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PALYTOXIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Palytoxin is a potent marine toxin isolated first from the zoanthid coral genus Palythoa. Also referred to as a type of ciguatera poisoning, palytoxin is found in ciguateric fish. It is a water-soluble polyether compound with a molecular weight of 2678.5.

Specific Substances

    A) SYNONYMS
    1) PTX
    2) Lima-make-o-Hana
    3) Molecular Formula: C129-H223-N3-O54
    4) CAS 11077-03-5
    5) Fish poisoning Palytoxin
    SPECIES ASSOCIATED WITH PALYTOXIN
    1) Palythoa toxica
    2) Zoanthid coral
    3) Blue humphead parrotfish
    4) Ostreopsis species
    5) Parrotfish, blue humphead
    6) Radianthus macrodactylus
    7) Serranid fish
    8) Xanthid crab

Available Forms Sources

    A) FORMS
    1) Palytoxin, a potent marine toxin isolated from marine coelenterates, consists of a long aliphatic, partially unsaturated chain with interspersed cyclic ether, hydroxyl and carboxyl groups. It is a large molecule containing 64 chiral centers and is a natural product (Kan et al, 2001; Frelin & Van Renterghem, 1995).
    B) SOURCES
    1) Palytoxin is a potent marine toxin isolated first from the zoanthid coral genus Palythoa. Also referred to as a type of ciguatera poisoning, palytoxin is found in ciguateric fish which inhabit tropical and subtropical seas rich in coral and also in at least two species of xanthid crab and the red alga, Chondria aramata (Budavari, 1996; Frelin & Van Renterghem, 1995). Palytoxin poisoning from serranid fish has been reported in Japan(Taniyama et al, 2002).
    2) Palytoxin was also isolated from Radianthus macrodactylus, a sea anemone, via high performance liquid chromatography (Mahnir et al, 1992).
    3) In Greece, the first report of shellfish contamination by a palytoxin-like compound has been observed. Bivalve mollusks found in the Eastern Mediterranean Sea contained putative palytoxin (p-PLT) by the natural presence of Ostreopsis species. At present, no reports of human toxicity have occurred, and may be due in part to ongoing biotoxin monitoring which limits shellfish harvesting and possible exposure to contaminated shellfish (Aligizaki et al, 2008).
    4) Palytoxin poisoning has been reported following an inadvertent skin injury (small cuts to several fingers) while cleaning a home aquarium containing zoanthid coral (Parazoanthus sp.) (Hoffmann et al, 2008).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) CDC CASE DEFINITIONS
    a) BACKGROUND
    1) Harmful algal blooms (HABs) are fast growing algae that are found worldwide, which can have a negative impact on the environment, as well as the health and safety of humans and animals. As part of the ongoing efforts by the Centers for Disease Control and Prevention (CDC), the Harmful Algal Bloom-related Illness Surveillance System (HABISS) collects data on the effects to human and animal health due to the potential environmental impact of HABs. The CDC has developed case definitions for HABs toxin-related diseases as part of their national surveillance efforts to support public health decision-making. The following information has been created to identify pertinent information related to a potential exposure to HABs. For further information regarding the reporting of suspected human illness due to HABs, please contact Lorraine C. Backer, PhD, MPH, Senior Scientist and Team Lead, National Center for Environmental Health, CDC, Atlanta, GA at lfb9@cdc.gov or Rebecca LePrell, MPH, HABISS Coordinator, National Center for Environmental Health, CDC, at gla7@cdc.gov
    b) ACUTE TOXICITY
