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Cardiovascular toxicology: poisoning, overdose and anaphylaxis

Adult poisoning that injures the heart and circulation: cardiovascular drug overdose, sodium channel and QT toxicity, cocaine and other stimulants, anaphylaxis, and allergic acute coronary syndrome.

Scope of cardiovascular toxicology

Cardiovascular toxicology covers three overlapping problems that a cardiologist is called to manage. The first is poisoning with drugs whose therapeutic target is the heart or vessels: beta-blockers, calcium channel blockers, digoxin, antiarrhythmic drugs, and central alpha-2 agonists such as clonidine. The second is cardiac injury from drugs prescribed for other purposes that block cardiac sodium or potassium channels, including tricyclic antidepressants, antipsychotics, antihistamines, antimalarials, and local anesthetics. The third is the cardiovascular effect of illicit stimulants, chiefly cocaine and methamphetamine, and of systemic allergic reactions, in which mast-cell mediators reach the coronary circulation.

Most of the evidence in this field comes from case series, poison center data, animal models, and expert consensus. The 2017 international consensus on calcium channel blocker poisoning graded every one of its recommendations on very low-quality evidence, and the 2020 systematic review of beta-blocker poisoning treatment judged the risk of bias high for every intervention. Recommendations therefore rest on physiology and accumulated experience, and early consultation with a medical toxicologist or regional poison center (in the United States, 1-800-222-1222) is part of standard care for life-threatening poisoning.

Chronic adverse effects of these drugs at therapeutic doses are covered in drug-induced cardiovascular disease; the pharmacology of each class is covered in its own hub, including calcium channel blockers and digoxin.

Epidemiology of cardiovascular drug poisoning

In 2024, US poison centers logged 2,092,689 human exposures. Cardiovascular drugs were the fourth most common substance class, at 5.12% of all human exposures, behind analgesics, household cleaning products, and antidepressants. Exposures with moderate or major outcomes or death have risen by about 4% per year since 2000, and the class of stimulants and street drugs showed the fastest growth in serious outcomes over the past decade. The National Poison Data System recorded 2,809 deaths after human exposure in 2024, 80.9% of them judged related to the exposure.

Calcium channel blockers carry the highest case fatality among cardiovascular drugs. In 2003, US poison centers recorded 9,650 calcium channel blocker ingestions with 57 deaths, more than one-third of all deaths attributed to cardiovascular drugs that year. In the same year, 15,350 beta-blocker ingestions led to 33 deaths.

The composition of calcium channel blocker poisoning has shifted toward dihydropyridines. In an Australian series of 236 overdoses from 2014 to 2023, amlodipine accounted for 62% of cases, and dihydropyridine overdoses tripled compared with the preceding decade. Diltiazem and verapamil were less common but more lethal. One-third of these patients developed a dysrhythmia, about half of diltiazem overdoses required intensive care, and mortality was 7% after diltiazem and 9% after verapamil, compared with 3% for the whole cohort.

Mechanisms of cardiotoxicity

Most cardiotoxic poisonings act through a small number of molecular targets. The electrocardiogram (ECG) and the bedside glucose often identify the target before the drug is known, and the target determines the antidote.

Molecular targets of cardiotoxic poisoning. Sodium channel and potassium channel blocking drugs follow the 2012 ECG review of poisoning in Current Cardiology Reviews; the clonidine effects follow the Catapres-TTS label.

Poisoning rarely affects one target alone. Propranolol blocks sodium channels as well as beta-receptors, sotalol blocks potassium channels, verapamil and diltiazem block sodium channels at high concentrations, and cocaine combines catecholamine excess with sodium channel blockade. Coingestion is common: in the Australian dihydropyridine series, 82% of hypotensive patients had also taken an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, which removes the renin-angiotensin response that would otherwise defend blood pressure against vasodilation.

Initial assessment, toxicology consultation, and monitoring

Resuscitation proceeds in parallel with identification of the toxin. Airway protection is secured early in patients with depressed consciousness, seizures, or shock, which also permits gastrointestinal decontamination. Continuous ECG monitoring, frequent or arterial blood pressure measurement, and large-bore intravenous or central access are established at presentation.

The history covers the agent, the formulation (immediate-release or sustained-release), the amount, the time of ingestion, coingestants, and whether the ingestion was intentional. Every patient with intentional self-poisoning, or a suspected malicious administration, is referred to an emergency department regardless of the dose reported. Pill counts, pharmacy records, and family or emergency medical services accounts supplement the history, which is often incomplete.

The initial laboratory set includes glucose, electrolytes including potassium, magnesium, and ionized calcium, creatinine, venous or arterial blood gas, lactate, hepatic function, troponin, and serum concentrations of acetaminophen and salicylate. A serum digoxin concentration is obtained when a cardiac glycoside is possible.

Bedside echocardiography separates the two mechanisms of shock that dominate beta-blocker and calcium channel blocker poisoning. A hyperdynamic ventricle with low systemic vascular resistance indicates vasoplegia, treated with vasopressors. A dilated, hypokinetic ventricle indicates cardiogenic shock, treated with inotropic therapy and high-dose insulin, with early discussion of mechanical support. In the Australian dihydropyridine series, 4 of the 8 patients who had echocardiography before high-dose insulin had global left ventricular dysfunction, despite the vasodilatory profile of the class. Pulmonary artery catheterization defines the same phenotypes when echocardiography is inconclusive; hemodynamic profiles are described in right heart catheterization and hemodynamics.

ECG findings in cardiotoxic poisoning

The 12-lead ECG in an undifferentiated poisoning identifies the dominant ion channel effect, predicts complications, and is repeated serially because toxicity evolves with absorption.

ECG findings in poisoning. QRS thresholds from a prospective study of 49 tricyclic antidepressant overdoses (1985); aVR threshold from 79 patients with tricyclic toxicity (1995); QTc risk marker, nomogram, and glycoside rhythms from the 2012 ECG review of poisoning.

The QTc threshold for prolongation is conventionally above 450 ms in men and 470 ms in women. Bazett's correction overestimates the QTc at the fast heart rates that are common in poisoning, so a prolonged QTc in a tachycardic patient overstates the risk of torsades. Measurement technique, rate correction, and the QT nomogram are covered in long QT syndrome and QT prolongation.

Gastrointestinal decontamination: activated charcoal and whole-bowel irrigation

Activated charcoal. The joint position statement of the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists states that single-dose activated charcoal is not given routinely. In volunteer studies with at least 50 g of charcoal, absorption fell by a mean of 47.3% when charcoal was given at 30 minutes, 40.1% at 60 minutes, 16.5% at 120 minutes, and 21.1% at 180 minutes. Charcoal may therefore be considered when a potentially toxic amount of an adsorbable poison was ingested within the preceding hour, and a benefit after one hour cannot be excluded. There is no evidence that charcoal improves clinical outcome, and it is contraindicated unless the airway is intact or protected. The 2017 calcium channel blocker consensus adopted these statements and recommended observation and consideration of decontamination after any potentially toxic ingestion (grade 1D).

Whole-bowel irrigation. Polyethylene glycol electrolyte solution given by nasogastric tube until the rectal effluent is clear can be considered for potentially toxic ingestions of sustained-release or enteric-coated drugs. The approach is particularly relevant when the patient presents more than 2 hours after ingestion, when charcoal is less effective. It is also used for body packers who have swallowed drug packets. Controlled data showing better outcomes are lacking. Whole-bowel irrigation is contraindicated with bowel obstruction, perforation, or ileus, with hemodynamic instability, and with an unprotected airway; the last two contraindications exclude many of the sickest patients with cardiovascular drug poisoning. Charcoal given with whole-bowel irrigation may be less effective, although the clinical relevance of this interaction is uncertain. Verapamil slows gastrointestinal transit, and sustained-release tablets of verapamil and diltiazem can form concretions that prolong absorption.

Observation periods, sustained-release preparations, and delayed toxicity

Sustained-release preparations delay the onset and prolong the duration of toxicity. An asymptomatic patient after the ingestion of a sustained-release calcium channel blocker can deteriorate many hours later, and a normal initial ECG and blood pressure do not exclude serious poisoning.

Observation periods after beta-blocker and calcium channel blocker ingestion. The 2005 out-of-hospital guidelines define the intervals after which an asymptomatic patient is unlikely to develop toxicity; a potentially toxic amount is more than a single therapeutic dose or the lowest reported toxic dose, whichever is lower. Any ingestion of excess beta-blocker with a calcium channel blocker, or by a patient with serious cardiovascular disease, warrants emergency department referral.

