Introduction

Two hundred years after its introduction inmedicine, digitalis, and particularly digoxin, con-

tinues to be used in Spain to treat congestiveheart failure and cardiac rhythm disorders, in par-ticular atrial fibrillation, although indications areincreasingly restricted1,2. Poisoning resulting from

Digitalis poisoning: the basis for treatmentwith antidigoxin antibodies

SANTIAGO NOGUÉ1, JUAN CINO2, EMILIA CIVEIRA3, JORDI PUIGURIGUER4,GUILLERMO BURILLO-PUTZE5, ANTONIO DUEÑAS6, DOLORS SOY7, RAQUEL AGUILAR8, NÚRIA COROMINAS7

1Sección de Toxicología Clínica, Área de Urgencias, Hospital Clínic, Barcelona, Grupo de Investigación“Urgencias: procesos y patologías”, IDIBAPS, Barcelona, Spain. 2Servicio de Cardiología, Hospital General deCatalunya, Sant Cugat del Vallés, Barcelona, Spain. 3Servicio de Medicina Intensiva, Hospital ClínicoUniversitario, Zaragoza, Spain. 4Servicio de Urgencias y Unidad de Toxicología Clínica, Hospital Son Espases,Palma de Mallorca, Spain. 5Servicio de Urgencias, Hospital Universitario, Tenerife, Spain. 6Unidad deToxicología Clínica, Hospital Río Hortega, Valladolid, Spain. 7Servicio de Farmacia, Hospital Clínic, Barcelona,España. 8Servicio de Farmacia, Hospital Josep Trueta, Girona, Spain.

Digitalis poisoning, particularly in persons under long-term digoxin therapy, is a reasonfor repeated visits to Spanish emergency departments. Acute poisoning is rare but mayoccur as a result of attempted suicide or the intake of plants that contain cardiacglycosides. Kidney failure modifies digoxin pharmacokinetics and is an important triggerfor severe adverse reactions to the drug. Clinical manifestations are nonspecific butusually include gastrointestinal events (nausea, vomiting, diarrhea, and abdominal pain)along with circulatory effects (hemodynamic instability, dizziness or lightheadedness,and syncope). Bradycardia (slow atrial fibrillation, conduction blocks) is common andmay cause asystole. Tachyarrhythmias may lead to ventricular fibrillation. In acutedigitalis poisoning, hyperkalemia is a risk factor for cardiac arrest. The digoxin plasmaconcentration can indicate the severity of the poisoning, provided the tissue-to-plasmaratio is at steady state. To treat acute poisoning, administer activated charcoal within thefirst few hours after digitalis intake. In such cases, or in poisoning during long-termdigoxin therapy, continuous electrocardiographic monitoring is essential and potassiumand magnesium concentrations should be brought within the normal range. The first-line treatment for bradycardia is atropine. Ventricular arrhythmias are treated withphenytoin or lidocaine. In life-threatening situations, antidigoxin antibodies must beused. They should be available in all referral or high-level tertiary care facilities and areadministered according to the total digoxin body load. [Emergencias 2012;24:462-475]

Keywords: Poisoning, digitalis. Emergency health services. Antidigoxin antibodies.

CORRESPONDENCE:Santiago NoguéSección de Toxicología ClínicaServicio de UrgenciasHospital ClínicC/ Villarroel, 17008036 Barcelona, SpainE-mail: SNOGUE@clinic.ub.es

RECEIVED:2-2-2012

ACCEPTED:14-3-2012

ACKNOWLEDGEMENTS:The authors wish to thank thefollowing colleagues for theircontributions to the final draftof the manuscript: Drs. MiguelGalicia, José Ramón Alonso, AnaFerrer, Lluis Marruecos, ÁngelBajo, Miguel Ángel Pinillos, JoséLuís Echarte and María LuisaIglesias. The present work wassupported by a grant (SGR2009/1385) from the“Generalitat de Catalunya”.

ADDENDUM:This paper reviews the main conclusions of a workshop on digitalis toxicity held on November 25, 2011 and organized by the Sectionof Clinical Toxicology at the Hospital Clínic of Barcelona. The authors of this work presented a paper related to digitalis poisoning andits treatment, receiving financial compensation from the GES enterprise which distributes anti-digoxin antibodies in Spain. None of theauthors have any professional relationship with GES, and the company was not involved in any writing of this manuscript and did notsupervise any of its contents.

462 Emergencias 2012; 24: 462-475

REVIEW ARTICLE Formaciónacreditada

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Emergencias 2012; 24: 462-475 463

chronic treatment with this drug, which has anarrow therapeutic index, is more common thanacute poisoning, but both are potentially fatal3,4.For these reasons, an expert group decided to re-view digitalis toxicity, with particular attention de-voted to treatment. We reviewed all documentsobtained through PubMed in English, Spanish orFrench, published between 1985 and 2011, usingthe following keywords: digoxin, digitoxin, car-dioactive steroids, acute poisoning, chronic poi-soning, intoxication, Fab fragments and digoxin-specific antibody fragments.

