"Where can I buy Prussian blue, please, please"
On the evening of February 22, some netizens publicly released news that his 1-year-old cousin niece was "thallium poisoned" and urgently needed medicinal Prussian blue, "where can I buy it, I urgently need this drug, please." "It has aroused widespread concern, and many netizens have left messages to provide medication channels."
Fujian Fuzhou Children's Hospital has taken urgent treatment measures and said the girl's condition has "not particularly deteriorated" and has now contacted the foreign hospital where the drug is stockpiled.
The "test data results" provided by netizens on February 21 showed that the patient was only 1 year old and had undergone urine and blood tests, "urine thallium 12800 μg/L, blood thallium 1857 μg/L".
The above netizens said that the cause of "thallium poisoning" was not clear and had been reported to the police. On the evening of the 22nd, the above netizens also updated the progress of medication on Weibo, saying that "the hospital has not yet determined the dose, so the dose may not be enough, and the drug side must also go through the procedures." The netizen also said that the cause of "thallium poisoning" is not clear, "my cousin (the child's mother) has gone to take notes." At present, the above Weibo has been deleted.
On the 23rd, Fuzhou Antai Police Station said that the police had gone to the hospital to investigate, and the matter has been handed over to the police at the place of the incident.
Unsolved, bizarre "thallium poisoning"
Thallium is a colorless and odorless rare heavy metal, thallium and its compounds are highly toxic nerve poisons, with a strong accumulation effect. The more clinically recognized gold standard for confirming thallium poisoning is to collect 24h urine of poisoned patients, and determine the thallium content by atomic absorption spectroscopy, and the urine thallium concentration exceeds 200 μg/L to confirm thallium poisoning. In terms of treatment, soluble Prussian blue is the drug of choice for the treatment of thallium poisoning.
The sensational "Zhu Ling Incident" in 1994 was thallium poisoning. Zhu Ling, a student at Tsinghua University, had bizarre symptoms of thallium poisoning during her time at the university, starting with stomach pain and unable to eat; then stomach discomfort; and finally her hair began to fall out and fell out within a few days.
(Zhu Ling before poisoning)
In 1995, professional testing believed that Zhu Ling was poisoned twice, and after the second poisoning, the thallium content in Zhu Ling's body far exceeded the lethal dose, and it was suspected that someone was deliberately poisoning, and it was recommended to take Prussian blue for detoxification, on the day of taking, the concentration of thallium ions in the blood began to decline, and the thallium in the body was expelled.
However, due to the long time that thallium ions remain in the body, Zhu Ling's nervous system was seriously damaged, vision was almost completely lost, and body function was also seriously damaged.
(Zhu Ling after poisoning)
Be wary of thallium poisoning
From Zhu Ling, a college student, a student at China University of Mining and Technology and a billionaire in Shantou in 2007, to a female worker in Dongguan in 2010, to an Anqing woman poisoning case in 2012, to the tragedy of a family of six in the thallium poisoning case in Linquan, Anhui, thallium poisoning incidents often occur.
Judging from the many poisoning cases that have occurred in recent years, the management of hazardous chemicals needs to be strengthened urgently.
The first symptom of thallium poisoning within 24 hours is gastrointestinal discomfort, typically nausea, vomiting, abdominal pain, and often constipation. If it is a mass symptom, the patient should consider seeking medical attention in time and contacting medical institutions with relevant testing methods in order to diagnose as soon as possible.
Expert Consensus on diagnosis and treatment of acute thallium poisoning in China (2021)
Acute thallium poisoning is a toxic reaction caused by a large amount of thallium compounds in a short period of time, mainly due to accidental ingestion or artificial causes, or by inhalation of large amounts of thallium-containing soot poisoning.
Acute thallium poisoning patients due to the hidden medical history, early clinical symptoms are not typical, the condition changes rapidly, clinicians lack of understanding, coupled with the differences in toxicology detection technology at all levels of hospitals, misdiagnosis, missed diagnosis or delayed diagnosis occurs from time to time.
In general, acute thallium poisoning is relatively rare, its diagnosis and treatment currently lacks a standardized plan, there is no corresponding expert consensus and guidelines, and the treatment of various medical institutions is obviously different. Once a major mass thallium poisoning incident occurs, if not handled properly, it will lead to a large number of casualties. The Poisoning and Treatment Professional Committee of the Chinese Society of Toxicology and the Poisoning Group of the Emergency Medicine Branch of the Chinese Medical Association, together with the Poison Treatment Center of the whole army, organized experts in the fields of pre-hospital emergency, emergency medicine, poisoning treatment, severe medicine and poison detection to jointly write this consensus, focusing on the early diagnosis and treatment process of acute thallium poisoning, and promoting the standardized diagnosis and treatment of acute thallium poisoning.