    1) Abdominal pain, nausea, vomiting, diarrhea, and a metallic taste in the mouth are prominent early symptoms. Other signs and symptoms include: acute respiratory distress, tachycardia, skeletal muscle tonic contractions, muscle pain, myoglobinuria, rhabdomyolysis, hemolysis, seizures, paresthesias, dysesthesia, dizziness, elevated liver enzyme levels, cyanosis, bradycardia, and renal failure. Respiratory failure due to myopathy has resulted in death.
    c) CHRONIC SYMPTOMS (Greater than 3 months)
    1) Palytoxin is a tumor promotor.
    d) FATALITY RATE
    1) At the time of this review, the fatality rate has not been established.
    e) TIME TO SYMPTOM ONSET
    1) Rapid
    f) DURATION
    1) The duration of symptoms is not well established. In one small case series (n=11), recovery times lasted for over one month, following ingestion of contaminated grouper.
    g) ROUTE OF EXPOSURE
    1) Consumption of contaminated crabs or finfish, possibly inhaling aerosols, and possible cutaneous or mucous membrane exposure to certain zoanthids of the genus Palythoa, particularly if the dermis is compromised.
    h) CAUSATIVE ORGANISM
    1) Ostreopsis species have been implicated as the ultimate source of palytoxin. The compound was first isolated from zoanthids in the genus Palythoa.
    i) TOXIN
    1) Palytoxin (PTX), a non-proteinaceous, complex terpenoid marine coelenterate toxin isolated from the zoanthid coral of the genus Palythoa.
    j) DOSE
    1) LD50 in humans is estimated to be 0.15 mcg/kg (e.g. approximately one-quarter of a contaminated crab or 3 contaminated fish livers).
    k) VECTOR
    1) Crab and finfish inhabiting tropical and subtropical seas rich in coral, particularly in the Pacific areas. Some possible vectors include aerosols generated by aquariums and coral culture facilities and certain zoanthids of the genus Palythoa.
    2) Clupeotoxism is a rare and serious illness caused by consumption of normally edible sardines and herrings (Clupeidae) or anchovies (Engaulidae). Clupeotoxism is now considered to be due to palytoxin and/or congeners.
    l) MECHANISM
    1) Palytoxin is a sodium-potassium channel activator and an extremely potent vasoconstrictor, affecting all muscle types. A depolarization occurs in cells with sodium entering the cells in exchange for potassium.
    m) LIKELY GEOGRAPHIC DISTRIBUTION
    1) Palytoxin can be found in tropical and subtropical seas rich in coral reefs, the Mediterranean Sea, and aquariums and coral culture facilities.
    n) DIFFERENTIAL DIAGNOSIS
    1) Other marine toxin poisonings (e.g. neurotoxic, paralytic, diarrheic or azaspiracid shellfish poisoning), scombroid fish poisoning, pesticide poisoning including organophosphate poisoning, cholinesterase inhibitor poisoning, microbial food poisonings and food allergies may have potentially similar clinical findings.
    o) SUSPECT CASE
    1) Consumption of fish in tropical or subtropical areas AND acute symptoms noted above, particularly a metallic or bitter taste soon after ingestion, severe muscle pain, myoglobinuria, elevated creatine phosphokinase level, and elevated liver enzyme levels.
    2) Dermal contact with a zoanthid, resulting in swelling and numbness, and possibly systemic effects.
    p) CONFIRMED CASE
    1) Suspect case along with laboratory confirmation of palytoxin in meal remnants, preferably via liquid chromatography-mass spectrometry, if available.
    q) ANIMAL SENTINEL DATA
    1) Early signs of palytoxin exposure in dogs include defecation and vomiting.
    r) REFERENCE
    1) (HABISS Work-Group et al, Jan 12, 2009)
    0.2.20) REPRODUCTIVE
    A) Palytoxin has caused a dose-dependent contraction of the human umbilical artery.
    0.2.21) CARCINOGENICITY
    A) Palytoxin is a known tumor promoter.

