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PLANTS-ACKEE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ackee is the common name for Blighia sapida. Because of the prevalence of this plant in Jamaica, poisonings by ackee are often called "Jamaican Vomiting Sickness". Poisoning generally occurs from ingesting the unripe fruit. The unripened fruit retains its toxicity even if cooked (Joskow et al, 2006; CDC, 1992).
    B) A similar syndrome has been associated with ingestion of renta yam (CDC, 1992).

Specific Substances

    1) ACKEE
    2) Blighia sapida (Konig)
    3) Isin
    4) Ishin
    5) Seso vegetal
    6) Akee
    7) Aki
    8) Arbre fricasse
    9) Akie
    10) Hypoglycin (related compound)
    11) 3-(methylenecyclopropyl)alanine (related compound)

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) DESCRIPTION: Ackee is a stiff-branched tree which has a trunk of up to 24 inches in diameter and grows to a height of 40 feet. The bark is gray and smooth. The leathery leaves are compound and pinnately divided, each having 6 to 10 thin, oblong shaped leaflets which are from 3 to 6 inches long and have a prominent middle vein. The small, greenish-white flowers form in clusters from the leaf stems. The fruit is a blunt, 3 sided, thick walled, leathery capsule 2 1/2 inches by 1 1/2 inches in diameter and pear shaped. These seeds are surrounded by an aril (fleshy coating) which is whitish in color, light textured and heavily impregnated with oil.
    B) TOXICOKINETICS: The primary toxic substances in ackees are 2 peptides called hypoglycin A (beta-methylene cyclopropyl-L-alpha-aminopropionic acid) and hypoglycin B (a dipeptide formed by hypoglycin A and glutamic acid) that are found in the arilli and seeds of the unripened fruit.
    C) EPIDEMIOLOGY: Most reported poisonings have occurred prior to 1955 and in Jamaica or the West Indies. Before 1957, the mortality rate was approximately 80%. Symptoms may be delayed for 2 to 6 hours, but once initiated, symptoms progress rapidly.
    D) WITH POISONING/EXPOSURE
    1) CLINICAL EVENTS: There are two main types of poisoning, the first where nausea and vomiting, often with quiescent periods, is replaced by drowsiness, vomiting, seizures, coma, and possibly death. The second being very similar to the first, but without the early nausea and vomiting. Hypoglycemia and hypotonia are also commonly reported effects following exposure.
    2) FATALITIES: In fatal cases the average time to death is 12.5 hours, but has been reported within 2 to 48 hours. One fatality was recorded as early as one hour after ingestion. Most of these cases involved patients who were underweight, had vitamin B deficiencies, angular stomatitis, glossitis, mosaic skin and hypochromotrichia. Of the limited data, children are also more likely to ingest the unripe fruit.
    0.2.7) NEUROLOGIC
    A) Coma is often seen in serious poisonings. Seizures may be seen either early or late in a poisoning. Clonic spasms or twitching of the limbs have also been described. Seizures occur in about 85% of all fatal cases.
    0.2.8) GASTROINTESTINAL
    A) Persistent vomiting is common. Diarrhea is usually absent, abdominal cramps/pain can occur.
    0.2.9) HEPATIC
    A) Hepatitis may develop.
    0.2.11) ACID-BASE
    A) Acidosis but not ketosis is often seen.
    0.2.12) FLUID-ELECTROLYTE
    A) Due to profuse vomiting, fluid and electrolyte abnormalities may exist.
    0.2.20) REPRODUCTIVE
    A) Hypoglycin A is teratogenic in rats and produces stunting and fetal resorptions in rabbits.

Laboratory Monitoring

    A) Blood sugar should be carefully monitored because severe hypoglycemia may occur.
    B) Fluid status should be monitored in all exposed patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression.
    B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    D) GLUCOSE: Intravenous glucose infusions have resulted in dramatic clinical recovery, but have also failed to prevent a fatality. Experiments have shown the action of hypoglycin is unlike that of insulin.
    E) FLUID AND ELECTROLYTE LOSS: Fluid and electrolytes should be monitored. Excessive loss may occur due to profuse vomiting.
    F) 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.
    G) RENAL FAILURE: Renal failure has been reported in some cases and may require hemodialysis.

