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Toxicity, Tetrodotoxin
Article Last Updated: Dec 10, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Theodore I Benzer, MD, PhD, Instructor in Medicine, Harvard Medical School; Director of Clinical Operations, Director of Toxicology, Department of Emergency Medicine, Massachusetts General Hospital
Theodore I Benzer is a member of the following medical societies: Alpha Omega Alpha and American College of Emergency Physicians
Editors: Robert Norris, MD, Chief, Associate Professor, Department of Surgery, Division of Emergency Medicine, Stanford University Medical Center; John T VanDeVoort, PharmD, ABAT, Director of Pharmacy, Sacred Heart Hospital; Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Author and Editor Disclosure
Synonyms and related keywords:
TTX, Japanese puffer fish, fugu, tetrodotoxin, tetrodotoxin toxicity, tetrodotoxin exposure, tetrodotoxin poisoning, tetrodotoxin ingestion, neurotoxin
Background
Poisoning with the neurotoxin tetrodotoxin (TTX) occurs after ingestion of various species of puffer fish (see Media file 1). The flesh of the puffer fish (ie, fugu) is considered a delicacy in Japan. It is prepared by chefs specially trained and certified by the government to prepare the flesh free of the toxic liver, gonads, and skin. Despite these precautions, many cases of tetrodotoxin poisoning are reported each year in patients ingesting fugu. Poisonings usually occur after eating fish caught and prepared by uncertified handlers. The toxic dose is not clear because puffer fish have different concentrations of tetrodotoxin. A dose of 1-2 mg of purified toxin can be lethal. Reported cases from the Centers for Disease Control and Prevention (CDC) have documented toxicity with ingestion of as little as 1.4 ounces of puffer fish. Tetrodotoxin also is found in the gastropod mollusc; in the eggs of horseshoe crabs; in newts of the genus Taricha; in the skin of Atelopid frogs; and in the skin and viscera of porcupine fish, globefish, balloon fish, blowfish, sunfish, toadfish, blue-ringed octopus, and some species of salamanders.
Pathophysiology
Puffer fish contain the potent neurotoxin tetrodotoxin. TTX is thought to be synthesized by a bacterial or dinoflagellate species associated with the puffer fish. The toxin is concentrated in the liver, gonads, and skin. The level of toxicity is seasonal, and, in Japan, fugu is served only from October through March. Tetrodotoxin is a heat-stable (except in alkaline environments) and water-soluble nonprotein. Tetrodotoxin is a heterocyclic, small, organic molecule that acts directly on the electrically active sodium channel in nerve tissue (see Media file 2). Tetrodotoxin blocks diffusion of sodium through the sodium channel, preventing depolarization and propagation of action potentials in nerve cells. All of the observed toxicity is secondary to the action potential blockade. Tetrodotoxin acts on the central and the peripheral nervous systems (ie, autonomic, motor, sensory nerves). Tetrodotoxin also stimulates the chemoreceptor trigger zone in the medulla oblongata and depresses the respiratory and vasomotor centers in that area.
Recent study using tetrodotoxin therapeutically shows that tetrodotoxin used in conjunction with bupivacaine prolonged the local anesthetic effect.1 If tetrodotoxin begins to be used clinically, the incidence of toxicity may increase.
Frequency
United States
Reports of tetrodotoxin poisoning are rare in the United States, but a 1996 report in the Morbidity and Mortality Weekly Report (MMWR) documents 3 cases of tetrodotoxin toxicity from persons who ingested contaminated fugu imported by a coworker from Japan.2
International
Despite the careful training and certification of fugu chefs in Japan, cases of mortality and morbidity from puffer fish ingestion continue to be reported. Estimates vary, but up to 50 deaths may occur each year from tetrodotoxin poisoning in Japan.
Mortality/Morbidity
Mortality rates are difficult to calculate, but estimates of mortality approach 50%, even with modern supportive medical care. Patients who live through the acute intoxication (ie, first 24 h) usually recover without residual deficits. Recovery takes days to occur.
Race
No known racial predilection exists. However, the poisoning is more common in Japanese people because of their dietary preferences for fugu.
History
- The first symptoms occur 15 minutes to several hours postingestion of tetrodotoxin-containing food. A recent report on toxicity found that initial symptoms may occur up to 20 hours after ingestion.
- Initial symptoms include lip and tongue paresthesias, followed by facial and extremity paresthesias and numbness.
- Salivation, nausea, vomiting, and diarrhea with abdominal pain develop early.
- Motor dysfunction with weakness, hypoventilation (may be from dysfunction of central and peripheral nervous systems), and speech difficulties then develop. A rapid ascending paralysis occurs over 4-24 hours. Extremity paralysis precedes bulbar paralysis, which is followed by respiratory muscle paralysis. Deep tendon reflexes are preserved early in the course of paralysis.