Epidemiology

Digoxin is most commonly implicated in med-ication poisoning treated in emergency depart-ments. Digitoxin is commonly used in Europe,and may cause poisoning in Spain. Also in Spaincan be found, even in public parks, plants con-taining cardiac glycosides (oleandrin and others)such as oleander (Nerium oleander) and yellowoleander (Thevethia peruviana) whose consump-tion could lead to poisoning with similar patho-physiology, diagnosis and treatment to those ofdigoxin. Exceptionally, there could also be casesof poisoning due to the intake of other plants likeDigitalis purpurea (foxglove), Digitalis lanata(woolly foxglove) or Convallaria majalis (Lily ofthe Valley), used in some alternative medicinetreatments or taken because of their allegedaphrodisiac properties.

Toxicokinetics

Digoxin is well absorbed orally, with a bioavail-ability of 65-80%. Its effects begin within 30-90minutes and peak at 4-6 hours, but this is delayedin the presence of food or with the simultaneousintake of anticholinergic drugs. Ten percent of theSpanish population have the Gram-positive anaer-obic bacterium Eubacterium lentum as part oftheir intestinal flora, which converts digoxin intoinactive metabolites and reduces its bioavailability.A change in this flora induced by taking certainantibiotics (clarithromycin and others) may favorthe absorption of digoxin.

It is hydrosoluble and binds poorly to plasmaproteins (20-25%), with apparent high distribu-tion volume (4-7 l/kg), even higher in children(16 l/kg). It is poorly metabolized in the liver (10-20%) and 75-80% is eliminated unchanged bythe kidneys5. The elimination half-life is prolonged

(35-45 hours) and in the presence of renal failurecan be extended to 3.5 - 5 days.

Types of poisoning, predisposing factorsand aggravating situations

Acute digitalis toxicity can arise from domesticaccidents in children or suicidal intake in adults. Itmay also occur by intake of plants with the activeprincipals of digitalis. But much more commonlyit is secondary to chronic treatment with thisdrug, usually women and the elderly > 70 yearson chronic treatment with digoxin and impairedkidney function, due to age (nephrosclerosis), de-hydration (vomiting, diarrhea, fever, reducing in-take) or association with other drugs (NSAIDs-non-steroidal anti- inflammatory drugs anddiuretics). It also has been reported to occur dueto dosage misunderstanding.

Predisposing factors for digitalis toxicity in-clude previous structural cardiomyopathies, chron-ic hypoxemia, metabolic alkalosis, hypothyroidismand advanced age6. Hypokalemia, hypomagne-semia, hypercalcemia and hypernatremia aggra-vate this toxicity as do concomitant antiarrhyth-mics. Some macrolides (erythromycin, amongothers) inhibit intestinal trans-membrane pumpflow, favoring digoxin absorption and therefore itstoxicity7.

Toxic doses

In adults, intakes of 2-3 mg may producesymptoms, but in acute poisonings it is rare tosee life-threatening cardiovascular disorders withdoses below 5 mg (20 tablets) of digoxin. Heartarrest is usually associated with doses above 10mg8. Survival after intakes of 20 mg has also beendescribed. In children, the toxic dose is around0.05 mg/Kg and 4 mg is potentially fatal.

Pathophysiological mechanism

In a specific, reversible and saturable manner,digoxin binds to the extracellular surface of theα subunit of the enzyme ATPase dependent onthe sodium pump, with two K+ ions being ex-changed for three Na+ ions. The enzyme block-ade increases intracellular Na+ concentration anddecreases that of K+, which in turn activates theexchange of Na+ and Ca2+ which leads to an in-put of Ca2+ which is stored in the sarcoplasmic

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464 Emergencias 2012; 24: 462-475

reticulum9. This mechanism explains, on the onehand, how hypokalemia situations increase theaffinity of of digoxin for ATPase and enhance itstoxicity, and on the other, why hyperkalemia be-comes an indicator of the severity of digitalispoisoning.

Increased intracellular Ca2+ generates positiveinotropism, one of the main effects sought indigitalis treatment, but when excessively in-creased it is also responsible for digitalis toxicity,since it exceeds the storage capacity of the sar-coplasm. This induces cyclic and unregulatedoutput, resulting in premature depolarizations,which explains the myocardial hyper-excitabilityand, if the threshold allows it, the sustained ar-rhythmia generated10.

ATPase inhibition also modifies the action po-tential, decreasing the rest phase and delayingdepolarization, which slows its duration. This ef-fect is evident in both pacemaker and conduc-tion cells, hence it decrease conduction frequen-cy and velocity11.

Another equally important mechanism of dig-italis poisoning is its vagal effect. Digoxin has ananti-adrenergic, inhibits sympathetic flow and in-creases vagal tone. The main consequence is re-duced heart rate.

Clinical manifestations

In acute poisoning the patient may beasymptomatic for 1-2 hours before symptomssuch as nausea, vomiting, diarrhea and abdomi-nal pain appear. There may also be lethargy,confusion and weakness, regardless of the hemo-dynamic situation. The absence of nausea andvomiting at 4 hours of ingestion suggests thatthe dose was probably not toxic12.

Chronic poisoning produces less specific ini-tial symptoms, such as loss of interest in dailylife activities, anorexia, nausea, vomiting, diar-rhea, abdominal pain, weight loss, delirium, con-fusion, drowsiness, headache, hallucinations andvisual disturbance (chromatopsia, particularlyxanthopsia)13. Occasionally patients complain ofinstability, syncope or fainting due to low cardiacoutput associated with altered heart rate.

