Bupropion Toxicity Research Articles

Predicting adverse cardiovascular events in emergency department patients with bupropion overdose.

Bupropion toxicity can lead to adverse cardiovascular events (ACVE), but delayed onset of toxicity makes risk stratification difficult. This study aimed to validate previously defined predictors of ACVE and identify novel predictors among patients presenting to the emergency department (ED) after bupropion overdose. This secondary analysis of prospective data from the Toxicology Investigators Consortium Core Registry analyzed adult acute or acute-on-chronic bupropion exposures from 2015 to 2018. The primary outcome was ACVE (any of the following: myocardial injury, shock, ventricular dysrhythmia, or cardiac arrest). Potential predictors of ACVE included previously derived predictors in the overall drug overdose population (prior cardiac disease, initial serum bicarbonate < 20 mEq/L, and initial QTc ≥ 500 ms), exposure circumstances, and initial serum lactate value. Candidate predictors were evaluated using univariate analysis and multivariable regression modeling. Receiver operator characteristic curves were used to derive optimal cutoff points for novel predictors, and prognostic test characteristics were calculated. Of 355 patients analyzed, ACVE occurred in 34 (9.6%) patients. Initial serum bicarbonate < 20 mEq/L (adjusted odds ratio [aOR] 4.42, 95% confidence interval [CI] 1.94-10.0) and initial QTc ≥ 500 ms (aOR 2.52, 95% CI 1.01-6.09) independently predicted ACVE. Exposure circumstances did not predict ACVE. Initial serum lactate > 5.2 mmol/L independently predicted ACVE (aOR 12.2, 95% CI 2.50-75.2) and was 90.7% specific with 80.3% negative predictive value. Metabolic acidosis and QTc prolongation were validated as predictors of ACVE in ED patients with bupropion overdose. Serum lactate elevation was strongly predictive of ACVE in this study and warrants further investigation.

Abstract 15659: Bupropion Overdose Requiring Veno-Arterial Extracorporeal Membrane Oxygenation

Introduction: Bupropion is a monocyclic antidepressant that inhibits dopamine and norepinephrine reuptake, with significant risk cardiotoxicity in overdose cases. Case: A 32-year-old transgender man with a history of Human Immunodeficiency Virus (on anti-retroviral therapy), poly-substance use disorder, and depression presented with an intentional bupropion overdose. On arrival the patient was noted to have seizures and a decreased mental status. He was intubated and treated with anti-epileptic medication. Initial EKG was sinus tachycardia with a QTc of 456 milliseconds. Transthoracic echocardiogram (TTE) showed severely reduced left ventricular ejection fraction (LVEF) that worsened over a 6 hour period from 40% of 25%. Serial EKGs showed progressive QTc prolongation to 635 milliseconds. Cardiac catheterization demonstrated angiographically normal coronary arteries and a Cardiac Index of 2.5 L/min/m 2 . Due to the rapidly prolonging QTc and the significant risk of ventricular tachycardia (VT), the decision was to proceed with Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO) cannulation after a multidisciplinary shock team discussion. A few hours after cannulation, patient suffered hemodynamically unstable VT, requiring electrical cardioversion (DCCV) with brief return to sinus rhythm (SR) and with subsequent VT recurrence, that responded to lidocaine and repeat DCCV. ECG normalized and the patient was decannulated from VA ECMO on hospital day 4. Repeat TTE showed recovery of LVEF to 60%. The patient was extubated and discharged to psychiatric rehabilitation. Conclusion: Cardiogenic shock and ventricular arrhythmias are well recognized complications from bupropion toxicity likely due to gap junction inhibition. VA ECMO cannulation should be considered as part of multidisciplinary team assessment for patients at high risk for hemodynamic or electrical collapse in toxidromes with marked cardiotoxicity.

