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Absorption of iron after experimental overdose of chewable vitamins
Absorption of Iron After Experimental Overdose of Chewable Vitamins LOUIS J. LING, MD,*t CARL S. HORNFELDT,* JAMES P. WINTER, MDt Even though ingestion 01 chewable iron preparations is much more common, treatment recommendations for iron overdose are usually based on experience with nonchewable preparations. To determine the optimal time to measure serum iron concentrations, live volunteers were given chewable iron in 5 mg/kg and 10 mg/kg doses and their serum iron concentrations monitored. Peak levels occurred at 4.2 and 4.5 hours, respectively, alter ingestlon, and levels dmwn at 3 hours were within 90% of the peak. Nausea and headache were experienced by all volunteers, and serum iron exceeded basellne total imn binding capacity in two subjects at the 1Omglkg dose. In minor imn overdose resulting from the ingestion of chewable vitamins, serum iron concentrations measured between 3 and 7 hours (95% confidence level 01 peak concentrations) may be adequate in assessing the peak serum iron concentration. (Am J Emerg Med lggl;g:24-26. Copyright 0 1991 by W.B. Saunders Company)
The overdose of chewable vitamins with iron remains one of the most commonly encountered potential poisonings in children. In 1988 there were 15,977 exposures to ironfortified vitamin tablets. Of these, 10,475 or 65.6% were children’s formulations. ’ Deferoxamine is a chelating agent used as an antidote in the treatment of iron poisoning. The decision to use deferoxamine is typically based on determination of serum iron concentrations (SIC).‘-” Various authors suggest a variety of different times for drawing SICs (Table 1) based on experience with nonchewable, adult iron supplements such as ferrous sulfate tablets. These nonchewable preparations are slowly and erratically absorbed.8.’ ‘.I2 Although chewable vitamins with iron are much more commonly ingested, we found only one reference that specifically addressed chewable forms of iron.’ In reviewing the literature, we were unable to find any information on the kinetics of iron absorption from chewable vitamins with iron. Therefore, we wished to test the hypothesis that ingestion of chewable vitamins would result in faster and more complete absorption of iron. Two different doses were used to determine whether the kinetics of iron absorption were zero-order (dose dependent) or first-order (time dependent), and whether the optimum time for determining serum iron concentrations is de-
pendent on the size of the ingested dose. If the absorbed iron from chewable vitamins does reach a predictable peak, we would be able to recommend the optimal time to obtain a single SIC for more accurate prediction of iron toxicity and eliminate the need for multiple samples. This would result in a savings in laboratory tests and emergency department staff time by decreasing the number of blood samples from the patient. METHODS
Approval was obtained from the Human Research Committee of the Hennepin County Medical Center as well as informed consent from all subjects. Five healthy men between the ages of 26 and 36 were enrolled. Before each phase, a total iron binding capacity was measured for each subject. It was sufficiently high that they were considered not at risk for iron toxicity. Subjects fasted for 12 hours and then were given 10 mg/kg elemental iron in the form of children’s chewable vitamins with iron. This dose is considered well below the currently accepted toxic dose of iron.4.” Tablets were well chewed and small amounts of water were permitted to facilitate ingestion. Clear fruit juice was offered ad libitum four hours after ingestion. SICs were drawn from a heparin lock prior to the administration of iron and every 30 minutes after ingestion for 6 hours; then every hour for an additional 2 hours. SICs were determined calorimetrically using a DuPont ACA Discrete Clinical Analyzer (Wilmington, DE). This protocol was repeated 6 months later with a dose of 5 mg/kg elemental iron with an additional serum iron determination at 12 hours. The initial peak SIC of all five volunteers was averaged to determine the mean peak time and 95% confidence interval. The SIC representing 90% of the peak and the corresponding mean time and 95% confidence interval were also calculated. A two-tailed Student’s t-test for paired data was performed to determine if the mean time to achieve peak concentrations produced by the two doses of iron was significantly different. A level of significance was established at P = .05. RESULTS
From the ‘Hennepin
Regional Poison Center, and the TDe-
