Digitalis Toxicity Research Articles

Immediate and delayed allergic reactions to Crotalidae polyvalent immune Fab (ovine) antivenom

Allergic reactions are the most commonly reported adverse events after administration of antivenoms. Conventional horse serum-based crotalid antivenom used in the United States (Antivenin [Crotalidae] polyvalent) can lead to both immediate and delayed hypersensitivity reactions. Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) has recently been approved for use in the United States. Experience from premarketing trials of this product and in the administration of other types of Fab, such as in digoxin poisoning, has demonstrated these fragments to be safe and effective, with a low incidence of sequella; however, allergic reactions can occur when any animal-protein derivatives are administered to human subjects. We report in detail the nature and course of allergic reactions that occurred in 4 patients treated with FabAV. Cases of anaphylaxis, acute urticaria, angioedema, and delayed serum sickness are described. All reactions were easily treated with some combination of antihistamines, epinephrine, and steroids, with prompt resolution of signs and symptoms enabling further dosing of antivenom as required. Several of these cases may have resulted from batches of antivenom contaminated with Fc fragments. The overall incidence of immediate and delayed allergic reactions to this product appears so far to be lower than that reported with conventional whole-immunoglobulin G (IgG) antivenom, but postmarketing surveillance is warranted. [Clark RF, McKinney PE, Chase PB, Walter FG. Immediate and delayed allergic reactions to Crotalidae polyvalent immune Fab (ovine) antivenom. Ann Emerg Med. June 2002;39:671-676.]

Use of Digoxin Monitoring in a Hospital Setting as an Essential Tool in Optimizing Therapy

Objective To determine what triggers the use of digoxin therapeutic drug monitoring (TDM) that adheres to established indications and the change in digoxin dosage after the result of monitoring is obtained. Methods This prospective study included 86 patients admitted to 6 medicine wards and 2 intensive cardiac care unit wards in a tertiary-care center. Data on patients' demographics, drug therapy, serum chemistry values, indications for digoxin therapy, indications for ordering the drug assay, timing of the blood sample relative to administration of the last dose, and physicians' decisions after attaining serum digoxin concentrations were collected. Results Eighty-six digoxin assays were evaluated. Indications for the use of a digoxin assay were mostly routine without a clear indication (66%); in only 22% of the assays were orders considered clinically justified. Eleven patients had concentrations >2 ng/mL, but only 8 patients had digoxin intoxication. In only 31% of patients did the medical staff respond to the results. In only 21% of patients with subtherapeutic drug concentrations was there a change in digoxin dose. Conclusions Although there are clear indications for the use of digoxin TDM, physicians seem to routinely order these blood tests. The clinicians did not adequately use the digoxin concentration data to optimize therapy. The assistance of a clinical pharmacist or pharmacologist is warranted for use of the assays, to optimize digoxin therapy.

Digoxin Assays: Frequent, Substantial, and Potentially Dangerous Interference by Spironolactone, Canrenone, and Other Steroids

A case of digoxin toxicity resulted from falsely low values with the MEIA II assay for digoxin (AxSYM; Abbott). The low results were caused by negative interference from canrenone and spironolactone, the latter of which has recently been advocated for the treatment of severe heart failure. Analytical interference from spironolactone has been reported, but little information is available for this effect with newer digoxin assays. We examined nine assays (AxSYM, IMx, TDx, Emit, Dimension, aca, TinaQuant, Elecsys, and Vitros for interference by spironolactone, canrenone, and three metabolites. Additionally, all routine digoxin measurements (AxSYM) over a period of 16.5 months (n = 3089) were monitored for interference. Suppression of the expected values by canrenone (3125 microg/L) was observed for the AxSYM (42% of expected value), IMx (51%), and Dimension (78%) assays. A positive bias was observed for the aca (0.7 microg/L), the TDx (0.62 microg/L), and the Elecsys (>0.58 microg/L). Twenty-five of 669 routinely monitored patients had falsely low results. Nineteen of these had potentially toxic concentrations of digoxin (Emit; >2.0 microg/L), although the AxSYM assay indicated therapeutic or less severe toxic concentrations (Delta(max) = 7.1 microg/L). Except for two unresolved cases, this was attributable to spironolactone, canrenone, hydrocortisone, or prednisolone. Standard doses of spironolactone (up to 50 mg/day) in patients with heart failure displayed inhibition <11%. The frequency and magnitude of the false-negative results particularly compromise the use of both microparticle enzyme immunoassays. Not only may toxic concentrations remain unidentified, but intoxication could occur should dosage be increased because of falsely low results. With 11 million digoxin tests/year ordered in the US, conceivably many patients could be adversely affected.

