Effects of digitalis on mortality in a large cohort of implantable cardioverter defibrillator recipients: results of a long-term follow-up study in 1020 patients.

AIMS: The effects of digitalis on mortality in patients with structural heart disease are controversially discussed. We aimed to assess the effects of digitalis administration in implantable cardioverter defibrillator (ICD) recipients. METHODS AND RESULTS: This retrospective analysis comprises 1020 consecutive patients who received an ICD at our institution and who were followed for up to 10 years (median 37 months). A total of 438 patients were receiving digitalis at the time of ICD implantation and 582 did not. Patients on digitalis were more often in atrial fibrillation and had more often a prolonged QRS duration of ≥120 ms, a severely impaired left ventricular ejection fraction, and higher New York Heart Association (NYHA) classification heart failure. Crude Kaplan-Meier analysis demonstrated significantly higher mortality in patients on digitalis (HR = 2.47; 95% CI 1.87-3.25; P = 0.001). After adjustment for patient characteristics found statistically significant in adjusted Cox regression analysis (age, gender, NYHA classification, and QRS duration of ≥120 ms), a HR of 1.65 remained (95% CI 1.14-2.39; P = 0.01). Patients on digitalis died more often from cardiac arrhythmic and cardiac non-arrhythmic causes than patients not on digitalis (P = 0.04). There was no difference in mortality between patients receiving digitoxin and those receiving digoxin (HR = 1.55; 95% CI 0.74-3.25; P = 0.25). CONCLUSION: In this large ICD patient population, digitalis use at baseline was independently associated with increased mortality even after careful adjustment for possible confounders. Digitalis should be used with great caution in this population.

Cardiovascular effects, pharmacokinetics and cross-reactivity in digitalis glycoside immunoassays of an antidiarrheal uzara root extract.

Uzara glycosides (UG) extracted from Xysmalobium undulatum are used for treating non-specific diarrhea.Cross-reactivity has been described for UG in digitalis glycoside assays but digitalis-like cardiac effects are controversially discussed. Therefore, we performed a randomized, singleblind cross-over study in 18 healthy volunteers receiving a commercially available Uzara product (Uzara® Lösung N, Stada AG, Bad Vilbel, Germany (ULN)), digoxin (1 mg, i.v., positive control) and placebo in double-dummy technique. Pharmacodynamic effects were quantified by means of ECG and impedance cardiography (ICG). After oral administration of ULN, main metabolites were determined using HPLC-MS/MS and digitalis-like serum levels (DLSL) were measured in two digitoxin and digoxin assays, respectively. In comparison to placebo, ULN did not change significantly any PD parameters whereas digoxin altered significantly area under the effect curve of several ECG and ICG parameters, respectively. Since some serum levels of three ULN ingredients (uzarin, uzarigenin and xysmalorin) were below LLQ, PK analyses could only be performed for allouzarigenin and revealed a marked inter-individual variability. Therefore, median values (min; max) were calculated as follows: Cmax = 0.39 (0.15; 1.81) ng/ml, tmax = 7.0 (3.0; 36.0) h, T1/2 = 5.2 (0.8; 23.6) h, AUC0-36h = 4.2 (0.8; 11.1) ng/ml×h, AUC0-∞ = 5.8 (1.8; 13.1) ng/ml×h. DLSL reached Cmax of 28 ng/ml and 1,980 ng/ml for digoxin and digitoxin, respectively. We could not observe significant cardiovascular pharmacodynamic effects after oral administration of the recommended single dose of Uzara extract to healthy volunteers. However, considerable DLSL could be detected, proving cross-reactivity of uzara components with the conventional digitalis assays used. However, none of the metabolites we had suspected to be the cause for the crossreactivity could be identified in reasonable quantities.

Diverse effects of stress and additional adrenocorticotropic hormone on digitalis-like compounds in normal and nude mice.