partment of Emergency Medicine, Hennepin County Medical Center, Minneapolis, MN. Manuscript received January 9, 1990; revision accepted August 1, 1990. Presented at the Annual Meeting of the Society for Academic Emergency Medicine, San Diego, CA, May, 1989. Address reprint requests to Dr. Ling: Hennepin Regional Poison Center, Department of Emergency Medicine, Hennepin County Medical Center, 701 Park Ave, Minneapolis, MN 55415. Key Worck: Iron, poisoning, kinetics, chewable vitamins with iron. Copyright 0 1991 by W.B. Saunders Company 0735-6757/91/0901-0006$5.00/O 24
The results are displayed in Table 2 and Figure 1. The peak serum iron concentration after administration of 5 mg/ kg elemental iron was 243 pg/dL occurring at 252 minutes (4.2 hours). This was not significantly different from the peak of 321 p.g/dL acheived at 270 minutes (4.5 hours) for the 10 mg/kg dose (P < .05). A level drawn at 3 hours was within 94% and 90% of the peaks of the 10 mg/kg and 5 mg/kg dose, respectively. Two individuals achieved peak SICs of 352 and 390 pg/dL after the 10 mg/kg dose, exceeding their baseline total iron binding capacities (TIBCs) of 333 and 378 pg/dL, respec-
LING, HORNFELDT, AND WINTER n IRON ABSORPTION FROM CHEWABLE VITAMINS
25
TABLE 1. Recommended Time to Draw Serum Iron Concentration After Ingestion Hours
Reference
6 Within 4 3-4 3-5 Within 4 4-6 4-6 (adult tabs) 2 (children’s tabs) 2-4 3-4 and 6-6
2 4 5 6 7 6 9 9 11 12
4
Z Q)
ZE
tively. Since TIBCs increase as SICs increase,13 these iron concentrations may not have exceeded their TIBCs at that point in time. By the end of 8 hours, however, SICs had dropped below their original TIBCs for both individuals. All five subjects experienced some degree of nausea and diarrhea after both doses. The onset of these symptoms ranged from 1.5 to 3 hours and had a mean duration of 3.1 hours. Headaches were also common beginning after 3.5 hours. All volunteers were asymptomatic at the end of the study period. Because of extremes in the weight of the five volunteers, the total dose of elemental iron ingested ranged from 585 to 930 mg for the 10 mg/kg dose and half that for the 5 mg/kg dose. No correlation was noted between the amount of iron ingested and the peak SIC for each individual or between the total dose and severity of side effects. DISCUSSION Unexpectedly, we found that 10 mg/kg elemental iron, described as a nontoxic dose of iron,4*” produced individual SICs that were close to baseline TIBCs in our subjects. This may be due to better absorption of iron from chewed versus unchewed tablets, or to the fasting state before administration of iron. Other preliminary reports13*‘4 support our suspicion that iron taken in chewable form may result in possible toxicity, even when the amount ingested is below the currently recommended dosage. Because numerous authors refer to the rapid decline of SICs after ingestion of toxic amounts of iron3.‘-’ we determined SICs for only 8 hours in the first phase of our study. However, since free iron was not present, we found that SICs remained elevated and were very slow to return toward baseline levels. Based on our findings, it appears that serum iron levels reach a peak between 4 and 5 hours with a 95% confidence TABLE 2. Summary of Results After Ingestion of Chewable Iron by Volunteers
Baseline TIBC (PglmL) SIC at baseline (FgldL) SIC at peak (cLg/dL) SIC at 6 hrs ()Lg/mL) Time until peak (min)
250
is
5 mglkg
10 mglkg
332 62 243 137 252
334 104 321 251 270
-
10
mu/kg
100
0
I
I
I
200
400
600
800
Time Post-Ingestion (min) FIGURE 1. Effect of iron in chewable form on serum iron concentration in five adult male subjects.
interval of 2.3 and 6.7 hours when the dose of elemental iron ingested produces serum iron concentrations approaching the TIBC. Because of the sustained elevation of the SIC, iron samples drawn after four hours should predict whether toxicity might occur after ingestion of moderate amounts of iron. It appears that a SIC drawn as early as 2 hours postingestion, as has been previously suggested,’ may not represent the peak level. CONCLUSIONS The results of this study indicate that after minor ingestion of iron in the form of chewable vitamins, the serum iron concentration reaches a peak at 4 to 5 hours, and the delay until the peak is not dependent on dose. SICs determined more than 4 hours after ingestion are near maximum and a 3-hour level is within 90% of peak concentrations. SICs may be surprisingly high when chewable tablets are ingested and may result in higher SICs than do nonchewable preparations. Gastrointestinal symptoms and headache can be present after moderate ingestion even at doses previously considered nontoxic. Further investigation is required before the kinetics of iron absorption from chewable vitamins can be fully understood. The authors thank Dr William 0. Robertson for his review of this manuscript and valuable suggestions.
