Mixed Drug Overdose Research Articles

Retrospective analysis of patterns of opioid overdose and interventions delivered at a tertiary hospital emergency department: impact of COVID-19

BackgroundOpioid-related overdoses cause substantial numbers of preventable deaths. Naloxone is an opioid antagonist available in take-home naloxone (THN) kits as a lifesaving measure for opioid overdose. As the emergency department (ED) is a primary point of contact for patients with high-risk opioid use, evidence-based recommendations from the Society of Hospital Pharmacists of Australia THN practice guidelines include the provision of THN, accompanied by psychosocial interventions. However, implementation of these guidelines in practice is unknown. This study investigated ED opioid-related overdose presentations, concordance of post-overdose interventions with the THN practice guidelines, and the impact, if any, of the SARS-CoV-2 (COVID-19) pandemic on case presentations.MethodsA single-centre retrospective audit was conducted at a major tertiary hospital of patients presenting with overdoses involving opioids and non-opioids between March to August 2019 and March to August 2020. Patient presentations and interventions delivered by the paramedics, ED and upon discharge from the ED were collated from medical records and analysed using descriptive statistics, chi square and independent T-tests.ResultsThe majority (66.2%) of patients presented to hospital with mixed drug overdoses involving opioids and non-opioids. Pharmaceutical opioids were implicated in a greater proportion (72.1%) of overdoses than illicit opioids. Fewer patients presented in March to August 2020 as compared with 2019 (26 vs. 42), and mixed drug overdoses were more frequent in 2020 than 2019 (80.8% vs. 57.1%). Referral to outpatient psychology (22.0%) and drug and alcohol services (20.3%) were amongst the most common post-discharge interventions. Naloxone was provided to 28 patients (41.2%) by the paramedics and/or ED. No patients received THN upon discharge.ConclusionsThis study highlights opportunities to improve ED provision of THN and other interventions post-opioid overdose. Large-scale multi-centre studies are required to ascertain the capacity of EDs to provide THN and the impact of COVID-19 on opioid overdose presentations.

1008 Incidental Solitary Cystic Mediastinal Lymphangioma with Mass Effect Complications: A Case Report

Abstract Introduction Cystic mediastinal lymphangiomas (CML) are exceedingly rare, representing <1% of cystic lymphangiomas (CL), and typically present before 2 years of age. Few cases describe adult presentations of solitary CML and none describe symptomatic cases with ‘mass-effect’ complications. We describe an incidental finding of a symptomatic solitary CML causing mass effect complications and our definitive surgical management. Case Report A 44-year-old Caucasian male presented with reduced responsiveness due to mixed drug overdose of fluoxetine and ibuprofen. Plain chest radiograph (CXR) revealed incidental new mediastinal widening. Thoracic computed tomography (CT) showed a well-defined lesion (75x63mm) in the right paratracheal region, with associated compression of the superior vena cava, left brachiocephalic vein and displacement of the azygos vein. Further questioning revealed 6-months history of non-productive cough, worsening dyspnoea on exertion and chest pain radiating to the right of the chest. Complete surgical resection was performed via posterolateral thoracotomy. It was seen compressing the 2nd and 3rd intercostal nerves. Enlarged lymph nodes at station 4 and 10 were excised and sent for analysis with aspirate from the excised lesion. Pathological gross examination showed a multiloculated cystic lesion containing thin straw-coloured fluid. Microscopically, it was thin walled with smooth muscle and scattered clusters of lymphocytes; its lining was markedly attenuated comprising bland flat endothelial cells, positive for CD-31. Lymph node samples showed reactive changes. Conclusions Although CMLs are benign, their location and growth in the mediastinum can result in compression of surrounding structures. Early detection and complete surgical resection are paramount to prevent such complications and lesion recurrence.