In either case, the above pathophysiologicalmechanisms can lead to extreme disturbance ofheart rhythm and/or negative inotropic effectswhich result in low blood pressure, oligoanuriaand even cardiogenic shock. In severe acute poi-soning, death within the first 4-6 hours may oc-cur13.

Biochemical alterations

Hyperkalemia often accompanies acute poison-ing and constitutes an indicator of severity. In astudy published before antidotes became avail-able, 50% of patients with K+ > 5 mEq/L died,and mortality reached 100% when potassium ex-ceeded 5.5 mEq/L14. Hypokalemia is common inchronic poisoning. It is necessary to evaluate renalfunction in the latter type of poisoning and as apredictor of the half-life of digoxin elimination, aswell as the acid-base balance and plasma concen-trations of calcium and magnesium.

Electrocardiographic alterations

In digitalis poisoning, some types of arrhyth-mia are possible, but none is pathognomonic(Table 1). More commonly, there are conductiondisturbances (sinus bradycardia, sinoatrial block,atrioventricular block-AVB, nodal rhythm etc.) andalso arrhythmias produced by increased excitabili-ty (non-paroxysmal atrial tachycardia with variableAVB, extrasystole, bigeminy, tachycardia and ven-tricular fibrillation). These alterations may beginwithin 2-4 hours of intake, but sometimes occur12 hours later or more, so acute poisoning pa-tients have to be monitored during at least 24hours.

A down-sloping “scooped out” ST depressionor sagging is characteristic of digoxin use, but notnecessarily of toxicity (Figure 1). It is most evidentin leads with a high R in the QRS complex (espe-cially V4 to V6) and may be associated with flat-tening or inversion of the T wave. These alter-ations are explained by the delay in phaserepolarization.

Table 1. Most frequent arrhythmias in digitalis poisoning

Associated with heart block Sinus bradycardiaSinoatrial blockAVBAtrioventricular dissociationAtrial fibrillation (preexisting, usuallythe reason for prescribing digoxin)with AVB

Atrial flutter (preexisting, usuallythe reason for prescribing digoxin)with AVB

Associated with automatism Atrial tachyarrhythmia with AVBJunctional tachycardiaVentricular extrasystoleBigeminyVentricular tachycardiaVentricular fibrillation

AVB: atrioventricular block.

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Reduced heart rate is usual in patients takingdigoxin due to its vagal effect. A previously affect-ed sinus node (eg. from ischemia) is highly sus-ceptible to such bradycardic effects. Conductionrate is reduced in both myocardial and especiallynodal tissue. This is usually a very early manifesta-tion of acute intoxication. Electrocardiographically,this is expressed by a long PR interval and AVB ofdifferent degrees, which can become cardiac ar-rest.

In the atrium there is also an increase in ex-citability; extrasystole and even ectopic tachycar-dia episodes are common (Figure 2). Atrial tachy-cardia with AVB is characteristic, and acceleratednodal rhythm may be seen (Figure 3).

Ventricular cells and Purkinje tissue are the ori-gin of malignant arrhythmias in digitalis poison-ing, produced by the combination of increasedautomatism and decreased Purkinje cell conduc-tion (Figures 4 and 5). Progressive bradycardiamay end in asystole and arrhythmias in tachycar-dia or ventricular fibrillation. One third of patientswho die do so because of bradyarrhythmia andtwo thirds because of ventricular arrhythmia, butbradycardia that is unresponsive to atropine maybe premonitory of ventricular fibrillation15.

Diagnosis

Anamnesis regarding the mode of digitalis in-take together with clinical symptoms (digestiveand cardio-circulatory) and compatible ECG find-

ings (Table 1), are the main elements of suspicionin chronic poisoning. In acute poisoning, patientsthemselves very often report deliberate ingestion.However, confirmation by laboratory tests is need-ed.

Laboratory tests for digoxin

The accepted therapeutic range is between 0.8and 1.9 ng/mL16, measured at least 6 hours afteringestion to really reflect the balance of digoxindistribution between plasma and tissue. If the pa-tient has self-injected digoxin, blood must not beextracted by the same route. Metabolic alterationsor other previously cited factors potentiate thecardiotoxicity of digoxin even at concentrationswithin the therapeutic range, although signs ofdigitalis toxicity are usually associated with con-centrations above 2 ng/mL. Some patients toler-ate digoxinemia of 2-3 ng/mL, but > 6 ng/mLrepresents a very high risk (> 50%) of cardiac ar-rest17.

Following a recent intake, decreasing digoxine-mia within 24 hours does not guarantee the ab-sence of risk, since such a decrease may corre-spond to a phase of distribution of the drug fromsystemic circulation to tissues and therefore high-er cardiac concentrations.

The analytical technique most frequently usedin Spain determines total digoxin concentrations.When anti-digoxin antibodies (ADA) are adminis-tered, the free fraction of digoxin in plasma pass-

Figure 1. A down-sloping “scooped out” ST depression or sagging characteristic of chronic digoxinuse, clearly visible in lead V6 (arrows) of the electrocardiogram of a 74 year-old woman.