Successful management of severe bupropion toxicity with lipid emulsion therapy: a complex case report and literature review

This case report presents the management of a 53-year-old female with a complex psychiatric history who ingested multiple medications, resulting in severe cardiovascular compromise and subsequent respiratory failure. The patient’s ingestion included clonidine, fluoxetine, gabapentin, quetiapine and bupropion. Initial treatment involved supportive measures, including fluid resuscitation, bicarbonate infusion and correction of electrolyte imbalances. Despite these interventions, the patient remained haemodynamically unstable, requiring multiple vasopressors. Lipid emulsion therapy was initiated and led to a remarkable improvement in the patient’s cardiovascular status. However, she developed acute respiratory distress syndrome (ARDS) and required prolonged mechanical ventilation. Steroid therapy was initiated to manage the ARDS, and the patient was successfully extubated on day 6. The case highlights the potential effectiveness of lipid emulsion therapy in managing bupropion toxicity, but emphasises the need for further research to establish clear guidelines on dosing, timing and safety protocols. Adverse effects associated with lipid emulsion therapy must be carefully considered. Individualised decision-making and patient-centred care is crucial in optimising outcomes in cases of bupropion toxicity.

A CASE OF STATUS EPILEPTICUS SECONDARY TO BUPROPION OVERDOSE TREATED WITH IV LIPID EMULSION THERAPY

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Bupropion is a norepinephrine/dopamine reuptake inhibitor useful in depression and smoking cessation, with seizures being its most well-known adverse effect. Here, we present a case of status epilepticus secondary to Bupropion overdose (OD), successfully treated with intravenous lipid emulsion (ILE) therapy. CASE PRESENTATION: A 21-year-old female with a past medical history of depression, anxiety, PTSD, and polysubstance abuse, presented to the emergency room with bizarre behavior. Her roommate reported finding empty pill bottles of bupropion, gabapentin, and propranolol at her apartment. On arrival, vitals were HR: 140, BP: 119/59, RR: 18, SpO2: 98%, and GCS: 12. Soon after, the patient had a tonic-clonic seizure that initially subsided on administering 2mg of Lorazepam. Post-seizure, she was tachycardic, diaphoretic with dry oral mucosa, and had dilated pupils with conjunctival injection. Pertinent laboratory findings included an arterial blood gas analysis suggestive of severe high anion gap metabolic acidosis secondary to elevated lactate of 13.2 mmol/L. Her urine toxicology was positive for amphetamine. Salicylates, acetaminophen, and alcohol levels were undetectable. CT head was unremarkable. She was transferred to ICU and intubated for an increasing frequency of seizures and status epilepticus. Despite being on lorazepam drip, her seizures continued and were also resistant to phenobarbital, levetiracetam, valproate, fentanyl, and propofol. Ventricular tachycardias further complicated her course with hemodynamic instability, requiring electro cardioversion and multiple vasopressors. The history of empty bottles of bupropion, positive amphetamine in urine toxicology, along with seizures and ventricular tachycardias, led to a suspicion of bupropion overdose. Intravenous lipid emulsion (ILE) therapy was administered, consequently reversing bupropion toxicity evidenced by cessation of seizures, decreasing vasopressor requirement, improvement in mental status, and extubation. DISCUSSION: Seizures, ventricular tachycardias, and QT prolongation are well-known side effects of bupropion OD, which can occur at any dose with higher incidences noted at higher doses. Positive amphetamines on urine toxicology are expected with bupropion use as their metabolites have chemical structures similar to amphetamine. Intravenous lipid emulsion therapy (ILE) was used in our patient as salvage therapy for bupropion overdose in the setting of hemodynamic instability and status epilepticus with effective reversal of toxicity. The proposed mechanism of action involves ILE sequestering lipophilic drugs such as bupropion followed by its removal via biliary excretion into the gut. However, the use of ILE lacks high-powered evidence, and further investigation is warranted to expand and strengthen the antidotal uses of ILE. CONCLUSIONS: ILE therapy can be used as an antidote for severe bupropion toxicity. REFERENCE #1: Bornstein K, Montrief T, Anwar Parris M. Successful Management of Adolescent Bupropion Overdose with Intravenous Lipid Emulsion Therapy. J Pediatr Intensive Care. 2019;8(4):242-246. doi:10.1055/s-0039-1693483 REFERENCE #2: Stall N, Godwin J, Juurlink D. Bupropion abuse and overdose. CMAJ. 2014;186(13):1015. doi:10.1503/cmaj.131534 REFERENCE #3: Casey ER, Scott MG, Tang S, Mullins ME. Frequency of false positive amphetamine screens due to bupropion using the Syva EMIT II immunoassay. J Med Toxicol. 2011 Jun;7(2):105-8. doi: 10.1007/s13181-010-0131-5. PMID: 21191682; PMCID: PMC3724447. DISCLOSURES: No relevant relationships by Mubashir Ayaz Ahmed, source=Web Response No relevant relationships by Shayet Hossain Eshan, source=Web Response No relevant relationships by sami hussein, source=Web Response No relevant relationships by Sudha Misra, source=Web Response No relevant relationships by Chenyu Sun, source=Web Response