Late rebound digoxin toxicity after digoxin-specific antibody fab fragments therapy in anuric patient

Late rebound digoxin toxicity after digoxin-specific antibody fab fragments therapy in anuric patient

Secretion of xenobiotics via multidrug resistance protein (MDR) in kidney: application to development of artificial "hybrid kidney"

This review deals with the functional significance of multidrug resistance protein (MDR) in the renal proximal tubule, and the possible application of MDR to an artificial "hybrid kidney" for the treatment of digoxin intoxication. Rhodamine 123 was used as a fluorescent substrate of MDR to measure the efflux of the drug across the luminal membrane in isolated perfused mouse proximal tubules. The efflux was completely blocked by the addition of verapamil to the lumen. In the proximal tubule from mdr1a/1b double-knockout mice, the secretion of rhodamine 123 was completely blunted. Another substrate of MDR, digoxin, after repeated administration, accumulated in the kidney to a much greater extent in the knockout mice than in controls, indicating that secretion of the drug occurred via MDR in kidney. We also established a system in which MDR-overexpressed renal cells were cultured on a hollow-fiber device. We evaluated the efficacy of this device for removing substrates of MDR from culture medium. The device selectively removed digoxin and doxorubicin from the medium in an in-vitro circulation system. The device was also confirmed to have a very high capacity for selective digoxin removal from circulating blood when it was employed in vivo in dogs with digoxin intoxication. This approach is expected to be employed in the future for the treatment of patients with drug intoxication.

Tensilon and the Diagnosis of Myasthenia Gravis: Are We Using the Tensilon Test Too Much?

Tensilon (edrophonium chloride) is a reversible acetylcholinesterase inhibitor used in the diagnosis of myasthenia gravis, diagnosis and treatment of arrhythmias, detection of early digitalis toxicity, reversal of neuromuscular blockade, and other medical conditions. Toxicity associated with Tensilon use has appeared in the literature for decades. This review discusses the risks of Tensilon and the information practitioners should know before administering the drug. We review the literature regarding serious toxicity of this drug and offer recommendations for its safe use. A careful medication history should be taken before the administration of Tensilon. Additionally, physicians should be aware of appropriate alternative methods of diagnosis before choosing to administer Tensilon. Physicians should be aware of the clinical situations where the Tensilon test no longer is indicated.

Effect of age on mortality, hospitalizations and response to digoxin in patients with heart failure: the DIG study

OBJECTIVESThis study was designed to determine the effect of increasing age on mortality, hospitalizations and digoxin side effects in patients with heart failure (HF), and to determine whether the effect of digoxin on clinical outcomes varies as a function of age.BACKGROUNDThe incidence and prevalence of HF increase with advancing age, but there are limited data on the clinical course and response to specific therapeutic interventions in elderly patients with HF.METHODSThe Digitalis Investigation Group (DIG) study was a prospective, randomized clinical trial involving 7,788 patients with HF randomized to digoxin or placebo and followed for an average of 37 months. In the present analysis, patients were stratified into five age categories: <50 years (n = 841), 50 to 59 years (n = 1,545), 60 to 69 years (n = 2,885), 70 to 79 years (n = 2,092) and ≥80 years (n = 425). Interactions between age and the following clinical outcomes were examined: total mortality, all-cause hospitalizations, HF hospitalizations, the composite of HF death or HF hospitalization, hospitalization for suspected digoxin toxicity and withdrawal from therapy because of side effects.RESULTSIncreasing age was an independent risk factor for total mortality, all-cause hospitalization, HF hospitalization, HF death or hospital admission, hospitalization for suspected digoxin toxicity and withdrawal from digoxin therapy (all p < 0.001). However, there were no significant interactions between age and digoxin treatment with respect to any of the major clinical end points.CONCLUSIONSIncreasing age is associated with progressively worse clinical outcomes in patients with HF. However, the beneficial effects of digoxin in reducing all-cause admissions, HF admissions, and HF death or hospitalization are independent of age. Thus, digoxin remains a useful agent for the adjunctive treatment of HF due to impaired left ventricular systolic function in patients of all ages.

