Letters to the Editor
The ]ournalo[ Pediatrics March 1973
In our study we demonstrated that the criteria of anemia employed by Pearson and associates, 1 for children ages 12 to 15, was in fact valid because it was accompanied by changes in red cell size and red cell hemoglobin content. These alterations can be eliminated by iron therapy and thus reflect a deficiency of an inorganic element in the subjects with hemoglobin values that fall below the accepted normal range. Thus the designation of anemia is more than just a statistical treatment of data; it reflects a correctable deviation from the nutritional optimal state. The second question posed by Dr. Kaufman is far more important and far harder to answer with precision at this time. The subtle manifestations of nutritional inadequacy are difficult to document. Certainly the modest reduction in level of hemoglobin is of no real consequence, but the deficiency as it affects other tissues may be detrimental. It should be pointed out that iron deficiency, like deficiencies of other nutritional elements such as folic acid or vitamin Bl_o, has generalized consequences and does not result in a decrease in the circulating hemoglobin level alone. Iron deficiency has been demonstrated to produce alterations in gastrointestinal function. It has been proposed that it also decreases resistance to infection and increases the tendency to pica. Preliminary evidence has been accumulated to suggest that iron deficiency may alter attention span, school performance, and visual perception in the iron-deficient infant and child, z, ~ In conjunction with Dr. Thomas Webb, we examined the scholastic performance, personality traits, and visual perception of our iron-deficient adolescents. In each instance, significant differences from the non-iron-deficient children could be observed. * Obviously more work is needed to document these relationships. I think Dr. Kaufman's use of the word "conform" is ill chosen. We are not discussing behavior or beliefs that should meet certain standards; rather, we are talking about health and, specifically, nutrition. In this regard everyone should ideally be the same.
2. Howell, D.: Consequences of mild iron deficiency in children, in Goldsmith, G., editor: Proceedings of Workshop Conference on Extent and Meanings of Iron Deficiency in the United States National Research Council. In press. 3. Sulzer, J. L., Goldsmith, G. A., and Smith, J. L.: Comparison of different types of nutritional intervention on behavioral measures of New Orleans kindergarten children, presented at the Ninth International Congress on Nutrition, Mexico City, September, 1972. 4. Webb, T., and Oski, F. A.: Unpublished observations.
Frank A. Oski, M.D. State University of New' York Upstate Medical Center Syracuse, N. Y. 13210
David H. Huffman, M.D. Ralph E. Kauffman, M.D. The University of Kansas Medical Center Kansas City, Kan. 66103
Serum levels of digoxin To the Editor: The recent observations by Krausula and associates, concerning the serum levels of digoxin in infants and children, are both timely and quite interesting. However, based upon recent studies in our laboratoryfl concerning the absorption of digoxin from different oral preparations, we feel that caution should be exercised before attributing the differences in the observed serum digoxin levels to differences in urinary excretion. In adults, we find the absorption of digoxin from a tablet is only 70 per cent whereas the absorption from an oral solution is complete when compared to a standard intravenous study. Since the children in their study under five years of age received digoxin in solution form and the children over five years of age received digo• in a tablet, it is most likely that the differences in blood levels are due, at least in part, to differences in absorption of digoxin related to differences in the bioavailability of the used preparations. Unfortunately, urinary excretion data were not presented and therefore evaluation of this factor is not possible. Since the concentrations of digoxin are changing during the periods studied, it is unfortunate that the authors did not collect the specimens at the same time during the "postabsorptive, and plateau mean" periods.
1. Pearson, H. A., McLean, F. W., and Brigety, R. E.: Anemia related to age, J. A. M. A. 215: 1982, 1972.
1. Krausula, R. W., Pellegrino, P. A., Hastreiter, A. R., and Soyka, L. F.: Serum levels of di-
Volume 82 Number 3
goxin in infants and children, J. PEDIATR. 81: 566, 1972. 2. Huffman, D. H., and Azarnoff, D. L.: The absorption of oral digoxin preparations, J. A. M. A. 222: 957, 1972.
Reply To the Editor: We are grateful for the comments of Drs. Huffman and Kauffman and for the opportunity to review the paper of Drs. Huffman and Azarnoff. 1 The problem raised in the letter has three aspects: bioavailability, peak absorption levels, and over-all shape of the absorption curve as determined by serum levels. Since absorption data are not available for infants and children, we elected to select an average time for both peak and plateau levels rather than arbitrarily choose a single time point to be representative of either phase. Studies in progress have confirmed the appropriateness of this method. The question of bioavailability of the elixir versus tablet is of minor importance in our study, 2 in that all children in Groups 1 and 2 received the elixir. Therefore, the significant difference in the postabsorptive serum levels between these groups could not have been due to differences in bioavailability. Furthermore, the postabsorptive peak levels were directly related to the dose administered, that is, infants in Group 1 received twice the dosage of the children in Group 3 (who received the tablet form) and their peak serum levels were twice as high. Nonetheless, recent studies3, 4 have demonstrated altered absorption of digoxin due to differences in tablet disintegration time or, probably of greater importance, differences in particle size. The study of Drs. Huffman and Azarnoff in four nondigitalized adults showed that cumulative urinary excretion of digoxin was lower when a
Letters to the Editor
single dose of 0.5 mg. was administered as a tablet rather than as an an alcohol-propylene glycol solution. However, in their study, only 57 per cent of an intravenous dose was found in the urine. Whether the discrepancy could be accounted for by incomplete urine collections, by residual in tissues, by interference by urinary components with the assay, or by the presence of the metabolites not detected by the radioimmunoassay employed is uncertain. In six determinations we have found that urinary excretion accounted for about 100 per cent of a maintenance dose administered intramuscularly. We agree with Drs. Huffman and Kauffman that our data are not yet sufficient to establish that the basis for the differences in observed serum digoxin levels was due to differential rates of urinary excretion. This problem is under active investigation in our laboratory.
Richard W. Krasula Lester F. Soyka, M.D. Department o/ Pharmacology University o[ Illinois at the Medical Center Chicago, Ill. 60680
REFERENCES 1. Huffman, D. H., and Azarnoff, D. L.: Absorption of orally given digoxin preparations, J. A. M. A. 222: 957, 1972. 2. Krasula, R. W., Pellegrino, P. A., Hastreiter, A. R., and Soyka, L. F.: Serum levels of digoxin in infants and children, J. PEDIATR. 81: 566, 1972. 3. Lindenbaum, J., Mellow, M. H., Blackstone, M. O., and Butler, V. J., Jr.: Variation in biologic availability of digoxin from four preparations, N. Engl. J. Med. 285: 1344, 1971. 4. Shaw, T. R. D., Howard, M. R., and Hamer, J.: Variation in the biological availability of digoxin, Lancet 2: 303, 1972.