Seafood Toxidromes

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Chapter 72 Seafood Toxidromes*

At least three-quarters of the world’s population lives within 10 miles (16 km) of the coast. One of many reasons why populations congregate near the sea is the abundance of food beneath the ocean’s surface. Seafood provides a significant percentage of protein in the diets of many cultures. Presently, 200 to 240 million tons of fish are harvested each year, with 50% of the total coming from coastal regions. Per capita fish consumption has increased in recent decades. Americans consume 7.3 kg (16.4 lb) of fish per person per year.185 The ocean is one of our last plentiful food resources. International trade has dramatically increased year-round availability of assorted seafoods, many of which come from distant geographic locations.441

Throughout time, humans have recognized that toxic seafood is associated with seasons of the year, phases of the moon, water temperature, weather conditions, waterfowl mortality, color of the waves that wash onto shore, and many other circumstances. Unfortunately, none of these factors has proven entirely reliable in predicting when seafood poisoning.

Marine creatures whose consumption can lead to poisoning include dinoflagellates, coelenterates, mollusks, echinoderms, crustaceans, fishes, turtles, and mammals. Most marine biotoxins are naturally occurring poisons derived directly from marine organisms, including phytotoxins (plant poisons) and zootoxins (animal poisons). Ingestible toxins may be classified by specific toxin or by the donor organ of origin ingested by the victim. Ichthyosarcotoxin is a general term for poison derived from the fresh flesh (muscle, viscera, skin, or slime) of any fish. Geographic location, dietary and clinical histories, and appropriate index of suspicion figure prominently in the diagnosis and treatment.

Data on food-borne disease outbreaks in the United States demonstrate that by vehicle of transmission for foodborne-disease outbreaks, finfish and shellfish represent 5.0% and 2.0%, respectively.79 Some 90% of outbreaks of seafood-related illnesses and 75% of individual cases come from contaminated raw molluscan seafood (e.g., oysters, clams), histamine poisoning (scombroid), and ciguatoxin found in reef fish species.340 In general, marine toxins are heat stable and largely unaffected by cooking. Marine poisoning causes mostly gastrointestinal and neurologic symptoms. Many marine toxins target voltage-gated sodium channels in myelinated and unmyelinated nerves, resulting in a range of peripheral neurologic effects.219

Monitoring Phytotoxin-Producing Marine Algae and Seafood Poisonings

Despite the increasing risk of human intoxication from contaminated seafood, standards and methods of screening and law enforcement vary worldwide.487 According to the U.S. Department of Agriculture, imports account for more than 55% of total U.S. seafood consumption. The largest sources of seafood imported into the United States are Canada, Asia, and Latin America. The U.S. Food and Drug Administration (FDA) has been criticized for inadequate inspection of all food imports.340 In 1995, the FDA switched to a new program for seafood safety known as the Hazard Analysis and Critical Control Point (HACCP) system. This program became mandatory for the seafood industry on December 18, 1997.151 The HACCP focuses on the following: (1) identification of sources and points of contamination; (2) levels of the hazard(s) of concern, transmission rate, and transport of microorganisms; and (3) the possibility of exposure of the consumer to the contaminant. HACCP concentrates on preventing hazards rather than relying on spot checks and random sampling of products. The most effective control strategies can then be implemented. For shellfish- and virus-associated diseases, data suggest that harvesting from unapproved sources is associated with more than 30% of outbreaks.292 Among imports, the biggest risks relate to histamines and scombroid poisoning, mainly from tuna and mahi-mahi that is imported from Argentina, Taiwan, and Ecuador. For foods traveling great distances, refrigeration is the most critical aspect of controlling illness. Although there has been progress in improving standards for imported seafood in the United States, only 5% to 7% of the 8500 firms importing seafood in the United States during 2002-2003 were inspected by regulators.113

The United States is the second largest importer of shrimp worldwide. Shrimp aquaculture currently accounts for approximately 30% of the world’s supply. The FDA has amended the food additive regulations to provide for the safe use of ionizing radiation for control of foodborne pathogens in fresh or frozen molluscan shellfish.152

