Cardiac Glycoside Plant Poisoning

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Practice Essentials

Cardiac glycosides are found in a diverse group of plants including the following[1] :

In addition, the venom gland of cane toad (Bufo marinus) contains large quantities of a purported aphrodisiac substance that has resulted in cardiac glycoside poisoning.[2]



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The plant shown is foxglove (Digitalis purpurea), which contains cardiac glycosides, not tropane alkaloids. © 2000 Richard Wagner

Ancient Egyptians and Romans first used plants containing cardiac glycosides medicinally as emetics and for heart ailments. Toxicity from herbal cardiac glycosides was well recognized by 1785, when William Withering published his classic work describing therapeutic uses and toxicity of foxglove, D purpurea.[3]

Therapeutic use of herbal cardiac glycosides continues to be a source of toxicity today. For example, human toxicity resulted when D lanata was mistakenly substituted for plantain in herbal products marketed to cleanse the bowel. Cardiac glycosides have been also found in Asian herbal products and have been a source of human toxicity.

Toxicity may occur after consuming teas brewed from plant parts or after consuming leaves, flowers, or seeds from plants containing cardiac glycosides. Significant toxicity usually is a result of suicide attempt or inappropriate self-administration for the therapeutic purposes.

See 11 Common Plants That Can Cause Dangerous Poisonings, a Critical Images slideshow, to help identify plant reactions and poisonings.

For patient education information, see the First Aid and Injuries Center, as well as Poisoning, Drug Overdose, and Activated Charcoal.

Pathophysiology

More than 200 naturally occurring cardiac glycosides have been identified. These bind to a site on the cell membrane, producing reversible inhibition of the sodium (Na+)-potassium (K+)-adenosine triphosphatase (ATPase) pump. This increases intracellular sodium and decreases intracellular potassium.

In myocytes, elevated intracellular sodium concentrations produce increased intracellular calcium concentrations via an Na+ -calcium (Ca++)-exchanger. In response to the increased intracellular calcium, the sarcoplasmic reticulum releases additional calcium intracellularly, resulting in depolarization of the cell.

As a result of this excessive intracellular calcium, enhanced cardiac contractions, which are delayed after depolarizations, occur. These clinically manifest as aftercontractions, such as premature ventricular contractions (PVCs). Cardiac glycosides also have vagotonic effects, resulting in bradycardia and heart block. Inhibition of Na+ -K+ -ATPase in skeletal muscle results in increased extracellular potassium and contributes to hyperkalemia.

Cardiac glycosides primarily affect cardiovascular, neurologic, and gastrointestinal systems. Of these, effects on the cardiac system are most significant. The pathophysiology that produces cardiotoxicity involves prolonging refractory period in atrioventricular (AV) node, shortening refractory periods in atria and ventricles, and decreasing resting membrane potential (increased excitability).

At therapeutic doses, cardiac glycosides also may increase inotropy. Any dysrhythmia characterized by both increased automaticity and depressed conduction is suggestive of cardiac glycoside toxicity.

Sinus rhythm with PVCs is the most common rhythm associated with digoxin toxicity. Other dysrhythmias often associated with cardiac glycoside toxicity include the following:

Dysrhythmias characterized by increased automaticity and conduction blockade, when combined, are highly suggestive of cardiac toxicity. These dysrhythmias include the following:

More than a single dysrhythmia may be present. Progression into a rapidly life-threatening rhythm, such as ventricular tachycardia, may occur abruptly.

Etiology

Exposure to plants containing glycosides can occur through ingestion of sap, berries, leaves, blossoms, or seeds, or of teas brewed from plant parts. Plant extracts also have been intentionally injected. Other implicated routes of exposures, perhaps more folkloric than well documented, include drinking water from a vase that has held lily-of-the-valley, eating food prepared with or stirred by poisonous plant parts, and inhaling smoke from burning plants.