1 Epidemiology
Thallium (Tl) has been used in many fields since its discovery. In the early 20th century, thallium compounds were used to treat diseases such as syphilis, gonorrhea, tuberculosis, hair overgrowth and ringworm, and were also used to make rodenticides. Due to multiple reported cases of poisoning, thallium preparations have been banned in most countries since the 1970s. At present, thallium and its compounds are still widely used in chemical reagents, electronics, military, aerospace, chemical, metallurgy, communications, etc., and have potential application value in the fields of optical fibers, radiation scintillators, optical permeability, radiation shielding materials, catalysts and superconducting materials. The radioisotope thallium-201 is used for melanoma diagnosis and cardiac scintigraphy, but in very small amounts [1,2].
At present, there is an increasing trend of acute thallium poisoning patients at home and abroad, and the causes of poisoning are mostly accidental or artificial. Between 1995 and 2005, 830 cases of thallium poisoning were reported from the U.S. Poison Data Center [3]. From 1965 to 2017, the domestic literature reported 375 cases of thallium poisoning. From September 2002 to August 2018, the PLA All-Army Poisoning Treatment Center admitted and treated 52 cases of acute thallium poisoning, all of which were caused by human causes [4].
In addition, traffickers or smugglers of drugs (opium, heroin) add heavy metals to drugs to increase the weight of drugs for more profit. Therefore, there are literature reports of thallium poisoning in drug abusers such as opium and heroin [5,6,7,8], and clinicians should pay attention to the differential diagnosis of thallium poisoning in drug abusers.
2 Toxic kinetics of thallium
Thallium is a highly toxic blue-gray heavy metal with atomic number 81 and a relative molecular mass of 204.383. The apparent volume of distribution (Vd) of thallium is large (3 to 10 L/kg) and hardly binds to plasma proteins [9]. Thallium ions are 1 valent (Tl+) and 3 valent (Tl3+), with a 150.0 pm radius of Tl+ ions and a radius of 88.5 pm for Tl3+ ions, and the toxicity of the 3-valent state is much greater than that of the 1-valent state [10]. Thallium salt is a colorless and odorless crystal, dissolved in water to form thallium or thallium compounds, without special taste. Thallium is highly bioavailable when taken orally[11], more than 90 percent; it is easily absorbed by inhalation or skin contact [12,13,14]. Thallium is distributed into cells within a few hours after ingestion, and the blood thallium content reaches the highest value 2 h after ingestion, and it is significantly reduced by 24 to 48 h. Thallium in the body is eventually excreted through urine and feces, inorganic thallium salt is mainly excreted through feces, and organic thallium salt is excreted in much the same amount through the urine and fecal pathways. Studies have shown that the toxicity of thallium and its compounds is several times that of the highly toxic pesticide DDT or dichlorvos, and higher than arsenide (arsenic trioxide), the lethal dose of thallium in humans is 10 to 15 mg/kg, the minimum lethal dose in adults can reach 8 mg/kg [3,15,16], and the lethal plasma content is 0.5 to 11.0 mg/L [3].
Similar to potassium ions, soluble thallium is easily absorbed through the gastrointestinal tract and easily enters the bloodstream in the form of ions, is present in red blood cells and travels with the blood to organs and tissues throughout the body. The thallium content is highest in the kidneys, followed by the testicles, followed by muscles, lymph nodes, gastrointestinal tract, heart, spleen, and liver. Thallium can cross the placenta and blood-brain barrier, causing disturbances in the reproductive system, causing damage to the fetus[17] and causing different toxic effects on the central and peripheral nervous systems [18]. Peng Xiaobo et al. [19] found that thallium can be measured in the cerebrospinal fluid of patients with thallium poisoning. The half-life of thallium in the human body is 10 to 30 days, depending on the route of intake, the degree of early constipation, and the enterohepatic circulation[1]. Thallium is excreted more slowly and can last for several months.
3 Mechanism of action of thallium poisoning
The mechanism of action of thallium poisoning is complex and has not yet been elucidated, and there are mainly the following possibilities.
3.1 Competitive inhibition of potassium ions by thallium:
Both the charge and radius of thallium ions are very similar to those of potassium ions, and biofilms are difficult to distinguish between the two. Studies have shown that the affinity of thallium ions to cell membranes is 10 times that of potassium ions, so thallium ions can replace potassium ions to intervene in a series of enzyme reactions, thereby affecting biological metabolism, such as sodium and potassium adenosine triphosphine (Na+-K+-adenosine triphosphate ase, Na+-K+-ATPase) and pyruvate kinase. Experiments by Belowitz and O\'Donnell [20] using ion-selective microelectrodes for in vitro ion flux determination have demonstrated that after 40 min of acute thallium poisoning, the potassium concentration in blood and lymphocytes is greatly reduced due to the inhibitory effect of thallium on Na+K+-ATPase. Pyruvate kinase is a key enzyme for glycolysis, and thallium has an affinity with 50 times that of potassium. Thallium replaces potassium to aggregate within the cell, interfering with this reaction, thereby interfering with the production of energy in the organism. In addition, Hasan et al. [21] found that thallium can also reduce the effects of the citric acid cycle on energy synthesis by inhibiting succinate dehydrogenase.
