A28: Antidotes in Depth

Poisoning with salts of thallium or cesium are uncommon causes of life-threatening toxicity where supportive care may be insufficient to alter outcome. Radioactive cesium can be released as part of a nuclear incident or dispersed as a “dirty bomb,” producing radiation poisoning with sub-toxic cesium doses. Prussian blue is an orally available cation exchange resin that definitively enhances elimination of thallium and cesium in humans and animals and improves survivability in animals.

Prussian blue, the first artificially synthesized pigment, was discovered unintentionally by Diesbach in 1704 while attempting to make another ­pigment, cochineal red lake. Although immediately popular in art and later in printing, it took approximately 250 years to recognize that Prussian blue could attract monovalent alkali metals into its crystal lattice. Subsequently, in 1963, Nigrovic demonstrated that Prussian blue enhanced cesium elimination from the gastrointestinal tract of rats given either oral or intraperitoneal cesium.³⁷ In 2003, the US Food and Drug Administration (FDA) approved Prussian blue (Radiogardase) for the treatment of thallium and radioactive cesium poisoning.

The Prussian blue literature is complicated by many confusing chemical and physical terms. The product synthesized by Diesbach, Fe₄[Fe(CN₆)]₃, commonly known as insoluble Prussian blue, is assigned the Chemical Abstracts Service (CAS) number 14038-43-8 and is the FDA-approved product Radiogardase (Fig. A28–1). Synonyms for Prussian blue include Berlin blue, Hamburg blue, mineral blue, Paris blue, and Pigment blue 27, among others.⁵⁶ These names are often used interchangeably to refer to both insoluble Prussian blue and a soluble (colloidal) Prussian blue that either has the molecular formula KFe[Fe(CN)₆]₃ or K₃Fe[Fe(CN)₆]₃. Thus “Prussian blue” also carries two additional CAS numbers: 25869-98-1 and 12240-15-2.³⁸ Compounds containing the same basic core structure, such as NH₄Fe[Fe(CN)₆]₃ (ammonium ferric ferrocyanide or Chinese blue) and sodium ferric ferrocyanide, may have similar efficacy in binding monovalent cations and are also sometimes incorrectly called Prussian blue. For the purpose of clarity, general statements that follow use the term “Prussian blue.” In many instances the terms “insoluble” and “soluble” are chosen to highlight differences between the compounds. Unfortunately, because many studies do not specify which Prussian blue is used, some inherent ambiguity persists in the literature. Radiogardase, the currently available pharmaceutical preparation, is the insoluble form of Prussian blue, possibly selected preferentially for its efficacy in cesium poisoning.

The crystal lattice of Prussian blue typically binds cationic potassium ions from the surrounding environment. However, because its affinity increases as the ionic radius of the monovalent cation increases, Prussian blue preferentially binds cesium (ionic radius: 1.69 Å) and thallium (ionic radius: 1.47 Å) over potassium (ionic radius: 1.33 Å).^8,18 Additionally, strong binding for rubidium (ionic radius: 1.48 Å) is demonstrated.⁴⁸ Thus, when given orally, Prussian blue binds unabsorbed thallium or cesium in the gastrointestinal tract, preventing absorption and reversing the concentration gradient to enhance elimination through gastrointestinal dialysis. Prussian blue can also interfere with enterohepatic circulation, causing a further reduction in tissue stores.

Insoluble Prussian blue remains almost exclusively in the gastrointestinal tract and is eliminated nearly entirely in feces at a rate determined by gastrointestinal transit time. In a radiolabeled study of healthy pigs, 99% of a single ingested dose was recovered unchanged in the stool.³³ In contrast, soluble Prussian blue is slightly absorbed based on the clinical finding of a blue discoloration that develops in the sweat and tears of patients undergoing prolonged therapy.¹⁴ This discoloration appears to be without clinical significance and resolves within days when therapy ceases. No significant food or drug interactions are known to exist.

In Vitro Adsorption

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

Thallium.

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 rats^18,49 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.

Radioactive Thallium.

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.

The radioactive isotope of cesium (¹³⁷Cs), a common byproduct of nuclear fission reactions, is a strong β and γ emitter with a physical half-life of more than 30 years and a biologic half-life of about 110 days. Another isotope (¹³⁴Cs) is only produced by neutron activation of the stable isotope (¹³³Cs) and has a physical half-life of about 2 years and a biologic half-life comparable to ¹³⁷Cs. Cesium is absorbed in the small bowel, distributes like potassium, and undergoes enteric recirculation in a manner comparable to thallium.²⁹ Approximately 80% of a given dose of cesium is eliminated in the urine, with 20% cleared in the feces.