While there are many plant sources of cardiac glycosides, common ones include the following:

Epidemiology

United States statistics

Toxic exposure to plants containing cardiac glycosides is rare. Of 44,021 single exposures to plants reported by the American Association of Poison Control Centers (AAPCC) in 2015, 1370 were due to exposure to plants containing cardiac glycosides. Cardiac glycoside exposure from plants accounts for approximately 3% of plant exposures and 0.07% of the 1.9 million human exposures in the 2015 report.[4]

International statistics

Deliberate ingestion of yellow oleander seeds (Thevetia peruviana), known as "lucky nuts," is a popular method of self-harm in northern Sri Lanka. Thousands of cases are reported yearly, with a case-fatality rate of untreated patients ranging between 5% and 10%.[5] Exposure rates may be higher in countries or communities that rely heavily on folk or herbal medicines including plants containing cardiac glycosides.

Age-related differences in incidence

AAPCC data from 2015 show the following age breakdowns for plant cardiac glycoside exposure[4] :

Prognosis

Unintentional ingestion of plants containing cardiac glycosides rarely results in death. However, other plants capable of inducing a similar syndrome of cardiac toxicity (eg, aconite) have been responsible for deaths after ingestion. When death occurs, it generally is due to lethal dysrhythmias and refractory hyperkalemia. The magnitude of hyperkalemia is predictive of outcome.

Complications

Complications of herbal cardiac glycoside toxicity are secondary to inadequate tissue perfusion caused by dysrhythmia-induced hypotension and include the following:

Mortality/morbidity

Factors increasing morbidity and mortality are similar to those affecting digoxin-poisoned patients and may be divided into host-specific and plant-specific categories. Host-specific factors include advanced age, renal impairment, myocardial ischemia, hypothyroidism, hypoxia, and electrolyte abnormalities (eg, hypokalemia, hyperkalemia, hypomagnesemia, hypercalcemia). Plant-specific factors include species, part ingested, specific type of cardiac glycosides contained in the plant, and concentration of cardiac glycosides.

Mortality is rare, but case reports documenting fatalities from oleander, foxglove, squill, and other related plants do exist. In 2015, although the AAPCC reported 2 deaths in 1370 exposures to cardiac glycoside–containing plants, during the same period, 18 fatalities were reported from 1253 exposures to pharmaceutical cardiac glycosides.[4]

The AAPCC noted moderate-to-major morbidity in less than 2% of cardiac glycoside–containing plant exposures. In contrast, moderate-to-major morbidity occurred in 48% of pharmaceutical cardiac glycoside exposures.[4] In part, this may reflect lower concentrations of bioactive cardiac glycosides in plants.

In addition, pharmaceutical exposures generally occur in an older population (>60 y) and more often are due to intentional ingestion. Most plant exposures occur in children younger than 6 years and are usually unintentional and without associated significant toxicity. More serious toxicity occurs with intentional ingestions by adolescents and adults.

History

As with all toxic exposures, the history should focus on answering the following 6 key questions:

Although acute and chronic plant cardiac glycoside toxicity are treated in similar manners, their noncardiac clinical manifestations differ. In acute toxicity, the following may be present:

In chronic toxicity, signs and symptoms are insidious, which can make diagnosis difficult. GI symptoms are nonspecific and include the following:

Neurologic symptoms include the following:

Visual disturbances manifest as follows:

Cardiac symptoms are similar in both acute and chronic toxicity and include the following:

Physical Examination

In the physical examination, the focus is on cardiovascular, neurologic, and GI systems. On vital signs, bradycardia or tachycardia may be seen. In the absence of concomitant ingestion, environmental exposure, thyroid disorder, or underlying infection, the patient generally is normothermic.

Examination findings for specific systems are as follows:

Neurologic findings are typically nonfocal, and pupillary reflexes are intact. Abnormal findings may include the following:

Approach Considerations

The workup may include the following tests and studies:

Depending on the patient’s presentation, other tests to consider may include the following:

The ECG is performed to assess the cardiac rhythm and look for signs of ischemia or infarction. Nonspecific ST segment and T wave abnormalities, consistent with "dig effect," (eg, ST "scooping" or "strain"-like pattern) may be noted. This does not signify toxicity; merely the presence of cardiac glycoside. Peaked T waves may occur in hyperkalemia.

Renal function tests are performed because renal impairment negatively impairs elimination of glycosides and may exacerbate hyperkalemia. In addition, renal insufficiency is associated with elevated endogenous digoxinlike immunoreactive factors that can give false-positive digoxin assay results.

