Calcium Channel Blocker Overdose: What Role Does Extracorporeal Membrane Oxygenation Have in Support? A Systematic Review of the Literature.

Extracorporeal membrane oxygenation (ECMO) has had increasing prevalence and indications in the last decade. Calcium channel blocker overdose (CCBOD) can lead to significant cardiopulmonary dysfunction and has also increased in recent years. CCBOD results in cardiac depression, vasoplegia, and hyperglycemia. Expert consensus recommends treatment with calcium, high-dose insulin, inotropes, and vasopressors. Our systematic review evaluated when to initiate ECMO in the CCBOD population and the mortality rate associated with use. Electronic literature review identified all relevant studies for CCBOD and ECMO. PRISMA guidelines for systematic review were followed. Three independent authors reviewed abstracts and full texts, and only CCB ingestion without polypharmacy was included. Two authors independently collected data, which included demographics, current medical treatments, ECMO type, and survival. From 314 abstracts, 25 papers were included with a median publication year of 2019. Twenty-six patients were included with an average age of 32.7 years and 42%/58% male/female. Average time on ECMO 4.3 days. VA and VV ECMO use were 92.3% and 7.7%, respectively, and 84.6% of patients survived to hospital discharge. Before ECMO, most patients received 4-5 medical treatments (53.8%). Our systematic review demonstrates ECMO is a newly used, yet valuable therapy for CCBOD when medical treatment fails. Survival to discharge after ECMO for CCBOD is substantially higher than standard VV or VA ECMO. Medical management is still the mainstay therapy for CCBOD, but we show that a persistently unstable patient may benefit from prompt evaluation at an ECMO center for treatment.

Single-Pass Albumin Dialysis as Rescue Therapy for Pediatric Calcium Channel Blocker Overdose.

Calcium channel blocker ingestions remain one of the leading causes of death related to cardiovascular medication ingestion in both adults and pediatric patients. We report a case of a 17-year-old, 103 kg female presenting after an intentional polypharmacy ingestion, including 500 to 550 mg of amlodipine. She presented with profound vasoplegia and cardiovascular collapse requiring high-dose inotropes and eventual life support with extracorporeal membrane oxygenation (ECMO). Current available treatments, designed for adults, including lipid emulsion and methylene blue, provided no sustained clinical improvement. This resulted in the initiation of single-pass albumin dialysis (SPAD). We aim to describe the clinical implications, amlodipine toxic dose effects, and clinical challenges associated with large pediatric patients and high-dose medications. We also discuss several challenges encountered related to dosing and concentration of medications, which led to fluid overload. Given the ongoing obesity epidemic, we routinely see pediatric patients of adult size. This will continue to challenge pediatric use of adult dosing and concentrations to avoid excessive fluid administration for high-dose medications, such as insulin and vasoactive agents. To our knowledge, this is the first successful case of using SPAD in conjunction with ECMO for salvage therapy after refractory life-threatening calcium channel blocker toxicity.

Characteristics of Adults Aged ≥18 Years Evaluated for Substance Use and Treatment Planning - United States, 2019.

In 2019, 65.8 million U.S. adults reported past-month binge drinking and 35.8 million reported illicit drug use or prescription pain reliever misuse during the past month; 20.4 million met diagnostic criteria for a substance use disorder during the past year (1). Approximately 81,000 persons died of a drug overdose* during May 2019-May 2020; excessive alcohol use contributes to an estimated 95,000 deaths per year (2). Persons with a substance use disorder are at elevated risk for overdose and associated harms (3). To examine the prevalence of past 30-day substance use patterns and the severity of problems experienced across seven biopsychosocial domains (alcohol, drug, employment, family, legal, medical, and psychiatric), CDC used 2019 data from the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO) Addiction Severity Index-Multimedia Version (ASI-MV) tool (4); these data are collected from adults aged ≥18 years who seek substance use treatment in the United States. Alcohol was the most commonly reported substance used during the past 30 days (35.8%), followed by cannabis (24.9%), prescription opioids (misuse) (18.5%), illicit stimulants (14.0%), heroin (10.2%), prescription sedatives or tranquilizers (misuse) (8.5%), cocaine (7.4%), illicit fentanyl (4.9%), and prescription stimulants (misuse) (1.8%).† Polysubstance use (use of two or more substances) during the past 30 days was reported by 32.6% of respondents. Among the biopsychosocial domains measured, 45.4% of assessments reported more severe problems with drugs; others reported psychiatric (35.2%), legal (28.8%), medical (27.4%), employment (25.0%), alcohol (24.2%), and family problems (22.8%). These findings highlight the complex nature of substance use in the United States, the interplay between substance use and mental illness, and the complex challenges that persons with substance use disorder face when seeking treatment. Actions to enhance comprehensive substance use programs that incorporate polysubstance use and co-occurring mental health problems into strategies for prevention, treatment, and response are needed, as is expanded linkage to services. CDC provides data and resources to equip and inform states, territories, and local jurisdictions to help improve opioid prescribing practices, improve linkage to care for the treatment of opioid use disorder, and prevent and reverse overdoses.§.

