Fab antibodies in treatment of digoxin poisoning are known to interfere with the analysis of digoxi

Fråga: Fab antibodies in treatment of digoxin poisoning are known to interfere with the analysis of digoxin concentration. For how long after administration of antibodies is this interference known to occur? Is there any reliable method to measure digoxin levels during Fab treatment?

Sammanfattning: The half-life of Fab antibodies is usually about 20 hours and a single dose should be eliminated in about four days. Elimination is delayed by impaired renal function. Hepatitis and perhaps other unknown factors can also cause delayed elimination. Ultrafiltration followed by fluorescence polarization immunoassay to obtain free digoxin levels is said to be a reliable method in some studies. Measuring free digoxin might be useful in cases of delayed elimination because of possible dissociation of digoxin-antibody complexes leading to slowly rising levels of free digoxin, and also if the initial dose of antibodies is suspected to be insufficient.

If digoxin therapy is to be restarted, laboratory values should be interpreted with special care.

Svar: The preparation of digoxin antibodies available on the Swedish market consists of Fab fragments of IgG sheep antibodies. Their use in digoxin poisoning is usually successful, but there are a few disadvantages. The amount of antibodies given is usually approximate, either due to unknown amount of digoxin intake or to uncertainties in high concentration values. The risk for allergic reactions increases with repeated administration. Also, the treatment is very expensive.

Following Fab administration, total serum levels of digoxin rise (10 to 20 times) due to mobilization of tissue bound digoxin to Fab fragments in the serum. Concomitantly free digoxin gets very low or undetectable. The digoxin-antibody-complex is pharmacologically inactive and is renally excreted (1,16). Half-lifes reported in different studies vary between 6 and 40 hours in subjects with normal kidney function with a mean of about 20 hours (1,4,15). In one study, primarily concerned with the kinetics of Fab fragments in 17 patients, the median half-life was 15 hours during the first day and 25 hours later on. Corresponding apparent distribution volumes were 26 and 54 litre which suggests intracellular penetration of Fab fragments (4).

In patients with renal impairment, the half-life may be considerably longer: 53, 130 and 143 hours have been reported in three patients the first of which was in haemofiltration treatment and the second in haemodialysis (2,3). During this long elimination period, the digoxin-antibody-complex may apparently dissociate again, and the concentration of free digoxin rise.

Delayed elimination of Fab fragments has also been reported in a child with both Hepatitis A and B infections. In this case, the Fab antibodies (given on suspicion of digoxin intoxication, which later on proved not to have occurred) interfered with the digoxin analysis for several weeks (8).

Fab antibodies will interfere with digoxin analysis in various ways depending on the method of analysis and on the amount of free Fab fragments in the sample. In a competitive test, for example, excess Fab fragments will bind to the labelled digoxin added and result in an apparent high digoxin concentration. In the study on Fab kinetics mentioned above (4), equilibrium dialysis was used to obtain free digoxin levels, but this is an expensive as well as time consuming procedure.

A literature review of ten articles concerning digoxin assay anomalies following Fab administration has been performed (5-14). The majority of these articles are based on one to three patients. One study includes eight subjects (13), and one is purely experimental (10). In four articles (three of which are by the same authors), it is concluded that ultrafiltration followed by FPIA (in one case FETI) is a useful method for measuring free digoxin levels, or at least better than a variety of immunoassays (FPIA, RIA, FETI, EMIT) without ultrafiltration (10-13). One article recommends it on the basis of three case reports to determine free digoxin in obese patients, in renal insufficiency and when the patient fails to respond to Fab (12). A recently published work stated that the Stratus system (a RPIA method) said to give reliable free digoxin results, but this is concluded on results from a single case (9).

The normal protein binding of digoxin, mostly to albumin, is about 25 per cent. This fraction will also be separated by ultrafiltration. 1 Kampa IS: The effect of Digibind on various digoxin immunoassays. AACC TDM/Tox 1993; 14: 183-185 2 Erdmann E, Mair W, Knedel M, Schaumann W: Digitalis intoxication and treatment with digoxin antibody fragments in renal failure. Klin Wochenschr 1989; 67: 16-19 3 Colucci RD, Chow M, Kluger J, Sailstad J, Findlay J, Long R: The pharmacokinetics of digoxin immune Fab, total digoxin and free digoxin in patients with renal impairment. Pharmacotherapy 1989; 9: 175 4 Schaumann W, Kaufmann B,Neubert P, Smolarz A: Kinetics of the Fab fragments of digoxin antibodies and of bound digoxin in patients with severe digoxin intoxication. Eur J Clin Pharmacol 1986; 30: 527-533 5 Wong SHY, Kelley C: Performance of the opous serum digoxin assay of samples with Dlif and Digibind. Clin Chem 1992; 38: 995 6 Kampa IS: Prolonged effect of Fab fragments on various digoxin in immunoassays. Clin Chem 1991; 37: 1001 7 Banner W Jr, Bach P, Burk B, Freestone S, Gooch WM III: Influence of assay methods on serum concentrations of digoxin during Fav fragment treatment. Clin Toxicol 1992; 30: 259-267 8 Nollet H, Verhaaren H, Stroobandt R, Belpaire F: Delayed elimination of digoxin antidotum determined by radioimmunoassay. J Clin Pharmacol 1989; 29: 41-45 9 Bizzaro N, Finco B, Milani L: Fab treatment in acute digitalis intoxication: reliability of serum digoxin determination with the stratus system. Clin Chim Acta 1993; 217: 225-227 10 Ujhelyi MR, Cummings DM, Green P, Ellison MJ, Vlasses PH: Effect of digoxin Fab antibodies on five digoxin immunoassays. Ther Drug Monit 1990: 12: 288-292 11 Natowicz M, Shaw L: Digoxin assay anomalies due to digoxin-specific Fab immunotherapy. DICP Ann Pharmacother 1991; 25: 739-741 12 Ujhelyi MR, Colucci RD, Cummings DM, Green PJ, Robert S, Vlasses PH, Zarowitz BJ: Monitoring serum digoxin concentrations during digoxin immune Fab therapy. DICP Ann Pharmacother 1991; 25: 1047-1049 13 Ujhelyi MR, Green PJ, Cummings DM, Robert S, Vlasses PH, Zarowitz BJ: Determination of free serum digoxin concentrations in digoxin toxic patients after administration of digoxin Fab antibodies. Ther Drug Monit 1992; 14: 147-154 14 Gibb I, Adams PC, Parnham AJ, Jennings K: Plasma digoxin: assay anomalies in Fab-treated patients. Br J Clin Pharmacol 1983; 16: 445-447 15 Martindale, The extra pharmacopoeia. 1993; 30th ed: 680 16 Wenger TL, Butler VP Jr, Haber E, Smith TW: Treatment of 63 severely digitalis-toxic patients with digoxin-specific antibody fragments. JACC 1985; 5: 118A-123A