Electrolyte Levels

Hyperkalemia is a primary manifestation of acute cardiac glycoside toxicity and an early predictor of need for antidotal therapy. Hypokalemia exacerbates cardiac glycoside toxicity, and it is more typical in chronic toxicity. It is usually secondary to the use of loop diuretics, poor dietary intake, diarrhea, and administration of potassium-binding resins.

Hypercalcemia and hypomagnesemia exacerbate cardiac glycoside toxicity. Magnesium and ionized calcium levels may be helpful, but serum magnesium levels do not reflect total body load of magnesium.

Cardiac Glycoside Level

Some plant glycosides cross-react with commonly used digoxin radioimmunoassays (RIAs) and digoxin fluorescence polarization immunoassays. Detectable levels of cardiac glycosides have been associated with ingestion of foxglove and oleander; however, levels do not correlate with severity of illness. A negative digoxin RIA does not rule out a plant glycoside exposure.

The following medical conditions are associated with elevated endogenous digoxinlike immunoreactive factors that can give false-positive digoxin assay results:

Approach Considerations

Management of plant cardiac glycoside poisoning is very similar to that for digoxin/digitoxin poisoning and follows the principles of care for toxicologic emergencies, which include the following:

For general supportive care, attention to airway, breathing, and circulation (ABCs) is paramount. Treat life-threatening conditions in accordance with advanced cardiac life support (ACLS) principles, except as outlined below. To prevent further exposure, remove plant parts brought with the patient from treatment area, particularly if the patient is suicidal. To prevent further absorption, oral administration of activated charcoal is recommended if no contraindications exist.

Prehospital and Emergency Department Care

Advanced life support (ALS) personnel should transport patients who have ingested herbal cardiac glycosides or significant amounts of plants known to contain cardiac glycosides. Prehospital care should focus on the ABCs, with special emphasis on supporting respiratory and cardiac function. Cardiac and pulse oximeter monitoring should be continuous.

Administer oxygen and start an intravenous (IV) line. Place the patient on continuous cardiac monitoring and pulse oximetry. Treat patients with altered mental status in accordance with standard protocols based on a fingerstick glucose determination and primary survey.

In patients with a protected airway and normal mental status, activated charcoal can be administered. Atropine should be given to patients with clinically significant bradycardia (eg, hypotension, change of mental status). Digoxin Fab fragment treatment should be given if indicated.

Fab Fragment Treatment

Sheep-derived digoxin antibody Fab fragments reportedly are effective for some plant cardiac glycosides. Consider using this agent in patients with life-threatening complications, such as ventricular dysrhythmias, hyperkalemia, high-degree heart block, and cardiac arrest that do not respond rapidly to conventional treatment.

Indications for digoxin antibody Fab fragments are the same for both pharmaceutical as well as nonpharmaceutical cardiac glycoside toxicity and include the following:

Digoxin levels are not meaningful after administration of digoxin-specific Fab fragments. The levels may not change or may be falsely elevated if a free digoxin assay is not used. Because onset of action of Fab fragments may take 30-60 minutes, intervening treatment of significant complications should occur.

Management of Complications

Complications of plant cardiac glycoside poisoning may include the following:

Bradydysrhythmia

Atropine and cardiac pacing may be tried. If atropine is not rapidly successful, consider administration of Fab fragments. Patients requiring transcutaneous cardiac pacing should receive Fab fragments prior to its initiation. Transvenous pacing and use of isoproterenol have resulted in degeneration of cardiac rhythms, so both of these should be avoided. Do not delay administration of Fab fragments because of pacemaker placement. Do not use overdrive pacing for the control of ventricular dysrhythmias.

Phenytoin and lidocaine may be used as antidysrhythmics if Fab fragments are not immediately available. However, it should be remembered that Fab fragments are the definitive antidote to cardiac glycoside poisoning.

Tachydysrhythmia

Phenytoin and lidocaine (which decrease automaticity without slowing atriovenous [AV] nodal conduction and increase fibrillation threshold) may be used to treat ventricular dysrhythmias.

Magnesium has been reported to reverse digoxin-induced dysrhythmias and may be useful as long as anuric renal failure is not present.

