309 CASE REPORT Severe digoxin intoxication: a case report of the use of digoxin-specific Fab antibody fragments Copyright (c) 2023 Slovenian Medical Journal. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Severe digoxin intoxication: a case report of the use of digoxin-specific Fab antibody fragments Huda zastrupitev z digoksinom: prikaz primera z uporabo za digoksin specifičnih Fab protitelesnih delcev Tadej Petreski,1 Metin Omerović,2 Viljemka Nedog,3 Miran Brvar,4 Ivana Sokolović3 Abstract Digoxin is a cardiac glycoside that has been used for several decades to treat heart failure and atrial fibrillation. Several doctors prescribe it to their patients, although it is not the first choice for either condition. In rare cases, intoxication can occur, leading to life-threatening cardiac arrhythmias. Here we report the case of an 84-year-old Caucasian woman who presented to the emergency department with dyspnoea, cough, and bilateral lower limb oedema. Eight days prior to her presentation, she had been prescribed methyldigoxin. As the patient had undiagnosed dementia and was taking medica- tion without supervision, she ingested toxic amounts of the drug. Electrocardiogram showed the presence of arrhythmia, which resolved after using digoxin-specific Fab antibody fragments. In elderly patients, special care should be exercised when prescribing drugs with narrow therapeutic windows. Izvleček Digoksin je srčni glikozid, ki se že več desetletij uporablja pri zdravljenju srčnega popuščanja in atrijske fibrilacije. Številni zdravniki pogosto predpisujejo to zdravilo, čeprav ni zdravljenje prve izbire pri tej bolezni. V redkih primerih lahko pride do zastrupitve, ki lahko vodi v življenje ogrožajočo srčno aritmijo. Predstavljamo primer 84-letne ženske, ki je prišla v Urgentni center zaradi težkega dihanja, kašlja in obojestranskega otekanja nog. Osem dni pred to obravnavo je pričela zdravlje- nje z metildigoksinom, ki je pri bolnici z neprepoznano demenco in uživanjem zdravil brez nadzora vodilo v zastrupitev. Elektrokardiogram je pokazal prisotnost aritmije, ki je izzvenela po uporabi za digoksin specifičnih protitelesnih delcev Fab. Zato je potrebna posebna pozornost ob predpisovanju zdravil z ozkimi terapevtskimi okni pri starostnikih. 1 Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Maribor, Slovenia 2 Centre for Emergency Medicine, University Medical Centre Maribor, Maribor, Slovenia 3 Department of Cardiology and Angiology, Clinic for Internal Medicine, University Medical Centre Maribor, Maribor, Slovenia 4 Centre for Clinical Toxicology and Pharmacology, Division of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia Correspondence / Korespondenca: Tadej Petreski, e: tadej.petreski@ukc-mb.si Key words: antidotes; cardiology; digoxin; elderly; toxicity Ključne besede: antidot; kardiologija; digoksin; starostniki; toksičnost Received / Prispelo: 11. 7. 2022 | Accepted / Sprejeto: 17. 2. 2023 Cite as / Citirajte kot: Petreski T, Omerović M, Nedog V, Brvar M, Sokolović I. Severe digoxin intoxication: a case report of the use of digoxin-specific Fab antibody fragments. Zdrav Vestn. 2023;92(7–8):309–13. DOI: https://doi.org/10.6016/ZdravVestn.3380 eng slo element en article-lang 10.6016/ZdravVestn.3380 doi 11.7.2022 date-received 17.2.2023 date-accepted Cardiovascular system Srce in obtočila discipline Case report Klinični primer article-type Severe digoxin intoxication: a case report of the use of digoxin-specific Fab antibody fragments Huda zastrupitev z digoksinom: prikaz primera z uporabo za digoksin specifičnih Fab protitelesnih delcev article-title Severe digoxin intoxication Huda zastrupitev z digoksinom alt-title antidotes; cardiology; digoxin; elderly; toxicity antidot, kardiologija, digoksin, starostniki, toksičnost kwd-group The authors declare that there are no conflicts of interest present. Avtorji so izjavili, da ne obstajajo nobeni konkurenčni interesi. conflict year volume first month last month first page last page 2023 92 5 6 309 313 name surname aff email Tadej Petreski 1 tadej.petreski@ukc-mb.si name surname aff Metin Omerović 2 Viljemka Nedog 3 Miran Brvar 4 Ivana Sokolović 3 eng slo aff-id Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Maribor, Slovenia Oddelek za nefrologijo, Klinika za interno medicino, Univerzitetni klinični center Maribor, Maribor, Slovenija 1 Centre for Emergency Medicine, University Medical Centre Maribor, Maribor, Slovenia Urgentni center, Univerzitetni klinični center Maribor, Maribor, Slovenija 2 Department of Cardiology and Angiology, Clinic for Internal Medicine, University Medical Centre