Indian Pediatrics 2003; 40:534-540 

Acute Iron Poisoning: Management Guidelines

From the Department of Pediatrics, B.P. Koirala Institute of Health Sciences, Dharan, Nepal and *Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Correspondence to: Professor Sunit C. Singhi, Head, Pediatric Emergency and Intensive Care Unit, Advanced Pediatric Center, PGIMER, Chandigarh 160 012, India.
E-mail: [email protected]

Abstract: Serum iron level may not be available and fully reliable in management decision and prognostication in our setting. An estimated ingestion of >60 mg/kg elemental iron, onset of symptoms, blood sugar >150 mg/dL, total leukocyte count >15,000 cumm and presence of iron tablets on abdominal radiograph indicates severe toxicity and need for chelation therapy. Appearance of ‘vin-rose’ color urine following a dose of desferrioxamine may be helpful, but is not seen consistently after chelation therapy. Early decontamination of gut (gastric lavage /whole gut irrigation), desferrioxamine infusion (15 mg/kg/hour in saline) and aggressive management of shock, and organ failure preferably in a PICU are mainstay of management, and has improved the outcome. Shock, coagulopathy (prothrombin index <50%), severe acidosis and acute liver failure are poor prognostic indicators. Guardians should be counseled about safe storage of iron tablets meant for adults, and general poisoning prevention measures.

Key words: Acute iron poisoning, Children, Desferrioxamine.

In case of an overdose, iron causes corrosive damages to gastrointestinal (GI) mucosa and can lead to acute hemorrhagic gastritis, massive fluid loss (because of third spacing), bleeding and shock(1). In addition, large amounts of ingested iron overwhelm normal gastrointestinal barriers, resulting in massive iron absorption. When serum iron level exceeds the body’s binding capacity, free iron produces an increase in reactive oxygen species (ROS) or so called oxygen, free radicals, such as hydroxyl radical, superoxide radical or hydrogen peroxide(2) leading to lipid peroxidation and cellular membrane damage. Enhanced generation of ROS can overwhelm cells’ intrinsic antioxidant defenses and result in "oxidative stress", a term used to describe cellular dysfunction caused by ROS induced damage to lipids, proteins and DNA(2).

Intracellularly, it exerts its toxic effect on mitochondria by shunting electrons away from the electron transport chain, uncoupling the oxidative phosphorylation(3). It leads to anerobic metabolism and thus metabolic acidosis. Iron also causes massive post-arteriolar dilatation, increased capillary permeability and coagulopathy leading to severe acidosis and shock, within first few hours. Myocardial failure, caused by ROS induced myocardial damage and other mechanisms(4,5) further contribute to shock. Besides the myocardium, iron affects almost every organ in the body being a systemic intra-cellular poison. It can cause acute periportal hepatic necrosis(6) and occasionally pulmo-nary damage, renal damage and pancreatic necrosis.

Clinical Features

Children below 5 years of age are particularly prone to iron poisoning as also with other accidental poisoning due to their activity level, curiosity and oral phase of development. It is more common in male children. Clinical effects of acute iron poisoning have been described in four progressive stages as shown in Table I. These are as follows:

Table I
Clinical Features and Time Course of Acute Iron Poisoning. 

stage	System involved	Onset of symptoms	Symptoms
I.	Gastrointestinal toxicity	0-3 hr	Vomitting, hematemesis, diarrhea, abdominal pain, restlessness, lethargy.
II.	Apparent stabilization	ti11 12 hr	Symptoms subside
III.	Mitochondrial toxicity	12-48 hr	Shock, acidosis, coma, seizures, hyperglycemia, coagulopathy, acute tubular necrosis, hypoglycemia.
	Hepatic necrosis	> 48 hrs	Jaundice, hepatic encephalopathy.
IV.	Gastric scarring	2-4 weeks	Gastric scarring, gastric/pyloric strictures.

