 age group (64.3%) and suicide attempt was predominant in the 19-29 age group (47.8%). The most common ingested CVMs admitted to EMDEU were calcium channel blockers (19.7%), beta-blockers (17.3%), angiotensin converting enzyme inhibitors and diuretics (11.8%). Most of the patients were asymptomatic (59.1%). Frequently observed symptom was altered consciousness (18.6%). Antihypertensive drugs are responsible for the most of the CVM exposures. Prospectively designed multi-centered studies are needed to reflect the epidemiological properties of cardiovascular drug exposures throughout our country and would be very valuable for the determination of preventive measures.

[Successful treatment of polymedicamentous poisoning with metoprolol, diltiazem and cilazapril].

INTRODUCTION: Poisoning caused by drugs with cardiodepressive effects is an urgent condition in medicine which is associated with high mortality rate regardless of modern therapeutic methods. Accidental or intentional poisoning whit these drugs produces heart activity depression and cardiovascular collapse as consequences. Current therapy for severe poisoning caused by beta-blockers and calcium channel blockers includes both unspecific and specific antidote therapy whit glucagon, as well as application of adrenergic drugs, calcium, phosphodiesterase inhibitors and hyperinsulinemia/euglycemia therapy. However, even whit the application of these drugs, prompt measures of unspecific detoxication therapy and cardiopulmonary reanimation are crucial for survival of patients with severe poisoning. CASE REPORT: A 28-year-old female patient was hospitalized for cardiogenic shock and altered state of conscioussnes (Glasgow coma score = 4), caused by acute poisoning with 2 g of metoprolol (Presolol), 1.8 g of diltiazem (Cortiazem) and 50 mg of cilazapril (Zobox). Prolonged cardiopulmonary resuscitation was applied during the first 16 hours of hospitalization, including administration of crystaline solutions (8 L), 17 mg of adrenaline, 4 mg of atropine, 4 mg of glucagone and 1.6 g of dopamine, with electro-stimulation by temporary pacemaker and mechanical ventilation. In a defined time period, normalized state of consciousness was registered, mechanical ventilation was stopped and normal heart activity and hemodynamic stability were accomplished. During hospitalization the patient was treated for mild pneumonia and after ten days, completely recovered, was released and sent to home treatment. CONCLUSION: Prompt measures of cardiopulmonary resuscitation and multidisciplinary treatment in intensive care units significantly increase the chances of complete recovery of a patient with severe poisoning caused by drugs with cardiodepressive efects.

[Extracorporeal life support for poisonings with cardiotoxicants]. / Assistance circulatoire dans les intoxications par cardiotropes.

Acute poisonings with cardiotoxicants are responsible of significant morbidity and incompressible mortality, mainly among youths. Their incidence is increasing. Death mainly results from cardiac failure refractory to pharmacological treatments as well as sudden cardiac arrest refractory to cardiopulmonary resuscitation. Determination of the exact mechanism of shock is essential to guide adequate treatments. Treatment is supportive including high-dosage catecholamines and may require antidotes. Administration of other inotropic agents (including glucagon, phosphodiesterase inhibitors, calcium salts, and euglycemic insulin) may be discussed, although their efficacy is still not clearly established. Extracorporeal life support allows organ perfusion until reversal of cardiac dysfunction and elimination of the toxicant. Several cases of survival using this exceptional technique were reported in the literature. Thus, based on these reports, extracorporeal life support has gained a recognized place in the therapeutic arsenal of acute poisonings.

Intravenous fat emulsion: a potential novel antidote.

Intravenous fat emulsions (IFE) are traditionally used as a component of parenteral nutrition therapy. Recently, IFE was used to resuscitate severe local anesthetic drug toxicity. This review focuses on the potential role of IFE in treatment of toxicity due to local anesthetics and other lipid-soluble drugs. The general properties of IFE, metabolic fate, and associated adverse events are described. Cases of local anesthetic toxicity treated with IFE are presented along with a discussion of the possible antidotal mechanisms. Initial investigations into the antidotal use of IFE for lipophilic central nervous and cardiovascular drug toxicity are also reviewed.

Cardiovascular challenges in toxicology.

The diagnoses and subsequent treatment of poisoned patients manifesting cardiovascular compromise challenges the most experienced emergency physician. Numerous drugs and chemicals cause cardiac and vascular disorders. Despite widely varying indications for therapeutic use, many agents share a common cardiovascular pharmacologic effect if taken in overdose. Standard advanced cardiac life support protocol care of these patients may not apply and may even result in harm if followed. This chapter discusses com-mon cardiovascular toxins and groups them into their common mechanisms of toxicity. Multiple agents exist that result in human cardiovascular toxicity. The management of the toxicity of each agent should follow a rationale approach. The first step in the care of all poisoned patients focuses on good supportive care.

[Acute poisoning with cardiovascular agents]. / Akutna trovanja kardiovaskularnim lekovima.

In order to determine the frequency, severity of poisoning, and the efficacy of the applied therapeutic measures, retrospective study of 391 patients treated for acute drug poisoning was performed during one-year period at the Clinic for Emergency and Clinical Toxicology and Pharmacology. In 49 (12.5%) patients cardiovascular agents were the cause of poisoning, most frequently beta-blockers and calcium antagonists (77.5%). Poisoning with antihypertensive agents was registered in 12.2% of patients, antiarrhythmics in 8.2%, and cardiotonics in 2.1%. Beta-blockers and calcium antagonists caused severe poisoning in over 40% of cases. Predominant clinical manifestations were registered on cardiovascular system, while central nervous system effects occurred secondary to cardiotoxicity. Symptomatic and supportive measures were performed most frequently, while specific agents, glucagon, calcium salts, and others, were used less often.

[Cardiovascular drugs poisoning in the elderly patients hospitalized in the Province Poisoning Center in Lublin in the years 1995-2001]. / Analiza zatruc lekami pierwotnie dzialajacymi na uklad sercowo-naczyniowy u pacjentów w wieku podeszlym hospitalizowanych w Wojewódzkim Osrodku Toksykologii w Lublinie w latach 1995-2001.

The aim of our research was retrospective analysis of poisoning with cardiovascular drugs (T46 according to ICD 10 classification) in patients over 59 years old, hospitalized in Province Poisoning Centre in Lublin, in the period from 1995 to 2001. There were hospitalized 288 patients at this time age, over 59 years old. Among this 16 persons were poisoned with cardiovascular drugs (one accidental and 15 suicidal intoxications), and 3 of them died. Different kinds of cardiovascular medications were used e.g. digoxin, nitrates, hypotensive drugs (as single and multiplied drug poisonings). At 3 of the patients depression was diagnosed.