The concentration-time profile of total digoxin following administration of Fab is dependent on the disposition of Fab because most of the total digoxin is bound to it [4, 8-11]. Minutes after Fab is administered, the total (bound and free) serum digoxin concentration increases 10 to 30 times and the free state of digoxin in plasma decreases from approximately 75% to 90% to 0% to 5% [4, 5, 8-18]. When total digoxin reaches a maximum concentration after Fab administration, the plasma concentrations decline in a two-phase fashion; the initial phase probably represents both plasma elimination and the distribution of free and Fab-bound digoxin out of vascular spaces. The second phase represents terminal plasma elimination, which has a half-life ranging from 16 to 30 hours in patients with normal renal function [4, 8, 10, 15]. Free digoxin, on the other hand, decreases rapidly after Fab administration and then increases or rebounds. The rebound in free digoxin peaks approximately 3 to 24 hours after Fab administration (in patients with normal renal function) and then declines more slowly at a rate dependent on Fab and renal and nonrenal routes of elimination [4, 8, 10]. Renal dysfunction is expected to alter the disposition of Fab and total and free digoxin because digoxin and Fab are eliminated through renal excretion. Case reports suggest that renal dysfunction prolongs the terminal elimination half-lives of both Fab and total digoxin and may delay the rebound in free digoxin [11, 12, 14, 19].

Because digoxin that is bound to Fab is pharmacologically inactive, the free digoxin concentrations are more important predictors of pharmacologic activity, but only a few case reports describe their use during Fab therapy [9, 16]. Monitoring free digoxin in selected digoxin-toxic patients receiving Fab therapy may be warranted to confirm suspected reintoxication, to assess the necessity and amount of supplemental Fab doses, and to determine the timing of subsequent digoxin therapy. The aims of our study were to characterize the disposition of total and free digoxin following the administration of Fab in patients with varying degrees of renal function and to describe the potential utility of monitoring free digoxin concentrations.

Methods

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Patients at Hartford Hospital (Hartford, Connecticut) and Henry Ford Hospital (Detroit, Michigan) who presented within the 18-month study period with clinical digoxin toxicity (as determined by their primary physician) were considered for entry into the study. Digoxin toxicity was defined by electrocardiographic changes; clinical symptoms such as nausea, vomiting, and central nervous system disturbances; and a digoxin concentration greater than 3.2 nmol/mL. Patients who received a Fab dose that was 50% or less than the recommended dose were excluded [20]. The study was approved by the institutional review committees of the participating institutions, and all patients gave written informed consent.

After Fab was administered, serial blood samples were drawn (before hemodialysis if applicable). In most cases, if the initial serum creatinine level was 221 µmol/L or less, blood was drawn every 12 hours for 72 hours; if the initial serum creatinine level was greater than 221 µmol/L, blood was drawn every 24 hours until the patient was discharged from the hospital [21]. All samples were analyzed after patients had been treated and discharged.

Sample Analysis

A baseline digoxin concentration was obtained at the time that digoxin toxicity was suspected, at least 4 hours after the last digoxin dose. These samples were analyzed by the digoxin assays available at the study institutions (radioimmunoassay and Baxter Dade Stratus) and reflected total digoxin concentrations (total digoxin concentrations in the absence of Fab resemble those of free digoxin) [13, 16]. Samples collected for this study were assayed by two systems that have been previously described [11, 18, 21, 22]. Most patient blood samples (n =12) were analyzed by a fluorescence polarization immunoassay (TDx, Digoxin II, Abbott Laboratories Diagnostic Division; Irving, Texas), and samples from patients 8 and 9 were analyzed using a modified immunofluorometric assay (Pharmacia Diagnostics, Fairfield, New Jersey).

