Physical work capacity and metabolic stress in subjects with iron deficiency anemia13

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1 Physical work capacity and metabolic stress in subjects with iron deficiency anemia13 Gerald W. Gardner, V. Reggie dgerton,4 Brian enewiratne, R. James Barnard,5 and Yoshinobu Ohira ABTRACT eventy-five female subjects with hemoglobin (Hb) levels ranging from 6.1 to 15.9 g/1 ml were identified in a preliminary screening program of tea estate workers in the Kandy area of ri Lanka (Ceylon). Venous blood samples were obtained for Hb, serum iron, total iron-binding capacity, P (partial pressure of oxygen when Hb is 5% saturated with oxygen), 2,3-diphosphoglycerate (2,3-DPG), and lactate determinations before performing an 1 8-mm multistage treadmill test. Heart rate (HR) was continuously monitored throughout the exercise period and for 3 mm during recovery. Blood samples taken after exercise were measured for lactate. For analysis purposes, seven groups were established with 1 g/ 1 ml Hb increments from 6 to 13 g/1 ml and one group of >13 g/1 ml. Performance values for the lowest Hb group compared to the highest Hb group as measured by total time on the treadmill (1.4 versus 18. mm), percentage of subjects that reached the highest work load ( versus 1%), HR/work load at 4.4 km/hr, 1% grade (176 versus 13 beats/mm), and postexercise lactate (4.9 versus 2.7 moles/ml of blood) all showed significant differences. The lowest Hb group also showed significantly increased oxygen delivery adaptation through higher 2,3-DPG levels (14.9 versus 11.3 moles/ml of blood) and higher P values (31.3 versus 27.8mm Hg) when compared to the highest Hb group. Because physical working capacity is significantly reduced by iron deficiency anemia, with a concomitant reduction in productivity, a strong case for its correction and prevention can be made on a basis of economics, as well as of health. Am. I. Clin. Nun. 3: , Iron deficiency anemia is found throughout the world and particularly in developing countries where agricultural productivity is of prime economic importance (1). ri Lanka (Ceylon) is such a country, and enewiratne et a!. (2) have reported that over 5% of the female workers on the tea estates were iron-deficient and anemic. In ri Lanka, tea production accounts for the langest percentage of that country s overseas funds. It is also known that physical work capacity in anemic subjects may be improved after iron supplementation, with a concomitant increase in circulating hemoglobin (Hb) (3,4). kblom et a!. (5) and dgerton et al. (6) have also shown that work performance can be improved almost immediately when the oxygen-carrying capacity of the blood is simply increased through blood transfusion. At present, however, there exists little if any evidence as to the precise level of Hb at which physical work capacity is significantly affected. The present study was undertaken to investigate the interrelationships of physical work capacity and selected physiological parameters related to work performance in subjects with a range of Hb concentrations who were engaged in daily work tasks routine for this population of estate laborers. Methods eventy-five female subjects, from a high country tea estate in the Kandy area of ri Lanka and with a 1 From the Departments of Kinesiology and urgery, University of California, Los Angeles, California, and Department of Medicine, University of ri Lanka, Peradeniya, ri Lanka. 2 This study was supported by the J. B. Williams Company, Inc., and a Biomedical Research upport grant from the United tates Public Health ervices. Address reprint requests to: G. W. Gardner, University of California, Los Angeles, Department of Kinesiology, Los Angeles, California 924. Member of the Brain Research Institute, University of California, Los Angeles, Califorma. upported by Career Development Award HL 52-1 from the United tates Public Health ervices. Downloaded from by guest on June 5, The American Journal of Clinical Nutrition 3: JUN 1977, pp Printed in U..A.