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466 Emergencias 2012; 24: 462-475

es from 75-90% to 0-5%, so the biological effica-cy of this treatment requires that this fraction bemeasured. If the laboratory determines the total,an increase should occur since the digoxin anti-body remains primarily in the vascular compart-ment and mobilizes tissue digoxin, while if it de-termines free digoxin then a decrease ofconcentration should occur. But technical prob-lems can make it very difficult to interpret the re-sult as the antibodies themselves can falsely de-crease "total" digoxin concentration. If antibodiesare used, the laboratory should ideally determine

the amount of free digoxin using a highly sensi-tive and specific technique, otherwise, exclusivelyclinical and electrocardiographic monitoring ispreferable18.

Laboratory tests may also detect the presenceof other compounds (digitoxin, cardiotoxicplants), but the analytical result does not reflectthe level of toxicity. They may also detect en-dogenous digoxin-like substances, especially inneonates, pregnant women, patients who haveperformed strenuous exercise, stress or patientswith end-stage renal disease, liver disease, sub-

Figure 2. Re-entrant tachycardia.

Figure 3. Accelerated nodal rhythm in severe chronic digitalis poisoning.

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arachnoid hemorrhage, congestive heart failure,insulin-dependent diabetes or acromegaly19. Treat-ment with spironolactone may interfere with thelaboratory technique20.

Treatment

Priorities and early symptomatic measures aredirected at the cardio-circulatory system which isthe main target of this poisoning (Figure 6). Vitalsigns, ECG monitoring, continuous determinationof acid-base balance, sodium, potassium, calcium,magnesium and serum digoxin are the first pa-rameters to be evaluated. If the ECG or clinical sit-uation is unstable, symptom management andthe use of an antidote can be vital. An intra-venous line should be established, with supple-mental oxygen supplied if necessary and intra-venous fluid therapy with control of centralvenous pressure (CVP). In chronic poisoning,digoxin and any other antiarrhythmic should bediscontinued.

In recent acute poisoning (< 6 h) gastrointesti-nal decontamination to prevent absorption shouldbe considered. Its effectiveness is dependent onhow soon it is implemented8. Activated carbon isundoubtedly the technique of choice. The mini-mum starting dose is 25 g which may be adminis-

tered orally, after an antiemetic (ondansetron 4mg/iv) to prevent vomiting. Since digitalis in-volves enterohepatic recirculation, some authorshave recommended repeating the same dosesevery two hours up to 5 times in severe cases, al-though no controlled studies exist to support thisoption21.

Hypokalemia is treated with supplementarypotassium until its concentration is > 4 mEq/L,and this is particularly suitable if ADA or dextrosesolutions are used, or if there are ventricular ar-rhythmias or AVB. The correction is made slowly,without exceeding 20 mEq/hour so as not to in-duce a state of hyperkalemia22.

Hyperkalemia should be corrected with ex-treme caution using insulin-glucose, bicarbonateor exchange resins and, if possible, with ADA athand. In fact, in acute intoxication, a K+ > 5mEq/L is an indication for use of these antibodies.Hyperkalemia may also be corrected with calciumsalts, but in digitalis toxicity they may induceasystole or malignant arrhythmias so are not rec-ommended. Neither is it advisable to treat hyper-kalemia with beta-adrenergics because of their ar-rhythmogenic potential. Hyperkalemia in thepresence of renal failure is an indication for he-modialysis.

The correction of hypocalcemia is subject tocontroversy and uncertainty about its cardiac ef-

Figure 4. Bradycardic atrial fibrillation with multifocal ventricular extrasystoles.

Figure 5. Self-limited episode of ventricular tachycardia in a 78 year-old man with severe digitalispoisoning (digoxinemia 8.4 ng/mL) and renal failure (creatinine 5 mg/dL).

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468 Emergencias 2012; 24: 462-475

fects; in cases of digitalis poisoning, calcium saltsshould not be administered, not even in cases ofcardiac arrest23.

Hypomagnesemia is common in chronic poi-soning due to the frequent use of diuretics inthese patients. In theory, the contribution of mag-nesium (1.5 g intravenously during 60 minutes)reduces myocardial irritability and improves con-duction; it is indicated if sustained ventricular ar-rhythmia is present, but this benefit has not beenconfirmed in controlled studies. Magnesium iscontraindicated in the presence of renal failure,bradyarrhythmia or AVB12.

Antiarrhythmics

For supraventricular bradyarrhythmias or symp-tomatic AVB, atropine is the drug of choice (Fig-ure 7)24. With ventricular frequency below 40

beats/min, 0.5 mg/iv in adults and 0.02 mg/kg inchildren should be administered, repeatable every5 minutes to a maximum of 4 times. An excess ofatropine may induce anti-cholinergic syndrome.The goal is to reverse the vagal effect, but successis not guaranteed because these bradyarrhythmiasmay be due to other mechanisms. Lack of re-sponse signals poor prognosis and constitutes areason to administer ADA. In extreme bradycardiathat is unresponsive to atropine, if antibodies arenot available, the use of a pacemaker should beconsidered. Isoproterenol is not indicated becauseof it ability to increase ventricular ectopic activity.