CPD article: Poisons affecting the cardiovascular system

Cardiac and cardiovascular function can be affected by numerous substances, including overdose of drugs for cardiac and cardiovascular conditions, drugs used in the management of other diseases, over-the-counter medicines and supplements, foods and natural toxins such as plants. A common cause of tachycardia in dogs is exposure to salbutamol from piercing an asthma inhaler. Cardiac drugs such as beta-blockers and calcium-channel blockers can cause hypotension and disrupt cardiac rhythm. Although severe cases are not common in companion animals, management may be complex, requiring high dose insulin therapy and/or lipid emulsion therapy. The methylxanthines caffeine and theobromine, which are found in foods, and caffeine in supplements, are readily accessible to pets and can cause central nervous system and muscle (including cardiac muscle) stimulation. Animals with pre-existing cardiac disease or those with a mixed cardiotoxic drug overdose are likely to be more at risk of effects after exposure to substances affecting the cardiovascular system. Support of cardiac and cardiovascular function is essential to prevent cardiac injury and maintain tissue perfusion. Specific management depends on the severity of clinical signs and the particular substance involved.

Poisons affecting the cardiovascular system

Cardiac and cardiovascular function can be affected by numerous substances, including overdose of drugs for cardiac and cardiovascular conditions, drugs used in the management of other diseases, over-the-counter medicines and supplements, foods and natural toxins such as plants. A common cause of tachycardia in dogs is exposure to salbutamol from piercing an asthma inhaler. Cardiac drugs such as beta-blockers and calcium-channel blockers can cause hypotension and disrupt cardiac rhythm. Although severe cases are not common in companion animals, management may be complex, requiring high dose insulin therapy and/or lipid emulsion therapy. The methylxanthines caffeine and theobromine, which are found in foods, and caffeine in supplements, are readily accessible to pets and can cause central nervous system and muscle (including cardiac muscle) stimulation. Animals with pre-existing cardiac disease or those with a mixed cardiotoxic drug overdose are likely to be more at risk of effects after exposure to substances affecting the cardiovascular system. Support of cardiac and cardiovascular function is essential to prevent cardiac injury and maintain tissue perfusion. Specific management depends on the severity of clinical signs and the particular substance involved.

Acute intoxications: markers for screening, diagnosis and therapy monitoring

Acute poisonings account for asignificant proportion of the patient population presenting to intensive care units, whereby mixed drug overdoses and prescription drug overdoses predominate. The aim of this article was to describe indications for screening, diagnosis and therapy monitoring in acute overdoses in the intensive care unit. To conduct this work, aliterature search was carried out and areview was written based on guidelines, case reports, expert opinions and scientific publications. Toxidromes are auseful tool for classification of clinical characteristics when the causative agent is initially unknown. Especially in critical care medicine, identifying and quantifying of the causative toxin by enzyme immunoassays, chromatography and mass spectrometry should be attempted. Intensive care treatment of patients with acute overdoses includes not only monitoring and support of vital functions but also methods for primary and secondary elimination of toxins. The indication for the use of extracorporeal procedures should be carefully evaluated and the method should be chosen based on protein binding and molecular size. Lipid emulsion therapy, high-dose insulin euglycaemia therapy and hyperbaric oxygenation are also increasingly used.

HHS in type 1 diabetes associated with medication overdose: can counter‐regulatory hormone suppression prevent diabetic ketoacidosis?

AbstractIn states of insulopaenic hyperglycaemia, counter‐regulatory hormone (CRH) excess is a driver of ketogenesis and thus diabetic ketoacidosis. We present a case of hyperglycaemic hyperosmolar state in a patient with type 1 diabetes mellitus, associated with a mixed drug overdose including agents with documented CRH suppressive effects. We postulate that the drugs taken in overdose protected against diabetic ketoacidosis, and suggest further investigation of pharmacological therapies aimed at inhibiting CRH responses which may protect against this life‐threatening complication in patients with type 1 diabetes. Copyright © 2016 John Wiley & Sons.

Early Career in Drug Abuse with Preference for γ-Hydroxybutyrate Resulted in a Mixed Drug Overdose Death

Early Career in Drug Abuse with Preference for γ-Hydroxybutyrate Resulted in a Mixed Drug Overdose Death The recreational drug of abuse γ-hydroxybutyric acid (GHB) is a depressant of the central nervous system (CNS) and is often encountered in blood and urine analysed during forensic case-work. Here we report the results of toxicological analysis of blood or urine from a person arrested for abuse of illicit drugs on 28 occasions over 13 years. GHB was identified on 21 occasions, either in blood (6 times) or urine (15 times). Another popular drug of abuse was amphetamine, which was identified 15 times. The man died from a mixed-drug overdose at the age of 29 years and post-mortem toxicology showed GHB concentrations of 200 mg/L in femoral blood and 4700 mg/L in urine. The much higher concentration of GHB in urine indicates that the concentrations in blood (and brain) were much higher than 200 mg/L during the ante-mortem period, owing to GHB’s short plasma elimination half-life of 30-60 min. An early intervention and treatment for substance abuse might have been more beneficial than conventional sanctions and penalties for petty drug offences.