3.2 The binding of thallium to mercapto interferes with its biological activity:
Thiol groups are involved in the synthesis of a variety of proteins or enzymes in living organisms, and their unique structure makes them easy to bind to heavy metals. The combination of thallium and thiol can lead to a decrease in the amount of thiol in animal serum, causing energy metabolism to be impaired [22]. Cysteine and glutathione are important thiol compounds in the body, the former play an important role in the synthesis of keratin, the latter is an important antioxidant in the organism, thallium ions combined with the former can lead to keratin production disorders, affecting the growth of skin spinous cells [23], which in turn affects the normal growth of hair and nails, which is the cause of hair loss in patients with thallium poisoning.
3.3 Thallium binds to riboflavin to form an insoluble complex:
Riboflavin is an essential nutrient in the human body and plays an important role in energy metabolism. Thallium binds to riboflavin to form an insoluble complex, causing a decrease in riboflavin content[24], thereby affecting oxidative phosphorylation of the oxidizing respiratory chain, causing energy metabolism disorders, resulting in symptoms of riboflavin deficiency such as scrotum dermatitis, corner erosion, seborrheic dermatitis, and conjunctival hyperemia. In addition, riboflavin deficiency can also affect the absorption of iron by organisms, reducing iron storage in the body and causing anemia.
3.4 Lipid peroxidation of thallium:
In rats treated with subfatal thallium, brain tissue striatum and cerebellar tissue showed significant lipid peroxidation compared with the uninfected control group [25]. Post-thallium poisoning neurologic symptoms are associated with lipid peroxidation of brain tissue caused by thallium, which inhibits the defense system of glutathione and glutathione peroxidase, leading to excess free radical production, accumulation in brain tissue causing damage, and causing corresponding neurological symptoms. The brain is an important target organ for thallium poisoning because brain tissue is rich in lipids and has a high metabolic rate of oxidation [3].
3.5 Thallium impairs mitochondrial function to induce oxidative stress:
Thallium can bind to thiol groups in mitochondria, causing oxidative phosphorylation and decoupling of mitochondria, causing energy synthesis to be blocked. In addition, Tl+ and Tl3+ can lead to an increase in reactive oxygen species such as hydrogen peroxide, stimulating the release of cytochrome C and aspartate-specific cysteine protease (caspase-9, caspase-3), resulting in cell death [26]. Korotkov et al. [27,28] observed in the thallium ion-induced rats in vivo cardiac mitochondria that thallium ions increased the permeability of the membrane in the mitochondria of the mitochondria of the mitochondria in the mitochondria of the mitochondrial body, and led to swelling and depolarization of the mitochondria; in the mitochondria of hepatocytes, the content of membrane thiol groups and the synthesis of mitochondrial energy decreased. Hanzel and Verstraeten[29] also pointed out in their study that thallium-mediated apoptosis is mainly related to inhibition of mitochondrial damage caused by mitochondrial depolarization and pore opening, and believes that thallium can additionally increase Fas content and increase the activity of caspase-8, thereby triggering both intrinsic and extrinsic apoptosis pathways.
3.6 Other mechanisms of action:
Other possible mechanisms of action of thallium include the cytotoxicity of thallium, the interference of protein production by the binding of thallium to ribosomes, the alteration of the properties of the liposomal membrane by thallium, and the effect of thallium on the body through the blood-brain barrier and the placental barrier.
4 Clinical manifestations
The clinical manifestations of thallium poisoning are mainly gastrointestinal symptoms, peripheral nerve symptoms, central nervous system symptoms, psychiatric symptoms, motor weakness and heart, liver, kidney damage, etc., which are non-specific manifestations. Different clinical manifestations depend on the dose of poisoning, age, underlying disease, how it enters the body, immune function, etc. Characteristic alopecia is an important clue in the diagnosis of thallium poisoning. Gastrointestinal symptoms, peripheral neuropathy, and hair loss are recognized as typical triads of acute thallium poisoning [9]. Among them, nervous system injury is the most important clinical symptom, but its severity is not consistent with the level of thallium and urine thallium content [30]. Typical symptoms of thallium poisoning usually appear 2 to 3 weeks after acute poisoning.
The course of thallium poisoning is divided into 3 stages: early symptoms generally appear within 48 hours, including nausea, vomiting, bloating, abdominal pain, constipation, and rare diarrhea, usually within a few hours of ingestion of the poison, but also tachycardia, hypertension, and chest pain. Medium-term symptoms appear in 2 days to 2 weeks, mainly neurological symptoms, other manifestations include: hair loss, erythematous changes in the palms and soles of the feet, and hyperpigmentation with eczematous skin changes; in some cases, acute kidney injury, hepatotoxicity, anemia, etc. Late symptoms include optic nerve atrophy with vision loss, movement disorders, speech disorders, intellectual abnormalities, memory impairments, anxiety, and depression.