Data Analysis

Pharmacokinetic parameters of free digoxin (maximum rebound, initial nadir, time to maximum rebound, mean maximum free fraction, and time to maximum free fraction) were determined by inspecting the digoxin concentration-time curve or free fraction-time curve. Total digoxin concentration-time data from the maximum total digoxin concentration observed following Fab therapy to the last data point obtained were fitted by nonlinear least-squares regression computed with PCNONLIN (Statistical Consultants; Lexington, Kentucky). The parameters estimated were elimination rate constants of the first and second phases of the total digoxin concentration-time profile, and ß, respectively, which were used to calculate the and ß phase half-lives, respectively. These parameters were poorly estimated in four patients (1, 2, 4, and 9) because the number of data points was insufficient, and therefore we have not reported them. Maximum and minimum values of total digoxin after Fab were determined by inspection of the concentration time curve. Data are reported as mean ± standard deviation.

Results

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Patient Demographic Characteristics and Clinical Presentation

Fourteen patients with suspected digoxin toxicity requiring Fab treatment were enrolled in the study (Table 1). Four patients had end-stage renal disease and were receiving chronic hemodialysis (patients 3, 9, 10, and 12), one had acute renal failure (patient 11), and the others had varying degrees of renal dysfunction (Table 1). Nine of the 14 patients had severe signs of digoxin toxicity (complete heart block or severe bradycardia [heart rate < 50 beats/min] or both with or without hemodynamic instability [n = 8] or hemodynamic instability [systolic blood pressure <100 mm Hg] only [n = 1]). Toxicity developed in 11 patients with chronic digoxin therapy, whereas 3 patients (patients 7, 12, and 13) became toxic shortly after they began digoxin therapy.

Pharmacokinetics of Digoxin following Fab Administration

Total digoxin concentrations ranged from 3.4 to 10.5 nmol/mL before Fab therapy. Following treatment with Fab, total digoxin levels increased rapidly, reaching a mean maximum concentration of 51.8 ± 22.7 nmol/mL within 24 hours Figure 1, which were 9.6 ± 5.8 times greater than the concentrations before Fab administration. Subsequently, total digoxin concentrations decreased in a two-phase fashion to a mean of 7.2 ± 4.7 nmol/mL (Figure 1). The mean half-life of the initial phase of the total digoxin elimination curve () was 11.6 ± 4.1 hours, whereas the half-life in the terminal elimination phase (ß) was 118 ± 57 hours. The elimination half-life values in patients with end-stage renal disease were longer than those in the other patients, 123 ± 18 compared with 112 ± 68 hours, respectively. Free digoxin following Fab therapy, on the other hand, decreased rapidly to a mean nadir of 0.62 ± 1.1 nmol/mL, which was observed at the first sampling time, 7 to 24 hours after administration of the antidote. Subsequently, free digoxin increased in all patients (except patient 11) to an average maximum concentration of 1.7 ± 1.3 nmol/mL, which occurred 77 ± 46 hours (range, 23 to 192 hours) after Fab therapy. The time to maximum free digoxin rebound, however, occurred later in patients with end-stage renal disease compared with the other patients (127 ± 40 hours compared with 55 ± 28 hours, respectively). The magnitude of the maximum free digoxin rebound, however, was similar between patients with and without end-stage renal disease (1.79 ± 0.96 compared with 1.61 ± 1.41 nmol/mL, respectively). The free fraction of digoxin after Fab therapy also decreased quickly to approximately 0% in most patients, but then increased to a mean maximum of 18.2% ± 10%.

View larger version (29K): [in this window] [in a new window]   Figure 1. Disposition of free and total digoxin time profiles. Total (open circles) and free (closed circles) digoxin concentrations, and free fraction (closed triangles) time profile for patients 2, 6, 10, and 12. The arrows shown for patients 2, 6, and 10 represent the time at which suspected digoxin reintoxication occurred with respect to the free digoxin concentration. The arrow for patient 12 represents the time when digoxin therapy was reinitiated with respect to the free digoxin concentration.