Lipid Resuscitation Reverses Multidrug-Induced Cardiogenic Shock

To the Editor: We read with interest the recent case report by Stellpflug describing the eventual recovery of a 30-year-old patient with severe cardiovascular instability due to mixed diltiazem, metoprolol, and amiodarone overdose. However, we have strong reservations about their conclusion that, “The treatment combination…….was successful for this patient in reversing severe drug-induced cardiogenic shock.” The patient received high-dose insulin for 85 min which the authors state, “…did not result in clinical improvement….” Then after intravenous lipid emulsion (ILE 20%) therapy, the authors report, “…. was associated with rapid improvement.” The chronology suggests to us that ILE saved the patient’s life after prolonged, ineffective high-dose insulin therapy. This conforms with many other reports of successful resuscitation with ILE in patients that did not respond to conventional (e.g., pressor) treatment. We believe the authors’ own comments strongly contradict their conclusion. Everyone would agree, we expect, that the report provides a rationale for further head-to-head laboratory comparison of ILE with high-dose insulin in treatment of mixed drug overdose and particularly calcium channel blocker-related cardiogenic shock. Dr. Weinberg was awarded with the United States patent 7 261 903 B1 “Lipid emulsion in the treatment of systemic poisoning.” The noncommercial website www.lipidregistry.org is intended for the purpose of case documentation. Neither salary nor support is derived from this website.

Free Oxycodone Concentrations in 67 Postmortem Cases from the Hennepin County Medical Examiner's Office

Heart blood free oxycodone concentrations in oxycodone-related and mixed drug overdose deaths were compared with those found incidentally at autopsy in medical examiner cases. Between 2000 and 2005, 67 oxycodone-positive postmortem cases were identified. Thirty of 67 cases (44.8%) were determined to be drug overdoses. Oxycodone alone was responsible for 7 of the 30 (23.3%) overdose deaths. Mean (median) oxycodone concentrations were 1.060 mg/L (0.824 mg/L) with a range of 0.270-3.390 mg/L. Three cases were accidents, three were suicides, and one was undetermined. The remaining 23 were mixed drug overdoses. Mean (median) oxycodone concentrations in these cases were 0.820 mg/L (0.470 mg/L) with a range of 0.014-3.800 mg/L. Sixteen mixed drug overdoses were accidental, and seven were suicidal. Where oxycodone was an incidental finding, 24 were natural, 6 accident, 4 suicide, 1 homicide, and 2 undetermined. The mean (median) concentrations in the incidental finding group were 0.330 mg/L (0.150 mg/L) with a range of 0.017-1.300 mg/L. In conclusion, the findings substantiate the considerable overlap that exists with blood oxycodone concentrations in cases where oxycodone alone was determined to be the cause of death compared with mixed drug overdoses and incidental findings. Free oxycodone concentrations in postmortem cases must be interpreted in the context of the deceased's past medical history and autopsy findings.

Fentanyl Concentrations in 23 Postmortem Cases from the Hennepin County Medical Examiner’s Office*

