In one of the many unforgettable cases I have had in the ED, there was a young patient who presented with nausea and vomiting. The interesting part of this case was the medication request – mannitol. I for sure thought the team had come back from CT where they discovered a huge intracranial hemorrhage with midline shift. I ran to the ED with the medication fully expecting the team to be mid-intubation. Catching my breath, I asked what the mannitol was for? The resident responded with, “Ciguatera poisoning!”
Ciguatera was something I never heard in my practice prior to moving to Miami (admittedly, I never used mannitol other than for managing increased ICPs). Ciguatera fish poisoning (CFP) is the most common worldwide fish poisoning. Annually, anywhere from 10,000 to 500,000 cases are reported; however, the true incidence is difficult to determine due to underreporting (1-3). It is the most common fish-related foodborne illness reported in the United States. CFP arises from ingesting fish containing ciguatoxin (CTX) and is not prevented by any storage, handling, or cooking method.
Microscopic algae, known as dinoflagellates from the Gambierdiscus spp., produce ciguatoxins (CTX), a class of tasteless, heat-stable, polycyclic toxins. These dinoflagellates grow on seaweed, living and dead coral, and other substrates in shallow tropical and subtropical waters (3). They are ingested by herbivorous reef fish, which in turn are consumed by larger carnivorous fish, with the latter serving as the primary source of human illness. CTXs are lipid-soluble and bioaccumulate through the food chain, having larger concentrations in larger carnivorous fish in tropical, pelagic (open) waters (these fish are more likely to cause toxicity in humans; however, ingestion of any reef fish may cause harm). There are case reports of passage of CFP as a result of human-to-human transmission through sexual intercourse and from nursing mother to infant and pregnant mother to fetus.
Examples of Fish Containing Ciguatoxin
Greater than 500 species of fish are associated with CFP. Examples of fish implicated in causing CFP are listed above. This poisoning is endemic in tropical and subtropical areas, particularly in the Caribbean and Indo-Pacific regions; however, due to international seafood trade, travel, and climate change, CFP is increasingly encountered in non-endemic regions (2, 3, 5, 6).
Photo credit: Kloss and Bruce. Video Flashcard: Ciguatoxin
CTX is tasteless, colorless, and odorless. It is not affected by any food storage or preparation techniques as it is heat and acid stable, and is stable for at least 6 months at commercial freezing temperatures (3-4). Interfering with neuronal voltage-gated sodium channels, CTXs render sodium channels open at resting membrane potential, causing an influx of sodium, which results in uncontrolled membrane depolarization and repetitive action potentials. Neuronal potassium channels may also be inhibited. The sodium influx draws water into the neurons and as animal evidence illustrates, results in axonal edema at the nodes of Ranvier. This swelling impairs saltatory conduction along the axon, slowing sensorimotor conduction velocities. Edema may also occur in Schwann cells and myelin fibers, affecting nerve conduction. Intracellular calcium also increases, disrupting cell-ion exchange mechanisms, producing fluid secretion and diarrhea (3, 5, 6)
Gastrointestinal (GI), neurological, and cardiovascular symptoms may occur and could begin as early as 6 hours post-ingestion. GI symptoms usually begin within 6 to 12 hours and may resolve spontaneously within 1 to 4 days. The most commonly reported GI symptom is diarrhea. Other symptoms include abdominal pain, nausea, and vomiting. Neurological symptoms present within the first 2 days of illness, often becoming more prominent after GI symptoms. These symptoms begin appearing within 24 hours post ingestion, but may be delayed up to 72 hours. Symptoms include paresthesias in the limb extremities and circumoral regions, metallic taste, pruritus, myalgias, and arthralgias. Sensation of loose teeth, headache, and dizziness may also occur. One of the coolest symptoms (no pun intended) is cold allodynia, which is pathognomonic for ciguatera toxicity. This distinctive neurologic symptom causes a reversal of temperature sensation: cold feels hot and hot feels cold. In essence, when a patient touches something cold it causes a burning sensation or dysesthesia, an unpleasant, abnormal sensation. Coma and hallucinations have also been reported. Neurological symptoms may persist for months and up to years. Cardiovascular symptoms generally manifest in the early stage of the illness and present as bradycardia and hypotension (2-7).