Maribor, Maribor, Slovenia Oddelek za kardiologijo in angiologijo, Klinika za interno medicino, Univerzitetni klinični center Maribor, Maribor, Slovenija 3 Centre for Clinical Toxicology and Pharmacology, Division of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia Center za klinično toksikologijo in farmakologijo, Interna klinika, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija 4 Slovenian Medical Journallovenian Medical Journal 310 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2023 | Volume 92 | https://doi.org/10.6016/ZdravVestn.3380 1 Introduction Atrial fibrillation is the most common sustained car- diac arrhythmia in adults worldwide, with an estimated prevalence between 2% and 4%. It is associated with sig- nificant morbidity and mortality and a high economic burden. Its treatment is integrated into the “ABC” pathway and under ‘B’ Better symptom management, ventricular rate control is a possible and important strategy for the management of patients for whom multiple medications such as beta-blockers, non-dihydropyridine calcium chan- nel blockers, digoxin, and amiodarone are available (1). Digoxin is a cardiac glycoside derived from the Dig- italis lanata plant, also known as foxglove, a poisonous plant described in the literature for several hundred years (2). Digoxin inhibits sodium-potassium adenosine tri- phosphatase (ATPase). It indirectly causes an increase in intracellular calcium of cardiac muscle cells by acting on ryanodine receptors and subsequently forming trans- membrane calcium channels and increasing cardiac con- tractility – inotropic effect (2-5). In addition, it causes an increase in vagal activity and a decrease in sinus node activity - negative chronotropic effect - and a prolonga- tion of excitation conduction in the atrioventricular node – antiarrhythmic effect (2,4). In the history of cardiology, it has been widely used to treat heart failure (HF) and AF. However, there are few studies evaluating its efficacy, and some observational studies even show possible evidence of harm (1,3,6). Digoxin has a narrow therapeutic range, which has been reduced over the last decade from 0.8 - 2.0 ng mL-1 to 0.5 - 0.9 ng mL-1, as several reviews have shown less harm especially at levels < 1.0 ng mL-1 compared to higher levels (3,4,7). The recommended dosage of digoxin depends on the route of administration, but should be adjusted to the patient’s renal function and serum levels (1,2). Digoxin is mainly excreted by the kidneys and has an elimination half-life of 1.5-2 days. In addition, lower body weight, hy- pokalaemia, hypomagnesaemia, and concomitant use of amiodarone, verapamil, macrolides, azole antifungals, and cyclosporine may result in higher digoxin serum levels due to the inhibition of P-glycoprotein transport (2,4,5). 2 Case report An 84-year-old Caucasian woman, previously treated for HF, AF, arterial hypertension (AH), and osteoporosis, presented to the emergency department (ED) of the Uni- versity Medical Centre (UMC) Maribor for shortness of breath, cough, and swelling of the lower extremities. She complained of exertional dyspnoea that had persisted for about two weeks and occurred with minimal activity. Ad- ditional information from her son revealed that she was already under the care of her general practitioner, who performed a chest X-ray (CXR) and started furosemide 40 mg twice daily, spironolactone 25 mg, and methyldi- goxin 0.1 mg once daily eight days prior to her presenta- tion at the ED. In addition, the electronic medical record confirmed that her chronic therapy consisted of vitamin D3 7000 IU per week, ferrous (III) sulphate 80 mg, per- indopril/indapamide 2/0,625 mg, and denosumab 60 mg per six months. History suggested possible memory impairment and the presence of dementia, while clinical examination re- vealed decreased breath sounds at the base of the right lung, cardiac arrhythmia with a systolic murmur, and bi- lateral pretibial pitting oedema. Her blood pressure was 150/82 mm Hg, heart rate 71 min-1, and peripheral oxy- gen saturation (SpO2) was normal. The electrocardiogram (ECG) at the time of the ED visit showed a left cardiac axis, an irregularly irregular rhythm with no discernible P waves, ventricular rate of 71 min-1, QRS complexes in pairs of two and three - possible ventricular bigeminy or trigeminy, and complete left bundle branch block (LBBB). CXR confirmed the presence of a right pleural effusion, an enlarged heart, and signs of congestion. Initial laboratory findings showed a normal complete blood count, elevated creatinine (93 µmol L-1), elevated gamma-glutamyl trans- ferase (1.84 µkat L-1), and lactate dehydrogenase (5.94 µkat L-1), and a low estimated glomerular filtration rate (49 ml min-1 1.73m-2). No electrolyte abnormalities were present: Na 135 mmol L-1, K 4.47 mmol L-1, Cl 105 mmol L-1, Ca 2.35 mmol L-1, Mg 0.98 mmol L-1. Based on the ECG changes shown in Figure 1 and the information about the newly prescribed methyldigoxin, we also tested serum di- goxin levels, which were elevated to above 5.0 µg L-1 (refer- ence range 0.5-0.9 µg L-1). Specific values could not be de- termined because specialised laboratory technicians were unavailable on call. When interviewed, the patient stated that she regularly took one tablet of methyldigoxin per day but could not remember the time of the last intake. She also reported a visual disturbance with a yellow colour. As part of the initial treatment at the ED, we pre- scribed furosemide 40 mg i.v. We consulted the toxicol- ogist at the national poison centre in Ljubljana, Slovenia, who recommended using activated charcoal 50 g p.o., 311 CASE REPORT Severe digoxin intoxication: a case report of the use of digoxin-specific Fab antibody fragments lactulose syrup 10 ml (6670 mg) p.o., and digoxin-specif- ic Fab antibody fragments. The patient was admitted to the cardiac intensive care unit. On admission, she received the digoxin-specific Fab antibody fragments (Digifab®) as instructed. Three vials (120 mg together) were diluted in 100 mL 0.9 % sodium chloride (NaCl) and infused i.v. over 30 minutes. In ad- dition, she received 20 g activated charcoal p.o. with lac- tulose 4 hours after the first dose. No premedication was given before the application of Fab antibody fragments. After completion of the infusion, another ECG was re- corded (see Figure 2), showing AF with a ventricular rate Figure 1: The patient´s ECG recorded upon presentation to the emergency department. Source: archive of University Medical Centre Maribor, Slovenia. Figure 2: The patient´s ECG recorded after treatment with digoxin specific Fab antibody fragments. Source: archive of University Medical Centre Maribor, Slovenia. 312 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2023 | Volume 92 | https://doi.org/10.6016/ZdravVestn.3380 of 71 min-1, LBBB, and resolution of QRS coupling. On admission, continuous ECG monitoring showed mild bradycardia, which later resolved and she was transferred to the Cardiology and Angiology Department ward. Se- rial measurements of digoxin and other laboratory val- ues are shown in Table 1. On further discussion with her son, he pointed out that 23 tablets of methyldigoxin 0.1 mg were missing from the pack that had been prescribed eight days before admission. Echocardiography revealed a normal-sized left ven- tricle with severely reduced ejection fraction (25-30%) and diffuse hypokinesia. The right ventricle was normal in size, with impaired systolic function (TAPSE 1.5 cm). Both atria were enlarged (LAVI 43 ml m-2, RAVI 40 ml m-2). She had mild mitral regurgitation, moderate aortic stenosis (mean gradient 35 mmHg) with mild regurgi- tation, mild tricuspid regurgitation, and severe pulmo- nary hypertension due to left heart disease with a max- imum gradient of 58 mmHg. Her therapy at discharge consisted of acetylsalicylic acid 100 mg, bisoprolol 1.25 mg, perindopril 4 mg, furosemide 40 mg, and spirono- lactone 25 mg. 3 Discussion This 84-year-old patient was admitted to our hos- pital and treated for digoxin intoxication. Considering all available information, we believe that possibly un- recognised dementia and poor participation of the pa- tient in taking the medication without supervision may have led to the intoxication with digoxin, as she took 23 tablets in 8 days, which amounted to about 3 tablets of methyldigoxin 0.1 mg daily. Adverse effects occur in up to 20 % of patients tak- ing digoxin, of which about 50 % are of cardiac origin. Because digoxin slows conduction through the si- noatrial and atrioventricular nodes, patients may suffer from various arrhythmias. The most common are sinus bradycardia, atrioventricular block, and ventricular Legend: eGFR – estimated glomerular filtration rate (CKD-EPI 2009 creatinine equation). Classification 1st day 2nd day 3rd day 6th day Reference values Digoxin (µg L-1) 5.26 7.26 4.1 1.8 0.5 - 0.9 Creatinine (µmol L-1) 93 103 103 74 49 - 90 eGFR (mL min-1 1.73-1 m-2) 49 43 43 64 80 - 120 Potassium (mmol L-1) 4.47 4.24 3.68 3.8 3.5 - 5.3 Table 1: Serial measurements of digoxin and other laboratory parameters. ectopy, including ventricular bigeminy or trigeminy, but atrial and junctional tachycardia with atrioven- tricular block, ventricular