Links to 2.1.9.6 Iron Teaching Resources

Iron Overdose

INTERVENTION CRITERIA

Ingested dose

< 10 – 20 mg/kg non – toxic
20 – 60 mg/kg potentially toxic
0 – 120 mg/kg toxic, but fatal outcome unlikely
120 mg/kg potentially fatal

Example:
Note that elemental quantity of iron in tablets needs calculation

5 x Fergon tablets (300 mg ferrous gluconate) ingested by a 10 kg toddler.
- 5 x 300 mg/10 kg = 150 mg/kg
- In fact only 11% (33 mg) of tablet is elemental iron.
- Therefore 5 x 33 mg/10 kg = 16.5 mg/kg

TOXIC MECHANISMS

1. Direct corrosive effect on the GIT

2. Metabolic acidosis
a. Conversion of Fe++ to Fe+++, binding to -OH and release of H+
b. Inhibition of mitochondrial respiration and lactic acid production
c. Decreased CO, vasodilatation, decreased peripheral perfusion and anoxia
d. Hypovolaemia secondary to; vomiting, diarrhoea, and GIT haemorrhage and third spacing
e. Hepatic failure

3. Cell death following lipid peroxidation due to production of free radicals

4. Coagulopathy
a. Initially due to direct iron inhibition of thrombin, then;
b. Secondary to hepatotoxicity and reduced production of factors II, VII, IX and X

PHASES OF INTOXICATION

1. Acute GIT (0.5 – 6 hours) - Nausea, vomiting, diarrhoea, corrosion, haematemesis
2. Latent (6 – 24 hours) – Asymptomatic period
3. Metabolic acidosis/multiorgan failure
4. GIT stricture formation (6 – 8 weeks)

INVESTIGATIONS

Serum Iron Level

Take four hours (2 – 6 hours) after overdose and repeat at 6 – 8 hours if sustained release formulation of iron ingested. Will be falsely low in presence of desferrioxamine.

10 – 30 mcmol/l normal range
30 – 60 mcmol/l significant toxicity unlikely
60 – 90 mcmol/l possible toxicity/symptomatic patients should be treated
90 mcmol/l treat regardless of clinical state

If significant ingestion:

ABG
Glucose
INR
U&E’s
FBC
Invasive blood pressure monitoring
X-ray - to ensure adequate decontamination

MANAGEMENT

Decontamination

Iron is well known to form drug concretions (pharmacobezoar) and/or become adherent to the gastric wall due to its corrosive effect. Activated charcoal is not effective.

a. whole bowel irrigation
b. gastroscopic removal
c. gastrotomy
X-ray review following decontamination procedures should be performed to ensure removal of drug from the GIT.

Antidote

Desferrioxamine
15mg/kg/hour - up to 80mg/kg/day in first day…
Continue treatment until serum iron ≤ 60 mcmol/l, patient asymptomatic and urine colour is no longer “vin rosé” (ensure no iron remains in the gut).

Note:
a. hypotension following rapid infusion (?anaphylactoid reaction)
b. renal failure occur if patient hypovolaemic
c. prolonged (greater than 24 hour) infusions associated with ARDS
d. interference with serum iron measurement (spurious reduction)
e. pre-disposes patient to Yersinia enterocolitica infection

Supportive care

a. aggressive fluid replacement
b. correction of acidosis (sodium bicarbonate)
c. correction of coagulation disorders (fresh frozen plasma)

Iron

OVERVIEW

Iron poisoning typically occurs in children. In children, the ingestion of 2-5 tablets may cause significant toxicity. Iron poisoning causes gastrointestinal toxicity followed by multiorgan failure. The specific antidote, desferrioxamine, should be used in patients with high iron concentrations before severe toxicity develops.

SUBSTANCES INCLUDED IN THIS CATEGORY

Elemental iron is the major source of toxicity. However iron is available in a large number of different salts. To calculate the mg of elemental iron in a preparation

Ferrous sulphate (dried) doses divided by 3.3
Ferrous sulphate (heptahydrate) doses divided by 5
Ferrous gluconate dose divided by 9
Ferrous fumarate dose divided by 3
Ferric chloride dose divided by 3.5
Ferrous chloride dose divided by 4

MECHANISM OF TOXIC EFFECTS

Iron toxicity develops when serum iron concentrations exceed the iron binding capacity of transferrin in blood. The free circulating iron damages many organs by direct cellular toxicity, effects on vasculature and the release of vasodilating mediators.

KINETICS IN OVERDOSE

Absorption

Iron is absorbed poorly in therapeutic doses in the duodenum and jejunum. However, with the development of gastrointestinal toxicity the extent and area of absorption is increased. Thus, the peak concentrations after iron poisoning occur later and the bioavailability is higher.

Distribution

Iron is transported in the blood by transferrin. When the binding sites on transferrin are saturated the unbound iron reacts with blood vessels and platelets.

Metabolism - Elimination

There is no significant natural route of elimination other than by gastrointestinal cell loss and blood loss.

CLINICAL EFFECTS

A severe iron poisoning leads to multiorgan failure however, there are two preceding phases

Gastrointestinal toxicity
Window period

Gastrointestinal effects

A severe haemorrhagic gastroenteritis occurs within a few hours of ingestion. Vomiting occurs in virtually all patients with severe poisoning but is not a specific sign. If fluid loss is significant there may be hypotension, acidosis and central nervous system signs.

