Successful treatment of severe calcium channel blocker poisoning, new experience with the guidance of invasive hemodynamic monitoring in a 17-year-old girl: a case report.

BACKGROUND: Calcium channel blocker poisoning is one of the most lethal cardiac drugs overdoses. Calcium and high-dose insulin infusion are the first-line therapy for symptomatic patients, and Intralipid emulsion infusion is useful for refractory cases. CASE PRESENTATION: In this report, we describe a 17-year-old Iranian girl who took 250 mg of the drug for a suicidal attempt and presented with refractory hypotension and non-cardiogenic pulmonary edema treated successfully with the guidance of invasive hemodynamic parameters. CONCLUSION: For complicated cases, in addition to supportive care and adjuvant therapy such as high-dose insulin and Intralipid, it is mandatory to utilize advanced hemodynamic monitoring to treat hypotension in severe calcium channel blocker poisoning to guide the treatment.

Insulin concentrations following termination of high-dose insulin euglycemic therapy.

INTRODUCTION: High-dose insulin therapy is used in patients with calcium channel blocker and beta-adrenergic antagonist overdoses. The pharmacokinetics of insulin are scantly reported following high-dose insulin therapy. We present two cases of persistently elevated insulin concentrations following high-dose insulin therapy. CASE REPORTS: A 50-year-old woman and a 45-year-old man experienced hypotension after overdosing on amlodipine and atenolol. They were treated with high-dose insulin therapy for 54 hours at 2 units/kilogram/hour and 48 hours at 10 units/kilogram/hour, respectively. Following termination, serum insulin elimination was studied. Insulin concentrations remained greater than 1,000 µU/mL (fasting reference 2.6-24.9 µU/mL) for longer than 4 hours (case 1) and 11 hours (case 2) and greater than 300 µU/mL for longer than 8 hours and 21 hours, respectively. Insulin concentrations decreased with apparent first-order elimination half-lives of 13.0 hours and 6.0 hours. DISCUSSION: Following high-dose insulin therapy, insulin concentrations remained elevated for longer than expected based on normal pharmacokinetics in therapeutic dosing. Three previous cases reported insulin half-lives of between 2.2 hours and 18.7 hours. The current cases add to the existing data that insulin has a variable but prolonged half-life following high-dose insulin therapy. CONCLUSIONS: These findings suggest that patients are at prolonged risk of hypoglycemia following cessation of high-dose insulin infusions.

A mobile addiction service for community-based overdose prevention.

Mainstays of opioid overdose prevention include medications for opioid use disorder (e.g., methadone or buprenorphine) and naloxone distribution. Inadequate access to buprenorphine limits its uptake, especially in communities of color, and people with opioid use disorders encounter multiple barriers to obtaining necessary medications including insurance, transportation, and consistent availability of telephones. UMass Memorial Medical Center and our community partners sought to alleviate these barriers to treatment through the deployment of a mobile addiction service, called the Road to Care. Using this approach, multidisciplinary and interprofessional providers deliver holistic addiction care by centering our patients' needs with respect to scheduling, location, and convenience. This program also extends access to buprenorphine and naloxone among people experiencing homelessness. Additional systemic and individualized barriers encountered are identified, as well as potential solutions for future mobile addiction service utilization. Over a two-year period, we have cared for 1,121 individuals who have accessed our mobile addiction service in over 4,567 encounters. We prescribed buprenorphine/naloxone (Suboxone®) to 330 individuals (29.4% of all patients). We have distributed nearly 250 naloxone kits directly on-site or and more than 300 kits via prescriptions to local pharmacies. To date, 74 naloxone rescue attempts have been reported back to us. We have demonstrated that a community-based mobile addiction service, anchored within a major medical center, can provide high-volume and high-quality overdose prevention services that facilitate engagement with additional treatment. Our experience is described as a case study below.

Large paracetamol overdose - Higher dose NAC is NOT required.

