CURRENT LITERATURE AND CLINICAL ISSUES
Energy consumption in infants with bronchopulmonary dysplasia Growth failure in infants with bronchopulmonary dysplasia remains one of the major clinical problems for pediatricians responsible for the care of these infants. Data from a number of studies, together with extensive clinical experience, demonstrate that a significant number of infants with BPD fail to thrive. 14 Inasmuch as a major proportion of lung growth occurs postnatally in humans, optimal growth of these infants is desirable so that "new" lung will develop normally and hence reduce the dependence of these infants on respiratory support. Several hypotheses have been proposed to explain the mechanism of failure to thrive. These include, for example, chronic hypoxemia, long-term multiple drug therapy, acid-base disturbance, heart failure, and failure to provide adequate caloric intake. In addition, because these infants' mechanical work of breathing is at a higher level in comparison with that of normal infants, a higher basal energy consumption has been postulated. With the widespread availability of indirect respiratory calorimetry equipment, measurements of energy expenditure in infants with BPD have been performed, resulting in six manuscripts from four different groups during the past few years. Weinstein and Oh 5 studied eight infants with BPD who were receiving supplemental oxygen at more than 4 weeks of age and compared them with matched control infants. The studies were performed immediately after a feeding, in a modified incubator with an open circuit system. The average caloric intake of infants with BPD was significantly less than that of control infants. The data revealed that the mean rate of oxygen consumption in infants with BPD was 25% more than that in the control infants. Using the same technique, Yunis and Oh 6 reported 9o2 in six infants with BPD who were receiving supplemental oxygen and compared them with six control infants. These studies were done after a 9-hour fast while the infants were receiving glucose at 4 or 12 mg/kg - min along with an amino acid mixture. The mean caloric intake before the study was approximately 20% higher in the BPD group. The 9o2 was higher in the BPD group and increased further with the higher rate of glucose infusion. The rate of carbon dioxide production, however, was similar in the BPD and control infants. Thus the respiratory quotient of infants with BPD who were receiving glucose at 4 m g / k g , rain, or 56% (28 kcal/ kg 9 day) of energy expenditure as carbohydrate, was mea662
sured to be 0.77 _+ 0.15. Increasing the glucose infusion to 12 mg/kg 9 min resulted in no change in RQ, which was 0.76 _+ 0.15. In contrast, the control infants, who were breathing room air, had an RQ of 0.88 _+ 0.15 while receiving glucose at 4 mg/kg 9 min. Their RQ increased to 0.92 _+ 0.20 (not statistically significant) when glucose infusion was increased to 22 mg/kg 9 rain. Yeh et al. 7 also reported a 33% higher rate of energy consumption in five infants with BPD who were also receiving supplemental oxygen. Kurzner et al. 8, 9 showed that infants with BPD and growth failure who were not receiving supplemental oxygen had a higher 9o2 compared with control infants or with infants with BPD who were thriving. Finally, Kao et al. I~ showed a higher 9o2 in infants with BPD; however, no control infants were examined. BPD RQ Vco2 ~/o2
Bronchopulmonarydysplasia Respiratoryquotient Rate of carbon dioxide production Rate of oxygen consumption