tachycardia, and ventricular fibrillation may also occur. Other adverse effects may include constipation, loss of appetite, nausea, vomiting, headache, malaise, fatigue, disorientation, yellow and green colour vision disturbances, and other visual dis- turbances (2,4). The treatment of acute digoxin intoxication varies widely, as no official evidence-based guidelines exist. However, several sources agree on the indications for treatment, namely life-threatening cardiac arrhythmias, cardiac arrest, and hyperkalaemia > 5 mmol L-1. In ad- dition, treatment should be considered if there is organ damage, severe gastrointestinal symptoms, acute inges- tion of > 10 mg digoxin in adults, or very high serum concentrations of digoxin >12 ng ml-1. Digoxin-specific antibody fragments are the most effective treatment and standard of care (4,5). The dosage depends on whether the intoxication is acute or chronic, as chronic intoxi- cation also leads to tissue deposition, and the use of di- goxin-specific antibody fragments leads to the binding of digoxin in the serum. In the case of acute intoxica- tion, the recommended number of vials is calculated ac- cording to the formula: 0.8 x the dose taken / 0.5. In the case of chronic intoxication and known serum digoxin concentration, the number of vials containing digox- in-specific Fab antibody fragments (40 mg) is calculated according to the following formula: serum digoxin con- centration (ng mL-1) x weight (kg) / 100. The dose re- sponse usually begins about 20 minutes after application and is completed after about 90 minutes. If the response is insufficient, a repeat dose should be considered after 30 minutes. The bound digoxin is later excreted in the urine with a half-life of about 20-30 hours compared to 160 hours of spontaneous elimination (4,8,9). Recent- ly, a study was published by Chan et al. in which they suggested using small, titrated doses of 1-2 vials, which resulted in a dose reduction of 65-75% and was safe and 313 CASE REPORT Severe digoxin intoxication: a case report of the use of digoxin-specific Fab antibody fragments efficient (10). In our case, the serum digoxin concen- tration was > 5.0 µg L-1 and the patient weighed about 60 kg. We used 5.0 µg L-1 for approximate calculation, which meant that we needed 3 vials. We then obtained the exact value of serum digoxin, which was 5.26 µg L-1. It is important to note that the effect of using digox- in-specific antibody fragments is assessed clinically and not by serial measurements of digoxin because serum digoxin is useless for diagnosing rebound toxicity, as it also measures digoxin bound to the antibodies (4). This is also evident in our case, where the patient clinically improved while the measured digoxin rose even higher on the second day. Therefore, we decided against further use of digoxin-specific antibody fragments. Other standards of care include a temporary pace- maker for high-grade atrioventricular block, antiar- rhythmic drugs such as lidocaine for ventricular ar- rhythmias, maintenance of acid-base status, serum magnesium, and serum potassium (4,5). Cardioversion should be avoided as it can lead to ventricular fibrillation (4). Dialysis or extracorporeal treatment is not recom- mended for digoxin intoxication as it does not remove digoxin. However, haemoperfusion with a beta-2-mi- croglobulin column has shown some beneficial effects (2,11). In addition, some case reports suggest plasma therapy in addition to Fab therapy in patients with renal failure (12). The main strengths of our manuscript are a well-doc- umented clinical vignette of an elderly patient with de- mentia, with information on serial measurements of se- rum digoxin up to 6 days and comparative ECGs before and after the use of Fab. 4 Conclusion Cardiac glycosides have long been known as drugs that have a place in cardiology because they have inotro- pic and chronotropic effects. However, studies evaluat- ing their efficacy and long-term benefits are lacking and should be conducted. Until then, their use is at the dis- cretion of the prescribing physician, who should try to optimise the patient’s therapy with other available drugs, as cardiac glycosides are not the first-line therapy, have a narrow therapeutic window, and there is a possibility of intoxication. However, if intoxication does occur, watch for the signs and symptoms mentioned and provide ap- propriate treatment. Conflict of interest None declared. Inform consent of the patient The patient gave informed consent for the publica- tion of her case. References 1. 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