Factors associated with seizure development after bupropion overdose: a review of the toxicology investigators consortium

Background Bupropion is an aminoketone antidepressant. A major concern in bupropion toxicity is seizure activity, which can occur up to 24 h from ingestion. It is difficult to predict which patients will have seizures. The purpose of this study is to identify clinical features associate with seizure after bupropion overdose. Methods We searched the Toxicology Investigators Consortium registry for a cases of poisoning by bupropion between January 1, 2014 and January 1, 2017 in patients aged 13–65. Demographic variables and clinical features were compared between patients who did and did not experience a seizure and presented as unadjusted odds ratios (OR). Multivariable logistic regression was used to calculate adjusted odds ratios (aOR) between clinical features and seizures. Results There were 256 cases of bupropion overdose remaining after inclusion/exclusion criteria were applied. Clinical features associated with seizure were QTc >500 (OR = 3.4, 95% CI: 1.3–8.8, p = 0.012), tachycardia (p > 140) (OR = 1.9, 95% CI: 1–3.561, p = 0.05), and age 13–18 years (2.4, 95% CI: 1.3–4.3, p = 0.005). The mean QTc value for patients experiencing a seizure was 482 ms (N = 95 IQR: 59 ms) versus 454 ms (N = 103, IQR: 43) in patients who did not experience seizure, however, it was not possible to identify a QTc cutoff with sensitivity or specificity to predict seizures. Conclusion Based on our analysis of data from the ToxIC registry, age (13–18), tachycardia (p > 140) and QTc >500 ms are associated with seizures in bupropion overdose; however, a specific QTc value may not be a useful predictor of seizures.

Serotonin toxicity from isolated bupropion overdoses

Background: Bupropion is a synthetic cathinone, which acts therapeutically through norepinephrine and dopamine reuptake inhibition. Recent evidence suggests that serotonin receptor activation occurs with high doses of bupropion and severe serotonin toxicity can occur after isolated bupropion overdoses. Prior observational studies may therefore underestimate the incidence of serotonin toxicity.Methods: A retrospective study of patients with bupropion toxicity at a toxicology referral center from 2015–2017 was performed. Patients who overdosed on other serotonergic medications were excluded. Serotonin toxicity was diagnosed retrospectively using Hunter Criteria.Results: Overall, 96 patients were identified with bupropion toxicity. Of these, 18 patients ingested bupropion in the absence of other serotonergic drugs. The incidence of serotonin toxicity was 33% in this population. Serotonin toxicity was more likely after a suicide attempt than those with an accidental ingestion or after recreational drug use. The median dose of bupropion ingested was 2,250 mg in the cohort diagnosed with serotonin syndrome.Conclusion: The incidence of bupropion induced serotonin toxicity is higher than reported. Clinicians should monitor for serotonergic toxicity when evaluating patients after bupropion overdose.

Reply to: Treatment of Bupropion Toxicity with Lipid Emulsion.

We thank the authors for these clinically important observations relating to the management of acute drug-related toxicity with intravenous lipid emulsion (ILE), particularly their discussion of laboratory data to discuss kinetics of the pharmacologic agents in the case presented.[1]