All these reports, despite the small sample sizes, concluded that energy expenditure is increased in infants with BPD and that increased energy expenditure may be responsible in part for their growth failure. However, these observations also raise some major concerns. For example, the study of Yeh et al. 7 showed that even in the presence of lower energy intake and higher energy expenditure, the rate of growth of infants with BPD was the same as in the control infants, suggesting a "lower energy cost of growth." Similarly, the low RQ of infants with BPD in the study of Yunis and Oh, 6 in the presence of glucose infusions, is surprising. Assuming that protein contributes approximately 8% to oxidative fuels (a conservative estimate), II the low respiratory quotient indicates that at both rates of glucose infusions, very little glucose was being oxidized (i.e., fuel utilized was almost entirely fat). In addition, measured 902 or energy consumption was greater when glucose was infused at a higher rate; this finding indicates greater fat oxidation in the face of increased glucose supply. Such a phenomenon is physiologically impossible. In an adult man, as in the control infants, increasing the glucose supply immediately increases carbohydrate oxidation, decreases fat oxidation, and spares nitrogen. 12, 13 An alternate explana-
Volume 116 Number 4
tion might be that the BPD infants were retaining carbon dioxide as bicarbonate. However, the entire bicarbonate pool would have to increase very rapidly to explain the observed discrepancy in RQ. 14 This explanation is also physiologically improbable. Issues of these kinds cause concern regarding the accuracy of measurement of xI02 in these studies. Respiratory calorimetry measures ~/o2 or X)co2 (Q) by means of the Fick principle: Q = F x AC. The flow (F) of gas through a hood that is placed over the subject's head is measured and maintained, and the difference (AC) between the oxygen and carbon dioxide concentrations of the gas entering and leaving the hood is measured. In, practice, this measured change in concentrations is very small, usually in the range of 0.2% to 0.5%. These small differences can be accurately determined with available technology (mass spectrometer gas analyzer, paramagnetic oxygen analyzer, infrared carbon dioxide analyzer). However, it is critical to have a constant and accurately measured concentration of oxygen and carbon dioxide entering the hood. This is not a problem in subjects studied in room air, but providing supplemental oxygen at an absolutely constant measured concentration is extremely difficult. For example, if the measured concentration of the ambient oxygen varies by 0.1% (i.e., 40.0% to 40.1%), and if the typical change in concentration across the hood is 0.2% to 0.5%, the potential error in the measured "~o2 value will then be 20% to 50%. Measurements of Vco2 may be less subject to error when supplemental oxygen is provided, because of the tow ambient concentration of carbon dioxide in the atmosphere (0.02% to 0.06%). In any case, the respiratory calorimetry system used in a particular study, as a whole, must be validated. This requires measuring the rate of combustion of a known substance (usually anhydrous alcohol or butane) and comparing the expected values with Vo2, Vco2 and RQ measurements obtained with that system] s-~7 Using this technique, most investigators report values of "VO2, Vco2, and RQ within 2% to 5% of the expected values when studies are performed in room air. No such validation has been reported when supplemental oxygen has been used, a situation in which error is most likely to occur. The risk of fire that is present when combustions are done in high oxygen may have prevented the investigators from validating the calorimetry systems. Several investigators have attempted unsuccessfully to resolve these problems. Thus the accuracy and reproducibility of the techniques used' in the studies under discussion should have been documented. It is likely that in the studies of the Chicago and Providence groups, the Vo2 but not Vco2 was overestimated. The Vco2 measurement, in theory, would be affected less by supplemental oxygen. In the study of Yunis and Oh, 6 Vco2 was not different in infants
Energy consumption in infants with BPD
663