In a prospective Australian series of 58 beta-blocker self-poisonings, every patient who developed toxicity did so within 6 hours of ingestion. Sotalol is the exception among beta-blockers: QT prolongation and torsades can appear late, and hypotension can reduce renal clearance and prolong the initial elimination half-life to about 30 hours.

Beta-blocker pharmacology, mechanism of toxicity, and high-risk agents

Mechanism of toxicity. Beta-1 receptor stimulation activates adenylyl cyclase through a stimulatory G protein, raising intracellular cyclic adenosine monophosphate (cyclic AMP). Cyclic AMP activates protein kinase A, which phosphorylates L-type calcium channels and phospholamban. The result is increased calcium entry, sarcoplasmic reticulum calcium uptake, contractility, and relaxation, and a steeper slope of phase 4 depolarization in the sinus node. Beta-blockade reverses each of these effects. In overdose the result is sinus bradycardia, slowed AV conduction with junctional escape or complete heart block, reduced contractility, and hypotension. Hypoglycemia follows from inhibition of hepatic glycogenolysis and gluconeogenesis, and bronchospasm from beta-2 blockade.

Agent properties. The toxicity of a given agent depends on properties beyond beta-blockade. Lipophilic agents (propranolol, metoprolol) cross the blood-brain barrier and cause delirium, coma, and seizures. Membrane-stabilizing activity, which is sodium channel blockade, is greatest with propranolol and produces QRS widening and ventricular arrhythmias. Agents with alpha-1 blocking activity, labetalol and carvedilol, add vasodilation. Intrinsic sympathomimetic activity (pindolol, acebutolol) attenuates bradycardia. Water-soluble agents excreted by the kidney (atenolol, sotalol, nadolol) accumulate in kidney failure and are dialyzable. Selectivity for the beta-1 receptor is lost at toxic doses.

High-risk patients. The interaction of beta-blockade with sympathetic tone explains the patients at greatest risk: those with heart failure, conduction disease, or myocardial infarction, and those who take another negative chronotrope or inotrope. Classification, receptor pharmacology, and pharmacokinetics of individual beta-blockers are covered in beta-blockers.

Propranolol. Propranolol is the most dangerous beta-blocker in overdose because it combines nonselective beta-blockade, high lipid solubility, and sodium channel blockade. In the Australian prospective series, propranolol was the only beta-blocker associated with seizures or death. Two-thirds of patients who ingested more than 2 g had a seizure, and a QRS duration above 100 ms was significantly associated with seizures. Propranolol is not significantly dialyzable, and the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup recommends against extracorporeal treatment for propranolol poisoning. Sodium bicarbonate has uncertain efficacy for propranolol-induced QRS widening, but the sodium channel component is treated like other sodium channel blocker toxicity.

Sotalol. Sotalol combines nonselective beta-blockade with class III potassium channel blockade. The Betapace label lists bradycardia, heart failure, hypotension, bronchospasm, and hypoglycemia as the expected effects, and in massive overdoses of 2 to 16 g, QT prolongation, torsades de pointes, ventricular tachycardia, and asystole. Because sotalol is not protein bound and is eliminated by the kidney, hemodialysis lowers plasma concentrations; EXTRIP suggests dialysis in severe sotalol poisoning with kidney impairment and suggests against dialysis based on the QT interval alone. Torsades from sotalol is treated with magnesium, potassium repletion, and overdrive pacing; QT management is covered under QT prolongation and torsades de pointes.

Atenolol, nadolol, and other water-soluble agents. These agents have little membrane-stabilizing activity and cause less CNS toxicity, but they accumulate in kidney failure. EXTRIP suggests hemodialysis for severe atenolol poisoning with kidney impairment and refractory bradycardia and hypotension.

Carvedilol and labetalol. Alpha-1 blockade adds vasodilation to bradycardia and negative inotropy, and neither drug is dialyzable.

Combined ingestions. In a German poison center series of 2,967 adult beta-blocker exposures, metoprolol was the agent reported most often, and seizures were reported more often with propranolol. There were no deaths after single-substance exposures; the one death followed coingestion of bisoprolol and verapamil.

Calcium channel blocker poisoning: dihydropyridine versus nondihydropyridine

Calcium channel blockers bind the alpha-1 subunit of the L-type voltage-gated calcium channel. In vascular smooth muscle, reduced calcium entry relaxes arterioles and lowers systemic vascular resistance. In the sinus and AV nodes, whose action potentials depend on calcium current, it slows automaticity and conduction. In ventricular myocytes, it reduces the trigger for calcium-induced calcium release and therefore contractility. In pancreatic beta cells, it blocks the calcium-dependent release of insulin, which produces hyperglycemia and leaves the stressed myocardium unable to use glucose.

The three chemical classes differ in tissue selectivity. Dihydropyridines (amlodipine, nifedipine, felodipine, lercanidipine) are vasoselective, and overdose produces vasodilatory hypotension with reflex tachycardia. The amlodipine label describes marked peripheral vasodilation and possibly reflex tachycardia, and notes that dialysis is unlikely to help because the drug is highly protein bound. The phenylalkylamine verapamil and the benzothiazepine diltiazem act on nodal tissue and myocardium as well as vessels, and overdose produces bradycardia, junctional rhythm, AV block, myocardial depression, and vasodilation together. Selectivity is lost at very high doses, so a large dihydropyridine overdose can also depress the myocardium and conduction. Binding sites, selectivity, and pharmacokinetics are covered in calcium channel blockers.

In the Australian series, dysrhythmias occurred in 35% of verapamil and 33% of diltiazem overdoses and in 1% of amlodipine overdoses, mostly junctional rhythms, with second-degree and complete heart block in a few patients. Hypotension and acute kidney injury rose with the dose of every agent. Among amlodipine overdoses requiring cardiovascular support, 90% received norepinephrine and 37% vasopressin, while 6 received high-dose insulin, 3 of whom had also taken a beta-blocker. Other features of calcium channel blocker poisoning include metabolic acidosis with a rising lactate, preserved consciousness despite profound hypotension, and noncardiogenic pulmonary edema after amlodipine, which is described with the class in calcium channel blocker poisoning.

Clinical features of beta-blocker and calcium channel blocker poisoning

Bradycardia and hypotension are shared, and several features separate the two classes at the bedside.

Distinguishing beta-blocker from calcium channel blocker poisoning. Mixed ingestions blur these distinctions, and treatment of shock does not wait for the agent to be identified.

Hyperglycemia in a bradycardic, hypotensive patient suggests calcium channel blocker poisoning, and hypoglycemia suggests beta-blockade. Neither is reliable in isolation: diabetes, stress, catecholamine infusions, and coingestants alter glucose, and coma with hypoglycemia occurs after many sedative overdoses.

Stepwise treatment of beta-blocker and calcium channel blocker shock

Treatment escalates by response and is guided by the hemodynamic phenotype. The 2017 international experts consensus on calcium channel blocker poisoning organized therapy in tiers of increasing severity. The same sequence is applied to beta-blocker poisoning, in which the 2020 systematic review found that catecholamines, vasopressors, high-dose insulin, and VA-ECMO were associated with lower mortality.

2017 experts consensus recommendations for calcium channel blocker poisoning in adults (Crit Care Med 2017). Grade 1 is a recommendation and grade 2 a suggestion; D denotes very low-quality evidence. No agreement was reached on phenylephrine, and glucagon and methylene blue were not recommended or suggested.

The 2023 American Heart Association (AHA) focused update on cardiac arrest and life-threatening toxicity due to poisoning also grades these interventions. Its recommendations for calcium channel blocker poisoning are tabulated with their classes in calcium channel blocker poisoning, and those for beta-blocker poisoning are summarized in beta-blocker overdose.

The tiers are not strictly sequential. The consensus workgroup could not prioritize one first-line therapy over another. It stated that first-line treatments are chosen for the effect needed in the individual patient: calcium and vasopressors for vasoplegia, insulin and inotropes for a failing ventricle, and atropine or pacing for bradycardia, often at the same time. A bolus of 10 to 20 mL/kg of crystalloid over 10 to 15 minutes, continued while the patient remains fluid responsive, is commonly used, although no formal recommendation was made.

Atropine and intravenous calcium for toxin-induced bradycardia and shock

Atropine. Atropine blocks vagal tone and is useful for hemodynamically significant bradycardia, but its effect is limited when bradycardia results from receptor or channel blockade. The 2017 consensus uses 0.5 mg every 3 to 5 minutes for a few doses. Failure of atropine prompts escalation to catecholamines, insulin, and pacing. Acute management of bradycardia, including the current adult atropine dose, is covered in bradycardia and atrioventricular block.

