Tetramine Toxicity

Etiology

Tetramine is an inexpensive rodenticide frequently sold outside the United States, where it is manufactured. Due to the regulations around its manufacture, sale, and ownership, it is sometimes purchased from illegal vendors.

Epidemiology

Tetramine synthesis was first documented in Germany in 1949. The substance's toxicity was discovered through occupational exposure to rayon fabric-impregnated flame retardants. Upholstery workers exposed to the fabric experienced multiple symptoms, including seizures. Further investigation confirmed that the flame retardant agents in the fabric (sulfamide and formaldehyde) reacted and formed tetramine.[2] Given the severity of its toxicity and lack of an antidote, it was internationally banned in the 1980s. The manufacture of tetramine is relatively simple, with readily available ingredients. Thus, illicit production has continued.

Most documented cases are in China, with more than 14,000 instances reported between 1991 and 2010.[3] China increased governmental regulations regarding tetramine in 2003, and reported cases declined in the three years following the regulatory change.[4] However, tetramine sales are still reported in China and other countries.[1] There has been one reported case in the United States. In 2002, a 15-month-old girl was playing with the powder from an applied rodenticide and began seizing. Despite aggressive therapy, she suffered multiple neurologic sequelae. Testing was performed, confirming the presence of tetramine.[5][6] 

No intentional poisoning cases have been documented in the United States. A notable case in China occurred when a food vendor poisoned his competitor's food with a tetramine rodenticide. In all, 300 customers were poisoned, and 42 deaths occurred.[1] Another case of attempted poisoning occurred at a school in Hunan province, where 120 students fell ill when a student tried to poison a teacher, but the tainted ingredients were unknowingly used to serve the school.[1] 

Due to its use in rural areas as an effective rodenticide, mass exposures are common in the countryside. In 2001, 200 individuals were exposed to tetramine in a rural area. In addition, due to the stability of tetramine in water for 6 weeks, there have been concerns that poisoned rats eaten by roaming dogs in rural areas may have toxic concentrations in their tissues through bioaccumulation.[1]

Pathophysiology

Tetramine is a noncompetitive GABAa channel antagonist, blocking this inhibitory chloride channel. Early studies noted similarities between tetramine and picrotoxin, another noncompetitive GABAa inhibitor. The chemical is classified as a cage convulsant based on its structure. The GABAa receptor is a pentameric structure composed of different subunits. Due to the potential variability in subunit composition and genetic variances within subunits, there is a large amount of heterogeneity in the subunit composition of the GABAa receptor in vertebrates.[7] 

Tetramine has a different affinity for different subunits, and further studies of this have noted that inhibition is incomplete, with a wide range of inhibition (46%-85%) dependent on the subunit makeup of the receptor it is inhibiting.[8] This range of inhibition, combined with the differences in GABAa subunit composition, speaks to a potential localization of toxicity in discrete areas of the central nervous system and a potential for varying degrees of toxicity based on the receptor structure composition of the poisoned individual.[7] This incomplete inhibition may also provide insight into the underlying mechanism of action of adjuncts used in poisoned patients. 

Tetramine also affects calcium dynamics in neurons and the frequency of spontaneous calcium oscillations.[9] These effects are similarly seen in toxicity caused by picrotoxin, suggesting a similar mechanism of action demonstrated in previous studies.

Toxicokinetics

Tetramine has the chemical formula C4H8NO4S2, and its chemical name is tetramethylenedisulfoteramine. Other names include TMDT, TETS, Dushuqiang (very strong rat poison), 4-2-4, and Sanbudado (takes 3 steps and keels over).[1][3] Animal studies report an LD50 as low as 0.1 mg/kg, and human LD50 estimates range from 0.1 to 0.3 mg/kg.[2][6] 

Tetramine is odorless, colorless, and persistent in the body and the environment.[1] Tetramine is water soluble.[3][5] The main route of exposure is through ingestion. There are occupational exposures through inhalation; it is not absorbed through the skin.[5] Absorption is rapid, with animal studies showing 90% absorption within 1 hour.[10] 

Thus, symptom onset is rapid, with most cases showing toxicity within 30 minutes of ingestion.[5] Tetramine excretion is mainly through the urine and is slow. A minor percentage (<20%) is excreted in the bile.[10] The presence of significant biliary recirculation has not been studied.

History and Physical

History should attempt to ascertain the amount of tetramine ingested and the time of ingestion. The possibility of co-ingestants should also be shown. The symptomatic onset is rapid. The physical exam should focus on the neurologic evaluation. Physical exam findings are generally nonspecific. Animal models suggest lethargy and tremor as early toxicity signs.[11] 

Common symptoms reported from minor toxicity include headache, nausea, vomiting, dizziness, and hallucinations.[12] Severe cases present with seizures, status epilepticus, multiorgan failure (likely sequelae of intractable seizures), and death.[12] 

Given the rapid nature of toxicity development, the patient may present in status epilepticus to the hospital setting, and other symptoms might not be prevalent by the time the patient arrives.