Two Cases of Digitalis Toxicity with Reversible and Severe Decrease of Visual Acuity

We performed electrophysiologic tests on two patients with digitalis toxicity who first had photophobia and xanthopsia and revealed reversible reduced visual acuity and binocular central scotoma. The patients were a 72-year-old male and a 54-year-old male who had symptoms of digitalis toxicity. The corrected visual acuity was severely decreased during digitalis toxicity, 0.02 oculus dexter (OD) and 0.1 oculus sinister (OS) in case 1 and 0.04 OD and 0.2 OS in case 2. But visual acuity recovered as the blood levels of digitalis decreased to the normal level and the corrected visual acuity was 0.7 OD and 0.8 OS in case 1 and 0.8 OD and 0.9 OS in case 2. We recorded 30 Hz-flicker electroretinogram (ERG), single flash ERG, photopic ERG, and scotopic ERG when digitalis blood levels were elevated and normal. Decreased amplitudes of 30 Hz-flicker ERG and photopic ERG suggested that photoreceptor function was disturbed at digitalis toxicity and cone dysfunction was more severely disturbed than rod dysfunction. 30 Hz-flicker ERG, as well as electrocardiogram and digitalis blood level, is a relatively convenient and useful measure of digitalis toxicity. It is necessary consiler toxicity when severe visual dysfunction is observed in patients with digitalis therapy.

Nursing protocol: artificial airway management.

The purpose of this study was to determine whether homecare workers can detect signs and symptoms indicative of potential adverse drug reactions (ADRs) in homecare patients, using a standardized observation list.This observational study involved 115 patients cared for by 2 homecare organizations in The Netherlands between April 2011 and August 2011. During routine home visits, homecare workers filled out a standardized observation list of signs and symptoms indicative of potential ADRs, namely, gastrointestinal and other bleedings, electrolyte disturbances, renal and heart failure, digoxin intoxication, constipation, disturbances of diabetic control, and falls. Their observations were compared against the medications that the patients were using and their known side effects, by a panel of clinical pharmacology experts. Sensitivity, specificity, and positive and negative predicted values of the standardized observations were calculated.In total, 234 signs and symptoms indicative of potential ADRs were observed by the homecare workers, 116 (49.6%) of which were considered drug related. More than one-half of the observed signs of gastrointestinal bleeding could be considered as drug related. Observed dizziness (64.1%) and drowsiness (53.3%) could be drug related in most cases, as could most cases (71.4%) of fainting spells (indicative of renal or heart failure). Seventeen of 20 observed falls could be drug related. The specificity of the standardized observation list was high, varying from 0.70 (confidence interval 0.62–0.77) to 0.97 (confidence interval 0.95–0.98).Signs and symptoms indicative of potential ADRs recorded by homecare workers using a standardized observation list can aid in the early recognition of ADRs in homecare patients.

The effects of captopril on serum digoxin levels in patients with severe congestive heart failure.

The effects of captopril on serum digoxin concentrations were studied in 8 patients with severe (NYHA Class IV) congestive heart failure. Serum digoxin concentrations were determined before and after the administration of captopril for 1 week in patients on chronic digoxin therapy. Each patient who was taking 0.25 mg of digoxin PO q.d., was administered 12.5 mg of captopril PO t.i.d. for 7 days. The peak serum concentration of digoxin (Cmax) before and after (on Days 0 and 7) captopril administration was 1.7+/-0.2 ng/ml and 2.7+/-0.2 ng/ml, the time to peak (tmax) was 2.4+/-0.5 h and 1.3+/-0.2 h, and the area under the 24-hour digoxin concentration-time curve (AUC0-24h) was 30.0+/-1.5 ng x h/ml and 41.7+/-3.4 ng x h/ml, respectively. While captopril caused a significant increase in peak serum concentration and the area under the digoxin concentration-time curve, it decreased the time to digoxin peak (p = 0.01, p = 0.04, p = 0.01, respectively). No patient developed evidence of digoxin toxicity. Concomitant administration of captopril with digoxin increases serum digoxin concentration in patients with severe congestive heart failure.

Removal of digoxin by column for specific adsorption of β2‐microglobulin: A potential use for digoxin intoxication

