Assessment of

Management Guidelines Acute Iron

Wendy Klein-Schwartz, PharmD,* Gary

Ingestion

M. Oderda, PharmD, MPH,* Richard L. Gorman, MD,* Fran Favin, PharmD,† S. Rutherfoord Rose, PharmD‡

A review of 339 treated acute iron ingestions was conducted to define treatment guidelines better. According to the poison center protocol, ingestions of 20-40 mg/kg of elemental iron required only home treatment, and ingestions of ≥40 mg/kg required hospital referral. Gastrointestinal symptoms developed in 23% of patients. There were no seriously ill patients. No serious toxicity developed in patients ingesting 40-60 mg/kg. In 199 cases in which the dose ingested was known, the mean dose was 39.5 mg/kg. The peak measured serum iron levels ranged from 12 to 539 μg/dl. In 129 cases with serum iron levels reported, increasing serum iron levels were associated with vomiting (p 0.006). Of 88 patients who received deferoxamine, 14 had urine color change. Urine color change was associated with symptoms (p 0.005) but not with iron dose or peak serum iron level. The poison center protocol was changed to home management for ingestions of 20-60 mg/kg unless significant symptoms developed and hospital referral for ingestions ≥ 60 mg/kg. =

=

ACUTE

21-month-old child and

common.

19-month-old-child.5,6

UNINTENTIONAL IRON ingestion is In 1988 the American Association of Poison Control Centers National Data Collection System reported 19,676 ingestions of iron-containing products. Children under six years of age accounted for 83.9% of these ingestions. Iron toxicity includes gastrointestinal (GI) symptoms, shock, acidosis, and hepatic necrosis. Ingestions above 20 mg/kg of elemental iron are considered potentially toxic.~ Although the lethal dose of elemental iron is usually fatalities have been re180 mg/kg or low as 300-600 mg in a with total doses as ported

approximately

750 mg in

a

Initial decisions concerning the necessity for treatand the appropriate treatment site in iron ingestions are based on the history of the amount ingested. This study determined the appropriate treatment location for acute iron ingestions. The relationship of amount ingested and symptoms to each other as well as to serum iron levels and to response to deferoxamine therapy was assessed. ment

greater, 2-1

Methods

retrospective chart review of iron ingestions reported to the Maryland Poison Center (MPC) in A

From the *Maryland Poison Center, University of Maryland School of Pharmacy and †Maryland General Hospital, Baltimore, Marylandand University Hospital of Jacksonville, Jacksonville, Florida.

Correspondence to: Wendy Klein-Schwartz, PharmD, Maryland Poison Center, 20 North Pine Street, Baltimore, MD 21201. Presented in part at the Annual Scientific Meeting of the AAPCC/AACT/ABMT/CAPCC in Vancouver, BC, October 1, 1987. Received for publication July 1989, revised September 1989, and accepted January 1990.

1985 and 1986

was

conducted. The MPC is

a re-

gional poison center that provides emergency information on poisonings by telephone to health professionals and the general public. Because iron intoxication is a frequent occurrence with the potential for serious toxicity, a protocol was developed to standardize

recommendations. Poison center based on review of published case re-

treatment

protocols

are

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ports and the consensus opinion of experts. Protocols are often based on limited data and tend to be aggressive in recommending therapeutic interventions. After protocol implementation, data collection and reevaluation is essential to assess the appropriateness of the protocol’s recommendations. The MPC protocol for iron overdose recommends ipecac syrup at home for ingestion of 20-40 mg/kg of elemental iron and health care facility referral for ingestions of >40 mg/kg of elemental iron. If the dose of iron ingested is unknown, the amount is assumed to be toxic, and the patient is referred to a health care facility. Referral to a health care facility is also recommended for symptomatic patients (other than mild GI symptoms) or intentional (suicidal) ingestions. Information regarding the ingestion is provided by the parent, caretaker, or a health care professional. Treatment recommendations for cases referred to a health care facility include GI decontamination with ipecac syrup or lavage, parenteral deferoxamine and laboratory evaluation including serum iron level at 2-4 hours postingestion. In a health care facility the GI decontamination method (ipecac or lavage) is selected by the health care professional. Cases are followed by telephone until the patient is no longer exhibiting toxic symptoms or they are discharged. Inclusion criteria were 1) acute iron ingestion (accidental or intentional), 2) ingested dose of iron required treatment, 3) no coingested substances (except multiple vitamins), and 4) complete follow-up evaluation. Information extracted from the standardized data collection instrument included age, weight, iron alone or multiple vitamin preparation containing iron, concentration of iron per tablet, amount of elemental iron ingested, number of people involved, signs and symptoms (including vomiting, hematemesis, diarrhea, abdominal pain, altered level of consciousness, acidosis, hypotension, shock, abnormal