Laboratory Monitoring

    A) Monitor vital signs and oxygenation.
    B) Evaluate for hemolysis: hemoglobin/hematocrit and urinalysis; urine myoglobin plasma free hemoglobin in patients with evidence of hemolysis.
    C) Monitor SGOT, LDH and CPK, to evaluate for muscle damage.
    D) Monitor serum electrolytes, specifically sodium and potassium concentrations, and renal function.
    E) Chromatographic methods for detecting palytoxin are used in research and food safety monitoring.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Oral absorption of palytoxin appears to be very rapid. Activated charcoal should only be used in rare cases where it can be administered soon after ingestion. No specific antidote is available. Supportive measures are useful in poisonings where seizures, respiratory distress, or cardiovascular compromise is seen.
    B) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    C) RHABDOMYOLYSIS: Administer sufficient 0.9% saline (10 to 15 mL/kg/hour) to maintain urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hr). Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output, but should only be considered if urine output is inadequate after volume status is restored. Urinary alkalinization is NOT routinely recommended.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: The LD50 in humans is estimated to be 0.15 mcg/kg. Palytoxin is usually encountered via ingestion of marine foodstuffs. As little as one quarter of a crab or 3 fish livers may produce serious reactions if contaminated.

Clinical Effects

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Acute poisonings resulted in dyspnea and shallow and rapid breathing (Sud et al, 2013; Kodama et al, 1989; Alcala et al, 1988).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) Fever and chills have been reported in patients after inhalational exposure to anemones of the Palythoa species (Davey et al, 2015; Sud et al, 2013; Bernasconi et al, 2012).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) A rise in systemic blood pressure may be seen after an initial decrease (Walker et al, 1977).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) 300 mg/24H produced a severe reaction in animals (RTECS , 2002).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) Metallic taste has been noted (Alcala et al, 1988).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Bradycardia has been reported in acute poisonings. Palytoxin is a known potent coronary vasoconstrictor.
    b) MECHANISM: Palytoxin exerts a cardiotonic effect in cardiac muscle. A depolarization of excitable membranes, including cardiac muscle, occurs (Kodama et al, 1989; Alcala et al, 1988).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Myocardial damage has been induced following consumption of palytoxin, a toxin found in blue humphead parrotfish (Okano et al, 1998).
    b) CASE REPORT: Negative T waves in leads III and aVf of an electrocardiogram have been reported following ingestion of palytoxin-containing fish. Echocardiography was normal during the clinical course. Serum CK-MB isozyme was reported to be 8.0% on the fourth hospital day (Okano et al, 1998).
    C) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia has been reported after inhalational exposure to palytoxin aerosolized from Palythoa corals (Davey et al, 2015; Sud et al, 2013).
    b) CASE REPORT: INHALATION: A 32-year-old man presented to the emergency department with a heart rate of 120 beats/minute, chest pain, and shortness of breath after inhaling steam emitted from a Palythoa coral that he had removed from his aquarium and drenched with boiling water in an attempt to kill it. He reported symptom onset immediately after inhalation. At presentation, his respiratory rate was 24 breaths/minute and his blood pressure was 140/80 mmHg. A 12-lead ECG revealed sinus tachycardia at 110 bpm without ST-T wave changes; QRS and QTc intervals were normal. Chest X-ray was negative for infiltrates or pneumothorax. A metabolic panel and cardiac enzymes showed no abnormalities. He was treated with 3 doses of nebulized albuterol, which relieved his shortness of breath but the chest pain remained. He was admitted for observation and discharged 24 hours later without sequelae (Majlesi et al, 2008).
    c) CASE REPORT: A 32-year-old man presented with hyperthermia, dyspnea, severe myalgias, vomiting, and an oral metallic taste about 5 hours after removing 70 pounds of Zoanthid coral out of an aquarium with his brother and leaving it exposed at home. His vital signs included a temperature of 39.2 degrees C, tachycardia (135 beats/min), tachypnea (28 breaths/min), and normal blood pressure and saturation (96% room air). Laboratory results were normal except for leukocytosis. The next day, his vital signs were normal, but he continued to have myalgias and dyspnea 2 days after discharge. His wife and brother developed headache, dyspnea, and myalgias a day after exposure. Lethargy and vomiting were also observed in his dog and cat (Davey et al, 2015).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DYSRHYTHMIA
    a) Direct cardiotoxicity resulting in atrioventricular block, extrasystoles, ventricular tachycardia, coronary vasoconstriction and ventricular fibrillation is seen in intact animals.
    1) Following an initial drop in blood pressure, a subsequent rise in blood pressure is seen, as well as changes in both the shape and rhythm of the ECG, notably, an S-T segment elevation corresponding to coronary vasoconstriction (Walker et al, 1977).
    2) VASOSPASM
    a) Coronary vasoconstriction has been shown in animals (Walker et al, 1977). Palytoxin is an extremely potent vasoconstrictor, affecting all muscle types. A depolarization occurs in cells with sodium entering the cells in exchange for potassium (Hirata et al, 1988).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY DISTRESS
    1) WITH POISONING/EXPOSURE
    a) Acute poisonings have resulted in dyspnea and shallow and rapid breathing (Davey et al, 2015; Kodama et al, 1989; Alcala et al, 1988).
    b) OSTREOPSIS SPECIES: Respiratory distress has been associated with toxins of the ostreopsis species including putative palytoxin (Pistocchi et al, 2012).
    c) Respiratory failure associated with muscular destruction over a 4-day period has resulted in death (Noguchi et al, 1987).
    d) CASE REPORT (INHALATION): A 32-year-old man presented to the emergency department with shortness of breath, chest pain, and tachycardia after inhaling steam emitted from a Palythoa coral that he had removed from his aquarium and drenched with boiling water in an attempt to kill it. He reported symptom onset immediately after inhalation. At presentation, his respiratory rate was 24 breaths/minute; however, his oxygen saturation was 100% on room air. Wheezing was noted to all lung fields. Other than tachycardia, ECG and Chest X-ray were within normal limits. He was treated with 3 doses of nebulized albuterol, which relieved his shortness of breath but the chest pain remained. He was admitted for observation and discharged 24 hours later without sequelae (Majlesi et al, 2008).
