Abstract
Thallium poisoning is a rare condition that is often misdiagnosed, delaying appropriate treatment. Left untreated, thallium toxicity can permanently damage the nervous and digestive systems or, in severe cases, lead to paralysis and death. It is most often treated by an oral administration of Prussian blue. Thallium has a long physiological half-life, and Prussian blue cannot sequester thallium outside the digestive tract. Therefore, the first priority in treating severe thallium poisoning is to lower blood levels as soon as possible. We report the case of a patient with supralethal blood levels of thallium treated successfully using combined hemoperfusion (HP) and continuous veno-venous hemofiltration (CVVH). Three rounds of HP alone decreased blood thallium levels by 20.2%, 34.8%, and 32.2%, while each of the five subsequent rounds of CVVH reduced thallium blood levels by 63.5%, 64.2%, 42.1%, 18.6%, and 22.6%. The reversal of symptoms and prevention of lasting neurological damage indicates that HP, CVVH, 2,3-dimercaptopropane-1-sulfonate, neuroprotective agents along with supportive therapy were used successfully to treat a case of severe thallium poisoning.
Thallium is a soft, malleable heavy metal distributed in nature at very low concentrations as univalent and trivalent compounds. It is highly toxic, however, with a lethal dose of 10–15 mg kg−1. 1 Early symptoms, mainly nonspecific neurological signs and digestive dysfunction, often do not point to thallium poisoning and so delay accurate diagnosis. Prussian blue is approved by the Food and Drug Administration to treat thallium poisoning but can only sequester the toxin remaining in the digestive tract. Hemoperfusion (HP) was also found to be an effective treatment for thallium poisoning. 2 Due to its long physiological half-life of 1.7–30 days, 1 thallium can remain in the body for days or even months, leading to a prolonged neurological dysfunction or permanent damage. Thus, the highest priority for the treatment is the rapid elimination of the poison at the early onset of intoxication.
The absorption and distribution of thallium in the human body involves three stages. 2 In the first stage (within 4 h of exposure), it is quickly absorbed from the digestive system into the bloodstream; in the second stage (4–24 h), thallium distributes within the central nervous system and other tissues; in the third stage, at approximately 24 h after exposure, thallium elimination begins. The time required for the elimination depends on the quantity of thallium absorbed (as well as on clinical interventions). 2 Thallium is excreted from the body in both feces and urine (2:1). 2 Thallium excreted by intestinal epithelial cells can be reabsorbed into the bloodstream and can enter the enterohepatic circulation, 2,3 whereas that excreted by the kidneys cannot be reabsorbed. Thus, elevated urine production is an early indicator of poisoning. Typical clinical symptoms are present when urinary thallium exceeds 500 μg L−1. 4 However, the early symptoms of thallium poisoning are often attributed to other more common diseases, and many signs, including alopecia and Mees’ lines, may not appear for 2–3 weeks in cases of low-level exposure. Furthermore, the source of thallium exposure (pesticides, industrial exposure, and intentional exposure) is usually unknown, so medical history is of limited value. Therapies for thallium poisoning mainly include forced diuresis, dimercapto compounds (such as 2,3-dimercaptopropane-1-sulfonate (DMPS)) that slow tissue uptake, Prussian blue that accelerates excretion in feces by incorporating the metal, and vitamins B1 and B12 that acts as a neuroprotectant protecting the nerve cells. However, clearance of thallium by these compounds is limited. Prussian blue can only incorporate unabsorbed thallium remaining in the digestive system, while the efficacy of dimercapto compounds is still unconfirmed. 5 Thallium binds to the sulfhydryl groups of enzymes and other proteins with high affinity, while forced diuresis can only eliminate free thallium. Pan 3 reported the case of a patient that developed neurological deficits despite 7 weeks of treatment with Prussian blue. Therefore, alternative detoxification strategies are still required, such as blood purification. Recently, we successfully used combined HP with continuous veno-venous hemofiltration (CVVH) in addition to Prussian blue to treat a patient poisoned with a supralethal dose of thallium.