Note: Child may directly go to stage III depending on severity of intoxication 

 

Stage-I (Stage of gastrointestinal toxicity): GI effects may contribute to systemic hypovolemia by causing ‘third spacing’ of fluid into the small bowel. In severe cases central nervous system depression and cardiovascular collapse can also occur in this stage. Mucosal damage may cause fever and leucocytosis whereas pancreatic and hepatic injury by absorbed iron can cause hyper-glycemia(1). Serum iron level may not be in toxic range (<350 µg/dL) as it peaks 4 to 6 hours after acute overdose(7).

Stage-II (Stage of apparent stabilization or quiescent phase): The apparent stabilization is said to be due to redistribution of free circulating iron from intravascular space into reticuloendothelial cells and intracellular compartment(1).

Stage-III (Stage of mitochondrial toxicity): Occasionally a child may directly go into shock and develop other features of Stage-III without manifesting GI symptoms. Besides hepatic injury, acute tubular necrosis, pulmonary hemorrhage, and acute respiratory distress syndrome may occur at this stage(8). Serum iron may be in nontoxic range due to its shift to intracellular compartment. In a severe poisoning (heavy ingestion) or if the child is left untreated for 48 hours, acute liver failure may occur manifesting with jaundice and/or hepatic encephalopathy, hypoprothrom-binemia and hypoglycemia. The lowest reported acute serum iron concentration associated with hepatoxicity is 1700 µg/dL(9) but we have seen it at much lower serum iron (unpublished observations).

Stage-IV (Stage of gastric scarring): This may occur after 2-6 weeks of acute poisoning in very severe cases and usually present with recurrent vomiting secondary to gastric outlet obstruction.

Assessment of Toxic Potential: Prediction of Severe Toxicity

When an asymptomatic child is brought with ingestion of iron tablets, his likelihood to develop toxicity needs be assessed to guide further therapy. Parameters used for assess-ment of severity of toxicity at arrival include clinical presentation, amount of ingested, serum iron level, and total iron-binding capacity.

Dose of ingested iron

Assessment could be based on the elemental iron content of the specific product as well as its formulation viz., rapid versus sustained release. When calculating the ingested dose one should remember that elemental iron per unit of tablet is only a fraction of weight of tablet. Ferrous sulfate, the most commonly ingested form of iron, is 20% elemental iron; ferrous fumerate has 32% elemental iron. Unreliability is inherent in poisoning and overdose histories. Hence, a child should be assumed to have consumed the higher value of possible ingested dose (e.g., if mother says 5-10 tablets, assume it is 10 tablets). The lethal dose of elemental iron is said to be 200-250 mg/kg, although GI symp-toms may be seen at dose of 15-30 mg/kg. Early GI effects i.e., vomiting and diarrhea may limit iron absorption as well as systemic toxicity.

A triage has been suggested based on amount of alleged iron ingestion(7):

< 20 mg/Kg - Little risk for toxicity. Decontaminate and observe for at least 6 hours.

20-60 mg/Kg - Moderate risk for toxicity. Decontaminate and observe for 6 hours. Consider desferrioxamine chelation therapy.

>60 mg/Kg - High risk for toxicity. Decontaminate and start chelation therapy.

Serum iron level

Peak serum iron level usually occurs between 4 and 6 hour of ingestion. A serum iron level more than 350 µg/dL between 2 to 6 hours post-ingestion is said to indicate significant intoxication and levels greater than 500 µg/dL suggest serious risk of severe (Stage III) manifestation(7). In our experience many patients arrive late, hence a serum iron level less than 350 µg/dL at arrival may not rule out serious intoxication. Another drawback with use of serum iron as a guide to therapy is that the report of serum iron should be available immediately to enable a timely therapeutic decision-making, which is not feasible in most of health care facilities in our country.

