Dr. Gustin's Blog

Aspirin--No longer Recommended for Primary Cardiac Disease Prevention

Aspirin is to date the most used drug worldwide and, in 2018, with some dispute about its real birth date, celebrated its 121st birthday; 2018 will most probably be remembered as the year when aspirin came of age, whereby multiple studies re-examined, and at least partially questioned, its risk/benefit ratio in various clinical settings.[1–4] While aspirin remains the cornerstone treatment for secondary prevention in patients with established cardiovascular disorders, three large, independent, and high quality randomized controlled trials have shed new light on aspirin in primary prevention.[2–4] These recent results now have to be incorporated within the context of previously existing evidence, which altogether questions the somewhat liberal use of aspirin that has so far been recommended by some,[5] but not by other, guidelines committees.[6]

In this issue of the European Heart Journal, Mahmoud and colleagues furnish the findings on a meta-analysis and trial sequential analysis of randomized trials evaluating the efficacy and safety of aspirin among patients without prior known history of atherosclerotic cardiovascular disease.[7] A total of 11 studies with 157 248 participants met the pre-defined inclusion criteria, amongst which were (i) a randomized study design; (ii) comparing aspirin vs. placebo/no aspirin control; (iii) in adult patients without prior history of atherosclerosis; and (iv) including 500 patients or more. It should be emphasized that unlike some previous meta-analyses,[8] which also were claimed to focus on primary prevention, studies including patients with known atherosclerosis and peripheral vascular disease without having yet experienced an ischaemic event or revascularization (the so-called 1.5 prevention setting) had been excluded for the analysis. Yet, a sensitivity analysis, which also included patients with an established atherosclerotic disorder, mainly in the peripheral system, is provided and yields almost identical implications for practice.

This updated meta-analysis focused on mortality as the principal endpoint. This did not differ between the aspirin and control groups [4.6% vs. 4.7%; relative risk (risk ratio (RR)) = 0.98, 95% confidence interval (CI) 0.93–1.02, P = 0.30], without heterogeneity across studies and no signal of any treatment effect at interaction testing across pre-defined subgroups including the 10-year risk, diabetes, mid-enrolment year, aspirin dose, risk of bias, and follow-up duration.

The incidence of major bleeding was higher with aspirin, yielding a 47% higher RR and a number needed to harm (NNH) in the range of 250.

Similarly, the risk of intracranial bleeding, which was a pre-defined component of the major bleeding definition in all except one study,[9] was increased with a 33% relative and 0.1% absolute (NNH =1000) difference.

Cardiovascular mortality or stroke did not differ in patients with or without aspirin, which seriously contributes to the unfavourable risk/benefit profile of aspirin in the primary prevention setting.

However, the incidence of myocardial infarction (MI) was lower with aspirin [2.0% vs. 2.3%, 95% CI 1.7–2.8%; RR = 0.82, 95% CI 0.71–0.94, P = 0.006, number needed to treat (NNT) = 333]. One may wonder whether trading a single MI for bleeding would be an acceptable option. The comparative prognostic implications of bleeding vs. a non-fatal MI for mortality have been investigated at least in the secondary prevention setting and, unsurprisingly, the outcomes depend on the severity of bleeding, with intracranial episodes greatly exceeding the prognostic role of an MI in terms of mortality.[10] Yet, the key upstream question remains of whether the effect of aspirin on MI prevention is real and reproducible in contemporary practice. When looking at the current pooled analysis, the effect size of aspirin on MI was characterized by a high degree of heterogeneity between the studies included (I 2 = 67%) and a secondary analysis excluding older trials with mid-enrolment year prior to 2000 showed the lack of aspirin benefit even on MIs in more recent trials (RR = 0.90, 95% CI 0.79–1.02, P = 0.10). This observation may have multiple and not necessarily mutually exclusive explanations. Mahmoud and colleagues place emphasis on the fact that old studies pre-dated the universal definitions of MI and used relatively insensitive cardiac markers for the diagnosis of an MI.

