Successful Treatment of Severe Digitoxin Intoxication with CytoSorb® Hemoadsorption.

While several intoxications can be successfully treated with specific antidotes, intoxications with the steroid glycoside digitoxin still represent a major challenge. Besides conventional approaches, CytoSorb® hemoadsorption might be another treatment option. We report on an 81-year-old female patient treated in our intensive care unit (ICU) with severe digitoxin intoxication, acute renal failure, and urinary tract infection (UTI). As physiological digitoxin elimination kinetics are known to appear slow, and also in regard to the renal failure, the decision was made to initiate continuous renal replacement therapy combined with CytoSorb hemoadsorption. The patient was hemodynamically stabilized within the first 4 h of treatment and initially required catecholamines to be stopped within 24 h of treatment. Pre- and post-adsorber drug level measurements showed a rapid elimination of digitoxin. Antibiotic treatment with piperacillin/tazobactam was initiated, and despite CytoSorb hemoadsorption therapy and its known potential to reduce plasma concentrations of several drugs, the UTI was successfully treated. After 3 days of CytoSorb treatment, digitoxin plasma levels were stable and almost normalized, and no clinical signs of intoxication were present. Five days after presentation, the patient was transferred from the ICU in a stable condition. CytoSorb hemoadsorption may be an easily available, efficient, and less cost-intensive therapy option than treatment with the Fab fragment, which is the currently recommended therapy for digitalis intoxications. Therefore, the use of CytoSorb might represent an alternative treatment for life-threatening complications of digitoxin intoxications.

Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning.

OBJECTIVE: Despite administration of Fab fragments in digitalis poisoning, high mortality rates are consistently reported. A previous study suggested that Fab fragments prescribed as first-line therapy might improve mortality rate. Our objective was to evaluate this approach. DESIGN: Retrospective chart review (January 1990 to January 2004). SETTING: University hospital intensive care unit. PATIENTS: Consecutive patients admitted for cardiac glycoside poisoning. INTERVENTION: First-line therapy with Fab fragments (with or without atropine) in either curative or prophylactic doses. MEASUREMENTS AND MAIN RESULTS: A total of 141 patients were admitted for digitalis poisoning of whom 66 received first-line Fab fragment therapy. Their median age was 74 years (25th to 75th percentiles: 51-83); 76% were women. Half were intoxicated by digitoxin and half by digoxin. Median serum concentration was 168 (108-205) ng/mL for digitoxin and 6.2 (4.3-13.5) ng/mL for digoxin. Conduction disturbances were reported in 45 cases (68%) and ventricular arrhythmia in six cases (9%). Fab fragments were administered as curative treatment in 21 patients (32%) and prophylactically in 45 patients (68%). The median cumulative dose was 4 (4-6) vials. No adverse effects were reported. Five patients (7.6%) died. CONCLUSIONS: First-line therapy with Fab fragments in patients with digitalis poisoning was associated with a low mortality rate.

[Digitalis poisoning treated with a specific antidote]. / Digitalisforgiftning behandlet med spesifikt antidot.

Toxicity by digitalis is a common problem in everyday clinical practice. In this paper three cases of severe poisoning with digitoxin with maximal S-digitoxin levels of 115, 150 and 239 nmol/l are described. All patients received specific digoxin Fab-fragment intravenously. Administration of antidotes resulted in a favourable outcome in all three patients. So far, the use of digoxin-specific antibodies has been limited to a few cases of severe intoxication where life-threatening arrhythmias and hyperkalaemia were present. We discuss whether a more liberal indication should be accepted.

Digitoxin intoxication with lethal outcome.

A 65-year old woman with known history of reactive depression and failed suicide attempts ingested 7 mg digitoxin at 09.00 h. After vomiting 4 hours later, she reported the drug intake to her husband who thereupon summoned a physician. Arriving at 16.00 h, the physician was informed about the suicide attempt, but failed to initiate any specific measures. After a second doctor's visit at 22.00 h, the patient was rushed to hospital in a moribund state. In spite of a gastric lavage, treatment with activated charcoal and insertion of a transvenous pacemaker, the patient died at 23.45 h with signs of total atrioventricular block. Digitalis fab fragments could not be administered in time. A calculation based on the plasma digitoxin concentration of 212 ng.ml-1 measured at 23.00 h indicated that nearly the entire ingested dose had been absorbed. Thus, neither the vomiting nor the gastric lavage eliminated significant amounts of the drug which had left the stomach without delay. Under these circumstances, the failure to initiate timely therapy with specific digitalis fab fragments ultimately contributed to the lethal outcome.

Massive digitoxin intoxication treated with digoxin-specific antibodies in a child.

A 20-month-old girl with massive digitoxin intoxication (initial digitoxin serum level: 629 ng/ml) was successfully treated with digoxin-specific antibody fragments (Fab). She presented with moderate signs of digitalis toxicity (somnolence, bradycardia, first-degree AV block) and improved rapidly during fractional Fab administration. Free serum-digitoxin disappeared after 6 vials of Fab (480 mg), but was measurable again on days 6 and 7. This case demonstrated that digoxin-specific antibodies, despite a 30-100 times lesser affinity for digitoxin, are effective in massive digitoxin intoxications. A rebound phenomenon may occur several days later and should be taken into consideration.