Treatment of Bupropion Toxicity with Lipid Emulsion

We have read with interest the case report, “Successful Management of Adolescent Bupropion Overdose with Intravenous Lipid Emulsion Therapy,” recently published in the Journal of Pediatric Intensive Care.[1] Lipid emulsion is effective in the treatment of acute toxicity induced by local anesthetics or nonlocal anesthetic drugs, including amitriptyline, bupropion, and verapamil, in pediatric patients.[2] A previous in vitro study reported that the magnitude of the reduction of the serum concentration of bupropion, which is a highly lipid-soluble antidepressant (log [octanol/water partition coefficient]: 3.2), was 46 by 2% lipid emulsion (Intralipid).[3] In addition, the magnitude of the sequestration of drugs with varied lipid solubility by lipid emulsion is dependent mainly on the lipid partition coefficient and partially on the volume of distribution, which appears to account for 88% of variations in the reduction of drug serum concentration by lipid emulsion.[3] As suggested by Bornstein et al, the lipid sink theory, which is considered the mechanism underlying the effect of lipid emulsion as a nonspecific antidote, states that lipid emulsion absorbs highly lipid-soluble drugs, such as bupivacaine (log [octanol/water partition coefficient]: 3.41), from the heart.[1] [4] However, the following comments should be considered to understand this case report well. First, the first administration of lipid emulsion improved the mental status of the patient.[1] On day 3, the second administration of lipid emulsion was performed due to the recurrence of an altered mental status.[1] The elimination half-life of bupropion is 29 ± 9 hours.[5] In addition, the absorption of a toxic dose following oral administration (enteral route) is more prolonged than that following intravenous administration, leading to extended toxicity.[6] In contrast, Intralipid has a very short half-life (13.7 ± 5.2 minutes).[7] Considering previous reports, the lipid phase of lipid emulsion appears to absorb highly lipid-soluble bupropion from the heart and brain for a very short period following lipid emulsion administration.[3] [7] Furthermore, 1% of plasma triglyceride concentration, which provides lipemic plasma without fat overload, is sufficient to exert scavenging and cardiotonic effects on the toxicity induced by an enteral overdose.[6] Thus, the altered mental status on day 3 following a marked improvement after the first administration of lipid emulsion may be ascribed to a greatly reduced concentration of Intralipid.[1] A previous report recommends the following lipid emulsion regimen to treat toxicity induced by enteral overdose: bolus administration of Intralipid 1.5 mL/kg for 1 minute and subsequently 0.25 mL/kg/min for an additional 3 minutes, followed by intravenous infusion of 0.025 mL/kg/min (up to 6.5 hours) to theoretically maintain a 1% plasma triglyceride concentration.[6] This regimen, as an adjuvant, can be used with supportive care in cases of toxicity induced by oral overdose.[6] However, further research in an in vivo model on the optimal dosing regimen of lipid emulsion for the treatment of toxicity following oral overdose of bupropion is needed because the pharmacokinetics of an oral overdose are different from those of intravenous overdose (e.g., local anesthetic systemic toxicity). Second, initially, lipid sink was widely accepted as the underlying mechanism of lipid emulsion treatment.[4] However, a previous study using a physiologically based pharmacokinetic model reported that lipid emulsion decreased only 11 and 18% bupivacaine concentrations in the heart and brain, respectively.[8] The free bupivacaine concentration was not significantly different between the control and lipid emulsion groups in an in vivo study after administration of a nontoxic dose of bupivacaine in humans.[9] Thus, lipid shuttle has recently been widely accepted as the mechanism of lipid emulsion treatment; it states that lipid emulsion absorbs lipid-soluble drugs, such as bupivacaine, from the heart and then the lipid emulsion, containing the sequestered lipid-soluble drug (e.g., bupivacaine), is transported to the liver and muscle for detoxification and storage, leading to enhanced redistribution.[4] We believe that this case report contributes valuable data on the efficacy of lipid emulsion treatment in bupropion toxicity and emphasizes the need for continuous infusion of lipid emulsion following the initial bolus administration in lipid emulsion treatment.