Paracetamol overdose is common in developed countries but less than 10% involve large ingestions exceeding 30 g or 500 mg/kg. High dose acetylcysteine (NAC) has been proposed in patients taking large paracetamol overdoses based on reports of hepatotoxicity despite early initiation of NAC treatment with the commonly used 300 mg/kg intravenous acetylcysteine regimen. The evidence from cohorts of patients treated with the standard NAC regimen after large paracetamol overdoses shows that it is effective in most patients. A small study in patients with paracetamol overdoses of 40 g or more and paracetamol concentrations above the 300 mg/L nomogram line showed that modification of the standard NAC regimen to provide a total of 400-500 mg/kg NAC over 21-22 h may reduce the risk of hepatotoxicity (peak ALT > 1000 IU/L) but the impact on development of hepatic failure, liver transplantation and mortality with this approach is presently unknown. Better risk stratification of patients taking paracetamol overdose may allow higher dose NAC and adjunctive treatments such as CYP2E1 inhibition and extracorporeal removal of paracetamol to be targeted to those patients at the highest risk of hepatotoxicity after a large paracetamol overdose.

Large paracetamol overdose-Higher dose acetylcysteine is required.

Paracetamol poisoning continues to be a worldwide problem and, despite the availability of an effective antidote, acetylcysteine (NAC), the optimal way to use this antidote, particularly following very large doses of paracetamol, has not been established. Recent case series have shown an increased toxicity from high doses of paracetamol, even in those receiving prompt NAC therapy, particularly in patients above the 300 mg/L nomogram treatment line. Clinical trial evidence supporting shorter NAC dosing now allows the possibility for intensifying treatment without the risk of very high rates of ADRs. New biomarkers also show the possibility of early identification of patients at risk of liver injury who might also benefit from increased intensity treatment. This article discusses these data and proposes a logical therapy for increasing NAC dosing which now requires clinical trial testing.

Guidelines and Policies: Implications for Individual and Population Health.

Rising rates of prescription opioids for chronic pain from the 1990s along with a concomitant worsening overdose crisis led to rapid evaluation and public health strategies to curb problems with prescription opioids. Guideline development, grounded in solid theory but based on limited evidence that translated into rigid and discordant policies, has contributed to controversies in pain management, worsening the treatment experience for people experiencing chronic pain and highlighting existing inequities from a system clouded with systemic racism. Newer public health approaches need to evaluate root causes and be more holistic addressing inequities as well as using trauma-informed principles.

U.S. Military veterans and the opioid overdose crisis: a review of risk factors and prevention efforts.

U.S. military veterans have been heavily impacted by the opioid overdose crisis, with drug overdose mortality rates increasing by 53% from 2010-2019. Risk for overdose among veterans is complex and influenced by ongoing interaction among physiological/biological, psychological, and socio-structural factors. A thorough understanding of opioid-related overdose among veterans, one that goes beyond simple pharmacological determinism, must examine the interplay of pain, pain treatment, and stress, as well as psychological and social experiences-before, during, and after military service. Comprehensive efforts to tackle the overdose crisis among veterans require interventions that address each of these dimensions. Promising interventions include widespread naloxone distribution and increased provision of low-threshold wrap-around services, including medications for opioid use disorder (MOUD) and holistic/complementary approaches. Interventions that are delivered by peers - individuals who share key experiential or sociodemographic characteristics with the population being served - may be ideally suited to address many of the barriers to opioid-related risk mitigation common among veterans. Community care models could be beneficial for the large proportion of veterans who are not connected to the Veterans Health Administration and for veterans who, for various reasons including mental health problems and the avoidance of stigma, are socially isolated or reluctant to use traditional substance use services. Interventions need to be tailored in such a way that they reach those more socially isolated veterans who may not have access to naloxone or the social support to help them in overdose situations. It is important to incorporate the perspectives and voices of veterans with lived experience of substance use into the design and implementation of new overdose prevention resources and strategies to meet the needs of this population. Key messagesU.S. military veterans have been heavily impacted by the opioid overdose crisis, with drug overdose mortality rates increasing by 53% from 2010-2019.The risks for overdose that veterans face need to be understood as resulting from an ongoing interaction among biological/physiological, psychological, and social/structural factors.Addressing drug overdose in the veteran population requires accessible and non-judgemental, low threshold, wraparound, and holistic solutions that recognise the complex aetiology of overdose risk for veterans.