    e) CASE SERIES (INHALATION): Palytoxin-induced acute pneumonitis developed in 3 patients (age range: 21 to 23 years) after inhalational exposure to anemones of the Palythoa species. All patients presented with dyspnea at rest, dry cough, nausea, headache, fever, and chills within 2 hours of installing a home aquarium and placing a piece of dead coral decorated with crust sea anemones on the bottom. One patient had seasonal asthma and had been using an on-demand short-acting bronchodilator and another was an occasional cigarette smoker. The arterial blood gas analysis of all patients revealed severe hypoxemia. In addition, all 3 patients had a marked leukocytosis and a mild increase in lactate dehydrogenase plasma concentration. On admission day, all chest x-rays were normal. On day 2, CT scans of the chests showed zones of patchy, pleural-based consolidation at both lung bases. On day 3, a pulmonary function test revealed a restrictive ventilatory pattern and a normal diffusion capacity. Mild diffuse bronchial swelling with clear bronchial secretion were observed on flexible bronchoscopy. All 3 patients recovered by day 3 following supportive care. On follow-up visit 2 weeks later, all pulmonary function tests were normal (Bernasconi et al, 2012).
    f) CASE SERIES: Four adults and 2 children developed respiratory distress (eg, chest tightness, shortness of breath, cough), myalgias, paresthesias, low-grade fevers and chills, and gastrointestinal symptoms (eg, nausea and vomiting) after inhalational exposure to palytoxin aerosolized from Palythoa corals. All patients recovered following supportive care (Sud et al, 2013).
    1) A 32-year-old man presented to the ED complaining of shortness of breath and chest tightness shortly after attempting to kill a Palythoa coral in his saltwater aquarium. He doused the oral with boiling water and subsequently inhaled the liberated steam after which his symptoms began. The patient's vital signs upon admission included an elevated HR (120 beats/min) and elevated respiratory rate (24 breaths/min). His physical examination showed scattered wheezing in all lung fields, and an ECG showed sinus tachycardia at 126 beats/min. Furthermore, a complete blood count showed a WBC count of 21,000/mcl (normal range: 3500 to 10,500/mcl. Following supportive care, including 3 doses of nebulized albuterol, his symptoms improved, but his chest tightness persisted. He was discharged after 24 hours with no other sequelae (Sud et al, 2013).
    2) Approximately 6 hours after cleaning a fish tank, a professional fish tank cleaner (a 42-year-old man), presented to the ED with shortness of breath. He had poured boiling water over a Palythoa coral and experienced shortness of breath immediately upon exposure to the liberated steam. He had a temperature of 101 degrees F and treated himself with OTC oral N-acetylcysteine and vitamin C before presentation. His temperature increased to 103 degrees F in the ED and his laboratory results revealed leukocytosis (16,000/mcl). He was treated with nebulized albuterol with some relief before leaving against medical advice (Sud et al, 2013).
    3) A 51-year-old man developed a dry cough shortly after being in close proximity of his fish tank while it was being cleaned. He presented to the ED 8 hours later when his cough worsened and he began to develop chills, myalgias, and fatigue. He was externally decontaminated by showering although his dry cough continued to worsen. He refused nebulized albuterol citing it causes migraine headaches. He continued to experience chills, myalgias, and fatigue during his 3-day hospital stay. His labs revealed leukocytosis peaking on day 2 (27,600/mcl) and elevated lactate dehydrogenase on admission (292 Units/L) but was normalized by day 3 (Sud et al, 2013).
    4) A 35-year-old woman developed a dry cough shortly after inhalational exposure to liberated steam from a nearby fish tank that was being cleaned. She presented to the ED 8 hours after exposure with dry cough, chills, myalgias, fatigue, and paresthesias in both upper extremities. She was externally decontaminated upon arrival to the ED although she developed nausea and had one episode of non-bilious, non-bloody vomiting. She continued to experience myalgias, fatigue, and nausea during her 3-day hospital stay, with some mild wheezing on day 2. Her white blood cell count peaked on hospital day 1 (16,400/mcl) and her admission CPK was mildly elevated (197 Units/L) but both trended down by day 3. She was told to avoid breastfeeding her 2-month-old child due to lack of data of palytoxin excretion in breast milk. Her symptoms improved 2 days after discharge (Sud et al, 2013).
    5) A 3-year-old boy developed a dry cough immediately after inhalational exposure to liberated steam from a nearby fish tank being cleaned. He also developed one episode of non-bilious, non-bloody vomiting and became extremely fatigue; his fatigued worsened which prompted a visit to the ED 8 hours after exposure. He underwent external decontamination and vital signs included elevated temperature (103.5 degrees F), HR (154 beats/min), and respiratory rate (34 breaths/min). The patient's labs measured leukocytosis peaking at day 2 (35,400/mcl) and an elevated LDH (331 Units/L), both of which trended down by hospital day 3. Patient was completely asymptomatic by hospital day 3 and was discharged accordingly (Sud et al, 2013).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) TREMOR
    1) WITH POISONING/EXPOSURE
    a) Palytoxin may cause a depolarization of muscle or nerve membranes, producing tremors and muscle spasms (Kodama et al, 1989). It also has been shown to induce norepinephrine release from adrenergic neurons (Habermann, 1989).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures have been reported in several patients (Noguchi et al, 1987; Kodama et al, 1989).
    C) FATIGUE
    1) WITH POISONING/EXPOSURE
    a) Generalized weakness has been reported following exposure (Sud et al, 2013; Hoffmann et al, 2008; Alcala et al, 1988; Kodama et al, 1989).
    D) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) GENERAL: Both circumoral and limb paresthesias have been reported by patients (Sud et al, 2013; Nordt et al, 2009; Kodama et al, 1989; Hoffmann et al, 2008), as has numbness (Alcala et al, 1988; Hoffmann et al, 2008).
    b) Dysesthesia (temperature reversal) may occur (Alcala et al, 1988).
    c) CASE REPORT: A 25-year-old woman, with intact skin, developed perioral paresthesia, metallic taste and hives (without respiratory involvement) shortly after handling a zoanthid coral contained in a home saltwater aquarium. The paresthesia resolved within 24 hours, but persistent edema and erythema of the hands required medical intervention. The patient completely recovered with supportive care (Nordt et al, 2009).