Molluscan poisoning is mainly a problem with domestic seafood. In 1991, California was the first state to require restaurants that serve or sell Gulf Coast oysters to warn prospective customers about possible deleterious effects from Vibrio contamination, particularly Vibrio vulnificus.378 Other states have since adopted these warning regulations. Additionally, fishermen are now required to refrigerate oysters within six hours after harvesting from the Gulf of Mexico. Regulations require oyster lot tagging, labeling, and record retention to facilitate trace-back investigations of outbreaks. The United States and Canada allow the sale of oysters if there are less than 10,000 colony-forming units per gram (CFU/g) of Vibrio parahaemolyticus. However, in outbreaks in the Pacific Northwest in 1997 and New York in 1998, oysters had less than 200 V. parahaemolyticus CFU/g of oyster meat, suggesting that human illness can occur at lower levels.77

Approximately one-third of U.S. shellfish beds carry bans or limitations on harvesting because of high levels of fecal coliform bacteria. The fecal indicator system for shellfish-harvesting waters has been effective in protecting consumers against general types of bacteria in fecal contamination. However, several pathogenic bacteria are not predicted by the system. The efficacy of methods for virus recovery may range from 2% to 47%.507 The most promising of the new detection methods are based on molecular techniques. Deoxyribonucleic acid (DNA) hybridization and the polymerase chain reaction (PCR) have the advantages of specificity for particular pathogens, sensitivity, and speed (most assays are completed within a few hours). PCR has been used in shellfish to detect Salmonella, Vibrio species, and viruses, including hepatitis A virus and norovirus. High-performance liquid chromatography (HPLC) has also been used to detect and quantify many shellfish toxins.* Phytotoxin-producing marine algae are responsible for the syndromes of paralytic, neurotoxic, and diarrhetic shellfish poisoning. Closure of fisheries (product harvest areas) depends on the density of algae. In some cases, the decision to close a fishery is based on the toxicity level in shellfish; in others, algae in the water and toxin in shellfish must both be found. In Florida, more than 5000 cells/L of Ptychodiscus brevis must be detected before fisheries are closed. The quarantine level of saxitoxin (a neurotoxin found in marine dinoflagellates) varies between countries and ranges from 40 to 80 mg of toxin per 100 g (3.5 ounces) of seafood, as determined through mouse bioassay.20 The higher number is used in the United States, as monitored by the Interstate Shellfish Sanitation Conference and the FDA.

The maximal acceptable concentration of diarrhetic shellfish toxin (okadaic acid) also varies between countries because of lack of precise analytic methods for quantification. Countries with established regulations apply 4 to 5 mouse units or 20- to 25-mg equivalents of okadaic acid as an acceptance limit. In the United Kingdom, the Ministry of Agriculture, Fisheries, and Food shellfish surveillance program tests harvested shellfish weekly from April to October and sporadically during the winter for the presence of toxins.410 The United States, Canada, and Portugal monitor for domoic acid (the cause of amnesic shellfish poisoning) and use 2 mg/100 g of seafood as the threshold. Ciguatoxins are monitored infrequently because of difficulties associated with the assay. In French Polynesia, ciguatoxin at 0.06 ng/g of seafood as determined by mosquito bioassay is considered toxic; in the United States (Florida, Hawaii), detection of the toxin at any level by immunoassay renders the fish unmarketable. Two primary features render toxin surveillance difficult: performance problems of the assays and impracticality of surveying every fish.

Sustainable and Safe Seafood Initiatives

Recently, there have been numerous initiatives by private, nonprofit, organizations to promote practices that will result in sustainable fisheries, restoration of marine ecosystems, and safer seafood arriving to markets. These initiatives include the industry-centric FishWise (www.fishwise.org), which encourages sustainable use of fisheries by educational and certification programs primarily directed toward producers/harvesters, distributors, and retailers in the industry. In addition, FishWise publishes a periodically updated list of fish containing a low level of mercury that is useful for both consumers and industry (Box 72-1). Other initiatives, such as those by Blue Ocean Institute (www.blueocean.org), include a more consumer-based focus with educational outreach that includes smartphone applications that provide instant, color-coded guides to sustainable seafood.

