Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

Available Forms Sources

A)

1) There is a wide variety of iron multivitamin preparations. These may be tablets, capsules, chewable, or in liquid form.
2) They may all differ slightly and it is important to obtain an accurate product history with each ingestion.
3) Range of elemental iron content of multivitamin with iron preparations: Chewable multivitamins with iron range from 10 to 18 mg per tablet, Adult multivitamins with iron range from 6 to 50 mg per tablet, Prenatal multivitamins with iron range from 36 to 65 mg per tablet.
4) A study by Issenman et al (1985) showed that over-use or use of more than one multivitamin preparation in the home was a significant risk factor in increasing the potential for overdose.

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Multivitamin and mineral supplements contain most of the vitamins and minerals associated with the Recommended Dietary Allowances (RDAs). In general, vitamin supplements contain similar vitamins and minerals, but are formulated for specific populations (ie, children, adults, men, women, pregnant women and older adults). However, no standard or regulatory definition is required to manufacture a multivitamin. This topic is limited to multiple vitamins and mineral products with iron (refer to Vitamins-Multiple for toxicity of products without iron).
B) TOXICOLOGY: The margin of safety for multivitamins is dependent on individual nutrients (eg, iron, vitamin A, vitamin D) and can vary by age group. Iron is a general cellular poison and is directly corrosive to the GI mucosa.
C) EPIDEMIOLOGY: It is estimated that one-third of Americans take supplements. Women are more likely to take multivitamins/supplements than men. Historically, iron poisoning was a common poisoning which was one of the leading causes of pediatric toxicologic deaths. Exposure has been reduced in recent years with improved packaging, but still has the potential for significant morbidity and mortality.
D) WITH THERAPEUTIC USE

1) GI upset and constipation may occur with therapeutic doses of iron. Adverse events are not typically reported with normal use of vitamin A and D.

E) WITH POISONING/EXPOSURE

1) OVERDOSE: Toxicity following acute overdoses with multivitamins WITHOUT iron is unlikely unless a massive amount has been ingested (refer to Vitamins-Multiple for toxicity of products without iron). In general, multivitamins WITH iron have produced less morbidity and mortality than iron tablets. However, it is the iron in these products which most often presents a toxic hazard. Although some vitamins such as vitamin A and D may cause toxicity, the ratio of these to iron almost always makes iron the more hazardous compound.
2) FAT SOLUBLE VITAMINS: Expected signs and symptoms of toxicity would be similar to individual vitamin preparations, especially fat soluble vitamins such as vitamin A and D. Hypercalcemia is characteristic of vitamin D toxicity. Excess vitamin A intake during pregnancy can lead to birth defects in infants. In severe toxicity, coagulopathies may develop in patients with a vitamin K-deficiency or those receiving warfarin following excess vitamin E intake. (SEE appropriate individual topics.)
3) WATER SOLUBLE VITAMINS: Most of the water soluble vitamins (ie, folic acid, thiamine (B1), riboflavin (B2), cyanocobalamin (B12), biotin, pantothenic acid) produce no acute toxic symptoms. Chronic ingestion of megadoses may be a more serious problem. An acute intravenous overdose of vitamin C has resulted in renal failure.
4) IRON POISONING: Ingestions of iron with multivitamins appear to have slightly different toxicity than iron alone, in that symptoms are often less dramatic and there are fewer corrosive effects.

a) MILD TO MODERATE POISONING: Vomiting and diarrhea may occur within 6 hours of ingestion.
b) SEVERE POISONING: Severe vomiting and diarrhea, lethargy, metabolic acidosis, shock, GI hemorrhage, coma, seizures, hepatotoxicity, and late onset GI strictures.
c) CLINICAL COURSE (May Not Occur In All Cases) includes the following:

1) PHASE I (0.5 to 2 hours) includes vomiting, hematemesis, abdominal pain, diarrhea, hematochezia, lethargy, shock, acidosis, and coagulopathy. Necrosis to the GI tract occurs from the direct effect of iron on GI mucosa. Severe gastrointestinal hemorrhagic necrosis with large losses of fluid and blood contribute to shock.
2) PHASE II includes apparent recovery; continue to observe patient closely.
3) PHASE III (2 to 12 hours after phase I) includes profound shock, severe acidosis, cyanosis, and fever. Increased total peripheral resistance, decreased plasma volume, hemoconcentration, decrease in total blood volume, hypotension, CNS depression, and metabolic acidosis have been demonstrated.
4) PHASE IV (2 to 4 days) includes possible hepatotoxicity. Thought to be a direct action of iron on mitochondria. Monitor liver function tests and bilirubin. Acute lung injury may also occur.
5) Phase V (days to weeks) includes GI scarring and strictures. GI obstruction secondary to gastric or pyloric scarring may occur due to corrosive effects of iron. Sustained-release preparations have resulted in small intestinal necrosis with resultant scarring and obstruction.

0.2.20)

A) Iron overdose in pregnancy can be fatal. Antidote treatment, if appropriate, should not be withheld. There is a risk of spontaneous abortion. Majority of second and third trimester iron overdoses will have normal outcomes.

0.2.22)

A) Yersenia enterocolitica septicemia has been seen in iron poisoned patients both treated and not treated with deferoxamine.

Laboratory Monitoring

A)

B)

C)

D)

E)

F)

G)

H)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Toxicity is unlikely following acute ingestion of a multiple vitamin preparation WITHOUT iron (refer to Vitamins-Multiple for toxicity of products without iron). Multivitamins with iron have produced less morbidity and mortality than iron tablets, but iron toxicity may occur. Supportive care with intravenous fluid hydration is usually sufficient for mild poisonings. Activated charcoal is not effective for iron ingestions. Patients who are symptomatic should be observed for clinical deterioration and development of acidosis. Abdominal x-rays should be obtained as tablets are generally radiopaque. When large amounts of tablets are visible on radiograph, consider whole bowel irrigation. An iron concentration should be measured 4 to 6 hours after the initial ingestion and then repeated in 2 to 4 hours. Patients who develop metabolic acidosis or are clinically worsening with IV hydration should be treated with chelation. Manage mild hypotension with IV fluids.

B) MANAGEMENT OF SEVERE TOXICITY

1) Chelation with deferoxamine is needed for patients with signs of severe poisoning including shock, acidosis, GI hemorrhage, and lethargy or coma. Consider chelation for serum iron concentrations greater than 500 mcg/dL (a patient will usually have significant signs and symptoms of toxicity). Patients may need blood transfusions if they have significant GI hemorrhage. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.

C) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal is not effective for iron ingestions. Most patients have spontaneous vomiting.
2) HOSPITAL: Activated charcoal does not adequately bind iron and is not useful. Studies have suggested that magnesium hydroxide antacids (5 mg magnesium hydroxide per gram of elemental iron ingested) decrease serum iron concentrations following a simulated overdose. Gastric lavage may be useful soon after ingestion in adults, but the nasogastric tubes used in children are not sufficiently large to remove tablets. In patients with large amounts of radiopaque tablets in the GI tract, whole bowel irrigation with polyethylene glycol should be considered. Endoscopic removal is another option for patients with a large number of tablets in the stomach.

D) AIRWAY MANAGEMENT

1) Patients who are comatose or with an altered mental status may need mechanical respiratory support and orotracheal intubation.

E) ANTIDOTE

1) DEFEROXAMINE can be used to chelate iron and should be used when there are signs of severe poisoning including shock, acidosis, GI hemorrhage, and coma. Deferoxamine is administered intravenously at a rate of 15 mg/kg/hour; it can be titrated up to a rate of 40 mg/kg/hour for patients with severe poisoning. However, hypotension may occur with high dose deferoxamine infusion and the rate should be slowed if this occurs. Deferoxamine should be continued for 12 to 24 hours and then titrated off if the patient is clinically improving. If the patient worsens as the deferoxamine is titrated off, it should be restarted. Prolonged (greater than 24 hours) high dose infusion of deferoxamine has been associated with acute lung injury and should be avoided. Patients receiving deferoxamine chelation are at increased risk for Yersinia enterocolitica sepsis.

F) ENHANCED ELIMINATION

1) Hemodialysis is not effective in removing iron, but may be necessary to remove deferoxamine-iron complexes in patients with renal insufficiency. Consider exchange transfusion in those patients with a serum iron exceeding 1000 mcg/dL who clinically deteriorate despite supportive care and intravenous chelation therapy.

G) PATIENT DISPOSITION

1) HOME CRITERIA: In general, multivitamins with iron have produced less morbidity and mortality than iron tablets. However, it is the iron in these products which most often presents a toxic hazard. Therefore, inadvertent ingestions of less than 40 mg/kg of elemental iron in patients who have only mild GI symptoms (self limited vomiting or diarrhea) can be watched at home.
2) OBSERVATION CRITERIA: Patients with more than mild symptoms, those who have ingested 40 mg/kg or more of elemental iron, or patients with intentional ingestions should be sent to a healthcare facility for evaluation.
3) ADMISSION CRITERIA: Patients who have hypotension, severe or worsening metabolic acidosis, GI hemorrhage, altered mental status, or a patient that requires chelation should be admitted.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings and for recommendations on determining the need for chelation or whole bowel irrigation. Consult a gastroenterologist for endoscopic removal if many tablets persist in the stomach.

H) PITFALLS

1) Total iron binding capacity (TIBC) is unreliable in iron overdose. The elemental iron component is the iron dosage of interest and needs to be calculated for any given iron formulation. Prolonged (greater than 24 hours) high dose infusion of deferoxamine has been associated with acute lung injury and should be avoided.

I) PHARMACOKINETICS

1) Peak concentrations vary slightly depending on the formulations.

J) TOXICOKINETICS

1) Increased iron absorption occurs during overdose because of disruption of GI mucosa as well as increased passive absorption because of a larger concentration gradient.

K) DIFFERENTIAL DIAGNOSIS

1) The differential diagnosis of an acute iron ingestion is extremely broad and would include any process causing vomiting and abdominal pain. Hemorrhage may or may not be noted initially.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) GI upset and constipation may occur with therapeutic doses of iron. Adverse events are not typically reported with normal use of vitamin A and D.