    d) CASE REPORT: A 32-year-old man developed paresthesia and numbness of the fingers after a dermal injury from contact with zoanthid coral (contaminated with high concentrations of palytoxin) while cleaning a home aquarium. Symptoms spread to the whole arm over the next 20 hours, but all symptoms resolved within 48 hours. At follow-up 4 weeks later, no persistent findings were reported (Hoffmann et al, 2008).
    E) FEELING NERVOUS
    1) WITH POISONING/EXPOSURE
    a) Restlessness may be seen in poisonings (Alcala et al, 1988).
    F) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) Dizziness may be seen in poisonings (Hoffmann et al, 2008; Alcala et al, 1988).
    G) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache has been reported in patients after inhalational exposure to anemones of the Palythoa species (Bernasconi et al, 2012).
    H) SLURRED SPEECH
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Speech disturbance was noted in an adult after collapsing approximately 18 hours after inadvertent dermal contact with zoanthid coral contaminated with high concentrations of palytoxin. All symptoms resolved within 48 hours and the patient had no recurring symptoms (Hoffmann et al, 2008).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEUROPATHY
    a) Palytoxin causes a depolarization of the membranes of myelinated fibers, spinal cord and squid axons. It also causes a release of norepinephrine from clonal rat pheochromocytoma cells (Tatsumi et al, 1984).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH POISONING/EXPOSURE
    a) Nausea, vomiting, abdominal cramps, and diarrhea are prominent early symptoms (Davey et al, 2015; Sud et al, 2013; Bernasconi et al, 2012; Alcala et al, 1988; Kodama et al, 1989).
    B) METALLIC TASTE
    1) WITH POISONING/EXPOSURE
    a) Metallic taste was reported in a woman shortly after handling a zoanthid coral. Her skin was intact at the time of exposure (Nordt et al, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Elevated liver enzymes, notably, CPK, LDH and SGOT may occur (Sud et al, 2013; Bernasconi et al, 2012; Kodama et al, 1989; Noguchi et al, 1987; Okano et al, 1998).
    b) CASE REPORT: Serum AST was elevated to 3,370 IU/L on the third day after ingestion of a fish containing palytoxin, and serum LDH was elevated to 7,100 IU/L on the fourth day in a 55-year-old man (Okano et al, 1998).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) MYOGLOBINURIA
    1) WITH POISONING/EXPOSURE
    a) Palytoxin poisoning has produced a dark brown urine (probably due to myoglobinuria), anuria, and renal failure (Alcala et al, 1988).
    b) Myoglobinuria has been seen in affected patients (Noguchi et al, 1987).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Both humans and animals have shown potassium release from erythrocytes, followed within hours by hemolysis (Ahnert-Hilger et al, 1982; Ozaki et al, 1984).
    B) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) Leukocytosis has been reported in patients after inhalational exposure to anemones of the Palythoa species (Davey et al, 2015; Sud et al, 2013; Bernasconi et al, 2012; Majlesi et al, 2008).
    b) CASE REPORT: INHALATION: A 32-year-old man developed leukocytosis with a WBC of 21,000 after inhaling steam emitted from a Palythoa coral that he had removed from his aquarium and drenched with boiling water in an attempt to kill it. He presented to the emergency department with chest pain, shortness of breath, wheezing, and tachycardia. With the exception of tachycardia, his ECG was normal. Further analysis showed that chest x-ray, metabolic panel, and cardiac enzymes were within normal limits. After receiving 3 doses of nebulized albuterol, his shortness of breath was relieved but the chest pain remained. He was admitted for observation and discharged 24 hours later without sequelae (Majlesi et al, 2008).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEMOLYSIS
    a) Palytoxin has caused a temperature dependent potassium loss from rat erythrocytes which is followed within hours by hemolysis (Ahnert-Hilger et al, 1982).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) WITH POISONING/EXPOSURE
    a) Potent skin irritation has been demonstrated (Nordt et al, 2009; Fujiki et al, 1986).
    B) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Excessive sweating was seen in a patient reported by (Kodama et al, 1989), and cold sweats in a patient reported by (Alcala et al, 1988).
    C) WEAL
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 25-year-old woman, with intact skin, developed perioral paresthesia, metallic taste and hives (without respiratory involvement) on her torso and extremities after handling a zoanthid coral contained in a home aquarium. The following day the urticarial rash was present bilaterally on her arms, thighs, abdomen, upper chest and back, along with edema and erythema of both hands. The patient was treated symptomatically with an intravenous histamine antagonist and corticosteroids; no permanent sequelae occurred (Nordt et al, 2009).
    D) CHILL
    1) WITH POISONING/EXPOSURE
    a) Shivering, myalgia and general weakness were reported in an adult approximately 2 hours after a dermal injury from contact with zoanthid coral (contaminated with high concentrations of palytoxin) while cleaning a home aquarium (Hoffmann et al, 2008).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IRRITATION
    a) 250 nanograms/4H caused a moderate reaction in rabbits (RTECS , 2002).
    2) SKIN DISORDER
    a) An increase in histidine decarboxylase activity occurred in mouse skin after application of Palytoxin (Kitamura et al, 1983).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) INCREASED MUSCLE TONE
    1) WITH POISONING/EXPOSURE
    a) Contractile responses are seen in both smooth and skeletal muscle (Kodama et al, 1989).
    b) A spinal seizure-like syndrome with tonic contractions of all muscle groups has developed within 48 hours (Kodama et al, 1989).
    B) MUSCLE PAIN
    1) WITH POISONING/EXPOSURE
    a) Severe muscle spasms, muscle pain and cramps have been experienced following exposure (Davey et al, 2015; Sud et al, 2013; Kodama et al, 1989; Noguchi et al, 1987). One adult experienced, myalgia approximately 2 hours after a dermal injury from contact with zoanthid coral (contaminated with high concentrations of palytoxin) while cleaning a home aquarium (Hoffmann et al, 2008).
    C) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Rhabdomyolysis may be induced following ingestion of palytoxin-poisoned fish. A 55-year-old man reported to the hospital with weakness and myalgia of his extremities 5 hours after eating the raw meat and liver of a blue humphead parrotfish. On the third day, a serum CK of 40,000 IU/L was reported. Serum aldolase and myoglobin and urinary myoglobin were elevated. Rhabdomyolysis was diagnosed.
    1) Following mannitol-alkaline diuresis once daily for 4 days, the patient recovered. Weakness and myalgias disappeared within 4 weeks (Okano et al, 1998).