Ichthyosarcotoxism

The term ichthyosarcotoxism describes a variety of conditions arising as the result of poisoning by fish flesh. Many toxins are generally not destroyed by heat or gastric acid. Various toxins are found in the musculature, viscera, blood, skin, or mucous secretions of the fish. Further classification is based on the specific organ system poisoned—for example, ichthyocrinotoxins (glandular secretions), ichthyohemotoxins (blood), ichthyohepatotoxins (liver), ichthyootoxins (gonads), ichthyoallyeinotoxins (hallucinatory), and gempylotoxins (purgative).

Ichthyocrinotoxication

Ichthyocrinotoxic fish poisoning is induced by ingestion of glandular secretions not associated with a specific venom apparatus; this usually involves skin secretions, poisonous foams, or slimes. Examples of these toxic fish are certain filefish, puffer fish, porcupinefish, trunkfish, boxfish, cowfish, lampreys, moray eels, and toadfish (Box 72-2). Cyclostome poisoning results from ingestion of the slime and flesh of certain lampreys and hagfishes. Pahutoxin and homopahutoxin have been isolated from secretions of the Japanese boxfish Ostracion immaculatus.159

Ichthyotoxic skin secretions may cause a bitter taste.177 Ingestion of ichthyocrinotoxins causes gastrointestinal symptoms within a few hours of ingestion, characterized by nausea, vomiting, dysenteric diarrhea, tenesmus, abdominal pain, and weakness. Most victims recover within 24 hours; however, some individuals have symptoms for up to 3 days. Therapy is supportive and based on symptoms. Additionally, some slime, such as “grammistin” from the soapfish (Rypticus saponaceus of the family Grammistidae), can cause contact irritant dermatitis.204 This dermatitis is managed with cool compresses of aluminum sulfate and calcium acetate (Domeboro). All suspect fish should be washed carefully with water or brine solution and skinned before being eaten.

Ichthyohepatotoxication

Ichthyohepatotoxic fish carry the toxin predominantly in the liver. The remainder of the fish may be nontoxic. Fish that are always toxic fall into two basic groups: (1) Japanese perch–like fish (e.g., mackerel, seabass, porgy, sandfish) and (2) tropical sharks (e.g., requiem fish, sleeperfish, cowfish, great white shark, catfish, hammerhead, angelfish, Greenland fish, dogfish).361 In addition, some skates and rays, whose phylogeny is similar to that of sharks, harbor ichthyohepatotoxins.

Ingestion of the Japanese perch–like fish group causes onset of symptoms within the first hour, with maximal intensity over the ensuing 6 hours.436 Symptoms include nausea, vomiting, headache, flushing, rash, fever, and tachycardia. No fatalities have been reported.

Ingestion of tropical shark liver (and occasionally of the musculature), such as that of the Greenland shark (Somniosus microcephalus), results in “elasmobranch poisoning” (Box 72-3).25 Symptoms are noted within 30 minutes of ingestion and include nausea, vomiting, diarrhea, abdominal pain, malaise, diaphoresis, headache, stomatitis, esophagitis, muscle cramps, arthralgias, paresthesias, hiccups, trismus, hyporeflexia, ataxia, incontinence, blurred vision, blepharospasm, delirium, respiratory distress, coma, and death. Recovery varies from several days to weeks. If only the flesh is eaten, the symptoms are mild and gastroenteric, with spontaneous resolution.

In 1993, 200 people in Madagascar were poisoned after ingesting a single shark identified as Carcharhinus leucas. They all experienced symptoms, and 30% died. Two liposoluble toxins were isolated from the shark liver and named carchatoxin-A and carchatoxin-B.46 Trimethylamine oxide, found in shark liver and flesh, has also been implicated in shark poisoning.13 A similar syndrome has occurred in sled dogs that ingest large quantities of shark flesh.

Therapy is supportive and based on symptoms. If the victim is treated within 60 minutes of ingestion of shark liver or other viscera, gastrointestinal decontamination with activated charcoal (50 to 100 g [1.8 to 3.6 ounces]) may be of value. Fish liver or any shark viscera should not be eaten. However, drying the flesh properly may minimize the toxicity.

Specific Fish-Related Toxic Syndromes

Three specific toxic syndromes related to fish consumption are scombroid, tetrodotoxin (puffer fish) poisoning (both described in Table 72-1), and grass carp gallbladder poisoning.