REFERENCES 1. Litovitz TL, Schmitz BF, Matyunas N, Martin TG: 1966 Annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1969;7 :495-545 2. Manoguerra AS: Management of acute iron poisonings. Clin Toxicol Consult 1960;3:3-10 3. Robotham JL, Lietman PD: Acute iron poisoning, a review. Am J Dis Child 1980;134:875-679 4. Lacouture PG, Lovejoy FH: Iron. In Haddad LM, Winchester JF (eds): Clinial Management of Poisoning and Drug Overdose, ed 1, Philadelphia, PA, Saunders, 1963, pp 644-648 5. Tong TG, Banner W, Jr: Iron poisoning. Arizona Poison Control System Newsletter, 1963;5:1-3
26
AMERICAN
JOURNAL
6. Henretig FM, Temple AR: Acute iron poisoning in children. Emerg Med Clin North Am 1984;2:121-132 7. Proudfoot AT, Simpson D, Dyson EH: Management of acute iron poisoning. Med Toxicol 1986;1:83-100 8. Banner W, Jr, Tong TG: Iron poisoning. Pediatr Clin North Am 1986;33:393-409 9. Goldfrank LR, Kulberg AG, Kirstein RM: Iron. In Goldfrank LR (ed): Goldfrank’s Toxicolooic Emergencies, ed 3, Norwalk, CT, ‘Appleton-Century-Crofts, 1986, pp 619-628 10. Engle JP, Polin KS, Stile IL: Acute iron intoxication: treatment controversies. Drug Intel1 Clin Pharm 1987;21:153-159
OF EMERGENCY
MEDICINE
n Volume 9, Number
11. Ellenhorn MJ, Barceloux DG: Medical York, NY, Elsevier, 1988, pp 1023-1030
1 n January
1991
Toxicology,
New
12. Rumack BH, Spoerke DS (ed): POISINDEX Information System, Micromedex Inc, Denver, CO (Edition expires 2/28/90) 13. Linakis JG, Lacouture PG, Woolf AD: Iron absorption from chewable multivitamins with iron vs. ferrous fumarate tablets. Vet and Hum Toxicol 1989;31(4):342 (abstr) 14. Burkhart K, Kulig K, Rumack BH, Hammond KB, Pearson JR, Ambruso D: The rise in the TIBC after iron overdose. Vet and Hum Toxicol 1989;31:365 (abstr)
The overdose of chewable vitamins with iron remains one of the most commonly encountered potential poisonings in children. In 1988 there were 15,977 exposures to ironfortified vitamin tablets. Of these, 10,475 or 65.6% were children’s formulations. ’ Deferoxamine is a chelating agent used as an antidote in the treatment of iron poisoning. The decision to use deferoxamine is typically based on determination of serum iron concentrations (SIC).‘-” Various authors suggest a variety of different times for drawing SICs (Table 1) based on experience with nonchewable, adult iron supplements such as ferrous sulfate tablets. These nonchewable preparations are slowly and erratically absorbed.8.’ ‘.I2 Although chewable vitamins with iron are much more commonly ingested, we found only one reference that specifically addressed chewable forms of iron.’ In reviewing the literature, we were unable to find any information on the kinetics of iron absorption from chewable vitamins with iron. Therefore, we wished to test the hypothesis that ingestion of chewable vitamins would result in faster and more complete absorption of iron. Two different doses were used to determine whether the kinetics of iron absorption were zero-order (dose dependent) or first-order (time dependent), and whether the optimum time for determining serum iron concentrations is de-
pendent on the size of the ingested dose. If the absorbed iron from chewable vitamins does reach a predictable peak, we would be able to recommend the optimal time to obtain a single SIC for more accurate prediction of iron toxicity and eliminate the need for multiple samples. This would result in a savings in laboratory tests and emergency department staff time by decreasing the number of blood samples from the patient. METHODS
Approval was obtained from the Human Research Committee of the Hennepin County Medical Center as well as informed consent from all subjects. Five healthy men between the ages of 26 and 36 were enrolled. Before each phase, a total iron binding capacity was measured for each subject. It was sufficiently high that they were considered not at risk for iron toxicity. Subjects fasted for 12 hours and then were given 10 mg/kg elemental iron in the form of children’s chewable vitamins with iron. This dose is considered well below the currently accepted toxic dose of iron.4.” Tablets were well chewed and small amounts of water were permitted to facilitate ingestion. Clear fruit juice was offered ad libitum four hours after ingestion. SICs were drawn from a heparin lock prior to the administration of iron and every 30 minutes after ingestion for 6 hours; then every hour for an additional 2 