The chemical formulation of Prussian blue influences the in vitro and, presumably, the in vivo adsorption of thallium ions. An early investigation demonstrated that the soluble form more effectively adsorbs thallium than the insoluble form.10 In a more rigorous study, the in vitro adsorptions of both forms were similar when thallium concentrations remained low.17 However, as thallium concentrations increased, the colloidal (soluble) form demonstrated far greater adsorptive capacity. Although not proven, this difference may occur because the soluble form contains more potassium and can therefore exchange proportionally more cation. Furthermore, the actual size of the crystal lattice alters its efficacy. Laboratory synthesized Prussian blue (with a crystal size of 176.8 Å) was compared with a commercial preparation (with a crystal size of 311.9 Å). The laboratory synthesized product adsorbed more thallium in vitro because its smaller size increased its surface area.18 In vitro analysis of the FDA-approved antidote demonstrated that pH and hydration state greatly influenced adsorption, with the maximal adsorptive capacity (MAC) predicted to be as high as 1400 mg of thallium/g at pH 7.5.67
In Vitro Comparison of Prussian Blue and Activated Charcoal
In one in vitro study, thallium was well adsorbed to Norit brand activated charcoal.17 Although numerical data are not supplied in the body of the paper, the 10% to 20% adsorption to activated charcoal demonstrated in a figure was far less than the results achieved with several different forms of Prussian blue tested simultaneously.17 Two other binding studies showed different results from the Norit activated charcoal study. An early investigation determined that the MAC of activated charcoal was 124 mg of thallium/g, whereas the MAC for Prussian blue was only 72 mg of thallium/g.19 More recently, a MAC of only 59.7 mg of thallium/g was calculated for CharcoAid activated charcoal, compared with a higher MAC for insoluble Prussian blue of 72.7 mg of thallium/g.15 Although the MACs for Prussian blue in these two studies are nearly identical, they differ significantly from the MAC reported above for the FDA approved formulation, possibly as a result of different experimental conditions.67 Similarly, the variable results for activated charcoal may also be a function of the study pH or the different types of activated charcoal used.
Animal Data: Kinetics, Tissue Concentrations, and Survival
Sublethal doses of thallium were used to evaluate the effects of various antidotes in rats over an 8 day period.19 Although the control group only eliminated 53% of the administered dose of thallium, 93% of the dose was eliminated in the activated charcoal, and 82% was eliminated in the insoluble Prussian blue groups. In contrast, other investigators demonstrated only a modest increase in thallium elimination in rats treated with oral activated charcoal while demonstrating a consistent benefit of Prussian blue.20
Multiple studies demonstrate that Prussian blue not only decreases the half-life of thallium in animals but also lowers thallium content in critical organs such as the brain and the heart.13,30,31,47,49 Half-lives are typically reduced by approximately 50% when Prussian blue is given with or without a cathartic. The rationale for the cathartic is that constipation is invariably present in humans and animals with severe thallium poisoning.
Only a few studies evaluate the effects of Prussian blue on survival. In these studies, a statistically significant survival advantage is shown in thallium poisoned rats18,49 and mice24 treated with Prussian blue. The experimental benefit is on the order of a 31% increase in the LD50 (median lethal dose for 50% of poisoned animals).50 Although most chelators have a limited or detrimental effect in thallium poisoning (Chap. 102) and dl-penicillamine has no demonstrable benefit as a single antidote, in an animal model the combined use of Prussian blue and dl-penicillamine not only decreased thallium concentration in critical tissues such as the brain but also enhanced survival.28 While interesting, these data are too premature to recommend the routine use of combined dl-penicillamine and Prussian blue in poisoned humans.