Range Of Toxicity

    A) MINIMUM LETHAL DOSE: The seeds, fruit ball and aril of the unripe fruit and the arils of the underdeveloped fruit are toxic. The ripe aril is considered non-toxic, but a rancid aril may also cause problems. On a weight basis, unripe seeds have 5 to 10 times as much toxin as the pods. Fatalities were reported in preschool children following ingestion of unripe ackee fruit.
    B) CASE SERIES: In a case series of 8 previously healthy children, a young child died after ingesting 4 roasted ackee seeds and the remaining 7 children developed various gastrointestinal events at various time intervals following the ingestion of roasted seeds and arils. One of the surviving children, developed a loss of consciousness followed by vomiting, extreme body weakness and hypoglycemia.

Clinical Effects

Summary Of Exposure

    A) DESCRIPTION: Ackee is a stiff-branched tree which has a trunk of up to 24 inches in diameter and grows to a height of 40 feet. The bark is gray and smooth. The leathery leaves are compound and pinnately divided, each having 6 to 10 thin, oblong shaped leaflets which are from 3 to 6 inches long and have a prominent middle vein. The small, greenish-white flowers form in clusters from the leaf stems. The fruit is a blunt, 3 sided, thick walled, leathery capsule 2 1/2 inches by 1 1/2 inches in diameter and pear shaped. These seeds are surrounded by an aril (fleshy coating) which is whitish in color, light textured and heavily impregnated with oil.
    B) TOXICOKINETICS: The primary toxic substances in ackees are 2 peptides called hypoglycin A (beta-methylene cyclopropyl-L-alpha-aminopropionic acid) and hypoglycin B (a dipeptide formed by hypoglycin A and glutamic acid) that are found in the arilli and seeds of the unripened fruit.
    C) EPIDEMIOLOGY: Most reported poisonings have occurred prior to 1955 and in Jamaica or the West Indies. Before 1957, the mortality rate was approximately 80%. Symptoms may be delayed for 2 to 6 hours, but once initiated, symptoms progress rapidly.
    D) WITH POISONING/EXPOSURE
    1) CLINICAL EVENTS: There are two main types of poisoning, the first where nausea and vomiting, often with quiescent periods, is replaced by drowsiness, vomiting, seizures, coma, and possibly death. The second being very similar to the first, but without the early nausea and vomiting. Hypoglycemia and hypotonia are also commonly reported effects following exposure.
    2) FATALITIES: In fatal cases the average time to death is 12.5 hours, but has been reported within 2 to 48 hours. One fatality was recorded as early as one hour after ingestion. Most of these cases involved patients who were underweight, had vitamin B deficiencies, angular stomatitis, glossitis, mosaic skin and hypochromotrichia. Of the limited data, children are also more likely to ingest the unripe fruit.

Vital Signs

    3.3.3) TEMPERATURE
    A) HYPOTHERMIA is often present. Although in the initial phase of poisoning the body temperature may rise slightly, most cases maintain normal or subnormal temperature (Hill, 1952).
    B) In an epidemic of fatal encephalopathy in preschool children exposed to unripe ackee fruit in Africa, all parents reported that their child felt cold at the onset of symptoms. Most children died before receiving medical care, and actually temperature was not recorded (Meda et al, 1999).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) In one case series (n=12) of acute ackee fruit poisoning, 4 of 12 patients developed tachycardia (Resiere et al, 2001).