[Thrombocytopenia caused by digitoxin overdose]. / Thrombopénie induite par un surdosage en digitoxine.

The authors report a new case of digitoxin-related thrombocytopenia. It involved a patient hospitalised for torsades de pointe in whom blood digitoxin was 85 micromols/l on admission. This rare complication progressed to a satisfactory conclusion in seven days. The mechanism is immuno-allergic and/or toxic since thrombocytopenia occurs only following therapeutic overdose. The prognosis is determined by the cardiac arrhythmia rather than the hemostasis abnormality. Treatment is symptomatic and should include the withdrawal of digitoxin which can be replaced by digoxin. Oral activated charcoal decreases the plasma half-life by blocking the enterohepatic cycle and is hence recommended in this situation.

Development of a sensitive radioimmunoassay for Fab fragments: application to Fab pharmacokinetics in humans.

Anti-sheep Fab fragment antisera were produced in rabbits using sheep digoxin-specific Fab fragments (Digidot) as immunogen. These antisera were used for the development of a radioimmunoassay (RIA) of sheep Fab fragments in human plasma and urine using 125I-labeled Fab fragments. Interference in the assays by digoxin, human proteins, and antibodies from different species was insignificant, but cross-reactivity between anti-sheep Fab antisera and goat IgG or Fab fragments was 22 to 67%. The limit of detection was 0.1 microgram/mL and the assay was linear over a 0.6-28 micrograms/mL range of Fab fragments. Intra- and interassay coefficients of variation were less than 6.9 and 10.5%, respectively. Accuracy of plasma and urine assays at various Fab fragment levels ranged from 96 to 106%. RIA was applied to the pharmacokinetic study of sheep digoxin-specific Fab fragments in one patient acutely intoxicated by digitoxin and treated with Digidot. The Fab elimination half-life was 12.1 hr. Steady-state volume of distribution and total-body clearance were 10.8 L and 23.4 mL/min, respectively. Unchanged Fab fragments (50 kD) and degradation products (25 kD) isolated by gel filtration chromatography of a urine sample cross-reacted with the anti-Fab antiserum.

The use of digoxin-specific Fab fragments for severe digitalis intoxication in children.

BACKGROUND: Because life-threatening digitalis intoxication is unusual in children, treatment with digoxin-specific-antibody Fab fragments (Fab) has rarely been reported. We describe the efficacy of Fab in the treatment of children with severe digitalis intoxication. METHODS: Twenty-nine children with intoxication due to digoxin (28) or digitoxin (1) received Fab at 21 participating hospitals between 1974 and 1986. Data were gathered about the patients' medical illnesses, doses and serum concentrations of digitalis, responses to Fab therapy, and outcomes. RESULTS: In the infants and young children with acute digoxin intoxication, the digoxin doses ranged from 0.30 to 0.96 mg per kilogram of body weight; two adolescents had severe intoxication after doses of only 0.20 and 0.26 mg per kilogram. The serum digoxin concentrations ranged from 3.0 to greater than 100 ng per milliliter (mean, 13.8). Atrioventricular block (present in 22 patients [76 percent]) was the most common sign of toxicity. All the patients in this series had severe disturbances of cardiac rhythm, hyperkalemia (mean serum potassium concentration, 5.4 mmol per liter), or both. In 27 patients (93 percent), digitalis toxicity resolved after the administration of Fab. Of the 19 patients for whom data were available on the timing of the response to Fab, 15 responded within 180 minutes. Three patients required retreatment with Fab. Seven died of complications unrelated to the administration of Fab. CONCLUSIONS: We recommend that Fab be used in the treatment of digitalis poisoning in infants and young children who have ingested greater than or equal to 0.3 mg of digoxin per kilogram, who have underlying heart disease, or who have a serum digoxin concentration of greater than or equal to 6.4 nmol per liter (greater than or equal to 5.0 ng per milliliter) in the elimination phase; and who also have a life-threatening arrhythmia, hemodynamic instability, hyperkalemia, or rapidly progressive toxicity. Adolescents, who are more sensitive to the toxic effects of digoxin than younger children, may require treatment with Fab after ingesting lower doses.

[Thrombocytopenia in digitoxin poisoning]. / Thrombozytopenie bei Digitoxin-Intoxikation.