TREATMENT OF ACUTE BUPROPRIONE TOXICITY WITH LIPID INFUSION AND PLASMAPHERESIS

SESSION TITLE: Plasmapheresis to the Rescue SESSION TYPE: Fellow Case Reports PRESENTED ON: 10/21/2019 3:15 PM - 4:15 PM INTRODUCTION: Bupropion is an atypical antidepressant used to treat major depressive disorder and other psychiatric conditions. The toxic side effects of bupropion include seizures, tachycardia, arrhythmias, and death. These side effects are dose and formulary dependent. We describe a case of acute bupropion toxicity from a suicide attempt with symptoms, which was treated with Intralipid infusion along with serial plasmapheresis. CASE PRESENTATION: A 19-year-old male was transferred from an outside hospital for suicide attempt with ingestion of 40 tablets of 150 mg sustained released (SR) bupropion for a total dose of 9 gm. He was not a candidate for any activated charcoal. The patient developed tonic-clonic seizures and the decision was made to initiate a bolus of 140 mL of 20% Intralipid before and during transport. On admission to our hospital he developed status epilepticus and had QTc prolongation (467 and 487). He was started on 800 mL lipid infusion immediately followed by serial plasmapheresis. The triglyceride levels were closely monitored. The patient received a total of 940 mL (140 mL bolus plus 800 mL continuous infusion) of intralipid along with 3 sessions of plasmapheresis. He remained seizure free and his QTc normalized and was successfully extubated. DISCUSSION: Bupropion is a highly lipid soluble and protein-bound medication. Mild toxicity includes dry mouth, nausea, insomnia, dizziness. Life-threatening toxicities include seizure and arrhythmias. Seizures are generally seen with an overdose of bupropion. Ingestion of 4.5-9 g of bupropion increases the likelihood of seizures. Treatment is mostly symptomatic and with benzodiazepines. Lipid infusions can be used as lipid rescue therapy for acute cardiovascular collapses. The mechanism is the same as the use of lipid infusion as rescue therapy in case of local anesthetic, tricyclic antidepressants or serotonin-specific reuptake inhibitor toxicities. The proposed mechanism involves lipids from the infusion binding to the offending drug and pulling it from the target tissue preventing its accumulation and minimizing the toxic effects. Despite several reports there seem to be increased risks and compilations associated with lipid infusions like acute respiratory distress syndrome, hypertriglyceridemia, pancreatitis, and cardiac toxicity. There are not many reports of the use of plasmapheresis in a timely manner (depending on the half-life of the drug) for an SR drug after lipid infusion to promote removal of all the lipid molecules including those bound to the offending drug thereby preventing toxicity from the drug and lipid infusion as well. In our case combination of both helped in stabilizing and treating the patient. CONCLUSIONS: Use of lipid infusion in conjugation with plasmapheresis for the treatment of acute bupropion toxicity with symptoms allows safe use of lipid infusion and ensures complete removal of offending drug. Reference #1: Tolentino Stephanie; Gharpure, Varsha; Tsifansky, Michael Critical Care Medicine: December 2013 Reference #2: Intravenous lipid emulsion in clinical toxicology Leelach Rothschild,corresponding author1 Sarah Bern,1 Sarah Oswald,1 and Guy Weinbergcorresponding author1,2 DISCLOSURES: No relevant relationships by Praful Tewari, source=Web Response

Pack in or go on: Topographic disorientation induced by bupropion sustained release tablet

The mechanism of effect of bupropion is unknown. The authors report a case of bupropion-associated topographic disorientation during bupropion treatment for smoking cessation. A 44-year-old female patient with a history not knowing where she is, the inability to recognize the surrounding buildings was admitted to neurology department. During her admission, her symptoms disappeared and she did not continue her medication. There was no abnormality in the investigation. It was concluded that the onset of symptoms was dose dependent. Bupropion may cause unusual neuropsychiatric behaviors. This case suggests that topographic disorientation may be the primary symptom of bupropion toxicity.

Bupropion Overdose: Significant Toxicity in Pediatrics

Bupropion is a commonly prescribed antidepressant and smoking cessation agent indicated for use in adults. Pediatric bupropion exposures reported to US poison control centers have increased in recent years. Both intentional and unintentional bupropion overdose can result in life-threatening toxicity. Bupropion toxicity is characterized by agitation, hallucinations, tachycardia, and delayed-onset seizures. This article reviews bupropion's pharmacology, pharmacokinetics, clinical manifestations, and management of toxicity.