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.§.

A comprehensive mobile health intervention to prevent and manage the complexities of opioid use.

OBJECTIVES: The Opioid Use crisis continues to be an epidemic with multiple known influencing and interacting factors. With the need for suitable opioid use interventions, we present a conceptual design of an m-health intervention that addresses the various known interacting factors of opioid use and corresponding evidence-based practices. The visualization of the opioid use complexities is presented as the "Opioid Cube". METHODS: Following Stage 0 to Stage IA of the NIH Stage Model, we used guidelines and extant health intervention literature on opioid apps to inform the Opioid Intervention (O-INT) design. We present our design using system architecture, algorithms, and user interfaces to integrate multiple functions including decision support. We evaluate the proposed O-INT using analytical modeling. RESULTS: The conceptual design of O-INT supports the concept of collaborative care, by providing connections between the patient, healthcare professionals, and their family members. The evaluation of O-INT shows a preference for specific functions, such as overdose detection and potential for high system reliability with minimal side effects. The Opioid Cube provides a visualization of various opioid use states and their influencing and interacting factors. CONCLUSIONS: O-INT is a promising design with a holistic approach to manage opioid use and prevent and treat misuse. With several needed functionalities, O-INT design serves as a decision support system for patients, healthcare professionals, researchers, and policy makers. Together, O-INT and the Opioid Cube may serve as a foundation for development and adoption of highly effective m-health interventions for opioid use.

Cardiotoxic Medication Poisoning.

Beta-blockers and calcium channel blockers result in a disproportionate number of fatalities from cardiac medication overdoses, and share similar characteristics. High-dose insulin is a superior therapy for both overdoses, but is likely synergistic with vasopressors; therefore we recommend starting vasopressors and high-dose insulin simultaneously. Digoxin remains an important cardiac poison and can likely be safely treated with smaller doses of fab fragments than in the past, except for patients in extremis. Extracorporeal membrane oxygenation is an invasive but promising nonspecific therapy for refractory shock from cardiotoxic overdose and should be considered primarily in cases of refractory cardiogenic shock.

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.

Activation of the adenosine A2B receptor even beyond the therapeutic window of N-acetylcysteine accelerates liver recovery after an acetaminophen overdose.

Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the USA. The short therapeutic window of the current antidote, N-acetylcysteine (NAC) highlights the need for novel late acting therapeutics. The neuronal guidance cue netrin-1 provides delayed protection against APAP hepatotoxicity through the adenosine A2B receptor (A2BAR). The clinical relevance of this mechanism was investigated here by administration of the A2BAR agonist BAY 60-6583, after an APAP overdose (300 or 600 mg/kg) in fasted male and female C57BL/6J mice with assessment of liver injury 6 or 24 h after APAP in comparison to NAC. BAY 60-6583 treatment 1.5 h after APAP overdose (600 mg/kg) protected against liver injury at 6 h by preserving mitochondrial function despite JNK activation and its mitochondrial translocation. Gender independent protection was sustained when BAY 60-6583 was given 6 h after APAP overdose (300 mg/kg), when NAC administration did not show benefit. This protection was accompanied by enhanced infiltration of macrophages with the reparative anti-inflammatory phenotype by 24 h, accompanied by a decrease in neutrophil infiltration. Thus, our data emphasize the remarkable therapeutic utility of using an A2BAR agonist, which provides delayed protection long after the standard of care NAC ceased to be effective.

Massive Nonfatal Hydroxychloroquine Ingestion in a Pediatric Patient.

BACKGROUND: Hydroxychloroquine overdose is rare but potentially lethal. Hydroxychloroquine overdose symptoms are characterized by central nervous system toxicity, cardiac toxicity, and hypokalemia. Recommended treatment consists of epinephrine, high-dose diazepam, and careful potassium repletion. Few pediatric hydroxychloroquine overdoses have been reported. CASE REPORT: We describe a 14-year-old girl who ingested 10 g (172 mg/kg) of hydroxychloroquine. She developed tachycardia, hypotension, and hypokalemia. She was intubated and treated with diazepam and epinephrine infusions and potassium supplementation. Her serum hydroxychloroquine concentration obtained 10 h after ingestion was 13,000 ng/mL (reference range 500-2000 ng/mL). The patient made a full medical recovery. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Pediatric hydroxychloroquine overdoses are reported rarely, and the toxic and lethal doses of hydroxychloroquine ingestion have not been established. This case of a teenaged patient who ingested 10 g of hydroxychloroquine and survived provides additional information that may be used to help establish toxic and lethal doses of ingestion.

