Evaluating plasma Digoxin concentration after an intravenous loading dose in patients with renal failure

Background: Digoxin is a medication of Glycoside family which is commonly prescribed for patients with atrial fi brillation, atrial fl utter, and heart failure. With a narrow therapeuticlevel(0.5–2 ng/mL), careful monitoring of digoxin blood level is necessary. Symptoms of digoxin toxicity include nausea, vomiting, visual changes, altered mental status, hyperkalemia, and cardiovascular collapse. As renal failure decreases the clearance of digoxin, and impaired renal function is common in heart failure, this population is at higher risk of toxicity. Methods & materials: In this prospective study, patients with chronic kidney diseasenondialysis (CKD-ND) who were admitted with heart failure or atrial fi brillation at university hospital, were enrolled. Digoxin-naive patients were treated with a 10 mcg/kg intravenous digoxin loading dose. Serum digoxin level was measured 6 to 12 hours after the last loading dose. Patients were followed for 48 hours for signs of toxicity. Correlation between therapeutic digoxin level and degree of renal failure was evaluated. The effect of serum electrolyte (magnesium, calcium, and potassium) concentration on digoxin level was determined. Pregnant women were excluded from study. Results: From 2018 to 2020, 87 CKD patients, (60 (69%) men and 27 (31%) women) aged from 31 to 92 years old, with a mean age of 70.51 ± 14.06 years were admitted to the cardiac unit. Near 80% of the cohort were CKD stage 3 and 4 patients. About half of patients had digoxin levels in therapeutic range (45 cases = 51.7%), followed by 24.1% with supra therapeutic and the other 24.1% with toxic levels. There was signifi cant relationship between GFR and serum digoxin concentration (p-value = 0.038); the lower the GFR was, the higher was the digoxin level and also between serum creatinine and digoxin level (p value: .04). Serum digoxin concentration had signifi cant correlation with serum magnesium level (p-value = 0.006). Conclusion: this study demonstrated that monitoring plasma Digoxin concentration after an intravenous loading dose in patients with renal failure can be very helpful to prevent digoxin toxicity. The lower the GFR was, the higher the digoxin level and the risk for toxicity if the bolus and even maintenance do not monitor meticulously. Research Article Evaluating plasma Digoxin concentration after an intravenous loading dose in patients with renal failure Vahid Eslami1, Fatemeh Mortezapour2, Shiva Samavat3, Shadi Ziae4 and


Introduction
Digoxin is one of the frequently prescribed medications with a narrow therapeutic range and many drug interactions [1,2].
Increasing cardiac output and thereby decreasing ventricular fi lling pressures are the potential benefi ts of digoxin therapy in heart failure patients as a positive inotropic agent [3].
Plasma half-life range of digoxin varies from 20 to 50 hours, which is variable with a bioavailability of approximately 66%. Steady state plasma concentrations of digoxin are also altered proportionally to renal clearance of creatinine. The bioavailability and biotransformation of digoxin do not seem to vary between healthy subjects and patients with renal insuffi ciency. As the volume of distribution is smaller in patients with severe renal failure that normal subjects, the loading dose has to be altered. On the basis of this assumption, with decreasing creatinine clearance, the total body clearance as well as the renal clearance of digoxin is reduced [4].
In patients with renal failure, the half-life of digoxin increases, so that even in end-stage renal disease, it can be up to 4-6 days [5]. Due to the renal excretion of digoxin, renal dysfunction can lead to higher plasma concentrations and consequent toxicity. Renal failure, congestive heart failure, old age, and electrolyte abnormalities such as low potassium, phosphate, or calcium may worsen the condition [6].
Glomerular fi ltration damages in Chronic Renal Failure (CRF) constantly increase the risk of atherosclerosis and other heart diseases [7]. Oxidative stress also plays a central role in cardiovascular dysfunction. Evidence shows that uremia and hemodialysis in CRF increase levels of reactive oxygen species [8,9]. Thus, renal dysfunction is common in heart failure patients and can increase related mortality especially in GFR<60 ml/min [10]. Optimum Serum digoxin concentration (SDC) is supposed to be about 0.8 ng/mL, and it is essential to monitor its plasma concentration, particularly when ejection fraction falls below45% [11,12]. Since Digoxin inhibits the sodium-potassium pumps and increases intracellular calcium in myocardial cells, patients with renal dysfunction are more prone to electrolyte imbalance in case of taking Digoxin [13]. Digoxin toxicity symptoms includes nausea, vomiting, visual changes, altered mental status, hyperkalemia, and cardiovascular collapse [14]. Perceiving renal function during the treatment of heart failure using digoxin is necessary to prevent possible complications [16]. The purpose of this study is to assess the plasma Digoxin concentration after an intravenous loading dose in patients with renal failure. Also, this study evaluates the relationship between serum digoxin level with demographic and clinical characteristics including age, sex, serum electrolyte values (sodium, potassium, and magnesium), and creatinine level.