The isotope ¹³⁷Cs is used clinically as a radiotherapy source in nuclear medicine and to irradiate banked blood. Although uncommon, radiologic disasters such as Fukushima, Chernobyl, and Goiânia (see Human data below) have resulted in lethal incorporation exposures. Additionally, concerns over the use of ¹³⁷Cs in “dirty bombs” have increased the potential need to treat patients with radioactive cesium poisoning. Toxicity from nonradioactive cesium is also reported. Many cases of QT interval prolongation and torsade de pointes are reported in patients taking cesium chloride either as a dietary supplement or for its alleged antineoplastic effects.^{4,6,22,40,46,51,57}

In Vitro Adsorption

Standard binding studies compared the ability of activated charcoal, sodium polystyrene sulfonate (SPS), and both soluble and insoluble Prussian blue to adsorb ¹³⁷Cs over a range of gastrointestinal pHs.⁶² Unlike thallium, the adsorption of cesium to activated charcoal was negligible. Comparable to thallium, SPS offered no benefit, likely because of preferential effects on potassium. Although both forms of Prussian blue adsorbed cesium, the insoluble form was consistently superior. A pH of 7.5 was selected to represent the pH of the small bowel lumen, the location where most adsorption would occur. At this pH, a MAC of 238 mg of ¹³⁷Cs/g of insoluble Prussian blue was determined. In an interesting extension, when the same authors bound insoluble Prussian blue to a hemoperfusion column, they demonstrated a clearance of approximately 100 mL/min of ¹³⁷Cs from plasma and projected that a 4 hour treatment would adsorb about 0.3 terabecquerel (TBq) of radioactive cesium.⁶³ When the FDA approved antidote was analyzed, like thallium, pH and hydration introduced significant variations in binding, with a MAC of 715 mg of cesium/g noted at pH 7.5.¹¹

Animal Data: Kinetics, Tissue Concentrations, and Survival

Small animal investigations with either ¹³⁴Cs or ¹³⁷Cs consistently demonstrate that Prussian blue therapy reverses the urine-to-stool elimination ratio from 8:1 to 0.3:1 and reduces the biologic half-life and the total body area under the curve by as much as 60%.^{32,36,37,48,52} For example, rats given oral ¹³⁴Cs retained 84.7% of the ingested dose at 7 days. Treatment with insoluble and soluble Prussian blue, as well as Chinese blue, produced ­significant reductions in retained cesium (only 6.36%, 2.63%, and 2.43% of the dose was retained at 7 days, respectively).⁹

In addition to human toxicity, concern over radioactive cesium incorporation into cattle milk and meat has resulted in a number of large animal model investigations. Daily Prussian blue therapy reduced radioactive cesium concentrations in sheep by as much as 42%.^16,43 Likewise, radioactive cesium transfer to milk was reduced by 85% in cows.⁵⁸ When dogs were contaminated with ¹³⁷Cs, Prussian blue reduced total body burden by as much as 51%.²⁶ Similar efficacy in reducing the amount of cesium was demonstrated in meat from pigs fed ¹³⁴Cs contaminated whey, with insoluble Prussian blue reducing activity from 359 Bq/kg to 11 Bq/kg over 27 days.⁹

Human Volunteer Studies

Two human volunteers ingested meals contaminated with ¹³⁴Cs to compare the efficacy of both the soluble and insoluble forms of Prussian blue with controls.⁹ At 14 days after exposure and without therapy, the volunteers retained 94.7% of the ingested dose, compared with retention of only 5.1% following therapy with insoluble Prussian blue and 4.9% following soluble Prussian blue. In another study, two volunteers demonstrated that Prussian blue decreased the biologic half-life of ingested radioactive cesium by approximately 33%.²³ Finally, in two volunteers, the effects of pretreatment were compared with simultaneous post-treatment Prussian blue. When a single dose of Prussian blue was administered 10 minutes before ¹³⁴Cs, absorption decreased from 100% (without therapy) to 3% to 10%. However, simultaneous administration of 0.5 or 1 g of Prussian blue with ¹³⁴Cs resulted in 38% to 63% absorption. Finally, when Prussian blue was given daily at a dose of 0.5 g every 8 hours in the post-absorptive phase, the biologic half-life of ¹³⁴Cs was reduced from 106 to 44 days.³⁵

Radioactive Cesium Poisoning in Humans

There are no controlled trials of Prussian blue in radioactive cesium poisoning. Experience is derived exclusively from treating disaster victims. In 1987, a number of people in Goiânia, Brazil, were incorporated with radioactive cesium from a discarded radiotherapy unit.³⁹ Although the reported total number of individuals treated is uncertain because of multiple reports that probably include the same patient several times, one group describes 37 patients who were given insoluble Prussian blue in doses ranging from 3 g/d in children up to 10 g/d in adults. Untreated, elimination kinetics were first order, and half-lives varied extensively from 39 to 106 days in adults (mean: 65.5 days in women and 83 days in men). Half-lives were shorter in children. Therapy with insoluble Prussian blue reduced half-lives by a mean of 32%,²¹ and reduced the retained cesium dose from between 51% and 84% of the total dose.²⁵

The nuclear disaster at Chernobyl, Ukraine, resulted in many cases of acute radiation exposure as well as incorporation into the population of radioactive iodine, cesium, and strontium. In one trial, insoluble Prussian blue was given to three victims of radioactive cesium incorporation many weeks after their exposure. The reported reduction in biologic half-life ranged from 12% to 52%.²⁷ The authors of this paper include data from the Chinese literature describing another six patients who demonstrated a similar reduction in the biologic half-life of cesium following Prussian blue therapy.