Neurologic

    3.7.1) SUMMARY
    A) Coma is often seen in serious poisonings. Seizures may be seen either early or late in a poisoning. Clonic spasms or twitching of the limbs have also been described. Seizures occur in about 85% of all fatal cases.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: A 9-year-old girl presented with an altered level of consciousness and lethargy of 21 hours duration. Symptoms developed approximately 2 hours after ingesting 6 roasted seeds and arils of ackee fruit. Vomiting occurred shortly after exposure. Initial treatment included IV fluids when she was transferred to a higher level of care and had a Glasgow Coma Score of 9. Laboratory studies were within normal limits with the exception of hypoglycemia which improved with 10% IV dextrose. The child gradually improved and was discharged on day 6 having fully recovered (Katibi et al, 2015).
    1) Seven other siblings also ate the fruit with 2 of the children eating 4 and 6 roasted ackee seeds, respectively. A 4-year-old child died at home after ingesting 6 seeds approximately 23 hours after ingestion. Another 9-year-old girl developed similar symptoms as the index case and was treated supportively and discharged to home on day 4 after ingesting 4 seeds. The remaining 5 children (between 4 and 10 years) ingested between 2 and 3 roasted seeds and aril and were initially asymptomatic. By day 4, they had developed intermittent abdominal pain and loose stools. No fever or vomiting occurred; laboratory studies were also normal. Each child received IV hydration and vitamin B complex and were discharged to home after 2 days. In these cases, toxicity appeared to be dose-dependent (Katibi et al, 2015).
    b) Coma is often develops in serious poisonings (Hill, 1952; CDC, 1992).
    c) In a retrospective cross-sectional study, coma was reported in 24 (41%) of 60 patients with acute ackee poisoning (Joskow et al, 2006).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures may develop either early or late in a poisoning. Clonic spasms and twitching of the limbs has also been described. Seizures occur in about 85% of all fatal cases (Hill, 1952). In another study of preschool children exposed to unripe ackee fruit, 27 (93%) children developed seizures (Meda et al, 1999).
    b) In one case series (n=12) of acute ackee fruit poisoning, 1 of 12 patients developed seizures (Resiere et al, 2001). In another study, seizures were reported in 18 (31%) of 60 patients with acute ackee poisoning (Joskow et al, 2006).
    c) Of 38 patients reported by CDC (1992), 8 of whom died, 24% developed seizures.
    C) TOXIC ENCEPHALOPATHY
    1) WITH POISONING/EXPOSURE
    a) WEST AFRICA: An epidemic of fatal encephalopathy was reported in Burkina Faso, west Africa, after the consumption of unripe ackee fruit in preschool children. Of the 29 cases reported, all died within 2 to 48 hours of exposure. The most common effects were hypotonia (97%), vomiting (66%), convulsions (93%), and coma (100%). Poisoning with unripe ackee fruit was suspected by the increased concentration of dicarboxylic acids (4 to 200 times higher) in the urine of cases as compared to controls (Meda et al, 1999).
    b) Ingestion of immature aril of ackee and other members of the soapberry family (Sapindaceae), including lychee, rambutan and longan by malnourished children has the potential to cause toxic hypoglycemic encephalopathy. The primary symptoms are associated with severe hypoglycemia and metabolic acidosis. Its suggested that outbreaks of acute encephalitis in children in Northern Vietnam could be associated with the harvesting of lychee (litchi) fruit rather than a viral etiology (Spencer et al, 2015).
    D) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) In one case series (n=12) of acute ackee fruit poisoning, the following neurological effects were reported: weakness and paresthesia (8/12), headache (4/12), drowsiness (2/12), and hypotonia (2/12)(Resiere et al, 2001).