A beta(2)-microglobulin adsorption column used for the treatment of dialysis-related amyloidosis removes serum beta(2)-microglobulin by recognition of lipophilic residue in the protein. No data are available for the adsorption of the highly lipophilic drug digoxin. In vivo clearance of digoxin with the beta(2)-microglobulin column was measured by a single use of the column in 8 patients receiving hemodialysis with a therapeutic level of digoxin. In vitro adsorption was evaluated by use of incubation with adsorbent of the column and digoxin or ranitidine, a hydrophilic drug. Clearance with the beta(2)-microglobulin column was further compared with that obtained by use of activated charcoal in the dogs intoxicated with digoxin. Digoxin concentration was reduced from 1.11 +/- 0.25 ng/mL to 0.57 +/- 0.15 ng/mL at 240 minutes after initiation of hemoperfusion with the column in the patients. Digoxin clearance with the beta(2)-microglobulin column was about 145 +/- 20 mL/min, with a blood flow rate of 160 to 220 mL/min (80% of plasma flow rate). Eighty-five percent of digoxin was adsorbed in vitro, and the capacity of the beta(2)-microglobulin column was not saturated until a toxic level was reached (50 ng/mL). This value was higher than that obtained with use of charcoal. In dogs with digoxin intoxication, digoxin clearance was 38.9 +/- 1.5 mL/min, with a blood flow rate of 50 mL/min (95% of plasma flow rate), which was almost twice as that achieved with charcoal. The degree of thrombocytopenia and leukopenia was small with use of the beta(2)-microglobulin column. These data suggested that the beta(2)-microglobulin column selectively adsorbs digoxin. This column is a promising tool for the treatment of digoxin intoxication, especially in patients undergoing hemodialysis.

Digoxin overdose: clinical features and management

Digoxin overdose: clinical features and management

Digoxin overdose: clinical features and managementVanessa Bara discusses the risk factors, antidotal therapy, and management of digoxin toxicity.

Digoxin is a digitalis glycoside extracted front the leaves of the plant Digitalis Lanata. more commonly known as Grecian foxglove. The digitalis glycosides are present in many plants including Digitalis purpura (foxglove), Nerium oleander (oleander) and Convallaria majalis (lily-of-the-valley). They are also found in some toads, such as Bufo bufo-bufo (European toad). Digitalis glycosides are believed to have been used for therapeutic benefit in the first century AD. More recently, detailed descriptions of the therapeutic use of foxglove from 200 years ago include recognition of the toxicity associated with its use.

Coadministration of Digoxin With Itraconazole in Renal Transplant Recipients

Digoxin toxicity is a major public health issue in the United States. Often this is due to drug interactions, and renal transplant recipients are at particularly high risk for drug-drug interactions. We present cases of 2 renal transplant recipients who received itraconazole and digoxin concomitantly and experienced digoxin toxicity. We have also reviewed the relevant literature to elicit the mechanisms, signs, and symptoms of digoxin toxicity in the presence of itraconazole. When clinicians know the potential drug-drug interactions that may lead to digoxin toxicity, the mechanisms of interaction, the signs and symptoms of digoxin toxicity, and appropriate monitoring, digoxin toxicity is largely preventable.

Calcium currents and arrhythmias: insights from molecular biology

Calcium channels are critical to normal cardiac function. They are involved in the generation and conduction of the action potential and in contraction. Three surface membrane channels have been identified. The L-type Ca channel is most abundant and is responsible for Ca entry into the cell that triggers contraction. T-type Ca channels are most prevalent in the conduction system and are probably involved in automaticity. A newly described TTX-sensitive calcium current may be important in “boosting” or enhancing conduction and contraction. The main intracellular Ca channel resides in the sarcoplasmic reticulum and is responsible for the release of the Ca that activates contraction. Oscillatory behavior of this channel influences the sarcolemmal membrane, causing delayed aftercontractions and arrhythmias such as those seen in digoxin toxicity. The on-going molecular characterization of these channels will enhance our knowledge of their normal function and dysfunction in disease states, leading to the development of new therapeutic agents to treat arrhythmias and contractile dysfunction.

Digoxin Toxicity : Evaluation in Clinical Practice with Pharmacokinetic Correlations.