Because she felt unwell, an 80-year-old woman who was receiving treatment with digitoxin (0.07 mg daily) raised the dose on her own initiative to twice or three times the previous level. She then experienced faintness, visual abnormalities and bradyarrhythmia (rate about 40/min). The ECG showed 2 degrees AV block. The digitoxin level was 70.8 ng/ml--far above the upper limit of the therapeutic range (7.5-25 ng/ml). One striking abnormality was thrombocytopenia (33,000/microliters), though the white and red cell counts were normal. Petechiae were not present and there was no evidence of internal bleeding. As the AV block had not produced any critical fall in ventricular rate, there was no need to start treatment with digitalis-binding antibody fragments (Fab fragments). Instead, the patient was given cholestyramine 4 g three times daily with the aim of interrupting the enterohepatic circulation of digitoxin. From then on the rise in platelet count paralleled the fall in digitoxin level. Seven days after discontinuing digitoxin the platelet count reentered the normal range (147,000/microliters). However, the digitoxin level (39.5 mg/ml) was still well above the therapeutic range.

Treatment of a patient with severe digitoxin intoxication by Fab fragments of anti-digitalis antibodies.

A massive digitoxin (DGTX) intoxication in a 36-year-old man (35 mg DGTX) was treated by prolonged and repeated i.v.-infusions of Fab fragments of anti-digitalis antibodies (FAB). Blood and urine samples were collected over a 98 h period for monitoring the efficacy and adequacy of FAB treatment. DGTX concentrations were determined after protein precipitation (release of FAB-bound and protein-bound DGTX) in unprocessed serum and urine samples, and after aliquots of these samples had been dialysed in vitro against DGTX-free buffer (elimination of DGTX not bound to FAB). The difference in DGTX concentration between the unprocessed and dialysed samples was the amount of DGTX bound to plasma proteins and the small fraction of unbound DGTX being relevant for the therapeutic and toxic effects of the drug. Before FAB therapy was started, the total serum DGTX concentration was 535 nmol/l. The first FAB infusion (320 mg) was started 11 h after drug ingestion. Since this amount of FAB was insufficient to bind all DGTX present in the serum, cardiac DGTX toxicity (total AV-block) persisted. During a second FAB infusion (400 mg) the patient reverted to regular AV-conduction. At this time most of the DGTX in serum was FAB-bound. Toxic symptoms (sinus arrest) reappeared twice and were accompanied by increasing amounts of non-antibody-bound DGTX in the serum. Additional application of FAB (2 x 80 mg) resulted in the immediate disappearance of arrhythmia. During FAB-treatment total DGTX serum concentrations and renal DGTX clearance rose, indicating redistribution of drug from tissue to serum and urinary elimination of FAB-bound DGTX, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of digitalis-glycoside levels in ocular tissues: a way to improve postmortem diagnosis of lethal digitalis-glycoside poisoning? II. Digitoxin.

Postmortem digitoxin levels in the choroid-retina and vitreous humor of patients who had undergone digitoxin therapy (therapeutic group) and in one case of suicidal digitoxin poisoning were measured and compared with levels in femoral vein blood, myocardium, kidney and liver. The results were interpreted in light of the medical history of each patient. The digitoxin level in the choroid-retina of the single case of suicidal poisoning was far higher than the choroid-retinal levels in the therapeutic group. In the latter, variation in choroid-retinal levels was comparable to that in the other tissues. In cases where the choroid-retina of the right and left eyes were examined, digitoxin levels in both eyes were essentially equal. There was no indication of significant changes in choroid-retinal levels due to postmortem diffusion of digitoxin into the vitreous body. Based on these results, determination of digitoxin levels in the choroid-retina could contribute to improving postmortem diagnosis of lethal digitoxin poisoning.

Repeated doses of activated charcoal and cholestyramine for digitoxin overdose: pharmacokinetic data and urinary elimination.

A 48-year-old man chronically treated with digitoxin and verapamil for prevention of atrial fibrillation voluntarily ingested 2.2 mg of digitoxin. Serum digitoxin concentrations and the urinary elimination of the drug were followed over a 12-day period. Urinary data indicate that a large percentage (50%) of the drug was eliminated renally despite administration of multiple doses of activated charcoal, cholestyramine and hyperosmotic laxatives. The possible interaction with two other drugs, heparin and verapamil, is also discussed.

Relationship between red blood cell potassium and plasma digitoxin concentrations in intoxicated patients.

After severe acute self-poisoning by cardiac glycosides, significant and persistent depletion of red blood cell K+ due to inhibition of Na+K+ ATPase is seen. Because of a delay between the time course of plasma digitalis concentrations and that of red blood cell K+ depletion, no direct relation exists between the two, and RBC K+ has hitherto not been considered useful as prognostic indicators of clinical outcome. In an effort to solve this problem, red blood cell K+ was measured by atomic absorption spectrophotometry and plasma digitoxin concentration assayed in six patients admitted to an intensive care unit after digitoxin self-poisoning. Using the effect compartment model of Sheiner, a relationship based on a sigmoid Emax model was able to relate the digitoxin concentration at the action site to red blood cell K+ depletion. Thus the duration of red blood cell K+ depletion could be predicted from two relative simple in vitro assays. Since RBC K+ is a marker of the inhibition of Na+K+ ATPase by digitoxin, this method could be of use for the management of patients self-poisoned with digitalis.