Elevated Serum Digoxin Concentration Research Articles

Elderly patients with suspected chronic digoxin toxicity: A comparison of clinical characteristics of patients receiving and not receiving digoxin-Fab.

The aim of the present study was to compare clinical features of patients with elevated serum digoxin concentrations who were treated with digoxin-Fab with those where the immunotherapy was not given by a tertiary hospital toxicology service. This was a retrospective series of patients with supratherapeutic serum digoxin concentrations referred to the toxicology service from August 2013 to October 2015. Data collected included demographics, presenting complaint, digoxin dose, other medications taken, serum digoxin, potassium and creatinine concentration on presentation and initial and post-digoxin-Fab heart rate. There were 47 referrals. Digoxin-Fab was administered in 21 cases. It was given more commonly when the heart rate was <51/min or serum potassium was >5.0 mmol/L. Patients receiving digoxin-Fab were more likely to be on maintenance therapy with beta-blockers or calcium channel blockers (95% vs 61%; OR 13.1; 95% CI 1.5-113) and/or potassium-sparing medications (95% vs 54%; OR 17.1; 95% CI 2.0-147). They had elevated serum creatinine (76% vs 42%; OR 8.2; 95% CI 1.9-34), higher serum potassium (median: 5.1 mmol/L vs 4.2 mmol/L, P = 0.02), higher serum digoxin concentration (median: 3.5 nmol/L vs 2.3 nmol/L, P = 0.02) and pretreatment heart rate <51/min (66% vs 31%; OR 4.5; 95% CI 1.3-15). There were no patients with ventricular arrhythmias or hypotension. Median heart rate increased by 10/min 1 and 4 h after digoxin-Fab. However, individual heart rate response to digoxin-Fab was variable. Digoxin-Fab was more commonly administered when heart rate was <51/min. It had a small effect on increasing heart rate; however, individual response to digoxin-Fab was variable as patients were using other negative chronotropic medications. In symptomatic bradycardic patients on multiple heart failure medications, positive chronotropic and potassium-lowering therapies should be considered in concert with digoxin-Fab.

Interaction between digoxin and dronedarone in the PALLAS trial.

Elevated serum digoxin concentration can cause toxicity, including death. Dronedarone increases digoxin concentration by P-glycoprotein interaction. In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of Standard Therapy Trial (PALLAS), dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation. The present analysis examines whether the dronedarone-digoxin interaction might explain these adverse outcomes. Subgroup analysis was performed to compare outcomes of patients on digoxin at baseline or not. In PALLAS, 1619 patients were randomized to dronedarone and 1617 to placebo, of whom 544 (33.6%) and 526 (32.5%) were receiving digoxin, respectively. Median (Q1,Q3) digoxin serum concentration on day 7 was 1.1 (0.7,1.5) ng/mL on dronedarone and 0.7 (0.5,1.1) ng/mL on placebo (P<0.001). Among patients on digoxin, there were 15 (8.6%/year) cardiovascular deaths on dronedarone and 2 (1.2%/year) on placebo (adjusted hazard ratio, 7.31; 95% confidence interval, 1.66-32.20; P=0.009). Among patients not on digoxin, there were 6 cardiovascular deaths on dronedarone (1.7%/year) and 8 on placebo (2.2%/year; adjusted hazard ratio, 0.67; 95% confidence interval, 0.23-1.95; P=0.46; interaction P value 0.01). In patients on digoxin, there were 11 arrhythmic deaths on dronedarone and none on placebo; and in patients not on digoxin, there were 2 arrhythmic deaths on dronedarone and 4 on placebo (P value for interaction 0.002). There was no interaction between baseline digoxin use and the adverse effect of dronedarone on heart failure events. In PALLAS, there was a strong effect of concurrent digoxin use on the adverse effect of dronedarone on cardiovascular death, but not on occurrence of heart failure. http://www.clinicaltrials.gov. Unique identifier: NCT01151137.

Sudden Blindness in a Hemodialysis Patient on Digoxin

A hemodialysis patient with atrial fibrillation and ischemic heart disease, already taking amiodarone and diltiazem, presented with complete blindness after commencing digoxin. A highly elevated serum digoxin concentration was discovered and treated with Digibind ® , with gradual but complete return of his vision. This case highlights a rare complication of digoxin potentiated by renal failure, medication interactions and poor communication. World J Nephrol Urol. 2014;3(2):100-102 doi: http://dx.doi.org/10.14740/wjnu155w

Positive and Negative In Vitro Interference of Chinese Medicine Dan Shen in Serum Digoxin Measurement