Management and Associated Toxicokinetics of Massive Valproic Acid Ingestion with High Flow Continuous Venovenous Hemodiafiltration.

INTRODUCTION: Valproic acid (VPA) toxicity commonly results in a self-limited state of CNS depression that is managed with supportive care and levocarnitine. In massive overdose, patients can develop toxic encephalopathy, shock, multisystem organ failure, and death. We present a case with relevant toxicokinetics of a patient presenting with a profoundly elevated VPA concentration resulting in survival, treated with supportive care including high-dose continuous venovenous hemodiafiltration (CVVHDF). CASE REPORT: A 17-year-old female presented to an emergency department after being found unresponsive at home with concern for massive VPA ingestion. She arrived obtunded and hypotensive with initial VPA concentration of 2226 mg/L, estimated 9 h post-ingestion. Her early hospital course was marked by hypotension requiring multiple vasopressors, and her workup was notable for multiple severe metabolic derangements. High-dose CVVHDF was initiated upon transfer to a tertiary children's hospital with the aim to enhance VPA removal and normalize metabolic derangements. At that time, her VPA concentration was 1071 mg/L. Apparent half-life of VPA improved modestly with extracorporeal treatment, but her metabolic derangements and hemodynamic instability corrected rapidly. Her clinical course was complicated by necrotizing pancreatitis, pancytopenia requiring transfusions of multiple cell lines, coma, and seizures. She ultimately recovered with normal neurological function.

Terapia de insulina y glucosa para el tratamiento de intoxicación grave con bloqueantes de canales de calcio en pediatría. Reporte de un caso / Insulin/glucose therapy for the treatment of severe calcium channel blocker poisoning in pediatrics. Case report

La intoxicación por bloqueantes de los canales de calcio es un cuadro poco frecuente en la población pediátrica. Los signos y síntomas pueden progresar de forma rápida y llevar al colapso cardiovascular y muerte. El sostén hemodinámico con inotrópicos y vasopresores no suele ser efectivo. La terapia con insulina y glucosa es un complemento eficaz del tratamiento inicial, que está ampliamente estudiado, y se utiliza en diferentes patologías con compromiso hemodinámico. Se presenta el caso de una paciente pediátrica con antecedente de ingestión de dosis altas de amlodipina con fines suicidas, con descompensación hemodinámica refractaria al tratamiento de soporte inotrópico habitual. A partir del tratamiento con insulina y glucosa, se logró la estabilidad hemodinámica, con evolución favorable de la paciente.

Calcium channel blocker poisoning is a rare condition in the pediatric population. Signs and symptoms can be rapidly progressive and lead to cardiovascular collapse and death. Hemodynamic support with inotropics and vasopressors is usually not effective. The insulin/glucose therapy is an effective complement to the initial treatment, which is widely studied and used in different pathologies with hemodynamic compromise. The case of a pediatric patient with a history of high-dose ingestion of amlodipine for suicidal purposes, with hemodynamic decompensation refractory to usual inotropic support treatment, is presented. From the insulin/glucose treatment, hemodynamic stability was achieved with a favorable evolution

γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology.

Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid present endogenously in the brain and used therapeutically for the treatment of narcolepsy, as sodium oxybate, and for alcohol abuse/withdrawal. GHB is better known however as a drug of abuse and is commonly referred to as the "date-rape drug"; current use in popular culture includes recreational "chemsex," due to its properties of euphoria, loss of inhibition, amnesia, and drowsiness. Due to the steep concentration-effect curve for GHB, overdoses occur commonly and symptoms include sedation, respiratory depression, coma, and death. GHB binds to both GHB and GABAB receptors in the brain, with pharmacological/toxicological effects mainly due to GABAB agonist effects. The pharmacokinetics of GHB are complex and include nonlinear absorption, metabolism, tissue uptake, and renal elimination processes. GHB is a substrate for monocarboxylate transporters, including both sodium-dependent transporters (SMCT1, 2; SLC5A8; SLC5A12) and proton-dependent transporters (MCT1-4; SLC16A1, 7, 8, and 3), which represent significant determinants of absorption, renal reabsorption, and brain and tissue uptake. This review will provide current information of the pharmacology, therapeutic effects, and pharmacokinetics/pharmacodynamics of GHB, as well as therapeutic strategies for the treatment of overdoses. Graphical abstract.

Plasmapheresis in the treatment of multi-drug intoxication involving levothyroxine sodium and calcium channel blockers: a case report.

Plasmapheresis, a procedure used to remove large molecular weight, protein-bound molecules from a patient's blood, has been shown to be useful in some cases of drug overdose. Levothyroxine sodium intoxication may result from the intentional or accidental ingestion of excessive amounts of the hormone, which can trigger a thyroid storm. However, case reports about the extremely large dose of 15,000 µg of thyroxine intoxication are extremely rare, and even combined with calcium channel blockers (CCBs) poisonings. We present a case of an intentional poisoning with high doses of thyroxine, diltiazem and amlodipine successfully treated with plasma exchange. A 40-year-old woman was admitted showing unconsciousness and sustained hypotension with high levels of thyroid hormones (THs). It was discovered that she had secretly ingested at least 15,000 µg of levothyroxine sodium and CCBs with unknown amounts of diltiazem and amlodipine. Following plasmapheresis, the levels of TH declined dramatically after each of the 4 sessions, with hemodynamics gradually stabilizing and mental state improving. The early and timely use of plasmapheresis appears to be a vital therapeutic tool for the management of acute and severe forms of l-thyroxine and CCB intoxication. Its use can prevent thyroid storm and reverse the disturbances in the patient's hemodynamic status.

Calcium channel blocker and beta blocker overdose, and digoxin toxicity management.

While relatively uncommon, an overdose of calcium channel blockers, beta blockers, or digoxin can result in significant morbidity and mortality, and management can be complex. An acute overdose will require different management strategies than chronic toxicity while on therapeutic dosing. Toxicity from these agents must be considered in bradycardic and hypotensive patients. This supplement provides an evidence-based overview of emergency department management of calcium channel blocker overdose, beta blocker overdose, and digoxin toxicity, and focuses on the caveats of treatment for each.

Emergency management of calcium channel blocker overdose.

Calcium channel blockers (CCBs) are commonly used in South Africa (SA) in the management of hypertension and other cardiovascular disease. Their ubiquitous availability makes them a common agent in drug overdose (OD), whether through accidental ingestion or deliberate self-harm. It is essential that medical practitioners know how to recognise and manage CCB OD, as severe CCB OD is often fatal. As there is a lack of local literature in SA, we highlight the general principles of management of CCB OD, as well as complications and problems that may be encountered during treatment. This narrative review is based on existing clinical guidelines, retrospective studies and systematic reviews on the emergency management of CCB OD. High-dose insulin euglycaemic therapy has become the mainstay of treatment in severe CCB OD. The rationale, the recommended protocol for its use and its adverse effects are described.

Toxicokinetics of hydroxychloroquine following a massive overdose.