E)

1) OVERDOSE: Toxicity following acute overdoses with multivitamins WITHOUT iron is unlikely unless a massive amount has been ingested (refer to Vitamins-Multiple for toxicity of products without iron). In general, multivitamins WITH iron have produced less morbidity and mortality than iron tablets. However, it is the iron in these products which most often presents a toxic hazard. Although some vitamins such as vitamin A and D may cause toxicity, the ratio of these to iron almost always makes iron the more hazardous compound.
2) FAT SOLUBLE VITAMINS: Expected signs and symptoms of toxicity would be similar to individual vitamin preparations, especially fat soluble vitamins such as vitamin A and D. Hypercalcemia is characteristic of vitamin D toxicity. Excess vitamin A intake during pregnancy can lead to birth defects in infants. In severe toxicity, coagulopathies may develop in patients with a vitamin K-deficiency or those receiving warfarin following excess vitamin E intake. (SEE appropriate individual topics.)
3) WATER SOLUBLE VITAMINS: Most of the water soluble vitamins (ie, folic acid, thiamine (B1), riboflavin (B2), cyanocobalamin (B12), biotin, pantothenic acid) produce no acute toxic symptoms. Chronic ingestion of megadoses may be a more serious problem. An acute intravenous overdose of vitamin C has resulted in renal failure.
4) IRON POISONING: Ingestions of iron with multivitamins appear to have slightly different toxicity than iron alone, in that symptoms are often less dramatic and there are fewer corrosive effects.

a) MILD TO MODERATE POISONING: Vomiting and diarrhea may occur within 6 hours of ingestion.
b) SEVERE POISONING: Severe vomiting and diarrhea, lethargy, metabolic acidosis, shock, GI hemorrhage, coma, seizures, hepatotoxicity, and late onset GI strictures.
c) CLINICAL COURSE (May Not Occur In All Cases) includes the following:

1) PHASE I (0.5 to 2 hours) includes vomiting, hematemesis, abdominal pain, diarrhea, hematochezia, lethargy, shock, acidosis, and coagulopathy. Necrosis to the GI tract occurs from the direct effect of iron on GI mucosa. Severe gastrointestinal hemorrhagic necrosis with large losses of fluid and blood contribute to shock.
2) PHASE II includes apparent recovery; continue to observe patient closely.
3) PHASE III (2 to 12 hours after phase I) includes profound shock, severe acidosis, cyanosis, and fever. Increased total peripheral resistance, decreased plasma volume, hemoconcentration, decrease in total blood volume, hypotension, CNS depression, and metabolic acidosis have been demonstrated.
4) PHASE IV (2 to 4 days) includes possible hepatotoxicity. Thought to be a direct action of iron on mitochondria. Monitor liver function tests and bilirubin. Acute lung injury may also occur.
5) Phase V (days to weeks) includes GI scarring and strictures. GI obstruction secondary to gastric or pyloric scarring may occur due to corrosive effects of iron. Sustained-release preparations have resulted in small intestinal necrosis with resultant scarring and obstruction.

Vital Signs

3.3.3)

A) FEVER has been reported with chronic vitamin A toxicity (Muntaner et al, 1990; Wason & Lovejoy, 1982; Scherl et al, 1992).

Heent

3.4.3)

A) DIPLOPIA is a common complaint in adults with chronic vitamin A toxicity (Lombaert & Carton, 1976; James et al, 1982; Muenter et al, 1971).
B) PAPILLEDEMA is a common finding and flame hemorrhages have been reported with chronic vitamin A intoxication (Morrice et al, 1960; Lombaert & Carton, 1976; Selhorst et al, 1984; Patel et al, 1988).
C) NYSTAGMUS may develop with chronic vitamin A intoxication (Lombaert & Carton, 1976; Katz & Tzagournis, 1972).
D) BLINDNESS: Chronic excessive ingestion of vitamin A may rarely cause optic atrophy and blindness (Goldfrank, 1994).

3.4.4)

A) WITH POISONING/EXPOSURE

1) TINNITUS may develop with chronic vitamin A intoxication (Morrice et al, 1960; Lombaert & Carton, 1976).

3.4.6)

A) GINGIVITIS: Hyperemia and bleeding of the gums may develop with chronic vitamin A intoxication (Muenter et al, 1971; Katz & Tzagournis, 1972; Baxi & Dailey, 1982).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) Venodilation with secondary hypotension may be seen 2 to 6 hours with moderate to severe iron poisonings (Tenenbein & Israels, 1988).

B) HEART FAILURE

1) WITH POISONING/EXPOSURE

a) Cardiac failure following severe acute iron poisoning has been reported (Tenenbein et al, 1986). Cardiac toxicity is a well-known complication of chronic iron overload.

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Pulmonary edema may be seen in severe iron intoxication, 12 hours to several days after ingestion (Tenenbein & Israels, 1988).

B) PLEURAL EFFUSION

1) Pleural effusions have been reported in a few patients with ascites from chronic vitamin A intoxication (Mendoza et al, 1988; Rosenberg et al, 1982; Noseda et al, 1985).

Neurologic

3.7.2)

A) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache is a common manifestation of chronic or acute vitamin A overdose (Patel et al, 1988; Cleland & Southcott, 1969; Nater & Doeglas, 1970) (Muentner et al, 1971) (LaManita & Andrews, 1981). Vitamins D and E may cause headache, irritability and fatigue with chronic toxicity (Goldfrank & Kirstein, 1986; Hamilton, 2002).

B) DROWSY

1) WITH POISONING/EXPOSURE

a) Early in an iron ingestion (30 minutes to 2 hours) one may see lethargy, restlessness, or confusion. It may also be seen in vitamin A overdoses.

C) BENIGN INTRACRANIAL HYPERTENSION

1) WITH POISONING/EXPOSURE

a) Benign increased intracranial pressure (pseudotumor cerebri) is a common feature in both acute and chronic vitamin A intoxication (Bhettay & Bakst, 1988; Farris & Erdman, 1982). Effects include headache, lethargy, vomiting, papilledema, stiff neck, and in infants bulging and delayed closure of the fontanelles (James et al, 1982; Morrice et al, 1960; Pasquariello et al, 1977; Silverman & Lecks, 1982).
b) Increased cerebrospinal fluid pressure may be noted on lumbar puncture (Farris & Erdman, 1982; Selhorst et al, 1984).
c) Enlarged ventricles may be noted on head CT (Scherl et al, 1992).

D) COMA

1) Coma may result with high iron serum levels (greater than 300 mcg/dl) (Chyka & Butler, 1993).

E) HYDROCEPHALUS

1) Hydrocephalus was reported in an infant who received 25,000 International Units of vitamin A daily for several months (Gottrand et al, 1986).
2) BULGING FONTANELLES or delayed closure of the fontanelles and splitting of the cranial sutures have been reported in infants with chronic vitamin A poisoning (Mahoney et al, 1980; Pasquariello et al, 1977; Scherl et al, 1992). Bulging fontanelles have also been reported with acute overdose (de Francisco et al, 1993).

F) OPTIC DISC EDEMA

1) CRANIAL NERVE ABNORMALITIES with chronic vitamin A toxicity may include papilledema, nystagmus and 6th nerve palsy (Morrice et al, 1960; Lombaert & Carton, 1976; Selhorst et al, 1984) Patel et al, 1988 Katz & Tzagournis, 1972).

G) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures have been reported in acute (Cleland & Southcott, 1969) and chronic vitamin A overdose (Schurr et al, 1983), but are not common.

H) ALTERED MENTAL STATUS

1) WITH POISONING/EXPOSURE

a) Mental status changes with chronic vitamin A overdose include lethargy, irritability, impaired attention span and emotional lability (Schurr et al, 1983; Bhettay & Bakst, 1988; Mahoney et al, 1980).
b) Lethargy, restlessness and/or confusion have been noted (30 minutes to 2 hours) following an iron overdose (Eggleston & Stork, 2015; Carlsson et al, 2008; Chyka & Butler, 1993; Chyka & Butler, 1993).

Gastrointestinal

3.8.2)

A) ABDOMINAL PAIN

1) The iron components may cause abdominal pain and bloody diarrhea within the first 30 minutes to 2 hours.

B) NAUSEA, VOMITING AND DIARRHEA

1) WITH POISONING/EXPOSURE

a) Nausea, vomiting, abdominal pain and anorexia are common after acute or chronic vitamin A overdose (Howard & Willhite, 1986; Silverman et al, 1987; LaMantia & Andrews, 1981).
b) Nausea, vomiting, diarrhea and hematemesis have been reported following an iron overdose (Fil et al, 2015; Eggleston & Stork, 2015; Carlsson et al, 2008; Wu et al, 2003; Gumber et al, 2013; Perrone, 2002).
c) Vitamin C, vitamin E, and niacin also cause nausea, vomiting, and diarrhea contributing to the iron poisoning symptoms (Hamilton, 2002).
d) Symptoms of vitamin D toxicity include anorexia, nausea, vomiting, abdominal pain, constipation and/or diarrhea (Barrueto et al, 2005; Gurkan et al, 2004; Ezgu et al, 2004; Pundzien et al, 2001; HSDB, 2001; Paterson, 1980).

C) GASTROINTESTINAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Hemorrhage, ulceration and necrosis of the esophagus, stomach, and bowel are common autopsy findings in fatal iron overdoses.
b) Gastrointestinal hemorrhage may be seen in the first few hours after ingestion.
c) CASE REPORT: After ingestion of enteric-coated iron tablets, 2 adults were noted to have distal isolated small bowel abnormalities. One patient had a 20 cm infarcted segment, and the other patient had a 30 cm stricture (Tenenbein et al, 1990).

D) INTESTINAL OBSTRUCTION

1) Although gastrointestinal obstruction may occur from pyloric or gastric scarring, it is less likely with multivitamins and iron than with iron tablets alone due to the lower local iron concentration.

Hepatic

3.9.2)

A) INJURY OF LIVER

1) WITH POISONING/EXPOSURE

a) BACKGROUND: Hepatotoxicity leading to death can occur following acute iron poisoning. Based on a review of the literature, patients developed hepatotoxicity within 24 to 48 hours and effects appear to be dose related. The primary site of hepatic injury is the periportal areas of the hepatic lobule (the principal site for hepatic regeneration), which may explain the increase in mortality and poorer prognosis. Rapid onset and periportal injury were also consistently reported in animal studies due to iron poisoning (Tenenbein, 2001).
b) MECHANISM: Iron-induced hepatotoxicity is a presumed result of free radical generation and lipid peroxidation. Iron catalyzes hydroxyl radical formation (the most potent-free radical), which initiates lipid peroxidation. Based on limited data, antioxidants may have a hepatoprotective role in iron poisoning. Further research is suggested to establish efficacy (Tenenbein, 2001).
c) INCIDENCE: Periportal hepatic necrosis is described in fatal cases, although it occurs rarely (McGuigan, 1996). Significant elevations of AST, ALT, LDH, and bilirubin occur 1 to 4 days postingestion in severe cases (Gleason, 1979; Comes et al, 1993).
d) CHRONIC INGESTION OF VITAMIN A

1) Hepatic toxicity is most frequently associated with excessive long term ingestion of vitamin A. The range of doses associated with hepatotoxicity are daily doses of 15,000 to 1,400,000 IU with a mean daily dose of 120,000 IU (Cheruvattath et al, 2006; Sarles et al, 1990).
2) Elevated levels of hepatic aminotransferases, alkaline phosphatase, and bilirubin and increased INR are common in chronic intoxication (Sarles et al, 1990; Geubel et al, 1991; Minuk et al, 1988; Inkeles et al, 1986a; Grubb, 1990; Nagai et al, 1999).

B) HEPATIC NECROSIS

1) Iron-induced liver necrosis rarely occurs. It may present one to four days after a massive ingestion (Gleason et al, 1979).

C) HEPATOSPLENOMEGALY

1) If chronic large doses of vitamin A have been taken, this may cause hepato-splenomegaly. Liver injury from Vitamin A is histologically defined as cirrhosis (Hamilton, 2002).

