IRON ToxicityMuhammad Asim Rana

MBBS, MRCP, MRCPS, EDIC, SF-CCM, FCCPDepartment of Critical Care Medicine

King Saud Medical City Riyadh, Saudi Arabia

Iron Metabolism

In healthy adults ~ 2 to 10% of dietary iron absorbed

• In iron deficiency states (including children) 80 to 90% is absorbed

• In overdose, there is proportionally less of an ingested dose absorbed compared to a therapeutic dose, however, damage to intestinal mucosa can increase absorption

Following absorption iron is bound to transferring and actively taken up by the liver during “first pass”. The remaining iron is transported by transferrin, primarily to the bone marrow.

Iron Metabolism

In overdose total iron binding capacity is surpassed and free Ferric iron (Fe+++) is present in the blood:

• Free protons are liberated leading to acidosis• Fe3+ + 3H2O FE(OH)3 + 3H+

• Fe+++ leads to production of the OH. radical, in turn causing lipid peroxidation and: - Local tissue injury – primarily the gut and liver- Mitochondrial damage with loss of cellular aerobic respiration

• Free iron is a vasodilator

• Direct depression of coagulation factors

Clinical sequel of Iron overload

Stages of iron poisoning Stage I Gastrointestinal 30m to 6 hrs

Stage II Latent phase 2 to 4 hrs

Stage III Shock / multiorgan failure / acidosis 2 to 24 hrs

Stage IV Hepatotoxicity 12 to 24 hrs

Stage V Gastrointestinal obstruction 1 to 7 wks

1ST Stage: – Develops within the first few hours after the

ingestion. The direct irritative effects of iron on the gastrointestinal (GI) tract produce abdominal pain, vomiting, and diarrhea. Hematemesis is not unusual.

– Vomiting is the clinical sign most consistently associated with acute iron toxicity. The absence of these symptoms within 6 hours of ingestion essentially excludes a diagnosis of significant iron toxicity.

2nd Stage (Latent Stage)– which may continue for up to 24 hours after

ingestion, the patient’s GI symptoms may resolve, thereby producing a false sense of security despite toxic amounts of iron being absorbed into the body.

– Patients may not be symptomatic but still appear ill and may have abnormal vital signs and evidence of poor tissue perfusion because of ongoing volume loss and worsening metabolic acidosis.

Watch Out Latent Phase !!!

A period where there is a deceptive apparent improvement in the patient’s gastrointestinal condition. It is often tempting to discharge such patients.

However, in the seriously poisoned, a metabolic acidosis is evolving. This may be compounded by a lack of adequate fluid resuscitation.

3rd Stage may appear early or develop hours after the second stage.

Loss of adequate tissue perfusion and multi-organ failure: – most deaths occur during this stage.

Shock occurs secondary to gastrointestinal haemorrhage, vomiting, third-spacing, vasodilatation, and reduced cardiac output (due to myocardial toxicity).

Multi-organ failure related to inadequate perfusion and direct toxicity ensues and results in:– Altered mental status / coma– Seizure– Acute renal failure– Metabolic Acidosis– Pulmonary oedema

4th Stage develops 2 to 5 days after ingestion. It

manifests as elevation of aminotransferase and may progress to hepatic failure.

Patients may suffer from:– Hypoglycaemia– Coagulopathy and haemorrhage– Jaundice– Hepatic encephalopathy / coma

5th Stage– which occurs 4 to 6 weeks after Ingestion, involves

gastric outlet obstruction secondary to the corrosive effects of iron on the pyloric mucosa.

In survivors mucosal injury may lead to the formation of strictures. Though usually occurring at the pylorus, they may be found throughout the gastrointestinal tract. Actual obstruction is, however, rare.

Diagnosis & Differentials The diagnosis of iron poisoning is based on the clinical

picture and the history provided by the patient, significant others, or out-of-hospital care providers.

Toxic effects have been reported after oral doses as low as 10 to 20 mg/kg elemental iron.

Moderate toxicity occurs at doses of 20 to 60 mg/kg elemental iron, and severe toxicity can be expected after doses larger than 60 mg/kg elemental iron.

What do you do? Take history of ingestion and decide:

– Ingestions of 40 to 60 mg/kg should be medically assessed; those above 60 mg/kg should be decontaminated.

Investigation

– Abdominal x-ray– Serum iron concentration at 2 to 4 hours post-ingestion

Investigations Laboratory work should be sent for

– Serum electrolytes, blood urea nitrogen– Serum glucose, coagulation studies – Complete blood count – Hepatic enzymes & serum iron level.

It is crucial to note that the determination of a single serum iron level does not reflect – what iron levels have been previously– what directions they are going– the degree of iron toxicity in the tissues.

Remember !