The purpose of this study was to compare blood fentanyl concentrations in fentanyl-related deaths with fentanyl concentrations found incidentally at autopsy, as well as with fentanyl concentrations found in hospitalized patients receiving fentanyl. Between the years 1997 to 2005, 23 fentanyl-positive postmortem cases were identified. Nineteen of 23 (82.6%) cases were deemed to be drug overdoses. Fentanyl alone was responsible for 8 of the 19 (42.1%) overdose deaths. Mean and median fentanyl concentrations were 36 (SD 38) microg/L and 22 microg/L, respectively, range 5-120 microg/L. Seven of the cases were accidental, one undetermined. The remaining 11 of the 19 (57.9%) cases were mixed drug overdoses. Fentanyl concentrations in these cases were 31 (SD 46) microg/L, range 5-152 microg/L. All of the mixed drug overdoses were determined to be accidental. Four cases where fentanyl was considered an incidental postmortem finding were determined to be natural deaths. In hospitalized inpatients (n = 11) receiving fentanyl 2 of the patients receiving fentanyl for chronic pain for more than 3 months had concentrations of 8.5 microg/L and 9.9 microg/L. The other nine inpatient concentrations were less than 4 microg/L. In conclusion, blood fentanyl concentrations found in cases where fentanyl alone was determined to be the cause of death were similar to cases where fentanyl was part of a mixed drug overdose. There was also considerable overlap between fentanyl concentrations in fentanyl-related overdose deaths compared to hospitalized patients being treated for chronic pain. Fentanyl concentrations in postmortem cases must be interpreted in the context of the deceased's past medical history and autopsy findings.

London audit of drug‐related overdose deaths: characteristics and typology, and implications for prevention and monitoring

To describe the circumstances and draft a typology of drug-related overdose deaths. London, 2003. An audit of 148 drug overdose deaths (involving heroin, methadone, dihydrocodeine, cocaine, amphetamine or MDMA) investigated by coroners during 2003. Information extracted on toxicology, pathology and circumstances were used to identify drug(s) implicated in the death. Poly- or multiple drug use was detected in the majority of deaths with at least 69 different combinations, including 66% for heroin and 42% for cocaine. Six categories of death were identified involving an opiate (100, 68%); cocaine (14, 9%); other controlled drug (five, 3%); mixed drug overdose (18, 12%); other prescribed drug (five, 3%); and other causes (seven, 5%). A witness was present and the death was not instantaneous in 92 (61%) cases, although evidence in the coronial file suggested that in the majority of cases the overdose went unnoticed until too late to intervene. In all, 15 (one in 10) of the deceased were released from prison within 3 months of death; and 37 (one in four) were reported as in receipt of a methadone prescription. Perhaps for the first time in the United Kingdom cocaine was detected in more drug overdose deaths than methadone. However, reducing heroin use is central to the prevention of drug-related deaths. We recommend that overdose prevention encompasses strategies to encourage a 'mutual duty of care' among problem drug users, and in the United Kingdom further investigation of the relationship of methadone treatment failures on overall trends in drug-related deaths is merited.

Fatal Overdoses Associated with Quetiapine

Quetiapine (Seroquel) is an atypical antipsychotic drug belonging to a new chemical class, the benzothiazepine derivatives. We present three cases from the Provincial Toxicology Center of British Columbia, Canada in which suicidal overdose deaths were associated with quetiapine. The blood specimens were initially subjected to a thorough qualitative analysis. Basic drugs were screened for by liquid-liquid extraction followed by gas chromatography-nitrogen-phosphorus (GC-NPD) and gas chromatography-mass spectrometry-electron impact detection utilizing both in-house and commercial search libraries. Acidic and neutral drugs were screened for by liquid-liquid extraction followed by high-performance liquid chromatography-diode-array detection. Volatiles were assayed by gas chromatography-flame-ionization detection. Quetiapine was assayed in biological specimens by basic extraction with n-butyl chloride and derivatized with 50 microL of MTBSTFA and separation by GC-NPD. Linearity was observed up to 2.0 mg/L. Samples with concentrations exceeding the linearity were diluted. These cases were chosen for study because they were all deaths as a result of suicidal ingestion of drugs in which quetiapine was considered a significant factor. The concentrations of quetiapine in these cases are 6-16 times greater than the upper reported therapeutic range (0.1-1.0 mg/L). In case #1, the concentrations of quetiapine found were 7.20 mg/L (19 micromol/L) in blood and 0.93 mg/L (2.4 micromol/L) in vitreous fluid. In case #2, the concentrations of quetiapine found were 16 mg/L in blood (42 micromol/L), 120 mg/kg (310 micromol/kg) in liver, and 1.8 mg/L (4.6 micromol/L) in vitreous fluid. In case #3, the concentrations of quetiapine found in femoral blood was 5.90 mg/L (15 micromol/L). In all cases, drugs in addition to quetiapine were detected, but in cases #1 and #2, the cause of death was considered to be a quetiapine overdose and the other drugs were not considered to be contributory. Case #3 was considered a mixed drug overdose.