D) TOXIC HEPATITIS

1) Chronic hypervitaminosis A may result in elevation of liver function tests, hepatic fibrosis, hepatosplenomegaly and hepatitis. In severe cases it may progress to cirrhosis, portal hypertension and ascites (Sarles et al, 1990; Geubel et al, 1991; Minuk et al, 1988; Inkeles et al, 1986; Grubb, 1990; Bioulac-Sage et al, 1988; Smith, 1989; Guarascio et al, 1983; Rosenberg et al, 1982; Jacques et al, 1979; Muenter et al, 1971; Russell et al, 1974; Baker et al, 1990; Noseda et al, 1985; Mendoza et al, 1988; Hamilton, 2002).

Genitourinary

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Renal insufficiency may develop in patients with hepatic failure from chronic vitamin A intoxication (Braitberg et al, 1995). Acute renal failure may occur in the later stages of iron poisoning (Goldfrank & Kirstein, 1986). Renal dysfunction (ie, elevated BUN and creatinine) without oliguria was also observed in an adult female following an acute ingestion of 600 mg of acitretin (metabolite of vitamin A) (Leithead et al, 2009).
b) Acute renal failure has developed due to compounding errors and inadvertent exposure to higher than reported amounts of Vitamin D due to improper reporting of the amount declared in over-the-counter dietary supplements or misunderstanding by consumers regarding dosage (eg, milliliters vs drops) (Smollin & Srisansanee, 2014; Conti et al, 2014; Marins et al, 2014).

B) KIDNEY STONE

1) Chronic Vitamin C toxicity may cause uricosuria and oxalate nephrolithiasis (Hamilton, 2002).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Anion gap metabolic acidosis is a common early finding in significant iron ingestions (Carlsson et al, 2008; Schonfeld & Haftel, 1989; Wu et al, 1998). Severe acidosis with fever and cyanosis may occur initially and during the third phase of an iron poisoning (Schonfeld & Haftel, 1989). The metabolic acidosis may persist for days in severe overdoses.
b) CASE SERIES: Sixteen cases of ferric chloride poisoning between the years of 1990-2001 were analyzed, and metabolic acidosis was reported in 25% of patients (Wu et al, 2003).
c) Acidosis may be partially due to release of hydrogen ions from conversion of ferrous (Fe++) to ferric (Fe+++) iron, subsequent reaction with water to form insoluble ferric hydroxide, thus liberating a hydrogen ion. However this is not proven conclusively (Reissmann & Coleman, 1955). Alternately, accumulation of lactic and citric acids via anaerobic metabolism may be the mechanism.

Hematologic

3.13.2)

A) LEUKOCYTOSIS

1) Leukocyte count greater than 15,000/mm(3) may correlate with a serum iron concentration of greater than 300 mcg/mL (Mann et al, 1989; Lacouture et al, 1981) (Chyka & Butler, 1992).

B) BLOOD COAGULATION PATHWAY FINDING

1) Early coagulopathy (4 to 8 hours postingestion) has been reported rarely and may be due to interference with enzymes of the coagulation cascade by free iron (Tenenbein & Israels, 1988). It is related to plasma concentrations of ferric iron.
2) Late coagulopathy (24 hours or more postingestion) is associated with severe hepatotoxicity and decreased levels of factors V, VII, IX, X, and fibrinogen (Tenenbein & Israels, 1988).

Dermatologic

3.14.2)

A) FLUSHING

1) If niacin (not niacinamide) is present there may be intense cutaneous flushing for 2 to 3 hours without subsequent toxicity due to histamine release (Hamilton, 2002).

B) SKIN FINDING

1) VITAMIN A (CHRONIC): Skin is often dry, scaling and pruritic. Seborrhea-like eruptions and changes in skin pigmentation may develop. Cheilosis, or fissuring of the skin around the mouth, and dry cracked lips are common (Lippe et al, 1981; Pasquariello et al, 1977) Inkels et al, 1986; (Muenter et al, 1971). Nails may be brittle or may separate from nail beds. Alopecia has been reported (Ruskin et al, 1992). Patients with chronic intoxication may develop chronic paronychiae of the fingers and toes (Jowsey & Riggs, 1968; Muenter et al, 1971).

C) GENERALIZED EXFOLIATIVE DERMATITIS

1) Peeling of perioral areas may progress to loss of skin layers over most of the body. Exfoliation of the skin occurs from one to several days after ingestion and may continue for several weeks (Coghlan & Cranswick, 2001; Nater & Doeglas, 1970).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) Serum glucose concentration greater than 150 mg/dL has been reported and may correlate with serum iron concentration of greater than 300 mcg/dL (Mann et al, 1989; Lacouture et al, 1981).

Reproductive

3.20.1)

A) Iron overdose in pregnancy can be fatal. Antidote treatment, if appropriate, should not be withheld. There is a risk of spontaneous abortion. Majority of second and third trimester iron overdoses will have normal outcomes.

3.20.2)

A) CONGENITAL ANOMALY

1) IRON - Study of iron overdosages and treatment on outcome of pregnancy revealed several teratogenic effects. Of 49 pregnant patients, 3 live births with abnormalities occurred (unstable hip joints, bilateral accessory nipples, webbed fingers on one hand). One aborted fetus was anencephalic (McElhatton et al, 1991).
2) VITAMIN A - There is a well-established association between some vitamin A congeners and a teratogenic outcome in infants whose mothers were exposed during pregnancy (Kizer et al, 1990).

a) Until further studies are completed the FDA's maximum recommended daily allowance of vitamin A (diet and supplements) is 8,000 IU for pregnant females (MMWR, 1987).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status following a significant overdose.
B) Serum calcium and phosphate levels should be monitored closely if vitamin D toxicity is suspected.
C) Plasma vitamin A levels may be helpful in diagnosis, but are not clinically useful in treatment.
D) Obtain serum aminotransferase levels, bilirubin, INR, and calcium levels in patients with chronic overdose of multivitamins which contain vitamin A.
E) Obtain iron levels as indicated following a significant exposure.
F) Obtain a complete metabolic panel and complete blood count.
G) Baseline arterial or venous blood gas in patients with severe toxicity.
H) Obtain an abdominal radiograph to evaluate for retained tablets.

4.1.2)

A) HEMATOLOGIC

1) Determine the CBC.

B) BLOOD/SERUM CHEMISTRY

1) Determine electrolytes, blood sugar, serum iron, and in severe cases LFT's.
2) SERUM IRON: Deferoxamine interferes with many laboratory determinations of SI resulting in a falsely low value. When possible, determine the SI and TIBC before initiating deferoxamine therapy.

a) The best time postingestion to draw serum iron levels is unknown. Absorptive and distribution variations have made it difficult to produce reliable curves or estimate time of peak levels.
b) As a guideline, most authorities recommend obtaining an initial level at 3 to 4 hours for liquid or coated tablet formulations (Tong & Banner, 1986; Bayer & Rumack, 1983). Peak absorption probably does not occur sooner than 1 to 2 hours or later than 6 hours.
c) SUSTAINED-RELEASE or ENTERIC-COATED preparations have extremely erratic kinetics. It may be best to draw 2 or more levels, 3 to 4 hours post-ingestion, and again at 6 to 8 hours.
d) CHEWABLE IRON: Peak iron level was 243 mcg/dl at 4.2 hours after ingestion of 5 mg/kg and peak iron level was 321 mcg/dl at 4.5 hours after 10 mg/kg in a study done in 5 adult male volunteers. (Ling et al, 1991).

3) Total iron binding capacity (TIBC) may be artificially elevated in the setting of acute iron overdose.

a) One study observed a reversible elevation of the TIBC in patients with acute iron poisoning that coincided with their acute hyperferremia. The authors hypothesized that this is a laboratory aberration. They evaluated reproducibility of TIBC levels by 500 laboratories on 10 samples. They reported the mean coefficient of variation was 16% which the authors deemed unsatisfactory as the sole criteria to base a clinical decision to start deferoxamine therapy. (Tenenbein & Yatscoff, 1991)

C) COAGULATION STUDIES

1) Determine PT or INR, and PTT in severe cases.

D) LABORATORY INTERFERENCE

1) SERUM IRON: Deferoxamine interferes with many laboratory determinations of SI resulting in a falsely low value. When possible, determine the SI and TIBC before initiating deferoxamine therapy.

Radiographic Studies

A)

1) If a patient is sent to a medical facility (usually for amounts of greater than 60 mg/kg), an abdominal x-ray should be obtained, since the tablets may be radiopaque, to determine if further lavage or emesis is necessary.
2) Chewable vitamin-iron products are less radiodense than iron tablets alone or prenatal vitamins with iron (Everson et al, 1989; O'Brien et al, 1986; Jaeger et al, 1981).

a) X-rays may appear similar to iron tablet ingestions where partial dissolution has occurred. Negative x-rays may be seen if late after the ingestion.
b) In a retrospective study of 93 pediatric patients who had ingested potentially toxic amounts of an iron supplement, only one of 30 patients had radiopaque densities that could be marginally visualized following an ingestion of a chewable iron supplement. The mean serum iron concentration was 270 mcg/dL in patients who had ingested a chewable iron supplement (Everson et al, 1989).

Methods

A)

1) TIBC/SUMMARY: rises factitiously in the presence of high concentrations of iron (Tenenbein & Yatscoff, 1989; Burkhart et al, 1991) or iron dextran (Hanchelroad & Rice, 1992) and the TIBC often exceeds the serum iron level in symptomatic patients (Chyka & Brady, 1989; Burkhart et al, 1991). For these reasons, the TIBC fails as a marker of iron toxicity in acute overdoses (Siff et al, 1999).

a) Other clinical considerations (signs and symptoms, metabolic acidosis, presence of iron on radiograph) should be used to determine need for chelation.
b) Siff et al (1999) noted that in a review of the literature, TIBC levels may not be a useful predictor of end-organ toxicity, nor an appropriate guide to deferoxamine therapy. The following reasons may limit its usefulness in the setting of overdose (Siff et al, 1999a):

1) In acute overdose, all methods of TIBC determination may be inaccurate; the presence of deferoxamine has been shown to cause an inaccurate TIBC; variability in TIBC readings; and lastly toxicity has been observed even when the TIBC level were greater than the serum iron concentration. In a clinical chemistry quality assessment program, interlaboratory variability of TIBC determination reported coefficients of variation ranging from 11.8% to 21.4% with a mean of 16% (Siff et al, 1999a).
2) Roberts et al (1999), however, suggested that a homogenous unsaturated iron-binding capacity (UIBC) method (equivalent to the difference between the amount of iron added and the excess unbound iron measured) can provide reliable TIBC results. This method is NOT reliable when the iron concentration exceeds 500 micrograms/dL (underestimates TIBC value) (Roberts et al, 1999).

a) No methods of TIBC determination are useful in the presence of deferoxamine due to its ability to interfere with TIBC by providing falsely elevated TIBC values with increasing deferoxamine concentrations (TIBC measurements should be obtained 4 hours after the last administration of deferoxamine to limit any interference) (Roberts et al, 1999).

c) For low serum iron concentrations, the presence of free iron may be determined by obtaining serum iron and iron binding capacity. If serum iron exceeds the total iron binding capacity, free serum iron may be present.
d) Using an ion exchange resin or excessive amounts of magnesium carbonate to bind free iron may improve the accuracy of TIBC measurements in iron overdose patients (Tenenbein & Yatscoff, 1991).
e) ANIMAL STUDY/DEFEROXAMINE: Bentur et al (1991) found that deferoxamine infusion in dogs falsely elevated laboratory measurements of TIBC. The magnitude of error was dependent on time after ingestion and time after deferoxamine administration (Bentur et al, 1991).