BACKGROUND: We report a patient with a massive hydroxychloroquine overdose manifested by profound hypokalemia and ventricular dysrhythmias and describe hydroxychloroquine toxicokinetics. CASE REPORT: A 20-year-old woman (60 kg) presented 1 h after ingesting 36 g of hydroxychloroquine. Vital signs were: BP, 66 mmHg/palpation; heart rate, 115/min; respirations 18/min; oxygen saturation, 100% on room air. She was immediately given intravenous fluids and intubated. Infusions of diazepam and epinephrine were started. Activated charcoal was administered. Her initial serum potassium of 5.3 mEq/L decreased to 2.1 mEq/L 1 h later. The presenting electrocardiogram (ECG) showed sinus tachycardia at 119 beats/min with a QRS duration of 146 ms, and a QT interval of 400 ms (Bazett's QTc 563 ms). She had four episodes of ventricular tachydysrhythmias requiring cardioversion, electrolyte repletion, and lidocaine infusion. Her blood hydroxychloroquine concentration peaked at 28,000 ng/mL (therapeutic range 500-2000 ng/mL). Serial concentrations demonstrated apparent first-order elimination with a half-life of 11.6 h. She was extubated on hospital day three and had a full recovery. CONCLUSION: We present a massive hydroxychloroquine overdose treated with early intubation, activated charcoal, epinephrine, high dose diazepam, aggressive electrolyte repletion, and lidocaine. The apparent 11.6 hour half-life of hydroxychloroquine was shorter than previously described.

Low dose Intralipid resuscitation improves survival compared to ClinOleic in propranolol overdose in rats.

BACKGROUND: Medication overdose is a prevalent issue and despite mixed reports of efficacy, the use of intravenous lipid emulsions, notably Intralipid®, for the management of toxicity from lipid-soluble drugs is becoming increasingly prevalent. Whether alternative lipid emulsion formulations have similar efficacy for resuscitation compared to Intralipid is not known. Here, we compared the efficacy of Intralipid and ClinOleic® for resuscitation following overdose with the lipid-soluble beta-adrenergic antagonist propranolol. METHODS: Male Sprague-Dawley rats (age 3-4 months) were anesthetized with isoflurane and instrumented for direct hemodynamic assessments. In Study One, rats (n = 22) were pre-treated with Intralipid 20% (n = 12) or ClinOleic 20% (n = 10) to determine whether the hemodynamic effects of propranolol could be prevented. In Study Two, rats were randomly assigned to Intralipid 20% (1, 2, or 3 mL/kg IV, n = 21) or ClinOleic 20% (1, 2, or 3 mL/kg IV, n = 20) resuscitation groups following propranolol overdose (15 mg/kg IV). In Study Three the effect of Intralipid 20% (1 mL/kg IV, n = 3) and ClinOleic 20% (1 mL/kg IV, n = 3) in the absence of propranolol was investigated. The primary endpoint in all studies was survival time (up to a maximum of 120 minutes), and secondary endpoints were time to achieve 50%, 75%, and 90% of baseline hemodynamic parameters. RESULTS: In Study One, pre-treatment with Intralipid prior to propranolol administration resulted in prolonged survival compared to pre-treatment with ClinOleic at low doses (1 mL/kg; P = 0.002), but provided no benefit at higher doses (3 mL/kg; P = 0.95). In Study Two, Intralipid conferred a survival advantage over ClinOleic, with 18/21 rats surviving 120 minutes in the Intralipid group and only 4/20 survivors in the ClinOleic group (P<0.0001). Median survival times (with interquartile ranges) for rats treated with Intralipid, and ClinOleic, and saline were 120 (80.5-120) min, 21.5 (3.25-74.5) min, and 1 (0.25-2.5) min respectively (P<0.001). Only 3/21 rats in the Intralipid group survived less than 30 minutes, whereas 12/20 ClinOleic treated rats had survival times of less than 30 minutes. The number of rats achieving 75%, and 90% of baseline mean arterial pressure was also greater in the Intralipid group (P<0.05 for both values). Treatment in Study Three did not alter survival times. CONCLUSIONS: Low-dose Intralipid (1, 2, or 3 mL/kg IV) confers a survival advantage up to 120 minutes post-propranolol overdose (the end-point of the experiment) and better hemodynamic recovery compared to ClinOleic (1, 2, or 3 mL/kg IV) in rats with propranolol overdose. As health care centres choose alternate intravenous lipid emulsions, limited availability of Intralipid could impact efficacy and success of overdose treatment for lipid-soluble drugs.