Dan Shen, a traditional Chinese medicine used in the management of cardiovascular diseases, is now available without prescription in the United States from Chinese herbal stores. We demonstrated digoxin-like immunoreactivity of Dan Shen in vitro. Because Dan Shen is used to treat cardiovascular disease, we studied potential interference of Dan Shen with serum digoxin measurement. Addition of microliter quantities of Dan Shen extract to digoxin pools prepared from patients receiving digoxin resulted in falsely elevated serum digoxin concentrations (positive interference) as measured by the fluorescence polarization immunoassay for digoxin (Abbott Laboratories, Abbott Park, IL). More interestingly, serum digoxin concentrations were falsely lowered (negative interference) when measured by the microparticle enzyme immunoassay, also marketed by Abbott Laboratories. Taking advantage of poor protein binding of digoxin (25%) and high protein binding of digoxin-like immunoreactive components of Dan Shen, we further demonstrated that the positive and negative interference of Dan Shen in serum digoxin measurement can be eliminated by monitoring the free digoxin concentration.

Digoxin Immune Fab Administration following an Unexplained Increase in Serum Digoxin Concentration

Objective: To report a case of digoxin immune Fab (DIF) administration following an unexplained increase in serum digoxin concentration in an asymptomatic patient with chronic renal failure. Case Summary: A 70-year-old man presented to the hospital with congestive heart failure, atrial fibrillation, chronic renal failure, and suspected digoxin toxicity. By day 3, he developed a more stable cardiac rhythm with nodal beats. His last known digoxin dose was 12 hours prior to admission. No explanation for an elevated serum digoxin concentration 48 hours after admission could be found. Despite absence of other signs of digoxin toxicity, DIF 80 mg iv was administered, and was immediately followed by 40 mg. Discussion: This case illustrates that elevated digoxin concentrations may be observed in patients with renal failure. These may not be true high concentrations because of the following potential factors: (1) the presence of digoxin-like factors, (2) increased biotransformation of digoxin, and (3) accumulation of metabolites that interfere with the assay. Digoxin metabolites are known to cross-react with the antibodies in commonly used digoxin immunoassays, and may be inappropriately interpreted to signal digoxin toxicity. Both the accuracy and reliability of digoxin immunoassay techniques have been questioned or challenged over the years. It is difficult to determine whether a reported toxic serum digoxin concentration represents the true concentration or cross-reactivity between digoxin metabolites and antibodies used in most digoxin immunoassays. Data Sources: Data collection sources included retrospective review of patient medical records, personal contact with one of the physicians involved in rendering patient care for interpretation of the electrocardiogram changes, clinical symptoms and rationale for DIF administration, and contact with the immunoassay technologist, who indicated that the fluorescence polarization immunoassay technique was used for analysis of digoxin concentrations. The medical literature then was reviewed. Conclusions: DIF should be reserved for use in symptomatic patients. Elevated digoxin concentrations must be evaluated for various factors that can cause falsely elevated values. Clinical signs and symptoms are critical in making the decision to use Fab. Antidotal measures should be based on correlation of patient symptoms with serum digoxin concentrations.

The influence of diltiazem hydrochloride on trough serum digoxin concentrations.

A significant drug interaction between verapamil and digoxin, resulting in elevated serum digoxin concentrations, has been well documented in the medical literature. However, a similar interaction between digoxin and the calcium channel blockers nifedipine and diltiazem has not been conclusively established. This study investigated the influence of diltiazem hydrochloride on trough serum concentrations of concurrently administered digoxin in eight healthy volunteers. During the control phase of the study, volunteers were administered digoxin 0.25 mg/d for 13 days, and subsequently judged to be at steady state by serial determinations of digoxin serum concentrations. Twenty-four hour urine collections were done for creatinine clearance and urinary digoxin clearance determinations. Phase II of the study involved the addition of diltiazem hydrochloride 30 mg qid to the on-going, daily regimen of digoxin. After 14 days of concomitant therapy, steady-state trough digoxin concentrations were again determined, as well as creatinine clearances and urinary digoxin clearances. This investigation demonstrates that concomitant administration of diltiazem hydrochloride with digoxin results in significantly elevated steady-state trough digoxin concentrations (0.32 +/- 0.07 ng/ml increasing to 0.48 +/- 0.06 ng/ml, p less than 0.01). Urinary digoxin clearance decreased from 223.5 +/- 35.7 ml/min to 153.4 +/- 17.5 ml/min (p less than 0.05). Creatinine clearances were unaltered. A review of the current literature on this topic is included.