2) SERUM IRON: Draw blood for serum iron determination into heparinized tubes before deferoxamine is administered to avoid a known drug-lab interaction.

a) The presence of the deferoxamine iron complex (ferrioxamine) may result in falsely low total serum iron values when assayed by some of the widely used analytical methods used to measure serum iron (Gervirtz & Wasserman, 1966; Wythe et al, 1986).

1) Its suggested that when available, serum iron concentrations should be monitored along with clinical signs and symptoms to effectively treat the overdosed patient (Roberts et al, 1999).
2) Serum iron concentrations should be measured by ATOMIC ABSORPTION SPECTROPHOTOMETRY, especially following therapy with deferoxamine in order to avoid this drug-lab interaction (Helfer & Rodgerson, 1966).
3) The addition of 0.5 mL of a 100 mL/L aqueous thioglycolic acid solution, when added to the standard ACA test packs, may remove the interference caused by deferoxamine in measuring serum iron levels (Wians et al, 1988). Hemolysis however may interfere with this technique.

3) URINE IRON: A method for measuring urine iron includes using thioglycolic acid and trichloroacetic acid to release iron from ferrioxamine and then a standard automated colorimetric procedure for the final measurement.

a) This method is not useful in patients with hemoglobin or myoglobin in the urine (Yatscoff et al, 1991).

4) VITAMIN A: Vitamin A concentration in biological samples can be determined by HPLC (Sowers & Wallace, 1990) (Sundaresan et al, 1994).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients who have hypotension, severe or worsening metabolic acidosis, GI hemorrhage, altered mental status, or a patient that requires chelation should be admitted.
B) Referral to a healthcare facility has been recommended for patients with an iron ingestion of greater than 40 mg/kg (Manoguerra et al, 2005; Klein-Schwartz et al, 1990).

6.3.1.2) HOME CRITERIA/ORAL

A) SUMMARY

1) In general, multivitamins with iron have produced less morbidity and mortality than iron tablets. However, it is the iron in these products which most often presents a toxic hazard.

a) Therefore, inadvertent ingestions of less than 40 mg/kg of elemental iron in patients with only mild GI symptoms (self limited vomiting or diarrhea) can be watched at home (Manoguerra et al, 2005).

2) Any patient developing severe symptoms (i.e., coma, hypotension, GI bleeding, protracted vomiting/diarrhea), and those with a deliberate overdose or ingesting 40 mg/kg or more should be referred to a healthcare facility (Manoguerra et al, 2005).

B) STUDIES

1) Retrospective evaluation of serious poisoning from children's chewable multivitamins was conducted. The review covered NDCS reports from 1985 to 1991, in which there were 74,601 exposures. There were a total of 35 major effects and no deaths reported.

a) During this same study period, 25,067 exposures to high potency adult formulations of iron were reported. There were a total of 125 major effects and 29 deaths (Anderson et al, 1993).

2) A review of the 1986 to 1988 AAPCC data on 54,168 iron poisoning cases revealed that multivitamins with iron accounted for 83% of total iron exposures, but only 11% of iron-induced mortality (Krenzelok, 1991).
3) Adults ingesting 20 mg/kg of iron, without GI decontamination, have developed moderate symptoms (Burkhart et al, 1991).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings, and for recommendations on determining the need for chelation or whole bowel irrigation. Consult a gastroenterologist for endoscopic removal if many tablets persist in the stomach.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with more than mild symptoms, those who have ingested 40 mg/kg or more of elemental iron, or patients with intentional ingestions should be sent to a healthcare facility for evaluation (Manoguerra et al, 2005).

Monitoring

A)

B)

C)

D)

E)

F)

G)

H)

Oral Exposure

6.5.1)

A) Activated charcoal is NOT effective for iron ingestions (Manoguerra et al, 2005). Most patients have spontaneous vomiting.

6.5.2)

A) SUMMARY

1) Activated charcoal does not adequately bind iron and is not useful. Studies have suggested that magnesium hydroxide antacids (5 mg magnesium hydroxide per gram of elemental iron ingested) decrease serum iron concentrations following a simulated overdose. Gastric lavage may be useful soon after ingestion in adults, but the nasogastric tubes used in children are not sufficiently large to remove tablets. In patients with large amounts of radiopaque tablets in the GI tract, whole bowel irrigation with polyethylene glycol should be considered. Endoscopic removal is another option for patients with a large number of tablets in the stomach.
2) An abdominal x-ray should then be obtained to determine the need for further decontamination. A negative X-ray does not rule out the possibility of an iron ingestion or the presence of iron in the gastrointestinal tract (Ng et al, 1979). Tablets may be radiopaque. Multivitamin with iron tablets, however, contain less elemental iron and therefore may not produce the distinct radiodensities seen with prenatal iron. The KUB may demonstrate a more diffuse pattern.

B) GASTRIC LAVAGE

1) Gastric lavage is typically indicated up to one hour after ingestion. When slow-release or enteric-coated iron tablets are involved, or there is evidence of iron on abdominal radiographs, gastric lavage may be indicated for a longer period of time post-ingestion.
2) LAVAGE TUBE SIZE: Because the size of orogastric tube that can be passed in a small child may not be of sufficient diameter to remove tablets or large tablet fragments and because iron is not well adsorbed by activated charcoal, decontamination can be difficult. The use of a large lavage tube (32 to 40 French) has been recommended in adults (Blanc et al, 1984; Engle et al, 1987; Greengard, 1975; Oderda et al, 1987; Proudfoot et al, 1986) and 32 French in children as young as 15 to 24 months of age (Gandhi & Robarts, 1962; Schauben et al, 1990).
3) Lavage with bicarbonate solutions or deferoxamine is NOT recommended.
4) CASE REPORT: A 15 year-old girl ingested 20 slow release iron tablets, and 6 hours after ingestion a X-ray showed a conglomerate of iron tablets in the patient's stomach area. Gastric lavage was performed and successfully cleared the iron conglomerate (Goldstein & Berkovitch, 2006).
5) 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.

6) 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.

7) 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.

8) 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).

9) 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) ABDOMINAL X-RAY PATTERNS

1) Tablets may remain in the gut and an abdominal X-ray should be obtained to determine if further lavage is necessary. As dissolution occurs, a diffuse density rather than discrete tablets may be seen.
2) Completely dissolved iron tablets/capsules may not be radiopaque (Jaeger et al, 1981a; Ng et al, 1979). A positive abdominal radiograph is more likely to be associated with severe toxicity (James, 1970).
3) CASE SERIES: In a retrospective study of 93 pediatric patients who had ingested potentially toxic amounts of an iron supplement, only 1 of 30 patients had radiopaque densities that could be marginally visualized following an ingestion of a chewable iron supplement. The mean serum iron concentration was 270 mcg/dL in patients who had ingested a chewable iron supplement (Everson et al, 1989).

D) WHOLE BOWEL IRRIGATION (WBI)

1) INDICATIONS

a) WBI is indicated in patients with documented undissolved tablets past the pylorus or with a large quantity dispersed throughout the gastrointestinal tract or with persistent tablets in the stomach despite attempts at decontamination (Schauben et al, 1990; Bock & Tenenbein, 1987; Tenenbein, 1985a).

2) Whole bowel irrigation may successfully remove iron tablets from the gut in children, adolescents, and pregnant women without complications or significant electrolyte changes (Everson et al, 1991; Tenenbein & Yatscoff, 1991a; Van Ameyde & Tenenbein, 1989; Schauben et al, 1990; Tenenbein, 1985).

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.

1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.

b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

4) CASE REPORT: The solution used successfully in a 16-year-old patient was GoLYTELY(R) infused down a nasogastric tube at 2 L/hour for 12 hours (Tenenbein, 1985a).
5) CASE REPORT: Whole bowel irrigation was used in a pregnant woman (38 weeks gestation) who ingested iron tablets, which were still visible in the stomach after orogastric lavage. No complications were reported (Van Ameyde & Tenenbein, 1989).
6) CASE REPORT: A 33-month-old boy (15 kg) received 44 L of PEG over 121 hours at rates of 300 to 1000 mL/hour starting 15 hours after ingesting 160 mg/kg of elemental iron. Concurrent metoclopramide 0.1 mg/kg IV every 6 hours was given. WBI was stopped when a X-ray revealed only 2 tablets remaining in the distal colon. The patient tolerated WBI without complications (Kaczorowski & Wax, 1994).

E) ENDOSCOPY

1) Endoscopic removal should be considered if WBI is ineffective and most of the pills are visible in the stomach on radiography.
2) CASE REPORT: A 45-year-old woman (50 kg) presented with gastrointestinal symptoms (nausea, vomiting, diarrhea) after ingesting 100 ferrous sulfate tablets (300 mg per tablet); approximate elemental iron ingestion was 120 mg/kg. After gastric lavage, repeat x-ray showed a radio-opaque conglomerate of tablets in the stomach's fundal region. Endoscopic removal was successfully performed to retrieve and break up a 5 cm mass of congealed tablets. The stomach was then irrigated with two liters of normal saline and remaining tablet particles aspirated. The patient made an uneventful recovery (Ng et al, 2008).
3) CASE REPORT: A 21-year-old man intentionally ingested 30 ferrous sulfate tablets (325 mg per tablet) and presented one hour later. Initial serum iron level was 246 mcg/dL, and an abdominal x-ray showed a conglomerate of tablets in the gastric fundus. The bezoar of tablets persisted following gastric lavage, and endoscopic removal commenced. The iron pills were retrieved and broken up; followed by extensive irrigation and suction. After the endoscopy-directed lavage, serum iron levels normalized to 120 mcg/dL (Atiq et al, 2008).

F) SURGICAL THERAPY

1) Emergency gastrotomy should be considered in those patients when emesis, lavage, and whole bowel irrigation are unsuccessful in removing intact iron tablets from the stomach after a massive overdose (Venturelli et al, 1982; Foxford & Goldfrank, 1985; Peterson & Fifield, 1980; Landsman et al, 1987).
2) LAPAROSCOPIC-ASSISTED GASTROTOMY: A 14-year-old girl ingested a large quantity of ferrous fumarate at a calculated potentially lethal dose of 70 mg/kg and presented 2 hours later with a Glasgow coma scale of 10. Her serum iron concentration was 65 mcmol/L (normal range, 5 to 27 mcmol/L) on presentation. In the PICU, she was administrated IV deferoxamine and a plain chest radiograph revealed a large radio-opaque mass in the stomach. Endoscopic view of the stomach revealed iron concretions smeared on the antral mucosa proximal to the pylorus. She underwent a laparoscopic-assisted gastrotomy and an iron bezoar was removed by digital disimpaction and copious saline irritation. After gastrotomy, her serum iron concentration decreased and she quickly recovered (Haider et al, 2009).
3) OTHER INDICATIONS FOR GASTROTOMY: Very large intragastric amounts of iron (greater than 100 mg/kg elemental iron) are found on radiograph; if a drug bezoar is suspected; or if there is evidence that iron is adhered to the gastric wall (Tenenbein & Yatscoff, 1991a).