2 WORK CAPACITY AND TR IN IRON DFICINCY ANMIA 911 mean age of 35 years (range 22 to 65 years), were identified with Hb levels ranging from 6.1 to 15.9 g/ 1 ml. The physical characteristics of the subjects are shown in Table 1. ubjects were transported to the laboratory in a fasted condition and underwent the following procedures. All were weighed and their height was determined. A venous blood sample was taken for the measurement of Hb, serum iron (e Fe), total iron-binding capacity (TIBC), 2,3-diphospholglycerate (2,3-DPG), partial pressure of oxygen when Hb is 5% saturated with oxygen (PM), and preexercise lactate levels. lectrocardiogram (CG) electrodes (Hewlett-Packard model 15A, Palo Alto, Calif.) were attached (trans.. thoracic, V5-V6) and a resting CG was recorded. The subjects then performed a standard multistage treadmill test in which they walked for 3 mm up a 1% grade at 1.59 km/hr. The speed was then increased to 3.18 km/hr for 3 mm, and to 4.77 km/hr for 3 mm, both at the 1 % grade. After that, the grade was changed to 14% and then 18%, and if possible, the top work load was 3 mm at 6.36 km/hr and 2% grade, giving a maximum possible work time on the treadmill (Quinton Instruments model 14-44A, eattle, Wash.) of 18 mm. The test was discontinued if any of the following conditions occurred: 1 ) the subjects completed the maximum exercise time on the treadmill (18 mm); 2) the subjects attained the target heart rate (HR) (95% of maximum as predicted for age); 3) the CG was abnormal according to the criteria of llestad (7); 4) local muscle fatigue made walking impossible; 5) the subject had severe respiratory distress; 6) the subject became dizzy and disoriented. The CG was monitored on an oscilloscope (Burdick C/25 monitor, Burdick Corp., Milton, Wise.) throughout the exercise period and for 3 mm of recovcry (lying). ix-second tracings were recorded on the electrocardiograph every 6 sec during the exercise and recovery periods for HR determinations. A postexercise venous blood sample for lactate determination was obtained 3 mm after the subject stopped exercising. Blood analyses employed the following procedures: Hb was determined with an Instrumentation Laboratories (IL) co-oximeter (models 182, 189, and 213, Boston, Mass.), and 2,3-DPG and lactate determinations were made using igma Kits (igma Chemical Co. models 35-UV and 826-UV, t. Louis, Mo.). Blood was collected in plastic syringes and capped immediately after it was withdrawn. Blood gas and ph analyses were completed within 2 mm of the time they were obtained. All P2 (IL 213) values used for PM determinations were corrected for ph 7.383, with blood ph measured on an IL 213. Oxygen saturation was determined on an IL At least two independent determinations on each sample were made for each parameter. The P determinations were made by plotting the percentage saturation and the P2 corrected for ph at a temperature of 37 C according to Astrup et al. (8) for venous blood before and after exercise. A line parallel to the standard oxygen saturation curve was drawn between the two points plotted and PM was determined from this plot. A one-way analysis of variance was used to determine the existence of differences among the eight subgroups of Hb levels. Then an unpaired t test was used to determine differences between any two groups. Results For analysis and graphic presentation, the data have been arranged into eight classifications. These include subjects with Hb 1evels falling between 6.Yand 13. g/1 ml in 1 g/1 ml increments (e.g., 6. to 6.9 g/ 1 ml) plus those subjects with Hb levels> 13.Og/1 ml. None of the subjects who were actually working in the fields at the time had a Hb level < 6. g/1 ml. Work performance Figure 1 shows the results of the treadmill test. Work time ranged from 1.4 ±.8 (mean ± M) mm for those subjects in the lowest Hb group to 1 8 mm for those subjects in the highest Hb group. All subjects in the latter group completed the 1 8-mm test. Performance times were lower in the groups with Hb values lower than g/1 ml (P <.5). The percentage of subjects who reached the maximum work load of 6.36 km/hr and 2% grade isshown in Figure 2. HR HR responses to the treadmill exercise are illustrated in Figure 3. HRs at rest in the Downloaded from by guest on June 5, 211 TABL 1 Characteristics of subjectsa Hb group No. Age Ht Wt c Fe flbc giloo ml yr cm kg pg/lt% ml ± ± ± ± ± ± ± ± ± 8 68 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 24 > ± ± ± ± ± 41 a Mean ± M.

3 912 GARDNR T AL C V 4 ± ** 2 1,1± 7 6 e I II - H b ( 9 I ml Blood) FIG. 1. Maximum treadmill work time in different Hb groups. Means (± M) were compared using an unpaired t test between the highest Hb group and each of the lower Hb groups (P <.5, P <.1 #{149}, P <.1***)..c a:2., C) (I) #{149}s Downloaded from by guest on June 5, 211 2: 6 ± I Hb (g/iooml Blood) FIG. 2. Percentage of subjects in each Hb group who reached the maximum work load of 6.36 km/hr and 2% grade. All of the subjects in the highest Hb group reached the peak work load, but none in the lowest Hb group. groups of 6. to 6.9 (P <.1) and 8. to 8.9 g/1 ml Hb (P <.1) and at 1 mm of recovery in 6. to 6.9 (P <.1), 7. to 7.9 (P <.5), and 8. to 8.9 g/1 ml Hb (P <.5) were significantly higher than those in the highest Hb group. xercise heart rates throughout three work loads were significantly higher in 6. to 6.9 (P <.1), 7. to 7.9 (P <.1), and 9. to 9.9 g/1 ml Hb groups (P <.5) than the group Hb > 13.Og/1 ml. There was no correlation between the maximal HR