Digitalis-like compounds (DLC) are steroidal hormones that are synthesized in, and released from, the adrenal gland, whose regulation may be directed by the hypothalamic-pituitary-adrenal (HPA) axis. Increasing evidence points to antitumour properties of these compounds and we hypothesized that the establishment of tumours in athymic nude mice may be facilitated by an abnormal synthesis or secretion of DLC. To explore this hypothesis, DLC concentrations were determined in the plasma, and in adrenal and hypothalamic tissues of nude compared to normal mice under basal conditions, and 30 min after a stress stimulus (i.p. injection of 100 micro l saline) with or without additional adrenocorticotropic hormone (ACTH) 1 micro g/per animal. Simultaneously, plasma corticosterone and serum adrenocorticotropic hormone (ACTH) concentrations were analysed. The basal DLC concentrations were similar in the plasma and the hypothalamus of both strains, whereas the basal adrenal DLC concentration was significantly lower in the nude mice compared to normal mice. The stress stimulus induced in normal mice a significant increase in DLC concentrations in the adrenal gland, the plasma and the hypothalamus. However, in nude mice, it caused an increase only in the adrenal gland and the hypothalamus, whereas the plasma DLC concentration was not affected. In both strains, the administration of ACTH in addition to injection stress did not provoke a further increase in DLC concentrations while inducing a significant increase in plasma corticosterone concentration. Regardless of the applied stimulus, the nude mice expressed significant lower DLC concentrations in the adrenal gland and the plasma compared to normal mice. The low basal adrenal DLC concentration in nude mice and their impaired DLC response towards stress- and ACTH stimulation both support an involvement of DLC in tumorigenesis.

A non-fatal case of intoxication with foxglove, documented by means of liquid chromatography-electrospray-mass spectrometry.

The non-fatal self-poisoning of a 36-year-old female patient, who ingested a concoction of foxglove (Digitalis Purpurea), is presented. On the admission, initial symptoms were nausea and vomiting, abdominal pain, and cardiovascular shock with sinus bradycardia. Blood and urine were assayed for 17 cardiotonic hetorosides, using a highly specific LC-MS procedure. Serum and urine specimens were collected over five days and analyzed by liquid chromatography-electrospray-mass spectrometry (LC-ES-MS). This accurate procedure allowed the determination of the digitalis glycosides and their metabolites in serum and urine. The serum concentrations of digitalis glycosides were maximum on the first day (gitoxin 13.1 ng/mL, digitoxin 112.6 ng/mL, digitoxigenin 3.3 ng/mL, and digitoxigenin mono-digitoxoside 8.9 ng/mL) and decreased over five days. We observed a peak gitaloxin level (112.6 ng/mL) on the fifth day only. After administration of atropine as well as dimeticone, alginic acid, and metoclopramide, health status improved. The peak urine concentrations were reached at hour 30 and were respectively 91.3 and 69.9 ng/mL for gitaloxin and digitoxin, while those of digitoxigenin, digitoxigenin mono-digoxoside and gitoxin were lower (respectively 0.7, 1, and 5.6 ng/mL). The patient was discharged on the fifth day when there were no residual symptoms.

Intrauterine therapy of fetal atrial flutter.

An increased awareness of fetal arrhythmias by obstetricians has resulted in a growing number of diagnosed cases of fetal cardiac problems. A fetus with atrial flutter diagnosed at 31 weeks of gestation was successfully converted to normal sinus rhythm in utero by maternal administration with digitalis. The fetal heart rate stayed in a normal rhythm with a maintenance dose of 0.5 mg/day. The fetus was delivered spontaneously at term and the neonatal heart rate has been in normal rhythm without any medical treatment.

[Current clinical interest in monitoring digoxinemia]. / Attualità dell'importanza clinica del monitoraggio della digossinemia.

After a short introduction about the current role of digitalis in the treatment of the supraventrical arrhythmias and about the factors that make often problematic the achievement of an optimal posology of the drug, the results relative to more recent 340 digoxinaemia determinations in patients of Policlinico in Palermo or in outpatients are presented. Just the 43.8% of the patients had a digoxinaemia value in the range considered therapeutic; just 45 patients (32.1%), out of the 140 in which the digoxinaemia had been monitored for, at least, 5 days, were in the therapeutic range at the first determination; the 47.8% of the patients were underdosed and the 38.8% of them showed higher values than the therapeutic range. Determination 5 or more days later showed digoxinaemia values in the therapeutic range in 112 patients (80%). According to the reported results, it may be presumed that the posology correction effectuated by the physician on these patients might have been driven by the digoxinaemia values, whose determination must be considered an unavoidable guide to the digitalis treatment.