Intravenous calcium. Raising extracellular calcium increases the gradient across partially blocked channels. Case series and animal studies show improved contractility and blood pressure. The regimen used most often in adults with calcium channel blocker poisoning is either 10% calcium chloride or 10% calcium gluconate. Calcium chloride is given as 10 to 20 mL (1 to 2 g) every 10 to 20 minutes or as an infusion of 0.2 to 0.4 mL/kg/h. Calcium gluconate is given as 30 to 60 mL (3 to 6 g) every 10 to 20 minutes or as an infusion of 0.6 to 1.2 mL/kg/h. Each milliliter of 10% calcium chloride contains about 1.4 mEq of elemental calcium and each milliliter of 10% calcium gluconate 0.465 mEq, so the threefold larger gluconate volumes deliver a similar amount of calcium. Calcium chloride is given through central or secure peripheral venous access, and calcium gluconate is chosen to limit peripheral vein irritation. The verapamil label describes hypotension and bradycardia that became responsive to atropine only after large doses of calcium chloride, close to 1 g/h for more than 24 hours.

Calcium is used in beta-blocker poisoning as well, where the evidence is weaker: hemodynamics improved in three of six case reports and in two animal studies, always together with other therapies.

High-dose insulin euglycemia therapy

Mechanism. In shock, the myocardium shifts from fatty acid to carbohydrate metabolism. Calcium channel blockade suppresses insulin release, and beta-blockade impairs glycogenolysis, so the stressed heart is starved of usable fuel. High-dose insulin acts through three mechanisms: a direct positive inotropic effect, increased myocardial glucose uptake and carbohydrate oxidation, and vasodilation of the microcirculation, which improves perfusion. Unlike catecholamines, it does not raise myocardial oxygen demand through tachycardia or increase afterload.

Evidence. Animal models showed survival with high-dose insulin superior to calcium salts, glucagon, epinephrine, and vasopressin. There are no randomized trials in humans. Case series associated insulin with lower mortality in beta-blocker poisoning, and in a consecutive series of 12 patients with toxin-induced cardiogenic shock treated with insulin at 1 to 10 units/kg/h while vasopressors were tapered or avoided, 11 survived. The one death occurred after insulin was stopped and a vasopressor restarted.

Dosing. Regular insulin is given as a bolus of 1 unit/kg, followed by an infusion of 1 unit/kg/h, with dextrose to maintain euglycemia and close monitoring of potassium. The infusion is titrated toward 10 units/kg/h in patients who do not respond to first-line therapy. Early protocols used a 0.5 unit/kg bolus and 0.5 to 1 unit/kg/h. Doses were raised as animal and clinical experience accumulated, and bolus doses up to 10 units/kg and infusions up to 22 units/kg/h have been given with good outcomes. The inotropic effect is not immediate, so insulin is started early and continued while other therapies act.

Glucose and potassium. Dextrose is given with insulin: 25 to 50 g of 50% dextrose initially in adults, adjusted to the measured glucose, followed by an infusion of about 0.5 g/kg/h titrated to frequent glucose measurements. Supplementation is usually required throughout therapy and for 24 hours or longer after insulin is stopped. Hypoglycemia was the most frequent adverse event in the consecutive series (19 episodes in 6 of 12 patients), followed by hypokalemia below 3.0 mEq/L in 8 patients; neither led to lasting harm. The fall in serum potassium reflects a shift into cells, not depletion of total body stores. Volume overload from dextrose and carrier fluid is the other recognized risk.

Dihydropyridines. High-dose insulin is a vasodilator, and its role when shock results from vasoplegia with preserved ventricular function is uncertain. Almost all large-animal studies used verapamil. In an Australian series of 50 hypotensive adults after dihydropyridine overdose, 10 received insulin at a median of 1 unit/kg bolus and 1.25 units/kg/h, mainly for left ventricular dysfunction on echocardiography; those patients were more severely ill and needed more vasopressors. US guidance recommends insulin for life-threatening calcium channel blocker poisoning without distinguishing the classes, whereas in the Australian series vasoplegia was treated with norepinephrine and vasopressin. Echocardiography before and during treatment reconciles the two approaches.

Antidote dose calculator for cardiotoxic poisoning

The calculator converts body weight into the weight-based doses described on this page. Doses of insulin, calcium, and lipid emulsion are those of the 2017 calcium channel blocker consensus. The glucagon dose is the propranolol label regimen; dextrose is the regimen given with high-dose insulin in the ECG review of poisoning; intramuscular epinephrine is the World Allergy Organization dose. All doses apply to adults.

Lipid emulsion at 0.25 mL/kg/min after one 1.5 mL/kg bolus reaches the 12.5 mL/kg daily maximum after 44 minutes, so a 60-minute infusion after one bolus exceeds the maximum. After three boluses the maximum is reached 32 minutes into the infusion. Calcium regimens are expressed as volumes of the 10% solutions; the bolus range is not weight based.

Glucagon, vasopressors, and inotropes in toxin-induced shock

Glucagon. Glucagon activates its own G protein-coupled receptor on cardiomyocytes and raises cyclic AMP without passing through the beta-receptor, which is why it has been used for decades as the antidote for beta-blocker poisoning. The evidence is weak. A systematic review of beta-blocker poisoning treatment found that glucagon was associated with minor hemodynamic improvement, mainly an increase in heart rate, in two case series, nine case reports, and five animal studies. In a multicenter series of 107 patients who received glucagon for suspected beta-blocker toxicity, heart rate rose by a mean of 4 beats/min 20 minutes after the dose, a statistically significant but clinically small change. Adverse effects were infrequent.

The propranolol label gives 50 to 150 µg/kg intravenously, followed by an infusion of 1 to 5 mg/h, for a positive chronotropic effect. Glucagon is one option among several for bradycardia and does not delay high-dose insulin, catecholamines, or pacing. The 2017 consensus did not recommend glucagon for calcium channel blocker poisoning.

Vasopressors and inotropes. The choice of catecholamine follows the hemodynamic phenotype. Norepinephrine is preferred for vasodilatory shock and when ventricular function has not yet been assessed. Epinephrine adds inotropy and chronotropy and is used when contractility and heart rate are both depressed; dobutamine is used for confirmed myocardial dysfunction when blood pressure allows. Doses far above those used in septic shock are often required: in the Australian dihydropyridine series, the median maximum norepinephrine dose was 1.15 µg/kg/min in patients who received insulin, compared with 0.27 µg/kg/min in those who did not.

Vasopressin is not used as the sole vasoactive drug in cardiogenic shock from calcium channel blocker poisoning because it lacked efficacy and worsened survival in animal models. As an adjunct to norepinephrine in vasoplegia it is widely used, but clinical data are limited. Dopamine produced inconsistent hemodynamic improvement in case series and is not suggested. Pharmacology, doses, and infusion calculations for each vasoactive drug are in vasopressors and inotropes.

Catecholamines raise myocardial oxygen demand and afterload. In a heart already depressed by channel blockade, a pure vasoconstrictor can lower cardiac output further. This is the physiologic argument for combining vasopressors with insulin and for early echocardiographic reassessment, and it was the rationale for the insulin protocol that tapered vasopressors in the consecutive case series.

Lipid emulsion, methylene blue, and other rescue therapy for refractory shock

Lipid emulsion. Intravenous lipid emulsion was introduced for local anesthetic systemic toxicity, and its proposed mechanisms are partitioning of lipophilic drugs into an intravascular lipid phase, direct inotropy, and metabolic effects on the myocardium. The 2016 recommendations of an international workgroup address three situations. Lipid is recommended in cardiac arrest from bupivacaine toxicity. As first-line therapy in life-threatening toxicity, the workgroup suggests not using lipid for calcium channel blockers, water-soluble beta-blockers, amitriptyline, bupropion, cocaine, diphenhydramine, lamotrigine, or malathion. When other therapies fail, lipid is suggested for other local anesthetics, amitriptyline, and bupropion, and the workgroup was neutral for all other toxins. Every recommendation rested on very low-quality evidence.