4 reached at the highest work load and Hb concentration. Lactate WORK CAPACITY AND TR IN IRON DFICINCY ANMIA 913 Preexercise blood lactate concentrations exercise lactate elevation was significantly greater in the groups of 6. to 6.9 (P <.1), 7. to 7.9 (P <.5) and 9. to 9.9 (P <.5) than> 13. g/1 ml Hb. This was particularly noticeable in the lowest two Hb groups (1 i to 4.86 and.8 to ** 6 ** 4 U I 12 8 psedi (km/h) Grad. o 1 (%) )Cb of all groups were similar (Fig. 4). Post : I, 4.77 I 2 3 lo (mins) Rest xercise Recovery FIG. 3. HR response at rest and three work loads and during 3 mm of recovery for each Hb group. ignificance of the differences of the group with a Hb of > 13. g/1 ml is compared with each of the lower Hb groups (P <.5., P <.1.., P <.1) Downloaded from by guest on June 5, 211 U) V V I., -J Post exercise I. I IO l2-.i3-i6 Hb (g/ioomibiood) FIG. 4. Mean (± M) pre- and postexercise lactate levels were compared between the highest Hb groups and each of the lower Hb groups using an unpaired t test (P <.5, P <.1).

5 914 GARDNR T AL. moles/ml of blood, respectively). A correlation coefficient of -.59 was found between Hb and brachial venous lactate concentration immediately after exercise. It should be noted that the subjects with the higher Hb worked longer and reached higher work loads. 2,3-DPG The relationship between 2,3-DPG and Hb levels is shown in Figure 5. The subjects with the higher Hb concentration generally had the lower 2,3-DPG concentration expressed as micromoles/gram of Hb, with a correlation of -.52 (P <.1). P5 The relationship of P5 values to Hb concentration is shown in Figure 6. A correlation coefficient of -.45 (P <.1) was found. The lower the Hb concentration, the higher the P5 values. Discussion The four parameters used within this study that are common indicators of work I U) 25 2 #{149} 5 #{149}... #{149} #{149}#{149} #{149}#{149} performance capacity were: total work time, percentage of the subjects who reached the maximal work load, HR response to work, and postexercise blood lactate. All four indicators clearly demonstrated that anemic subjects have a lower work tolerance than subjects with a normal Hb level. The precise level of Hb at which one can expect to see a decrement in work tolerance was also indicated. ubjects with Hb concentrations between 1 1. and 11.9 g/1 ml showed approximately a 2% decrease in their work tolerance when compared to subjects with Hb concentrations of greater than 13. g/1 ml (Fig. 1). This 2% decrease is based on either the heart rate response to work or actual work performance, and is consistent with the 2% lower productivity of anemic Indonesian workers reported by Basta and Churchill (9). As is shown in Figure 7, there is approximately a 4.7% elevation of HR at a moderate work load with each g/1 ml decrease in Hb below 13 g/1 ml. kblom et al. s (5) data also indicated that work performance as measured by V2 max could be improved if the Hb #{149}: #{149} #{149} #{149} #{149}: Downloaded from by guest on June 5, 211. a I, N I #{149} #{149} #{149} r-.52 n. 73 p<.$ 6 8 $ 2 4 $6 Hb (g/looml Blood) FIG. 5. Relationship between Hb and 2,3-DPG/tmoles/gIb. 2,3-DPG = -.79 (Hb)

6 WORK CAPACITY AND TR IN IRON DFICINCY ANMIA #{149}. 3 #{149} #{149} 26 r -.45 n 44 p<.$ H b ( g / $ ml Blood) FIG. 6. Relationship between Hb and P11,. P = -.4 (Hb) ) a: 8) I C 8) In 8.) U C 4 3j 24. r n. - L. r -.97 p<.l II _I_ I I I I I - 6- I- -I 2-.I3-----i6. Downloaded from by guest on June 5, 211 Hb(g/lOOml FIG. 7. Percentage increase of mean HR relative to the value in the subjects with a Hb> 13. g/1 ml of blood for each Hb group at a work load of 4.77 km/hr, 1% grade. in HR = -4.7 (Hb) Blood) levels were increased above the 13. g/1 ml level through reinfusion. The above studies all support the concept of a very close relationship between Hb level and work performance and indicate that the level of Hb need not change markedly before there is a signficant change in physical work tolerance. Postexercise lactate concentrations also appear to be directly related to the degree of anemia, and indicate the relative contribution of anaerobic metabolism to the overall metabolic stress of the exercise task. Lower lactate concentrations were observed after exercise in the subjects with the highest Hb concentrations, in spite of the fact they worked longer and at higher work loads. (Figs. 1 and 4). The greater metabolic stress in the anemic subjects should also be noted in light of the