Immunologic

    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ALLERGIC REACTION
    a) Histamine is released from rat mast cells in a bell-shaped response curve (Chatwal et al, 1982).

Reproductive

    3.20.1) SUMMARY
    A) Palytoxin has caused a dose-dependent contraction of the human umbilical artery.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) LABOR ABNORMAL
    1) A dose-dependent contraction of the umbilical artery has resulted in humans (Ishida et al, 1985).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Palytoxin is a known tumor promoter.
    3.21.3) HUMAN STUDIES
    A) NEOPLASM
    1) Even at low levels, palytoxin may be a threat because of its high potency as a tumor promoter (Fukui et al, 1987).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Palytoxin has demonstrated anticancer activity against Ehrlich ascites tumor and P-388 lymphocytic leukemia in mice (Quinn et al, 1974) Walker, 1977).

Genotoxicity

    A) An unscheduled DNA synthesis has occurred in human lung cells.
    B) Cell Type: lung; Dose: 1 pmol/L (RTECS , 2002).

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) CDC CASE DEFINITIONS
    a) BACKGROUND
    1) Harmful algal blooms (HABs) are fast growing algae that are found worldwide, which can have a negative impact on the environment, as well as the health and safety of humans and animals. As part of the ongoing efforts by the Centers for Disease Control and Prevention (CDC), the Harmful Algal Bloom-related Illness Surveillance System (HABISS) collects data on the effects to human and animal health due to the potential environmental impact of HABs. The CDC has developed case definitions for HABs toxin-related diseases as part of their national surveillance efforts to support public health decision-making. The following information has been created to identify pertinent information related to a potential exposure to HABs. For further information regarding the reporting of suspected human illness due to HABs, please contact Lorraine C. Backer, PhD, MPH, Senior Scientist and Team Lead, National Center for Environmental Health, CDC, Atlanta, GA at lfb9@cdc.gov or Rebecca LePrell, MPH, HABISS Coordinator, National Center for Environmental Health, CDC, at gla7@cdc.gov
    b) ACUTE TOXICITY
    1) Abdominal pain, nausea, vomiting, diarrhea, and a metallic taste in the mouth are prominent early symptoms. Other signs and symptoms include: acute respiratory distress, tachycardia, skeletal muscle tonic contractions, muscle pain, myoglobinuria, rhabdomyolysis, hemolysis, seizures, paresthesias, dysesthesia, dizziness, elevated liver enzyme levels, cyanosis, bradycardia, and renal failure. Respiratory failure due to myopathy has resulted in death.
    c) CHRONIC SYMPTOMS (Greater than 3 months)
    1) Palytoxin is a tumor promotor.
    d) FATALITY RATE
    1) At the time of this review, the fatality rate has not been established.
    e) TIME TO SYMPTOM ONSET
    1) Rapid
    f) DURATION
    1) The duration of symptoms is not well established. In one small case series (n=11), recovery times lasted for over one month, following ingestion of contaminated grouper.
    g) ROUTE OF EXPOSURE
    1) Consumption of contaminated crabs or finfish, possibly inhaling aerosols, and possible cutaneous or mucous membrane exposure to certain zoanthids of the genus Palythoa, particularly if the dermis is compromised.
    h) CAUSATIVE ORGANISM
    1) Ostreopsis species have been implicated as the ultimate source of palytoxin. The compound was first isolated from zoanthids in the genus Palythoa.
    i) TOXIN
    1) Palytoxin (PTX), a non-proteinaceous, complex terpenoid marine coelenterate toxin isolated from the zoanthid coral of the genus Palythoa.
    j) DOSE
    1) LD50 in humans is estimated to be 0.15 mcg/kg (e.g. approximately one-quarter of a contaminated crab or 3 contaminated fish livers).
    k) VECTOR
    1) Crab and finfish inhabiting tropical and subtropical seas rich in coral, particularly in the Pacific areas. Some possible vectors include aerosols generated by aquariums and coral culture facilities and certain zoanthids of the genus Palythoa.
    2) Clupeotoxism is a rare and serious illness caused by consumption of normally edible sardines and herrings (Clupeidae) or anchovies (Engaulidae). Clupeotoxism is now considered to be due to palytoxin and/or congeners.
    l) MECHANISM
    1) Palytoxin is a sodium-potassium channel activator and an extremely potent vasoconstrictor, affecting all muscle types. A depolarization occurs in cells with sodium entering the cells in exchange for potassium.
    m) LIKELY GEOGRAPHIC DISTRIBUTION
    1) Palytoxin can be found in tropical and subtropical seas rich in coral reefs, the Mediterranean Sea, and aquariums and coral culture facilities.
    n) DIFFERENTIAL DIAGNOSIS
    1) Other marine toxin poisonings (e.g. neurotoxic, paralytic, diarrheic or azaspiracid shellfish poisoning), scombroid fish poisoning, pesticide poisoning including organophosphate poisoning, cholinesterase inhibitor poisoning, microbial food poisonings and food allergies may have potentially similar clinical findings.
    o) SUSPECT CASE
    1) Consumption of fish in tropical or subtropical areas AND acute symptoms noted above, particularly a metallic or bitter taste soon after ingestion, severe muscle pain, myoglobinuria, elevated creatine phosphokinase level, and elevated liver enzyme levels.
    2) Dermal contact with a zoanthid, resulting in swelling and numbness, and possibly systemic effects.
    p) CONFIRMED CASE
    1) Suspect case along with laboratory confirmation of palytoxin in meal remnants, preferably via liquid chromatography-mass spectrometry, if available.
    q) ANIMAL SENTINEL DATA
    1) Early signs of palytoxin exposure in dogs include defecation and vomiting.
    r) REFERENCE
    1) (HABISS Work-Group et al, Jan 12, 2009)

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and oxygenation.
    B) Evaluate for hemolysis: hemoglobin/hematocrit and urinalysis; urine myoglobin plasma free hemoglobin in patients with evidence of hemolysis.
    C) Monitor SGOT, LDH and CPK, to evaluate for muscle damage.
    D) Monitor serum electrolytes, specifically sodium and potassium concentrations, and renal function.
    E) Chromatographic methods for detecting palytoxin are used in research and food safety monitoring.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor SGOT, LDH and CPK, as indicators of muscle damage.
    4.1.3) URINE
    A) URINALYSIS
    1) Urinalysis positive for blood but with few or no RBC's is an early indication of hemolysis. Monitor for myoglobinuria.

Methods

    A) CHROMATOGRAPHY
    1) Isolation of palytoxin may be accomplished using successive column chromatography or thin layer chromatography (Fukui et al, 1987; Noguchi et al, 1987; Alcala et al, 1988).
    B) SPECTROMETRY
    1) Kan et al (2001) described a NMR spectrometry method (using methanol as a solvent) in addition to gradient enhancement and 3D Fourier transform to elucidate hydrogen and carbon NMR signals of palytoxin.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient suspected of ingesting palytoxin should be monitored in a controlled setting until all signs and symptoms of toxicity have subsided.