Lipid emulsion has risks. The 2017 consensus cited concern, from an animal model of oral poisoning, that it may increase absorption of drug still in the gut, and it interferes with laboratory analyses. For calcium channel blocker poisoning, the 2017 consensus places lipid in the refractory tier and in cardiac arrest, and the 2023 AHA update recommends against its routine use. The dose most commonly used is a 1.5 mL/kg bolus of 20% emulsion, repeated up to twice until clinical stability, followed by 0.25 mL/kg/min for 30 to 60 minutes, within a maximum of 12.5 mL/kg in 24 hours. Treatment of local anesthetic systemic toxicity, in which lipid is first-line, is covered with other special circumstances in adult cardiac arrest.

Methylene blue and other agents for vasoplegia. Distributive shock from calcium channel blocker poisoning involves activation of nitric oxide synthase and the nitric oxide-cyclic guanosine monophosphate (cyclic GMP) pathway. Dihydropyridines in particular increase endothelial nitric oxide production, and coingestion of renin-angiotensin blockers removes a counter-regulatory pressor system. Methylene blue inhibits guanylate cyclase and nitric oxide synthase and scavenges nitric oxide. It has been used for refractory vasoplegia from sepsis, anaphylaxis, cardiac surgery, and calcium channel blocker poisoning, but evidence is limited to case reports and small series, and the 2017 consensus did not recommend it. Methylene blue is a reversible monoamine oxidase A inhibitor and can precipitate serotonin syndrome with serotonergic drugs, causes hemolysis in glucose-6-phosphate dehydrogenase deficiency, and colors the urine blue-green. High-dose hydroxocobalamin and angiotensin II have been used for the same purpose with even less evidence. Doses and the evidence in other vasoplegic states are described in vasopressors and inotropes.

Cardiac pacing and venoarterial ECMO in toxin-induced shock

Cardiac pacing. Pacing treats bradycardia and AV block but not the vasodilation or myocardial depression that accompany them. In calcium channel blocker poisoning, case series describe frequent failure to capture and hemodynamic improvement mainly in patients whose contractility is preserved. The 2017 consensus therefore suggests pacing for unstable bradycardia or high-grade AV block without significant loss of contractility. Pacing starts transcutaneously and moves to transvenous pacing when transcutaneous capture is effective and the patient remains dependent. When electrical capture does not restore blood pressure, contractility or vascular tone is the limiting factor, and insulin, inotropes, vasopressors, and mechanical support follow. In sotalol poisoning, temporary overdrive pacing prevents pause-dependent torsades. Temporary pacing technique is covered in bradycardia and atrioventricular block.

Venoarterial ECMO and mechanical circulatory support. Cardiotoxic poisoning is a favorable indication for temporary circulatory support. The heart is usually structurally normal, the injury is reversible as the drug is metabolized, and patients are often young. VA-ECMO supplies circulation and gas exchange until drug effects wane.

In a retrospective cohort from two French university hospitals, 62 patients had persistent cardiac arrest or severe shock from drug poisoning. Survival was 86% (12 of 14) with extracorporeal life support and 48% (23 of 48) without it. No patient with persistent cardiac arrest survived without extracorporeal support, and the association persisted after adjustment for severity (adjusted odds ratio for death 0.18).

The 2017 consensus suggests VA-ECMO for refractory cardiogenic or mixed shock with a significant cardiogenic component and in cardiac arrest, in centers where it is available. Because transfer during refractory shock is hazardous, the decision to contact an ECMO center is made early, when shock fails to respond to first-line therapy, not after cardiac arrest. Left ventricular distension on peripheral VA-ECMO in a nonejecting, poisoned heart can require venting. Cannulation, unloading, complications, and weaning are covered in cardiogenic shock. The workgroup was neutral on the microaxial flow pump and other ventricular assist devices because clinical experience was insufficient.

Extracorporeal removal: hemodialysis for atenolol and sotalol

The EXTRIP workgroup has graded the role of dialysis and related techniques for both classes.

EXTRIP recommendations for beta-blocker poisoning (Crit Care 2021) and calcium channel blocker poisoning (Clin Toxicol 2021). When dialysis is used for atenolol or sotalol, intermittent hemodialysis is preferred over other modalities, cessation is based on clinical improvement, and during sotalol dialysis serum magnesium is kept above 1 mmol/L (2.4 mg/dL) and potassium at 4.5 to 5 mEq/L.

The determinants of dialyzability are small molecular size, low protein binding, a small volume of distribution, and limited endogenous clearance. Atenolol and sotalol meet these criteria, especially when kidney function is impaired; propranolol, with high lipid solubility and a large volume of distribution, does not. The calcium channel blockers are highly protein bound, and no clinical data suggest benefit from dialysis. The QT interval can remain prolonged at therapeutic sotalol concentrations, so it is not used as a target for stopping dialysis.

Cardiac arrest from poisoning

High-quality cardiopulmonary resuscitation (CPR) and defibrillation are unchanged in poisoning, and toxin-specific therapies are added to the standard algorithm. In calcium channel blocker poisoning, the 2017 consensus recommends intravenous calcium during arrest, even if calcium has been given before, and lipid emulsion if not yet given, and suggests a further dose of lipid and VA-ECMO where available. In sodium channel blocker toxicity, hypertonic sodium bicarbonate is given for wide-complex arrest. In digoxin poisoning, digoxin immune Fab is the specific treatment.

Arrest from poisoning differs from arrest of cardiac origin in two ways. The cause is often reversible within hours as the drug is cleared, and the heart is often structurally normal, which is the rationale for extracorporeal CPR. In the French cohort, every survivor of persistent arrest from drug poisoning had received extracorporeal support. The 2017 workgroup recognized that a long period of low flow may be associated with worse outcomes but found the evidence unclear on when resuscitation becomes futile, and resuscitation is therefore continued while extracorporeal support is mobilized. Toxin-specific modifications of the arrest algorithm are summarized in adult cardiac arrest, and extracorporeal CPR is covered in the same hub. Care after return of circulation, including asphyxial and toxic arrest, is covered in post-cardiac arrest care.

Digoxin, sodium channel blocker, and QT-prolonging drug poisoning

Digoxin and digoxin immune Fab. Digoxin inhibits the sodium-potassium ATPase. Toxicity combines enhanced automaticity (atrial tachycardia with block, accelerated junctional rhythm, ventricular bigeminy, bidirectional ventricular tachycardia) with impaired sinus and AV nodal conduction. Acute ingestion produces gastrointestinal symptoms and hyperkalemia, which reflects the degree of pump inhibition and predicts death; chronic toxicity occurs at lower concentrations in older patients with declining kidney function, hypokalemia, or interacting drugs such as amiodarone. Digoxin immune Fab is the specific treatment for life-threatening arrhythmia, hemodynamic compromise, or marked hyperkalemia after acute ingestion, and hemodialysis does not remove digoxin. Risk factors, clinical features, Fab indications, and the management of potassium, calcium, and magnesium are covered in digoxin; Fab dosing, with a calculator, is covered in digoxin immune Fab dosing.

Sodium channel blockers. Blockade of the fast sodium channel slows phase 0 of the ventricular action potential. Conduction slows throughout the ventricle, more in the right ventricle, which produces QRS widening, a terminal R wave in aVR with a rightward terminal 40-ms axis, right bundle branch block morphology, and a Brugada pattern. Severe blockade causes hypotension from reduced contractility, sine-wave wide-complex tachycardia that is difficult to distinguish from ventricular tachycardia, bradycardia, and asystole. Tachycardia and acidosis increase sodium channel blockade, so seizures and the metabolic acidosis they cause worsen cardiac toxicity.

The causes include tricyclic antidepressants, class IA and IC antiarrhythmic drugs, cocaine, diphenhydramine, propranolol, carbamazepine, chloroquine and hydroxychloroquine, and bupropion, along with venlafaxine and some antipsychotics in large overdoses. The flecainide label lists extreme QRS widening, PR and QT prolongation, AV block, ventricular tachycardia, asystole, and cardiac arrest after overdose. It notes that hemodialysis does not remove flecainide and warns that the long half-life (12 to 27 hours at usual doses) and nonlinear kinetics at high doses can require prolonged supportive care. Antiarrhythmic drug overdose is described further in antiarrhythmic drugs.

Sodium bicarbonate. Hypertonic sodium bicarbonate is the antidote for toxin-induced sodium channel blockade. The literature supports a raised serum sodium concentration, alkalemia, or both as the mechanism of benefit. A trial of bicarbonate, conventionally an initial bolus of 1 to 2 mEq/kg with ECG monitoring, is given when the QRS exceeds 100 ms. The desired effect is narrowing of the QRS, ideally below 100 ms, and repeated boluses are given for hypotension or ventricular arrhythmia. Bicarbonate has been used for sodium channel blockade from citalopram, cocaine, flecainide, diphenhydramine, propoxyphene, and lamotrigine, and its efficacy is uncertain for bupropion, propranolol, and taxine-containing plants. Sodium, potassium, and arterial pH are monitored during repeated dosing, and a pH above 7.55 is avoided; the hypokalemia that alkalemia causes can worsen QT prolongation.