Total iron binding capacity (TIBC)

TIBC has been used widely as a predictor of end organ toxicity and as a guide to deferoxamine therapy(10). It is held that when TIBC is greater than serum iron concentration no free iron is present to cause toxicity. However, TIBC fails as a marker of toxicity on several counts. The laboratory methods to measure TIBC are inaccurate in the setting of iron overload, presence of desferrioxamine -used as antidote makes TIBC measurement inaccurate, and studies have demonstrated iron toxicity even when TIBC was greater than serum iron(10).

Early clinical assessment and simple laboratory screening

These are quite predictive of patients whose iron levels are greater than 350 µg/dL. Initial assessment of these patients should therefore include careful recording of vital signs, mental status, X-ray abdomen, leuko-cyte count, blood glucose, coagulation studies, hepatic enzymes, blood gases and urea and electrolytes. Significant vomiting or diarrhea, shock, coma, iron tablets on abdo-minal radiograph, coagulopathy, metabolic acidosis (serum bicarbonate <15 mEq/L), hyperglycemia (blood sugar >150 mg/dL) and leucocytosis (TLC >15,000/cumm) all show a high correlation with elevated serum iron(11). These may be useful indicators of severe toxicity, and help in therapeutic decision making (Fig.1). If child remains asympto-matic for 6 to 8 hours after ingestion, further intervention is usually not required. Some recommend a desferrioxamine (40- 50 mg/Kg, maximum 1 g) challenge test immediately at admission to detect toxic potential while decontamination is being performed. If color of urine becomes ‘vin-rose’, excess free iron is present(7). However, a change of urine color to vin-rose is not a consistent finding even if serum iron is >350 µg/dl and it may lead to a delay of 1 to 3 hours.

 

 

 

 

Radio graph +ve or                       Ramains                                    Lab results -
Serum Fe>350 or                         asymptomatic, but                      Normal.
Symptoms appear                        WBC >15000 or                          Remains
                                                  Blood glucose > 150                     asymptomatic

 

 

Admit                                                                                          Discharge

 

       Positive                  Desferrioxamine challenge                    Negative

Fig. 1. Initial approach to an asymptomatic patient with iron ingestion.

Decontamination

Gastric lavage with the largest available tube should be done at the first-contact health care facility if a child has ingested iron in excess of 20 mg/Kg or is symptomatic. The use of a small bore nasogastric tube has no role in the management of iron tablet ingestions as these will not allow the passage of intact tablets, large fragments of tablets or small concretions. A post lavage abdominal radiograph should be obtained to look whether lavage has cleared all the tablets from stomach; if not, lavage should be repeated. Tap water or normal saline is the best lavage solution; bicarbonate, phosphate, magnesium hydroxide or desferrioxamine do not have any proven advantage. If facilities for further management are not available, the child should be referred to a tertiary care center as early as possible. At the referral receiving center, gastric lavage must be done in all the cases irrespective of their treatment at peripheral health facility.

Whole bowel irrigation (WBI) may benefit children in whom abdominal X-ray reveal tablets beyond the pylorus or throughout the gastrointestinal tract(7). In situations, where abdominal X-ray is not possible, it is better to give WBI after gastric lavage for rapid and effective cleansing of gut. WBI is also indicated when serum iron level continues to rise despite proven decontamination efforts (2). For WBI, polyethylene glycol lavage solution (Peglec®) may be given through nasogastric tube at rate of 30-40 ml/Kg/hr for 4-8 hours. It will cause diarrhea within 20 minutes and clear effluent will be apparent in as early as 90 minute(12). Peglec® is safe for children and does not cause fluid and electro-lyte changes(13). Alternatively, nasogastric infusion of normal saline (30-40 ml/hr) for 2-3 hours may be used.

Activated charcoal has been used to adsorb ingested iron and is likely to be effective especially in ferrous sulfate over-dose(14,15) but it is not used often because of widely held belief that it binds poorly to iron.

Iron Chelation Therapy

Desferrioxamine (or deferoxamine) is the only approved iron chelator currently available for clinical use as a specific antidote. Each 100 mg of desferrioxamine binds to 9 mg of elemental iron producing ferrio-xamine complex, which gets excreted by kidney(16).