Pharmacological and mechanical management of calcium channel blocker toxicity.

Cardiovascular instability associated with calcium channel blocker toxicity comprises a small percentage of overdose presentations, yet they are associated with a high mortality rate. We detail the management of a 64-year-old man who took an intentional overdose of 840 mg nimodipine. We include the treatment he received and highlight the scarcity of evidence behind the use of gastric decontamination, calcium, glucagon, intravenous lipid emulsion, high-dose insulin therapy, sodium bicarbonate, vasopressors and methylene blue in calcium channel blocker toxicity. Additionally, the article explores the use of electrical pacing and venoarterial extracorporeal membrane oxygenation (VA-ECMO). Following successful weaning of VA-ECMO, the patient was successfully extubated but remained neurologically impaired due to hypoxic-ischaemic brain injury, critical care polyneuropathy and renal failure requiring dialysis. He has cerebral performance category 3; he has mild cognitive impairment but able to perform some activities of daily living independently and communicate his thoughts and needs. He requires no respiratory or cardiovascular support.

Critical Care Pain Management in Patients Affected by the Opioid Epidemic: A Review.

The rapid rise in the opioid epidemic has had a deleterious impact across the United States. This increase has drawn the attention of the critical care community not only because of the surge in acute opioid overdose-related admissions, but also due to the increase in the number of opioid-dependent and opioid-tolerant patients being treated in the intensive care unit (ICU). Opioid-related issues relevant to the critical care physician include direct care of patients with opioid overdoses, the provision of sufficient analgesia to patients with opioid dependence and tolerance, and the task of preventing long-term opioid dependence in patients who survive ICU care. This review identifies the challenges facing the ICU physician working with patients presenting with opioid-related complications, discusses current solutions, and suggests future areas of research and heightened ICU clinician attention.

Evaluation of activated charcoal and lipid emulsion treatment in model of acute rivaroxaban toxicity.

AIM: Reducing or reversing the toxicity effects of new oral anticoagulants is an important question.The purpose of the present study is to evaluate the effect of lipid emulsion (LE) and Activated Charcoal (AC) therapy on the intoxication of rivaroxaban, on mice. METHODS: Adult male Balb/c mice weighing approximately 30g were used in the study. Seven groups were assigned, with six mice in each group. Groups were defined; given only rivaroxaban, given only LE, given only AC, after the administration of rivaroxaban LE applied group in the 1st hour, after the administration of rivaroxaban LE applied group in the 3rd hour, after the administration of rivaroxaban AC applied group in the1st hour, after the administration of rivaroxaban AC applied group in the 1st hour and LE applied group in the 3rd hour. PT and Anti-Factor Xa activity were measured in all blood samples from subjects. RESULTS: A statistically significant difference was found when all groups were compared in terms of mean PT values and Anti-FactorXa values. However, no statistically significant difference was found in the mean PT and Anti-FactorXa values when only rivaroxaban administrated group and after the administration of rivaroxaban LE and/or AC applied groups were compared one to one. No deaths occurred in groups during the observation. CONCLUSION: Although the administration of either AC or LE alone or in combination resulted in a decrease in the mean values of PT and anti-Factor Xa, in case of rivaroxaban toxicity, but one-to-one comparison of the groups was not statistically significant.

Knowledge of Opioid Overdose and Attitudes to Supply of Take-Home Naloxone Among People with Chronic Noncancer Pain Prescribed Opioids.