G) ANTACIDS

1) Magnesium hydroxide and calcium carbonate containing antacids may be safely used in therapeutic doses to help reduce iron absorption (O'Neil-Cutting & Crosby, 1986; Banner & Tong, 1986). In one randomized crossover study, volunteers ingested 5 mg/kg elemental iron followed 1 hour later by 4.5 grams of magnesium hydroxide per gram of ingested iron (Wallace et al, 1998). Magnesium hydroxide significantly reduced iron absorption in the 12 hours following iron ingestion. In another randomized controlled trial, administration of MgOH (5:1 ratio to elemental iron) did not affect iron absorption in humans after a supratherapeutic dose (10 mg/kg) of iron (Snyder & Clark, 1999).

H) NOT RECOMMENDED

1) ORAL COMPLEXATION: Oral administration of dilute sodium bicarbonate or Fleets Phosphosoda Enema to complex intragastric iron is NOT recommended.

a) IN VITRO bicarbonate and phosphate form relatively insoluble complexes with iron (Czajka et al, 1981), however in vivo they probably complex at best 15% of the available iron in the stomach.
b) Use of dilute phosphosoda in this setting has caused life threatening hypernatremia, hyperphosphatemia and hypocalcemia (Geffner & Opas, 1980). It would require repeated administration of sodium bicarbonate to maintain the gastric pH in the desired range to maintain complexation, with the inherent risk of hypernatremia.
c) ANIMAL: Studies in dogs, pigs, and rats have found no beneficial effects from oral administration of bicarbonate or phosphate in preventing iron absorption (Dean & Krenzelok, 1985; Dean et al, 1988; Dean & Krenzelok, 1987).

I) ACTIVATED CHARCOAL

1) Iron binds weakly to activated charcoal; it is generally NOT RECOMMENDED unless there are significant coingestants involved(Yonker et al, 1980; Decker et al, 1968).
2) 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.

3) 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).

4) IN VITRO STUDY: The adsorptive capacity of activated charcoal for ferrous sulfate (a 1.49% ferrous sulfate stock solution was prepared with distilled water) was tested in 3 pH environments (pH = 1.5, 4.5, or 7.5). Simulated gastric fluid was prepared with the final pH of these 3 test solutions adjusted with hydrochloric acid or sodium hydroxide. At a pH of 4.5 or 7.5, activated charcoal had significant (p < 0.01) adsorptive capacity for iron as compared to the negligible amount at a pH of 1.5. An alkaline pH environment promoted formation of insoluble iron complexes, which may have indicated some reduction in iron solubility. The authors suggested further in vivo studies (Chyka et al, 2000).
5) IN VIVO STUDY: A study was conducted with male Sprague-Dawley rats (a total of 53 completed the study) to determine whether activated charcoal altered the gastrointestinal absorption of toxic doses of iron as ferrous sulfate. The rats were randomized to one of five groups, and given the following treatments: (1) control given only 3 mL of distilled water; (2) 100 mg elemental iron + 1 mL distilled water; (3) 1:1 ratio of activated charcoal to iron (100 mg elemental iron + 100 mg activated charcoal); (4) 2:1 ratio of activated charcoal to iron; and (5) 4:1 ratio of activated charcoal to iron. Across the 4 treatment groups, mean serum iron concentrations did not differ at the various sampling times (ie, 1 hour, 4 hours, and 8 hours after iron administration), except at 1 hour for groups 4 {serum iron concentration 737) and 5 {serum iron concentration 1251}. The results indicated that activated charcoal did not alter iron absorption into the bloodstream. The authors suggested this study did not support earlier in vitro reports of the potential benefits of activated charcoal to limit ferrous sulfate absorption from the gastrointestinal tract (Gades et al, 2003).
6) The iron-deferoxamine complex has also been shown to have some affinity for charcoal (Yonker et al, 1980).
7) DEFEROXAMINE/CHARCOAL SLURRY: A prospective, crossover study in healthy volunteers found that an oral slurry of deferoxamine mesylate (DFO) and activated charcoal (AC) reduced the GI absorption of ferrous sulfate (Gomez et al, 1997).

a) Prior studies indicated that AC could adsorb iron from solutions that contain DFO. A premixed 1:3 (weight/weight) DFO (8 grams)/AC (25 grams of 20% weight/volume) slurry was given to volunteers (a previous in vitro study determined that ferrioxamine was maximally bound to AC at this ratio).
b) AUC (p = 0.042) and Cmax (p = 0.017) were significantly lower in all subjects given the slurry versus the control limbs; Tmax iron concentration was not significantly affected.
c) The combination of oral deferoxamine and activated charcoal has not been studied in poisoned patients and it is not recommended for routine clinical use at this time.

8) ANIMAL DATA: In a rat model, male and female rats were given iron sulfate at a dose of 200 mg/kg. The effects of activated charcoal (AC) and deferoxamine (DFO) with or without sodium bicarbonate were analyzed to determine if iron absorption was reduced from the digestive tract. An oral slurry of AC (100 mg/mL and 200 mg/mL) was given at a dose of 500 and 1000 mg/kg, along with a 75 mg/mL suspension of DFO given at a dose of 150 mg/kg. The coadministration of sodium bicarbonate also occurred.

a) RESULTS: The findings revealed that oral dosing with DFO and AC (separately and simultaneously, immediately or 10 to 20 minutes after dosing) did NOT prevent iron absorption from the digestive tract. However, DFO significantly decreased the elevated serum iron concentrations, presumably by chelating the already absorbed iron; sodium bicarbonate seemed to enhance this effect. Coadministration of sodium bicarbonate further decreased serum iron concentrations at 3, 5, and 6 hours after iron administration. When given alone, AC had NO effect on iron absorption (Eshel et al, 2000).
b) In another study using male rats only, AC was also found to NOT alter the extent of iron absorption (Gades et al, 2000).

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Toxicity is unlikely following acute ingestion of a multiple vitamin preparation WITHOUT iron (refer to Vitamins-Multiple for toxicity of products without iron). Multivitamins with iron have produced less morbidity and mortality than iron tablets, but iron toxicity may occur. Supportive care with intravenous fluid hydration is usually sufficient for mild poisonings. Activated charcoal is not effective for iron ingestions. Patients who are symptomatic should be observed for clinical deterioration and development of acidosis. Abdominal x-rays should be obtained as tablets are generally radiopaque. When large amounts of tablets are visible on radiograph, consider whole bowel irrigation. An iron concentration should be measured 4 to 6 hours after the initial ingestion and then repeated in 2 to 4 hours. Patients who develop metabolic acidosis or are clinically worsening with IV hydration should be treated with chelation. Manage mild hypotension with IV fluids.

2) MANAGEMENT OF SEVERE TOXICITY

a) Chelation with deferoxamine is needed for patients with signs of severe poisoning including shock, acidosis, GI hemorrhage, and lethargy or coma. Consider chelation for serum iron concentrations greater than 500 mcg/dL (a patient will usually have significant signs and symptoms of toxicity). Patients may need blood transfusions if they have significant GI hemorrhage. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.

B) MONITORING OF PATIENT

1) Monitor vital signs and mental status following a significant overdose.
2) Serum calcium and phosphate levels should be monitored closely if vitamin D toxicity is suspected.
3) Plasma vitamin A levels may be helpful in diagnosis, but are not clinically useful in treatment.
4) Obtain serum aminotransferase levels, bilirubin, INR, and calcium levels in patients with chronic overdose of multivitamins which contain vitamin A.
5) Obtain iron levels as indicated following a significant exposure.
6) Obtain a complete metabolic panel and complete blood count.
7) Obtain a baseline arterial or venous blood gas in patients with severe toxicity.
8) Obtain an abdominal radiograph to evaluate for retained tablets as indicated.

C) ASYMPTOMATIC

1) ASYMPTOMATIC PATIENT

a) Decontamination is recommended if greater than 40 mg/kg of elemental iron has been ingested or if the amount ingested is unknown. Decontamination efficacy should be monitored by following serial KUBs until no tablets are seen.

1) NEGATIVE KUB: Observe patient for 6 hours; if no symptoms develop (minor or major) then toxicity is unlikely and no further follow-up is necessary (Lacouture et al, 1981).
2) As dissolution occurs, a diffuse density rather than discrete tablets MAY be seen. Completely dissolved iron tablets/capsules may not be radiopaque (Jaeger et al, 1981a).
3) POSITIVE KUB: Evacuate gastric contents again and repeat x-ray. Determine CBC, blood sugar, electrolytes, and serum iron.
4) Blood should be drawn into a heparinized tube for determination of serum iron. Deferoxamine interferes with many laboratory determinations of serum iron resulting in falsely low values (see Laboratory Section).
5) When possible, determine serum iron before initiating deferoxamine therapy.

b) Institute DEFEROXAMINE THERAPY if the patient becomes symptomatic (more than transient nausea/vomiting, diarrhea, lethargy, hypotension, bloody emesis or diarrhea) or acidotic. Consider deferoxamine if peak serum iron is greater than 350 to 500 mcg/dL (most patients with serum iron in this range are symptomatic). Peak serum iron level is usually between 3 to 6 hours post-ingestion.

1) Peak levels may be delayed with enteric-coated products or in cases of bezoar formation.

2) SYMPTOMATIC PATIENT

a) Evacuate stomach promptly. Obtain an abdominal and chest x-ray to evaluate for residual tablets. If tablets remain in the stomach evacuate stomach again and repeat X-ray. If tablets persist in the stomach or are visible beyond the pylorus, begin whole bowel irrigation.

1) NOTE: As dissolution occurs, a diffuse density rather than discrete tablets may be seen. Completely dissolved iron tablets/capsules may not be radiopaque (Jaeger et al, 1981a).

b) DETERMINE SERUM IRON, CBC, ELECTROLYTES, AND BLOOD GLUCOSE

1) Blood should be drawn into red top or heparinized tubes (consult laboratory for specific recommendations) for determination of serum iron.
2) Deferoxamine interferes with many laboratory determinations of serum iron resulting in falsely low values (see Laboratory Section). When possible, determine serum iron before initiating deferoxamine therapy.
3) The best time to draw a serum level(s) postingestion is unknown. Absorptive and distribution variations have made it difficult to produce reliable curves or estimate time of peak levels.
4) As a guideline, most authorities recommend obtaining an initial level at 3 to 4 hours for liquid or coated tablet formulations (Tong & Banner, 1986a; Bayer & Rumack, 1983).
5) Peak absorption probably does not occur sooner than 1 to 2 hours or later than 6 hours. SUSTAINED-RELEASE or ENTERIC-COATED preparations have extremely erratic kinetics.
6) It may be best to draw 2 or more levels, 3 to 4 hours postingestion, and again at 6 to 8 hours postingestion.
7) Institute DEFEROXAMINE THERAPY in any symptomatic patient (more than transient nausea/vomiting, diarrhea, lethargy, hypotension, bloody emesis or diarrhea) or acidotic. Consider deferoxamine if peak serum iron is greater than 350 to 500 mcg/dL (most patients with serum iron in this range are symptomatic). Peak is usually between 3 to 6 hours postingestion.

a) Peak levels may be delayed with enteric-coated products or in cases of bezoar formation.