Use cardioversion only as a last resort, since it may induce intractable ventricular fibrillation. Fab fragments should be given with cardioversion. If time permits, cardioversion should be attempted after a loading dose of phenytoin and at a significantly reduced initial power setting of 5-10 J.

Quinidine and procainamide may enhance cardiac glycoside toxicity by slowing conduction across AV node; both should be avoided. Beta-blockers and calcium channel blockers have questionable value.

Hyperkalemia

Life-threatening hyperkalemia (>5.5 mEq/L) may be seen with acute toxicity and results from a redistribution phenomenon rather than increased body stores. Glucose, insulin, sodium bicarbonate, and albuterol may be administered to facilitate redistribution of potassium intracellularly. However, albuterol may precipitate cardiac dysrhythmias. Life-threatening hyperkalemia should be treated with Fab fragments.

Calcium should be avoided. Overloading of myocytes with calcium is associated with development of a "stone heart," increased dysrhythmias, and a higher rate of death.

A pilot study in a porcine model shows that, in contrast to earlier studies, IV calcium administration to treat hyperkalemia secondary to cardiac glycoside toxicity resulted in no benefit or harm. However, the authors do not recommend its use in the clinical setting until more definitive studies are undertaken.[6] Theoretically, calcium can be used after administration of Fab fragments and reversal of cardiac glycoside toxicity.

Forced diuresis, hemoperfusion, and hemodialysis are ineffective in enhancing the elimination of digoxin because of its large volume of distribution. Hemodialysis will efficiently remove potassium from extracellular fluid.

Cardiac arrest

Give 10-20 vials of Fab fragments and continue to treat with standard ACLS protocols. Prolonged efforts at resuscitation may be warranted until Fab fragments begin to work. Phenytoin and lidocaine are antidysrhythmics of choice in patients poisoned with cardiac glycosides.

A Cochrane review on antidotes for acute cardiac glycoside poisoning that specifically looked at yellow oleander suggests that some evidence supports multiple-dose activated charcoal (MDAC) and antidigoxin Fab fragments, but notes that these may not be effective in toxicity caused by other plant cardiac glycosides.[7] The authors conclude that considering the cost limits in developing countries, where most poisonings take place, research to develop less expensive antidotes is needed.

Hospital Admission

Admit patients who show any signs of cardiac glycoside toxicity to a monitored setting for observation and further care. Intensive or cardiac care unit admission is indicated for patients with severe signs of toxicity, or in whom Fab fragments were used without resolution of symptoms.

Patients treated with Fab fragments and with complete resolution of symptoms may be admitted to a monitored setting. Clinicians should be aware of possibility of delayed toxicity if GI decontamination was not completed (especially for plant leaves in the GI tract).

Transfer

Arrange transfer to another facility with sufficient resources and expertise to care for patient under the following circumstances:

Transfer is usually to a tertiary care center with a medical toxicologist.

Consultations

The following consultations may be appropriate:

Long-Term Monitoring

Patients meeting the following criteria (measured serially over time) may be discharged:

Follow-up with primary care provider should be arranged within 1-2 days following unintentional ingestions of cardiac glycosides. Close follow-up is mandatory if psychiatry recommends discharge of a patient after intentional ingestion of cardiac glycosides or for any patient with underlying cardiac disease.

Medication Summary

Categories of drugs used to manage cardiac glycoside plant toxicity include the following:

Hyperkalemia usually results from acute overdose and represents redistribution of potassium from intracellular to extracellular compartment; therefore, drugs of choice include agents that promote potassium redistribution from extracellular to intracellular compartments. Avoid calcium, as it may exacerbate effects of cardiac glycosides and may promote rhythm deterioration when used in this context.

Activated charcoal (Actidose-Aqua, Actidose/Sorbitol EZ-Char, Kerr Insta-Char)

Clinical Context:  Activated charcoal is used in emergency treatment for poisoning caused by drugs and chemicals. A network of pores adsorbs 100-1000 mg of drug per gram of activated charcoal. Activated charcoal does not dissolve in water.