In sustained supraventricular tachycardia withsymptoms (hypotension, dizziness, syncope)phenytoin can be used (100 mg intravenously, re-peatable within 5 minutes). Full arrhythmia withatrial fibrillation or flutter and very rapid ventricu-lar response is infrequent and does not respond

Figure 6. General algorithm for evaluation and treatment in digitalis poisoning. ADA: anti-digoxin anti-bodies; TBBD: total body burden of digoxin

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Emergencias 2012; 24: 462-475 469

to phenytoin. Esmolol can be tried (0.5 mg/kg/ivin 1 minute followed by continuous infusion of0.05 mg/kg/min). These arrhythmias should notbe subject to cardioversion because it may triggerirreversible heart arrest. If there is no response tothese drugs and rhythm disorders compromisehemodynamic stability, we must resort to the useof antibodies25.

For ventricular arrhythmias, lidocaine is usedand, especially, phenytoin when ADA are notavailable. Both are able to reduce ventricular ex-citability without worsening atrioventricular con-duction, and may even improve it. Phenytoindose is an intravenous bolus of 50 mg everyminute or 100 mg every 5 minutes, until the ar-rhythmia is controlled or to a maximum of 1g inadults or 20 mg/kg in children. If uncontrolled,continue with 2 mg/kg/iv/12 hours. Lidocainedose is an intravenous bolus of 1.5 mg/kg fol-lowed by a continuous infusion of 2.5-4 mg/minin adults and 50 ug/kg/min in children. Some ar-rhythmias refractory to lidocaine and phenytoin(drugs not recommended by some26) have re-sponded favorably to amiodarone8.

In ventricular tachyarrhythmia, magnesium hasbeen used at doses of 1.5 g administered intra-venously during 20 minutes (25 mg/kg in chil-dren, to a maximum of 1.5 g), even if the patientshows no hypomagnesemia. If he/she has hypo-magnesemia, one can administer 1 g/h in contin-uous infusion, closely monitoring respiratory rateand magnesemia. Class IA antiarrhythmics (quini-dine, procainamide, disopyramide) are contraindi-

cated. Beta-blockers may be useful in treatingventricular arrhythmias, but may precipitate com-plete AVB and worsen the situation. If used, intra-venous esmolol is recommended because it has avery short elimination half-life (9 min)25.

Ventricular tachycardia, which may respond tointravenous magnesium sulphate, is another clearindication for immediate administration of ADA. Ifthere is hemodynamic compromise, this shouldbe reversed while antibodies are administered.Ventricular fibrillation must also be reversed, fol-lowed by ADA to prevent recurrence.

In hypotension, one should increase plasmavolume, within limits13, and correct hypoxemia ifpresent. Alpha and beta adrenergics are potential-ly arrhythmogenic and should be avoided. In re-fractory cases, noradrenaline is the drug of choice.

Hypertension is rare. One should be very care-ful in correcting it, but if considered necessarythen one should use drugs with a short half life;the use of vasodilators can induce marked hypop-erfusion of vital organs.

The use of pacemakers has very limited indica-tions, since they do not guarantee control ofrhythm disorders, and intra-cardiac placement isnowadays totally contraindicated, especially inacute poisoning, since they can induce malignantarrhythmias27. But some authors have obtainedgood results in cases of chronic poisoning, andrecommend pacemakers in patients with ad-vanced AVB or symptomatic bradycardia, pro-grammed at low frequencies (55-60 beats/min) tominimize their arrhythmogenic effect28. In general,

Figure 7. Initial treatment of ionic and electrocardiographic disorders. Some may constitute an indication for administering anti-di-goxin antibodies. ADA: Anti-digoxin antibodies; AVB: atrioventricular block; VF: ventricular fibrillation.

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470 Emergencias 2012; 24: 462-475

however, it is considered that such patientsshould receive ADA and pacemakers are only indi-cated in the absence of ADA or awaiting delivery.

Transthoracic cardioversion to reverse supra-ventricular tachyarrhythmia has been associatedwith fatal ventricular arrhythmia and should there-fore not be used for this purpose29. Patients with apossible indication for cardioversion must be treat-ed with ADA. However, cardioversion or defibrilla-tion is indicated in situations of unstable or pulse-less ventricular tachycardia and ventricularfibrillation. In these situations the recommendationis to start with low energy (10-25 J) and pre-treat,if possible, with lidocaine or amiodarone. Oncecardioversion has been achieved, ADA should alsobe administered to prevent recurrence.

Heart arrest is an indication for ADA. The effectis not instantaneous, so the duration of advancedcardiopulmonary resuscitation should be pro-longed30. Percutaneous cardiopulmonary bypasshas also been used, with a continuous flow pumpoxygenator providing extracorporeal oxygenationand circulatory support during some hours31. In-travenous lipid infusion has shown benefits in thissituation, probably due to the low lipid solubilityof digoxin32.

ADA have been available in clinical practice forover 35 years33, but uniform guidelines have notbeen established by the scientific community be-cause no controlled trials have been performed todemonstrate their effectiveness. The literaturecontains only seven observational case series(Table 2)15,34-39.

Yet despite this low level of scientific evidence,many authors believe ADA constitute the first lineof treatment in severe digitalis intoxication, inboth adults and children, since they may effec-tively and safely reverse potentially fatal cardiacarrhythmias40-43. In Spain, ADA are available asnon-nationally produced drugs through the Span-ish Agency of Medicines and Health Products(DigiFab®) at a cost (in November 2011) of544.96 € per vial of 40 mg.