Scombroid

Scombroid, the most commonly reported seafood poisoning in the United States, occurs after eating fish with high levels of accumulated histamine or other biogenic amines. The first report of scombroid poisoning was published in 1830 and involved five sailors who consumed bonito fish, a member of the Scombridae family, hence the name of the syndrome.276 Other members of the family Scombridae include albacore, bluefin and yellowfin tuna, mackerel, saury, needlefish, wahoo, and skipjack. Non-Scombridae fish that produce scombroid include mahi-mahi (dolphin-fish), kahawai, sardine, black marlin, pilchard, anchovy, herring, amberjack (yellowtail or kahala), and the Australian ocean salmon Arripis truttaceus.313,417,433,462 Most of these fish species are rich in free histidine in their muscle tissues.216 Scombroid poisoning accounts for 3% of food-related outbreaks reported to the Centers for Disease Control and Prevention (CDC) in Atlanta.80 Underreporting is likely because of the short duration of illness and its resemblance to an allergic reaction. Because greater numbers of previously considered nonscombroid fish are now recognized as “scombrotoxic,” Prescott377 has suggested that the syndrome be more appropriately called pseudoallergic fish poisoning.

Pathophysiology

During conditions of inadequate preservation or refrigeration, the musculature of dark-fleshed or red-muscled fish undergoes bacterial decomposition.33,361 The normal surface bacteria Proteus morganii, Klebsiella pneumoniae, Aerobacter aerogenes, Escherichia coli, Alcaligenes metalcaligenes, and others have been implicated in the putrefactive process, which includes decarboxylation of the amino acid L-histidine to histamine and saurine (a phosphate salt of histamine).462 This most often occurs when fish is held at ambient or high temperatures for several hours.113 The term saurine originated because of the association of scombrotoxism with saury, a Japanese dried fish delicacy.214 Because of this process, “scombrotoxin” was initially thought to be histamine, which is commonly found in large amounts in the flesh of the fish usually implicated. Evidence initially suggesting that histamine may be the causative toxin of scombroid fish poisoning was presented in an investigation of a small outbreak.327 The urinary excretion of histamine and its metabolite, N-methylhistamine, was measured in three persons in this series who had scombrotoxism after ingestion of marlin. There was no increase in the principal metabolite of prostaglandin D2 (a mast cell secretory product considered to indicate release of histamine from mast cells), supporting the hypothesis that the excess histamine was from the fish rather than endogenously produced in the victims. Histamine levels greater than 20 to 50 mg/100 g are frequently noted in scombrotoxic fish, and it is not unusual to record levels in excess of 400 mg/100 g.417 However, it is possible that some other compound may be responsible for scombroid symptoms, because the syndrome cannot be reproduced solely by administration of equal or even massive doses of histamine by the oral route. Histamine is rapidly inactivated by enzymes in the gastrointestinal tract and on first pass through the liver, with very little reaching systemic circulation. Other compounds, such as cadaverine or putrescine, may be present in the decomposed fish flesh and may either facilitate the absorption or inhibit the gastrointestinal or hepatic degradation of histamine.396,462 Whatever the causative toxin, it is heat stable and not destroyed by cooking. Affected fish typically have a sharply metallic or peppery taste but may be normal in appearance and color. Not all persons who eat a scombrotoxin- or histamine-contaminated fish become ill, possibly because of uneven distribution of decay within the fish.

Clinical Presentation

The effects of scombroid fish poisoning occur within minutes after consumption of the fish. The symptoms are similar to an allergic reaction (which it is not) and typically include headache, diffuse erythema, sense of warmth without elevation in core temperature, nausea, vomiting, diarrhea, abdominal cramps, conjunctival injection, pruritus, dizziness, and burning sensation in the mouth and oropharynx.30,246,313 Flushing of the head, neck, and upper torso is characteristic. Severe effects, such as bronchospasm, generalized urticaria, hypotension, palpitations, and dysrhythmias, have been reported but are not frequent.174,214 In most healthy victims, the syndrome is self-limited, resolving within 6 to 12 hours. In rare cases, symptoms can persist beyond 24 hours.216 In patients with preexisting respiratory or cardiac disease, the effects of the poisoning can precipitate more severe illness.49,313 Scombroid reactions may be markedly more severe in patients taking isoniazid (INH) because of this compound’s blockade of gastrointestinal tract histaminase.485 Death has never been reported after scombroid poisoning. Assays of histamine and its metabolite in urine samples of scombroid-poisoned patients demonstrated elevated levels compared to controls, although histamine measurement is neither common clinical practice nor recommended. Histamine levels poorly correlate with clinical manifestations and do not affect management decisions.