If one plots the use of statins and the relative risk reductions for MI across the 11 included studies, an obvious association emerges between no or minimal use of statins and greater absolute effect of aspirin on MI prevention.

Among the contemporary studies evaluating aspirin in primary prevention, only the Japanese Primary Prevention Project observed a significant MI benefit with aspirin.[9]Interestingly, in this study, >70% of the patients had known dyslipidemia, but only 51% of them received statins during the course of the study.[9]

In the HOT trial, allocation to aspirin was also associated with a significant 35% MI risk reduction.[11] Yet, only 7% of the patients were treated with lipid-lowering drugs, and the mean total cholesterol was 235 mg/dL, suggesting a non-negligible proportion of patients with hypercholesterolaemia who may have derived benefit from lipid-lowering agents.[11] In primary prevention trials, the use of statins is known to be associated with a 25% decrease in the risk of major vascular events for every 1 mmol/L decrease in the LDL cholesterol level (rate ratio with statin vs. placebo, 0.75; 95% CI 0.69–0.82).[12] This statistically significant benefit was associated with an excellent safety profile and was not associated with the bleeding risks observed consistently throughout all aspirin trials.

Moreover, an intriguing observation regarding cholesterol levels and MI benefit of aspirin in the primary prevention setting comes from the Physicians' Health Study, which ante-dated the availability of statins.[13] In this trial, a significant interaction was noted between baseline cholesterol level and relative risk reduction for MI, with greater benefit observed in patients with the highest baseline cholesterol levels. Hence, taken together, current evidence raises concerns that aspirin can significantly contribute to MI prevention in patients when properly treated with lipid-lowering agents as per todays' practice and guidelines.

The recent results of the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), where high-dose icosapent ethyl led in the primary prevention setting to a consistent reduction of the primary composite ischaemic endpoint, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, without a significant increase in bleeding risk—albeit with a higher incidence of atrial fibrillation or flutter whose implications and mechanisms need to be better understood—further highlights the key role of lipid-lowering agents even in patients in whom the median LDL cholesterol level was 75.0 mg/dL at baseline.[14]

Whether routine antiplatelet agents, other than aspirin, will still have a possible role in high-risk patients in the truly primary prevention setting remains unclear, but it appears rather unlikely given the well-known trade-off between risks and benefits observed consistently across all antithrombotic agents investigated so far.

The issue of the management of patients fulfilling the 1.5 prevention setting, i.e. in whom an atherosclerotic disorder has been established prior to the occurrence of an ischaemic event or to the development of related symptoms, still remains unresolved. A pragmatic approach in this setting might be a selected use of aspirin only for patients on the low bleeding risk spectrum in the hope that this strategy might maximize the benefits over the risks.[15]

The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS, NCT01991795) is designed to evaluate the efficacy and safety of ticagrelor in >20 000 patients aged 50 years or more with type 2 diabetes with known coronary artery disease but without a history of an MI or stroke. Patients are being randomized to ticagrelor 60 mg twice daily or placebo in a double-blinded fashion. The primary endpoint is the composite of cardiovascular death, MI, or stroke at 48 months. Results of the THEMIS trial are expected in early 2019 and will greatly contribute to our current understanding about the future role of antiplatelet agents as a primary means to avoid the consequences of plaque rupture in patients who may have ongoing yet asymptomatic plaque rupture episodes. Meanwhile, we should get ready to say a farewell to aspirin even in asymptomatic patients in whom an atherosclerosis disorder is not established, irrespective of the anticipated risk of future ischaemic events or concomitant cardiovascular risk factors.