Arrhythmia management in sodium channel blockade. Other sodium channel blockers, including class IA and IC drugs, worsen toxicity and are avoided. Lidocaine has been used for refractory ventricular arrhythmia. Amiodarone, with its sodium channel, beta-blocking, and QT-prolonging effects, has not been studied in poisoning and is not a preferred agent. Lipid emulsion is suggested for amitriptyline toxicity when other therapies fail. The differential diagnosis of wide-complex tachycardia is covered in ventricular tachycardia.

QT prolongation and torsades de pointes. Blockade of the rapid delayed rectifier potassium current prolongs repolarization, generates early afterdepolarizations, and produces torsades de pointes, typically after a pause and in the presence of bradycardia, hypokalemia, or hypomagnesemia. In overdose, sotalol, dofetilide, class IA drugs, methadone, antipsychotics, citalopram and escitalopram, and macrolide and fluoroquinolone antibiotics are the usual causes, and coingestion of several QT-prolonging drugs adds risk.

Management consists of stopping all QT-prolonging drugs, giving intravenous magnesium for torsades or for a QTc above 500 ms with signs of impending torsades, and correcting potassium. Pause-dependent torsades is prevented by increasing the heart rate with transvenous overdrive pacing or isoproterenol; the sotalol label lists direct-current cardioversion, transvenous pacing, epinephrine, and magnesium sulfate for torsades after sotalol overdose. Drug lists, risk factors, QTc thresholds, and the acute treatment of torsades are covered in long QT syndrome and QT prolongation.

Clonidine and other central alpha-2 agonists

Clonidine stimulates central alpha-2 adrenergic receptors and reduces sympathetic outflow. The clonidine label describes the sequence in overdose: hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased reflexes, and miosis. Large overdoses cause reversible conduction defects or dysrhythmias, apnea, coma, and seizures. Signs generally appear within 30 minutes to 2 hours.

There is no specific antidote. Atropine treats bradycardia, intravenous fluids and vasopressors treat hypotension, and vasodilators treat hypertension. Naloxone may help with respiratory depression, hypotension, or coma, and occasionally causes paradoxical hypertension. Dialysis is unlikely to enhance clearance. After removal of a transdermal system, plasma concentrations persist for about 8 hours and decline slowly over several days, and an ingested patch may be removed with whole-bowel irrigation. Abrupt withdrawal of clonidine causes rebound hypertension, which is covered in hypertensive emergency.

Cocaine pharmacology, epidemiology, and mechanisms of ischemia

Pharmacology. Cocaine blocks presynaptic reuptake of norepinephrine, dopamine, and serotonin, producing a sympathomimetic syndrome of tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, and agitation. It also blocks cardiac sodium channels, an effect amplified by tachycardia and acidosis, and at high doses it widens the QRS and depresses contractility like a class I antiarrhythmic drug. It blocks potassium channels and prolongs the QT interval. When cocaine is taken with alcohol, the liver forms cocaethylene, which intensifies sodium and potassium channel blockade.

Vascular effects. Cocaine increases endothelin-1, impairs nitric oxide-dependent and acetylcholine-induced vasodilation, and activates platelets. The resulting conditions for myocardial ischemia are increased oxygen demand from tachycardia and hypertension, reduced supply from coronary vasoconstriction, and thrombosis from platelet activation and a prothrombotic state, superimposed in chronic users on accelerated atherosclerosis.

Methamphetamine and synthetic cathinones. These drugs produce the same acute syndrome through release of catecholamines from nerve terminals. Acute management is the same as for cocaine.

Epidemiology and infarction risk. Cocaine use is common among young adults presenting with chest pain. In 2016, an estimated 18.2 million people worldwide used cocaine, about one-third of them in North America. Cocaine was implicated in about 40% of US emergency department visits related to drug misuse in the period covered by a 2019 review of cocaine and cardiovascular health.

In a prospective multicenter study of 246 patients with cocaine-associated chest pain in six US emergency departments, 5.7% had myocardial infarction by creatine kinase MB (CK-MB) criteria. The patients were young (median age 33 years), and most were male (71.5%) and smokers (83.3%). Chest pain began a median of 60 minutes after cocaine use. No clinical feature separated patients with infarction from those without, and an ischemic ECG had a sensitivity of only 35.7% for infarction. In population and cohort studies summarized in the 2019 review, cocaine use was associated with myocardial infarction and acute coronary syndrome in younger adults, with associations that weakened after adjustment for smoking and other behaviors.

Coronary vasospasm and thrombosis. In 29 patients undergoing catheterization for chest pain (16 others received saline), intranasal cocaine at 2 mg/kg, close to the dose used for topical anesthesia, raised heart rate and blood pressure and reduced coronary sinus blood flow. It narrowed the left coronary artery by 8% to 12%, with the same response in patients with and without coronary disease. The alpha-adrenergic blocker phentolamine returned all values to baseline, establishing that the vasoconstriction is mediated by alpha-adrenergic stimulation. Myocardial oxygen demand therefore rises while supply falls.

Thrombosis is the second mechanism. In chronic users, accelerated atherosclerosis, left ventricular hypertrophy, and coronary aneurysms add a fixed substrate: coronary artery aneurysms were found in 30.4% of cocaine users undergoing angiography, compared with 7.6% of nonusers.

Evaluation of cocaine-associated chest pain: ECG, troponin, and observation

ECG. Abnormal ECGs are reported in 56% to 84% of patients with cocaine-associated chest pain. In a matched comparison of patients aged 18 to 35 years with controls, the frequency of ECG diagnoses did not differ, and J-point and ST elevation from early repolarization accounted for many of the abnormal tracings. The ECG is therefore neither sensitive nor specific for infarction in this population: in the multicenter cohort, its positive predictive value was 17.9% and its negative predictive value 95.8%. ST elevation that meets criteria for ST-elevation myocardial infarction (STEMI) is still managed as STEMI, and comparison with prior tracings and serial ECGs separates early repolarization from evolving infarction.

Troponin. Baseline ECG abnormalities and marker elevations not caused by myocardial necrosis, including creatine kinase (CK) from skeletal muscle injury, make infarction difficult to diagnose after cocaine use. In 246 admitted patients, troponin I identified necrosis with diagnostic accuracy equivalent to CK-MB, and 86% of troponin-positive patients who underwent angiography had significant coronary disease. Cardiac troponin is the biomarker of choice; high-sensitivity assays and rapid rule-out pathways are discussed in non-ST-elevation acute coronary syndrome.

Observation. In a prospective study of 302 patients at low to intermediate risk who were managed in a chest pain observation unit, discharge after 9 to 12 hours without ischemic ECG changes, troponin elevation, or cardiovascular complications was safe. No patient died of a cardiovascular cause within 30 days, and nonfatal infarction occurred in 4 of 256 patients with follow-up (1.6%), all of whom had continued to use cocaine.

Differential diagnosis. Chest pain after cocaine also arises from aortic dissection, which is described under aortic dissection after cocaine, and from noncardiac thoracic causes. CT angiography is obtained when the pain, pulse deficits, or a blood pressure differential suggest dissection.

Treatment of cocaine toxicity: benzodiazepines, nitrates, phentolamine, and cooling

Benzodiazepines. Benzodiazepines are the first-line treatment of cocaine toxicity. They reduce central sympathetic outflow and thereby lower heart rate, blood pressure, agitation, and temperature, and they treat seizures. In a randomized, double-blind trial of 40 patients with potential cocaine-associated acute coronary syndrome, diazepam, nitroglycerin, and the combination relieved chest pain to a similar degree, and the combination offered no advantage over either drug alone. Doses are repeated and titrated to calm the patient, with airway monitoring.

Nitroglycerin and phentolamine. Nitroglycerin relieves cocaine-induced coronary vasoconstriction and lowers blood pressure, and it is given for chest pain and hypertension. Phentolamine, a nonselective alpha-adrenergic antagonist, reversed cocaine-induced coronary vasoconstriction in the catheterization studies and is used in small intravenous doses for hypertension or ischemia that persist after a benzodiazepine and a nitrate.