Multi-organ dysfunction as a presentation of calcium channel blocker intoxication.

SummaryWe report the case of a 73-year-old woman who intentionally ingested 400 mg of amlodipine in a suicidal attempt who initially presented with hypotension which persisted despite aggressive therapy with fluid resuscitation, multiple pressor support, high-dose insulin therapy and calcium infusion. Her haemodynamic instability evolved to include bradycardia requiring atropine and transcutaneous pacing. Eventually she required salvage therapy with intravenous lipid emulsion (ILE) therapy . Despite all aggressive therapy, she developed multi-organ failure resulting in death. The literature on high-dose insulin euglycaemic therapy (HIET) and ILE therapy shows mixed results with some showing significant improvement in haemodynamic status. In our case, it had no significant positive impact on the outcome.

Single bag high dose intravenous N-acetylcysteine associated with decreased hepatotoxicity compared to triple bag intravenous N-acetylcysteine in high-risk acetaminophen ingestions.

INTRODUCTION: There is controversy that the triple bag intravenous (IV) N-acetylcysteine (NAC) regimen may be underdosing the sickest patients in its current, common usage. We hypothesize that a higher dose IV NAC regimen improves some outcomes. METHODS: We conducted a poison center based retrospective observational study from January 1, 2016 to December 31, 2017 comparing a single bag higher dose IV NAC regimen (150 mg/kg over 1 h, 15 mg/kg/hour) to the triple bag IV NAC regimen (150 mg/kg over 1 h, 12.5 mg/kg/hour for 4 h, 6.25 mg/kg/hour). In a high-risk population of patients with acetaminophen ingestion (defined as multiplication product ≥ 10,000 mg/L IU/L, not acute ingestions receiving NAC within 8 h, and not hepatotoxic on first contact), we evaluated the rate of hepatotoxicity, peak transaminase, and rate of laboratory coagulopathy. RESULTS: 89 patients met the inclusion criteria. 12 of the 23 patients (52%) who received triple bag NAC became hepatotoxic and 10 (43%) became coagulopathic, while only 19 of 66 patients (29%) who received single bag NAC became hepatotoxic and 15 (23%) became coagulopathic; p = .043 and .057, resp. Mean peak transaminase was 4481 IU/L vs 2143 IU/L in those receiving triple bag NAC vs single bag NAC, difference of means 2338 IU/L; p = .026. CONCLUSION: In this exploratory study of a high-risk population of patients with acetaminophen ingestions, the single bag IV NAC regimen was associated with lower peak transaminase and fewer patients becoming hepatotoxic as compared to the triple bag IV NAC regimen.

Evaluation of N-acetylcysteine dose for the treatment of massive acetaminophen ingestion.