References

  1. Vranckx P, Valgimigli M, Juni P, Hamm C, Steg PG, Heg D, van Es GA, McFadden EP, Onuma Y, van Meijeren C, Chichareon P, Benit E, Mollmann H, Janssens L, Ferrario M, Moschovitis A, Zurakowski A, Dominici M, Van Geuns RJ, Huber K, Slagboom T, Serruys PW, Windecker S, GLOBAL LEADERS Investigators. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet 2018;392:940–949.
  2. Gaziano JM, Brotons C, Coppolecchia R, Cricelli C, Darius H, Gorelick PB, Howard G, Pearson TA, Rothwell PM, Ruilope LM, Tendera M, Tognoni G; ARRIVE Executive Committee. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet 2018;392:1036–1046.
  3. Group ASC, Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, Aung T, Haynes R, Cox J, Murawska A, Young A, Lay M, Chen F, Sammons E, Waters E, Adler A, Bodansky J, Farmer A, McPherson R, Neil A, Simpson D, Peto R, Baigent C, Collins R, Parish S, Armitage J. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018;379:1529–1539.
  4. McNeil JJ, Wolfe R, Woods RL, Tonkin AM, Donnan GA, Nelson MR, Reid CM, Lockery JE, Kirpach B, Storey E, Shah RC, Williamson JD, Margolis KL, Ernst ME, Abhayaratna WP, Stocks N, Fitzgerald SM, Orchard SG, Trevaks RE, Beilin LJ, Johnston CI, Ryan J, Radziszewska B, Jelinek M, Malik M, Eaton CB, Brauer D, Cloud G, Wood EM, Mahady SE, Satterfield S, Grimm R, Murray AM, ASPREE Investigator Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018;379:1509–1518.
  5. Bibbins-Domingo K, U.S. Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2016;164:836–845.
  6. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corra U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Lochen ML, Lollgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren WMM, Binno S, ESC Scientific Document Group. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315–2381.
  7. Mahmoud AN, Gad MM, Elgendy AY, Elgendy IY, Bavry AA. Efficacy and safety of aspirin for primary prevention of cardiovascular events: a meta-analysis and trial sequential analysis of randomized controlled trials. Eur Heart J 2019;40:607–617.
  8. Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849–1860.
  9. Ikeda Y, Shimada K, Teramoto T, Uchiyama S, Yamazaki T, Oikawa S, Sugawara M, Ando K, Murata M, Yokoyama K, Ishizuka N. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial. JAMA 2014;312:2510–2520.
  10. Valgimigli M, Costa F, Lokhnygina Y, Clare RM, Wallentin L, Moliterno DJ, Armstrong PW, White HD, Held C, Aylward PE, Van de Werf F, Harrington RA, Mahaffey KW, Tricoci P. Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial. Eur Heart J 2017;38:804–810.
  11. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998;351:1755–1762.
  12. Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, Evans S, Law M, MacMahon S, Martin S, Neal B, Poulter N, Preiss D, Ridker P, Roberts I, Rodgers A, Sandercock P, Schulz K, Sever P, Simes J, Smeeth L, Wald N, Yusuf S, Peto R. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532–2561.
  13. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989;321:129–135.
  14. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM, REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2018;in press.
  15. Costa F, van Klaveren D, James S, Heg D, Raber L, Feres F, Pilgrim T, Hong MK, Kim HS, Colombo A, Steg PG, Zanchin T, Palmerini T, Wallentin L, Bhatt DL, Stone GW, Windecker S, Steyerberg EW, Valgimigli M, PRECISE-DAPT Study Investigators. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet 2017;389:1025–1034.

Kratom Products from Southeast Asia are Contaminated with Heavy Metals

Final results of tests performed by the US Food and Drug Administration (FDA) on 30 kratom products confirm the presence of heavy metals, including lead and nickel, at concentrations not considered safe for human consumption, the FDA said Wednesday.

The FDA first warned of "disturbingly" high levels of heavy metals, including lead and nickel, last November, as reported by Medscape Medical News.  The FDA has posted a list of the kratom products and concentrations of heavy metals found in them on its website. Based on reported patterns of kratom use, heavy kratom users may be exposed to levels of lead and nickel many times greater than the safe daily exposure, the FDA warns in a statement.

Based on these test results, the typical long-term kratom user could potentially develop heavy metal poisoning, which could include nervous system or kidney damage, anemia, high blood pressure, and increased risk of certain cancers, the agency adds.

