Recurrent digoxin overdose and treatment with digoxin-specific Fab antibody fragments

A case of overdose with digoxin on three separate occasions is presented. The patient received digoxin-specific Fab antibody fragments on each presentation without adverse effects. A discussion of digoxin toxicity and specific treatment follows. Immunologic aspects of therapy are emphasized.     

Determination of free digoxin concentrations in serum for monitoring Fab treatment of digoxin overdose

A rapid method for assessing the free digoxin concentration in the serum of digoxin-overdosed patients receiving treatment with digoxin-specific Fab fragments has been developed. For this method, a protein-free ultrafiltrate is prepared from the patient's serum, and the digoxin in the ultrafiltrate (free digoxin) is measured by fluorescence polarization immunoassay. Both the inaccuracies associated with measurements of total digoxin by immunoassay in the presence of Fab and the long turnaround time associated with measurements of free digoxin by equilibrium dialysis were avoided. Good correlation was observed between measurements of free digoxin by this ultrafiltration technique and by equilibrium dialysis. The ultrafiltration method was used to evaluate the concentrations of free digoxin in a digoxin-overdosed patient treated with Fab at our hospital. In retrospect, the results suggest that her hospital stay could have been shortened by a timely appreciation of her increased concentration of free digoxin. Using the ultrafiltration method, one can determine free digoxin concentrations quickly, conveniently, and accurately in the clinical laboratory. This procedure therefore should be a valuable aid in monitoring the efficacy and adequacy of Fab treatment.     

Acute digoxin overdose: use of digoxin-specific antibody fragments

An acute ingestion of 6 to 7 mg digoxin as a suicidal gesture in a 76-year-old man with chronic heart disease is presented. The patient arrived in the emergency department approximately 5 hours after ingestion with a normal serum potassium and increasing numbers of multifocal premature ventricular contractions. Digoxin-specific antibody fragments were administered. The patient developed ventricular tachycardia and ventricular fibrillation and was eventually stabilized 35 minutes after the Fab fragments were infused. A review of the pharmacology and indications for use of digoxin-immune Fab fragments is also presented.     

Reversal of lethal digoxin toxicity in guinea pigs using monoclonal antibodies and Fab fragments

To extend the potential application of digoxin-specific immunoglobulin (Ig) (Fab) fragments for the reversal of advanced digitalis intoxication, monoclonal digoxin-specific antibodies were obtained by fusion of myeloma cell lines with spleen cells from mice immunized with a digoxin-serum albumin conjugate. The monoclonal antibody from the cell line designated Dig 26-10 had high affinity (KA = 5 X 10(9) M-1) and specificity for digoxin and was tested for its efficacy in the reversal of advanced, otherwise lethal digoxin toxicity in guinea pigs given a loading dose of 500 micrograms of digoxin per kg b.wt. i.v. followed by continuous infusion of digoxin at 10 (IgG-treated group) or 50 (Fab-treated group) microgram/kg/min. Control animals given nonspecific rabbit or mouse Igs after the onset of digoxin-toxic ventricular arrhythmias all died. Administration of monoclonal digoxin-specific antibody as intact IgG in doses stoichiometrically equivalent to the digoxin dose fully reversed digoxin toxicity in six of eight animals and prolonged survival somewhat in the remaining two animals. Fab fragments from the Dig 26-10 monoclonal antibody were even more effective, with rapid reversal (mean time 7 min) of all arrhythmias and survival of all animals so treated. We conclude that murine monoclonal antibodies and their Fab fragments are capable of reversing advanced and otherwise lethal digoxin-induced arrhythmias in a guinea-pig experimental model and offer potential advantages over polyclonal antibodies in the management of this clinically important problem.     