with BPD and control infants at low rates of glucose infusion. If energy consumption is calculated from ~/coa rates, with the RQ in BPD infants and control infants assumed to be the same, no differences in the two groups are observed. Kurzner et al. 8' 9 found no difference in Vo2 (and energy expenditure) between control subjects and normally growing BPD infants studied at 6 months of age.The studies were performed in room air, which eliminated the difficulties of measuring X)o2 in high ambient oxygen concentration. However, they did show a significantly higher ')02 in BPD infants with growth failure, as defined by height and weight at less than the 10th percentile. These infants were clinically well, were at home, and were not receiving supplemental oxygen. They were therefore i n a recovery phase, and their lower prealbumin levels suggested a recent state of protein calorie malnutrition. Because infants recovering from malnutrition are known to have high rates of postprandial energy expenditure, 17 the higher '~o2 measured in those with BPD and growth failure may be a reflection of the recovery phase of previous malnutrition and may not be related to BPD per se, We return to the primary question: Is energy consumption increased in infants with bronchopulmonary dysplasia? We believe that the answer may be yes for infants who have increased mechanical work of respiration. However, we anticipate the magnitude of increase to be small because of the chronicity of the problem and the small contribution of the respiratory muscles to overall energy consumption. ~8 Although energy consumption by respiratory muscles can increase acutely, data regarding sustained increase for a prolonged period are lacking, particularly in infants and children. In this context, the study of Kao et al. I~ is significant in that improvement in pulmonary mechanics and reduction in mechanical power of breathing by theophylline and diuretics did not change the ~'o2 in infants with BPD. Thus further accurate information is necessary before we start high-calorie supplemental feedings to meet the energy demands of infants with BPD. Satish C. Kalhan, MBBS, FRCP Scott C. Denne, MD Division of Neonatology, Department of Pediatrics Case Western Reserve University Cleveland, OH 44106 Indiana University Indianapolis, IN 46202 REFERENCES
I. Vohr BR, Bell EF, Oh W. Infants with bronchopulmonary dysplasia: growth pattern and neurological and developmental outcome. Am J Dis Child 1982;136:443-7. 2. Markestad T, Fitzhardinge PM. Growth and development in children, recovering from bronchopulmonary dysplasia. J PEbtAXR 198 t ;98:597-602. 3. Yu VYH, Orgill AA, Luin SB, Bajuk B, Astbury J. Growth
664
4.
5. 6.
7.
8.
9.
10.
Kalhan and Denne
The Journal of Pediatrics April 1990
and development of very low birthweight infants recovering from bronchopulmonary dysplasia. Arch Dis Child 1983; 58:791-4. Frank L, Sosenko IRS. Undernutrition as a major contributing factor in the pathogenesis of bronchopulmonary dysplasia. Am Rev Respir Dis 1988;138:725-9. Weinstein MR, Oh W. Oxygen consumption in infants with bronehopulmonary dysplasia. J PEDIATR 1981 ;99:958-6 l. Yunis KA, Oh W. Effects of intravenous glucose loading on oxygen consumption, carbon dioxide production, and resting energy expenditure in infants with bronchopulmonary dysplasia. J PED1A'rR 1989;115:127-32. Yeh TF, McClenan DA, Ayahi OA, Pildes RS. Metabolic rate and energy balance in infants with bronchopulmonary dysplasia. J PEDIATR 1989;114:448-51. Kurzner SI, Garg M, Bautista DB, Sargent CW, Bowman CM, Keens TG. Growth failure in bronchopulmonary dysplasia: elevated metabolic rates and pulmonary mechanics. J PEOIATR 1988;112:73-80. Kurzner SI, Garg M, Bautista DB, ct al. Growth failure in infants with bronchopulmonary dysplasia: nutrition and elevated resting metabolic expenditure. Pediatrics 1988;81:379-84. Kao LC, Durand D J, Nickerson BG. Improving pulmonary function does not decrease oxygen consumption in infants with bror~chopulrno~ary dysplas~a. J PEDIATR 1988; ~] 2:6 ! 6-2 ].