liver function), serum iron levels, presence of an urine color change (as judged by the treating health

professional), treatment received, response to treatment, and patient outcome. Vomiting after ipecac syrup administration was attributed to the ipecac not to the iron. In cases in which many children were involved and the exact amount ingested by each child was unknown, the amount ingested was considered to be unknown. For data analysis in this study, serum iron levels reported as normal were assumed to be < 150

syrup

~g/dl. Information was entered into a computerized data base (dBase III) and analyzed with a statistical package (SPSS PC). Statistical analysis included t-test, chisquare, and analysis of variance with p < 0.05 considered a statistically significant difference. Results

2-year study period, 339 iron ingestion cases the inclusion criteria. The median age was 3 years (range, 9 months to 33 years). The amount of iron ingested was known in 199 (58.7%) cases and ranged from 20 to 301 mg/kg (mean, 39.5 mg/kg). In 103 cases in which more than one person was involved and the exact dose ingested by each person could not be determined, the dose was considered to be unknown. Abdominal pain, vomiting, and/or diarrhea occurred in 22.2% of patients. Death, shock, acidosis, or liver damage was not reported in any patient in this series. In the 199 cases in which the dose of iron was known, there was no difference in the mean dose ingested by symptomatic patients compared with asymptomatic patients (42.2 mg/kg vs. 38.5 mg/kg; 0.33). Differences approached statistical signifip cance in overall symptom occurrence between the dose ranges (20-40 mg/kg, 40-60 mg/kg and >60 mg/kg; p 0.058, chi-square; Table 1). There was In the

met

=

=

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statistically significant difference in the developof any of the specific clinical effects when compared with amount ingested. The concentration of iron in the dosage form (i. e., the mg of elemental iron/tablet) did not correlate with whether symptoms developed. no

(90.9%)

ment

toms.

In the 109 cases in which a measured serum iron level was reported, the mean peak serum iron level was 245.5 1Lg/dl (range, 12-539 1Lgjdl). In an additional 20 cases, the serum iron level was reported as normal. Vomiting (p 0.006, chi-square) occurred more frequently with increasing serum iron level 1Lgjdl, 150-250 1Lgjdl, 250-350 ranges (_450 1Lg/dl). Differences approached statistical significance in overall symptom occurrence between the serum iron level ranges (p = 0.057, chi-square). There was no statistically significant difference between the occurrence of abdominal pain or diarrhea and serum iron level ranges. Breakdown of serum iron level and clinical effects is detailed in Table 2. There were 31 patients who ingested between 40-60 mg/kg of iron. Symptoms including diarrhea, vomiting, and/or abdominal pain occurred in 13 of these patients. In 24 (77.4%) of these cases, there were serum iron levels measured that ranged from 36-385 1Lg/dl. Despite the reported dose ingested and measured serum iron levels, no one in this group developed serious symptomatology. GI decontamination with ipecac syrup decreased the likelihood of subsequent development of symptoms. Only 15.5% of the patients who received ipecac syrup developed symptoms, compared with 87.1 % for those not receiving ipecac syrup. In patients ingesting 40-60 mg/kg of iron, 3/20 (15.0%) receiving ipecac developed symptoms, while 10/ 111 =