D) HYPOTENSIVE EPISODE

1) Institute life support measures; correct electrolyte abnormalities, treat shock with fluids or whole blood; support respirations; monitor blood sugar carefully (rule out hypoglycemia) and correct coagulopathy.
2) 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.

3) 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).

4) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

E) DEFEROXAMINE

1) DEFEROXAMINE INDICATIONS: Institute intravenous deferoxamine chelation therapy in any patient with signs and/or symptoms of significant iron poisoning including lethargy, coma, hypotension, severe persistent vomiting and diarrhea, shock or metabolic acidosis. Transient nausea and vomiting occurring immediately after ingestion, that resolves without therapy, generally does not warrant treatment in the absence of other symptoms or laboratory abnormalities (Tenenbein, 1996).
2) Chelation should also be considered in patients with peak serum iron concentrations of 500 mcg/dL or more; the vast majority of these patients will have clinical evidence of iron poisoning (Tenenbein, 1996).
3) EFFICACY

a) Deferoxamine binds 8.5 mg of elemental iron per 100 mg of the chelate.
b) In thalassemic patients 750 mg of deferoxamine intramuscularly bound 15 mg of iron, while intravenously, given over 24 hours it bound 50 mg of iron (Lovejoy, 1983; Lovejoy, 1982).

4) DOSING

a) ACUTE IRON INTOXICATION

1) ADULT DOSE: Administer deferoxamine by continuous IV infusion at a rate of 15 mg/kg/hour. It can be titrated up to a rate of 40 mg/kg/hour for patients with life-threatening iron toxicity, although hypotension may occur with higher doses, and the rate should be decreased if this develops (Seifert, 2004).
2) PEDIATRIC DOSE: Administer deferoxamine by continuous IV infusion at a rate of 15 mg/kg/hour (Seifert, 2004). Infusion rates up to 35 mg/kg/hour have been used in children with severe overdoses without adverse effects (Boehnert et al, 1985), although hypotension may occur with higher doses, and the rate should be decreased if this develops (Seifert, 2004).
3) PATIENTS IN SHOCK: Correct intravascular volume depletion to avoid further hypotension induced by deferoxamine.

b) DURATION OF INFUSION

1) Duration of infusion is generally 12 hours in patients with moderate poisoning, up to 24 hours in patients with severe poisoning. The patient should be titrated off the infusion if clinically improving. If the patient worsens as the deferoxamine is titrated off, it should be restarted. Infusions of greater than 24 hours have been associated with acute lung injury and should be avoided (Seifert, 2004; Tenenbein et al, 1992).
2) CASE SERIES: Severe or fatal pulmonary toxicity developed in 8 of 14 patients who received infusions of longer than 24 hours. Pulmonary toxicity did not develop in 29 patients treated for less than 24 hours (Tenenbein et al, 1992a).
3) OTHER ROUTES OF ADMINISTRATION

a) Gastric lavage with deferoxamine solution is NOT RECOMMENDED. Intramuscular administration is NOT RECOMMENDED in patients with acute iron overdose.

c) DURATION OF THERAPY

1) Duration of infusion is 12 hours in patients with moderate poisoning, up to 24 hours in patients with severe poisoning. The patient should be titrated off the infusion if clinically improving. If the patient worsens as the deferoxamine is titrated off, it should be restarted. Infusions of greater than 24 hours have been associated with acute lung injury and should be avoided (Seifert, 2004; Howland, 1996).

d) VIN ROSE TEST

1) Pink to orange-red urine indicates excretion of ferrioxamine (chelated iron), although frequently urine color change does not occur (Freeman & Manoguerra, 1981; Oderda et al, 1987a; Harchelroad & Rice, 1992).
2) Loss of the 'vin rose' color may be used as an endpoint for deferoxamine therapy. However, because the color is concentration dependent, absence of color does not necessarily suggest the absence of the chelant or ferriuresis (Yatscoff et al, 1991).

5) ADVERSE EFFECTS

a) PULMONARY TOXICITY

1) Adult respiratory distress syndrome has been reported in patients receiving prolonged high dose infusions (15 milligrams/kilogram/hour for 45 to 98 hours) for acute iron poisoning (Tenenbein et al, 1992). Severe or fatal pulmonary toxicity developed in 8 of 14 patients who received infusions of longer than 24 hours. Pulmonary toxicity did not develop in 29 patients treated for less than 24 hours (Tenenbein et al, 1992).
2) A "pulmonary syndrome" has been associated with high dose intravenous (10 to 25 milligrams/kilogram/hour) deferoxamine therapy for several days for acute and chronic iron overload patients; features can include tachypnea, dyspnea, hypoxemia, cyanosis, fever, eosinophilia, preceding urticaria, and/or interstitial infiltrates (Ioannides & Panisello, 2000; Freedman et al, 1990; Scanderbeg et al, 1990; Benson & Cheney, 1992; Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).

a) ONSET: usually 3 to 9 days after initiating deferoxamine therapy (Anderson & Rivers, 1992).

3) Pulmonary toxicity may be related to the duration of infusion and high daily doses (Macarol & Yawalkar, 1992).

b) SEPSIS

1) The use of deferoxamine in patients with acute iron overdose or chronic iron overload has been associated with Yersinia enterocolitica septicemia, and with mucormycosis in chronic iron overloaded patients (Boelaert et al, 1993; Melby et al, 1982a).
2) Deferoxamine may have provided the iron siderophore growth factor required by the bacteria Yersinia and the fungus Rhizopus (Boelaert et al, 1993).

c) VISUAL AND AUDITORY TOXICITY

1) Impaired color vision, bilateral scotomas, night blindness, decreased visual acuity and retinal pigmentation have been reported in patients receiving chronic deferoxamine treatment (Bene et al, 1989; Pengloan et al, 1987; Olivieri et al, 1986; Blake et al, 1985; Davies et al, 1983). Cataracts, retinal abnormalities and night blindness have been reported (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012; Yokel, 1994).
2) Hearing disturbances have been reported, including tinnitus and hearing loss (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).

d) HIGH-DOSE DEFEROXAMINE: A 22-year-old woman with an extremely high serum iron concentration (4573 mcg/dL) after ingesting 180 tablets of 300 mg ferrous sulfate (216 mg/kg elemental iron), received high-dose IV deferoxamine (15 mg/kg/hr started 8 hours after ingestion, increased to 30 mg/kg/hr 2 hours later, and then decreased to 15 mg/kg/hr 4 hours later). Despite severe gastrointestinal complications and metabolic acidosis, she rapidly recovered following supportive care and did not developed any adverse effects from high-dose deferoxamine (Noble et al, 2015).

6) PREGNANCY

a) PREGNANCY RECOMMENDATION

1) Based on case reports which have suggested benefit to the maternal patient and no adverse effects on fetuses, it is recommended that deferoxamine treatment not be withheld from pregnant patients (Singer & Vichinsky, 1999a).
2) Deferoxamine is pregnancy category C (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).

b) HUMAN DATA

1) Of 25 pregnant iron overdose patients treated with deferoxamine, 20 (80%) delivered healthy full-term babies. Six patients had serum levels of greater than or equal to 90 micromoles/liter, and all six delivered healthy full-term babies after gastric decontamination and deferoxamine therapy (McElhatton et al, 1991a).
2) A review of published cases of iron poisoning in pregnant women found that women who developed end organ damage secondary to iron overdose were more likely to suffer spontaneous abortion, preterm delivery and maternal death than patients who did not develop end organ damage (Tran et al, 2000).

c) ANIMAL DATA

1) Fetal serum iron concentrations did not change significantly when deferoxamine was infused intravenously into pregnant ewes (third stage of gestation) (Curry et al, 1990).
2) No measurable deferoxamine or ferrioxamine was detected in fetal blood up to 4 hours following intravenous administration to pregnant ewes (Curry et al, 1990).

d) CASE REPORT: A 27-year-old, at 27 weeks gestation, ingested 24 mg/kg of elemental iron and had an initial serum iron level of 603 mcg/dL (normal range, 50 to 170 mcg/dL). Chelation therapy included deferoxamine started at 1 gram/hour (15 mg/kg/hour) and was continued for 2 hours; ferritin levels dropped to normal within 48 hours. At 32 weeks, a 2420 gram infant with normal Apgar scores was delivered. The infant was discharged to home on day 7 with no further follow-up reported (Tran et al, 1998).
e) CASE REPORT/CHRONIC THERAPY: An 18-year-old with a history of thalassemia, chronic hepatitis, and iron overload became pregnant and stopped her DFO therapy. By 16 weeks gestation her ferritin level had reached 6000 ng/mL. At 18 weeks gestation DFO was restarted at a dose of 40 mg/kg via SQ infusion 4 days/week and intravenous treatment of 50 mg/kg every 2 weeks. At 26 weeks, the subcutaneous dose was increased to 50 mg/kg/day and intravenous dose to 80 mg/kg. A MediPort was inserted at 30 weeks to administer DFO at 50 mg/kg/day. The patient gave birth at 38 weeks gestation. At 10 month follow-up, the child was developmentally age-appropriate, and evaluation for DFO toxicity (ie, audiogram, skeletal survey for bone dysplasia, and ophthalmology exam) was negative (Singer & Vichinsky, 1999).

F) 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, 2010; 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).

G) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

H) TRANSPLANTATION OF LIVER

1) Fulminant hepatic failure, requiring liver transplantation, has been reported in several patients after iron overdose (Fil et al, 2015; Comes et al, 1993; Taalikka et al, 1999).

I) EXPERIMENTAL THERAPY

1) DEFEROXAMINE CONJUGATES: Deferoxamine conjugated to dextran or hydroxyethylstarch did not produce hypotension and persisted longer than free deferoxamine (Mahoney et al, 1989). These conjugates improved survival and prevented hepatotoxicity in a mouse model.
2) PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE (PS-ODNs) is a synthetic nucleotide used for chemotherapy and may have potential for use as a heavy metal chelator including iron. PS-ODNs are modified DNA molecules with sulfur replacing nonbinding oxygen on the phosphate backbone, which creates a stable poly-anionic molecule. In vitro studies indicate that it binds iron.

a) Iron excretion was measured in 16 patients receiving PS-ODNs, with a history of relapsed or refractory acute myelogenous leukemia or myelodysplastic syndrome. Doses were given for 10 days by continuous intravenous infusion with adverse effects monitored. Urinary iron excretion increased by 7.5 fold during therapy. The authors suggested that PS-ODNs may have a therapeutic role as a heavy metal chelator (Angle et al, 2000).

