Digoxin intoxication is a life-threatening condition that may result in a refractory atrioventricular block and ventricular arrhythmias. Digoxin-specific antibody fragments are safe and effective in managing severe toxicity. Although digoxin poisoning is very rare, the likelihood of a severe digoxin overdose occurrence in a setting where the expensive Fab fragments are not available is very high. We report a case of chronic oral digoxin intoxication resulting in symptomatic bradycardia. Due to the severity of the intoxication and no digoxin-specific antibody fragments in this patient setting, we performed intermittent hemodialysis. After intermittent serial hemodialysis, symptomatic bradycardia was improved and there was a reduction in digoxin serum concentration.
The incidence of digoxin intoxication is sporadic nowadays. This may be due to the limited indications and decreased use of digoxin [1,2]. Since 1990, digoxin usage has declined due to the short therapeutic dose range and the high incidence of digoxin intoxication. In 2021 United States reported 2513 cases of digoxin intoxication, of which 27 patients died. Meanwhile, incidents in Indonesia have not been widely reported [3].
Digoxin intoxication is more likely to occur in the elderly population; electrolyte disturbances (hypokalemia, hypomagnesemia and hypercalcemia), decreased kidney function, advanced age, myocardial infarction and the use of interacting drugs (diuretics, amiodarone, beta-blockers, benzodiazepines, macrolide antibiotics and propylthiouracil). The above conditions can cause chronic digoxin intoxication, even when digoxin is given at a therapeutic dose [4].
The primary management of digoxin intoxications is digoxin immune Fab (Fab), which effectively controls digoxin intoxication symptoms [5]. However, the management of digoxin intoxication in Indonesia is still constrained by the availability of Fab. Therefore, if a case of digoxin intoxication occurs, only supportive therapy can be performed. This case report explains the management of digoxin intoxication in patients with decreased renal function using hemodialysis (HD). Some recent studies suggested that HD is generally considered ineffective as a treatment for digoxin intoxication due to the large Volume of Distribution (VD) of digoxin. However, several studies still supported the use of HD in cases of digoxin intoxication [5]. We report a case of chronic digoxin intoxication with decreased renal function managed by intermittent serial HD.
A 61-year-old man, a building material dealer, was referred to Sanglah Hospital to manage suspected digoxin intoxication. The patient came with complaints of nausea and vomiting. These complaints have been felt in the last two days after taking digoxin with a dose of 0.25 mg twice daily. Nausea was initially mild and gradually worsened, mainly when the patient ate. The patient also complained of vomiting in the form of food eaten by the patient before. Initially, the patient vomited 3-5 times a day and kept getting worse until the patient decided to seek treatment. The patient also complained of anxiety and cold sweats. Complaints of pounding, tightness and chest pain were denied. The patient was only able to drink a sip of water; therefore, the patient's urine production began to decrease to ±500 mL/24 hours (0.28 mL/kg body weight (BW)/hour).
The patient's previous medical history is of not routinely treated hypertension and non-hemorrhagic stroke (SNH). In the last treatment, hemodialysis was performed three times due to the worsening condition (Table 3).
The patient has been treated with oral furosemide at a dose of 40 mg once daily and digoxin at a dose of 0.25 mg once daily due to his cardiac problem. After the third hemodialysis, kidney function improved and the hemodialysis was discontinued. However, the patient has taken digoxin at a dose of 0.25 mg twice daily for eight days without the doctor's knowledge.
The patient began complaining of nausea and vomiting that started to appear two days after taking digoxin at a dose of 0.25 mg twice a day. Complaints of nausea and vomiting worsened, so the patient went to a private clinic. The patient was suspected of having digoxin intoxication after consuming digoxin for 27 days with a total dose of 8.75 mg, accompanied by an increase in creatinine serum of 3.69 mg/dl. The patient decided to do hemodialysis due to the rise in creatinine serum from 2.77 mg/dL to 3.69 mg/dL, accompanied by symptoms of nausea, vomiting and decreased urine production, suspected due to digoxin intoxication. After that, the patient was referred to Sanglah Hospital for further treatment.