Gastrointestinal

    3.8.1) SUMMARY
    A) Persistent vomiting is common. Diarrhea is usually absent, abdominal cramps/pain can occur.
    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Persistent vomiting is common (McTague & Forney, 1994; Larson et al, 1994; CDC, 1992) and may be severe (Resiere et al, 2001).
    b) INCIDENCE: In one case series (n=12) of acute ackee fruit poisoning, severe vomiting was reported in 11 of 12 patients (Resiere et al, 2001). In another study of 60 patients with ackee fruit poisoning, 58 (97%) reported vomiting (Joskow et al, 2006).
    c) CASE REPORTS: A 9-year-old girl presented with an altered level of consciousness and lethargy of 21 hours duration. Symptoms developed approximately 2 hours after ingesting 6 roasted seeds and arils of ackee fruit. Vomiting occurred shortly after exposure. Initial treatment included IV fluids when she was transferred to a higher level of care and had a Glasgow Coma Score of 9. Laboratory studies were within normal limits with the exception of hypoglycemia which improved with 10% IV dextrose. The child gradually improved and was discharged on day 6 having fully recovered (Katibi et al, 2015).
    1) Seven other siblings also ate the fruit with 2 of the children eating 4 and 6 roasted ackee seeds, respectively. A 4-year-old child died at home after ingesting 6 seeds approximately 23 hours after ingestion. Another 9-year-old girl developed similar symptoms as the index case and was treated supportively and discharged to home on day 4 after ingesting 4 seeds. The remaining 5 children (between 4 and 10 years) ingested between 2 and 3 roasted seeds and aril and were initially asymptomatic. By day 4, they had developed intermittent abdominal pain and loose stools. No fever or vomiting occurred; laboratory studies were also normal. Each child received IV hydration and vitamin B complex and were discharged to home after 2 days. In these cases, toxicity appeared to be dose-dependent (Katibi et al, 2015).
    B) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) In one case series (n=12) of acute ackee fruit poisoning, 9 of 12 patients developed abdominal pain (Resiere et al, 2001). In another study, abdominal pain was reported in 15 (28%) of 60 patients with acute ackee poisoning (Joskow et al, 2006).
    C) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea is usually absent (Lampe & McCann, 1985) as are abdominal cramps and pain (Morton, 1971). Diarrhea and abdominal pain developed in one case of chronic ackee ingestion (Larson et al, 1994).

Hepatic

    3.9.1) SUMMARY
    A) Hepatitis may develop.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Jaundice (total bilirubin 25.6 mg/dL, direct bilirubin 13.9 mg/dL) and elevated liver function tests (alkaline phosphatase 278 U/liter, AST 99 U/liter, ALT 194 U/liter) developed in a 27-year-old man who chronically ate ackee fruit. Liver biopsy revealed centrilobular necrosis. All laboratory abnormalities resolved after exposure ceased (Larson et al, 1994).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATIC FUNCTION ABNORMAL
    a) When hypoglycin A was injected into rats, liver glycogen almost completely disappeared (Patrick, 1954).