who did

not

receive

ipecac developed symp-

Deferoxamine was administered parenterally to 88 patients. The dose of iron ingested by these patients was 20-40 mg/kg in 11 patients, 40-60 mg/kg in 16 patients, h60 mg/kg in 15 patients, and unknown in 46 patients. A urine color change indicating the presence of ferrioxamine was noted in 14 patients. The development of a urine color change occurred more frequently in symptomatic patients than in asymptomatic patients given deferoxamine (p 0.005, chisquare). There was no difference in the occurrence of urine color change in patients with serum iron levels < 350 Agldl (p = 1.00, chi-square) and those with serum iron levels > 350 ~g/dl (Table 3). The amount ingested also was not predictive of the development of a urine color change. =

=. ,

-.. ;

I

To

_

=,.-. ,

=,.ji=j,aj_=,,,=- ,-.. i~ of- iron

~~~‘3‘

e,,,

that--

,

~

~

;=,z --

in i

elemental

tron, 12°/g

ferrous ferrous fumqr£te( ~ ’ Comment

Initial assessment of the potential for toxicity in an iron ingestion is based on the amount of elemental iron ingested. Iron salts contain varying amounts of elemental iron. For example, ferrous sulfate is 20%, ferrous gluconate is 12%, and ferrous fumarate is 33% iron. Iron is toxic to the gastrointestinal tract, liver, and cardiovascular and central nervous systems. Within the first few hours of ingestion, vomiting, hematemesis, abdominal pain, and diarrhea occur as a result of the corrosive effect of iron on the GI tract. Hypotension and shock may result acute

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products. Because it is the free iron that is toxic, iron levels greater than the total iron-binding capacity (TIBC) are evidence that toxicity may iron

serum

When the TIBC is not available, serum iron levels > 350 gg/dl are considered potentially toxic. In this series, development of symptoms was associated with increasing serum iron levels. However, only 20 patients had serum iron levels 350 gg/dl, and the highest serum iron level was 539 ~g/dl. None of these patients developed serious symptoms. This is not unexpected, as shock, coma, and other serious symptoms are usually associated with serum iron levels > 500 ~g/ dl.8 Specific antidotal therapy for iron overdose is deferoxamine. Deferoxamine mesylate chelates iron to form ferrioxamine, which is renally excreted. Ferrioxamine produces a urine color change to an orange or red color, classically vin rose. The indications for deferoxamine in the MPC protocol for iron poisoning were history of >_40 mg/kg ingested, serum iron > TIBC, serum iron 350 ~g/dl, and/or serious symptoms. In this series, 88 patients received deferoxamine. The point may be raised that if patients who ingested >_40 mg/kg all received deferoxamine, then the absence of serious symptoms in this group could be attributed to antidotal therapy. However, 24 of 55 patients in the >_40 mg/kg group did not receive deferoxamine; toxicity did not develop in these 24 patients either. There was no relationship between the amount of iron ingested or the serum iron level and the development of a urine color change after deferoxamine. The only statistically significant predictor of a urine color change after deferoxamine was the presence of symptoms. Patients with symptoms were three times more likely to have a urine color change with deferoxamine than those without symptoms. A previous study concluded that the amount of iron as ferrioxamine excreted in the urine of iron poisoned patients may not always be visually detectable.’ These findings would suggest that urine color change is not a reliable indicator of potentially toxic serum iron levels and should not be used as the sole decision making parameter for continuing deferoxamine occur.

from fluid and blood loss.

Lethargy and coma may be quiescent period of 2-12 hours, shock, metabolic acidosis, and hepatic necrosis will develop in some patients. Deaths usually occur during this phase of the intoxication. Several weeks after the ingestion pyloric scarring and stenosis may propresent. After

a

duce GI obstruction. The minimum toxic and lethal doses of iron have not been well established. Although 180 mg/kg of elemental iron or greater is generally considered the lethal dose, case reports of deaths with much lower doses of iron in children have resulted in aggressive triage and treatment recommendations at lower doses.2-6 The minimum toxic dose is poorly defined. At one point, hospital admission was recommended for all ingestions of >30 mg/kg.7 This is no longer