Diagnosis of CFP consists of presenting symptoms, time course, history of eating reef fish, and the exclusion of other diagnoses (particularly other marine ingestion toxicities such as paralytic and neurotoxic shellfish poisonings, scombroid, and tetrodotoxin). Scombroid, another common fish poisoning, is associated with oceanic fish, with symptoms largely attributed to histamine reaction (swelling, flushing, hives, etc.). Other items on the differential include botulism, enterovirus, bacteremia, and organophosphate poisoning. CFP also shares clinical features with polyneuropathies such as multiple sclerosis. Currently, the gold standard for the confirmation of CFP is the detection of CTX in the flesh of the consumed fish. CTX may be detected in fish flesh through a number of assays; however, these tests are rarely available to the treating physician and are not completed in a timely fashion that would impact acute clinical management (2-6).
Management of CFP is largely supportive, treating hypovolemia with intravenous fluids, correcting electrolyte abnormalities, and using atropine in instances of bradycardia. Mannitol may also be used in the treatment of CFP. The use of mannitol is two-fold: (1) to reduce symptoms in the acute phase of illness (primarily neurologic symptoms); and (2) shorten the duration of symptoms beyond the acute phase. The beneficial effects of mannitol is thought to be attributed to the osmotic reduction of neuronal edema. Mannitol may also act as a scavenger of free radicals produced by CTX, may reduce the action of CTX at sodium and/or potassium channels, and may increase dissociation of CTX from its binding site. Mannitol is an osmotic diuretic, therefore, patients must be adequately resuscitated prior to initiating therapy. Mannitol is dosed at 0.5 - 1 g/kg (commonly 1 g/kg), is administered over 30 - 45 minutes, and should be given within 48 - 72 hours of toxic fish ingestion, although benefits have been observed weeks after ingestion (2-5).
The use of mannitol began in the 1980s, when 2 patients were treated with mannitol for presumed cerebral edema due to ciguatera poisoning. The ciguatera symptoms quickly and unexpectedly improved. This serendipitous discovery led to the use of mannitol in 22 additional patients with presumed CTX exposure. Mannitol was administered as 1 g/kg in this case series. This total group of patients consisted of 9 women and 15 men, ranging in age from 6 to 66 years of age. Mannitol was administered if the following criteria were met: paresis, vomiting severe enough to require fluid replacement, diarrhea at a frequency greater than one time per one and a half hours, muscle pain restricting ambulation, and hypotension requiring therapy (8).
After receiving mannitol, 18 out of 24 patients were released from the ED or hospital within 24 hours, 4 hospitalized for 48 hours, and 2 patients were hospitalized for 7 days. The mean time of symptom onset to mannitol administration was 10 hours in 21 patients. In 17 of 23 patients, all neurologic and neurosensory symptoms responded to mannitol within 10 minutes, and were completely resolved within 48 hours. The mean time to complete resolution of neurological symptoms of all cases was 10 hours. The authors concluded that mannitol should be considered in patients with signs and symptoms consistent with CFP (8).
When reviewing the evidence beyond the case series by Palafox et. al., much of the literature is anecdotal and reported in case reports and case series. There are two randomized trials comparing mannitol to other therapies. One trial by Bagnis et. al. compared mannitol to a combined infusion of glucose, calcium gluconate, pyridoxine, and ascorbic acid. In this study, patients who received mannitol had greater improvement in symptoms compared to the combination therapy (2, 6).
The other trial was a single center, randomized, double-blind trial by Schnorf et. al., that compared mannitol to normal saline for patients presenting with suspected CFP. This study found similar rates of the resolution of symptoms between mannitol and normal saline groups; however, there were limitations to this trial. Patients were treated all the way up to 672 hours post exposure (for maximal benefit, it is recommended to treat within the initial 48 to 72 hours), only observed for 24 hours (benefits may be seen 48 to 72 hours after the administration of mannitol), and was not known if this was the initial episode of CFP, as subsequent episodes could be more severe (2, 6, 9)
As a result, through case studies, case series, and anecdotal reports, mannitol should be considered for patients presenting with CFP that present within 48 to 72 hours of exposure. Patients presenting beyond 72 hours should be evaluated on a case by case basis prior to administering mannitol. Always consult your poison center for poisonings and overdoses at 1-800-222-1222.
When patients present with nausea and vomiting in the ED, don’t just brush off the symptoms as typical - always inquire if they have had any seafood, and what type - it could be ciguatera.
Ruben Santiago, PharmD, BCPS, BCCCP
Associate Residency Program Director, Emergency Medicine
Jackson Memorial Hospital
Miami, FL Twitter: @thepeoplesruben
Reviewed and edited by: Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)
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