"Over the last year, the FDA has issued numerous warnings about the serious risks associated with the use of kratom, including novel risks due to the variability in how kratom products are formulated, sold and used both recreationally and by those who are seeking to self-medicate for pain or to treat opioid withdrawal symptoms," FDA Commissioner Scott Gottlieb, MD, said in the statement.

Gottlieb said the FDA has been "attempting to work" with the companies whose kratom products contain high levels of heavy metals.  The agency has released the final laboratory results to the public to "help make sure consumers are fully informed of these risks." "The data from these results support our public warning about the risk of heavy metals in kratom products. The findings of identifying heavy metals in kratom only strengthen our public health warnings around this substance and concern for the health and safety of Americans using it," he added.

No Approved Use Kratom is derived from the leaves of the kratom tree (Mitragyna speciosa), which is native to Thailand, Indonesia, and Papua New Guinea. The botanical's popularity has been increasing in the United States, with manufacturers — and those who take it — claiming it can help treat pain, anxiety, depression, and more recently, opioid withdrawal. Last year, an analysis of kratom by FDA scientists found that its compounds act like prescription-strength opioids. In addition to heavy metal contamination, kratom products have also been found to be contaminated with Salmonella, resulting in numerous illnesses and product recalls. Kratom has been linked to numerous deaths in the United States. There are currently no FDA-approved uses for kratom, and the agency has advised against using kratom or its psychoactive compounds mitragynine and 7-hydroxymitragynine in any form and from any manufacturer.

Health providers are encouraged to report any adverse reactions related to kratom products to MedWatch, the FDA's safety information and adverse event reporting program.

Drug Overdoses: Current Trends

Drug overdose remains a significant concern worldwide, with nearly half a million deaths annually. In the United States, drug overdoses are the leading cause of death for adults younger than 55 years. Drug-related deaths now outnumber those attributed to motor vehicle accidents and homicides. According to information from the Centers for Disease Control and Prevention (CDC), the drugs most commonly involved in overdose deaths include opioids (eg, fentanyl, heroin, oxycodone), cocaine, methamphetamines, and benzodiazepines. There are other drugs that can cause death including MDMA and various synthetic drugs.

Naloxone has been lifesaving in many scenarios, so the CDC recently issued recommendations regarding its use in patients taking opioids. The CDC recommends that clinicians strongly consider prescribing or coprescribing naloxone and providing education about its use in these types of patients taking opioids:

  • Those who are receiving opioids at a dosage of 50 morphine milligram equivalents per day or greater
  • Those who have respiratory conditions such as chronic obstructive pulmonary disease or obstructive sleep apnea (regardless of opioid dose)
  • Those who have been prescribed benzodiazepines (regardless of opioid dose)
  • Those who have a nonopioid substance use disorder, report excessive alcohol use, or have a mental health disorder (regardless of opioid dose)

The CDC also recommends naloxone in patients who are at high risk for experiencing or responding to an opioid overdose, including the following:

  • Those known to use heroin or illicit synthetic opioids or misuse prescription opioids
  • Those using other illicit drugs such as stimulants, including methamphetamine and cocaine
  • Those receiving treatment for opioid use disorder, including medication-assisted treatment with methadone, buprenorphine, or naltrexone
  • Those with a history of opioid misuse who were recently released from incarceration or other controlled settings where tolerance to opioids has been lost

Most of the deaths from synthetic opioids are from fentanyl. Most of the increases in fentanyl deaths in recent years do not involve prescription fentanyl but are related to illicitly made fentanyl mixed with or sold as heroin—with or without the users' knowledge—and increasingly sold as counterfeit pills.

In the event of an overdose, pertinent history may be obtained from bystanders, family, friends, or emergency medical services (EMS) providers. Pill bottles, drug paraphernalia, or eyewitness accounts may assist in the diagnosis of opioid toxicity. Occasionally, a trial of naloxone administered by an EMS provider is helpful to establish the diagnosis in the prehospital setting.