Digitalis-induced visual disturbances with therapeutic serum digitalis concentrations.

OBJECTIVE: To assess the role of digitalis in the development of visual symptoms severe enough to warrant ophthalmologic consultation in patients who received digitalis and who had no other clinical or laboratory evidence of digitalis toxicity. DESIGN: Clinical case study. SETTING: Neuro-ophthalmology referral practice. PATIENTS: Six elderly patients (aged 66 to 85 years) who received digitalis were referred to ophthalmologists for evaluation of photopsia (five patients) or decreased visual acuity (one patient). No patient had chromatopsia or nonvisual clinical manifestations of digitalis intoxication at the time of examination. MEASUREMENTS: All patients had serum digitalis concentrations within or below the therapeutic range. In most patients, the electroretinographic cone b-wave implicit time was longer than normal. RESULTS: Discontinuation of digitalis therapy, which was possible in five patients, was followed by resolution of visual symptoms and by shortening of the b-wave implicit time. Characteristic features of digitalis-induced photopsia were its dependence on illumination and its tendency to be localized in peripheral visual fields. CONCLUSIONS: In an elderly patient receiving digitalis, the development of photopsia characterized by innumerable points of light in the peripheral visual fields or a decrease in visual acuity raises the possibility that the patient's visual disturbance may have been digitalis induced. Digitalis-induced visual disturbances other than chromatopsia or disturbances of color vision may occur in elderly patients who have no other clinical manifestations of digitalis intoxication and who have a serum digitalis concentration within or below the therapeutic range.

[An unusual case of "catecholamine necrosis" caused by accidental digitalis poisoning]. / Un raro caso di "necrosi catecolaminica" da intossicazione digitalica accidentale.

Toxic manifestations of digitalis are one of the most prevalent adverse drug reactions encountered in clinical practice. The estimated incidence is about 20% in hospitalized patients in the USA. The authors describe a rare case of myocardial "catecholamine necrosis" (anteroseptal myocardial infarction) during accidental digitalis intoxication. A male patient, 75 years old, suffering from cirrhosis and ascites, take on by mistake a tablet of digoxin 0.25 mg. four times at day for eleven days. He hadn't heart disease in the past. At the eleventh day the patient showed a deep tiredness and so he was submitted to a clinical examination and electrocardiogram. The ECG demonstrated an anteroseptal myocardial infarction in the second-third electrical stage. The patient was hospitalized. The successive examination revealed: very high plasma digitalis concentrations; an increase of the serum levels of CPK and LDH; a significant increase of plasmatic and urinary catecholamine levels which return to normal values after fifteen days; apical akinesia at the echocardiographic examination; no signs of residual myocardial ischemia to the echo-dypiridamole stress test; normal coronary artery to the coronary arteriography and absence of coronary artery spasm to the ergonovine test. Furthermore the abdominal echography and the abdominal computerized tomography didn't reveal surrenal disease but showed an important liver disease. The patient was free from other cardiac events in the follow-up. Generally, during the digitalis intoxication we observe various rhythm and conduction disturbances. Instead in this case no serious arrhythmias were registered and the main expression of the drug toxicity was an anteroseptal myocardial infarction with undamaged coronary artery. Also the usual extracardiac symptoms and signs of the digitalis intoxication were absent in this case. All these observations can be explained with the pathological increase of the cathecholamine levels, indirectly induced by digitalis; with the direct toxic effect of the drug at the myocardic level; with the contemporary absence of ionic disturbances; with the concomitant liver disease. The direct toxic effect of the digitalis produced an increase in calcium ions availability for the electromechanical coupling and an increase of the intramyocardial pressure; the increase of the adrenergic activity determined contemporary an increase in the oxygen consumption of the myocardial cells, a rise of vascular tone and coronary artery tone and a reduction of the duration of the diastole. All these factors provoked a "primary and secondary" ischemia which evolved toward a real "cathecholamine necrosis" and produced a myocardial infarction. This hypothesis explains the myocardial infarction in absence of injury at the coronary arteriography and without coronary spasm at the ergonovine test; moreover it explains the transient increase in cathecholamine plasma levels observed in the acute phases an normalized after fifteen days. The "cathecholamine necrosis" is an anatomical definition, nevertheless in our opinion it gives account of the rare clinical situation observed.