When the patient came to our General Hospital for the first time, he was compos mentis, blood pressure of 80/60 mmHg, heart rate of 42 beats/minute, respiration rate of 20 times/minute and normal axillary temperature and oxygen saturation. Cardiac examination revealed a
heart rate of 42 beats per minute with an irregular rhythm, no signs of cardiac enlargement and no additional heart sounds were found. Examination of the extremities revealed a weak pulse, with a Capillary Refill Time (CRT) >2 seconds and cold in all four extremities.
The results of the laboratory examination (28/01/2021) showed impaired kidney function (Sc = 2.89 mg/dL) accompanied by hypokalemia (K = 3.3 mmol/L) which can be seen in Table 1 and 2. The results of the ECG examination after taking digoxin with a total dose of 8.75 mg (for 27 days of taking digoxin) was junctional rhythm with a heart rate of 43 beats/minute, LAD and OMI inferior (Table 3).
Radiological examination showed a normal cardiac shape with a large cardiac size and a 55% cardiothoracic ratio (CTR) and no consolidation or nodules in the lungs. Bedside echocardiography examination revealed normal cardiac chamber dimensions, Left Ventricular Hypertrophy (LVH) concentric remodeling, Ejection Fraction (EF) of 58%, global normokinetic, mild atrial regurgitation, Estimated Right Atrial Pressure (ERAP) of 8 mmHg.
On the evaluation of circulation, the patient appeared restless, blood pressure of 80/60 mmHg and heart rate of 42 beats/minute with cold extremities. This indicates that the patient has symptomatic bradycardia. Management of symptomatic bradycardia caused by digoxin intoxication is with immediate discontinuation of digoxin, followed by administration of atropine sulfate in a 0.5 mg intravenous bolus dose, repeated every 3-5 minutes up to a maximum dose of 3 mg. After atropine was given, complaints of nausea and vomiting persisted. Blood pressure did not increase (80/60 mmHg), heart rate did not increase 40 (beats/minute). Then the patient was given dopamine drip therapy of 5 mcg/kg BW/min.
The results of the serum digoxin examination one day after the first HD were found to be above the normal limit of 2.92 ng/mL (0.8-2 ng/mL) which can be seen in Table 3. This confirms the patient's diagnosis were Symptomatic bradycardia et causa digoxin intoxication, Old myocardial infarction inferior and Acute on Chronic Kidney Disease (ACKD) et causa prerenal on Chronic Kidney Disease (CKD) et causa suspected nephrosclerosis (NS).
Table 1: Laboratory Results in the First Admission at Sanglah General Hospital
Laboratory | Results | Referral Value |
WBC | 6.68×103/μL | 4.1-11.0×103/μL |
HGB | 12.16 g/dL | 13.5-17.5 g/dL |
HCT | 38.76% | 41.0-53.0% |
PLT | 187×103/μL | 150-440×103/μL |
Albumin | 4.00 g/dl | 3.40-4.80 g/dl |
BUN | 13.0 mg/dL | 8.00-23.00 mg/dL |
Creatinine | 2.89 mg/dL | 0.70-1.20 mg/dL |
Potassium | 3.30 mmol/L | 3.50-5.10 mmol/L |
Sodium | 135 mmol/L | 136-145 mmol/L |
Calcium | 8.3 mg/dl | 8.4-9.7 mg/dl |
Inorganic Phosphorus | 3.10 mg/dl | 2.5-4.5 mg/dl |
Uric Acid | 6.3 mg/dl | 2.0-7.0 g/dl |
Random blood glucose | 110 mg/dL | 70-140 |
pH | 7.40 | 7.35-7.45 |
pCO2 | 37.0 | 35-45 mmHg |
pO2 | 139 | 80-100 mmHg |
BEecf | -1.9 | -2-2 mmol/L |
HCO3 | 22.9 | 22-26 mmol/L |
Table 2: Results of Serial Monitoring of Renal Function and Electrolytes
| 4/1/21 | 12/1/21 | 26/1/21 | 28/1/21 | 31/1/21 | 1/2/21 | 2/2/21 | 3/2/21 | 5/2/21 | 14/9/21 | 28/9/21 | Referral Value |
BUN | 36.1 | 14 | 31 | 13.0 | 19.6 | 18.7 | 6.6 | 6.9 | 3.2 | 21 | 22.7 | 8.00-23.00 mg/dL |
Sc | 3.44 | 2.77 | 3.69 | 2.89 | 3.25 | 3.25 | 1.91 | 2.4 | 2.03 | 2.70 | 2.80 | 0.70-1.20 mg/dL |