Calcium channel blockers. A dihydropyridine such as nicardipine lowers blood pressure without blocking beta-receptors, and nondihydropyridine calcium channel blockers relieve coronary vasospasm. These agents are used for persistent hypertension after benzodiazepines. The management of severe hypertension from sympathomimetic drugs, including drug choice and blood pressure targets, is covered in hypertensive emergency.

Antiplatelet therapy. Aspirin is given to patients with suspected acute coronary syndrome after cocaine use, as in other patients, unless the evaluation suggests aortic dissection or intracranial hemorrhage.

Hyperthermia and rhabdomyolysis. Hyperthermia, rhabdomyolysis, aortic dissection, intracranial hemorrhage, and myocardial infarction are sought in every patient with severe sympathomimetic toxicity. Benzodiazepines lower temperature by controlling agitation, and external cooling, sedation, and intubation are added when agitation cannot be controlled. Rhabdomyolysis is treated with intravenous fluids, with monitoring of potassium and kidney function, and it contributes to the CK elevation that confounds the diagnosis of infarction.

Beta-blockers after cocaine: the unopposed alpha controversy

The concern that beta-blockade worsens cocaine toxicity rests on physiology and a small number of studies. When catecholamine levels are high, blockade of vasodilating beta-2 receptors leaves alpha-1–mediated vasoconstriction unopposed. In a randomized, double-blind catheterization study of 30 patients, intracoronary propranolol after intranasal cocaine further reduced coronary sinus blood flow and increased coronary vascular resistance without changing blood pressure. The authors concluded that beta-blockers should probably be avoided in cocaine-associated ischemia. Animal studies and case reports of worsened hypertension supported the same conclusion.

Clinical outcome data point in the other direction. Retrospective cohorts of patients with chest pain and positive cocaine toxicology found no excess of myocardial infarction, ventricular arrhythmia, or death with beta-blockers. A 2018 meta-analysis of five studies with 1,794 patients found no significant difference in myocardial infarction (odds ratio 1.36) or all-cause mortality (odds ratio 0.68). These retrospective data carry confounding by indication and cannot settle the question.

US guidance therefore advises against beta-blockers in patients with acute coronary syndrome who show signs of acute cocaine or methamphetamine intoxication (euphoria, tachycardia, or hypertension). It accepts a combined alpha- and beta-blocker for hypertension or tachycardia after a vasodilator has been given. The class of recommendation and the guideline statements are given in non-ST-elevation acute coronary syndrome and in hypertensive emergency. The restriction applies to the period of acute intoxication; a beta-blocker indicated for heart failure with reduced ejection fraction or after myocardial infarction is started once intoxication has resolved.

Labetalol and carvedilol. Labetalol combines alpha-1 and nonselective beta-blockade, but beta-blockade predominates: the label estimates the ratio of alpha- to beta-blockade at about 1:3 after oral and 1:7 after intravenous administration. Carvedilol has equipotent alpha-1 blocking activity in both enantiomers and nonselective beta-blocking activity in one. Neither drug eliminates the theoretical concern, because their beta effect exceeds their alpha effect, and they are used for persistent hypertension or tachycardia after benzodiazepines and vasodilators.

Cocaine-associated myocardial infarction, aortic dissection, and arrhythmias

Myocardial infarction and reperfusion. In a retrospective study of 130 patients with cocaine-associated myocardial infarction at 29 US hospitals, patients had a mean age of 38 years, 91% smoked tobacco, and 88% had used cocaine in the preceding 24 hours. Infarcts were evenly divided between anterior (45%) and inferior (44%) locations, and most were non-Q-wave (61%). Complications occurred in 36%, including ventricular tachycardia, bradyarrhythmia, heart failure, and supraventricular tachycardia, and 90% of patients with complications had them within 12 hours of presentation. In-hospital mortality was 0%.

Reperfusion follows the same criteria as in other patients with STEMI, and primary percutaneous coronary intervention (PCI) is preferred because angiography distinguishes thrombotic occlusion from vasospasm and because early repolarization in young users can mimic ST elevation. When primary PCI is not available in time, fibrinolysis follows the standard indications and contraindications, and severe hypertension and aortic dissection are excluded first. Choice of stent and duration of dual antiplatelet therapy take account of adherence and continued drug use; these choices are discussed in non-ST-elevation acute coronary syndrome. ECG criteria and the management of STEMI are in ST-elevation myocardial infarction.

Aortic dissection. In the International Registry of Acute Aortic Dissection, cocaine use was documented in 1.8% of 3,584 patients enrolled from 1996 to 2012: 1.4% of type A and 2.4% of type B dissections. Cocaine users were younger, more often male and Black, and more often tobacco users. A history of hypertension was no more frequent, although patients with cocaine-related type B dissection were more often hypertensive at presentation. Type B dissection was proportionally more common than in other patients. Cocaine-related dissection was reported mainly at US sites. In-hospital mortality for cocaine-related type A dissection was lower than for type A dissection from other causes, a difference attributed to the younger age of the patients. Management is covered in acute aortic syndromes.

Arrhythmias. Sinus tachycardia is nearly universal. Supraventricular tachycardia, atrial fibrillation, ventricular ectopy, ventricular tachycardia, and ventricular fibrillation occur from catecholamine excess, ischemia, and sodium and potassium channel blockade. Wide-complex tachycardia after cocaine use may represent sodium channel blockade, and hypertonic sodium bicarbonate is used as for other sodium channel blockers. Lidocaine is included in reviews of cocaine-induced dysrhythmia, and amiodarone has not been studied in poisoning. QRS and QT prolongation follow large doses. Bradyarrhythmia occurred in 26 of 130 patients with cocaine-associated infarction.

Chronic cocaine and methamphetamine cardiomyopathy, atherosclerosis, and secondary prevention

Chronic cocaine use is associated with left ventricular hypertrophy, myocardial fibrosis, dilated cardiomyopathy, myocarditis with contraction band necrosis, and accelerated coronary atherosclerosis. In cohort studies summarized in the 2019 review of cocaine and cardiovascular health, cocaine users had higher prevalence of coronary calcium, coronary stenosis, and carotid plaque, and higher cardiovascular and all-cause mortality, although several associations weakened after adjustment for smoking and other behaviors. Methamphetamine-associated heart failure is increasing in prevalence, affects men predominantly, and has preserved ejection fraction in up to 44% of patients. Female sex, abstinence, and guideline-directed therapy are associated with recovery, and chamber dimensions on echocardiography and fibrosis on biopsy predict how much the ventricle recovers after abstinence. Methamphetamine also causes pulmonary arterial hypertension. These chronic effects are covered in drug-induced cardiovascular disease.

Abstinence is the most effective secondary prevention. In the observation unit study, every recurrent myocardial infarction within 30 days occurred in a patient who continued to use cocaine. Counseling and referral for treatment of stimulant use disorder are part of discharge after any cocaine-related cardiovascular event, together with smoking cessation, because most patients also smoke. Standard secondary prevention, including antiplatelet therapy and statins, is given after infarction from cocaine as after any infarction, and a beta-blocker indicated after infarction is started once the patient is no longer intoxicated.

Anaphylaxis: cardiovascular manifestations, epinephrine, and patients taking beta-blockers

Anaphylaxis is a serious systemic hypersensitivity reaction that is usually rapid in onset and may cause death. The World Allergy Organization defines severe anaphylaxis by potentially life-threatening compromise of the airway, breathing, or circulation, and notes that it may occur without typical skin features or circulatory shock. Skin signs are absent in 10% to 20% of reactions, which delays recognition. The global incidence is 50 to 112 episodes per 100,000 person-years, and the estimated lifetime prevalence is 0.3% to 5.1%.

World Allergy Organization 2020 amended criteria: anaphylaxis is highly likely when either criterion is fulfilled. The 2023 US practice parameter update also revised the diagnostic criteria.

Cardiovascular manifestations. Mast-cell and basophil mediators (histamine, tryptase, chymase, platelet-activating factor, leukotrienes, and prostaglandins) cause arterial and venous dilation, increased capillary permeability with rapid loss of intravascular volume, and reduced venous return. Mast cells reside in the myocardium and in the intima and adventitia of the coronary arteries, so the heart is a target organ: coronary vasospasm, myocardial depression, arrhythmias, and acute coronary syndromes occur. Shock in anaphylaxis is therefore distributive and hypovolemic, sometimes with a cardiogenic component. Myocardial infarction can occur during anaphylaxis and is also in the differential diagnosis.