4.1 Digestive Symptoms:
The digestive symptoms of acute thallium poisoning are rarer than those of general heavy metal poisoning, appear in the early stage of poisoning and lack specificity, and are manifested as nausea and vomiting, and may also have symptoms such as bloating, abdominal pain, diarrhea, and constipation. Among them, constipation is more common than diarrhea, manifested as diarrhea and constipation alternately, and in severe cases, paralyzing intestinal obstruction, gastrointestinal bleeding and pancreatitis-like manifestations [19] may occur, and are often misdiagnosed as digestive diseases such as "gastroenteritis and pancreatitis".
4.2 Neurologic symptoms:
Neurologic symptoms are the main symptoms of acute thallium poisoning, which generally appear 3 to 1 week after poisoning, and the clinical process is characterized by acute development and gradual improvement [31,32,33], and its pathogenesis is characterized by important clues to the diagnosis of thallium poisoning. Neurologic symptoms begin with symmetrical numbness and soreness in the lower extremities, and gradually worsen and spread upwards to the legs, trunk, and upper extremities. Early manifestations are hyperalgesia, inability to stand and stroke, numbness at the end of the finger (toe) with burning-like severe pain, extreme hyperalgesia, and refusal to touch both lower limbs, called "burning foot syndrome"; then pain sensation and decreased touch are distributed in the form of "gloves and socks", which can be accompanied by weakened Achilles tendon reflex; there may also be movement disorders, starting with mild weakness in both lower limbs, followed by lower extremity paralysis and muscle atrophy. Toxic optic neuropathy can lead to optic nerve atrophy, ocular paralysis, and nystagmus [13]. In severe cases, peripheral facial palsy and damage to the central nervous system lead to toxic encephalopathy manifested by drowsiness, delirium, convulsions, convulsions, or coma.
4.3 Hair loss:
Alopecia is the most specific manifestation of acute thallium poisoning, typically occurring 1 to 3 weeks after poisoning [34]. Hair is braced and shedding, manifested by alopecia areata or hair loss at all; in severe cases, pubic hair, beard, eyebrows, armpit hair, etc. are also shed within 10 to 20 days, but the inside of the eyebrows is often not affected. Hair often begins to grow at week 4 and recovers completely after about 3 months.
4.4 Damage to the mucous membranes of the skin:
Mees lines, the white horizontal stripes of the nail surface, are white crescent-shaped stripes that appear on the nails after thallium poisoning, often appearing 3 to 4 weeks after poisoning. In addition, nonspecific symptoms such as excessive keratosis of the skin, ichthyosis, tan pigmentation, acne, pimples, and red and black of the oral mucosa may occur.
4.5 Psychiatric symptoms:
Patients with acute thallium poisoning may present with altered mental state and psychotic changes. Early manifestations are apathy, anxiety, depression, memory impairment, inattention and other neurasthenic syndromes, followed by hallucinations, mania, disorientation, intellectual decline, inattention, impaired memory and language fluency, impaired consciousness and other symptoms of encephalopathy. Behavioral abnormalities can also be an important clue in the diagnosis of acute thallium poisoning [12].
4.6 Other systemic symptoms:
Patients with thallium poisoning can develop cardiotoxic reactions within 48 h [34], manifested by sinus tachycardia, hypertension, angina, chest tightness, palpitations, and nonspecific ST-T segment changes on ecG. Interstitial pneumonia, lung infection, dyspnea occur in the respiratory system, and respiratory failure can occur in severe cases. Because thallium is mainly excreted by the kidneys, urinary system manifestations such as hematuria and proteinuria often appear.
4.7 Effects of thallium poisoning on the fetus:
The risk of thallium exposure during pregnancy increases as thallium toxicity increases, with prenatal exposure to thallium causing decreased mitochondrial DNA replication in newborns[35], resulting in an increased probability of preterm fetal birth [36], and a higher risk of low body mass in newborns [37]. Qi et al. [38] studies have shown that the effect of thallium exposure during pregnancy on children's physical development has a significant gender effect, with the increase in umbilical cord blood thallium levels, the height and body mass of < 2-year-old girls show a downward trend.
5 Auxiliary examination
5.1 Laboratory tests:
The significant increase in thallium content in blood and urine is the "golden index" for diagnosing acute thallium poisoning. Thallium is excreted mainly through feces and urine, and because urine sampling is more convenient and effective, urine thallium can reflect the thallium load in vivo to some extent [36,37,39], and urine thallium lasts longer than blood thallium. At present, the thallium content is mainly determined by graphite furnace atomic absorption method or inductively coupled plasma mass spectrometry (ICP-MS) [34].