Na |
| 133 | 136 | 135 | 139 | 138 | 141 | 138 | 138 | 139 | 136 | 136-145 mmol/L |
K |
| 2.9 | 3.2 | 3.30 | 2.93 | 3.27 | 2.35 | 3.39 | 3.20 | 4.43 | 4.6 | 3.50-5.10 mmol/L |
Table 3: Results of Serial Serum Digoxin Concentration Monitoring
| Result | (The day after the 1st HD) | (The day after 3rd HD) | Referral Value |
Digoxin# | 2.92 ng/mL | 0.48 ng/mL | 0.8-2 ng/mL |
The definitive treatment for digoxin intoxication was the administration of Fab. At that time, Fab was not available at Sanglah General Hospital. Initial treatment with medication at Sanglah General Hospital had not been able to improve the patient's complaints of nausea and vomiting, heart rate (±50 times/min) and blood pressure 100/60 mmHg (with dopamine support 5 mcg/kg body weight/min). The results of the serum digoxin examination the day after the first HD were found to be above the normal limit of 2.92 ng/mL (0.8-2 ng/mL). This caused the HD to be resumed on 01/02/2021 at Sanglah General Hospital with a tunneled double lumen catheter access in the right internal jugular vein using the sustained low efficient dialysis (SLEED) method, blood flow rate (QB) of 150 ml/minute, dialysis fluid flow rate (QD) of 300 ml/minute, ultrafiltration (UF) of 0,5-1 L with a standard bolus of 2000 units of heparin and a maintenance dose of 1000 units/hour.
After doing HD twice as a treatment for digoxin intoxication and ACKD et causa prerenal on CKD et causa suspected NS, there was increase in the patient's pulse rate to an average of 62 beats/minute with improving complaints of nausea and vomiting. Dopamine drip therapy of 5 mcg/kg BW/min was discontinued. The 3rd HD was carried out again because nausea and vomiting persisted, even though there had been an improvement in the average heart rate of 70-80 beats/minute and the patient's ECG showed 1st degree atrioventricular (AV) block.
After the 3rd HD, the patient no longer complained of nausea and vomiting. Serum digoxin examination after the 3rd HD was found to be 0.48 ng/mL (0.8-2 ng/mL), therefore the patient was allowed to go home. The patient was not planned to do HD regularly because there was an improvement in Sc from 3.33 mg/dL (30/1/21) to 2.03 mg/dL (5/2/21) with urine production reaching 0.9 cc/kg BW/hour. The patient was monitored for 1 year after digoxin intoxication, similar complaints did not reappear and urine production was good, therefore HD was not continued.
In this case, the patient presented with clinical nausea, vomiting and bradycardia. These complaints raised after the patient took digoxin at a dose of 0.25 mg once daily for 19 days and a dose of 0.25 mg twice a day for 8 days, with a total dose of 8.75 mg. The patient is suspected of having chronic digoxin intoxication since it occurred with subacute drugs use, inappropriate dosing or therapeutic doses with decreased renal function [7]. Chronic intoxication is more common in older people with renal impairment, even though digoxin is given at therapeutic doses. Intoxication is also more likely to occur in patients with hypokalemia caused by oral furosemide. In this case, patient was elderly with decreased renal function, accompanied by hypokalemia which made it easier for digoxin intoxication to occur.
Symptoms of chronic digoxin intoxication are often atypical. Gastrointestinal symptoms such as anorexia, nausea, vomiting, diarrhea and abdominal pain may occur in 25% of patients with serum digoxin concentrations of ±1.5 ng/mL and up to 60% at concentrations of ±2.5 ng/mL [6]. This is consistent with clinical manifestations that occurred in this patient who came with the main complaint of nausea and vomiting.