Treatment

Gastric decontamination for scombroid poisoning is not indicated because symptoms occur rapidly and vomiting can be a primary effect of the toxin. Symptoms can be lessened or controlled with administration of histamine-1 (H1) receptor antagonists, such as diphenhydramine or hydroxyzine, administered initially in doses of 25 to 50 mg orally or intravenously. Histamine-2 (H2) receptor antagonists (e.g., cimetidine, famotidine) have also been shown to relieve most of the symptoms; perhaps a combination of H1 and H2 receptor antagonists would be most effective.44,188 Vomiting is usually controlled by an antihistamine, but occasionally requires addition of a specific antiemetic, such as ondansetron. The persistent headache of scombroid poisoning may respond to cimetidine or a similar drug if standard analgesics are not effective.18 Intravenous fluids and inhaled bronchodilators should be used as needed. Vasopressors are rarely necessary because hypotension is usually mild and responds to intravenous fluid administration. Corticosteroids are generally not indicated, because this illness is a toxic reaction and not immune mediated.

Prevention

The only effective method for prevention of scombroid fish poisoning is consistent temperature control at <−40° F (≤4.4° C) at all times between catching and consumption.113 It has been difficult to reduce the occurrence of scombroid poisoning in the United States; recreational catches likely plays a major role.216 No fish should be consumed if it has been handled improperly or has the smell of ammonia. Fresh fish generally has a sheen or oily rainbow appearance; “dull” packaged fish should be avoided. If an episode of scombroid poisoning is recognized, it is important to report it promptly to local public health authorities to prevent additional exposures, particularly if the food was served in a public eating establishment.215

Tetrodotoxin Poisoning

Tetrodotoxin (TTX) is a potent neurotoxin found in a variety of creatures and has been isolated from animals of four different phyla, including puffer fish, California newt, blue-ringed octopus, poison dart frogs, ivory shell, and trumpet shell. TTX is characteristic of the order Tetraodontiformes.449 The suborder Tetrodontoidei contains three families of fish (Tetraodontidae, Diodontidae, and Canthigasteridae), including puffer fish (toadfish, blowfish, globefish, swellfish, balloonfish, toado) and porcupinefish. Sunfish (Mola species) are members of the suborder Moloidei. Tetrodotoxin was named around 1911 after searching for the active ingredient in fugu ovaries.156 Isolation of the chemical was achieved in the 1950s. In the 1970s, the major toxin in certain poison dart frogs was identified as TTX. Crystalline TTX was isolated in 1978. The puffer fish is one of the better-recognized species that contains TTX. These fish can be found in both fresh and salt water and can inflate their bodies to a nearly spheric shape using air or seawater.193 Human TTX poisonings have also occurred after consumption of gastropod mollusks.523 Envenomation from the blue-ringed octopus is rare.150

Puffer fish poisoning has been recognized for millennia. Ancient Asian literature documents the dangers of eating puffer fish.193 There are references to puffer fish in hieroglyphics of the ancient Egyptian dynasty of 2700 BC. Scholars suggest this fish was known to be poisonous during Egyptian times. Mosaic sanitary laws against eating fish without fins and scales may have been derived to avoid fish containing TTX; the TTX-containing fish in the region inhabited by the Israelites were scaleless.193

Captain James Cook, the British explorer, recorded in 1774 his experience after eating a piece of liver from a puffer fish purchased from a native fisherman during his voyages in the Pacific Ocean.495 Before preparing the fish for eating, it was described and drawn. Cook tasted the liver and wrote of a vivid feeling of extraordinary weakness and numbness.193 There has been some contention that TTX (also known as puffer powder) was used as a component of Haitian voodoo potion in the zombie ritual.475 This has been challenged on grounds, among others, that under the usual conditions of extreme alkaline storage, any TTX in a “zombie potion” would be decomposed irreversibly into pharmacologically inactive products.243,526