Acid-Base

    3.11.1) SUMMARY
    A) Acidosis but not ketosis is often seen.
    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Metabolic acidosis is often seen, but not accompanied by ketosis (Hill, 1952; Bressler et al, 1969). The acidosis may be due to large accumulations of dicarboxylic acids (Tanaka et al, 1976).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH POISONING/EXPOSURE
    a) Severe pruritus may develop in patients with jaundice (McTague & Forney, 1994).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) Severe hypoglycemia has been reported in human cases (Katibi et al, 2015; Jelliffe & Stuart, 1954), and is a common finding (Resiere et al, 2001; Joskow et al, 2006). Blood glucose levels as low as 3 milligrams per 100 mL have often been recorded (Tanaka et al, 1976).
    b) While hypoglycin reduces blood sugar, the level of circulating insulin is normal (Tanaka, 1987).
    c) In one case series (n=12) of acute ackee fruit poisoning, all patients developed hypoglycemia (3.9 mmol/L [1.1-4.4]) with most patients (n=10) requiring intravenous glucose administration and the remaining two receiving oral glucose replacement (Resiere et al, 2001).
    d) Quere et al (1999) reported that children exposed to the ackee fruit had a mean blood sugar of 34 g/L with some as low as 10 g/L. In this report, survival was dependent on children being treated with intravenous glucose within the first 2 to 3 hours after onset of symptoms.
    e) At autopsy, two children with ackee poisoning were found to have severe hypoglycemia (mean serum glucose 0.32 g/L [0.10 to 0.70]), and low concentrations of glucose in the cerebrospinal fluid (mean concentration 0.16 g/L [0 to 0.47]) (Meda et al, 1999).
    f) CASE REPORTS: A 9-year-old girl presented with an altered level of consciousness and lethargy of 21 hours duration. Symptoms developed approximately 2 hours after ingesting 6 roasted seeds and arils of ackee fruit. Vomiting occurred shortly after exposure. Initial treatment included IV fluids when she was transferred to a higher level of care and had a Glasgow Coma Score of 9. Laboratory studies were within normal limits with the exception of hypoglycemia which improved with 10% IV dextrose. The child gradually improved and was discharged on day 6 having fully recovered (Katibi et al, 2015).
    1) Seven other siblings also ate the fruit with 2 of the children eating 4 and 6 roasted ackee seeds, respectively. A 4-year-old child died at home after ingesting 6 seeds approximately 23 hours after ingestion. Another 9-year-old girl developed similar symptoms as the index case and was treated supportively and discharged to home on day 4 after ingesting 4 seeds. The remaining 5 children (between 4 and 10 years) ingested between 2 and 3 roasted seeds and aril and were initially asymptomatic. By day 4, they had developed intermittent abdominal pain and loose stools. No fever or vomiting occurred; laboratory studies were also normal. Each child received IV hydration and vitamin B complex and were discharged to home after 2 days. In these cases, toxicity appeared to be dose-dependent (Katibi et al, 2015).
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOGLYCEMIA
    a) Hypoglycin A and B both have marked hypoglycemic activity when tested in animals. Blood sugar fell to under 20 mg/dl accompanied by marked decreases in liver glycogen (Hassall & Reyle, 1955).

