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wikitox:2.1.9.6_iron [2018/09/01 09:00] (current)
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 +Links to [[:​wikitox:​2.1.9.6_iron_teaching_resources|2.1.9.6 Iron Teaching Resources]]
 +
 +----
 +
 +====== 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:
 +
 +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
 +
 +===== 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 distinct phases:
 +
 +**Acute gastrointestinal toxicity (0.5–6 hours post ingestion)**
 +
 +A severe haemorrhagic gastroenteritis (nausea, vomiting, diarrhoea, corrosion, haematemesis) 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.
 +
 +**Latent or window period (4–12 hours post ingestion)**
 +
 +During this period gastrointestinal symptoms improve.
 +
 +**Metabolic acidosis/​multiorgan failure (6–72 hours post ingestion)**
 +
 +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.
 +
 +**GIT stricture formation (2–6 weeks post ingestion)**
 +
 +===== 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 (as well as blood gases and invasive blood pressure monitoring) need to be repeated regularly in patients who develop gastrointestinal or other toxicity.
 +
 +==== Serum 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
 +
 +**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
 +
 +===== 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
 +===== TREATMENT =====
 +
 +==== Supportive ====
 +
 +Severe poisoning requires close monitoring (CVP line, arterial line, regular electrolytes,​ blood gases and blood sugar) and enthusiastic [[:​wikitox:​3.4.8_fluid_resuscitation|volume replacement]]. Patients may require blood transfusions,​ fresh frozen plasma and correction of acidosis.
 +
 +==== GI Decontamination ====
 +
 +Iron is well known to form drug concretions (pharmacobezoar) and/or become adherent to the gastric wall due to its corrosive effect. [[:​wikitox:​3.2.2.2.3_activated_charcoal|Activated charcoal]] is not effective as iron is not adsorbed by charcoal.
 +
 +**[[:​wikitox:​3.2.2.2.4_whole_bowel_irrigation_lavage|Whole bowel irrigation]]**
 +
 +Patients with confirmed exposure to a potentially toxic dose should have [[:​wikitox:​3.2.2.2.2_gastric_lavage|gastric lavage]] and [[:​wikitox:​3.2.2.2.4_whole_bowel_irrigation_lavage|polyethylene glycol whole bowel irrigation]] if they present within 4 hours and:
 +
 +  * have undissolved tablets on abdominal x-ray
 +  * have taken sustained release or enteric coated iron tablets
 +
 +If persistent iron present on X-ray then consider:
 +
 +  * **Gastroscopic removal**
 +  * **Gastrotomy**
 +X-ray review following decontamination procedures should be performed to ensure removal of drug from the GIT.
 +
 +==== 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 are based on clinical symptoms and/or iron concentrations.
 +
 +Note:
 +
 +  * Hypotension following rapid infusion (a possible anaphylactoid reaction)
 +  * Renal failure can occur if patient hypovolemic
 +  * Prolonged (greater than 24 hour) infusions associated with non-cardiogenic pulmonary oedema
 +  * Interference with serum iron measurement (spurious reduction)
 +  * Pre-disposes patient to Yersinia enterocolitica infection
 +
 +**//​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)
 +
 +OR
 +
 +  * 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 [[:​wikitox:​non_cardiogenic_pulmonary_oedema|non-cardiogenic pulmonary oedema]].
 +
 +===== LATE COMPLICATIONS,​ PROGNOSIS - FOLLOW UP =====
 +
 +Patients with initial severe gastrointestinal toxicity may develop gastric and pyloric scarring and obstruction.
 +
 +===== REFERENCES =====
 +
 +[[http://​www.ncbi.nlm.nih.gov/​entrez/​query.fcgi?​cmd=Retrieve&​db=PubMed&​list_uids=8187690&​dopt=Abstract|Mills KC, Curry SC.]] Acute iron poisoning. Emergency Medicine Clinics of North America 1994;​12:​397-413. \\
 +[[http://​www.ncbi.nlm.nih.gov/​entrez/​query.fcgi?​cmd=Retrieve&​db=PubMed&​list_uids=8800185&​dopt=Abstract|Tenenbein M.]] Benefits of parenteral deferoxamine for acute iron poisoning. Journal of Toxicology - Clinical Toxicology 1996; 34(5):​485-9.
 +
  
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