An autopsy case of combined drug intoxication involving verapamil, metoprolol and digoxin

We present here a fatal poisoning case involving verapamil, metoprolol and digoxin. A 39-year-old male was found dead in his room, and a lot of empty packets of prescribed drugs were found near the corpse. The blood concentrations of verapamil, metoprolol and digoxin were 9.2 μg/ml, 3.6 μg/ml and 3.2 ng/ml, respectively. The cause of death was given as cardiac failure, hypotension and bradycardia due to a mixed drug overdose of verapamil, metoprolol and digoxin, based on the results of the autopsy and toxicological examination. We speculate that the toxicity of verapamil is potentiated by drug interaction with metoprolol and digoxin.

Serotonin syndrome and drug combinations: focus on MAOI and RIMA.

Serotonin syndrome is a potentially life-threatening complication of psychopharmacological drug therapy. The syndrome is produced most often by the concurrent use of two or more drugs that increase brainstem serotonin activity and is often unrecognized because of the varied and nonspecific nature of its symptomatology. Serotonin syndrome is characterized by alterations in cognition, behavior, autonomic nervous system function and neuromuscular activity. The purpose of this study was to investigate the possibility that any serotomimetic substance alone or in combination may give rise to serotonin syndrome, that this condition is not confined to the use of newly introduced substances, and that the newer reversible inhibitors of monoamine oxidase type A (RIMAs) are at decreased risk for this phenomenon than older, classical (irreversible) monoamine oxidase inhibitors (MAOI). This is a hypothesis-generating study based on a review of all published cases of adverse effects arising in patients receiving serotomimetic substances or combinations. A wide range of substances were involved in 226 cases published worldwide since 1950 where there was any use of single or combined serotomimetic treatments. Of the 226 cases, 105 fulfilled the Sternbach criteria for serotonin syndrome. Some classes of drugs and individual substances were more commonly represented. This may arise from product utilization patterns or from the specific properties of the individual products. However, moclobemide, a RIMA, was represented in only 9 of the 226 published cases and 3 of the 105 defined serotonin syndromes, either in multi-drug combinations and/or in mixed drug overdose. One explanation for the small number of cases involving RIMAs could be the reversibility of these new products. In addition the small number of reports on moclobemide could be an effect of its short availability in routine use during the period of the literature review. We conclude that a spectrum of serotonergic hyperactivity, through to a defined serotonin syndrome, may arise from the use or combination of any serotomimetic substance, as this is a consequence of the mechanism involved, rather than the use of any specific product such as the new antidepressants. We further conclude that this condition is not confined to the use of newly introduced substances and that the newer reversible inhibitors of monoamine oxidase type A (RIMAs) may be at decreased risk for this phenomenon than older, classical (irreversible) (MAOI). Given that a spectrum of serotonergic hyperactivity was observed, this analysis prompts redefinition of the currently accepted criteria for serotonin syndrome.

Safety and Effectiveness of Nalmefene vs. Naloxore in Opioid and Mixed Drug Overdose in the Prehospital Care Setting

Safety and Effectiveness of Nalmefene vs. Naloxore in Opioid and Mixed Drug Overdose in the Prehospital Care Setting

Adverse reactions to flumazenil in mixed drug overdose involving tricyclic antidepressants

AbstractObjectives To describe two cases of status epilepticus and major cardiac toxicity following flumazenil administration in mixed benzodiazepine and tricyclic antidepressant overdose. To review the reported major adverse reactions to flumazenil. To suggest guidelines for flumazenil use in the management of overdose. Clinical featuresFlumazenil was administered to two patients who were comatose following ingestion of benzodiazepines and tricyclic antidepressants. Both suffered immediate convulsions and major cardiac toxicity.InterventionsOne patient received DC defibrillation and respiratory support, the other respiratory support and cardiopulmonary bypass.OutcomesBoth patients required admission to the Intensive Care Unit. The patient requiring cardiopulmonary bypass died of multi‐system failure, the other survived.ConclusionsFlumazenil should not be used to reverse coma due to coingestion of benzodiazepines and tricyclic antidepressants, or undifferentiated coma in which tricyclic antidepressant intoxication may be present.