Evaluation

Diagnosis is mainly clinical, and the primary managing team must maintain a high index of suspicion for tetramine toxicity. There are case reports of documented electroencephalography (EEG) changes, including diffuse slow waves, spike-and-slow waves, and sharp and slow waves in children.[13] Leukocytosis, rhabdomyolysis, and thrombocytopenia are reported in documented cases.[3] 

Multiple studies describe diagnostic testing; however, these tests are not readily available, limiting their benefit in the clinical setting. Gas chromatography with nitrogen phosphorous detection is described as a sensitive technique to detect tetramine.[14] Other methodologies described include gas chromatography/mass spectroscopy.[15] 

No pathognomonic findings are reported on CT imaging or MRI for tetramine toxicity.

Findings on autopsy note lung edema and congestion in all documented cases.[3] There is bleeding in most organs, with subarachnoid hemorrhage found in 27.5% of cases on autopsy review.[3] The mechanism for multi-site hemorrhages is unclear and may be related to sequelae of intractable seizures, although this is inconclusive.

Treatment / Management

Universal precautions are recommended to limit exposure to healthcare providers. As stated earlier, tetramine is unlikely to be absorbed through intact skin.

Treatment should be started as early as possible as tetramine is rapidly absorbed after oral ingestion, and neurotoxicity occurs suddenly.

Gastric Decontamination

In acute confirmed ingestions, it is reasonable to consider gastric decontamination. The LD50 of tetramine is such that decreasing absorption may mitigate toxicity. However, no robust data or human studies suggest mortality benefits. Regardless, gastric lavage has been reported as a recommended treatment by clinicians with experience treating tetramine poisoning.[16](B3)

An animal study on the effects of activated charcoal use in tetramine-poisoned rabbits demonstrated a decrease in the elimination half-life by 55% and a reduction in the area under the curve by 70%, indicating tetramine is readily bound by activated charcoal.[10] This data would suggest that activated charcoal may be beneficial in early presentations. However, given the high likelihood of seizures, the risk of aspiration must be considered if the patient's airway is not protected through endotracheal tube placement.(B3)

There are no studies on biliary recirculation, and the benefit of multi-dose activated charcoal is unclear.

Pharmacologic Treatment

A distinctive characteristic of tetramine toxicity is refractory seizures. Multiple classes of drugs have been studied in animals with variable effects. Aggressive and early escalating treatment is recommended regardless of the agents chosen to treat tetramine toxicity. In a case series of 15 patients with tetramine toxicity, the authors advocate for early mechanical ventilation to avoid any hesitancy in escalating treatment with benzodiazepines.[16](B3)

Benzodiazepines

Benzodiazepines are one of the more common agents used in reported cases. Molecular studies demonstrated midazolam had the best inhibition of tetramine binding to the GABA receptor compared to diazepam and phenobarbitol. However, this has not been studied in humans.[17] A comparison in an animal poisoning model noted both high-dose diazepam and midazolam improved survival.[18] Animal studies reported improvement in seizure resolution with diazepam but no change in death rate at 60 minutes.[19] (B3)

Sedative Hypnotics

Early animal studies suggest aggressive sedative therapy with an agent such as phenobarbital is beneficial.[20] 

Molecular studies suggested propofol appears to have similar efficacy as midazolam in blocking tetramine binding to the GABA receptor.[17](B3)

NMDA Receptor Inhibitors

Ketamine was studied in mice, and with higher doses (70 mg/kg intraperitoneal), convulsions decreased, and the 60-minute death rate was decreased.[19](B3)

Adjuncts

Where tetramine cases are more commonly seen, treatment adjuncts are used frequently. Randomized controlled trials in humans for these adjuncts are lacking, and reports of the effects are limited to animal studies and case reports/series.

Pyridoxine

Vitamin B6 has been reported as a helpful adjunct in cases of tetramine toxicity. Data is limited on efficacy, and the exact mechanism is unclear. As previously mentioned, tetramine is a noncompetitive inhibitor of the GABAa receptor. Pyridoxine is used in other poisons that cause neurotoxicity, such as gyromitra and isoniazid toxicity. These agents contribute to seizures by depleting the active form of pyridoxine, pyridoxal 5-phosphate, an essential cofactor in GABA formation. Animal studies have demonstrated that pyridoxine combined with sodium 2,3-dimercaptopropanesulfonate (DMPS) decreased convulsions.[21](B3)

Sodium 2,3-dimercaptopropanesulfonate (DMPS)

DMPS, a chelating agent for heavy metals, has been suggested as a treatment modality for tetramine-poisoned patients. In addition to being used as a combination treatment with pyridoxine, animal studies demonstrated the potential benefit of DMPS alone. Proposed mechanisms involve the sulfhydryl groups and their ability to modulate the function of various ion channels. Rat studies showed decreased convulsions with DMPS alone due to the potentiation of GABA at the receptor site.[22](B3)