3) ORAL CHELATORS

a) Oral iron chelators have not been used to treat acute iron overdose. They should be considered in patients with recent, large ingestions in whom maximal deferoxamine therapy may not be sufficient.
b) DEFERASIROX: In a double-blind, placebo-controlled, randomized, crossover study, deferasirox, an oral chelator used for chronic iron overload, was found to significantly reduce serum irons levels when administered 1 hour after an acute iron ingestion of 5 mg/kg of elemental iron in 8 healthy volunteers. Baseline serum iron concentrations were similar between the 2 groups. The treatment group received 20 mg/kg of deferasirox 1 hour after the acute iron ingestion. The primary endpoints were area under the iron concentration-time curve from baseline to 12 hours and from baseline to 24 hours. Significant differences were observed between the placebo and treatment groups for the area under the iron concentration curve at 1 to 12 hours (577 mcmol-hr/L and 392 mcmol-hr/L {difference 185 mcmol-hr/L}, 95% confidence interval (CI) for the difference of 15.8 to 353 mcmol-hr/L) and at 1 to 24 hours (808 mcmol-hr/L and 598 mcmol-hour/L {difference 210 mcmol-hr/L}, 95% CI for the difference of 54.4 to 366.7 mcmol-hr/L), respectively (Griffith et al, 2011).
c) HYDROXPYRIDONE CHELATORS: Hydroxpyridone chelators such as 1,2-dimethyl-3-hydroxypyrid-4-one (deferiprone) are currently being investigated for the treatment of chronic iron-overloaded patients (Olivieri et al, 1990; Richardson & Ponka, 1998).

1) This agent was shown to be effective in removing iron in cases of beta-thalassemia and myelodysplasia. It was more effective when given with ascorbic acid (Kontoghiorghes et al, 1987).
2) In subchronic (3 month) toxicity studies in animals, Berdoukas et al (1993) reported 1,2-dimethyl-3-hydroxypyrid-4-one (deferiprone) to be toxic to proliferating tissues, especially the bone marrow. Deferiprone may have serious side effects including agranulocytosis, neutropenia, arthropathy, GI disorders, zinc deficiency, and fluctuations in liver function (Berdoukas et al, 1993; Hoffbrand & Wonke, 1997; Diav-Citrin & Koren , 1997; Kowdley, 1998).

d) PYRIDOXAL ISONICOTINOYL HYDRAZONE (PHI) is a tridentate chelator. In studies of thalassemic patients dosed at 30 mg/kg/day, a net iron excretion of approximately 0.12 mg/kg/day was seen. This value is much less than the desired 0.5 mg/kg/day iron excretion typically needed to obtain a negative iron balance in this patient population, but it has been argued PHI's iron excretion ability may be sufficient for patients who are not transfusion dependent. More studies are necessary to determine PHI's therapeutic potential (Hershko et al, 2005).
e) BIS-HYDROXYPHENYL-TIRAZOLE is a new class of tridentate iron-selective synthetic chelators. One compound in this class (ICL670) has shown efficacy as a once daily oral option for iron overload. Clinical trials involving 63 patients demonstrated a decrease of 1.5 mg iron/gram dry liver weight after 6 months of therapy at a dose of 20 mg/kg/day. This decrease in iron is equivalent to that seen with standard dosing of parenteral deferoxamine 40 mg/kg/day. More studies are necessary to determine ICL670's therapeutic potential (Hershko et al, 2005).

4) DEFERIPRONE

a) ANIMAL STUDIES

1) Berkovitch et al (2000) studied the effects of orally administered deferiprone on rats given 612 mg/kg elemental iron orally (equivalent to the LD50 in this species). Two groups of rats received oral deferiprone at 800 mg/kg with one of the groups receiving a repeat dose 2 hours later. The results indicated that coadministration of 800 mg/kg deferiprone with iron decreased mortality from 30% to 6.6% after 2 hours, 40% to 16.6% after 12 hours, and from 53.3% to 20% after 24 hours (Berkovitch et al, 2000).

a) Mortality was also significantly decreased among rats given 2 repeated doses of deferiprone from 0%, 9%, and 18% at 2, 12, and 24 hours post iron administration, respectively. The findings indicated that morbidity and mortality were significantly reduced following deferiprone administration (Berkovitch et al, 2000).

2) DEFERIPRONE and SODIUM BICARBONATE: Barr et al (1999) also examined rats after receiving elemental iron (20 mg/kg) and sodium bicarbonate (1 mEq/kg) followed by immediate deferiprone treatment and another group receiving treatment 15 minutes after exposure. Serial iron levels indicated that deferiprone significantly reduced serum iron levels, but the effectiveness was delayed in the group receiving deferiprone 15 minutes after iron dosing (Barr et al, 1999).
3) LACK OF EFFECT: Hung et al (1997) found that in female Swiss albino mice with iron poisoning, deferiprone failed to decrease iron induced toxicity and appeared to increase mortality when compared to controls. The safety of a premixed deferiprone-iron mixture was examined and found to be nontoxic at doses up to 6 micromoles/gram iron and 18 micromoles/gram deferiprone; however deferiprone given alone was toxic at doses greater than 9 micromoles/gram (Hung et al, 1997).

b) HUMAN STUDIES

1) CHRONIC THERAPY: Olivieri et al (1998) examined the long-term safety of oral deferiprone in patients with thalassemia major and found that deferiprone did not adequately control body iron burden as evidenced by elevated hepatic iron concentrations (annual liver-biopsies were completed) and may worsen hepatic fibrosis (Olivieri et al, 1998).

a) Several authors, however, question the interpretation of the histological evidence and suggested that progression of hepatic fibrosis was not present (Tricta & Spino, 1998; Callea, 1998).
b) Of patients receiving deferiprone therapy, elevated liver function tests have been most frequently reported in patients infected with hepatitis C. During chronic therapy the raised serum transaminase levels gradually settled to pretreatment levels or lower after 3 months of therapy. An increase in ALT levels has also been reported in some patients receiving deferiprone therapy. Symptoms were considered to be mild and transient and resolved with cessation of therapy (Diav-Citrin & Koren , 1997).
c) Another small study conducted by Stella et al (1998) examined 20 patients with thalassemia major with half being treated with deferiprone, and found NO statistically significant difference between liver-biopsy results of those treated with deferiprone or deferoxamine. The authors suggested that deferiprone may NOT cause the progression of liver damage (Stella et al, 1998).

2) MULTICENTRE STUDY: A prospective open-label one year study of deferiprone was conducted to evaluate the incidence of adverse events. 187 patients (ranging in age from 10 to 41 years) were enrolled in the trial. Seventy-four patients (40%) had previously undergone splenectomy, and 142 (76%) were seropositive for hepatitis C. A daily dose of 25 mg/kg body weight was given three times daily for a total daily dose of 75 mg/kg deferiprone; with the dose adjusted as needed (Cohen et al, 2000).

a) ADVERSE EVENTS: The most frequently reported adverse event was reddish discoloration of the urine which was attributable to the excretion of the iron-deferiprone complex. Gastrointestinal symptoms (nausea and vomiting) were the next most common and usually resolved after the first few weeks of therapy without a change in the drug regimen. Arthropathy (13%) was not uncommon, and was more likely to occur with a higher ferritin level. The mean alanine transaminase (ALT) levels were significantly higher than baseline for all patients that completed the study. Agranulocytosis and milder forms of neutropenia were reported at rates of 0.6/100 and 5.4/100 patient years, respectively. This rate was lower than previously reported. Hematologic disorders resolved with drug cessation (Cohen et al, 2000).
b) SECONDARY OUTCOME: This study noted that individuals with the highest initial ferritin levels had the most significant decline (Cohen et al, 2000).

c) SUMMARY

1) It has been suggested that deferiprone can effectively reduce iron levels in most patients using the existing dosing protocols (ie, deferiprone 75 to 120 mg/kg/day), but further study is required to determine the optimal deferiprone dose (Kontoghiorghes et al, 2001). In most dose-response studies, a dose of 75 mg/kg body weight was the minimal daily dose required to achieve a negative iron balance in patients with thalassemia major (Diav-Citrin & Koren , 1997).
2) At the time of this review, the use of this agent remains uncertain for acute and chronic exposure.

5) OTHER/CHRONIC TOXICITY: Animal studies conducted in rats and primates indicated that subcutaneous injection of N,N-bis(2-hydroxybenzyl)ethylenediamine-N, N-diacetic acid (HBED) was an effective alternative to deferoxamine for the chronic treatment of transfusional iron overload (Bergeron et al, 1998).

Enhanced Elimination

A)

1) Consider exchange transfusion in those patients with a serum iron exceeding 1000 mcg/dL who clinically deteriorate despite supportive care and intravenous chelation therapy.
2) CASE REPORT: An 18-month-old girl (12 kg) presented to the emergency department after the ingestion of 5300 mg of iron (442 mg of elemental iron/kg; serum iron concentration 447 mcg/dL on admission). Despite standard therapy (gastric lavage, whole bowel irrigation, and intravenous deferoxamine) for 2 hours, her serum iron increased to 1362 mcg/dL (244 mcmol/L). Exchange transfusion (ET) 9 hours postingestion reduced serum iron to 134 mcg/dL (24 mcmol/L). Her serum iron level decreased further to 40 mcg/dL (7 mcmol/L) after plasmapheresis for 5 hours. She was extubated 18 hours after ET (Carlsson et al, 2008). The authors suggested that ET should be started within 12 hours of ingestion if possible. They also concluded that plasmapheresis after ET was unnecessary in this patient.
3) In one study performed in dogs, the amount of iron removed by exchange transfusion was much greater than that removed by deferoxamine (Movassaghi et al, 1969).

B)

1) CASE REPORT: An 18-month-old boy (weight 11 kg) presented with diarrhea and vomiting after ingesting about 1625 mg (147 mg/kg) of ferrous sulfate. He later became drowsy, requiring intubation and ventilation. X-ray of the abdomen revealed 13 tablet fragments. Despite standard therapy (gastric lavage, whole bowel irrigation, and intravenous deferoxamine 15 mg/kg/hr, total at least 360 mg/kg in 24 hours), his serum iron concentration increased to 700 mcmol/L (3906 mcg/dL) 6 hours after ingestion. He developed elevated ALT (359 Units/L) and coagulopathy with kaolin partial thromboplastin time at 74.5 s and prothrombin time at 16.5 s, requiring vitamin K, fresh frozen plasma, and cryoprecipitate. Approximately 14 hours postingestion, he underwent continuous veno-venous hemofiltration (CVVH) for 17 hours and his serum iron concentration quickly decreased to 24.5 mcmol/L (137 mcg/dL). Despite signs of organ damage, he gradually recovered and was discharged on day 5 (Milne & Petros, 2010).
2) CASE REPORT: An 18-year-old woman presented with persistent vomiting, abdominal pain, lethargy, altered mental status, tachycardia (124 beats/min), and severe anion gap metabolic acidosis about 8 hours after ingesting 50 ferrous sulfate tablets (100 mg of elemental iron per 335 mg tablet; 100 mg/kg of elemental iron). Following supportive care, including gastric lavage, whole bowel irrigation, continuous renal replacement therapies, continuous venovenous hemodiafiltration (dialysate rate: 1000 mL/hr, replacement rate: 1000 mL/hr, blood flow rate 100 to 150 mL/hr, and ultrafiltration rate 0 mL/hr), and deferoxamine therapy (10 to 15 mg/kg/hr IV continuous rate), her condition gradually improved. Her serum iron concentration decreased from 2150 to 160 mcg/dL (reference range: 40 to 150 mcg/dL) 24 hours after ingestion (Gumber et al, 2013).
3) ANIMAL DATA: In a dog model of iron intoxication, continuous arteriovenous hemofiltration (CAVH) was performed with deferoxamine administered by the arterial port. CAVH removed the iron-deferoxamine complex but not free iron (Banner et al, 1989). The efficiency of total iron removal was less than predicted because significant amounts of deferoxamine were removed without bound iron, probably because insufficient mixing in the arterial line limited the formation of ferrioxamine.