Digoxin poisoning can cause arrhythmias including premature atrial or ventricular depolarization, ventricular fibrillation and ventricular tachycardia [9,10]. Most patients without a previous history of cardiac disease will develop sinus bradycardia with various types of AV block and supraventricular arrhythmias. Symptoms of bradycardia alone may occur in 10% of patients with serum digoxin concentrations of ±1.5 ng/mL and up to 50% at concentrations of ±2.5 ng/mL. Patient's ECG examination showed first-degree AV block with a heart rate of 97 beats/min, LAD and OMI before taking digoxin. After taking digoxin for 27 days with a total dose of 8.75 mg, there were changes in the patient's ECG, namely junctional rhythm with a heart rate of 43 beats/minute, Left Anterior Descending (LAD) artery and Old Myocardium Infarction (OMI) inferior. Changes in the patient's ECG after taking digoxin for a long time confirmed the possibility of digoxin intoxication.
The safe range of digoxin serum concentrations ranges from 0.5-2.0 ng/mL to control heart rate. Currently, the safe range used is 0.5-0.8 ng/mL, which is effective in the management of heart failure and has a low incidence of toxicity [5]. Eighty-seven percent of patients with evidence of toxicity had serum digoxin concentrations more than >2.0 ng/mL [9]. Toxicity may occur at lower serum digoxin concentrations in conditions of hypokalemia, hypercalcemia or hypomagnesemia [10]. In this case, the initial result of the serum digoxin concentration after the first HD was 2.92 ng/mL. This high digoxin concentration confirmed the patient's suspicion of digoxin intoxication, thus explaining the cause of the patient's complaints of nausea, vomiting and bradycardia.
Digoxin intoxication causes a decrease in an effective circulating volume where there is a decrease in blood flow to the kidneys resulting in a decrease in GFR and urine production. The patient had a history of decreased renal function with risk factors for hypertension so the patient was diagnosed with ACKD et causa prerenal on CKD et causa suspect NS. The condition of severe nausea and vomiting causes the patient to become severely dehydrated and digoxin intoxication explains the occurrence of prerenal factors as the cause of ACKD. This is consistent with the explanation in some literature that chronic intoxication tends to occur in patients with decreased renal function. This is because the elimination of digoxin through the kidneys is decreased.
The mechanism of digoxin intoxication is by reversibly inhibiting-the sodium-potassium ATPase pump channel in cardiac myocytes causing an increase in sodium levels in the cells. The increase in intracellular sodium causes extracellular sodium to move through other channels in place of calcium ions. The influx of calcium causes contraction of cardiac myocytes, which is followed by a slowing of conduction and a prolonged refractory period. The sodium-potassium ATPase pump channel normally causes sodium to leave the cell and potassium into the cell. Inhibition of this channel will cause an increase in serum potassium levels. Under conditions of hypokalemia, digoxin intoxication is more likely to occur. This will slow down depolarization and trigger arrhythmia. The result of the laboratory examination (28/01/2021) showed hypokalemia (Potassium serum = 3.3 mmol/L). This facilitated the occurrence of digoxin intoxication in the patient.
In this case, clinical manifestations of nausea, vomiting and bradycardia, a history of using digoxin in 27 days, an elderly patient with decreased kidney function (GFR 22.42 mL/min/1.73 m2), with a serum concentration of digoxin 2.92 ng/mL, confirmed the diagnosis of digoxin intoxication. The mechanism of action of the toxic effect of digoxin is to inhibit the binding of Na+-K+ ATPase to cardiac cell membranes, thereby reducing potassium concentrations and increasing intracellular sodium and calcium concentrations, resulting in a slowing of depolarization and triggering arrhythmias. Patients with decreased kidney function will cause high concentrations of digoxin in cardiac tissue.
Management of patients with digoxin poisoning is to stop drug administration and prevent further drug administration, symptomatic therapy, electrolyte correction, antiarrhythmics (phenytoin, lidocaine, magnesium sulfate), administration of atropine sulfate, dopamine and electrical pacemaker if needed. It is very important to perform a gastric lavage because of the possibility of delayed absorption. Examination of serum digoxin concentration should be done 6 to 8 hours after the last digoxin consumption to determine the condition of total body digoxin stores. However, in conditions of overt signs of toxicity, digoxin serum concentrations should be checked immediately. Although it is not readily available in Indonesia, Fab is the first choice to treat symptoms of cardiac and non-cardiac toxicity in patients with severe digoxin intoxication. Fab therapy will rapidly bind to circulating digoxin, then release digoxin from the sodium-potassium ATPase pump channel so that the sodium, potassium and calcium concentrations in cardiac cells become normal. This will restore the conduction system and the normal rhythm of the heart [14].