Reproductive

    3.20.1) SUMMARY
    A) Hypoglycin A is teratogenic in rats and produces stunting and fetal resorptions in rabbits.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) Hypoglycin A is teratogenic (exencephalocoele and syndactyly) in rats (IP) and produces stunting and fetal resorptions in rabbits (Persaud, 1968) 1968b). Mechanism is said to be due to hypoglycin A inhibition of aceyl dehydrogenase-flavin dependent oxidation reaction and can be prevented by riboflavin phosphate (Keeler & Tu, 1983) Persaud, 1971).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Blood sugar should be carefully monitored because severe hypoglycemia may occur.
    B) Fluid status should be monitored in all exposed patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Blood sugar should be carefully monitored because severe hypoglycemia may occur. Levels as low as 3 mg/100 mL have been recorded (Tanaka et al, 1976; Resiere et al, 2001).
    2) Monitor fluid status in all exposed patients. Severe vomiting has been reported following exposure to unripe ackee fruit.
    4.1.3) URINE
    A) URINARY LEVELS
    1) Identification of methylene cyclopropylacetic acid (a metabolite of hypoglycin) and excretion of large quantities of unusual dicarboxylic acids such as 2-ethylmalonic, 2 methylsuccinic, glutaric, adipic acid is diagnostic of hypoglycin poisoning (Tanaka et al, 1976).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Blood sugar should be carefully monitored because severe hypoglycemia may occur.
    B) Fluid status should be monitored in all exposed patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    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) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    C) ACTIVATED CHARCOAL
    1) 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.
    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).
    6.5.3) TREATMENT
    A) DEXTROSE
    1) Intravenous infusions of glucose have resulted in dramatic clinical recovery (Hassal et al, 1954) (Hill et al, 1955), but have also failed to prevent a fatality (Jelliffe & Stuart, 1954). The symptoms of hypoglycemia following ackee poisoning can be exacerbated by malnutrition. Animal experiments have shown that the mechanism of action of hypoglycin is not that of insulin. Rabbits poisoned by hypoglycin have died in spite of glucose injection (Chin et al, 1957).
    2) Recent case series suggest that survival in children with hypoglycemia from ackee fruit ingestion is dependent on treatment with intravenous dextrose within the first 2 to 3 hours after the onset of symptoms (Quere et al, 1999).
    3) ANIMAL STUDY: In one study, the efficacy of methylene blue (MB; 0, 2, 4, 6, 8, 10, 12, and 14 mg/kg every 30 minutes) and glucose (G; 10%; 1, 1.5, 2, 2.5, and 3 g/kg IP every 2 hours over a 6 hour period), alone and in combination (MB plus G), as a treatment for ackee apple poisoning was evaluated in mice (144 mice; 6 groups of 24 mice). The main outcomes of the study were early mortality (until day 3) and late mortality (day 14) (Barennes et al, 2004).
    a) Glucose was more effective than MB and had the same survival as MB in conditions of early treatment. Overall, more mice survived in G and G plus MB groups than in MB group (75% and 25%, respectively). Survival in the G alone group was the same as survival in the G plus MB group. Hepatitis or hepatic cirrhosis did not occur in animals from any groups. The authors recommended early sugar, glucose, or dextrose administration in the field (Barennes et al, 2004).
    B) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Fluids and electrolytes should be monitored. Excessive loss may occur due to profuse vomiting.
    C) 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).
    D) VITAMIN B COMPLEX
    1) Vitamin B deficiencies are often associated with ackee fruit poisoning. Teratogenesis in animals can be prevented by pretreatment with riboflavin phosphate (Persaud, 1971). Animal studies of hypoglycin poisoning suggests that riboflavin and glycine may be useful following human ackee exposure (Sherratt & Turnbull, 1999). The proposed mechanism of action of this tetratogensis is the same as that of the hypoglycemic effect (Keeler & Tu, 1983), therefore, vitamin B supplements should be considered.
    2) There are no clinical studies evaluating the efficacy of treatment with riboflavin, but Hill (1952) and Hill et al (1955) recommended it on an empiric basis before the mechanism of action was known.
    E) EXPERIMENTAL THERAPY
    1) L-CARNITINE: Several animal studies have addressed the use of L-carnitine for treatment of hypoglycin-induced hypoglycemia. Mice given L-carnitine have shown both positive and negative responses to this agent (Borum, 1983; Entman & Bressler, 1967; Marley & Sherratt, 1973). The effectiveness of this agent has not been assessed in humans (Di Palma, 1987).
    2) METHYLENE BLUE: Based on the biochemical similarities between ackee poisoning and ifosfamide encephalopathy, methylene blue has been suggested as a possible treatment in potentially fatal encephalopathy that can occur after exposure (Kupfer & Idle, 1999). Methylene blue may restore hepatic gluconeogenesis by oxidizing NADH to NAD. Theoretically, the use of methylene blue in combination with riboflavin may help to promote new flavoprotein synthesis during the early stages of endemic encephalopathy.
    3) ANIMAL STUDY: In one study, the efficacy of methylene blue (MB; 0, 2, 4, 6, 8, 10, 12, and 14 mg/kg every 30 minutes) and glucose (G; 10%; 1, 1.5, 2, 2.5, and 3 g/kg IP every 2 hrs over a 6 hour period), alone and in combination (MB plus G), as a treatment for ackee apple poisoning was evaluated in mice (144 mice; 6 groups of 24 mice). The main outcomes of the study were early mortality (until day 3) and late mortality (day 14) (Barennes et al, 2004).
    a) Methylene blue showed a trend towards efficacy on early mortality (P=0.07) but not on late mortality. For early survival, MB 8 mg/kg was the most effective with no deaths by day 3. When methylene blue was administered 6 hours or later after poisoning, the treatment was ineffective. Glucose was more effective than MB and had the same survival as MB in conditions of early treatment. Overall, more mice survived in G and G plus MB groups than in MB group (75% and 25%, respectively). Survival in the G plus MB group was the same as survival in the G only group. Hepatitis or hepatic cirrhosis did not occur in animals from any groups. If used, MB should be administered in multiple doses and the first administration should be performed early, at least within 3 hours of intoxication; however in this study it did not provide any additional benefit over treatment with glucose alone (Barennes et al, 2004).
    F) ACUTE RENAL FAILURE SYNDROME
    1) Renal failure has been reported in some cases and may require hemodialysis.

