New Zealand National Poisons Centre

1. New Zealand National Poisons Centre

2. IRON OVERDOSE

3. IRON 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.

4. TOXIC MECHANISM • 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

5. SIGNS AND SYMPTOMS “Classic” 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

6. STAGE I – GASTROINTESTINAL • Initial symptoms are secondary to direct irritant and corrosive effect of iron. In larger overdoses, lipid peroxidation causes further injury. Complaints include: • Epigastric pain • Nausea / vomiting • Diarrhoea • In more severe cases • Haematemesis • Vasodilation • Third spacing • Hypotension • Metabolic acidosis may also develop during this initial stage leading to the latent phase being “by-passed”.

7. STAGE II – 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.

8. STAGE III – SHOCK, MULITORGAN FAILURE, ACIDOSIS • Loss of adequate tissue perfusion and multiorgan failure: most deaths occur during this stage. • Shock occurs secondary to gastrointestinal haemorrhage, vomiting, third-spacing, vasodilation, and reduced cardiac output (due to myocardial toxicity). • Multiorgan failure related to inadequate perfusion and direct toxicity ensues and results in: • Altered mental status / coma • Seizure • Acute renal failure • Pulmonary oedema

9. STAGE IV – HEPATOTOXICITY • Hepatic dysfunction is a poor prognostic sign. Patients suffer related: • Hypoglycaemia • Coagulopathy and haemorrhage • Jaundice • Hepatic encephalopathy / coma

10. STAGE V – GASTROTINESTINAL OBSTRUCTION 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.

11. DIAGNOSIS • History of ingestion • 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

12. HISTORY OF INGESTION Note that the elemental quantity of iron in tablets needs calculation. 5 x Fergon tablets (300 mg ferrous gluconate) ingested by a child: 5 x 300 mg / 10 kg = 150 mg/kg In fact only 11% (33 mg) of the tablet is elemental iron: 5 x 33 mg/10 kg = 16.5 mg/kg

13. DECONTAMINATION • Activated charcoal will not bind iron, therefore it is necessary to administer whole bowel irrigation. • Appropriate decontamination is recommended: • For ingestions greater than 60 mg/kg elemental iron • Follow WBI with AXR to ensure removal of iron

14. INTERVENTION CRITERIA • Less than 60 umol/L (335 ug/dL) • Discharge into the care of a responsible guardian 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

15. INTERVENTION CRITERIA • 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

16. INTERVENTION CRITERIA Greater than 90 umol/L (500 ug/dL) Admit regardless of symptoms for management, including treatment with desferrioxamine

17. CHELATION • Indicated in all cases with signs of systemic intoxication and especially those with an high anion gap metabolic acidosis. • Desferrioxamine • 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

18. SUPPORTIVE CARE Cardiovascular Hypotension is a significant problem and may be due to haemorrhage, third spacing, vasodilation and compromised cardiac output. Initially robust fluid replacement is required. In severe cases invasive blood pressure monitoring is warranted to guide management.

19. 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. Acute Liver Failure A poor prognostic sign: requires management of hypoglycaemia, coagulopathy (factor replacement), and early consultation with a liver unit.

20. GIT PLASMA LABILE POOL TISSUES Fe Fe Fe-Trans Fe CNS Lungs Heart Liver Pancreas Fe Fe Fe Fe Fe Fe Fe-Trans Fe Fe Fe Fe Fe Fe-Trans Fe Fe Fe Fe Fe Fe Fe Fe CNS Lungs Heart Liver Pancreas Fe Fe-Trans Fe Fe Fe Fe-Trans Fe Fe Fe-Trans Fe Fe Fe