In this case, digoxin was discontinued and emergency management in patients with cases of intoxication was done. Symptomatic management of bradycardia in the form of oxygen administration, bolus atropine sulfate and continued administration of dopamine drip is recommended by the American Heart Association 2020 [15]. The next most important treatment is the administration of Fab as an antidote for digoxin intoxication. However, in this case, the Fab cannot be given because it is not available. The management of this patient's ACKD is treating the underlying cause (digoxin intoxication), fluid resuscitation and administration of inotropes. This treatment is not sufficient to overcome the increasing Sc accompanied by an oliguria condition so, it is necessary to do HD. Hemodialysis aims to maintain fluid, electrolyte, acid-base balance, prevent worsening of kidney function and reduce serum digoxin levels [17].
Extracorporeal treatments (ECTRs) were not the mainstay of therapy for digoxin intoxication because the estimated digoxin elimination results are quite low when compared to the concentration of digoxin in the body.
Hemodialysis (HD) is not the mainstay of therapy for digoxin intoxication because the estimated digoxin elimination results are quite low when compared to the concentration of digoxin in the body.
A serial case report in 21 patients with End-Stage Renal Disease (ESRD) has showed that HD was able to eliminate 3-3.8% of the total digoxin in the body [7].
Digoxin's small molecular weight and low protein binding are not barriers in HD. The main barrier is the large digoxin VD, of which most of the digoxin is in the tissues. After HD, there will be the elimination of digoxin in the circulation but there will be a transfer of digoxin back from the tissues to the circulation. This causes the need for repeated HD, resulting in a significant decrease in VD to relieve symptoms of intoxication. After undergoing medical treatment for symptomatic bradycardia in this patient, there was no improvement where the patient's average heart rate was still less than 60 beats per minute accompanied by symptoms of nausea and vomiting. The HD treatment performed on this patient was also suggested by the extracorporeal treatments in poisoning (EXTRIP) workgroup.
In this case, HD management for digoxin intoxication therapy has been carried out according to EXTRIP recommendations, namely; in patients with an impaired renal function who experienced digoxin intoxication, where Fab was not available in health services at that time.
Management of the 2nd HD in this patient was able to improve the patient's heart rhythm from the junctional rhythm with a heart rate of 43 times/minute requiring dopamine mcg/kg BW/min to normal Atrial Fibrillation (AF) rhythm ventricular response (mean heart rate 62 beats/min) without dopamine administration. After the 3rd HD, the complaints of nausea and vomiting disappeared. The use of intermittent serial HD as an alternative to Fab as a therapy for digoxin intoxication, in this case, has proven successful in overcoming the symptoms of digoxin intoxication.
Examination of serum digoxin concentration values was carried out several hours after HD was performed. Measurement of digoxin concentration during the HD process is not recommended, this is due to the rebound mechanism of digoxin from the tissue to the circulation after the HD process. High plasma clearance in a short time (intermittent HD) is not able to eliminate the body's stores of digoxin significantly. For example, HD with digoxin clearance of more than 100 mL/min was able to reduce serum digoxin half-life by >90%. However, it was only able to reduce <5% of the dose of digoxin consumed. In this case, digoxin serum was tested twice. Both examinations were performed >6 hours after HD so that the results can be used as a reference for diagnosis and monitoring of digoxin intoxication. The results of serum digoxin examination after third HD showed a decrease from 2.92 ng/mL to 0.48 ng/mL (0.8-2 ng/mL). This proves that in this case, the use of serial HD was beneficial in reducing serum digoxin.
List of Abbreviation
BW : Body weight
SNH : Non-Hemorrhagic stroke
Fab : Digoxin immune Fab
HD : Hemodialysis
VD : Volume of distribution
BW : Body Weight
CTR : Cardiothoracic ratio
LVH : Left ventricular hypertrophy
EF : Ejection fraction
ACKD : Acute on chronic kidney disease
CKD : Chronic kidney disease
NS : Nephrosclerosis
SLEED : Sustained low efficient dialysis
QB : Blood flow rate
QD : Dialysis fluid flow rate
UF : Ultrafiltration
AV : Atrioventricular
LAD : Left Anterior Descending
OMI : Old Myocardium Infarction
ECG : Electrocardiography
AF : Atrial fibrillation
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