Digoxin-specific antibody fragments in the treatment of digoxin toxicity

Context. Digoxin-specific antibody fragments (digoxin-Fab) are widely regarded as a safe and effective treatment for the management of acute and chronic digoxin poisoning. Calculated equimolar doses of digoxin-Fab are high, very expensive, and infrequently used. Objective. To review the pharmacology, efficacy, effectiveness, indications, safety and the dosage of digoxin-specific antibody fragments. Methods. Pubmed, Embase, Medline and Cochrane were searched from 1946 to May 2013 using the terms digoxin, digoxin-specific Fab, and digoxin antibody. Pharmacology and kinetics of digoxin and digoxin-Fab. Digoxin acts via inhibition of Na⁺/K⁺ ATPase. It has a narrow therapeutic index. Digoxin has 60–80% bioavailability, a mean plasma half-life of 40 h and a volume of distribution (Vd) of 5–10 L/kg and low protein binding (20%). A 40-mg vial of digoxin-Fab (DigiFab) binds 0.5 mg digoxin. Digoxin-Fab has a mean plasma half-life of 19–30 h and a Vd of 0.4 L/kg. The half-lives of both digoxin and digoxin-Fab are prolonged in renal failure to over 100 h. Efficacy and effectiveness of digoxin-Fab. There were no randomised clinical trials examining the use of digoxin-Fab for acute or chronic digoxin poisonings. Ten case series with a total of 2,080 patients have reported on the use of digoxin-Fab in digoxin poisoning. In three large case series of 430 acute and 1308 chronic poisonings, response rates to digoxin-Fab vary from 80–90% to 50%. The time for reversal of digoxin toxicity is reported to be 30–45 min. Studies with pharmacokinetic data showed that free digoxin concentration fell to almost zero within a few minutes following the administration of digoxin-Fab. Digoxin-Fab was used more frequently in acute than chronic digoxin poisoning with a higher reported success rate when used in acute overdose. It is sometimes recommended to use full neutralisation doses (based on serum concentration × Vd or ingested dose). It has also been proposed to use half this dose. Indications for digoxin-Fab. Patients who have life-threatening tachy–bradyarrhythmias, hyperkalaemia (> 6 mmol/L) or haemodynamic instability with an elevated digoxin concentration (> 2 μg/L or 2.6 nmol/L). The lowest effective digoxin-Fab dosing regimen has not been established. Safety of digoxin-Fab. Adverse events such as exacerbation of heart failure, increased ventricular rate and hypokalaemia are uncommon (< 10%). Recrudescence of digoxin toxicity and allergic reactions are infrequent. Digoxin-Fab dosing in acute poisoning. Digoxin load based on ingested dose will generally overestimate digoxin-Fab doses as bioavailability is 60–80%, and further reduced by vomiting and activated charcoal. Digoxin load based on concentration also will be overestimated when the concentration is taken before distribution is complete (around 6 h). Much smaller doses of digoxin-Fab can eliminate the digoxin in the central compartment (Vd ≈ 55 L). In imminent cardiac arrest, it may be justified to give a full neutralising dose. Otherwise, based on pharmacokinetic modelling, it is recommended to give 80 mg bolus digoxin-Fab, repeated as required according to clinical parameters because the onset of clinical response is usually rapid. Most patients would be expected to require a total of less than half of the calculated neutralising dose using this strategy. Digoxin-Fab dosing in chronic poisoning. Even if digoxin load is estimated following distribution (> 6 h), excessive neutralisation doses may still be calculated because of variation in Vd due to equations failing to account for lean body weight, age and renal failure. In practice, it is suggested to give 40 mg (1 vial) digoxin-Fab at a time and repeat after 60 min if patient is still symptomatic, sooner if patient is clinically unstable. In general, 40–120 mg (1–3 vials) should be sufficient. Conclusions. Digoxin-Fab is safe and indicated in all patients with life-threatening arrhythmias and an elevated digoxin concentration. However, calculated full neutralising doses of digoxin-Fab are expensive and may not be required. In acute poisoning, a small bolus of 80 mg, repeat if necessary, titrated against clinical effect, is likely to achieve equivalent benefits with much lower total doses. With chronic poisoning, it may be simplest to give 40 mg (1 vial) digoxin-Fab at a time and repeat after 60 min if there is no response.     

Effects of sheep digoxin-specific antibodies and their Fab fragments on digoxin pharmacokinetics in dogs.

Intact sheep antidigoxin antibodies and their Fab fragments have both been found to exert profound effects on digoxin pharmacokinetics in [3H] digoxin-treated dogs. Both classes of molecule remove digoxin from the extravascular space and sequester it in the circulation in protein-bound form, a form in which the digoxin is presumably inactive. These two classes of molecule differ, however, in that the intact antibody molecules interfere with digoxin excretion, thereby promoting the retention of the glycoside; this retained digoxin is eventually released in free, active form when the administered antibody is metabolically degraded. In contrast, urinary excretion of digoxin continues in Fab-treated dogs, with significant quantities of digoxin being excreted promptly in the urine in complex with Fab fragments. These differences in urinary excretion, together with the probable decreased immunogenicity of sheep antidigoxin Fab fragments, suggest that such fragments possess potential advantages over intact antibody molecules for use in the therapy of life-threatening digoxin intoxication in man.     

Current considerations in digoxin usage.

Basic considerations in biotransformation and pharmacodynamics are presented as a basis for understanding clinical usage. The role of polarity in determining a given glycoside's duration of action and extent of biotransformation is emphasized. The pharmacokinetics are summarized emphasizing the fact that digoxin is not completely absorbed by oral administration. The important relationship of serum digoxin levels to myocardial content and apparently to myocardial response is reviewed. This relationship and the development of precise methods for measurement of digoxin in serum provide the clinician with accurate means to assess myocardial tolerance for digoxin under diverse clinical circumstances. This review includes discussion of methods of digitalization, appropriate use of serum levels, apparent and real resistance to digoxin, and apparent and real sensitivity to digoxin. The limitations of serum levels as a precise guide to toxicity are analyzed. Finally, new developments in use of immunologic therapy for digoxin intoxication are presented.     