Monitoring

    A) Monitor vital signs and oxygenation.
    B) Evaluate for hemolysis: hemoglobin/hematocrit and urinalysis; urine myoglobin plasma free hemoglobin in patients with evidence of hemolysis.
    C) Monitor SGOT, LDH and CPK, to evaluate for muscle damage.
    D) Monitor serum electrolytes, specifically sodium and potassium concentrations, and renal function.
    E) Chromatographic methods for detecting palytoxin are used in research and food safety monitoring.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Oral absorption of palytoxin appears to be very rapid.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Oral absorption of palytoxin appears to be very rapid.
    2) Activated charcoal may be useful if administered roughly within 30 minutes of ingestion. Because of the intense diarrhea and potential electrolyte imbalances caused by palytoxin, cathartics are not recommended.
    3) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    4) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor oxygenation, hemoglobin, hematocrit, plasma free hemoglobin, urinalysis and perhaps other indices of hemolysis.
    2) Monitor serum enzymes, specifically, CPK, LDH and SGOT for severity of muscle damage.
    3) Monitor urine for myoglobinuria. A dark brown urine may be indicative of myoglobinuria.
    4) Monitor serum electrolytes, specifically sodium and potassium levels.
    B) SUPPORT
    1) Frequent monitoring of vital signs and support of vital functions (pulse, blood pressure, respirations) may be required.
    C) HEMOLYSIS
    1) Transfusion of blood or packed red blood cells may be required.
    2) Urine alkalinization with sodium bicarbonate and maintenance of an adequate urine output may help to prevent renal damage from RBC breakdown products.
    D) AIRWAY MANAGEMENT
    1) If CNS and respiratory depression occur, ensure airway patency and adequacy of oxygenation and ventilation. Endotracheal intubation, supplemental oxygenation, and assisted ventilation could be required.
    E) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    7) PHENYTOIN/FOSPHENYTOIN
    a) Benzodiazepines and/or barbiturates are preferred to phenytoin or fosphenytoin in the treatment of drug or withdrawal induced seizures (Wallace, 2005).
    b) PHENYTOIN
    1) PHENYTOIN INTRAVENOUS PUSH VERSUS INTRAVENOUS INFUSION
    a) Administer phenytoin undiluted, by very slow intravenous push or dilute 50 mg/mL solution in 50 to 100 mL of 0.9% saline.
    b) ADULT DOSE: A loading dose of 20 mg/kg IV; may administer an additional 5 to 10 mg/kg dose 10 minutes after loading dose. Rate of administration should not exceed 50 mg/minute (Brophy et al, 2012).
    c) PEDIATRIC DOSE: A loading dose of 20 mg/kg, at a rate not exceeding 1 to 3 mg/kg/min or 50 mg/min, whichever is slower (Loddenkemper & Goodkin, 2011; Prod Info Dilantin(R) intravenous injection, intramuscular injection, 2013).
    d) CAUTIONS: Administer phenytoin while monitoring ECG. Stop or slow infusion if dysrhythmias or hypotension occur. Be careful not to extravasate. Follow each injection with injection of sterile saline through the same needle (Prod Info Dilantin(R) intravenous injection, intramuscular injection, 2013).
    e) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over next 12 to 24 hours for maintenance of therapeutic concentrations. Therapeutic concentrations of 10 to 20 mcg/mL have been reported (Prod Info Dilantin(R) intravenous injection, intramuscular injection, 2013).
    c) FOSPHENYTOIN
    1) ADULT DOSE: A loading dose of 20 mg phenytoin equivalent/kg IV, at a rate not exceeding 150 mg phenytoin equivalent/minute; may give additional dose of 5 mg/kg 10 minutes after the loading infusion (Brophy et al, 2012).
    2) CHILD DOSE: 20 mg phenytoin equivalent/kg IV, at a rate of 3 mg phenytoin equivalent/kg/minute, up to a maximum of 150 mg phenytoin equivalent/minute (Loddenkemper & Goodkin, 2011).
    3) CAUTIONS: Perform continuous monitoring of ECG, respiratory function, and blood pressure throughout the period where maximal serum phenytoin concentrations occur (about 10 to 20 minutes after the end of fosphenytoin infusion) (Prod Info CEREBYX(R) intravenous injection, 2014).
    4) SERUM CONCENTRATION MONITORING: Monitor serum phenytoin concentrations over the next 12 to 24 hours; therapeutic levels 10 to 20 mcg/mL. Do not obtain serum phenytoin concentrations until at least 2 hours after infusion is complete to allow for conversion of fosphenytoin to phenytoin (Prod Info CEREBYX(R) intravenous injection, 2014).
    F) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
    G) HYPOTENSIVE EPISODE
    1) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    2) ISOPROTERENOL INDICATIONS
    a) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
    b) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
    c) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    3) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    H) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    I) BRADYCARDIA
    1) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) EFFICACY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Abstracts

Case Reports

    A) ACUTE EFFECTS
    1) A 49-year-old man, living in the Philippines, became ill within minutes after eating about one-fourth of a crab (Demania reynaudii) containing palytoxin. Initial symptoms exhibited were dizziness, tiredness, nausea, cold sweats, and a metallic taste in his mouth. Shortly thereafter, he complained of numbness of the extremities, restlessness, vomiting, and severe muscle cramps. Upon hospitalization, the patient suffered from alternating periods of normal heart rate and severe bradycardia (30 beats/min), rapid and shallow breathing, cyanosis around the mouth and hands, and anuria, leading to renal failure. The patient was treated with atropine, diphenhydramine, meperidine, and epinephrine which apparently failed to provide relief to this patient. He died about 15 hours after ingestion (Alcala et al, 1988).
    B) ADVERSE EFFECTS
    1) A 54-year-old man and a 79-year-old woman ingested a parrotfish (Ypiscarus ovifrons) in Japan which contained palytoxin. On admission to the hospital, both patients exhibited signs of dyspnea, myalgia, convulsions and myoglobinuria. Elevated serum levels of CPK, LDH and SGOT were seen in both patients. The man recovered within 7 days; however, the woman patient died in 4 days from respiratory arrest associated with muscle destruction (Noguchi et al, 1987).
    C) ADULT
    1) CONTAMINATED MACKEREL: A previously healthy 35-year-old man ate 2 smoked mackerel which were contaminated with palytoxin. Within a few hours he showed signs of ciguatera poisoning, including excessive sweating, weakness, abdominal cramps, diarrhea, nausea, and circumoral paresthesia, as well as paresthesia of the extremities, temperature reversal, muscle spasms and tremor. The patient was hospitalized when the muscle spasms worsened to become uncontrollable tonic contractions of all muscle groups, which occurred about 48 hours after ingestion. Because of extreme respiratory distress, the patient was intubated. The patient's CPK, LDH and SGOT levels were extremely elevated, reflecting muscle spasm severity. His urine was reported to be dark brown, most probably due to myoglobinuria. The patient was hospitalized for 9 days and given only symptomatic therapy (Kodama et al, 1989).