Non-Radioactive Cesium Poisoning in Humans

Two cases describe the use of Prussian blue for patients with non-radioactive cesium poisoning. A 58 year-old woman presented with syncope, polymorphic ventricular tachycardia, hypokalemia, and a QT interval of 590 msec after taking cesium chloride as an alternative therapy for cancer. The apparent half-life of cesium was reported as 7.9 days during Prussian blue therapy in comparison to 86.6 days after therapy. The authors state that there were no adverse effects of therapy.⁵⁷ Similarly, a 65 year-old woman presented with syncope and was found to have multiple episodes of torsade de pointes, hypokalemia, and a QT interval of 620 msec after taking cesium chloride for 6 weeks. Therapy with insoluble Prussian blue (3 g/d) was associated with a reduction in the apparent half-life for cesium from 61.7 to 29.4 days.⁴

Dosage and Administration

The manufacturer of Radiogardase recommends that for radioactive cesium poisoning, adults and adolescents 13 years or older receive a total daily dose of 9 g divided into 3 g, three times per day. Children aged two through twelve years should receive a total daily dose of 3 g divided into 1 g, three times per day. While the manufacturer offers no recommendation in children under the age of two years, administering 150 to 250 mg/kg/d in divided doses would be appropriate. Although these are the same doses used for thallium poisoning, therapy for cesium poisoning should be continued for at least 30 days. Even though there are no recommendations of other criteria to determine the end point of therapy, quantitative and radiologic evaluations of cesium elimination should be performed. Capsules can be opened and mixed in liquids and given via nasogastric tube for patients unable to swallow. Since constipation does not commonly occur with either radioactive or non-radioactive cesium poisoning, neither routine cathartic administration nor the use of a high fiber diet is recommended.

Animal studies show no adverse effects of therapeutic doses.⁴² Oral lethal doses are not known or projected for humans, but are likely to be astronomic given that there is no or minimal absorption of Prussian blue and the absence of local toxicity in the GI tract. The only significant adverse effects reported in humans receiving therapeutic doses are constipation and hypokalemia,⁵⁵ and the constipation may be related more to the thallium toxicity than to Prussian blue.

Although there is some concern regarding the potential for cyanide liberation from Prussian blue, this release appears to be quantitatively minimal. Cyanide release from soluble Prussian blue was less than 3 mg/24 h in simulated gastric fluid.⁶¹ When three human volunteers were given 500 mg of soluble Prussian blue (radiolabeled with⁵⁹ Fe, either in the ferric or ferrous position and with ¹⁴C on the CN), only 2 mg of cyanide were absorbed.³⁴ Over the physiological range of potential gastrointestinal pH, the maximal cyanide release from insoluble Prussian blue is only 135 μg/g at pH 1.^65,66 When extrapolated even for repeated therapeutic doses, only a trivial amount of cyanide would be liberated.

Insoluble Prussian blue is listed as pregnancy category C. Because of the severe consequences of poisoning from radioactive cesium and thallium, and the lack of systemic absorption of insoluble Prussian blue, a risk-to-benefit analysis would favor the use of the antidote in all poisoned pregnant patients.

Insoluble Prussian blue (Radiogardase) is available as a 0.5 g blue powder in gelatin capsules for oral administration manufactured from Haupt Pharma Berlin GmbH for distribution by HEYL Chemisch-pharmazeutische Fabrik GmbH & Co. KG, Berlin (281-395-7040; fax 281-395-2320; see information at www.heyltex.com). Prussian blue is part of the US Strategic National Stockpile, which can be accessed at CDC emergency response hotline: 770-488-7100; and is also stored at REAC/TS, Oak Ridge: emergency number 865-576-1005. Thirty capsules retail for about $100 and have a 5 year shelf life.

• Prussian blue is a crystalline lattice that adsorbs radioactive and non-radioactive isotopes of thallium and cesium.

• Animal data demonstrate the ability of Prussian blue to prevent absorption, enhance elimination, and improve survival following thallium or cesium administration.

• Although human data are limited, the use of Prussian blue appears beneficial in case reports and small case series.

• Since Prussian blue is essentially non-toxic, it should be used whenever severe thallium or cesium poisoning is suspected.

• If Prussian blue is unavailable, activated charcoal can be substituted for thallium poisoning, but not for cesium poisoning.

Acknowledgment

Part of this chapter was adapted, with permission from the publisher, from Hoffman RS: Thallium toxicity and the role of Prussian blue in therapy. Toxicol Rev. 2003;22:29–40.

References