7 916 GARDNR T AL. The authors wish to acknowledge the cooperation of the staff of the Clinical Research Unit, General Hospifact that the erythrocytes had adapted to the anemia in a way which theoretically promotes oxygen unloading in skeletal muscle (1, 1 1 ). The slope of the regression line in Figure 5 suggests that for every 1 g of Hb/ 1 ml below normal one could expect a.8 mole/g of Hb increase in 2,3-DPG. It has been demonstrated repeatedly that elevated 2,3-DPG shifts the Hb-2 dissociation curve to the right (1-12), which was generally the case when the actual P5 was determined in resting and postexercise yenous blood samples. The P5 values increased as Hb concentration decreased (r = -.45, Fig. 6). According to the slope shown in Figure 6, for every gram change in Hb/1 ml the P5 will change.4 mm Hg. This value is similar to that reported by Lenfant et al. (1 3), although the correlation coefficient is not as high. The true functional significance of a P5 shift to actual tissue oxygenation has been questioned (14), but further investigations are warranted. ome studies have failed to find a decrement in parameters related to work performance, e.g., oxygen uptake rate (15, 1 6), but one should not expect the rate of oxygen uptake to be lower for a given submaximal work regardless of the anemic 1evels (15). A decrement in oxygen consumption would probably be seen only at work loads equivalent to a V2 max as reported by kblom et al. (5). Also, the initial levels of Hb must be considered, and one should expect some difficulty in identifying significant changes in maximal work capacity with changes in Hb of <1. g/1 ml. The findings of the present study demonstrate a close relationship between work performance capacity and Hb concentration and are consistent with several previous reports in rats and humans (3, 4, 9, 15, 18, 19). Whereas a recent study (2) has suggested that the iron deficiency is perhaps a more influential factor in altering physical work capacity, we still support the view that any decrement seen will be proportional to the degree of anemia. Further studies supporting this view will be presented in a subsequent report. tal, Kandy, ri Lanka, and the assistance of Mr. W. H. Beteju of the Hantane Tea state. References 1. BNGOA, J. M. The problem of malnutrition. WHO Chronicle 28: 3, NWIRATN, B., J. HTrIARACHCHI, AND K. NWIRATN.. ome problems in the management of anemia in tea estate workers in ri Lanka. J. Trop. Med. Hygiene 77: 177, RICON, P. The effect of iron supplementation on the physical working capacity in the elderly. Acta Med. cand. 188: 361, GArnmR, G. W., V. R. DGRTON, R. J. BAR- NARD, AND. M. BRNAUR. Cardiorespiratory, hematological and physical performance responses of anemic subjects to iron treatment. Am. J. Chin. Nutr. 28: 982, KBLOM, B., A. N., GOLDBRG, AND B. GULLBR- 114G. Response to exercise after blood loss and rein.fusion. J. Appl. Physiol. 33: 175, DGRTON, V. R., J. HTrIARACHCRI, G. W. GARDNR, R. J. B.aAar, B. NWIRATN, AND Y. Oma.. Immediate work tolerance improvement with infusion of whole blood. In: Proceedings of the Xth International Congress of Nutrition, p. 174, International Congress of Nutrition, Kyoto, Japan, Liismi, M. H. tress Testing Principles and Practice. Philadelphia: F. A. Davis, Asmup, P., K. AGL, J. W. VRINGHAU, AND. MUNON. The influence of temperature and ph on the dissociation curve of oxyhemoglobin of human blood. cand. J. Chin. Invest. 17: 515, BATA,.., AND A. CHURCHILL. Iron deficiency anemia and the productivity of adult males in Indonesia. World Bank taff Working Paper No. 175, Washington, D.C.: World Bank, CHANUTIN, A., Ai it R. R. CHURNIH. ffect of organic and inorganic phosphates on the oxygen equilibrium of human erythrocytes. Arch. Binchem. Biophys. 121: 96, BNCH, R., AND R.. BNCH. The effect of organic phosphates from the human erythrocyte on the allosteric properties of hemoglobin. Binchem. Biophys. Res. Commun. 26: 162, THOMA, H. M.,.. LFRANK, R.. IRWIN, H. W. Fitm s, AND P. R. CALDWLL. The oxyhemoglobin dissociation curve in health and disease. Am. J. Med. 57: 331, LNFANT, C., J. D. TORRANC, R. WOODON, C. A. FINCH. Adaptation to hypoxia. In: Red Cell Metabolism, edited by J. Brewer. New York: Plenum Press, 197, pp WOODON, R., B. WRANN, AND J. DArriiR. ffects of erythrocyte 2,3-DPG and hemoglobin concentration on 2 delivery and work performance. Chin. Res. 2: 628, BUTLR,.,. LARH AND F. TANZI. Iron enzymes in iron deficiency. VII. Oxygen consumption measurements in iron deficient subjects. Am J. Med. ci. 239: 759, 196. Downloaded from by guest on June 5, 211

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