A single low serum level does not exclude the diagnosis of iron toxicity because there are variable times to peak level after ingestion of different iron preparations.

Serum iron levels have limited use in directing management because excess iron is toxic intra- cellularly and not in the blood.

Remember !

In general, serum levels between 300 and 500 µg/dL correlate with mild systemic toxicity and iron levels between 500 and 1,000 µg/dL are associated with significant morbidity. The total iron-binding capacity (TIBC) is currently thought to have little value in the assessment of iron-poisoned patients because it becomes falsely elevated in the presence of elevated serum iron levels or desferoxamine.

Remember !

A plain radiograph of the kidneys, ureters, and bladder may show iron in the GI tract; however, many iron preparations are not routinely detected, so negative radiographs do not exclude iron ingestion.

Initial Care

Patients who have remained asymptomatic for 6 hours after ingestion of iron and who have a normal physical examination do not require medical treatment for iron toxicity.

Patients whose symptoms resolve after a short period and who have normal vital signs usually have mild toxicity and require only supportive care. – This subset of patients still requires an observation period.

Intervention Criteria

Less than 60 umol/L (335 ug/dL) Discharge if

– - Asymptomatic, and– - Iron not detected on abdominal x-ray, and– - Formulation ingested was not sustained release or enteric-

coated Observe and repeat iron serum concentration at 4 to 6 hours

post-ingestion if:– - Patient symptomatic (treatment may be indicated by

severity), or– - Iron detected on abdominal x-ray, or– - Sustained release or enteric-coated formulation ingested

60 to 90 umol/L (335 to 500 ug/dL) Observe and repeat serum iron concentration at 4 to 6

hours post-ingestion if:– Asymptomatic, and– Iron not detected on abdominal x-ray, and– Sustained release or enteric-coated formulation

ingested 

Admit for management if:– Symptomatic– Iron detected on abdominal x-ray

Greater than 90 umol/L (500 ug/dL)

Admit regardless of symptoms for management, including treatment with desferrioxamine

Subsequent Management

– Patients should receive supplemental oxygen, be placed on a cardiac monitor, and have 2 large-bore intravenous (IV) lines established.

– Patients should receive vigorous IV crystalloid infusion to help correct hypovolemia and tissue hypoperfusion.

Subsequent Management– Patients who present within 2 hours of ingestion

should undergo gastric lavage.

– Activated charcoal does not bind iron, and its use is not recommended.

– Whole bowel irrigation with polyethylene glycol solution has been demonstrated to be efficacious. Administration of 250 to 500 mL/h in children and 2L/h in adults via nasogastric tube may clear the GI tract of iron pills before absorption occurs.

– Antiemetics such as promethazine (25 mg intramuscularly [IM] in adults; 0.25-0.5mg/kg IM in pediatric patients) or ondansetron (4 mg IV in adults; 0.1mg/kg to a maximum dose of 4 mg in adults;0.1 mg/kg to a maximum dose of 4 4mg in pediatric patients) should be administered.

– Coagulopathy should be corrected with vitamin K1 (5-25 mg. subcutaneously (SQ) and fresh-frozen plasma 10-25 mL/kg in adults; 10 ml/kg in pediatric patients). Blood should be typed and screened or cross matched, as necessary.

– Deferoxamine is a chelating agent that can remove iron from tissues and free iron from plasma. Deferoxamine combines with iron to form water soluble ferrioxamine, which is excreted in the urine. Deferoxamine is safe to administer to children and pregnant women.

– Patients with mild iron toxicity may be treated with deferoxamine 90 mg/kg IM, up to 1 g in children and 2 g in adults. The dose may be repeated every 4 to 6 hours, as clinically indicated.

Desferrioxamine Indicated in all cases with signs of systemic intoxication and

especially those with an high anion gap metabolic acidosis.

15 mg/kg/hr up to 80 mg/kg/d Continue until acidosis reversed and symptoms have resolved

(do not rely on vin rosè coloured urine).

Note:• Hypotension following too rapid infusion• Renal failure in hypovolaemic patients• Prolonged (>24 hour) infusion associated with ARDS• Interference with serum iron measurement

Chelation Therapy

Chelation Therapy

Supportive Care

Cardiovascular– Hypotension is a significant problem and may be

due to haemorrhage, third spacing, vasodilatation and compromised cardiac output.

– Initially robust fluid replacement is required. – In severe cases invasive blood pressure monitoring

is warranted to guide therapy.

Supportive Care

Acute Renal Failure

– Acute renal failure generally occurs secondary to shock.

– Haemodialysis should be employed increase removal of iron-chelate, it will not remove iron itself.

Supportive Care

Acute Liver Failure

– A poor prognostic sign: – requires management of

hypoglycaemia, coagulopathy (factor replacement) early consultation with a liver unit.

Thank You !