Management of severe bupropion poisoning with intravenous lipid emulsion

Background: Bupropion toxicity is characterized by central nervous system and cardiovascular toxicity. Intravenous lipid emulsion (ILE) has been suggested as a treatment by some for the treatment of refractory bupropion toxicity. This recommendation is based largely on published case reports and cases presented at scientific meetings. The objective of this study is to characterize the outcomes of patients with suspected bupropion toxicity in which ILE was administered and the indications for its use.Methods: Electronic records from one regional poison center were searched for intentional bupropion ingestions from 1 January 2009 through 31 December 2015. Cases in which ILE was administered or death was listed as the outcome were further analyzed.Results: There were 1274 cases of suspected bupropion ingestion reported during the study period with 14 reported deaths. Nine cases of ILE administration were identified. Of these, four patients expired and five survived. One of the survivors had neurologic sequelae necessitating placement in a long-term care facility. Patient complications after ILE administration were common and included continued hypotension in 7 cases, recurrent seizures in 3 patients, ARDS in two patients, and renal failure in one patient.Conclusions: The high mortality and complication rate after ILE in this study sample does not reflect the positive outcome benefit seen in previous published case reports. Further characterization of the efficacy and complications of ILE in bupropion toxicity is needed.

Dilated and Unreactive Pupils and Burst-Suppression on Electroencephalography due to Buproprion Overdose

Burst-suppression pattern on electroencephalography (EEG) occurs upon dissociation of the cortex from underlying brain structures. Unless the pattern is a physiologic consequence of administered sedatives, this electroencephalographic pattern is indicative of a poor neurologic outcome and high mortality. We report a case of a 29-year-old female thought to be brain dead based on initial physical examination and EEG findings of burst-suppression, who was later found to have supratherapeutic serum levels of bupropion. This is the second documented case of burst-suppression pattern on EEG in a patient who overdosed on bupropion. We propose that burst-suppression in the setting of bupropion toxicity may revert with drug clearance.

Response to: ‘Intravenous Fat Emulsion Therapy: Can It be Tried Without Sufficient First‐Line Treatment Modalities?’

We wish to thank Dr. Zamani for his comments and the opportunity to clarify the treatment of poisoned patients. While we agree that at this moment the use of intravenous fat emulsion (IFE) therapy for patients with life-threatening poisoning from cardiotoxic lipophilic drugs should be only considered after routine care is provided, we emphatically disagree with Dr. Zamani's definition of routine care. Although the use of calcium 1 and glucagon 2 is frequently recommended for calcium channel blocker and beta-adrenergic antagonist toxicity, there are no controlled trials that establish their optimal dosing. Furthermore, the use of either calcium and/or glucagon in bupropion toxicity is entirely unknown. The patient we described had failed acceptable initial doses of calcium and glucagon that would have been used for empiric treatment of cardiotoxic overdose and was receiving high doses of norepinephrine at the time IFE therapy was considered. Increasing norepinephrine further may have improved the blood pressure at the cost of end-organ vasoconstriction and subsequent ischaemia. Instead, we chose to administer IFE, based on published success 3 in hopes of sequestering a lipid-soluble toxin and obviating the need for another toxic drug (norepinephrine). Finally, most of the adverse effects associated with IFE, as noted in the article cited by Dr. Zamani, are with prolonged total parenteral nutrition and therefore cannot be extrapolated to short administration of lipid resuscitation therapy 4.

Life-Threatening Bupropion Ingestion: Is There a Role for Intravenous Fat Emulsion?

Intravenous fat emulsion (IFE) is emerging as a novel antidote in clinical toxicology. Its current usage is extending beyond local anaesthetic toxicity into management of severe toxicity from some lipophilic drugs. We present a 51-year-old woman with severe bupropion toxicity whose haemodynamic status transiently improved after IFE. Serum analysis demonstrated an increase in serum concentration of hydroxybupropion, an active metabolite of bupropion, after IFE administration, lending support to one of the proposed mechanisms of IFE. A 51-year-old woman presented to the emergency department with generalised tonic-clonic convulsions lasting approximately 30 sec., and a wide complex rhythm on her ECG that was suggestive of myocardial sodium channel blockade. Despite sodium bicarbonate therapy, the patient developed profound hypotension refractory to high-dose norepinephrine. IFE was administered with haemodynamic improvement over the course of 30 min., followed by a significant decrease in norepinephrine requirement. The patient had an episode of ventricular tachycardia 24 hr after presentation, and received a second infusion of IFE. Analysis of serum for a panel of myocardial sodium channel blocking drugs revealed that significant bupropion ingestion had occurred. Bupropion poisoning may produce life-threatening clinical effects, and IFE may be considered in cases of severe haemodynamic instability. Further studies would be instrumental in determining the optimal clinical situations for utilisation of IFE.