Incidence of hospitalization for digitalis toxicity among elderly Americans.

OBJECTIVE: To document the prevalence of digitalis use and the incidence of hospitalization caused by digitalis toxicity. DESIGN: Observational cohort followed for 6 years. SETTING: Urban community. PARTICIPANTS: Persons were eligible if they were (1) enrolled in the Yale Health and Aging Project and (2) using digitalis when interviewed in 1982 or 1985. The Project comprises a sample of noninstitutionalized persons aged 65 years and over living in New Haven, Connecticut. METHODS: Between 1982 and 1988 when a Project participant was hospitalized in New Haven, a researcher reviewed the medical record and coded up to 16 International Classification of Diseases-Class 9 (ICD-9) diagnoses. To identify hospitalizations caused by digitalis, we reexamined records with ICD-9 codes suggesting toxicity. We confirmed the admission illness was an adverse drug reaction with a decision algorithm. RESULTS: The prevalence of digitalis use was 13% in 1982 and 12% in 1985. The incidence of hospitalization caused by definite or probable toxicity was 4.2% (95% confidence interval = 0.3% to 8.1%) over 6 years. Manifestations of toxicity were malaise or gastrointestinal symptoms (two patients) and heart block plus malaise or gastrointestinal symptoms (six patients). Use of quinidine was associated (P < .05) with toxicity. CONCLUSION: Knowledge about the incidence of severe, morbid toxicity may help clinicians estimate and compare the risks and benefits of digitalis and alternate therapies.

Clinical features and management of digitalis poisoning--rationale for immunotherapy.

The intensity of gastrointestinal and visual symptoms together with hyperkalemia and the characteristic ECG features make diagnosis of acute digitalis intoxication relatively easy. Death results mainly from ventricular fibrillation or from ventricular asystole or pump failure. Mesenteric infarct may also occur in elderly patients. Previous assessment of outcome has shown that mortality increases in patients exhibiting five prognostic factors: 1) advanced age; 2) heart disease; 3) male sex; 4) high-degree atrioventricular block; 5) hyperkalemia. Conventional treatment includes gastric lavage, activated charcoal and supportive care. First-line antiarrhythmic therapy is usually atropine, because of bradycardia-induced arrhythmia. Ventricular pacing is a toxicodynamic treatment that may be helpful in both bradycardia-induced arrhythmia and high-degree atrioventricular block. Pacing is difficult to handle and can result in serious adverse effects. Immunotherapy has two advantages. First, a strong toxicodynamic effect due to quick reversal of digitalis-induced dysrhythmias, hyperkalemia, and myocardial depression, by reactivation of membrane ATPases. Second, a toxicokinetic effect due to accelerated renal excretion of Fab-digitalis complexes. Since this therapy is well tolerated and efficient, we recommend early administration of Fab fragments as soon as poor prognostic factors are identified.

[Specifying for the general physician. Digitalis therapy in elderly patients]. / Especificando para o generalista. A terapêutica digitálica no doente idoso.

The experimental and clinical evidence on the decreased efficacy of digitalis on old age are reviewed. The trials on the efficacy of digitalis on elderly in heart failure and sinus rythm, are analysed and we try to characterize the sub-group of responders. So we try to explain the criteria to choose the therapeutic dose, to avoid intoxication and to interpret the seric concentrations. We describe the pharmacocynetics of digitalis on old people on heart failure which can explain the susceptibility to intoxication. We reviewed the incidence of digitalis intoxication on old age and the difficulties on its recognition.

Results of multicenter studies of digoxin-specific antibody fragments in managing digitalis intoxication in the pediatric population.