11. Kalhan SC, Gilfillan CA. Intrauterine nutrition and the newborn. Proceedings of the Oxford Symposium. In: Jones CT, Nathanielsz PW, eds. The physiological development of the fetus and newborn. New York: Academic Press, 1985:739-46. 12. Wolfe RR, Allsop JR, Burke JF. Glucose metabolism in man: responses to intravenous glucose infusion. Metabolism 1979; 28:210-20. 13. Mosora F, Lefebvre P, Pirnay F, Lacroix M, Luyckx A, Duchesne J. Quantitative evaluation of the oxidation of an exogenous glucose load using naturally labeled 13C-glucose. Metabolism 1976;25:1575-82. 14. Irving CS, Lifschitz CH, Wong WW, Boutlon TW, Nichols B1, Klein PD. Characterization of HCO~-/COz pool sizes and kinetics in infants~ Pediatr Res 1985;19:358-63. 15. Denne SC, Kalhan SC. Glucose carbon recycling and oxidation in human newborns. Am J Physiol 1986;251:E71-7. 16. Marks KH, Coen P, Kerrigan JR, Francalancia NA, Nardis EE, Snider MT. The accuracy and precision of an open-circuit system to measure oxygen consumption and carbon dioxide production in neonates. Pediatr Res 1987;21:58-65 17. Brooke OG, Ashworth A. The influence of malnutrition on the postprandial metabolic rate and respiratory quotient. Br J Nutr 1972;27:407-15, 18. Roussos C, Macklem PT. The respiratory muscles. N Engl J Med 1982;307:786-97.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the 1990 issues of THE JOURNAL OF PEDIATRICS are available to subscribers (only) from the Publisher, at a cost of $48.00 ($64.00 international) for Vol. 116 ( J a n u a r y - J u n e ) and Vol. 117 (July-December), shipping charges included. Each bound volume contains subject and a u t h o r indexes, and all advertising is removed, Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram, with the Journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C.V. Mosby Company, Circulation D e p a r t m e n t , 11830 Westline Industrial Dr., St. Louis, M O 63146-3318, U S A / 8 0 0 - 3 2 5 - 4 1 7 7 , ext. 7351.
Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.
Energy consumption in infants with bronchopulmonary dysplasia Growth failure in infants with bronchopulmonary dysplasia remains one of the major clinical problems for pediatricians responsible for the care of these infants. Data from a number of studies, together with extensive clinical experience, demonstrate that a significant number of infants with BPD fail to thrive. 14 Inasmuch as a major proportion of lung growth occurs postnatally in humans, optimal growth of these infants is desirable so that "new" lung will develop normally and hence reduce the dependence of these infants on respiratory support. Several hypotheses have been proposed to explain the mechanism of failure to thrive. These include, for example, chronic hypoxemia, long-term multiple drug therapy, acid-base disturbance, heart failure, and failure to provide adequate caloric intake. In addition, because these infants' mechanical work of breathing is at a higher level in comparison with that of normal infants, a higher basal energy consumption has been postulated. With the widespread availability of indirect respiratory calorimetry equipment, measurements of energy expenditure in infants with BPD have been performed, resulting in six manuscripts from four different groups during the past few years. Weinstein and Oh 5 studied eight infants with BPD who were receiving supplemental oxygen at more than 4 weeks of age and compared them with matched control infants. The studies were performed immediately after a feeding, in a modified incubator with an open circuit system. The average caloric intake of infants with BPD was significantly less than that of control infants. The data revealed that the mean rate of oxygen consumption in infants with BPD was 25% more than that in the control infants. Using the same technique, Yunis and Oh 6 reported 9o2 in six infants with BPD who were receiving supplemental oxygen and compared them with six control infants. These studies were done after a 9-hour fast while the infants were receiving glucose at 4 or 12 mg/kg - min along with an amino acid mixture. The mean caloric intake before the study was approximately 20% higher in the BPD group. The 9o2 was higher in the BPD group and increased further with the higher rate of glucose infusion. The rate of carbon dioxide production, however, was similar in the BPD and control infants. Thus the respiratory quotient of infants with BPD who were receiving glucose at 4 m g / k g , rain, or 56% (28 kcal/ kg 9 day) of energy expenditure as carbohydrate, was mea662