Due to industrial activities, approximately 5,000 t thallium is released into the environment each year [39]. Increased thallium levels in tap water, vegetables, fruits, and animals also increase human low-dose thallium intake, so there are small amounts of thallium in healthy people, and generally blood thallium < 2 μg/L. It is generally believed that blood thallium > 100 μg/L, urine thallium > 200 μg/L is diagnostic, but there is currently no uniform standard for poisoning limits. Thallium in hair remains stable over long periods of time, so testing for thallium in hair can assess the time and dose of poisoning in patients [40,41]. ICP-MS has been reported to determine thallium content in hair [41]. Children show higher case fatality rates in acute thallium poisoning events and lower blood thallium levels than in adults [15]. Observations have suggested that in children with very low thallium levels (urine thallium levels of 13.4 to 60.1 μg/L)[42], even in the absence of significant symptoms of toxicity, there may be early liver, kidney, and cardiac laboratory markers abnormalities, and long-term prognosis is not ideal, especially the impact on myocardial function can become more severe over time.
Early stages of acute thallium poisoning may present with elevated leukocytes, orthochrome orthocytic anemia, thrombocytopenia, hypokalemia, and hyponatremia [14]. Almost all patients with thallium poisoning have hepatic impairment and are manifested by elevated alanine aminotransferase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (γ-glutamyltransferase, γ-GT), and total bilirubin (TBil), Some myocardial damage presents with elevated creatine kinase (CK).
5.2 Electrophysiological examination:
Patients with acute thallium poisoning present early with symmetrical acral sensory impairment without significant limb dyskinesia and muscle atrophy, neuromyography may have neurogenic impairment, and slowing of motor nerve conduction velocity (MCV) and sensory nerve conduction velocity (SCV). Therefore, electromyography is a sensitive method for early diagnosis of thallium poisoning. As the disease worsens, motor nerve detection often shows that the latency period of the ulnar nerve and the total peroneal nerve is prolonged, the amplitude of the common peroneal nerve and the tibia nerve is reduced and the conduction rate is slowed down, the mid-center, ulnar, and gastrointestinal nerves of the sensory nerve are prolonged and the amplitude is reduced, and the conduction velocity of the median nerve, ulnar nerve, radial nerve, and gastrocnemone nerve is slowed down [43].
EEG in patients with acute thallium poisoning often shows mild-to-moderate abnormal EEG. Gastrocnemius muscle biopsy involves decreased myelinary nerve fiber density, demyelinating changes, and axon degeneration. Cutaneous nerve biopsy often shows a large number of loss of epidermal nerve fibers, decreased density of nerve fibers in the epidermis layer, incomplete keratinization of the skin, swelling of hair follicles filled with keratin and necrotic adipose tissue, and vacuolar degeneration of the basal layer of the skin [33]. Visual and auditory evoked potentials may be abnormally altered in the early stages. Electroretinalography may have abnormal changes before clinical symptoms of acute thallium poisoning are present, which is of some value for early diagnosis of poisoning [44].
5.3 Imaging tests:
Because radiation cannot penetrate thallium, early abdominal x-rays are available for patients with acute thallium poisoning ingested through the digestive tract. Brain edema is seen on CT of the brain during acute thallium poisoning. Magnetic resonance imaging (MRI) of the brain can show low-signal changes in T1-weighted images and high-signal changes in T2-weighted images.[32] Brown et al. [45] believe that thallium selectively accumulates in the cerebral cortex, brainstem, and cerebellum in the brain, and at the same time finds that the β-galactosidase, lysosomal enzyme activation, and lipid peroxidation associated with toxic doses occur at the accumulation site, resulting in corresponding MRI lesions in the above sites.
6 Diagnosis
6.1 Diagnostic basis:
There is a history of suspicious exposure to thallium, a triad of gastrointestinal symptoms, peripheral neuropathy and hair loss, and a preliminary diagnosis can be made by excluding similar diseases caused by other causes, and can be confirmed by combining increased blood and unirrhaleum in blood and urine.
6.2 Classification of the condition
6.2.1 Mild:
In addition to nausea, vomiting, abdominal pain, diarrhea or constipation, fatigue, loss of appetite and other symptoms, there are also the following: (1) distal extremities, especially pain allergies, numbness, pain, or pain, hypotactic sensation, loss of touch in a "glove, sock holster" distribution, can be accompanied by decreased Achilles tendon reflex; (2) significant hair loss, finger (toe) nails appear Michael's streaks; (3) neuromyography shows neurogenic damage.
6.2.2 Moderate:
On the basis of mild intoxication, there are also the following items: (1) distal pain sensation and tactile impairment of the limbs up to the elbow and above the knee, with the loss of Achilles tendon reflex, or deep sensory obvious impairment with sensory ataxia; (2) decreased muscle strength of the limbs to grade 4; (3) cranial nerve damage; (4) one of the mild cardiovascular system, respiratory system, nervous system, liver, and kidney damage.