C)

1) Deferoxamine administered 30 minutes before and during hemodialysis did not enhance the net removal of iron in chronically iron-overloaded patients undergoing dialysis (Roxe et al, 1990).

Abstracts

Range Of Toxicity

Summary

A)

B)

Minimum Lethal Exposure

A)

1) Fatalities have occurred following pediatric ingestions of 1200 mg to 4500 mg of elemental iron.
2) Lethality may be modified by adequate supportive care and treatment. Of 17 pediatric cases reported prior to the use of deferoxamine, 8 (47%) resulted in death (Spencer, 1951; Forbes, 1947; Thomson, 1947; Thomson, 1950; Roxburgh, 1949).
3) For ferrous iron, the estimated lethal dose is 0.3 grams/kg body weight (Baselt, 2000).
4) FATAL HEPATIC INJURY: The lowest serum iron level that was associated with hepatic injury was 1700 mcg/dL (304 mcmol/L) in a 17-year-old pregnant woman who died of iron overdose-induced hepatic failure (Tenenbein, 2001).

B)

1) PEDIATRIC

a) In a series of 12 children who all received gastric lavage and deferoxamine, all survived (Whitten et al, 1965).
b) In a review of cases of children who developed severe iron intoxication, defined as coma or shock, definitive therapy (chelators, exchange transfusion) resulted in survival in 12 of 14 (86%), supportive care resulted in survival in 14 of 26 (54%), and no therapy resulted in survival in 0 of 10 (Whitten et al, 1965).
c) In another series of 28 children with shock or coma due to iron poisoning, 25 (89%) survived after deferoxamine therapy (Westlin, 1966).

Maximum Tolerated Exposure

A)

1) Ingestion of less than 40 mg/kg generally does not cause significant toxicity, although mild GI irritation may develop (Manoguerra et al, 2005).
2) One case series found that hospital referral values as high as 61 mg/kg of iron do not adversely impact patient outcomes (Benson et al, 2003).
3) In one study, 27.6% of 380 children with an iron ingestion of 40 mg/kg to 60 mg/kg became symptomatic (Oderda et al, 1987).
4) In one series of 59 iron-poisoned children 15/20 with serum iron greater than 500 mcg/dL were symptomatic and were considered to be moderately or severely poisoned (James, 1970). In addition, another study found a significant correlation between serum iron levels above 500 mcg/dL and coma. Nine of 13 with serum iron less than 300 mcg/dL were mildly poisoned or asymptomatic (Chyka & Butler, 1993).
5) Of 22 patients with initial levels between 300 and 500 mcg/dL, 14 were moderately or severely poisoned and 8 were mildly poisoned or asymptomatic (James, 1970).

B)

1) In general, water soluble multivitamins do not represent a serious toxic hazard.

C)

1) Acute ingestion of 300,000 International Units (children) or 1 million or more International Units (adults) may result in toxicity with an onset of symptoms of 12 to 24 hours (Windhorst & Nigra, 1982).
2) No significant toxic effects were noted in children ingesting multivitamins containing 1500 to 225,000 Units of vitamin A (Dean & Krenzelok, 1988).
3) LACK OF EFFECT/PEDIATRIC: Three children between the ages of 30 months to 5 years consumed between 100 to 150 chewable jelly vitamins each containing 2000 International Units (200,000 to 300,000 International Units of vitamin A) of vitamin A as retinyl palmitate and 200 International Units of vitamin D over several days and were asymptomatic with no physical findings on exam. Serum retinol concentrations were increased above the reference range (0.7 to 1.5 micromol/L) in one child but slowly declined over time. Serum retinyl palmitate concentrations were elevated at the time of admission in 2 of the patients with levels of 371 and 437 nmol/L, respectively (reference median concentration: less than 244 nmol/L). Serial blood samples were followed at regular intervals for 6 months with concentrations remaining elevated in one patient for over 3 weeks after exposure. At 6 months, concentration for the 3 patients were 280, 260 and 220 nmol/L, respectively. No clinical complications occurred in any child. Other laboratory studies including serum hydroxyvitamin D remained normal throughout the study period (Lam et al, 2006).

D)

1) The following information is for vitamin D in general (Brin M, 1976):

a) Chronic ingestion of vitamin D in excess of 1600 Units may cause toxicity.
b) Daily ingestion in excess of 75,000 Units/day in adults will produce the toxic symptoms associated with hypervitaminosis D.
c) Decreased renal function may prevent excretion thereby resulting in elevated serum levels and enhance the possibility of toxicity.

2) INFANT: Daily ingestion of 2000 to 6300 Units/day may inhibit the growth of a normal child, while as little as 1000 Units/day can produce the infantile hypercalcemia syndrome in hypersensitive infants (Brin M, 1976).
3) TOLERABLE UPPER INTAKE LEVELS: PEDIATRIC: 0 to 6 months: 1000 International Units/day; 7 to 12 months: 1500 International Units/day; 1 to 3 years of age: 2500 International Units/day; 4 to 8 years of age: 3000 International Units/day; ADULT: Greater or equal to 9 years of age: 4000 International Units/day (Office of Dietary Supplements, National Institutes of Health, 2011).

Pharmacology Toxicology

Pharmacologic Mechanism

A)

1) Two thirds of the body's iron is present as hemoglobin, and the remainder is stored iron in the reticuloendothelial system mostly as hemosiderin and ferritin (Harju, 1989).
2) In a healthy man the loss of iron is replaced by the absorption of approximately 1 mg of iron daily, in women the average loss is greater because of menstruation and amounts to approximately 2 mg daily.

B)

Physicochemical

Animal Toxicology

Clinical Effects

11.1.13)

A) OTHER

1) IRON - Small animals may exhibit signs of iron toxicity such as vomiting and diarrhea within 6 hours of ingestion. Apparent recovery is followed within 0 to 18 hours by shock, CNS depression, GI hemorrhage, acidosis, and liver failure.

a) Oliguria and anuria may occur secondary to shock-induced renal failure (Beasley et al, 1989).

2) PERACUTE SYNDROME - This mimics an anaphylactic shock reaction, causing vascular collapse and rapid death (Beasley et al, 1989).

Treatment

11.2.1)

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample blood for analysis.
4) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

5) Due to lack of reports of large animal intoxication with this substance, the following sections address small animals (dogs and cats) only. In the case of a poisoning involving large animals, consult a veterinary poison control center.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.

1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
2) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
3) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

b) ORAL BINDING AGENT - Eggs have been used orally within a few hours of ingestion to help physically bind the compound. Administration of Milk of Magnesia (5 to 15 milliliters per os) precipitates iron and diminishes its absorption (Beasley et al, 1989).
c) ACTIVATED CHARCOAL - Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube.
d) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

11.2.5)

A) GENERAL TREATMENT

1) PERACUTE SYNDROME - If the animal is presented before death, initiate immediate treatment to keep an open airway and treat for anaphylaxis:

a) Administer doxylamine succinate (1 to 2.2 milligrams/kilogram subcutaneously or intramuscularly every 8 to 12 hours), dexamethasone sodium phosphate (1 to 5 milligrams/kilogram intravenously every 12 to 24 hours), or prednisolone (1 to 5 milligrams/kilogram intravenously every 1 to 6 hours).
b) Treat severe reactions with epinephrine (DOGS: 0.02 milligram/kilogram of 1:1000 diluted to 5 to 10 milliliters in saline, intravenously or subcutaneously; CATS: 0.1 milliliter of 1:1000 diluted to 5 to 10 milliliters in saline intravenously or intramuscularly).

2) SMALL ANIMALS, SUBACUTE EXPOSURE - Treatment must be aggressive. Prognosis for survival without organ damage is poor.

a) Maintain life support, especially respiratory function. Keep intubated and supply oxygen and artificial respiration as necessary.
b) Begin supportive fluid therapy (66 milliliters/kilogram/24 hours of standard solutions intravenously). Increase dosage to compensate for emesis, diarrhea, diuresis or other fluid loss.
c) Take abdominal radiographs to find iron masses in the stomach.
d) Add sodium bicarbonate to the intravenous fluids if metabolic acidosis is suspected. (If using lactated ringers solution and precipitate forms upon addition of bicarbonate, discard and substitute a different solution).

1) Formula for bicarbonate addition when blood gases are available: milliequivalents bicarb added = base deficit x 0.5 x body weight in kilograms. Give one half of the determined dose slowly over 3 to 4 hours intravenously.
2) Continue to dose based on blood gas determinations. When blood gases are not available, administer 1 to 4 milliequivalents/kilogram intravenously slowly over 4 to 8 hours.

e) DEFEROXAMINE is a chelation agent available at human hospitals to enhance the excretion of iron. Dose: 40 milligrams/kilogram intramuscularly every 4 to 8 hours. Deferoxamine may also be given intravenously at a rate of less than 15 milligrams/kilogram/hour.

1) If given too rapidly, deferoxamine will cause hypotension and shock. The urine may turn a reddish-brown color; therapy is continued until the urine no longer changes color (Beasley et al, 1989).

f) ASCORBIC ACID - In large oral doses doubles the iron excretion after administration of Desferal. Dose: 60 milligrams/kilogram once to twice daily (Beasley et al, 1989).
g) If the patient survives the acute phase, hepatic insufficiency may necessitate treatment including supportive care, maintaining electrolyte balance, cleansing enemas, dietary restrictions, and systemic antibiotics.
h) Gastric irritation and disturbances may be treated with label dosages of cimetidine and sucralfate.

Range Of Toxicity

11.3.2)

A) SPECIFIC TOXIN

1) Ingestion of 20 to 40 milligrams of elemental iron per kilogram body weight may result in toxicity.
2) Ingestion of greater than 60 milligrams of elemental iron per kilogram body weight is potentially serious.
3) Oral lethal dose has been estimated at 200 to 300 milligrams/kilogram.

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample blood for analysis.
4) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

5) Due to lack of reports of large animal intoxication with this substance, the following sections address small animals (dogs and cats) only. In the case of a poisoning involving large animals, consult a veterinary poison control center.

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.

1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
2) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
3) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

b) ORAL BINDING AGENT - Eggs have been used orally within a few hours of ingestion to help physically bind the compound. Administration of Milk of Magnesia (5 to 15 milliliters per os) precipitates iron and diminishes its absorption (Beasley et al, 1989).
c) ACTIVATED CHARCOAL - Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube.
d) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

Sources

A)

1) Iron is found in large quantities in human drug preparations such as multivitamins and iron supplements in tablet form. Iron is also the main component of some oral contraceptive tablets.

References

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MULTIVITAMINS-IRON

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Endocrine

Reproductive

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Pharmacologic Mechanism

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Sources

General Bibliography