- Finally, cardiac dysfunction with hypotension and dysrhythmias (bradycardia), central nervous system (CNS) dysfunction (eg, coma), and seizures develop. Patients with severe toxicity may have deep coma, fixed nonreactive pupils, apnea, and loss of all brain stem reflexes.
- Death can occur within 4-6 hours. Typically, death occurs from respiratory muscle paralysis and respiratory failure.
Physical
- Loss of sensory and motor neuron function is a prominent finding.
- Ascending paralysis with respiratory depression.
- Cyanosis occurs with respiratory failure.
- Hypotension can occur with myocardial dysfunction.
- Cardiac rhythm disturbances, especially bradycardia, atrioventricular (AV)–nodal block, and bundle-branch block, can be life threatening.
- GI effects are not prominent, but vomiting and abdominal tenderness can occur.
Causes
- Ingestion of tetrodotoxin causes the syndrome.
- Almost all toxicity is caused by the ingestion of fugu, but other species of animals have been shown to produce tetrodotoxin (eg, California newt, parrot fish, blue-ringed octopus). A death from ingestion of tetrodotoxin from a California newt has been documented.
CBRNE - Botulism
Gastroenteritis
Guillain-Barré Syndrome
Heart Block, First Degree
Heart Block, Second Degree
Heart Block, Third Degree
Hypocalcemia
Lambert-Eaton Myasthenic Syndrome
Myasthenia Gravis
Octopus Envenomations
Toxicity, Ciguatera
Toxicity, Scombroid
Toxicity, Shellfish
Lab Studies
- No specific laboratory test that confirms tetrodotoxin ingestion exists; thus, dietary history is key for diagnosis.
- Mouse bioassays for paralytic shellfish toxin (ie, saxitoxin) exist that are positive with tetrodotoxin and research chromatography techniques, but neither is available in the acute clinical situation. Tetrodotoxin also may be detected by fluorescent spectrometry.
- Measure routine serum electrolytes, calcium, magnesium, and ABGs to rule out metabolic causes of diffuse sensory and motor neuron dysfunction.
Imaging Studies
- Patients with evidence of cyanosis or respiratory insufficiency should have a chest x-ray to exclude local lung pathology (eg, aspiration pneumonia).
- Obtain a plain film and upright x-ray of the abdomen in patients with persistent vomiting or severe abdominal pain to exclude obstruction or hollow viscus perforation.
- Perform a CT scan of the brain if the patient exhibits any focal neurologic dysfunction or seizures.
Prehospital Care
- Provide prehospital care with careful attention to the airway, breathing and circulation (ABC's).
- Patients may require endotracheal intubation for oxygenation and airway protection in the setting of muscle weakness and respiratory failure, which can occur soon after ingestion of the tetrodotoxin.
- Cardiac dysfunction may require IV intervention with fluids, pressors, and antiarrhythmics.
- Severely poisoned patients may be very weak, have difficulty speaking, and be unable to provide a history. Thus, clues from the environment and bystanders are very important.
Emergency Department Care
- Focus initially on the ABCs.
- Secure the airway before frank respiratory failure or aspiration occurs.
- Establish an IV early in the event acute antiarrhythmics or vasopressors are needed.
- Remove toxin from the intestinal tract by the usual toxicologic modalities. The use of nasogastric or orogastric lavage is theoretically beneficial but can be complicated by aspiration and damage to the esophagus. The administration of activated charcoal (with or without a cathartic) is recommended for all symptomatic patients.
- If vomiting has occurred, gastric lavage is not indicated.
- Carefully monitor vital signs and oxygenation in the ED because patients can decompensate suddenly. Treat all alterations in vital signs aggressively.
- Further treatment focuses on supporting cardiovascular function until the toxin is eliminated from the body.
- No specific antidote has been tested in humans. An animal study using monoclonal antibodies against TTX has been done.3 Monoclonal antibodies were shown to be life saving in mice treated both before and after the ingestion of a lethal dose of TTX. Further studies are needed to document the efficacy in humans.
- In another animal study, 4-aminopyridine (a potassium channel blocker) was used in guinea pigs intoxicated with tetrodotoxin or saxitoxin.4 A dramatic improvement in respiratory, cardiac, and CNS status occurred after administration of the drug. No human studies of this drug for use in tetrodotoxin poisoning are in progress.
No drug has been shown to reverse the effects of tetrodotoxin poisoning. Treatment is symptomatic. Specific drug efficacy has only been documented anecdotally.
Anticholinesterase drugs (eg, neostigmine) have been proposed as a treatment option but have not been tested adequately.
Drug Category: GI decontaminants
Empirically used to minimize systemic absorption of the toxin. May only benefit if administered within 1-2 h of ingestion.
| Drug Name | Activated charcoal (Liqui-Char) |
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| Description | Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.