Medication Adjuncts Under Investigation

Neurosteroids

Neurosteroids are another class of drugs undergoing research as a treatment for tetramine toxicity. Neurosteroids interact with GABAa receptors both in the synaptic cleft and at extrasynaptic GABAa receptors, the latter of which are not sensitive to benzodiazepines.[23] Activation of these extrasynaptic receptors leads to tonic inhibition instead of phasic inhibition at the synaptic cleft.[7] Neurosteroids are positive allosteric modulators and can increase benzodiazepine affinity to the GABAa receptor when bound at the same complex.[24] (B3)

In addition to the modulating effects of neurosteroids, there appears to be a synergistic effect of benzodiazepines and neurosteroids. Combination therapy of diazepam and allopregnanolone (a neurosteroid used to treat postpartum depression) demonstrated normalization of tetramine-induced synchronous calcium oscillations in rodents and improved survival from ten percent to 90%.[25]

Extracorporeal Removal

Extracorporeal removal of tetramine has been implemented in many instances of poisoning through various modalities, including plasma exchange, hemodialysis (HD), high volume hemofiltration (HVHF), continuous venovenous hemofiltration (CVVH), and charcoal hemoperfusion. There have not been large comparison studies in humans. Expert opinion on this as a treatment is mixed, and recommendations vary.[26][15][27] If extracorporeal is used as treatment, early initiation may result in decreased time to recovery based on a case series.[28](B3)

Charcoal hemoperfusion appears to be the more common modality, as studies have demonstrated that this method does remove tetramine from the body quickly. A two-hour session removed 1 mg of tetramine (measured from the perfusion device) when the initial plasma concentration was 100 mcg/L.[26] That result is compared to urinary excretion of 80 mcg at 48 hours recorded in the same study. Lab analysis also showed decreased efficacy during longer sessions, suggesting that the perfusion filter was saturated with tetramine and became ineffective.[26] A logistical issue is charcoal hemoperfusion is not reliably available, even in large metropolitan hospitals, which may affect treatment strategy.[29] (B2)

There are conflicting reports concerning extracorporeal removal. Some studies document pre-filtration and post-filtration concentrations in patients and note no significant change in concentration, bringing into question the efficacy of extracorporeal removal.[26] Other case series also note this phenomenon with a recurrence of seizures in the days following hemoperfusion.[13] However, different case series document improvement in tetramine concentrations after hemoperfusion, suggesting that the conflicting results are more likely related to the differences in tetramine amount ingested for each individual in the reported cases.[30] (B2)

Given the distribution of tetramine throughout the body, this observation is thought to be more likely due to the redistribution of tetramine from body tissues into the serum, as studies have documented that tetramine is removed by charcoal hemoperfusion by directly analyzing the filter contents.[26][15] 

A case of a patient that received high-volume hemofiltration seven days after poisoning noted a decrease in tetramine concentration from 0.95 mcg/mL to 0.35 mcg/mL. The following day the serum concentration rebounded to 0.53 mcg/mL, and charcoal hemoperfusion was performed, lowering the concentration to 0.40 mcg/mL.[12] (B3)

Serum rebound is frequently reported in published cases. Thus, additional sessions may be indicated. Eighteen patients received hemoperfusion followed by CVVH, which was more effective at removing tetramine.[28] This may mitigate rebound after hemoperfusion, though more study is needed. 

Extracorporeal Removal on Long-term Outcomes

A case series of 17 children with an unintentional ingestion of tetramine compared outcome differences in those that received charcoal hemoperfusion and those that did not; the non-hemoperfusion group had a higher incidence of seizures.[13] (B2)

EEG abnormalities were monitored at regular intervals, and the hemoperfusion group had a resolution of EEG abnormalities at six months, whereas the non-hemoperfusion group took a year to recover. This same study noted a quicker time to recovery in individuals that received multiple occurrences of hemoperfusion.[13] This is reported in the literature, as stated previously.(B2)

Differential Diagnosis

• Sodium monofluoroacetate toxicity
• Stimulant abuse
• Isoniazid toxicity
• Organophosphate compound toxicity
• Serotonin toxicity
• Hydrazine toxicity
• Hypoglycemia
• Severe electrolyte derangements

Prognosis

Left untreated, severe tetramine toxicity is invariably fatal. With rapid and aggressive escalating treatment, mortality is notably diminished. In an observational study of confirmed cases in China from 2000 to 2012, there were 3526 cases and 225 deaths (6%).[4]

Complications

Complications surrounding tetramine toxicity are neurological in nature. Pediatric studies have documented prolonged EEG changes after treatment.[13] 

Seizures are a common complication after the acute toxicity phase. A follow-up study of 370 previously healthy poisoning survivors noted that 55% had seizures at follow-up. Of those who were seizure-free at the follow-up, most had been placed on antiepileptic medication initially and were seizure-free off the drug by an average of 2.3 years. Of the remaining 195 patients with seizures, most experienced tonic-clonic seizures, while the minority (39) had partial seizures.[31] Of those surveyed, a minority had other neurologic sequelae, such as gait instability, cognitive deficits, and intractable epilepsy.[31] These long-term sequelae are also reported in case literature.[6]

It should be noted that a small number of patients with minor toxicity experience long-term complications of seizures without having seizures at the initial presentation. At follow-up in the previous observational study, all of these patients continued to have seizures.