6.2.3 Severe:
On the basis of moderate toxicity, there are also the following items: (1) the muscle strength of the extremities is reduced to grade 3 or less, or the distal muscles of the limbs are significantly atrophied; (2) one of the moderate- and severe cardiovascular system, respiratory system, nervous system, liver, and kidney damage occurs.
The classification of damage to the cardiovascular, respiratory, nervous system, liver, and kidneys is based on the poisoning severity score recommended by the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) in conjunction with the International Chemical Safety Program and the European Commission in 1998. PSS）[46]。
7 Differential diagnosis
Early thallium poisoning needs to be distinguished from gastroenteritis, pancreatitis and other digestive tract diseases. Neurologic symptoms should be differentiated from Guillain-Barre syndrome (GBS), botulinum toxin poisoning, lead or arsenic poisoning, diabetic neuropathy, acute carbon monoxide poisoning, etc.
7.1 GBS：
Generally, there is a history of gastrointestinal tract, respiratory tract infections, and vaccinations more than 1 to 4 weeks before the onset of illness. Acute or subacute onset, unipolar course, mostly peaking at about 2 weeks, stopping progression at 4 weeks. The main clinical feature is progressive, symmetrical muscle weakness with decreased or absent deep tendon reflexes [47] (table 1).
7.2 Botulinum toxin poisoning:
There is usually a history of eating contaminated food or injecting botulinum toxin, and typical symptoms are diplopia, dysarthria, pronunciation, and dysphagia, no sensory impairment, and clear consciousness [48,49]. Nerve injury presents with bilateral cranial neuropathy associated with symmetrical muscle weakness [50], which usually begins first in the trunk and upper extremities, then in the lower extremities, with urinary retention and constipation common. Patients with foodborne poisoning have severe symptoms and often have dyspnea requiring endotracheal intubation and adjuvant therapy with mechanical ventilation.
7.3 Lead poisoning:
There is a general history of lead exposure, and symptoms include abdominal pain (lead colic), constipation, arthralgia, muscle pain, headache, anorexia, decreased libido, difficulty concentrating and short-term memory impairment, irritability, excessive fatigue, sleep disturbances, etc.; confusion, seizures, and encephalopathy may occur in severe poisoning. Anemia and lead lines may be seen on examination; blood lead or urinary lead is elevated.
7.4 Arsenic poisoning:
It is generally caused by occupational contact or accidental ingestion and man-made, nausea, vomiting, abdominal pain, diarrhea, swill-like feces (sometimes with blood), which can cause renal insufficiency and even circulatory failure. Neurologic symptoms are multiple peripheral neuritis and radiculitis, manifested by muscle pain, numbness in the extremities, pinprick sensations, weakness of the upper and lower limbs, symptoms from the distal to the proximal end of the symmetrical development of the characteristics, the feeling gradually decreased or disappeared; severe patients may have a hanging foot, hanging wrist, with muscle atrophy, Achilles tendon reflex loss. Increased urinary arsenic or blood arsenic.
7.5 Diabetic neuropathy:
Diabetic neuropathy is one of the most common chronic complications of diabetes mellitus, involving the central and peripheral nerves, which are particularly common and most common in distal symmetrical multiple neuropathy. It is mainly manifested by bilateral limb pain, numbness, and paresthesias, such as ant walking, coldness, and burning sensation, but there is a long history of diabetes mellitus with a slow onset and a long course of disease, which can be identified.
7.6 Acute carbon monoxide poisoning:
There is a history of carbon monoxide exposure, the patient suddenly appears comatose, the skin mucosa is cherry red, and the carboxyhemoglobin is elevated; in severely poisoned patients, they may have impaired consciousness and enter a deep coma. Some patients with acute poisoning are re-comatose after waking up after a false healing period of 2 to 30 days, and complications such as dementia zombie psychosis, tremor paralysis syndrome, sensorimotor disorders or peripheral neuropathy are present, which is called acute carbon monoxide poisoning delayed encephalopathy.
8 Treatment
Treatment principles for acute thallium poisoning: remove poisons as soon as possible, reduce the absorption of poisons, and remove thallium in the body in time to reduce the absorption of thallium compounds in the digestive tract; use special detoxification drugs as soon as possible; when neurological symptoms and other organ function damage occur, timely give comprehensive treatment such as neurotrophicity and symptomatic support. The treatment process for acute thallium poisoning is shown in Figure 1.