Administer activated charcoal as soon as possible after poison ingestion. Repeated doses may help to lower systemic levels of ingested compounds. The first dose may be given with a cathartic (eg, sorbitol); subsequent doses should be given without a cathartic, as often as q2-6h, and should not be given in presence of ileus.

Digoxin immune FAB (DigiFab)

Clinical Context:  This agent consists of sheep-derived IgG antibodies to digoxin. It may be helpful in certain situations, including hyperkalemia not quickly responsive to standard treatments, life-threatening dysrhythmias, and cardiac arrest.

Because serum digoxin/digitoxin levels do not reflect ingested amount of plant cardiac glycoside, drug levels should not be used to calculate Fab dose in these cases. Elevated serum levels of digoxin or digitoxin only confirm exposure. An undetectable level of serum cardiac glycosides does not rule out exposure. Elevated serum potassium should be a useful indicator when considering this agent.

Class Summary

Activated charcoal adsorbs ingested medication remaining in the gastrointestinal tract and creates a concentration gradient to "pull back" medication circulating in the bloodstream. It is most effective if administered within 1 hour of ingestion. In selected cases, repeated doses may be beneficial if the toxin is entero-hepatically metabolized, allowing a second opportunity to bind it and remove it from the body.

Digoxin immune FAB is a specific antidote that may be effective in some forms of cardiac glycoside plant poisoning. This agent has been used successfully in patients with oleander toxicity and may cross-react with other cardiac glycosides.

Insulin regular human (Humulin R, Novolin R)

Clinical Context:  The adult dose of glucose plus insulin is 50 g glucose plus 20 U regular insulin IV over 1 hour. The pediatric dose is 0.5-1 g glucose/kg; 1 U regular insulin IV is given for every 3 g of total glucose.

Class Summary

Intravenous administration of regular insulin along with glucose (in the form of 50% dextrose in water [D50W]) redistributes potassium intracellularly. Onset of action is 30 min and duration of action is 4-6h.

This regimen is used for life-threatening hyperkalemia (>5.5 mEq/L). It should be used cautiously with digoxin Fab as profound hypokalemia may occur. The serum glucose level should be monitored and additional D50W administered if needed.

Sodium Bicarbonate (Neut)

Clinical Context:  Intravenous sodium bicarbonate, followed by continuous infusion used for its alkalization properties to maintain a serum pH of 7.5-7.55, has reversed hypotension and resulted in narrowing of the QRS complex in isolated case reports.

Class Summary

Alkalosis created by bicarbonate leads to a redistribution of potassium intracellularly. Onset of action is 5-10 min and duration of action is 1-2 h. This agent is used for life-threatening hyperkalemia (>5.5 mEq/L). Use cautiously with digoxin Fab as profound hypokalemia may occur.

Atropine IV/IM (AtroPen)

Clinical Context:  Atropine is used for bradycardia and conduction blocks in standard Acute Cardiac Life Support (ACLS) doses: 0.5-1 mg or 0.04 mg/kg IV every 5 min, no more than 3 mg. Doses < 0.1 mg in children or 0.5 mg in adults may lead to paradoxical bradycardia.

Class Summary

Used to treat variety of bradydysrhythmias and tachydysrhythmias occurring with cardiac glycoside toxicity.

Phenytoin (Dilantin, Phenytek)

Clinical Context:  Phenytoin prolongs effective refractory period and depresses spontaneous depolarization in ventricular tissues. Phenytoin is useful for ventricular dysrhythmias, such as ventricular fibrillation, ventricular tachycardia, and premature ventricular contractions. It is the drug of choice for cardiac glycoside–induced tachydysrhythmia following digoxin FAB fragments. This agent is the only antidysrhythmic that stabilizes myocardium and improves conduction through the atrioventricular (AV) node. Monitor serum phenytoin levels closely to ensure therapeutic levels of 10-20 mcg/mL.

Class Summary

Phenytoin may reverse digitalis-induced prolongation of the action potential in myocardial cells and may suppress digitalis-induced tachydysrhythmia.

Lidocaine (Xylocaine)

Clinical Context:  Lidocaine is a class IB antiarrhythmic that increases the electrical stimulation threshold of the ventricle, suppressing automaticity of conduction through the tissue.