Pharmacodynamics of Digoxin after Fab Therapy

After Fab therapy, all patients had partial or complete resolution of their signs and symptoms of digoxin toxicity (see Table 1), which appeared to be temporally related to the decline in free digoxin. Fab therapy reversed the therapeutic benefits of digoxin in five patients [patients 1, 3, 5, 10, and 12]. These patients experienced relapses of their underlying conditions: four patients had a rapid ventricular response to atrial fibrillation 24 to 72 hours after Fab therapy, and patient 10 had an exacerbation of congestive heart failure and pulmonary edema 24 to 48 hours after Fab therapy. Atrial fibrillation in patient 12 was treated by reinitiating digoxin therapy approximately 48 hours after Fab treatment, resulting in a dramatic increase in the free digoxin concentration (from 0.65 nmol/mL 40 hours following Fab therapy to 2.7 nmol/mL 68 hours after Fab therapy) and control of the rapid ventricular response (see Figure 1).

Three patients had suspected recrudescence of digoxin toxicity. Patient 2 received supplemental Fab therapy because signs and symptoms of digoxin reintoxication were observed 8 hours after the initial Fab dose. The patient, however, did not respond to the second Fab dose. Free digoxin concentrations were undetectable (<0.13 nmol/mL) for 48 hours after the first and second Fab doses and thus were predictive of the initial lack of response and the need for the second Fab dose. Patient 6 had atrial arrhythmias and frequent ventricular ectopy with concomitant symptoms of digoxin toxicity. Following Fab therapy, the ventricular ectopy was infrequent until approximately 72 to 90 hours after therapy. At that time, ventricular ectopy became more frequent, and nonsustained ventricular tachycardia occurred. No medication changes had been made, and the patient's electrolyte values were normal. The patient's free digoxin rebounded (2.0 nmol/mL) at the approximate time that signs of reintoxication occurred (see Figure 1). Patient 10 had complete heart block, which reverted to normal sinus rhythm within 12 hours of Fab therapy. Seven days after Fab therapy [168 hours], the patient began experiencing episodes (3 to 6 seconds) of sinus exit block, junctional bradycardic rhythms, and nonsustained ventricular tachycardia for 3 days that subsided without intervention. These arrhythmias were not related to medication changes or electrolyte disturbances (K⁺, 3.6 mmol/L to 4.5 mmol/L). Free digoxin concentrations at this time were 0.9 to 1.0 nmol/mL (see Figure 1).

Discussion

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Currently, clinicians treating patients with Fab must be guided solely by clinical findings. We used a rapid assay method, however, to determine both free and total serum digoxin concentrations in the presence of Fab. The clinically relevant findings of our study are that digoxin, following the administration of Fab, was excreted slowly in our predominantly elderly patients with evidence of renal dysfunction, and that a rebound increase in free digoxin to peak concentrations occurred approximately 1 to 8 days (mean, 77 hours) after Fab administration.

In our patients, total and free digoxin were eliminated more slowly from the systemic circulation compared with patients with normal renal function. The elimination half-life of total digoxin in the present study (68 to 261 hours) was similar to digoxin half-life (68 to 177 hours) reported in renally impaired patients not receiving Fab therapy [23, 24]. Case reports (serum creatinine, 88.4 to 716 µmol/L) have described the elimination half-life of total digoxin following Fab therapy to be similar to that shown by our data, ranging from 24 to 330 hours [11, 14, 25]. Except for two outliers, the longest elimination half-life values for total digoxin in the current study were seen in patients with end-stage renal disease (serum creatinine > 442 µmol/L). These data further support the theory that renal dysfunction slows the elimination rate of total digoxin following Fab therapy.

Free digoxin concentrations, on the other hand, increased, peaked, and then decreased as total digoxin concentrations decreased. It has been proposed that the time in which free digoxin concentrations rebound to a maximum concentration may be affected by renal function [11, 18]. We observed that the time to maximum free digoxin rebound was longer in patients with end-stage renal disease. Others have had similar observations in patients with renal failure [11, 14]. These data, therefore, suggest that the rebound in free digoxin may be affected by renal function, although the mechanisms involved cannot be determined from these data.