METHODS: The use of N-acetylcysteine (NAC) remains the standard of care for treatment of acetaminophen (APAP) toxicity and overdose. Currently, there is growing evidence to suggest that massive acetaminophen overdose is associated with increased hepatotoxicity despite timely administration of NAC. This raises the question as to whether an increased dose of intravenous (IV) NAC should be used in the setting of massive APAP ingestion. This study aimed to evaluate the rate of hepatotoxicity after massive APAP overdose treated with 3 different NAC treatment regimens. METHODS: This was a retrospective cohort study conducted by electronic medical record review of cases reported to a statewide poison control system between 2007 and 2020. Inclusion criteria were single APAP or APAP combination-medication ingestion; acute massive acetaminophen (APAP) ingestion (defined as APAP concentration ≥ 2 times above the Rumack-Matthew 150 nomogram); received one of the three NAC regimens: standard dose IV NAC, oral (PO) NAC, or high dose IV NAC. The risk of hepatotoxicity was evaluated using a multivariate logistic regression model with standard dose IV NAC as the base variable for comparison. RESULTS: A total of 373 patients met inclusion for the study. Of those, 135 cases were treated with standard dose IV NAC, 121 cases treated with PO NAC, and 117 cases treated with high dose IV NAC. The risk of developing hepatotoxicity was not statistically significant between the high dose IV NAC (OR 1.05, 95% CI 0.52 - 2.09) or oral NAC (OR 0.69, 95% CI 0.33 - 1.46) when compared to standard dose IV NAC. When adjusted for APAP combination medications, initial APAP ratio, initial elevated AST/ALT, and treatment within 8 h, there remained no difference between treatment regimens. CONCLUSION: This study was unable to detect a large absolute reduction in the rate of hepatotoxicity after massive APAP ingestion in patients treated with high dose IV NAC or PO NAC when compared to standard dose IV NAC; even when treatment was initiated within 8 h of ingestion.

Refractory Shock from Amlodipine Overdose Overcomed with Hyperinsulinemia.

Intoxication from calcium channel blockers exhibits almost 50% mortality rates. Amlodipine is a long-acting dihydropyridine and inappropriate dosage poses a great threat for profound vasodilation, hypotension, and refractory vasopressor-resistant shock. A 72-year-old woman with unremarkable medical history presented to the emergency department due to amlodipine overdose after a suicide attempt attributed to COVID-19 pandemic severe anxiety disorder. Vital signs at presentation: heart rate 82 beats/ min, arterial pressure 72/55 mmHg, and oxygen saturation 98%. Resuscitation was initiated with intravenous infusion of normal saline 0,9%, noradrenaline, and calcium chloride, while activated charcoal was orally administrated; however, blood pressure remained at 70/45 mmHg. Abruptly, she experienced acute pulmonary edema and was finally intubated. We commenced high-dose insulin infusion with Dextrose 10% infusion to maintain euglycemic hyperinsulinemia. Hemodynamic improvement occurred after 30 min, systolic blood pressure raised to 95 mmHg, and decongestion was achieved with intravenous furosemide. Insulin effect was dose-dependent and patient's hemodynamic status improved after insulin uptitration. Eight days later, the patient was weaned from the mechanical ventilation and she was successfully discharged after 14 days. High-dose intravenous infusion of insulin up to 10 units/kg per hour appears as an inotropic agent possibly through alterations in myocardial metabolism of fatty acids and augmentation of insulin secretion and uptake. This regimen possibly exhibits additional vasotropic properties. We conclude that euglycemic hyperinsulinemia is a potentially advantageous treatment in CCB toxicity.

Successful Treatment with Integrated Chinese and Western Medicine for Massive Colchicine Overdose: A Case Report.

A 42-year-old male was hospitalized 13.5 hours after ingestion of 50 mg (approximately 0.7 mg/kg) colchicine in a suicide attempt. The patient developed gastrointestinal dysfunction, grade IV myelosuppression, and restrictive respiratory failure without occurrences of cardiovascular collapse or fatal dysrhythmias. Emergency treatment with integrated Chinese and Western medicine was started and the patient fully recovered without long-term complications. This report describes a massive overdose of colchicine successfully treated with integrated Chinese and Western medicine. Current treatment options are reviewed.

Therapeutic plasma exchange to mitigate flunixin meglumine overdose in a cria.

OBJECTIVE: To describe the use of therapeutic plasma exchange (TPE) in the treatment of flunixin meglumine overdose in a cria. CASE SUMMARY: A 3-day-old alpaca cria was diagnosed with ureteral obstruction and agenesis resulting in severe bilateral hydronephrosis. During hospitalization, the cria inadvertently received a flunixin meglumine overdose of >65 mg/kg. Here, we report the use of lipid emulsion and TPE to mitigate flunixin meglumine toxicosis. TPE appeared to prevent any flunixin-induced kidney or gastrointestinal injury, even in a patient with congenital defects of the urinary tract. NEW INFORMATION PROVIDED: This is the first report of the use of TPE in a cria.