Class Summary

These agents are used to treat a variety of bradydysrhythmia and tachydysrhythmia occurring with cardiac glycoside toxicity.

Magnesium sulfate (MgSO4)

Clinical Context:  Magnesium sulfate possesses antidysrhythmic properties that are beneficial in treatment of digoxin toxicity. Its mechanism is not entirely understood but may suppress delayed afterdepolarizations, reactivate the Na+-K+-ATPase pump, and block the action of the cardiac glycosides at the sarcolemma Na+-K+-ATPase pump.

Magnesium is a cofactor in enzyme systems involved in neurochemical transmission and muscular excitability. Although serum magnesium levels may be normal, existence of intracellular hypomagnesemia has been hypothesized; therefore, magnesium may be beneficial.

For torsade de pointes, ACLS protocol for patients with a pulse calls for 1-2 g (diluted in 50-100 mL 5% D5W) given by slow IV infusion over 5-60 minutes, then 0.5-1 g/hr IV. For cardiac arrest, the dosage is 1-2 g (diluted in 10 mL D5W) infused over 5-20 minutes.

Class Summary

Magnesium is useful as a temporizing antiarrhythmic agent until digoxin Fab fragments are available. It may be a lifesaving adjunct in the treatment of digoxin-induced ventricular tachycardia or ventricular fibrillation.

Author

Raffi Kapitanyan, MD, Assistant Professor of Emergency Medicine, Rutgers Robert Wood Johnson Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Douglas R Landry, MD, Consulting Staff, Department of Emergency Medicine, Sentara Bayside Hospital

Disclosure: Nothing to disclose.

Mark Su, MD, MPH, FACEP, FACMT, Consulting Staff and Director of Fellowship in Medical Toxicology, Department of Emergency Medicine, North Shore University Hospital

Disclosure: Nothing to disclose.

Chief Editor

Michael A Miller, MD, Clinical Professor of Emergency Medicine, Medical Toxicologist, Department of Emergency Medicine, Texas A&M Health Sciences Center; CHRISTUS Spohn Emergency Medicine Residency Program

Disclosure: Nothing to disclose.

Acknowledgements

B Zane Horowitz, MD, FACMT Professor, Department of Emergency Medicine, Oregon Health and Sciences University; Medical Director, Oregon Poison Center; Medical Director, Alaska Poison Control System

B Zane Horowitz, MD, FACMT is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Medical Toxicology

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

References

  1. Oerther SE. Plant poisonings: common plants that contain cardiac glycosides. J Emerg Nurs. 2011 Jan. 37 (1):102-3. [View Abstract]
  2. Gowda RM, Cohen RA, Khan IA. Toad venom poisoning: resemblance to digoxin toxicity and therapeutic implications. Heart. 2003 Apr. 89(4):e14. [View Abstract]
  3. Bessen HA. Therapeutic and toxic effects of digitalis: William Withering, 1785. J Emerg Med. 1986. 4(3):243-8. [View Abstract]
  4. Mowry JB, Spyker DA, Brooks DE, Zimmerman A, Schauben JL. 2015 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 33rd Annual Report. Clin Toxicol (Phila). 2016 Dec. 54 (10):924-1109. [View Abstract]
  5. Eddleston M, Ariaratnam CA, Sjostrom L, Jayalath S, Rajakanthan K, Rajapakse S. Acute yellow oleander (Thevetia peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital. Heart. 2000 Mar. 83(3):301-6. [View Abstract]
  6. Hack JB, Woody JH, Lewis DE, et al. The effect of calcium chloride in treating hyperkalemia due to acute digoxin toxicity in a porcine model. J Toxicol Clin Toxicol. 2004. 42(4):337-42. [View Abstract]
  7. Roberts DM, Buckley NA. Antidotes for acute cardenolide (cardiac glycoside) poisoning. Cochrane Database Syst Rev. 2006 Oct 18. CD005490. [View Abstract]

The plant shown is foxglove (Digitalis purpurea), which contains cardiac glycosides, not tropane alkaloids. © 2000 Richard Wagner

The plant shown is foxglove (Digitalis purpurea), which contains cardiac glycosides, not tropane alkaloids. © 2000 Richard Wagner