Abstracts

Case Reports

    A) PEDIATRIC
    1) A 6-year-old girl went to bed well, but at 0500 the next morning vomited twice. She did not complain of any pain. She was "ill" most of that next day, and slept fairly well that night. On day 3, she started vomiting again, almost immediately she had a seizure, became comatose and died that afternoon. The food eaten was unknown, part of a "soup" of yam, banana, and ackee (Scott, 1916).
    2) A 12-year-old girl was at school all day feeling well. At 1600 she had abdominal pain and vomited three times. While attempting to return home she vomited several more times. She arrived home at 2000, and soon afterwards became comatose. She died at midnight. The amount ingested was unknown (Scott, 1916).

Range Of Toxicity

Summary

    A) MINIMUM LETHAL DOSE: The seeds, fruit ball and aril of the unripe fruit and the arils of the underdeveloped fruit are toxic. The ripe aril is considered non-toxic, but a rancid aril may also cause problems. On a weight basis, unripe seeds have 5 to 10 times as much toxin as the pods. Fatalities were reported in preschool children following ingestion of unripe ackee fruit.
    B) CASE SERIES: In a case series of 8 previously healthy children, a young child died after ingesting 4 roasted ackee seeds and the remaining 7 children developed various gastrointestinal events at various time intervals following the ingestion of roasted seeds and arils. One of the surviving children, developed a loss of consciousness followed by vomiting, extreme body weakness and hypoglycemia.

Minimum Lethal Exposure

    A) SUMMARY
    1) It is generally thought that the seeds, the fruit wall, aril of the unripe fruit and the arils of an underdeveloped berry are toxic. Although the ripe aril is considered non-toxic, the rancid aril has caused problems and a normal ripe aril still contains small amounts of the hypoglycin (Joskow et al, 2006; Hassall & Reyle, 1955). As the fruit ripens, a decrease in hypoglycin (one of 2 toxins isolated from the arilli and seeds of the unripened ackee) levels occurs in the aril (from 1000 to less than 0.1 ppm), and it can be safely eaten, but the seeds have 2 to 3 times more hypoglycin and the concentration remains near 1000 ppm even if the fruit is ripe. Even if cooked, the unripened ackee retains its toxicity (Joskow et al, 2006).
    2) The mortality of untreated ackee poisonings is approximately 80% (Arnold, 1978).
    B) CASE SERIES
    1) FIELD STUDY
    a) In a retrospective, cross-sectional investigation, 60 cases of ackee poisoning were identified following an outbreak in Haiti. Ages ranged from 6 months to 88 years (median 7 years; mean 15 years). Thirty-six deaths were reported with 17 (47%) deaths occurring within 12 hours after onset of illness, 24 (67%) died within 24 hours, and 29 (81%) died within 48 hours. Symptoms began within 24 hours of ingesting ackee fruit in 36 (60%) patients. Vomiting occurred in almost all cases. Central nervous system events included loss of consciousness (n=25), coma (n=24), and convulsions (n=18). Hypoglycemia was documented in 10 (19%) patients (Joskow et al, 2006).
    2) PEDIATRIC
    a) An epidemic of fatal encephalopathy was reported in Burkina Faso, west Africa, after the consumption of unripe ackee fruit in preschool children. Of the 29 cases reported, all died within 2 to 48 hours of exposure. The most common effects were hypotonia (97%), vomiting (66%), convulsions (93%), and coma (100%).
    1) The natural toxin found in the unripe ackee fruit is hypoglycin A, which is a 100 times higher than those in ripe fruit. Hypoglycin A poisoning is also associated with high concentrations of dicarboxylic acids in urine. Of the cases reported, increased concentrations of dicarboxylic acids (4 to 200 times higher) occurred in the urine as compared to controls (Meda et al, 1999).
    C) CASE REPORTS
    1) EIGHT SIBLINGS: A 9-year-old girl presented with an altered level of consciousness and lethargy of 21 hours duration. Symptoms developed approximately 2 hours after ingesting 6 roasted seeds and arils of ackee fruit. Vomiting occurred shortly after exposure. Initial treatment included IV fluids when she was transferred to a higher level of care and had a Glasgow Coma Score of 9. Laboratory studies were within normal limits with the exception of hypoglycemia which improved with 10% IV dextrose. The child gradually improved and was discharged on day 6 having fully recovered (Katibi et al, 2015).
    a) Seven other siblings also ate the fruit with 2 of the children eating 4 and 6 roasted ackee seeds, respectively. A 4-year-old child died at home after ingesting 6 seeds approximately 23 hours after ingestion. Another 9-year-old girl developed similar symptoms as the index case and was treated supportively and discharged to home on day 4 after ingesting 4 seeds. The remaining 5 children (between 4 and 10 years) ingested between 2 and 3 roasted seeds and aril and were initially asymptomatic. By day 4, they had developed intermittent abdominal pain and loose stools. No fever or vomiting occurred; laboratory studies were also normal. Each child received IV hydration and vitamin B complex and were discharged to home after 2 days. In these cases, toxicity appeared to be dose-dependent (Katibi et al, 2015).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) HYPOGLYCIN A
    1) LD50- (ORAL)RAT:
    a) 90 mg/kg
    B) HYPOGLYCIN B
    1) LD50- (ORAL)RAT:
    a) 180 mg/kg -- approximately