hours. SICs were determined calorimetrically using a DuPont ACA Discrete Clinical Analyzer (Wilmington, DE). This protocol was repeated 6 months later with a dose of 5 mg/kg elemental iron with an additional serum iron determination at 12 hours. The initial peak SIC of all five volunteers was averaged to determine the mean peak time and 95% confidence interval. The SIC representing 90% of the peak and the corresponding mean time and 95% confidence interval were also calculated. A two-tailed Student’s t-test for paired data was performed to determine if the mean time to achieve peak concentrations produced by the two doses of iron was significantly different. A level of significance was established at P = .05. RESULTS
From the ‘Hennepin
Regional Poison Center, and the TDe-
partment of Emergency Medicine, Hennepin County Medical Center, Minneapolis, MN. Manuscript received January 9, 1990; revision accepted August 1, 1990. Presented at the Annual Meeting of the Society for Academic Emergency Medicine, San Diego, CA, May, 1989. Address reprint requests to Dr. Ling: Hennepin Regional Poison Center, Department of Emergency Medicine, Hennepin County Medical Center, 701 Park Ave, Minneapolis, MN 55415. Key Worck: Iron, poisoning, kinetics, chewable vitamins with iron. Copyright 0 1991 by W.B. Saunders Company 0735-6757/91/0901-0006$5.00/O 24
The results are displayed in Table 2 and Figure 1. The peak serum iron concentration after administration of 5 mg/ kg elemental iron was 243 pg/dL occurring at 252 minutes (4.2 hours). This was not significantly different from the peak of 321 p.g/dL acheived at 270 minutes (4.5 hours) for the 10 mg/kg dose (P < .05). A level drawn at 3 hours was within 94% and 90% of the peaks of the 10 mg/kg and 5 mg/kg dose, respectively. Two individuals achieved peak SICs of 352 and 390 pg/dL after the 10 mg/kg dose, exceeding their baseline total iron binding capacities (TIBCs) of 333 and 378 pg/dL, respec-
LING, HORNFELDT, AND WINTER n IRON ABSORPTION FROM CHEWABLE VITAMINS
25
TABLE 1. Recommended Time to Draw Serum Iron Concentration After Ingestion Hours
Reference
6 Within 4 3-4 3-5 Within 4 4-6 4-6 (adult tabs) 2 (children’s tabs) 2-4 3-4 and 6-6
2 4 5 6 7 6 9 9 11 12
4
Z Q)
ZE
tively. Since TIBCs increase as SICs increase,13 these iron concentrations may not have exceeded their TIBCs at that point in time. By the end of 8 hours, however, SICs had dropped below their original TIBCs for both individuals. All five subjects experienced some degree of nausea and diarrhea after both doses. The onset of these symptoms ranged from 1.5 to 3 hours and had a mean duration of 3.1 hours. Headaches were also common beginning after 3.5 hours. All volunteers were asymptomatic at the end of the study period. Because of extremes in the weight of the five volunteers, the total dose of elemental iron ingested ranged from 585 to 930 mg for the 10 mg/kg dose and half that for the 5 mg/kg dose. No correlation was noted between the amount of iron ingested and the peak SIC for each individual or between the total dose and severity of side effects. DISCUSSION Unexpectedly, we found that 10 mg/kg elemental iron, described as a nontoxic dose of iron,4*” produced individual SICs that were close to baseline TIBCs in our subjects. This may be due to better absorption of iron from chewed versus unchewed tablets, or to the fasting state before administration of iron. Other preliminary reports13*‘4 support our suspicion that iron taken in chewable form may result in possible toxicity, even when the amount ingested is below the currently recommended dosage. Because numerous authors refer to the rapid decline of SICs after ingestion of toxic amounts of iron3.‘-’ we determined SICs for only 8 hours in the first phase of our study. However, since free iron was not present, we found that SICs remained elevated and were very slow to return toward baseline levels. Based on our findings, it appears that serum iron levels reach a peak between 4 and 5 hours with a 95% confidence TABLE 2. Summary of Results After Ingestion of Chewable Iron by Volunteers
Baseline TIBC (PglmL) SIC at baseline (FgldL) SIC at peak (cLg/dL) SIC at 6 hrs ()Lg/mL) Time until peak (min)
250
is
5 mglkg
10 mglkg
332 62 243 137 252
334 104 321 251 270
-
10
mu/kg
100
0
I
I
I
200
400
600
800
Time Post-Ingestion (min) FIGURE 1. Effect of iron in chewable form on serum iron concentration in five adult male subjects.
