PubMed · 712954
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R Tideiksaar. 1978-12-01. Detecting digitalis toxicity.. https://doi.org/10.1001/jama.1978.03290230034016
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The aim of the study was to compare the results of digoxin assays performed using fluorescence polarization immunoassay (FPIA) on the TDxFLx and a dry chemistry enzyme immunoassay (EIA) on the Vitros 950. Within-run CV amounted to 8.52-10.49% for FPIA and 2.47-5.39% for EIA. Between-run CV amounted to 6.41-8.97% for FPIA and 3.40-5.04% for EIA. Analytical bias ranged from 2.57-4.0% for FPIA and from 9.86-11.9% for EIA. In comparative studies the correlation coefficient was 0.878; Deming regression analysis yielded a slope of 1.057 (95% CI: 0.573 to 1.541) and intercept of 0.078 (95% CI: -0.391 to 0.547), and the Passing-Bablok agreement test yielded a slope of 1.111 (95% CI: 0.988 to 1.212) and intercept of 0.094 (95% CI: -0.018 to 0.182). The mean digoxin concentration in patients' sera measured by EIA was significantly higher than that measured by FPIA (1.347 vs. 1.196 ng/ml, p<0.02). The mean absolute difference between results amounted to 0.146 ng/ml (95% CI: 0.0261 to 0.266). In comparison to EIA, FPIA yielded a higher number of subtherapeutic concentrations <0.5 ng/ml (29.7% vs. 21.8%) and a lower number of digoxin concentrations >1.2 ng/ml (25.7% vs. 35.6%). These discrepancies occurred in approximately 10% of samples. The obtained results showed different analytical performance and method-dependent differences in the distribution of results. This indicates the necessity to harmonize digoxin immunoassays if two different analytical systems are used in the same clinical setting.
This review provides current information on the use of antigen-binding fragments (Fab) from cleaved antibodies to treat poisoning with digoxin and other potent, low formula mass poisons, such as colchicine and tricyclic antidepressants. Anti-digoxin Fab fragments have been used successfully for many years in the management of severe poisoning with digoxin, digitoxin, and a range of other structurally related compounds, including cardiotoxins from Nerium and Thevetia sp. (oleander) and Bufo sp. (toads). However, their main use remains treating digoxin poisoning. Equimolar doses of anti-digoxin Fab fragments completely bind digoxin in vivo. The approximate dose of Fab fragments (mg) is 80 times the digoxin body burden (mg). If neither the dose ingested nor the plasma digoxin/digitoxin concentration is known, in an adult 380 mg of anti-digoxin Fab fragments should be given. The dose for elderly patients or those with renal impairment should be similar to that for those with normal renal function. Fab fragments have a plasma half-life of 12-20 hours, but this can be prolonged in patients with renal impairment. Analysis of serum ultrafiltrate using an immunoassay shown not to have matrix bias remains the most accurate approach to measuring free digoxin in the presence of anti-digoxin Fab fragments. The antibody fragments are given intravenously over 15-30 minutes after dilution to at least 250 mL with plasma protein solution, 0.9% (w/v) sodium chloride, or deionised water, except in infants where the volume infused can be reduced. Factors limiting the efficacy of Fab fragments are the dose, the duration of the infusion and any delay in administration. Guidelines for Fab fragment administration in children include (i) dilution to a final Fab concentration of 10 g/L in either 5% (w/v) dextrose or 0.9% (w/v) sodium chloride; (ii) infusion through a 0.22 microm filter; (iii) administration of the total dose over a minimum of 30 minutes; and (iv) avoiding coadministration of other drugs and/or electrolyte solutions. Fab fragments are generally well tolerated. Adverse effects attributable to Fab treatment include hypokalaemia and exacerbation of congestive cardiac failure; renal function could be impaired in some patients. Fab fragment preparations for treating acute colchicine and tricyclic antidepressant poisoning have been developed, but are not available commercially. Colchicine poisoning is rare in Western countries, and pharmacological management together with supportive care is usually effective even in severe tricyclic antidepressant overdosage. Attempts have been made to produce anti-paraquat antibodies capable of enhancing paraquat elimination from the lung, but thus far all such attempts have proved unsuccessful.
Digitalis glycoside poisoning is an important clinical problem and the development of digoxin-specific antibody fragments (Fab) 30 years ago has changed clinical practice. Nevertheless, doubts still exist as to the appropriate dose indications for therapy. This paper reviews relevant literature, describes the difficulties associated with current treatment protocols and proposes an approach to therapy, which is based on theoretical principles and evidence gleaned from currently available clinical data sets. In patients with 'acute' poisoning, serum digoxin concentrations do not equate to the total body burden, as tissue distribution will not have occurred, and the calculations for present protocols, which use serum concentrations, are therefore likely to result in too much antibody being administered. Since a therapeutic quantity of digoxin will have little effect in a normal individual, complete neutralisation of all digoxin is also unnecessary. The pharmacokinetic and dynamic logic of using a smaller initial loading dose than predicted from total body calculations is rational. It is recommended that half the calculated loading dose, either based on serum concentration or history, should be administered and the impact on clinical features observed. If a clinical response is not seen within 1-2 hours, a further similar dose should be given. In the event of a full response, patients should be monitored for 6-12 hours; a second dose should only be given in the event of recurrence of toxicity. In patients with 'chronic' digoxin poisoning, the serum digoxin concentration will reflect the total body load. However, since such patients are invariably receiving digoxin for therapeutic purposes, full neutralisation is again not indicated. In addition, tissue redistribution of digoxin from deeper stores will occur following the binding of biologically active digoxin in the circulation. This process will occur over a number of hours and if the total calculated dose of antibody is administered in a single bolus, significant quantities will be excreted prior to redistribution of digoxin. Pharmacokinetic logic, therefore, suggests that half the calculated loading dose, based on serum concentration, should be administered and the impact on clinical features observed; a second dose should be given in the event of recurrence of toxicity.