For maximum effect, administer within 30 min of ingesting poison. Generally mixed and given with a cathartic (eg, 70% sorbitol), except in young pediatric patients in whom electrolyte disturbances may be of concern. |
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| Adult Dose | 1 g/kg (typically 50 g) PO; may repeat once at one-half original dose (0.5 g/kg) if large ingestion is suspected |
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| Pediatric Dose | <2 years: Cathartic not recommended
Administer as in adults (usually 15-30 g) |
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| Contraindications | Documented hypersensitivity; poisoning or overdose of mineral acids and alkalies; unprotected airway with absent gag reflex |
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| Interactions | May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix with sherbet, milk, or ice cream (decreases adsorptive properties) |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Monitor for presence of bowel sounds to minimize risk of charcoal ileus; not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before administration; after emesis with ipecac syrup, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black |
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Drug Category: Cholinergic agents
May be useful in reversing the neurological complications of the venom; however, they should not be a substitute for airway management.
| Drug Name | Neostigmine (Prostigmin) |
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| Description | Although not clinically proven, neostigmine has been used anecdotally to restore motor strength. Inhibits destruction of acetylcholine by acetylcholinesterase, which facilitates transmission of impulses across myoneural junction.
Repeat doses based on patient's response. |
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| Adult Dose | 0.5 mg IM
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| Pediatric Dose | 0.02 mg/kg IV or 0.04 mg/kg IM
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| Contraindications | Documented hypersensitivity; GI or GU obstruction |
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| Interactions | Atropine antagonizes muscarinic effects; effects of neuromuscular agents are increased |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Caution in epilepsy, asthma, bradycardia, hyperthyroidism, cardiac arrhythmias, or peptic ulcer; anticholinesterase insensitivity can develop for brief or prolonged periods |
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Further Inpatient Care
- Admit all patients with documented or suspected puffer fish ingestion to an ICU.
- Symptoms usually develop within 6 hours but may be delayed for 12-20 hours.
Prognosis
- Mortality rates are difficult to establish; however, anecdotal reports suggest 50-60% mortality, even with good supportive care.
- Symptoms may last several days, even in nonlethal ingestions.
- One report suggests that prognosis is good if the patient survives the first 24 hours.
Patient Education
Medical/Legal Pitfalls
- Tetrodotoxin ingestion presents several medical and legal issues.
- Tetrodotoxin poisoning is a public health issue and mandates a report to the department of public health if the ingestion was related to toxic levels of TTX in food. The source of the toxin must be established to prevent further exposures. A call to the local department of public health documenting possible concerns should suffice to meet the ED physician's responsibility in this area.
- Be aware of the possibility of intentional poisoning. Obtain a complete psychiatric evaluation for the patient if it appears that the ingestion was a suicide attempt. In addition, the police should be involved if it is possible that another person poisoned the patient.
- Padera RF, Tse JY, Bellas E, Kohane DS. Tetrodotoxin for prolonged local anesthesia with minimal myotoxicity. Muscle Nerve. Dec 2006;34(6):747-53. [Medline].
- San Diego Department of Environmental Health, FDA. Tetrodotoxin poisoning associated with eating puffer fish transported from Japan--California, 1996. MMWR Morb Mortal Wkly Rep. May 17 1996;45(19):389-91. [Medline].
- Rivera VR, Poli MA, Bignami GS. Prophylaxis and treatment with a monoclonal antibody of tetrodotoxin poisoning in mice. Toxicon. Sep 1995;33(9):1231-7. [Medline].
- Chang FC, Spriggs DL, Benton BJ, et al. 4-Aminopyridine reverses saxitoxin (STX)- and tetrodotoxin (TTX)-induced cardiorespiratory depression in chronically instrumented guinea pigs. Fundam Appl Toxicol. Jul 1997;38(1):75-88. [Medline].
- Ahasan HA, Mamun AA, Karim SR, et al. Paralytic complications of puffer fish (tetrodotoxin) poisoning. Singapore Med J. Feb 2004;45(2):73-4. [Medline].
- FDA/CFSAN resources page. Pufferfish poisoning. Food and Drug Administration Web site. Available at: http://vm.cfsan.fda.gov/~mow/chap39.html. Accessed January 20, 2005. [Full Text].
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- Mills AR, Passmore R. Pelagic paralysis. Lancet. Jan 23 1988;1(8578):161-4. [Medline].
- Sims JK, Ostman DC. Pufferfish poisoning: emergency diagnosis and management of mild human tetrodotoxication. Ann Emerg Med. Sep 1986;15(9):1094-8. [Medline].
- Sun KO. Management of puffer fish poisoning. Br J Anaesth. Oct 1995;75(4):500. [Medline].
- Xu QH, Zhao XN, Wei CH, Rong KT. Immunologic protection of anti-tetrodotoxin vaccines against lethal activities of oral tetrodotoxin challenge in mice. Int Immunopharmacol. Jul 2005;5(7-8):1213-24. [Medline].
Toxicity, Tetrodotoxin excerpt Article Last Updated: Dec 10, 2007
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