In humans, the most common exposure to TTX is through the ingestion of fugu, a special preparation of puffer fish.73 Sporadic cases have been reported in the United States.84 In Japan, chefs must undergo a rigorous certification process before they are allowed to prepare fugu. Fillet of the puffer fish contains very minute concentrations of TTX. Fugu is served raw with paper-thin slices placed into an ornate configuration. The presence of small quantities of TTX gives the desired effect of slight oral tingling. Importation of fugu into the United States is illegal, but smuggling has resulted in cases of poisoning. At least 50 of the more than 100 species of these fish have been involved in poisonings of humans or may be intermittently toxic.395 Many nonfish species also contain TTX (Box 72-4).

Many years ago, when TTX was thought to be found exclusively in pufferfish, it was controversial whether TTX was endogenous. It is now known that TTX is accumulated through the food chain, in a several-step process starting with marine bacteria as the primary source of TTX.342 TTX may be produced by Pseudomonas species that live on the skin of the puffer fish.533 This would explain the transmittal of toxicity between toxic and nontoxic fish through skin contact. Other investigators have found that Vibrio and other species isolated from the intestines of puffer fish produce TTX.502 The exact origin of TTX in the food chain, however, remains unknown. The distribution of TTX in pufferfish appears to be species-specific. In general, the liver and ovaries have the highest toxicity, followed by intestines and skin.342 Female fish are considered more toxic than are males because there are especially high concentrations of TTX in ovaries. Musculature is less toxic, but still may contain a significant amount of TTX. The toxin is heat stable and not inactivated by freezing. There occurs seasonal variation of TTX concentration, with peak levels during spawning season. TTX is likely accumulated as a biologic defense agent.342

Pathophysiology

Tetrodotoxin blocks the action potentials in nerves by binding to the pores of the voltage-gated, fast sodium channels in nerve cell membranes. TTX has a unique nonprotein structure and is widely used as a research tool to study sodium channels. Mouse bioassays demonstrate that the minimal lethal dose of TTX by intraperitoneal injection is 8 to 20 mg/kg.328 The interaction of TTX with the sodium channel is thought to be stoichiometric, with each TTX molecule interfering with one channel. TTX affects the spike-generating process of sodium channels, not the resting or steady-state voltage.242

TTX interferes with both central and peripheral neuromuscular transmission. Although it is not a depolarizing agent, in animals it causes depression of the medullary respiratory mechanism, intracardiac conduction, and myocardial and skeletal muscle contractility. At the microcellular level, the mechanism of action of TTX is linked to the axon rather than to the nerve endplate. TTX blocks axonal transmission by interfering with sodium conductance within the depolarized regions of the cell membrane, perhaps by acting at a metal cation binding site in the sodium channel, without affecting presynaptic release of acetylcholine or its effects on the neuromuscular junction.4,207 There is no apparent effect on potassium permeability.393 Saxitoxin, implicated in paralytic shellfish poisoning, has essentially the same action as does TTX on the nerve membrane, although it is believed to have a discrete receptor.246 The poison in freshwater puffers may be composed of TTX or saxitoxin, the predominant toxin depending on the species. The LD50 (dose at which 50% die) for mice is 10 mg/kg when TTX is administered by intraperitoneal, intravenous, or subcutaneous routes.473

Animal studies suggest that TTX has a peripheral effect that results in vasodilation independent of α- or β-adrenergic receptors.226,245,292 Further studies suggest a dose-dependent action. At low doses, systemic blood pressure is lowered, although perfusion pressure is initially maintained. Higher doses of TTX result in a profound fall in blood pressure.242 Experiments with animal models using TTX from blue-ringed octopi demonstrate similar profound hypotension. Agonists (norepinephrine or phenylephrine) have been the most effective agents in raising blood pressure in models of TTX poisoning.150