Case report
A lawyer who was 40-year-old male weighing 75 kg presented with numbness and stabbing pains in the arms and legs that had started 2 days prior to examination. His medical history was unremarkable, and he was in good general health prior to symptom onset. Twelve hours after supper on February 1, 2010, he felt numbness in all four limbs accompanied by a pricking sensation but did not report pain in the limbs, nausea or vomiting, abdominal pain, diarrhea, respiratory difficulty. The presenting symptoms worsened over the following 2 days, when he was examined for pain and formication in the lower limbs, and was initially diagnosed with Guillain–Barré syndrome. Results of a computed tomography scan of the cervical and thoracic vertebra were unremarkable. Nonetheless, symptoms persisted, worsened, and eventually spread to proximal body parts. Later that day, he was informed by his girlfriend, who had access to thallium through her work as a laboratory technician, that she intentionally contaminated his supper with thallium nitrate. Thallium is strictly controlled in China. He was referred to the emergency department of our hospital for further treatment. At the time of admission, his vital signs observed were body temperature, 37.4°C; pulse, 94 bpm; respiration, 17 bpm; and blood pressure, 133/93 mmHg. He was conscious, and muscular tone was normal, with muscle strength at grade 3 (on a five-point scale). He felt numbness in both palms, the dorsal side of the distal finger joints, and below both ankle joints. Pain and tactile senses were normal. Review of other physical systems was noncontributory. Blood analysis by the poison detection laboratory of the 307 Hospital of the PLA revealed blood thallium levels of 3764 ng mL (reference values blood thallium concentration <0.1 ng mL−1) as measured by inductively coupled plasma mass spectrometry. 6 Results of other examinations, including electrocardiogram, chest x-ray, and routine blood analysis (alanine transaminase, aspartate aminotransferase, total bilirubin, electrolytes, hemostasis, and coagulation) were unremarkable.
Treatments
Medication
Prussian blue, provided by the Research Institute of Drug and Medicament of Academy of Military Medical Sciences, was dissolved in 200 mL of 20% mannitol and administered at 250 mg kg−1 day−1. The solution was administered orally in four-divided doses to eliminate thallous salts from the digestive tract. Potassium salt was given to displace thallium ion bound to Na+-K+-ATP and to maintain blood potassium at 4.0–4.5 mmol L−1. In addition, DMPS (250 mg day−1) was given via intramuscular injection in order to accelerate the removal of thallium and prevent absorption by tissue. Vitamin B1, vitamin B12, and nerve growth factor 7 were used as neuroprotective agents. Other treatments included symptomatic and supportive treatments such as visceral function support, water electrolytes, and acid–base equilibrium maintenance, infection prophylaxis, and fluid infusion.
Blood purification
Blood purification involved HP and CVVH. At 2 h and 24 h after admission, HP was performed for 5 h. At 47 h, HP was repeated for 2.5 h. The patient was then treated with 5 rounds of CVVH on days 3, 7, 11, 14, and 21 for a total treatment duration of 231.5 h. Equipment and treatment condition are shown in Table 1.
Equipment, treatments, and duration of blood purification.
HP: hemoperfusion; CVVH: continuous veno-venous hemofiltration.
Results
Symptoms and signs
In the days following admission, numbness and pain in the distal arms and legs spread proximally. Symptoms were most severe on day 5, with numbness spreading to 10 cm above the knees and 6 cm above the elbows, accompanied by intense muscle pain and tenderness of the skin. On day 6, symptom severity began to ease and numbness began to retreat to distal areas of the limbs. Limb pain was markedly reduced by day 15. At the time of discharge, numbness was limited to the thumbs, index fingers, and toe tips. No pain was reported and no neurological deficits were found. Alopecia occurred 1 week after the initial symptoms. Transverse white lines across the nail plate (Mees’ lines), a typical sign of heavy metal poisoning and renal failure, were not observed.