Patients with opioid toxicity characteristically have a depressed level of consciousness. Opioid toxicity should be suspected when the clinical triad of central nervous system (CNS) depression, respiratory depression, and pupillary miosis are present. Clinicians must be aware that opioid exposure does not always result in miosis (pupillary constriction), and that respiratory depression is the most specific sign. Drowsiness, conjunctival injection, and euphoria are frequently seen.

Drug screens are widely available but rarely alter clinical management in patients with uncomplicated overdoses. Drug screens are most sensitive when performed on urine. Positive results are observed up to 36-48 hours postexposure, but wide variations are possible depending on test sensitivity, dose, route of opioid administration, and the patient's metabolism. In patients with moderate to severe toxicity, performing these baseline studies is appropriate:

  • Complete blood cell (CBC) count
  • Comprehensive metabolic panel
  • Creatine kinase (CK) level
  • Arterial blood gas (ABG) determinations

According to American Heart Association guidelines, clear evidence suggests that cocaine can precipitate acute coronary syndrome, and that trying agents that show efficacy in the management of acute coronary syndrome may be reasonable in patients with severe cardiovascular toxicity. Agents that may be used as needed to control hypertension, tachycardia, and agitation include:

  • Alpha-blockers (eg, phentolamine)
  • Benzodiazepines (eg, lorazepam, diazepam)
  • Calcium channel blockers (verapamil)
  • Morphine
  • Sublingual nitroglycerin

The American Heart Association does not recommend any one of these agents over another in the treatment of cardiovascular toxicity due to cocaine; however, benzodiazepines are often used as first-line treatment.

Cardiopulmonary complaints are the most common presenting manifestations of cocaine abuse and include chest pain (frequently observed in long-term use or overdose), MI, arrhythmia, and cardiomyopathy. In individuals with cocaine-associated MI, median times to the onset of chest pain vary with the route or form of cocaine use: 30 minutes for intravenous use, 90 minutes for crack, and 135 minutes for intranasal use.

Temperature dysregulation is also a problem with cocaine intoxication. Hyperthermia is a marker for severe toxicity, and it is associated with numerous complications, including renal failure, disseminated intravascular coagulation, acidosis, hepatic injury, and rhabdomyolysis. Dopamine plays a role in the regulation of core body temperature, so increased dopaminergic neurotransmission may contribute to psychostimulant-induced hyperthermia in cocaine users, including those with excited delirium.

No laboratory studies are indicated if the patient has a clear history of cocaine use and mild symptoms.

If a history of cocaine use is absent or if the patient has moderate to severe toxicity, appropriate laboratory tests may include:

  • CBC count
  • Electrolytes, blood urea nitrogen, creatinine, and glucose levels (basic metabolic panel)
  • Glucose level
  • Pregnancy test
  • Calcium level
  • ABG analysis
  • CK level
  • Troponin level (cocaine use does not affect the specificity of troponin assays)
  • Urinalysis
  • Toxicology screens

Acute and long-term methamphetamine use may lead to abnormal findings on examination of the following organ systems:

  • Cardiovascular
  • CNS
  • Gastrointestinal
  • Renal
  • Skin
  • Dental

There are specific cardiovascular findings associated with acute and long-term methamphetamine use:

  • Tachycardia and hypertension is frequently observed
  • Atrial and ventricular arrhythmias may occur
  • Chest pain from cardiac ischemia and infarction following methamphetamine use has been reported, and patients are at risk because of accelerated atherosclerosis from chronic use; acute aortic dissection or aneurysm has been associated with methamphetamine abuse
  • Hypotension may be observed with methamphetamine overdose with profound depletion of catecholamines
  • Acute and chronic cardiomyopathy results directly from methamphetamine cardiac toxicity and indirectly from chronic hypertension and ischemia; intravenous use may result in endocarditis; patients may have dyspnea, edema, and other signs of acute congestive heart failure exacerbation

The euphoric effects produced by methamphetamine, cocaine, and various designer amphetamines are similar and may be difficult to clinically differentiate. A distinguishing clinical feature is the longer pharmacokinetic and pharmacodynamic half-life of methamphetamine, which may be as much as 10 times longer than that of cocaine.