Range Of Toxicity

Summary

    A) TOXICITY: The LD50 in humans is estimated to be 0.15 mcg/kg. Palytoxin is usually encountered via ingestion of marine foodstuffs. As little as one quarter of a crab or 3 fish livers may produce serious reactions if contaminated.

Minimum Lethal Exposure

    A) TOXICITY
    1) The LD50 in humans is estimated to be 0.15 mcg/kg body weight (Kodama et al, 1989).

Maximum Tolerated Exposure

    A) Palytoxin is usually encountered via ingestion of contaminated marine foodstuffs. As little as one quarter crab or 3 fish livers may produce serious reactions.
    B) DERMAL EXPOSURE
    1) CASE REPORT: A 25-year-old woman with intact skin developed palytoxin poisoning (i.e., perioral paresthesia, metallic taste and hives on her torso and extremities) after handling a zoanthid coral contained in a home aquarium. The following day the urticarial rash was present bilaterally on her arms, thighs, abdomen, upper chest and back, along with edema and erythema of both hands. The patient was treated symptomatically with an intravenous histamine antagonist and corticosteroids; no permanent sequelae occurred (Nordt et al, 2009).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 50 ng/kg (RTECS , 2002a)
    2) LD50- (INTRAMUSCULAR)RAT:
    a) 240 ng/kg (RTECS , 2002a)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 710 ng/kg (RTECS , 2002a)
    4) LD50- (INTRATRACHEAL)RAT:
    a) 360 ng/kg (RTECS , 2002a)
    5) LD50- (ORAL)RAT:
    a) >40 mcg/kg (RTECS , 2002a)
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 400 ng/kg (RTECS , 2002a)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) MUSCLE - A contractile response in both smooth and skeletal muscle is seen due to a slow and irreversible depolarization of the plasma membrane in skeletal muscle cells by inducing an inward, Na+ dependent current (Frelin & Van Renterghem, 1995; Hirata et al, 1988).
    B) HEART - A cardiotonic effect in cardiac muscle and a depolarization of muscle membranes is seen (Hirata et al, 1988).
    C) NEURONS - Norepinephrine is released from adrenergic neurons (Hirata et al, 1988).
    D) RBC'S - Potassium is released from erythrocytes (Hirata et al, 1988).

Toxicologic Mechanism

    A) CARDIAC TOXICITY -
    1) Palytoxin causes a depolarization and a decrease in the amplitude, upstroke velocity and duration of action potential in papillary muscle. These effects appear to be due to an increase in the sodium permeability of the cardiac cell membrane. The depolarization of the plasma membrane drives Na+ into the cells, thus promoting Ca++ influx by L-type Ca++ channels and by the Na+/Ca++ exchanger. A direct action on the cardiac muscle membrane due to an increase in calcium permeability occurs (Frelin & Van Renterghem, 1995; Hirata et al, 1988).
    2) Evidence suggests that palytoxin probably binds with sodium, potassium-ATPase at ouabain receptor sites. An ion pump is converted to an open ion channel and the ion gradient across the membrane collapses (Kodama et al, 1989; Hirata et al, 1988; Ozaki et al, 1984).
    B) NEURONAL CELLS -
    1) In neuronal cells, palytoxin depolarizes the plasma membrane by increasing its Na+ permeability. With depolarization and an influx of Na+, a promotion of Ca++ influx by voltage dependent Ca++ channels and Na+/Ca++ exchange occurs (Frelin & Van Renterghem, 1995).
    2) With higher concentrations, palytoxin stimulates neurotransmitter release via pheochromocytoma cells and brain synaptosomes independently of circulating external Na+. This implies an action independent of the membrane depolarization, of voltage dependent Ca++ channels or of Na+/Ca++ exchange activity (Frelin & Van Renterghem, 1995).
    3) It has been suggested that palytoxin may acidify cells, thus resulting in Na+ influx by the Na+/H+ antiporter and possibly Ca++ influx by the Na+/Ca++ antiporter (Frelin & Van Renterghem, 1995). In cardiac cells, this may alter the functioning of the Na+/Ca++ exchanger and lead to dysrhythmias.
    C) BLOOD VESSELS -
    1) Following an intravenous palytoxin injection in animals, a profound vasoconstriction, an increase in systemic blood pressure, massive pulmonary hypertension and death are reported. The vascular actions of palytoxin are directed towards 3 cell types: vascular smooth muscle cells, nerve terminals and vascular endothelial cells. A depolarization of the plasma membrane opens L-type Ca++ channels, promotes Ca++ influx and contractions (Frelin & Van Renterghem, 1995).
    a) Perivascular nerve terminals undergo membrane depolarization and release of norepinephrine, which on turn binds to alpha-1-adrenoceptors on smooth muscle cells and induces a contraction through an activation of phospholipase C, the mobilization of intracellular Ca++ stores and the activation of protein kinase (Frelin & Van Renterghem, 1995).
    b) Palytoxin acts on vascular endothelial cells probably by the release of NO. It also induces the release of prostaglandins from the aorta (Frelin & Van Renterghem, 1995).
    D) Palytoxin converts Na+/K+ pumps into nonselective cationic channels, possibly by disrupting the normal strict coupling by opening one access pathway in the Na+/K+ ATPase and closing the other(Artigas & Gadsby, 2003).
    E) The N-terminus of the Na(+), K(+)-ATPase alpha-subunit acts as an inactivation gate of palytoxin-induced pump channel(Wu et al, 2003).

Physicochemical

Physical Characteristics

    A) Palytoxin is a white amorphous hygroscopic solid. It is soluble in water; it is insoluble in ether, chloroform, acetone and sparingly soluble in methanol and ethanol (Budavari, 1996).

Molecular Weight

    A) 2531.24 (RTECS , 2002)

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) Early signs of palytoxin poisoning in dogs include defecation and vomiting (Hirata et al, 1988).

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