Clinical Presentation

Clinical manifestations typically develop within 30 minutes of ingestion but may be delayed by up to 4 hours. During a 2002 outbreak in Bangladesh of 37 people (from eight families) who were poisoned from inadequately prepared puffer fish, 31 of the victims developed symptoms within two hours and eight died.2 Death has been recorded within 17 minutes of exposure. The extent and type of symptoms vary according to the individual and amount of TTX ingested. Usually, paresthesias of the lips and tongue are followed by several signs as mild as diaphoresis, to life-threatening, such as hypotension, respiratory failure, and coma.84 Other commonly described symptoms include weakness, headache, body paresthesias, and gastrointestinal symptoms such as nausea, vomiting, and abdominal pain. Hypersalivation, ataxia, cyanosis, dysphagia, aphonia, dyspnea, blurred vision, bronchorrhea, and bronchospasm have also been described.2,84,93 Early miosis may progress to mydriasis with poor pupillary light reflex.473 A disseminated intravascular coagulation-like syndrome is heralded by petechial skin hemorrhages that can progress to bullous desquamation and diffuse stigmata of prolonged coagulation. Hypotension can be profound and may be refractory to treatment. Bradycardia and atrioventricular node conduction abnormalities may be present. Complete cardiovascular collapse with respiratory paralysis precedes death. Normal consciousness may be maintained until shortly before death.156,473 In some older reports, 60% of victims died, most within the first 6 hours. Survival past 24 hours is a good prognostic sign.

Treatment

Treatment of TTX is primarily supportive with aggressive airway management and assisted ventilation.429 Decontamination should be considered with 1 g/kg of activated charcoal given as soon as practical following presentation. Atropine may be used to treat bradycardia in conjunction with adequate oxygenation (SaO2 > 92%). Intravenous fluid resuscitation should be initiated for hypotension; however, use of vasopressors may be required to maintain perfusion. α-Agonists such as phenylephrine or norepinephrine are more likely to be effective. No antidote is currently available to treat TTX poisoning; however, studies are ongoing.

Cholinesterase inhibitors, such as edrophonium and neostigmine, have been used to treat victims of TTX poisoning with mixed results. Some case reports have suggested subjective improvement in neurologic symptoms after administration of cholinesterase inhibitors.90,473 A recent case series suggested that neostigmine may help overcome respiratory muscle paralysis, which is the predominant cause of death.90 Other case reports noted no improvement after infusion of these compounds.2,301,470 Antihistamines and steroids have also been utilized without clear benefit.301

A minor intoxication with TTX may be limited to paresthesias and mild dysphagia. In such a case, the victim should be observed in the emergency department or intensive care unit for at least 8 hours to detect deterioration, particularly in respiratory function. The victim should not be discharged until the symptoms are clearly improving. Although water soluble, TTX is very difficult to remove from fish, even by cooking. It is prudent to avoid all puffers, even when prepared by an expert.

Grass Carp Gallbladder Poisoning

Fish gallbladder has long been used as a folk remedy in China and southeast Asia. In a case series of 17 patients from Vietnam, the most common reason for ingestion was for symptoms of arthritis.522 The toxin is found in the bile of freshwater fish of the family Cyprinidae. Grass carp (Ctenopharyngodon idellus) accounts for 80% of freshwater gall bladder poisoning in China.267 Serious illness is attributed to the nephrotoxic and hepatotoxic properties of a toxin found in the bile.85 The toxic ingredient is 5-α-cyprinol sulfate, a 27-carbon salt, which is heat stable and not destroyed by ethanol.18,263 Most cases have occurred in Hong Kong, Taiwan, and South Korea. Two cases were reported in the United States in immigrants who ate raw gallbladders from carp caught in Maryland.70 One of the patients required hemodialysis for acute renal failure.

Several hours after ingestion, abdominal pain, nausea, vomiting, and watery diarrhea develop. This can be accompanied by marked elevations in concentrations of liver enzymes (aspartate and alanine aminotransferases).118 The hepatitis is usually self-limited, although fulminant liver failure has been reported in one patient. It was unknown if this patient had underlying liver disease prior to the intoxication.522 Nephrotoxicity occurs in moderate to severe poisonings and may be profound, leading to oliguric or nonoliguric renal failure within 48 to 72 hours after ingestion.398,522 Renal and liver biopsies demonstrate acute tubular necrosis and hepatocellular injury. With appropriate supportive care, including dialysis, patients typically recover. Acute renal failure accounts for more than 80% of deaths, although mortality rate has declined, likely due to advances in intensive care and renal salvage therapy.267