Window period

During this period (about 4-12 hours post overdose) gastrointestinal symptoms improve.

Multiorgan failure

Subsequently systemic toxicity develops with pronounced effects on the following organs

Gastrointestinal tract

severe haemorrhagic gastroenteritis
occasional gastrointestinal perforation

Central nervous system

lethargy
coma
convulsions

Cardiovascular system

intractable hypotension
pulmonary oedema

Renal toxicity

renal failure
acute tubular necrosis

Metabolic acidosis

severe lactic acidosis is common

Hepatotoxicity

severe hepatic necrosis may occur with peak ALT/AST occurring 1-4 days post ingestion
this may be complicated by
- hypoglycaemia
- coagulopathy

Coagulopathy
An early and a late type of coagulopathy may occur. The early type is probably due to a direct effect of iron on the coagulation cascade. It occurs rapidly and the aPTT is generally longer than the PT. It resolves rapidly when iron concentrations fall.

The late type is due to hepatic failure and a notable effect on the prothrombin time will not occur until after 24 hours. It may continue to get worse for several days, however, by analogy with paracetamol poisoning, it is likely that a PT that continues to rise after 3 to 4 days indicate a very poor prognosis.

INVESTIGATIONS

Patients should have the following investigations done urgently

Iron concentration
Full blood count and coagulation studies
Electrolytes
Glucose
Abdominal X-ray

Iron concentrations are used to determine the need for specific treatment. Abdominal X-rays may identify radio-opaque tablets however their absence does not exclude iron overdose. A raised white cell count and hyperglycaemia commonly occur early in poisoning. Other tests serve as a baseline with which to determine subsequent toxicity. These tests need to be repeated regularly in patients who develop gastrointestinal or other toxicity.

DETERMINATION OF SEVERITY

This may be done using clinical state, dose ingested and/or iron concentrations.

Dose ingested

Estimation of toxicity based on dose of elemental iron ingested

< 10-20 mg/kg - non toxic
20-60 mg/kg - potentially toxic
60-120 mg/kg - toxic but fatal outcome unlikely
> 120 mg/kg - potentially fatal

Iron concentrations

Iron concentrations give a good guide to subsequent chances of toxicity and guide therapy. Blood must be taken for iron concentrations prior to therapy with desferrioxamine.

10 - 30 micromol/L - normal range
30 - 60 micromol/L - significant toxicity is unlikely
60 - 90 micromol/L - possible toxicity/symptomatic patients should receive desferrioxamine
> 90 micromol/L - intravenous desferrioxamine therapy is indicated irrespective of clinical state

Conversion factor

mg/L x 17.92 = micromol/L
micromol/L x 0.056 = mg/L

TREATMENT

Supportive

Severe poisoning requires close monitoring (CVP line, arterial line, regular electrolytes, blood gases and blood sugar) and enthusiastic volume replacement. Patients may require blood transfusions, fresh frozen plasma and correction of acidosis.

GI Decontamination

Iron is not adsorbed by charcoal.

Patients with confirmed exposure to a potentially toxic dose should have gastric lavage and polyethylene glycol whole bowel irrigation if they present within 4 hours

have undissolved tablets on abdominal x-ray
have taken sustained release or enteric coated iron tablets

Antidotes

Desferrioxamine

Mechanism of action
Desferrioxamine chelates ferric irons. Desferrioxamine causes redistribution of iron from tissue sites back into plasma and the iron desferrioxamine complex is renally eliminated. Indications for desferrioxamine may be based on iron concentrations and clinical symptoms.

Indications
Desferrioxamine treatment should be started if

peak serum iron 3-6 hours after ingestion is
- above 90 micromol/L (normal range 10-30) or
- 500 micrograms/dL (normal range 60-180)

serum iron is over 60 micromol/L or serum iron not available AND significant symptoms of iron toxicity
- Gastrointestinal haemorrhage
- Severe hypotension
- Central nervous system signs
- Acidosis (therapy should be commenced without waiting for serum iron concentrations)

Desferrioxamine challenge
This test is often unreliable and is therefore no longer recommended.

Desferrioxamine dose
Desferrioxamine is given intravenously at a rate of 15 mg/kg body weight/hour. Reduce dose by 50% in severe renal impairment.
The urine will often, but not always, change to a vin rose colour.

Patients should receive an IV fluid bolus of 20 mL/kg normal saline before starting desferrioxamine to maintain intravascular volume and because the desferrioxamine-iron complex is renally cleared.

Ceasing desferrioxamine
Treatment should be continued until serum iron concentrations fall below 60 micromol/L and the urine (if it changed colour) has returned to normal. This normally means 6-8 hours of treatment but may be substantially longer in severe poisoning. Use of desferrioxamine for greater than 24 hours may result in non-cardiogenic pulmonary oedema.

LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP

Patients with initial severe gastrointestinal toxicity may develop gastric and pyloric scarring and obstruction.

REFERENCES

Mills KC, Curry SC. Acute iron poisoning. Emergency Medicine Clinics of North America 1994;12:397-413.
Tenenbein M. Benefits of parenteral deferoxamine for acute iron poisoning. Journal of Toxicology - Clinical Toxicology 1996; 34(5):485-9.