There is no published experience describing human poisoning with radioactive thallium. Prussian blue has demonstrable efficacy in an animal model of radioactive thallium poisoning, as would be expected because the ionic radii of isotopes are generally similar. In one small study, insoluble Prussian blue decreased the biologic half-life of radioactive thallium in rats by approximately 40%.3 Many humans receive radioactive thallium (201 Tl) chloride as part of myocardial scintigraphy, with a typical adult dose of 110 megabecquerels (MBq). Recent concerns about excess radiation exposure following the termination of diagnostic testing have led to the evaluation of Prussian blue to enhance post-imaging elimination. In vitro evidence suggests a MAC of 5000 MBq/g.2 In a controlled trial, where Prussian blue was given to a patient post myocardial scintigraphy, radioactivity was reduced 18% and 30% after 24 and 48 hours, respectively.2
Thallium Poisoning in Humans
A thorough analysis of the efficacy of Prussian blue in thallium poisoning is severely hampered by many factors. First, and most importantly, there are no controlled human trials. Second, although multiple patients have received Prussian blue in the setting of thallium poisoning, many were simultaneously treated with a variety of therapies, including forced potassium diuresis, single- or multiple-dose activated charcoal, and either hemodialysis or hemoperfusion. Thus, it is impossible to determine the specific effects of Prussian blue on morbidity or mortality, and even toxicokinetic data must be interpreted with caution. Third, many reports fail to specify the exact type of Prussian blue used. Those investigations that do specify the type of Prussian blue typically employed the soluble form, which is presently unavailable as a pharmaceutical preparation in the United States. Discussions of the available data in the following sections are limited by these considerations.
Three patients, in 1971, were the first to receive Prussian blue as a treatment for thallium poisoning.17 Although daily fecal thallium concentrations were not determined in two of the three patients because of severe constipation, an approximately sevenfold increase in fecal thallium elimination over baseline was attributed to Prussian blue therapy in the third patient. Subsequently, many humans with thallium poisoning have received Prussian blue, with or without a cathartic, as part of their therapy.1,5,7,8,12,17,41,44,45,53,59,60,64 Unfortunately, other components of therapy that may have confounded the effects of Prussian blue in these cases include single- or multiple-dose activated charcoal and the use of d-penicillamine, dimercaprol, ethylenediaminetetraacetic acid (EDTA), succimer, 2,3-dimercaptopropane-1-sulphate (DMPS), forced potassium diuresis, and either hemodialysis or hemoperfusion. There are no controlled human trials of any of these modalities alone or in combination, and most of the data presented are based on single case reports or small case series.
One of the largest series was comprised of 11 thallium poisoned patients who were treated with soluble Prussian blue.53 This report not only demonstrated the tolerability of Prussian blue, but also was the first to systematically evaluate its fecal elimination. In all individuals studied, fecal elimination remained high, even when urinary elimination fell, suggesting selective redistribution of thallium into the gut.53 Although the authors commented on clinical improvement in these patients, the lack of controlled data makes these subjective observations difficult to interpret. Similarly, a substantial reduction in thallium half-life was demonstrated when Prussian blue was compared with no therapy at all in patients with thallium poisoning.8 More recently, a series of 14 patients with delayed presentation (9–19 days) were reported. These patients were treated with DMPS, followed by Prussian blue and hemodialysis, and 13 survived. Data are insufficient to make inferences about the effects of Prussian blue alone or as part of this treatment regimen.54
Dosage and Administration
The dosage of Prussian blue has never been investigated systematically in either humans or animals. In most of the case reports and series mentioned above, a total dose of 150 to 250 mg/kg/d was administered orally or via a nasogastric tube in two to four divided doses.53 Because constipation or obstipation is often present or expected, Prussian blue is generally administered dissolved in 50 mL of 15% mannitol.55 Although any cathartic may be appropriate, mannitol is used most frequently, possibly because of concerns over the risks associated with repeated doses of magnesium or sorbitol (Antidotes in Depth: A2). The manufacturer of Radiogardase recommends that adults and adolescents with thallium poisoning receive a total dose of 9 g divided daily (3 g every 8 hours) and that children receive a total dose of 3 g divided daily (1 g every 8 hours). Although the manufacturer does not recommend using a cathartic, a high fiber diet is advocated when constipation is present. Because Prussian blue is well tolerated, the editors of this text continue to favor the 150 to 250 mg/kg/d dosing because it provides more antidote with limited adverse consequence, as most of the published experience has used this dose with essentially no adverse effects. In addition, because many severely poisoned patients cannot eat, the use of a cathartic should be considered when constipation is consequential.
The end point of therapy is similarly poorly defined. By convention, Prussian blue is usually continued until urinary thallium concentrations fall below 0.5 mg/d. Although this end point may not be a perfect measurement of thallium burden, as small amounts of fecal elimination continue, even when urinary elimination has diminished,53 most laboratories are not equipped to measure fecal thallium concentrations. In patients who remain significantly symptomatic, Prussian blue therapy could be continued for a short period past the 0.5 mg/d endpoint on an individual basis.