practice. Although toxicity may occur at doses of 20-60 mg/kg, this study determined that serious outcomes are unlikely at these doses. Of 175 cases with ingestions of 20-60 mg/kg, 45 (25.7%) developed GI symptoms as their only manifestation of iron toxicity. Symptoms were less likely to develop in patients given ipecac syrup. There was no evidence of metabolic, cardiovascular, CNS, or hepatic toxicity despite that in 15 of 31 cases (48.4%) with ingestions of 40-60 mg/kg the patients did not recommon

ceive deferoxamine. Serious toxicity also was absent in the 24 cases involving ingestions of h60 mg/kg. However, a larger percentage of patients (62.5%) received deferoxamine. The smaller number of cases and the more aggressive antidotal therapy make assessment of toxicity in doses greater than 60 mg/kg impossible in

this

study population.

Serum iron levels are used to assess the potential for toxicity and to evaluate the effectiveness of chelation therapy. Serum iron levels should be obtained 2-4 hours after ingestion for nonsustained release

therapy. In evaluating the data in this study, a number of potential problems need to be considered because of its retrospective design. These would include that the information was obtained from the poison center form and not the medical record, the exact time of the serum iron level determinations could not always 319

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be verified, and the assay for serum iron level may have varied from one health care facility to another. This study relies on clinical histories for determination of the dose ingested and initial decision making relative to the potential seriousness of the intoxication. It is a close approximation of the information clinicians use to make their initial management decisions. It is clear that treatment in a health care facility and determination of serum iron levels are not necessary for all iron ingestions. Yet it is unclear where to draw the line. This study helps to define the dosage ranges in which aggressive treatment is unnecessary. Although there were no seriously intoxicated patients in this study group, the data generated suggest

FIG. 1.

initial

and treatment guidelines. Subsequent management decisions are based on repeated clinical exams, developing symptomatology, and laboratory evaluation in some cases. No serious symptoms occurred in this evaluation of 339 cases of iron ingestions. Considering the relative lack of toxicity of iron in 175 patients ingesting 20-60 mg/kg of iron, it may be possible to handle these cases at home with ipecac syrup and close home follow-up care (Fig. 1). Further evaluation of this revised protocol using a prospective design is warranted. Until additional studies are available to delineate more clearly the toxicity of doses of iron >_ 60 mg/kg, these cases should continue to be referred to

triage

Triage algorithm for acute iron ingestions.

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health care facility for GI decontamination, evaluation of serum iron level, and (possibly) deferoxamine

a

Health care professionals are encouraged to consult their poison center for up-to-date triage and treatment protocols for iron poisoning.

3. 4. 5.

153-9.

acute

iron

ingestion.

Hoppe JO, Marcelli GMA, Tainter ML. A review of the toxicity of iron compounds. Am J Med Sci 1955;230:558-9. Greenblatt DJ, Allen MD, Koch-Weser J. Accidental iron poisoning in childhood: six cases including one fatality. Clin Pediatr 1976;15:835-8.

6.

1. Litovitz TL, Schmitz BF. 1988 Annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1989 (in press). 2. Engle JP, Polin KS, Stile IL. Acute iron intoxication: treatment controversies. Drug Intell Clin Pharm 1987;21:

of

Clin Toxicol 1971;4:603-13.

therapy.

References

McEnery JT. Hospital management

Spencer IOB. Ferrous sulphate poisoning in children. J 1951;2:1112-7.

Br Med

7. Stein M, Blayney D, Feit T, et al. Acute iron poisoning in children. West J Med 1976;125:289-97. 8. Westlin WF. Deferoxamine in the treatment of acute iron poisoning: clinical experiences with 172 children. Clin Pediatr 1966;5:531-5. 9. Eisen TF, Lacouture PG, Woolf A. Visual detection of ferrioxamine color changes in urine. (abstract) Vet Hum Toxicol 1988;30:369-70.

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Assessment of management guidelines. Acute iron ingestion.

A review of 339 treated acute iron ingestions was conducted to define treatment guidelines better. According to the poison center protocol, ingestions...
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