Desferrioxamine is given as continuous intravenous infusion in normal saline at 15 mg/kg/hour (maximum daily dose 360 mg/kg, and total 6 g). A higher rate of infusion may cause hypotension(16). Disappearance of vin-rose urine, which is attributed to presence of desferrioxamine-iron complex, is traditionally considered as end-point for desferrioxamine therapy. However, normal urine color in presence of high serum iron has been reported(17) making the decision regarding the end point difficult. Stable clinical state of the patient combined with urine color in response to desferrioxamine, and if possible a serum iron <100 µg/dL is probably the more appropriate end-point.

In peripheral health care facilities establishing and maintaining intravenous line may be difficult. In such situations intra-muscular desferrioxamine (50 mg/kg up to 1 g every 4 hr) can be used. However, it may not be effective in patients with poor perfusion. A dose of intramuscular desferrioxamine should also be given to a child is who is on the way to a referral center for further management Desferrioxamine along with exchange trans-fusion is indicated in patients with free iron level >1000 µg/dl. Patients with renal failure require hemodialysis to remove desferri-oxamine-iron complex(18).

Other chelator therapies are still experimental. Efficacy of orally administered iron chelator deferiprone in acute iron poisoning is still under investigation though findings from experimental studies in animals hold promise for its use in humans(19). A new high molecular weight iron chelator has been produced by coupling desferrioxamine (DFO) to hydroxyethyl starch (HES). Intravenous infusion of this new chelator HES-DFO is well tolerated and produced substantial and prolonged chelation and stimulates urinary iron excretion(20).

Experimental studies in mouse suggest that vitamin E and selenium function synergistically in the myocardium to provide important antioxidant defenses in iron overloaded states(21). Use of antioxidants though very logical, has not been reported so far in human studies.

Life Support Measures

If facilities are available, these children should be managed in Pediatric Intensive Care Unit. Initial resuscitative requirement include management of airway, establishment of a venous access and fluid resuscitation using normal saline or Ringer lactate solution. Blood transfusion may be required to replace the blood loss in hematemesis and malena. A severely intoxicated child needs careful monitoring for vital signs, gastrointestinal hemorrhage, fluid intake and output, blood gases and electrolytes. Hemodynamic and respiratory monitoring is helpful in early detection and management of life threatening complications particularly shock. Manage-ment of shock requires fluids, a CVP line for continuous assessment of intravascular volume, and inotrops (dopamine upto 15 µg/kg/hr) to support failing myocardium. Maintenance of an adequate urine output (» 1 ml/kg/hr) is essential to prevent renal failure and to promote excretion of iron-deferoxamine complex. In later stages, some patients may need ventilatory, hepatic and/or renal support. Early liver transplant should be considered in those with hepatic necrosis (9).

Outcome

Most patients with iron poisoning respond well to conservative therapy. Shock has been closely linked to the outcome and had led to death in all patients if left untreated. Early chelation therapy reduces mortality. Occurrence of acute liver failure with iron poisoning is associated with high mortality(9). It is because of direct cytopathic effect of iron on periportal area of hepatic lobules(6), which is the primary site of hepatic regeneration(9). In our experience, patients who died had either shock and/or, acute liver failure and on laboratory investigation a prothrombin Index >50% or acidosis (serum bicarbonate <12.5 mEq/L). Majority of survivors have normal outcome and excellent long-term prognosis. However, patients must be carefully followed up for occasional development of gastric scarring and liver fibrosis.

Contributors: AKB did early literature search and wrote first draft of the paper. SS was involved in conceptualization, further literature search and writing final draft. He will act as guarantor to the paper.

Funding: None.

Competing interests: None stated.

Key Messages

• Inital diagnosis of acute iron poisoning should depend on history, presence of tablets on abdominal radiographs, high blood sugar and leucocyte count in symptomatic children. • Early decontamination of gut, desferioxamine infusion and management of shock are mainstay of treatment.

 

 References