Methamphetamine can cause significant CNS and psychiatric activation, so patients who present to emergency departments for acute intoxication often require physical restraint and pharmacologic intervention. Hyperactive or agitated patients can be treated with droperidol or haloperidol, which are butyrophenones that antagonize CNS dopamine receptors and mitigate the excess dopamine produced from methamphetamine toxicity. These medications should be administered intravenously, with doses adjusted based on the symptoms. Droperidol has been subject to a black box warning by the US Food and Drug Administration based on concerns of QT prolongation and the potential for torsades de pointes. As a result, some institutions restrict its use. However, it is important to note that the black box warning specifies dementia-related psychosis and is not supported by the literature for doses below 2.5 mg.

If sedation fails to reduce blood pressure, antihypertensive agents such as beta-blockers and vasodilators are effective in reversing methamphetamine-induced hypertension and tachycardia. With regard to choice of beta-blockers, labetalol is preferred because of its combined anti–alpha-adrenergic and anti–beta-adrenergic effects. Labetalol has been shown to safely lower mean arterial pressure in patients with positive cocaine test results. Carvedilol, like labetalol, is a nonselective beta-blocker with alpha-blocking activity and may also be effective for this indication. Esmolol is advantageous because of its short half-life but must be administered via intravenous drip. Metoprolol has excellent CNS penetration characteristics and may also ameliorate agitation.

Oral benzodiazepine overdoses, without co-ingestion of another drug, rarely result in significant morbidity (eg, aspiration pneumonia, rhabdomyolysis) or mortality; however, in mixed-drug overdoses, they can potentiate the effect of alcohol or other sedative-hypnotic agents. Overdose of ultrashort-acting benzodiazepines (eg, triazolam) is also more likely to result in apnea and death than overdose with longer-acting benzodiazepines. Of the individual benzodiazepines, alprazolam is relatively more toxic than others in overdose.

Immunoassay screening techniques are most commonly performed when benzodiazepine overdose is suspected. These tests typically detect benzodiazepines that are metabolized to desmethyldiazepam or oxazepam; thus, a negative screening result does not rule out the presence of a benzodiazepine.

As with any overdose, the first step is an assessment of the patient's airway, breathing, and circulation, and any issues should be addressed rapidly. In any patient with an altered mental status, blood glucose level should be checked immediately. The cornerstone of treatment in benzodiazepine overdoses is good supportive care and monitoring. Single-dose activated charcoal is not routinely recommended because the risks far outweigh the benefit. Altered mental status greatly increases the risk of aspiration following an oral activated charcoal dose.

Flumazenil is a competitive benzodiazepine receptor antagonist and the only available specific antidote for benzodiazepines. Its use in acute benzodiazepine overdose is controversial, however, and its risks usually outweigh any benefit. In long-term benzodiazepine users, flumazenil may precipitate withdrawal and seizures; in patients taking benzodiazepines for a medical condition, flumenazil may result in exacerbation of the condition. Flumazenil should not be used in patients with long-term benzodiazepine use or in any patient at an increased risk of having a seizure, including those with a seizure history, head injury, co-ingestion of a benzodiazepine and tricyclic antidepressant or other proconvulsant, or even a possible ingestion of a proconvulsant.

In general, when it is the sole agent used, the clinical presentation of heroin poisoning and its diagnosis hold little challenge for experienced healthcare practitioners. The diagnosis of heroin poisoning should be suspected in all comatose patients, especially in the presence of respiratory depression and miosis.

Respiratory depression, due to heroin's effect on the brain's respiratory centers, is a hallmark sign of overdose. However, the presence of tachypnea should prompt the search for complications of heroin use, such as pneumonia, acute lung injury, and pneumothorax, or an alternative diagnosis, such as shock, acidosis, or CNS injury. Tachypnea may also be seen in overdoses of pentazocine or meperidine.

Symptoms generally develop within 10 minutes of intravenous heroin injection. Patients who survive heroin poisoning commonly admit to using more than their usual dose, using heroin again after a prolonged period of abstinence, or using a more concentrated street sample. Coma, respiratory depression, and miosis are the hallmarks of opioid overdose.

