Arun K. Baranwal
Sunit C. Singhi
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.
. Emesis and Lavage
. Abdominal radiograph
. Send serum iron
. Blood glucose and counts
. Observe fox six 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.
|
|
1. Anderson AC. Iron poisoning in children.
Curr Opin Pediatr 1996; 6: 289-294.
2. Ercal N, Gurer-Orban H, Aykin-Burns N.
Toxic metals and oxidative stress part I: Mechanisms involved in
metal-induced oxidative damage. Curr Top Med Chem 2001; 1:
529-539.
3. Robotham JL, Lietman PS. Acute iron
poisoning: A review. Am J Dis Child 1980; 134: 875-879.
4. Link G, Saada A, Pinson A, Konijn AM,
Hershko C. Mitochondrial respiratory enzymes are a major target
of iron toxicity in rat heart cells. J Lab Clin Med 1998; 131:
466-474.
5. Bartfay WI, Hou D, Lehotay DC, Luo X,
Bartfay E, Backx PH, et al. Cytotoxic aldehyde generation
in heart following acute iron-loading. J Trace Elem Med Biol
2000; 14: 14-20.
6. Pestaner JP, Ishak KG, Mullick FG, Centeno
JA. Ferrous sulfate toxicity: A review of autopsy findings. Biol
Trace Elem Res 1999; 69: 191-198.
7. Schauben JL, Augenstein WL, Cox J, Sato R.
Iron poisoning: Report of three cases and a review of
therapeutic intervention. J Emergency Med 1990; 8: 309-319.
8. Ioannides AS, Panisello JM. Acute
respiratory distress syndrome in children with acute poisoning:
the role of intravenous desferri-oxamine. Eur J Pediatr 2000;
159: 309-319.
9. Tenenbein M. Hepatotoxicity in acute iron
poisoning. Toxicol Clin Toxicol 2001; 39: 721-726.
10. Siff JE, Meldon SW, Tomasssoni AJ.
Usefulness of the total iron binding capacity in the evaluation
and treatment of acute iron overdose. Ann Emerg Med 1999; 33:
73-76.
11. Lacouture PG, Wason S, Temple AR, Wallace
DK, Lovejoy FH Jr. Emergency assessment of severity of iron
overdose by clinical and laboratory assessment J Pediatr 1981:
99: 89-91.
12. Michael KA, DiPiro JT, Bowden TA, Tedesco
FJ. Whole-bowel irrigation for mechanical colon cleaning. Clin
Phann 1985; 4: 414-424.
13. Tenenbein M. Whole bowel irrigation in
iron poisoning. J Pediatr 1987; III: 142-145.
14. Chyka P A, Butler A Y, Herman MI. Ferrous
sulfate adsorption by activated charcoal. Vet Hum Toxicol 2001;
43: 11-13.
15. Jones S, All B. Towards evidence-based
emergency medicine–Best BETs from the Manchester royal
infirmary. Activated charcoal and gastric absorption of iron
compounds. Emerg Med J 2002; 19: 49.
16. Whitten CF, Gibson GW, Good BS, Goodwin
JF, Brough AJ. Studies in acute iron poisoning. I.
Desferrioxamine in the treatment of acute iron poisoning:
clinical observations, experi-mental studies, and theoretical
considerations, Pediatrics, 1965; 36: 322-335; and Studies in
acute iron poisoning. II. Further observations on
desferrioxamine in the treatment of acute experimental iron
poisoning, Pediatrics, 1966; 38: 102-110.
17. Klein-Schwartz W, Oderda GM Gorman RL
Favin F, Rose SR. Assessment of management guidelines in acute
iron ingestion. Clin Pediatr 1990; 29: 316-321.
18. Banner W, Tong TG. Iron Poisoning.
Pediatr Clin North Am 1986; 33: 393-409.
19. Berkovitch M, Livne A, Lushkov G, Segal
M, Talmor C, Bentur Y, et al. The efficacy of oral
deferiprone in acute iron poisoning. Am J Emerg Med 2000; 18;
36-40.
20. Dragsten PR, Hallaway FE, Hanson GJ,
Berger AE, Bernard B, Hedlund BE. First human studies with a
high-molecular-weight iron chelator. J Lab Clin Med 2000; 135:
57-65.
21. Bartfay WJ, Hou D, Brittenham GM, Bartfay E, Sole MJ,
Lehotay D, et al. The synergistic effects of vitamin E
and selenium in iron-overloaded mouse hearts. Can J Cardio11998;
14: 937-941.
|