The goal of Fab therapy is to inhibit the toxic pharmacologic effects of digoxin by preventing it from interacting with its effector site for a sustained period. Fab does this by binding digoxin, thereby decreasing the availability of free digoxin at the effector site. Therefore, it may be clinically important to monitor free digoxin concentrations in these patients. In most patients, free digoxin concentrations decrease rapidly after Fab therapy but then rebound, although rarely exceeding digoxin's therapeutic range. In our study, free digoxin concentrations in two patients exceeded 1.5 nmol/mL. Patient 6 had suspected digoxin reintoxication when the free digoxin level rebounded to 1.6 nmol/mL, and patient 13, who appeared to receive an insufficient neutralizing dose of digoxin, was not affected by a markedly elevated free digoxin concentration (5.2 nmol/mL). Other investigators have reported cases of recurrence of digoxin toxicity following Fab therapy, although few have monitored free digoxin levels [4, 26]. One case report, however, did describe an association between a large rebound in free digoxin (7.7 nmol/mL within 12 hours) following Fab therapy and a lack of electrocardiographic improvement [25].

The utility of monitoring digoxin concentrations during Fab therapy has not been evaluated. It is possible that the prospective monitoring of free digoxin concentrations in some of the patients in our study may have affected treatment decisions and overall patient outcome. If we had known that the free digoxin concentrations in patient 2 were < 0.2 nmol/mL, we might not have given supplemental Fab doses and may have diagnosed the problem more quickly (see Figure 1). Knowing the free digoxin concentration in patients 6 and 10, in whom digoxin reintoxication was suspected, may have aided the clinician in diagnosing the cause and shortening the time that these patients required scarce cardiac-monitored beds (see Figure 1). Monitoring of the free digoxin concentration would have speeded the reinitiation of digoxin therapy in patient 12, who required additional digoxin therapy within 36 hours of Fab administration to control a rapid ventricular response to atrial fibrillation (120 beats/min). Reinitiation of digoxin therapy (intravenous digoxin, 0.25 mg) in this patient resulted in a large increase in free digoxin concentration (3.3 nmol/mL) and a therapeutic response (see Figure 1). The subsequent free digoxin concentrations were blindly maintained above 1.3 nmol/mL, with oral digoxin, 0.125 mg every other day, resulting in adequate rhythm control (ventricular rate, 60 to 88 beats/min). Patient 3 would have also benefited from monitoring of free digoxin concentration: his hospital stay was prolonged because the attending physician refused to discharge the patient (who was admitted with a diagnosis of digoxin toxicity) with a high or unreliable digoxin concentration.

Study Limitations

Our study lacked a homogeneous study group, had infrequent blood sampling, and imprecisely measured renal function. Nevertheless, the sampling strategy provided enough data points to characterize the and ß rate constants of total digoxin in most patients. In addition, the blood samples were not obtained beyond 3 to 4 total digoxin elimination half-lives in most patients, which may increase the variability of this parameter. The 12- to 24-hour sampling intervals may have missed the exact time of maximum free digoxin rebound and maximum peak free fraction; they must be interpreted as an approximation within the sampling interval.

Clinical Implications

This study provides useful information regarding the time needed to eliminate digoxin from the systemic circulation in Fab-treated patients with renal dysfunction (serum creatinine > 190 µmol/L). We observed that the rebound of free digoxin levels to peak concentrations, which usually occurred between 1 and 8 days, was observed later in patients with end-stage renal disease. Therefore, to ensure that the rebound in free digoxin has occurred without reintoxication, patients with renal dysfunction who receive Fab therapy should be monitored clinically and electrocardiographically longer than patients with normal renal function. When possible, free serum digoxin concentrations during Fab therapy should be monitored to provide additional data to assess the likelihood of rebound digoxin toxicity and the dosage required to treat it. Monitoring free digoxin concentrations may also help properly time reinitiation of subsequently required digoxin therapy. The clinical state of the patient, however, should determine the need for supplemental Fab therapy as well as subsequently required digoxin therapy.

Presented in part at the 21st annual meeting of the Society of Critical Care Medicine, San Antonio, Texas, 28 May 1992.