ADA are immunoglobulin fragments obtainedfrom sheep that have been immunized with adigoxin derivative and produce antibodies. Frag-mentation eliminates the antigenic portion andreduces its size, enabling glomerular filtration buthindering output from the plasma compartment43.Always administered intravenously, they have lowdistribution volume (0.25-0.50 L/kg) and are pri-marily eliminated by the kidneys (66%). Undernormal conditions, their elimination half-life is 14-30 hours, but this can be ten-fold greater in pa-tients with renal failure.

The affinity of digoxin for ADA is greater thanfor biological membranes, which facilitates directand immediate binding to the free fraction ofplasma and its extraction from the extra-vascularcompartment due to concentration gradient.Studies in vivo have shown that ADA neutraliza-tion capacity is equimolar; in practice this meansthat according to molecular weight 40 mg ofADA neutralize 0.59 mg of digoxin, although themanufacturers and some authors cite this relation-ship as 40mg ADA/0.50 mg of digoxin44.

As a general rule, ADA are indicated for bothchildren and adults in potentially life-threateningsituations associated with cardiovascular toxicityinduced by digitalis glycosides such as digoxinand digitoxin45, but this also includes other digi-talis glycosides (oleandrin and others) present invarious plants46-49. These situations involving vitalrisk are summarized in Table 326,50,51. Some authorshave also added the acute intake of more than 4mg (in children) or 10 mg (in adults) of digoxin.Lapostolle et al also consider that ADA are indicat-ed in any digitalis poisoning that meets two ormore of the following criteria: male, age over 55years, underlying heart disease, bradycardia withsecond or third degree AVB, ventricular rate < 60beats/min and K+ > 4.5 mEq/L39.

However, none of the ADA treatment plans de-scribed in the literature has been validated by arandomized controlled trial. ADA dosage has of-ten been calculated according to the total bodyburden of digoxin (TBBD) assuming equimolarneutralization. This means that, roughly, 40 mg ofADA will neutralize 0.5 mg of digoxin (0.625 mgaccording to some authors43). Other authors con-sider that patients with chronic toxicity with equalclinical manifestations need a lower dose of ADAbecause their TBBD is lower43.

In acute poisoning, TBBD can be estimatedfrom the amount of digoxin ingested, assuming80% bioavailability (amount absorbed) (Table 4).But this may be inaccurate because of uncertaintyabout the amount ingested, possible spontaneousvomiting or the effectiveness of therapeutic meas-ures, such as activated charcoal, which may reducethe bioavailability of digoxin. This method is onlyacceptable if digoxinemia cannot be determined.

In acute or chronic poisoning, TBBD can be es-timated with much greater precision using digox-in plasma concentration, measured in a bloodsample obtained at least 6 hours after ingestion,assuming that the apparent volume of distribution(Vd) is about 5 L/kg (Table 5)5. In patients withchronic renal failure or hypothyroidism, digoxinVd is lower, which may lead to overestimation of

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the real amount of ADA needed. From this calcu-lation of TBBD one can estimate the amount ofADA needed (Table 5), assuming that each vial of40 mg will neutralize 0.5 mg of digoxin. But it isnot necessary to neutralize all the TBBD since thebody tolerates a certain amount of digoxin (0.35to 0.70 mg in adults and 0.05 to 0.10 mg in chil-dren) without any adverse reaction. An initial half-dose has been proposed; if there is inadequate re-sponse in 1-2 hours, the remaining 50% can beadministered43. If there is still no response, fur-ther doses up to a maximum of 800 mg totaldose should be given; the absence of response tosuch high doses indicates some other cause of thecardiocirculatory disorder. For example, a patientweighing 75 kg with digoxinemia of 4 ng/mLwould have a TBBD of 1.5 mg, and the total doseof ADA would be 120 mg, initially administering50% (60 mg). For the intake of plant glycosides,it is practically impossible to calculate the TBBD;the recommendation in such cases with signs ofsevere cardiotoxicity is to administer an initial em-pirical 5 vials (200 mg) of ADA.

In life-threatening situations, some authors haveproposed using an empirical dose of 160 mg ADA,repeated after one hour if the clinical or electrocar-diographic signs have not resolved. This conserva-tive approach involves less risk for the patient and,

in the case of acute intoxication, reduces treat-ment cost by 12%52. It can also be used in cases ofcardiotoxic plant intake when the amount, timelapse since intake and digoxin plasma levels areunknown to the attending physician.

When a patient is admitted with cardiac arrestor this occurs shortly after admission and digitalisintoxication is suspected, it is recommended thatresuscitation include the immediate administrationof 400 mg of ADA, repeatable within an hour inthe absence of response and considering that thepatient is neurologically recoverable.

Table 2. Scientific evidence on the effectiveness and safety of anti-digoxin antibodies (ADA) in digitalis poisoning

Author Study design Nº cases Mortality Adverse Comments Study quality Level of evidence(year) (type of patients) (%) effects according according

(%) to SIGN* to SIGN*

Smolarz Prospective 34 cases 5,8 No ADA improve survival Low 3(1985) observational (adults) compared with historical

case series series.Wenger Prospective 63 cases 7,6 No They rapidly reverse life- Low 3(1985) observational (adults) threatening arrhythmias

multi-centrecase series

Antman Prospective 150 cases 28,6 9 The high mortality rate was Medium 3(1990) observational (125 adults and attributed to the severity of

multi-centre 25 children) underlying heart disease.case series

Hickey Prospective 717 cases 24 7 2.8% relapse of signs Low 3(1991) observational (adults) of poisoning, after good

multi-centre initial response.case series

Woolf Prospective 29 cases 24,1 8,3 Good initial response to Low 3(1992) observational (children and ADA by children. Mortality

multi-centre adolescents) rate was attributed tocase series underlying heart disease.