CHARACTERISTICS OF DIGOXIN INTERACTION WITH QUINIDINE, VERAPAMIL AND AMIODARONE: IN VIVO AND IN VITRO STUDIES

Recently several drugs which are commonly coadministered with digoxin have been shown to cause toxic accumulation of the cardiac glycoside. The interactions with quinidine and verapamil have been attributed in part to reduced renal clearance of digoxin. Since GFR is not altered it appears that renal tubular secretion of digoxin must be inhibited. We studied the effect of amiodarone on serum digoxin concentrations (SDC) in 10 children aged 0.5-18 yrs. There was a 68-800% increase in SDC (P<.025) when both drugs were used in normally recommended doses. Digoxin renal clearance was reduced by 10-44% without corresponding alteration in creatinine clearance. A similar interaction was demonstrated in rats. The addition of amiodarone 30 mg/kg/day caused SDC to increase from 0.68±0.08 (mean ± SD) to 11.22 ± 2.16 ng/ml (P<0.005). Subsequent studies in vitro have examined the effect of quinidine, verapamil, and amiodarone on the uptake of 125I digoxin in renal cortical slices of rats. Therapeutic concentrations of quinidine (5 ug/ml), verapamil (500 ng/ml), and amiodarone(2 ug/ml) caused significant inhibition of digoxin uptake by renal slices (26%, 15%, and 16% respectively) (P<.01). Quinidine and verapamil were shown to cause further dose-dependent inhibition of digoxin uptake. These studies support the suggestion that elevated SDC is induced by reduction in the tubular secretion of digoxin caused by quinidine, verapamil, and amiodarone. Whenever these drugs are added to digoxin therapy, follow-up assessment of SDC is mandatory.

Cardiac arrhythmias in patients on maintenance hemodialysis.

17 patients on maintenance hemodialysis were monitored for cardiac arrhythmias using ambulatory electrocardiographic recording. Atrioventricular dissociation was found in a patient with an elevated serum digoxin concentration, intradialytic supraventricular tachycardia had been present in a second patient during acute uremic pericarditis prior to the study. Ventricular premature beats (VPB) were absent or of low grade (occasional/uniform) in 14 patients and did not increase on dialysis. 3 patients had potentially dangerous VPB of higher grades (multiform, salvos or R on T) which occurred on or after dialysis in 2. 2 of these 3 patients were overdigitalized, and 2 had severe cardiac disease (amyloid, old myocardial infarction). Several other risk factors (age, hypertension, cardiac hypertrophy, smoking, hyperlipidemia, electrolyte changes) did not seem to be of importance for VPB. In these patients on maintenance hemodialysis, potentially dangerous VPB were rare and occurred mainly during or after dialysis in patients with preexisting heart disease and/or digitalization.

Digoxin and Low-Birth-Weight Infants

In their recent communication, Johnson et al suggested that conventional digoxin use may be sufficiently toxic forlow-birth-weight infants to prompt consideration of alternative therapies. This conclusion was supported by their detection of digitalis associated illness in 9/18 small premature infants receiving digoxin in doses of 0.003 to 0.005 mg/kg twice per day. The documentation of abnormally elevated serum digoxin concentrations in 7/9 patients further supports the possibility of clinically significant digoxin toxicity. Akin to the findings of Berman et al and Pinsky et al, this investigation only confirms the observation that overdosage of infants with digoxin may result in digitoxicity.

Oleander Interference in the Digoxin Radioimmunoassay in a Fatal Ingestion

An elderly woman allegedly ingested oleander leaves and died. Ventricular arrhythmias and asystole were unresponsive to cardiopulmonary resuscitation, pharmacologic agents, and cardioversion. The patient, who had no access to digoxin, had an initial serum digoxin concentration of 5.8 ng/mL. Cross-reactivities between oleander extract and pure oleandrin and digoxin in the digoxin radioimmunoassay were 100:1 and 29,000:1, respectively. We postulate that glycosides in oleander leaves produced the elevated serum digoxin concentration. Based on an assumed volume of distribution of the oleander glycosides of 1 L/kg, the calculated lethal dose absorbed by our patient was 200 times greater than lethal doses in several animal species and corresponded to the absorption of 4 g of oleander leaves.

Digitoxin elimination reduced during quinidine therapy.

Elevated serum digoxin concentrations and clinical toxicity have been reported in patients receiving quinidine. The present study was undertaken to ascertain whether a similar interaction occurs between quinidine and another cardiac glycoside, digitoxin, and if so to evaluate the pharmacokinetic basis in five healthy volunteers. In the presence of quinidine the serum digitoxin concentration was elevated, the mean digitoxin elimination half-life was increased from 87.8 +/- 11.6 to 218.3 +/- 20.6 h (mean +/- SEM) (p < 0.01), and mean total body clearance was reduced from 5.01 +/- 1.18 to 1.87 +/- 0.20 mL/h x kg (p < 0.052). No change was observed in the apparent volume of distribution or in the volume of the central compartment for digitoxin. The data suggest that the mechanism for this interaction is a reduction in elimination and not displacement of digitoxin from tissue binding sites.