Pharmacology Toxicology

Toxicologic Mechanism

    A) SUMMARY - The natural toxin found in unripe ackee fruit is hypoglycin A (a water-soluble liver toxin). Concentrations can be 100 times higher than those in ripe fruit. Hypoglycin A and its major metabolite, methylenecyclopropylacetic acid (MCPA), are potent hypoglycemic agents with the underlying mechanism being a decrease in the rate of fatty acid beta oxidation, likely due to inhibition of acyl dehydrogenase flavin-dependent oxidation (Barennes et al, 2004; Meda et al, 1999) The metabolism of hypoglycin leads to hypoglycemia in humans (Joskow et al, 2006).
    1) ANIMAL DATA - Within 3 hours of being injected by hypoglycin, rat liver mitochondrial cells became swollen, pale and finally burst (Morton, 1971). The proposed mechanism of action is a reduction in the rate of fatty acid beta-oxidation possibly by inhibition of acyl dehydrogenase flavin dependent oxidation (Von Holt et al, 1966; (Borum, 1983; Entman & Bressler, 1967).
    2) Hypoglycin A and its metabolites specifically inhibit several acyl-coenzyme A dehydrogenases causing accumulation of short chain fatty acids and medium chain dicarboxylic acids (Trauner et al, 1976; Tanaka et al, 1976; Meda et al, 1999). Due to this sequestration and transport inhibition, fatty acids conjugated with carnitines (eg, octanoylcarnitine) accumulate in the urine (Joskow et al, 2006).
    a) In a study of ackee fruit poisoning, urine analyses identified two specific carnitines, octanoylcarnitine and hexanoylcarnitine in most samples. Octanoylcarnitine, the most sensitive carnitine derivative to the effects of hypoglycin A, was elevated in 4 of 6 case-patients and hexanoylcarnitine was elevated in 5 case-patients. Postmortem samples had the highest concentration of both carnitines (Joskow et al, 2006).

Animal Toxicology

Clinical Effects

    11.1.8) LAGOMORPH/RABBIT
    A) Toxicity in some animals is often delayed. Between 15 and 24 hours passed in some rabbits poisoned fatally (Doughty & Larson, 1960).

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