Taboulet Retrospective 51 cases 29 No Better response with Low 3(1993) observational (adults) ADA than controls with

multi-centre un grupo control en loscase series pacemaker

Lapostolle Retrospective 66 cases 7,6 No ADA administered in lower Low 3(2008) observational (adults) risk situations compared

multi-centre with usage criteria incase series criteria in other series

*SIGN = Scottish Intercollegiate Guidelines Network (Harbour R, et al. BMJ. 2001;323:334-6).

Table 3. Life-threatening situations associated with digitalispoisoning and with indication for anti-digoxin antibodies

– Bradyarrhythmia with ventricular rate < 40 beats/min and noresponse (ventricular rate remains < 60 beats/min) to repeated dosesof 0.5 mg/iv atropine (up to 2 mg).

– Ventricular extrasystole with risk of tachycardia or ventricularfibrillation (frequent ventricular extrasystole, doublets, triplets,multifocal or R on T phenomenon).

– Ventricular tachycardia.– Ventricular fibrillation.– Asystole.– Cardiogenic shock.– Kaliemia > 5 mEq/L in the presence of other signs of digitalispoisoning in acute intoxication.

– Digoxin plasma levels > 6 ng / mL (> 6 hour post-ingestion).(Modified from Dawson, et al. Therapeutic Drug Monitoring in drugoverdose. Br J Clin Pharmacol. 2001;52:97S-102S).

S. Nogué et al.

472 Emergencias 2012; 24: 462-475

The presence of renal failure does not affectthe dose of ADA, although it markedly prolongsthe elimination half-life of the toxin.

In administering ADA, each vial of 40 mg mustbe diluted in 4 mL of sterile water and the variousdissolved vials must then be diluted in 100 mL ofsaline solution (0.9% sodium chloride). It shouldbe administered intravenously during about 30minutes, except in critical situations (tachycardia,ventricular fibrillation or heart arrest) when itmust be administered in bolus form. In youngchildren, reduce the final dilution. After thelyophilized product has been reconstituted, itshould be used immediately or stored in a fridgefor use within a maximum of 4 hours. It is notnecessary to perform a sensitivity test prior to ad-ministration, as was previously done with otherADA, since anaphylaxis or hypersensitivity reac-tions have not been described to date.

The initial response to ADA is generally ob-tained within a mean 19 minutes (range 0-60min) and complete response in approximately 88minutes (range 30-360 min)36.

Regarding adverse reactions to ADA, a para-doxical effect of decreased cardiac output hasbeen described, exacerbation of congestive heartfailure due to suppression of the inotropic effectof digitalis and a rapid ventricular response in pa-tients with previous atrial fibrillation by suppress-ing the effect of digitalis on the atrioventricularnode35. Hypokalaemia has also been described: re-activation of Na-K-ATPase involves input of potas-sium in cardiomyocytes35.

Allergic reaction is rare (0.8% of cases pub-lished before the year 2000)53. The possibility ofpatients becoming sensitized to ADA exists, but inpatients who have received ADA up to 3 times noallergic symptoms were observed54.

No interactions with other drugs have been re-ported. Risks to the fetus if used during pregnan-cy are unknown, as is ADA content excreted inhuman milk. It is therefore advisable to assess therisk/benefit in pregnant patients and possibly sus-pend breastfeeding. There is no absolute con-traindication against the use of ADA.

Digitalis-ADA binding is not irreversible andthere could be dissociation as the antibody is se-creted by the kidneys, which may induce a “flare”of cardiovascular toxicity after 4-6 or more hours,but usually less severe. This mandates monitoringof the ECG and possible hemodynamic instabilityduring at least 24 hours.

In patients with renal failure, the eliminationhalf-life of ADA may be prolonged (123 ± 16hours), but it is still shorter than that of digoxin(144 hours) and clinical relapse may occur 5-7 dayslater, so one week of observation and ECG moni-toring is necessary. To reduce the risk of relapse as-sociated with a dissociation of the ADA-digoxincomplex, one should consider plasma exchangestarting at 3 hours after ADA administration, sincehemodialysis or hemodiafiltration are ineffective55.

The use of ADA reduces the concentration ofplasma potassium, so the ionogram should beclosely monitored in the first 3 hours.

Regarding the supply of ADA in health care, inthe year 2006, a group of Spanish experts estab-lished recommendations on the availability of an-tidotes, specifying that ADA should be available atleast at the reference hospitals of each province56.However, Aguilar et al showed that in that year inCatalan hospitals, only 25% of the high tech cen-ters surveyed actually stored ADA57. Based on thedosing recommendations established in this pa-per, high-tech hospitals should have a supply of800 mg of ADA (20 vials).