Material and methods
This prospective study was conducted in patients with Heart Failure (HF) or Atrial Fibrillation (AF) with underlying chronic kidney dysfunction who referred to the university hospital, from 2018 to 2020. In this study, 87 patients aged 31 to 92 years were hospitalized in the cardiac care unit and after obtaining informed written consent, they were included in the study. All the study protocols were approved by the Ethics Committee of Shahid Behesti University of Medical Sciences.
All the information was recorded in patients' electronic record.   Table 1 Serum digoxin level was in therapeutic range in almost half of the patients (45 cases = 51.7%), while21 cases (24.1%) had supra therapeutic levels and toxic levels was observed in 21 cases (24.1%). Laboratory fi ndings of different groups and correlation with Digoxin therapeutic concentration are shown in the Table 2. There was no signifi cant differences between clinical signs of digoxin toxicity like nausea and vomiting between groups.

Discussion
Our study shows a signifi cant correlation between the measured digoxin serum concentration with GFR (P value= 0.03) and Creatinine (p value= 0.04), while no correlation was found with age and gender. It was also shown that although there was a signifi cant correlation between digoxin levels and magnesium and sodium levelin two groups , correlations with different stages of renal function (GFR) were not observed.
These results are the same as reported in similar studies [17,18].
Digoxin, as a digitalis glycoside, improves the hemodynamic and neurohormonal perturbations which plays a crucial role in Heart Failure (HF) induced renal dysfunction. Abnormal energy metabolism increased production of reactive oxygen species (ROS), and defects in excitation-contraction are the hallmarks of Heart Failure due to impaired ventricular fi lling or blood ejection [19,20]. Digoxin increases intracellular calcium in myocardial cells and inhibits the sodium-potassium pump, besides, induces an increase in intracellular Na+ and Ca2+ [21].
However, our study did not show a signifi cant relationship between sodium and potassium levels with digoxin levels, which may be due to minor changes in the levels of electrolytes. However, the difference in sodium levels between the two groups with Digoxin therapeutic and toxicity concentration, was signifi cant.
A case-control study of patients who took digoxin for a long time and had a toxic level compared with those who recently received a therapeutic dose of digoxin reported that There were no differences between case and control groups with creatinine, age, or sex [22].
The fi ndings show that there is a signifi cant direct  Creatinine levels are used to monitor chronic kidney disease [28]. GFR less than 10.0 ml per minute per 1.73 m 2 considers as end-stage renal disease and they are higher risk for cardiovascular events compared to other stages [29]. A study in 2018 introduced urea and serum creatinine as the best criteria for predicting mortality in patients with chronic digoxin poisoning [30].

Conclusion
This study emphasize on importance of weight adjusted doseselection ofdigoxin not only in the maintenance dose but also in the bolus dose and demonstrated that monitoring plasma Digoxin concentration after an appropriate and measured intravenous loading dose in patients with renal failure can be very helpful to prevent digoxin toxicity. By checking the serum level of digoxin during treatment and the level of serum electrolytes, including magnesium, it can be ensured that no digoxin poisoning will occur, and in cases with digoxin toxic symptoms, the necessary procedures are taken.