To evaluate digoxin pharmacokinetic parameters using Bayesian estimation in 60 patients, and to identify factors that appeared to affect the risk of digoxin toxicity. 60 patients with serum digoxin concentrations were evaluated retrospectively. We collected demographic, clinical and laboratory data, and information on concurrent medications and clinical and electrocardiographic features of digoxin toxicity. The incidence of digoxin toxicity was evaluated in 50 patients. Serum digoxin concentrations were measured with fluorescence polarisation immunoassay Individual pharmacokinetic parameters were estimated by Bayesian method using Abbottbase Pharmacokinetic Systems. Signs of digoxin toxicity were present in 23 patients (46%). Patients without signs of digoxin toxicity had a significantly lower mean serum digoxin concentration than patients with signs, 1.99 ± 0.9 μg/L vs 2.7 ± 1.5 μ.g/L, respectively (p = 0.047). Patients with serum digoxin concentrations >2.2 μg/L differed significantly from those with values ≤2.2 μg/L, respectively, for the following parameters: age (82.0 ± 8.0 vs 72.0 ± 16.0 years; p = 0.005), serum creatinine levels (133.0 ± 55.0 vs 106.0 ± 26.0 μmo1/L; p = 0.012), bodyweight (57.4 ± 12.8 vs 69.2 ± 17.8kg; p = 0.01), volume of distribution (208.5 ± 89.5 vs 315.7 ± 91.2L; p = 0.0001), total clearance (1.60 ± 0.65 vs 3.4 ± 1.5 L/h; p = 0.0001), and elimination half-life (94.2 ± 28.6 vs 72.4 ± 16.7h; p = 0.001). Estimation of optimal dose showed that the doses recommended in intoxicated patients should be 3.5 times lower to reach the therapeutic range. Digoxin concentrations were higher in patients with toxicity. Older age enhanced the risk of digoxin toxicity. Monitoring digoxin concentrations may help to confirm suspected digitalis toxicity.

Differential pharmacokinetics of digoxin in elderly patients.

Digoxin remains one of the most commonly prescribed of all cardiac medications. The main indications for digoxin usage include atrial fibrillation and heart failure; both these conditions are more prevalent in older patients. Given the aging population and the increasing incidence of heart failure we would expect prescribing of digoxin to remain as frequent or to even increase in older patients. Older patients are also more likely to develop toxicity and diagnosis of digoxin toxicity can be difficult in this group. Numerous components contribute to the development of toxicity in older patients, ranging from aging-related changes in renal function or body mass to polypharmacy and possible interactions with digoxin. It is therefore important to understand how the pharmacokinetics of digoxin may be altered in the older population. Application of basic pharmacological principles may be helpful in anticipating these problems. This review describes the pharmacokinetics of digoxin, the changes in pharmacokinetics with increasing age and how concomitant disease states or drug interactions may affect the pharmacokinetics of digoxin. Greater knowledge about the causes and prevention of digoxin toxicity should further reduce the morbidity and mortality arising from digoxin toxicity, especially in the elderly population.

Experimental urethane anaesthesia prevents digoxin intoxication: electrocardiographic and histological study in rabbit

An electrocardiographic and histological study was performed in rabbit to detect the effects of urethane (ethyl carbamate) intraperitoneal (i.p.) anaesthesia in digoxin intoxication, since it has been previously shown that this anaesthetic and digitalis glycosides exert specific peripheral effects on the cardiovascular system involving central structures of the autonomic nervous system. We observed that i.p. urethane anaesthesia prevented the onset of the electrocardiographic signs of digitalis intoxication, as well as inhibiting the appearance of histological myocardial alterations after treatment with toxic digoxin doses. On the other hand, lethal arrhythmias and severe myocardial damage were observed in animals that had not undergone preliminary urethane anaesthesia. These results indicate that the effect exerted by urethane in preventing the toxic action of digoxin is probably due to a decrease of sympathetic activity in anaesthetized animals by centrally mediated sympathetic inhibition.

Part 6: Advanced Cardiovascular Life Support

Part 6: Advanced Cardiovascular Life Support

Selection of peptidic mimics of digoxin from phage-displayed peptide libraries by anti-digoxin antibodies

Since the initial report of the development of methodology to generate high-affinity digitalis-specific (digoxin) antibodies, these antibodies have proven extremely useful tools to monitor digoxin levels in digitalized patients and, as Fab fragments, to reverse toxic digoxin effects in life-threatening digoxin overdoses. These antibodies (both digoxin-specific and ouabain-specific) have been used extensively by investigators for the identification and characterization of putative endogenous digitalis-like factors. In this study, we used two well-characterized mouse anti-digoxin monoclonal antibodies (mAbs), designated 26–10 and 45–20, as binding templates with which to select short bacteriophage-displayed (pIII protein inserted) peptides that are capable of binding to these mAbs and mimicking the conformational structure of digoxin. Selective enrichment from two phage-displayed random peptide libraries enabled us to isolate and identify distinct 15 and 26 amino acid residue peptide inserts that bind with high avidity and idiotypic specificity to the selecting mAbs. Among these displayed inserts a subset was identified whose mAb binding is inhibited by digoxin and whose corresponding synthetic peptides inhibit phage binding. They, therefore, appear to bind at the mAbs digoxin-binding sites. These data provide the first clear evidence that short polypeptides can serve as surrogates for the low molecular mass hapten digoxin.