Digitalis toxicity continues to be a problem for pediatric patients undergoing therapy with cardiac glycosides for heart failure or arrhythmias, as well as in accidental ingestions. In this article the previous use of digoxin-specific antibody Fab fragments to treat digitalis overdose or intoxication in children is reviewed. The case reports cited in the medical literature and the 57 pediatric cases gathered as a result of the multicenter clinical trial and postmarketing surveillance study reported here indicate that digoxin-specific antibody Fab fragments are effective in ameliorating signs of digitalis poisoning in children. Not only can Fab fragments rapidly eradicate potentially life-threatening arrhythmias and conduction defects, but they are also effective in treating hyperkalemia and other noncardiac manifestations of digitalis toxicity. In the small samples of patients studied to date, complications have been minimal and no allergic reactions to digoxin-specific Fab fragments have been observed. Recommendations for the management of digitalis intoxication in children are outlined.

Recognition and management of digitalis intoxication: implications for emergency medicine.

Digitalis intoxication is among the most common serious adverse drug reactions in clinical medicine. While the recent development of a radioimmunoassay to accurately measure serum concentrations of digoxin has been of assistance, digitalis intoxication remains a difficult diagnosis to make with certainty. The difficulty in diagnosing digitalis intoxication arises from the nonspecificity of its associated signs and symptoms. The most common symptoms include fatigue, weakness, nausea, and anorexia. These symptoms can occur with many illnesses other than digitalis intoxication. Similarly, the electrocardiographic disturbances caused by cardiac glycosides may be nondiagnostic. The arrhythmias commonly associated with digitalis toxicity are often nonspecific and can be a reflection of the patient's underlying heart disease. The measurement of serum digoxin levels is useful, but studies have demonstrated overlap of the levels between groups with and without toxicity. Due to the modulation of the cardiac effects of digitalis glycosides by such clinical variables as underlying myocardial or renal disease, electrolyte and acid-base imbalances, and other factors, the correlation of toxicity with particular serum digoxin concentrations may vary. Because of the inherent difficulties in confirming the diagnosis of digitalis intoxication in some cases, digoxin-specific Fab antibodies may play a role as a diagnostic tool. Certainly, digoxin-specific Fab antibodies play a significant part in the treatment of digitalis intoxication. Fab antibodies have been successfully used to reverse the effects of digoxin, digitoxin, and oleander poisoning. These antibodies are useful in the treatment of acute and chronic digitalis intoxication in all age groups, including geriatric and pediatric populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Digitalis-like activity in human plasma: relation to blood pressure and sodium balance.

PURPOSE: On the assumption that renal tubular cells are more important as the target cells for a natriuretic factor than blood cells, we used a well-characterized cultured renal tubular cell line, Madin-Darby canine kidney (MDCK), cells to monitor the circulating digitalis-like factor in human plasma and examine its role in the regulation of blood pressure and sodium balance. SUBJECTS AND METHODS: We investigated the effects of plasma on binding of radioactive ouabain to monolayered MDCK cells in order to determine the level of a circulating digitalis-like factor. First, we measured specific 3H-ouabain binding to MDCK cells in the presence of plasma from 71 outpatients (34 normotensive subjects and 37 hypertensive patients) after incubation for 4 hours. Second, we measured specific 3H-ouabain binding after incubation of cells with plasma from 16 hospitalized subjects (eight normotensive subjects and eight hypertensive patients) receiving low and high sodium diets. RESULTS: In Study 1, ouabain binding was lower by 30% with plasma from hypertensive patients than with plasma from normotensive subjects (p less than 0.01). There was a significant negative correlation between individual subject's systolic or mean blood pressure and ouabain binding (r = -0.34, p less than 0.01 or r = -0.29, p less than 0.01). In Study 2, ouabain binding was also significantly reduced by 25% in the presence of plasma from hypertensive subjects as compared with plasma from normotensive subjects irrespective of sodium intake (p less than 0.01). A significant negative correlation was also found for all subjects between either systolic, diastolic, or mean blood pressure and ouabain binding (r = -0.58, p less than 0.01, r = -0.51, p less than 0.01, or r = -0.55, p less than 0.01, respectively). With the changes from low to high sodium intake, there was a corresponding decrease in ouabain binding (p less than 0.01) and an increase in sodium excretion (p less than 0.01). A significant negative correlation was observed between these two parameters (r = -0.47, p less than 0.05). CONCLUSIONS: These findings suggest that a circulating digitalis-like factor, which may act on renal tubular cells as the ouabain-displacing compound, is increased in patients with essential hypertension and also demonstrate that plasma levels may be influenced by changes in dietary sodium intake.