Diagnosis. Serum tryptase rises from about 15 minutes to 3 hours after onset and peaks at 1 to 2 hours; a normal level does not exclude anaphylaxis. Baseline tryptase is measured at least 24 hours after resolution, and a peak above 1.2 times baseline plus 2 ng/mL supports acute mast-cell activation.

Epinephrine. Intramuscular epinephrine is the first treatment. The dose for adults and teenagers is 0.01 mg/kg of the 1 mg/mL solution to a maximum of 0.5 mg, injected into the anterolateral thigh and repeated every 5 to 15 minutes if symptoms persist. Intravenous bolus epinephrine can cause fatal arrhythmias and is not used for initial treatment. When the reaction is refractory to intramuscular doses, epinephrine is given as a titrated intravenous infusion in a monitored setting, with intravenous crystalloid for volume loss. Glucocorticoids are commonly given to prevent protracted or biphasic reactions, but evidence of benefit is lacking and their routine use is controversial; antihistamines treat cutaneous symptoms and do not replace epinephrine. About half of biphasic reactions occur within 6 to 12 hours, and patients with severe reactions are observed. Epinephrine in anaphylactic shock and the management of refractory distributive shock are covered in vasopressors and inotropes.

Anaphylaxis in patients taking beta-blockers. Beta-blockers and angiotensin-converting enzyme inhibitors have been associated with more severe allergic reactions, although the effect is not fully established. Beta-blockade blunts the beta-adrenergic effects of epinephrine, and epinephrine may be less effective in patients taking beta-blockers.

Intravenous glucagon is used in anaphylaxis that does not respond to epinephrine, particularly in patients taking beta-blockers, although the evidence is very limited. Its cyclic AMP-raising effect does not depend on the beta-receptor.

The 2023 US practice parameter update concludes that for most medical indications, the risk of stopping or changing a beta-blocker or angiotensin-converting enzyme inhibitor may exceed the risk of more severe anaphylaxis if the medicine is continued. This holds especially in patients with insect sting anaphylaxis. A beta-blocker prescribed for coronary disease, heart failure, or arrhythmia is therefore continued in most patients with a history of anaphylaxis, after a discussion of the risks with the patient.

Kounis syndrome: definition, epidemiology, and types I to IV

Kounis syndrome is an acute coronary syndrome caused by an allergic, hypersensitivity, anaphylactic, or anaphylactoid reaction. The same mediators that produce anaphylaxis act on the coronary arteries, where they cause vasospasm, erode or rupture atherosclerotic plaque, or trigger thrombosis of a stent or graft. The concept of allergic angina was incorporated into the spectrum of dynamic coronary obstruction in 1998.

Epidemiology. In the first prospective emergency department study, from Turkey, the incidence was 19.4 cases per 100,000 admissions, and Kounis syndrome accounted for 3.4% of patients presenting with allergic reactions. In a US analysis of 235,420 hospitalizations for anaphylactic or hypersensitivity reactions between 2007 and 2014, Kounis syndrome was identified in 1.1%, and in-hospital mortality was 7%, compared with 0.4% in patients without it. In a prospective Greek study of 200 patients with type I hypersensitivity reactions, myocardial injury was found in 12%, and half of these cases (6% of the cohort) were attributed to Kounis syndrome. Reported patients have a mean age of about 54 years, and 64% to 74% are men. Only 10% to 31% have a prior history of allergy.

Types I, II, III, and IV. The four types differ in mechanism, coronary substrate, and outcome.

Subtypes of Kounis syndrome. Frequencies from pooled reviews of published cases (155 to 350 cases per review), summarized in the 2026 review of allergic acute coronary syndromes; in the 2017 review of 175 cases, 72.6% were type I, 22.3% type II, and 5.1% type III, and mortality was 2.9%.

The types are not fixed. Vasospasm and thrombosis can coexist in the same event, and a patient who presents with type I physiology can progress to plaque rupture. Each type is further classified by the presence or absence of myocardial necrosis, as allergic unstable angina or allergic myocardial infarction.

Kounis syndrome: mast-cell mediators, triggers, presentation, and diagnosis

Mast-cell activation. The best-known pathway is immunoglobulin E (IgE)-mediated: after sensitization, allergen cross-links IgE on the high-affinity receptor of mast cells and triggers degranulation. IgE-independent pathways explain reactions on first exposure and in nonatopic patients. These include complement anaphylatoxins, immunoglobulin G (IgG)-mediated activation, and direct stimulation of the mast-cell receptor Mas-related G protein-coupled receptor X2 (MRGPRX2) by opioids, fluoroquinolones, vancomycin, neuromuscular blocking agents, and several anesthetics. All pathways converge on a rise in intracellular calcium and the release of histamine, tryptase, chymase, platelet-activating factor, leukotrienes, prostaglandins, and cytokines.

Mediators by type. In type I, histamine (through H1 receptors), leukotrienes, thromboxane, platelet-activating factor, and angiotensin II generated by chymase contract coronary smooth muscle. In type II, tryptase and chymase activate matrix metalloproteinases that degrade the fibrous cap, and the inflammatory and prothrombotic mediators convert a stable plaque into a ruptured or eroded one. Mast cells accumulate in the culprit region before plaque rupture even in acute coronary syndromes without an allergic trigger, which links the allergic syndrome to the biology of ordinary infarction.

Laboratory confirmation. Serum tryptase is the most specific marker of mast-cell activation. Normal tryptase is below 11.5 ng/mL, and a rise of at least 20% plus 2 ng/mL above baseline is the preferred dynamic criterion. Tryptase is elevated in 80.6% to 87.7% of tested patients with Kounis syndrome. Histamine peaks within 1 to 5 minutes and has a half-life of about 8 to 30 minutes, so it is rarely captured, and morphine given before sampling confounds the measurement. Total IgE is elevated in about three-quarters of tested patients and eosinophilia in about half, but neither establishes causation, and negative IgE tests do not exclude the syndrome because IgE-independent pathways are common. Cardiac troponin is elevated in 60.6% to 78.1% of adults.

Triggers. A trigger is identified in 93.7% of reported cases. Drugs account for about 44%, and antibiotics are the leading class: amoxicillin accounts for nearly 40% of antibiotic-related cases, and ceftriaxone is the most frequently reported cephalosporin. Nonsteroidal anti-inflammatory drugs tend to affect younger patients, and contrast media older patients. Iodinated contrast is among the most commonly reported triggers and one of the most severe. In contrast-triggered cases, cardiac arrest occurred in 23.1% and death in 7.7%, and pulseless electrical activity and asystole are more frequent than ventricular fibrillation. Gadolinium and ultrasound microbubble contrast agents have also been implicated.

Other triggers include insect stings, foods, environmental allergens, anesthetic agents and neuromuscular blockers during surgery, and the metals and polymers of stents and other implanted devices. Several drugs used to treat acute coronary syndrome, including aspirin, clopidogrel, heparin, epinephrine, and corticosteroids, have themselves been reported as triggers. Allergic reactions account for about 3% to 4% of perioperative coronary spasm.

Presentation. Chest pain is the predominant symptom (59.1% to 86.8%), with dyspnea in 30.6% to 52.4%. Rash, urticaria, or pruritus is documented in no more than 30% of adults, so the allergic component can be missed. Hypotension occurs in up to 70% and anaphylactic shock in 15% to 33%. ST elevation is the dominant ECG pattern (43% to 76%), most often inferior, and ventricular fibrillation occurs in about 10%. Echocardiography shows regional wall-motion abnormalities in 50% to 79% of patients, and these recover in up to 92.9%.

Diagnosis. The diagnosis rests on the temporal association of an allergic reaction with an acute coronary syndrome, supported by tryptase and confirmed by coronary anatomy. Coronary angiography is performed in most patients and is the means of distinguishing the subtypes. Angiographically normal or nonobstructive coronary arteries are found in 42% to 55%, and critical stenosis or thrombotic occlusion, mainly in types II and III, in 32% to 42%. Epicardial spasm is visualized in only 10% to 16% of angiograms, because spasm resolves before angiography, responds to vasodilators already given, or involves the microcirculation. Angiography is not delayed in patients with risk factors, persistent symptoms, ongoing ECG changes, or hemodynamic instability.

Intracoronary imaging distinguishes rupture, erosion, and spasm, and in type III, aspiration of stent thrombus with histologic examination for eosinophils and mast cells is the diagnostic standard. Patch testing for stent metals supports hypersensitivity in type III. Cardiac magnetic resonance imaging (MRI) in type I shows edema and early gadolinium enhancement without late enhancement, a pattern of reversible ischemic injury. It distinguishes Kounis syndrome from myocarditis and takotsubo syndrome, both of which are in the differential diagnosis of myocardial injury during anaphylaxis. Coronary CT angiography can exclude obstructive disease in younger, stable, low-risk patients. Provocation testing with acetylcholine after recovery can identify inducible epicardial or microvascular spasm. The evaluation of myocardial infarction with nonobstructive coronary arteries is covered in non-ST-elevation acute coronary syndrome.