Mild hypotension and mild bradycardia are commonly observed with heroin use. These are attributable to peripheral vasodilation, reduced peripheral resistance and histamine release, and inhibition of baroreceptor reflexes. In the setting of heroin overdose, hypotension remains mild. The presence of severe hypotension should prompt a search for other causes of hypotension, such as hemorrhage, hypovolemia, sepsis, pulmonary emboli, and other causes of shock.

Gastric lavage in the setting of oral heroin overdose is generally not recommended because it has no documented value. Furthermore, gastric lavage is contraindicated in "body packers" and "body stuffers," who have ingested packages of drugs, because the procedure may rupture a package. Activated charcoal is becoming increasingly controversial because of the risk of aspiration and charcoal pneumonitis. It may be indicated for orally ingested narcotics with large enterohepatic circulation (eg, propoxyphene, diphenoxylate) but is of no value in pure heroin overdose.

Toad Venom Psychedelics for Depression and Anxiety

A very interesting study has recently been done on the effects of a psychedelic substance in a small mitigated-psychedelic dose in the treatment of resistant depression and anxiety. The following is a synopsis of the key points from a recent Medscape article.  The relevance of this study to toxicology is that psychelics can have severe side-effects, some even long-lasting or permanent, even in customary doses, as noted below. Practitioners who treat their patients with these substances should be aware of the medicolegal liability and health risks.

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Fluoroquinolones are dangerous and can lead to a medical malpractice action

FDA Warns of Aortic Aneurysm Risk With Fluoroquinolones.

The US Food and Drug Administration (FDA) issued a warning today that fluoroquinolone use can increase the risk of aortic aneurysm.

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Cannabis-Linked ER Visits Increasing

The number of cannabis-associated emergency department (ED) visits has risen sharply since marijuana was legalized in Colorado. New data show that although inhalable cannabis use accounts for most of these visits, edible cannabis is tied to a disproportionate number of visits, and patients present with different symptoms.

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SMOKE INHALATION AND ADVERSE HEALTH CONSEQUENCES:

There are approximately 1.4 million fires each year in the United States.[1] In 2016, 81% of civilian fire-related deaths occurred in residences/homes (Table 1).[1] The National Fire Incident Reporting System (NFIRS) found that smoke inhalation was a factor in 85% of all residential fire fatalities between 2013 and 2015. 

Thus, personal injury cases that stem from residential or occupational fires must take into consideration the science behind smoke inhalation. The following article is an overview of the toxic gas produced when combustible materials ignite, how to treat it, and how Emergency Physicians can err in their evaluation and treatment of smoke inhalation victims. 

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Intoxication and ER deaths from Synthetic Cannabinoids

Synthetic cannabinoids are part of a group of drugs called new psychoactive substances (NPS). NPS are unregulated mind-altering substances that have become newly available on the market and are intended to produce the same effects as illegal drugs. Some of these substances may have been around for years but have reentered the market in altered chemical forms, or due to renewed popularity.

Individuals reported acquiring the contaminated synthetic cannabinoid products (i.e., K2, spice, synthetic marijuana, and legal weed) from convenience stores, dealers, and friends, in counties across the state.

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Update on EMTALA Law

Randy Strickland walked into the ER at North Metro Medical Center burning with fever and trembling. He told the nurse at the triage desk that he was nauseated and felt like he needed to throw up. The emergency room was nearly empty. Randy waited in the waiting room, yet repeated visits by his wife and son to the triage desk didn't bring Randy any closer to getting care. Over the next 2 hours, he lost his ability to speak or respond to questions. His breathing became labored. Finally, on a trip to the bathroom, his legs buckled as he held onto his wife and son for support. No one came out to help them so they dialed 911 but were told that the ambulance will not respond to a hospital.The 911 dispatcher told them to get Randy out to his car in the parking lot, where paramedics could pick him up and bring him in the ambulance door of the hospital. 

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