Surveillance of poisoning and drug overdose through hospital discharge coding, poison control center reporting, and the Drug Abuse Warning Network

There is no gold standard for determining poisoning incidence. We wished to compare four measures of poisoning incidence: International Classification of Diseases 9th Revision (ICD-9) principal (N-code) and supplemental external cause of injury (E-code) designations, poison control center (PCC) reporting, and detection by the Drug Abuse Warning Network (DAWN). We studied a case series at two urban hospitals. We assigned ICD-9 N-code and E-code classifications, determining whether these matched with medical records. We ascertained PCC and DAWN system reporting. A total of 724 subjects met entry criteria; 533 were studied (74%). We matched poisoning N-codes for 278 patients (52%), E-code by cause in 306 patients (57%), and E-code by intent in 171 patients (32%). A total of 383 patients (72%) received any poisoning N-code or any E-code. We found that PCC and DAWN reporting occurred for 123 of all patients (23%) and 399 of 487 eligible patients (82%), respectively. In multiple logistic regression, factors of age, hospital admission, suicidal intent, principal poisoning or overdose type, and mixed drug overdose were statistically significant predictors of case match or report varying by surveillance measure. Our findings indicate that common surveillance measures of poisoning and drug overdose may systematically undercount morbidity.

Flumazenil in mixed benzodiazepine/tricyclic antidepressant overdose: A placebo-controlled study in the dog

This study evaluates the cardiac and neurologic risks associated with the antagonization of the benzodiazepine component of mixed drug overdoses, when cyclic antidepressants are also implicated. Twenty-four mongrel dogs were anesthetized and ventilated. Electroencephalogram, electrocardiogram, and tidal carbon dioxide and arterial pressure were continuously recorded. Amitriptyline (1 mg/kg/min) associated with midazolam (1 mg/kg + 1 mg/kg/h) was infused in 12 of the dogs. Midazolam was replaced by saline in the other 12. Drug administration was continued until signs of cardiotoxicity (QRS prolongation greater than 120 milliseconds or sustained arrhythmias) occurred. At that moment, midazolam effects were suddenly reversed by administration of flumazenil 0.2 mg/kg in six dogs out of each group. Placebo was administered in the others. Reactions were observed for the next 120 minutes. Midazolam-induced sedation efficiently protects (P less than .02) against seizures due to amitriptyline toxicity. This protective effect is counteracted by flumazenil. Midazolam has limited influence on the cardiac toxic effects of amitriptyline. The bolus of flumazenil is, however, associated with a significant worsening of electrocardiogram disturbances, and two sudden deaths were recorded. The mechanism of this effect remains unclear, as it could be unrelated to the antagonization of midazolam sedation. Given the problem of extrapolating animal data to humans, these results suggest that bolus administration of high doses of flumazenil in mixed intoxication implicating benzodiazepine and cyclic antidepressants has the potential to precipitate convulsions and/or arrhythmias. A slowly titrated administration of the antidote, as usually recommended, could prevent these effects.

Impaired Water Homeostasis following Mixed Carbamazepine and Phenobarbital Overdose

Both carbamazepine and phenobarbital are known to have antidiuretic properties when administered chronically. We describe a case of acute impairment of body water homeostasis following mixed drug overdose with carbamazepine and phenobarbital. Serum carbamazepine concentrations correlated with alternating states of diuresis and antidiuresis. We recommend close monitoring of fluid and electrolyte status in carbamazepine overdose.

Risks and Benefits of Therapy with Flumazenil (Anexate®) in Mixed Drug Intoxications

Flumazenil, the first specific benzodiazepine (BZD) antagonist, is one of the most innovative drugs to become available within the last few years. Flumazenil is indicated for the reversal of the centrally depressant effects of BZDs, in BZD-induced anaesthesia, in BZD sedation in intensive care and in patients comatose after drug overdoses including BZDs. A conference of experts experienced in the treatment of mixed drug overdoses by various means, including flumazenil, was held in order to try to reach a consensus regarding the safe use of flumazenil in this indication. From the knowledge and experience gained to date, it was concluded that flumazenil may be useful and safe in the treatment of suspected BZD and mixed drug overdoses, provided that the appropriate precautions are observed.