Table 4. Estimation of the total body burden of digoxin (TBBD) based on the dose ingested in acute digoxin poisoning

Formula for calculating TBBD Example of dose ingested Example of TBBD

[Nº tabs] x [mg/tab] x [Bioavailability]* 25 tabs of 0.25 mg 25 x 0.25 x 0.8 = 5 mg*The bioavailability of digoxin (80% of the ingested dose) is independent of the patient’s age and weight.

Table 5. Estimation of the total body burden of digoxin (TBBD) based on plasma concentration after reaching stationary equilibriumstate

Example of age Formula for calculating TBBD Example of Example of TBBD Example ofand weight plasma need

concentration for ADA*

Adult (67 Kg) [digoxin plasma levels in ng/mL] x 6 ng/mL 6 x 5 x 67 = 2 mg 160 mg (4 vials)[Apparent distribution volume in L/kg] x [weight in kg]

Child (16,7 Kg) [digoxin plasma levels in ng/mL] x 6 ng/mL 6 x 5 x 16,7 = 0,5 mg 40 mg (1 vial)[Apparent distribution volume in L/kg] x [weight in kg]

*The theoretical dose of ADA (anti-digoxin antibodies) is calculated on the assumption that 40 mg of ADA neutralizes 0.5 mg of digoxin.

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Emergencias 2012; 24: 462-475 473

The need to administer the antidote in situa-tions of extreme urgency makes it advisable thatreferral hospitals in each province which are situ-ated more than 1 hour from high-tech centersshould also stock it. In this case, the amount ofantidote should be 50% of that previously men-tioned (i.e. 400 mg, in 10 vials). ADA must bekept refrigerated at 2-8°C. In municipal or countyhospitals, ADA stocks are not necessary, but alldigitalis poisoned patients should be transferredby medicalized units to such referral hospitals.

For renal and extra-renal clearance, diuresisand hemodialysis or hemoperfusion are ineffectiveat significant extraction of digoxin, mainly due toits extensive volume of distribution. In patientswith acute renal failure administered with ADA,plasmapheresis could allow extraction of digoxin-ADA complexes before they dissociate and causerebound cardiotoxicity, but this potential benefithas not been demonstrated58.

Patient location and period of observation

Digitalis poisoning is serious and, from the be-ginning, the patient must be monitored continu-ously while risks are evaluated, treatment adminis-tered and until r isk of death is consideredimprobable. The process usually requires morethan 24 hours, in both acute and chronic poison-ing. This surveillance can be carried out in theemergency department, but preferably in an areaof critical or intensive care: sudden malignant ar-rhythmia or asystole may occur and, therefore,the area of observation should be materiallyequipped and staffed by professionals qualified toperform advanced cardiopulmonary resuscitation.Capacity to monitor digoxinemia is also necessary.

Once over the period of major risk period,with no signs, symptoms and ECG changes relat-ed to digitalis poisoning and with digoxin con-centrations < 2 ng/mL, the patient can be dis-charged. If ADA are administered, the observationperiod should be at least 24 hours later, extendedfurther in the presence of renal failure.

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Tratamiento de la intoxicación digitálica. Bases para el uso de los anticuerpos antidigital

Nogué S, Cino J, Civeira E, Puiguriguer J, Burillo G, Dueñas A, Soy D, Aguilar R, Corominas N

La intoxicación digitálica, sobre todo asociada a un tratamiento crónico con este fármaco, es un motivo recurrente deconsulta a los servicios de urgencias españoles. La intoxicación aguda es excepcional y podría presentarse tanto en unatentativa de suicidio como por la ingesta de plantas presentes en nuestro medio y que contienen glucósidos digitálicos.La insuficiencia renal, al modificar la cinética de la digoxina, es un importante factor precipitante de reacciones adversasy graves a este medicamento. Las manifestaciones clínicas son inespecíficas, y predominan las digestivas (náuseas, vómi-tos, diarreas, dolor abdominal) y circulatorios (inestabilidad, mareos, síncope, lipotimia). Las bradiarritmias (fibrilaciónauricular lenta, bloqueos de conducción) son frecuentes y pueden acabar en asistolia. Las taquiarritmias podrían condu-cir a la fibrilación ventricular. En las intoxicaciones agudas, la hiperpotasemia es un factor de riesgo de parada cardiaca.La concentración plasmática de digoxina permite evaluar la gravedad de una intoxicación, siempre y cuando se haya al-canzado el equilibrio de distribución entre las concentraciones plasmáticas y tisulares. El tratamiento de la intoxicaciónaguda precisa la administración de carbón activado en las primeras horas tras la ingesta. En las intoxicaciones agudas opor tratamiento crónico, es necesaria la monitorización electrocardiográfica continua y normalizar, en caso necesario, lasconcentraciones de potasio y magnesio. Las bradiarritmias se tratan con atropina como fármaco de primera elección ylas arritmias ventriculares con fenitoína o lidocaína. Las situaciones de riesgo vital requieren el uso de anticuerpos antidi-gital, y se recomienda la disponibilidad de este antídoto en los hospitales considerados de referencia o alta tecnología, elcual deberá dosificarse en función de la carga corporal total de digoxina. [Emergencias 2012;24:462-475]

Palabras clave: Intoxicación digitálica. Servicio de urgencias. Anticuerpos antidigital.