Objective: Take-home naloxone (THN) is recommended in response to pharmaceutical opioid-related mortality. Some health professionals are reluctant to discuss THN for fear of causing offense. The aims of this study were to assess knowledge of opioid overdose and attitudes toward THN for opioid overdose reversal in people with chronic noncancer pain (CNCP). Design: Prospective cohort study. Setting: Australia, September to October 2015. Subjects: A subset of participants (N = 208) from a cohort of people prescribed restricted opioids for CNCP. Methods: Questions added in the two-year telephone interviews examined knowledge of overdose symptoms and attitudes toward community supply of naloxone. Associations with overdose risk factors and naloxone supply eligibility criteria with attitudes toward naloxone were explored. Results: Fourteen percent reported ever experiencing opioid overdose symptoms. Participants correctly identified fewer than half of the overdose signs and symptoms. After receiving information on naloxone, most participants (60%), thought it was a "good" or "very good" idea. Few participants reported that they would be "a little" (N = 21, 10%) or "very" offended (N = 7, 3%) if their opioid prescriber offered them naloxone. Positive attitudes toward THN were associated with male gender (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.09-3.50), past year cannabis use (OR = 2.52, 95% CI = 1.03-6.16), and past year nicotine use (OR = 2.11, 95% CI = 1.14-3.91). Conclusions: Most participants had positive attitudes toward THN but low knowledge about opioid overdose symptoms. Strategies for educating patients and their caregivers on opioid toxicity are needed. THN may be best targeted toward those with risk factors in terms of overdose prevention and acceptability.

Aggressive Treatment of Life-Threatening Hypophosphatemia During Recovery From Fulminant Hepatic Failure: A Case Report.

Acute liver failure secondary to acetaminophen overdose can be a life-threatening condition, characterized by severe electrolyte derangements. Hepatocyte regeneration is associated with phosphorous utilization and is a known complication of liver recovery following injury. We report the case of profound, life-threatening hypophosphatemia following recovery from acute fulminant liver failure. As the liver enzymes normalized, serum phosphorous levels plummeted. Our patient required an aggressive, individualized phosphorus replacement regimen, which resulted in a continuous infusion of intravenous (IV) sodium phosphate, titrated to a maximum rate of 30 mmol/h or 0.5 mmol/kg/h. The patient required over 400 mmol of total IV and oral phosphorous over the course of 48 hours. An aggressive approach to phosphorous replacement was done safely and effectively. Traditional replacement protocols are not adequate to sustain patients with this degree of hypophosphatemia. This is the first report to utilize a continuous infusion of phosphate with a maximum reported rate (0.5 mmol/kg/h). Our report summarizes a novel and safe approach for clinicians to maximally support these patients through high-dose, continuous infusion phosphorous administration.

Accidental Concentrated Hydrogen Peroxide Ingestion Associated with Portal Venous Gas.

A case of a 52-year old male patient who presented to the emergency department with severe nausea and vomiting following accidental ingestion of H2O2. A computed tomography (CT) abdomen performed at our institution demonstrated extensive portal venous gas throughout the liver with few gas droplets seen in the extrahepatic portal vein portion. Pneumatosis was also noted in the wall of the gastric antrum. Upper GI Endoscopy was done revealing diffuse hemorrhagic gastritis and mild duodenal bulb erosion. The patient was treated with hyperbaric oxygen. On the second day of admission, the patient was able to eat without difficulty or pain. Accidental ingestion of high concentration H2O2 solution has been shown to cause extensive injury to surrounding tissues. The injury occurs via three main mechanisms: corrosive damage, oxygen gas formation, and lipid peroxidation. We report a case of accidental ingestion of a highly concentrated (35%) solution of H2O2 causing portal venous gas.

Massive diltiazem and metoprolol overdose rescued with extracorporeal life support.

The management of overdoses of cardioactive medications in the emergency department can be challenging. The reversal of severe toxicity from one or more types of cardioactive medication may fail maximal medical therapies and require extreme invasive measures such as transvenous cardiac pacing and extracorporeal life support. We present a case of massive diltiazem and metoprolol overdose refractory to maximal medical therapy, including intravenous calcium, glucagon, vasopressors, high dose insulin, and lipid emulsion. The patient experienced refractory bradydysrhythmia that responded only to transvenous pacing. Extracorporeal life support was initiated and resulted in successful organ perfusion and complete recovery of the patient. This case highlights the potential utility of extracorporeal life support in cases of severe toxicity due to multiple cardioactive medications.