Acute massive digoxin overdose: survival without use of digitalis-specific antibodies

Acute massive digoxin overdose may result in life-threatening arrhythmias, with reported mortality of up to 20% prior to the introduction of digitalis-specific antibodies. Digitalis-specific Fab antibody fragments remain under experimental protocol and are not widely available. Interpretation of serum digoxin levels and indications for the use of Fab are not clearly established. The authors report a case of massive digoxin overdose in an 18-month-old child with the highest reported digoxin level (48 ng/ml) with which a victim survived without the need for Fab administration. She developed only mild manifestations of digitalis intoxication, and her serum potassium never exceeded 5.2 mEq/l. Her course may be explained by the distribution kinetics of digoxin, which follows a two-compartment model, and the relative resistance of children to digitalis intoxication. This case emphasizes the need for better criteria than the digoxin level for the administration of Fab. The serum potassium concentration, which is usually elevated in acute type digitalis intoxication, may be a better predictor of the need for Fab in acute massive digitalis ingestion.     

Fatal digoxin poisoning: An unsuccessful resuscitation with use of digoxin-immune Fab

A 1-month-old infant suffered cardiac arrest shortly after presentation to the emergency department. The child had a history of heart disease treated with digoxin. The infant died despite intensive resuscitative efforts, including the use of digoxin-specific Fab antibodies. A brief discussion of this case and the use of digoxin-specific antibodies is presented.     

Update on treatment of pediatric pain with surgical considerations

The assessment, treatment, and prevention of pediatric pain pose a special challenge to surgeons and others involved in the care of children. The experience of pain is subjective, and infants and many children are unable to verbalize their level of discomfort. Therefore, it is the responsibility of physicians and nurses to be educated and trained to identify nonverbal signs of pain and discomfort, anticipate the experience of pain associated with specific procedures and diagnoses, and initiate the appropriate use of analgesics as well as nonmedicinal strategies to relieve this pain.     

Fab fragments of ovine antibody to colchicine enhance its clearance in the rat

Abstract

Context. Colchicine is an anti-inflammatory alkaloid used for the treatment of acute gout, but has a narrow therapeutic index. Colchicine overdoses are relatively rare, but have high mortality requiring rapid treatment. Objective. To evaluate the ability of a newly available ovine fragment antigen-binding (Fab) antibody to colchicine (ColchiFab^?) to protect rats against renal and other injury 24 h after colchicine ingestion. Materials and methods. Rats were gavaged with colchicine (5 mg/kg), then 2 h later injected intraperitoneally with 5 ml of sterile saline, or Fab anti-colchicine, a newly available ovine antibody to colchicine. Samples of blood were taken at 1, 2, 5 and 24 h after gavage, and urine was collected from 5 to 24 h after gavage. Concentrations of colchicine in tissue, blood and urine were measured by liquid chromatography/mass spectrometry, concentrations of Fab anti-colchicine, urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 or KIM-1 by enzyme-linked immunosorbent assay or ELISA, while concentrations of creatine kinase and creatinine (Cr) were measured enzymatically. Results. Colchicine equilibrated rapidly throughout the body and increased serum creatine kinase. Fab anti-colchicine also rapidly redistributed to the blood and remained at high concentrations over 24 h. Fab anti-colchicine caused a rapid 7.1-fold increase in serum colchicine level, followed by excretion of both colchicine and Fab anti-colchicine through the urine. This was associated with the accumulation of colchicine in the kidney, a reversal of colchicine-induced diarrhoea, and increasing urinary NGAL level; from 168 ± 48 to 477 ± 255 ng/mmol Cr [mean ± standard deviation or SD]. Discussion. Fab anti-colchicine greatly increased the clearance of colchicine, although increasing NGAL level suggested the presence of mild kidney damage. Conclusion. These data suggest clinical utility for Fab anti-colchicine in the treatment of colchicine overdose.     

Nutritional considerations in pediatric oncology

OBJECTIVES: To summarize the characteristics of a nutrition care plan for pediatric patients, specifically pediatric screening, assessment, and treatment protocols. DATA SOURCES: Review articles, manuals, and textbooks. CONCLUSIONS: Nutritional support of pediatric patients with cancer differs from adults because of their unique nutritional needs, their wide age range (infants to adolescents), and the psychosocial aspects of treating the entire family. IMPLICATIONS FOR NURSING PRACTICE: To participate in the prevention and treatment of malnutrition in the pediatric patient with cancer, nurses require an understanding of nutrition care in this specialized population.     

Dosing considerations in the pediatric patient.

Pediatric patients experience unique differences from the adult population in pharmacokinetic parameters and, consequently, require individualized dosing. Medications useful in pediatric medicine often lack a therapeutic indication and dosing guideline for this population. In addition, the absence of an available pediatric dosage form for some medications increases the potential for dosing errors and may produce serious--sometimes fatal--complications in young patients. It is important to select an appropriate medication and dose based on individualized pharmacokinetic considerations: one must evaluate a patient's age, size, and level of organ maturity, and not simply administer a "small adult" dose. Thus specific dosing guidelines and useful dosage forms for pediatric patients need to be developed in order to optimize therapeutic efficacy and limit, or prevent, serious adverse side effects.