Treatment of Kounis syndrome, including type III stent thrombosis

Treatment addresses the allergic reaction and the acute coronary syndrome at the same time, and several standard drugs for each can worsen the other.

Allergic reaction. The trigger is removed. Intravenous corticosteroids (hydrocortisone 1 to 2 mg/kg/day or methylprednisolone 80 to 125 mg) and H1 and H2 antihistamines given slowly are used in most reported cases. In type I without anaphylactic shock, anti-allergic therapy alone may resolve symptoms and ECG changes.

Epinephrine. Intramuscular epinephrine, 0.3 to 0.5 mg in adults, is indicated for anaphylaxis or anaphylactic shock despite coronary ischemia, because untreated anaphylaxis is lethal. Epinephrine can aggravate ischemia and vasospasm and activates platelets, and bypass graft thrombosis and stent thrombosis have been reported after its administration, but a temporal association alone does not establish causation. Epinephrine was used in 18% to 36% of unselected reported cases. It may be less effective in patients taking beta-blockers, who may benefit from intravenous glucagon.

Vasodilators. Intravenous nitroglycerin, started at 5 to 10 µg/min and increased by 10 µg/min every 5 minutes, and intravenous verapamil or diltiazem relieve vasospasm in hemodynamically stable patients. Nitrates are withheld when anaphylaxis has caused hypotension, because they worsen it. Spasm visualized at angiography responds to intracoronary nitroglycerin or a calcium channel blocker. Long-term vasodilators have not been shown to prevent recurrence.

Opioids and beta-blockers. Morphine, codeine, and meperidine promote mast-cell degranulation and are avoided for chest pain. Beta-blockers are avoided in type I because they may worsen spasm by leaving alpha-adrenergic vasoconstriction unopposed and blunt the response to epinephrine.

Coronary therapy. Type II is treated as an acute coronary syndrome with antiplatelet therapy, anticoagulation, and revascularization, and type III as stent thrombosis with thrombus aspiration and histologic examination of the aspirate. PCI is required in about 22% to 31% of adults. Antithrombotic agents are chosen with knowledge that some of them can be the trigger. Complement-mediated reactions to intravenous agents may be attenuated by premedication with antihistamines and corticosteroids and by slower infusion. After recovery, allergy evaluation identifies the culprit, and the patient carries an epinephrine autoinjector and avoids the trigger.

Type III Kounis syndrome and stent thrombosis. Type III Kounis syndrome is stent thrombosis (IIIa) or in-stent restenosis (IIIb) caused by hypersensitivity. The trigger is either an external allergen in a patient with a stent or a component of the stent itself: the metal strut, the polymer, or the eluted drug. It was first described as a separate category in 2010 and divided into its two subgroups in 2017. Patients are older, predominantly male, and more likely to present with STEMI. Reported mortality is the highest of the subtypes, up to 18%, reflecting abrupt occlusion, extensive ischemia, cardiogenic shock, and malignant arrhythmias.

The diagnostic standard is histologic examination of aspirated thrombus, which shows eosinophil and mast-cell infiltration. Cutaneous patch testing can identify sensitization to the metallic components of the stent. The proportion of type III cases among reported Kounis syndrome has risen with wider use of intracoronary imaging and thrombus histology. Type III Kounis syndrome is part of the differential diagnosis of early or late stent thrombosis without an obvious mechanical cause, particularly when it follows a new drug, contrast, or another allergic exposure, or when eosinophilia is present. General management of stent thrombosis and antiplatelet therapy are covered in dual antiplatelet therapy.

Disposition, prognosis, and follow-up after cardiotoxic poisoning

Disposition. Patients with a potentially toxic ingestion of a cardiovascular drug are observed with continuous ECG monitoring for the intervals in the observation table, which are longest for sustained-release verapamil and for sotalol. Patients with bradycardia, hypotension, conduction delay, QT prolongation, or a need for vasoactive drugs are admitted to intensive care. The duration of treatment matches the duration of drug effect: high-dose insulin infusions in the consecutive series lasted a mean of 23.5 hours, and dextrose was still needed after insulin stopped, with wide variation between patients. In the Australian calcium channel blocker series, the median hospital stay was 21 hours overall and 39 hours after diltiazem. Patients who need escalating support are transferred early to a center with ECMO.

Prognosis. Mortality from calcium channel blocker overdose was 3% overall, 7% after diltiazem, and 9% after verapamil in the Australian series. Propranolol was the only beta-blocker associated with death in the prospective Australian beta-blocker series, and combined ingestions carry additional risk. Acute kidney injury occurred in 21% of calcium channel blocker overdoses, and digital necrosis after high-dose norepinephrine was reported in the high-dose insulin series. Anoxic brain injury follows cardiac arrest before effective support. Cocaine-associated myocardial infarction carries low in-hospital mortality, and late outcome depends on whether drug use continues. Kounis syndrome type I usually recovers completely, while type III carries the highest mortality.

Follow-up. After intentional overdose, psychiatric assessment is completed before discharge, and the cardiovascular regimen is reviewed to reduce access to drugs that are lethal in overdose. Propranolol is avoided in patients at risk of self-poisoning. Ventricular function is reassessed when myocardial depression was present. The underlying indication for the poisoning drug is reconsidered: for example, a beta-blocker prescribed after infarction or for heart failure is resumed once the patient is stable. After anaphylaxis or Kounis syndrome, the patient is referred for allergy evaluation and given an epinephrine autoinjector.

Sources of error in cardiovascular toxicology

• Discharging a patient with a normal initial examination after ingestion of sustained-release verapamil or diltiazem. Toxicity can begin many hours later; the 2005 guideline considers symptoms unlikely only after 24 hours for sustained-release verapamil and 18 hours for other sustained-release calcium channel blockers.
• Attributing bradycardia and hypotension to one drug without measuring glucose. Hyperglycemia favors calcium channel blockade, hypoglycemia favors beta-blockade, and a serum digoxin concentration excludes cardiac glycosides.
• Reserving high-dose insulin as a last resort. Its inotropic effect is not immediate, so it is started early, alongside other first-line therapy, in life-threatening poisoning with myocardial dysfunction.
• Treating every calcium channel blocker overdose with the same drug. Dihydropyridine vasoplegia with a hyperdynamic ventricle responds to norepinephrine and vasopressin; a depressed ventricle responds to insulin and inotropes. Echocardiography distinguishes them.
• Stopping dextrose when insulin is stopped. Hypoglycemia can recur for 24 hours or longer afterward.
• Interpreting hypokalemia during high-dose insulin as potassium depletion. The fall in potassium is an intracellular shift.
• Giving repeated lipid emulsion boluses without tracking the total. The 12.5 mL/kg daily maximum is reached 44 minutes into a 0.25 mL/kg/min infusion after one bolus.
• Requesting hemodialysis for propranolol, amlodipine, diltiazem, or verapamil poisoning. None is dialyzable; atenolol and sotalol are the exceptions.
• Treating wide-complex tachycardia from sodium channel blocker poisoning with procainamide or another class IA or IC drug. Hypertonic sodium bicarbonate is the treatment.
• Waiting for cardiac arrest before contacting an ECMO center. Transfer in refractory shock is hazardous, and the decision is made when first-line therapy fails.
• Diagnosing myocardial infarction after cocaine use from ST elevation of early repolarization or from an elevated CK. Serial ECG comparison and troponin are the reliable measures.
• Giving a beta-blocker to a patient with active signs of cocaine intoxication, or withholding one indefinitely after intoxication has resolved when it is indicated for heart failure or after infarction.
• Missing aortic dissection in a young patient with chest pain after cocaine use. Pain with pulse deficits or a blood pressure differential calls for CT angiography.
• Withholding epinephrine from a patient with anaphylactic shock and ST elevation. Anaphylaxis is the immediate threat, and epinephrine remains indicated in Kounis syndrome with anaphylaxis.
• Treating chest pain in Kounis syndrome with morphine, which releases histamine, or with nitrates in a hypotensive patient.
• Stopping a beta-blocker indefinitely because of a history of anaphylaxis. For most cardiac indications, continuing the beta-blocker carries less risk.

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