Changes in blood thallium during treatment
The patient’s blood level of thallium decreased during blood filtration treatment. On day 23, blood thallium dropped to 24 ng mL−1, and he refused further CVVH; on day 33, blood thallium was only 9 ng mL−1 (Figure 1). Blood thallium levels declined by 20.2%, 34.8%, and 32.2%, respectively, after each of the three HP treatments and by 63.5%, 64.2%, 42.1%, 18.6%, and 22.6%, respectively, after each of the five CVVH treatments (Figure 2).
Decrease in blood thallium during HP and CVVH treatment. HP: hemoperfusion; CVVH: continuous veno-venous hemofiltration.
Thallium clearance rate by HP and CVVH. Clearance rate by HP or CVVH (ng mL−1) = (pre–post)-HP or CVVH blood thallium concentration (ng mL−1)/pre-HP or CVVH blood thallium concentration (ng mL−1). HP: hemoperfusion; CVVH: continuous veno-venous hemo-filtration.
Adverse effects
The number of thrombocyte plunged to 78 × 109 L−1 during HP treatment (Figure 3). During CVVH treatment, adverse effects included errhysis at the sites of venous catheterization, ecchymoma and ecchymosis on the buttocks, and purple subcutaneous hematoma of the right wrist and hand were observed. These affected areas were compressed and treated by topical medications. Signs improved markedly when the site of venous catheterization was changed.
Thrombocyte count changes between pre-HP and post-HP. HP: hemoperfusion.
Discussion
HP can remove toxins with molecular weights between 113 and 4000 D from the bloodstream, including toxic heavy metals like thallium (204.4 D). 8 Based on the toxicokinetics of thallium, Moore et al. 2 suggested that HP is effective within 48 h of exposure to thallium and that activated charcoal is an efficient absorbent. 8 Li et al. 9 reported that HP was still effective even after exposure for 15–30 days . In our patient, blood thallium was extremely high at admission, and HP on days 1, 2, and 3 reduced blood thallium by 20.2%, 34.8%, and 32.2%, respectively, indicating HP can remove significant quantities of thallium. However, clinically effective HP can destabilize fluid and osmotic balance, reduce thrombocyte count, and cause hypocalemia. 9 Indeed, thrombocyte count fell by 63.5% after three HP treatments, so this method was discontinued (Figure 3).
CVVH refers to therapies that continuously and slowly remove water and solute. 6 It was first proposed by Kramer in 1977 to help patients suffering from renal failure with unstable body fluid regulation, and modern systems are capable of filtering, convecting, and trapping molecules as small as 50 kDa. 10 Dehua 11 found that CVVH could continuously remove tetramine from the body because of its small molecular mass and undissolved in water. For the same reason, we applied CVVH immediately after HP treatment in our thallium poisoning case. Blood thallium dropped successively by 63.5%, 64.2%, 42.1%, 18.6%, and 22.6% after each of the five CVVH treatments, respectively; so most (four of five treatments) CVVH rounds cased a significantly larger drop in blood thallium than following a round of HP. Figure 2 shows that CVVH maintains a relatively constant clearance rate as the thallium concentration falls, greatly facilitating the clearance of low but still toxic thallium levels. This continuous clearance effect of CVVH successfully circumvents the rebound effect and ensuing relapse of clinical symptoms. In addition to thallium removal, CVVH also clears secondary metabolites, inflammatory factors, and mediators, and helps maintain water, electrolyte, and acid–base balance. 12 Common complications of CVVH are coagulation, bleeding, thrombosis, thrombocytopenia, infection, allergy, and hypothermia. Among these complications, only bleeding at access sites and thrombocytopenia occurred. The drop in thrombocyte count was relatively less except following the fourth CVVH, where platelet levels dropped to 32 × 109 L−1.
In conclusion, HP, CVVH, DMPS, neuroprotective agents along with supportive therapy were used successfully to treat a case of severe thallium poisoning. To eliminate toxic metals, timely HP and CVVH are recommended as adjuncts to conventional therapies (emesis, gastric lavage, catharsis, dieresis, and oral administration of Prussian blue) to quickly remove absorbed thallium and reduce toxicity, particularly to the central nervous system. Nevertheless, further studies are required to develop better approaches with fewer adverse effects.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.