interval of 2.3 and 6.7 hours when the dose of elemental iron ingested produces serum iron concentrations approaching the TIBC. Because of the sustained elevation of the SIC, iron samples drawn after four hours should predict whether toxicity might occur after ingestion of moderate amounts of iron. It appears that a SIC drawn as early as 2 hours postingestion, as has been previously suggested,’ may not represent the peak level. CONCLUSIONS The results of this study indicate that after minor ingestion of iron in the form of chewable vitamins, the serum iron concentration reaches a peak at 4 to 5 hours, and the delay until the peak is not dependent on dose. SICs determined more than 4 hours after ingestion are near maximum and a 3-hour level is within 90% of peak concentrations. SICs may be surprisingly high when chewable tablets are ingested and may result in higher SICs than do nonchewable preparations. Gastrointestinal symptoms and headache can be present after moderate ingestion even at doses previously considered nontoxic. Further investigation is required before the kinetics of iron absorption from chewable vitamins can be fully understood. The authors thank Dr William 0. Robertson for his review of this manuscript and valuable suggestions.
REFERENCES 1. Litovitz TL, Schmitz BF, Matyunas N, Martin TG: 1966 Annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1969;7 :495-545 2. Manoguerra AS: Management of acute iron poisonings. Clin Toxicol Consult 1960;3:3-10 3. Robotham JL, Lietman PD: Acute iron poisoning, a review. Am J Dis Child 1980;134:875-679 4. Lacouture PG, Lovejoy FH: Iron. In Haddad LM, Winchester JF (eds): Clinial Management of Poisoning and Drug Overdose, ed 1, Philadelphia, PA, Saunders, 1963, pp 644-648 5. Tong TG, Banner W, Jr: Iron poisoning. Arizona Poison Control System Newsletter, 1963;5:1-3
26
AMERICAN
JOURNAL
6. Henretig FM, Temple AR: Acute iron poisoning in children. Emerg Med Clin North Am 1984;2:121-132 7. Proudfoot AT, Simpson D, Dyson EH: Management of acute iron poisoning. Med Toxicol 1986;1:83-100 8. Banner W, Jr, Tong TG: Iron poisoning. Pediatr Clin North Am 1986;33:393-409 9. Goldfrank LR, Kulberg AG, Kirstein RM: Iron. In Goldfrank LR (ed): Goldfrank’s Toxicolooic Emergencies, ed 3, Norwalk, CT, ‘Appleton-Century-Crofts, 1986, pp 619-628 10. Engle JP, Polin KS, Stile IL: Acute iron intoxication: treatment controversies. Drug Intel1 Clin Pharm 1987;21:153-159
OF EMERGENCY
MEDICINE
n Volume 9, Number
11. Ellenhorn MJ, Barceloux DG: Medical York, NY, Elsevier, 1988, pp 1023-1030
1 n January
1991
Toxicology,
New
12. Rumack BH, Spoerke DS (ed): POISINDEX Information System, Micromedex Inc, Denver, CO (Edition expires 2/28/90) 13. Linakis JG, Lacouture PG, Woolf AD: Iron absorption from chewable multivitamins with iron vs. ferrous fumarate tablets. Vet and Hum Toxicol 1989;31(4):342 (abstr) 14. Burkhart K, Kulig K, Rumack BH, Hammond KB, Pearson JR, Ambruso D: The rise in the TIBC after iron overdose. Vet and Hum Toxicol 1989;31:365 (abstr)