8.1 Removal of poisons:
Early acute thallium poisoning is given gastric lavage, diarrhea, diuresis and other treatments. Oral poisoning patients as soon as possible with water, 2% sodium thiosulfate or 1% sodium iodide gastric lavage, and then infused with 20% mannitol or 50% magnesium sulfate 40 ~ 60 mL oral diarrhea, the internationally recognized method is to use polyethylene glycol whole gastrointestinal lavage, promote intestinal toxic discharge, reduce absorption. After that, oral activated charcoal adsorption of poisons, oral intake of thallium dose of larger dose of activated charcoal 50 ~ 100 g, followed by 10 ~ 20 g each time, 3 times a day. Acute thallium poisoning is mostly insidious poisoning and usually cannot be effectively managed early.
Thallium is excreted by the kidneys in prototype, appropriate rehydration combined with intravenous diuretics is beneficial to maintain appropriate circulating volume, and appropriate potassium supplementation is maintained at the high limit of the normal reference value range (4.5 to 5.0 mmol/L) is also conducive to increasing thallium discharge. However, because potassium can be mobilized from within cells to cause redistribution of thallium, which may cause worsening of neurological symptoms, potassium supplementation is not advocated for the first 48 hours after acute poisoning.
8.2 Blood purification:
Blood purification is the most effective technical means to remove poisons from the body. Blood purification is highly recommended in patients with severe thallium poisoning, which significantly improves the clearance of thallium in the body compared to renal and fecal clearance [9]. Indications for the use of blood purification for acute thallium poisoning: (1) high suspicion of thallium poisoning based on history or clinical features; (2) blood thallium content > 400 μg/L; (3) acute kidney injury caused by thallium poisoning.
Blood purification should be carried out as soon as possible, and blood purification can be carried out 24 to 48 hours after thallium poisoning to maximize the removal of the total amount of thallium in the body. The distribution of target organs such as the central nervous system is gradually completed 24 h after poisoning, and the blood purification treatment is started before it is completely distributed to other tissues of the human body, which will minimize the total thallium load in the body and improve the prognosis of thallium poisoning. Indication for discontinuation of blood purification: Blood thallium content < 100 μg/L for at least 72 h.
Since thallium is a small molecular substance, it hardly binds to plasma proteins, the Vd is large, and the toxicokinetics conform to the two- or three-chamber model. Blood purification treatment is divided into two stages: acute early stage (24 to 48 hours after poisoning) and acute post-stage (48 hours after poisoning to stop blood purification). Highly effective blood purification modes such as intermittent hemodialysis (IHD) or hemoperfusion (HP) are the best options in the early acute stage, and IHD or HP intervals can be combined with inefficient blood purification modes to achieve maximum therapeutic intensity; in the late acute stage, inefficient blood purification modes such as continuous veno-venous hemodialysis (CVVHD), continuous veno-venous hemodialysis filtration (CVVHDF), or continuous veno-venous hemofiltration (CVVH) is dominant [51]. Due to the low clearance efficiency of peritoneal dialysis and the low intensity of plasmapheresis therapy, it is not recommended to treat acute thallium poisoning with blood purification methods such as peritoneal dialysis and plasma exchange [9,52]. One case report showed that hemodialysis cleared 21 percent of thallium ingestion [53], suggesting that hemodialysis promoted thallium clearance more than forced diuresis [54]. Another case report showed that hemodialysis cleared approximately 10 mg of thallium within 1 h, twice as much as the kidneys could reach at the same time period [55]. HP also provides stable and efficient removal of thallium from the blood, and HP should be treated with HP as early as possible in patients with severe thallium poisoning, even after 48 hours of poisoning [19]. Tian Tian et al. [56] found that the blood thallium content after HP was significantly reduced by atomic absorption method, and more than 90% of thallium could be adsorbed after four perfusions.
At present, the literature on blood purification treatment for thallium poisoning is a case report, there are no randomized controlled studies, and further clinical research is needed, especially the position of continuous renal replacement therapy in the treatment of thallium poisoning needs to be evidence-based. Thallium poisoning is relatively rare, and the early blood purification mode is basically IHD or HP; in recent years, CVVHDF, CVVHD, and CVVH have been widely used in the clinic and occupy an important position in the treatment of small molecules, low protein binding rate, and water-soluble toxin poisoning [57].
8.3 Antidote drugs:
The U.S. Food and Drug Administration (FDA) approved Prussian blue for the treatment of thallium poisoning in October 2003. Potassium ions in Prussian blue can be exchanged with thallium ions in the stomach, biliary tract and small intestine, thereby blocking the hepatobic circulation of thallium and promoting its excretion through feces, thereby reducing the absorption of poisons and promoting excretion. Animal studies have shown that the above effects of Prussian blue can reduce the neurotoxicity of thallium [1]. Several clinical and basic studies have shown that Prussian blue has a good therapeutic effect [19,23,58]. The recommended use of Prussian blue capsules (330 mg per capsule) for military special needs produced by the Institute of Military Medicine of the Domestic Academy of Military Sciences is to use 10 h during the day, 2 capsules per hour, and rest at night (6 600 mg/day, a total of 15 days) [59], and the dosage of the drug can be adjusted according to the dose of poisoning.
Common adverse effects of Prussian blue are hypokalemia and constipation, so electrolyte changes should be monitored for use, potassium supplementation, and laxatives if necessary [30]. Prussian blue has been shown to have teratogenic effects in animal experiments, but its effects on human fetuses have not been reported in the literature. Conventional metal complexants such as D-penicillamine, 2,3-dimercaptobutyric acid, sodium dimercaptopropanesulfonate, etc. alone are ineffective in the treatment of thallium poisoning.
8.4 Prussian blue combined with blood purification therapy:
Prussian blue or HP are effective measures for the treatment of thallium poisoning, and the results of basic studies and clinical observations have initially shown that the combination of the two has a therapeutic effect of "1+1>2", especially for the early treatment of patients with moderate to severe acute thallium poisoning [58,60]. Even in patients with delayed diagnosis of thallium poisoning, Prussian blue combined with hemodialysis or HP has some efficacy [16].
8.5 Supportive care
8.5.1 Oxygen therapy and mechanical ventilation:
Patients with acute thallium poisoning should be routinely given oxygen when they have dyspnea and hypoxemia, and should be given mechanical ventilation and airway management in the event of respiratory failure or acute respiratory distress syndrome (ARDS).
8.5.2 Application of antimicrobials:
Since acute thallium poisoning can lead to multi-organ damage, reduced immunity, easy to cause complications such as lung infection, antibacterial drugs should be applied in time. It is recommended to use penicillins, cephalosporins, macrolides and other antibacterial drugs that have less damage to the liver and kidneys. Sensitive antimicrobials should be applied immediately and directly as soon as there is definitive evidence of infection.
8.5.3 Pain management:
Thallium poisoning peripheral nerve damage can cause neuropathic pain, severe hyperalgesia, slight touch can cause severe pain, affecting the patient's sleep and mental condition, etc., so it needs to be dealt with in time. Neuropathic pain treatment includes a combination of opioids, anticonvulsants, and antidepressants [13]. Opioids include piperidine and morphine, anticonvulsants include gabapentin and carmazepine, and antidepressants include amitriptyline.
8.5.4 Nutritional Support:
Acute thallium poisoning can cause energy metabolism disorders, and gastrointestinal symptoms are obvious in the early stages of poisoning, and a light diet should be encouraged. When severe gastrointestinal symptoms such as paralytic intestinal obstruction occur, parenteral nutritional support should be strengthened. The effect of enteral and parenteral nutritional support on the prognosis of acute thallium poisoning remains to be explored.
8.5.5 Other treatments:
Acute thallium poisoning can cause peripheral and central nervous system damage, and confirmed patients should be treated with nutritional nerve drugs and supplemented with adequate B vitamins [61]. Potassium supplementation can increase blood potassium concentration, promote the exchange of potassium ions with thallium ions, allow thallium ions to move out of cells into the bloodstream to promote excretion, or may compete with potassium to block the absorption of thallium by the renal tubules. The application of Prussian blue can also cause low potassium, and potassium supplementation should be paid attention to in treatment. Patients with constipation are treated with lactulose; those with eczema and pruritus are given antihistamines and calamine lotions to relieve symptoms; and those with psychiatric symptoms are given antipsychotic drugs such as ozapine.
9 Prognosis
After timely and effective treatment, patients with acute thallium poisoning can fully recover; however, the case fatality rate of severe poisoning is high, and different degrees of sequelae can also be left behind. The cause of death is closely related to delayed diagnosis, missed diagnosis, misdiagnosis and mistreatment, and mainly death from respiratory failure. Some patients have mild or moderate sequelae of sensory nerve fibers distal to the lower extremities, while other sequelae include movement disorders, vision loss, speech impairment, intellectual abnormalities, memory impairment, anxiety, and depression [62], which can be recovered through active rehabilitation exercises.
10 Conclusion
Thallium salt is a highly toxic substance, listed as a terrorist agent, and the poisoning caused by it has become a serious social problem. After understanding the general characteristics of thallium toxic substances, familiar with the clinical manifestations of acute thallium poisoning, early toxicity detection or poison identification, timely and accurate blood purification or Prussian blue and related symptomatic supportive treatment, the vast majority of patients with acute thallium poisoning can be recovered and cured. Missed diagnosis, misdiagnosis, and delayed diagnosis are the most fundamental causes of poor prognosis in patients with acute thallium poisoning. For patients with acute thallium poisoning who are highly suspected or critically ill, it is recommended to be referred to the Poisoning Treatment Specialist Center for further diagnosis and treatment in a timely manner.
Source: Emergency Medical Information Synthesized from
Southern Metropolis Daily, China Critical Illness Emergency Medicine, Good Doctor, Xinhua News Agency
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