sured to be 0.77 _+ 0.15. Increasing the glucose infusion to 12 mg/kg 9 min resulted in no change in RQ, which was 0.76 _+ 0.15. In contrast, the control infants, who were breathing room air, had an RQ of 0.88 _+ 0.15 while receiving glucose at 4 mg/kg 9 min. Their RQ increased to 0.92 _+ 0.20 (not statistically significant) when glucose infusion was increased to 22 mg/kg 9 rain. Yeh et al. 7 also reported a 33% higher rate of energy consumption in five infants with BPD who were also receiving supplemental oxygen. Kurzner et al. 8, 9 showed that infants with BPD and growth failure who were not receiving supplemental oxygen had a higher 9o2 compared with control infants or with infants with BPD who were thriving. Finally, Kao et al. I~ showed a higher 9o2 in infants with BPD; however, no control infants were examined. BPD RQ Vco2 ~/o2
Bronchopulmonarydysplasia Respiratoryquotient Rate of carbon dioxide production Rate of oxygen consumption
All these reports, despite the small sample sizes, concluded that energy expenditure is increased in infants with BPD and that increased energy expenditure may be responsible in part for their growth failure. However, these observations also raise some major concerns. For example, the study of Yeh et al. 7 showed that even in the presence of lower energy intake and higher energy expenditure, the rate of growth of infants with BPD was the same as in the control infants, suggesting a "lower energy cost of growth." Similarly, the low RQ of infants with BPD in the study of Yunis and Oh, 6 in the presence of glucose infusions, is surprising. Assuming that protein contributes approximately 8% to oxidative fuels (a conservative estimate), II the low respiratory quotient indicates that at both rates of glucose infusions, very little glucose was being oxidized (i.e., fuel utilized was almost entirely fat). In addition, measured 902 or energy consumption was greater when glucose was infused at a higher rate; this finding indicates greater fat oxidation in the face of increased glucose supply. Such a phenomenon is physiologically impossible. In an adult man, as in the control infants, increasing the glucose supply immediately increases carbohydrate oxidation, decreases fat oxidation, and spares nitrogen. 12, 13 An alternate explana-
Volume 116 Number 4
tion might be that the BPD infants were retaining carbon dioxide as bicarbonate. However, the entire bicarbonate pool would have to increase very rapidly to explain the observed discrepancy in RQ. 14 This explanation is also physiologically improbable. Issues of these kinds cause concern regarding the accuracy of measurement of xI02 in these studies. Respiratory calorimetry measures ~/o2 or X)co2 (Q) by means of the Fick principle: Q = F x AC. The flow (F) of gas through a hood that is placed over the subject's head is measured and maintained, and the difference (AC) between the oxygen and carbon dioxide concentrations of the gas entering and leaving the hood is measured. In, practice, this measured change in concentrations is very small, usually in the range of 0.2% to 0.5%. These small differences can be accurately determined with available technology (mass spectrometer gas analyzer, paramagnetic oxygen analyzer, infrared carbon dioxide analyzer). However, it is critical to have a constant and accurately measured concentration of oxygen and carbon dioxide entering the hood. This is not a problem in subjects studied in room air, but providing supplemental oxygen at an absolutely constant measured concentration is extremely difficult. For example, if the measured concentration of the ambient oxygen varies by 0.1% (i.e., 40.0% to 40.1%), and if the typical change in concentration across the hood is 0.2% to 0.5%, the potential error in the measured "~o2 value will then be 20% to 50%. Measurements of Vco2 may be less subject to error when supplemental oxygen is provided, because of the tow ambient concentration of carbon dioxide in the atmosphere (0.02% to 0.06%). In any case, the respiratory calorimetry system used in a particular study, as a whole, must be validated. This requires measuring the rate of combustion of a known substance (usually anhydrous alcohol or butane) and comparing the expected values with Vo2, Vco2 and RQ measurements obtained with that system] s-~7 Using this technique, most investigators report values of "VO2, Vco2, and RQ within 2% to 5% of the expected values when studies are performed in room air. No such validation has been reported when supplemental oxygen has been used, a situation in which error is most likely to occur. The risk of fire that is present when combustions are done in high oxygen may have prevented the investigators from validating the calorimetry systems. Several investigators have attempted unsuccessfully to resolve these problems. Thus the accuracy and reproducibility of the techniques used' in the studies under discussion should have been documented. It is likely that in the studies of the Chicago and Providence groups, the Vo2 but not Vco2 was overestimated. The Vco2 measurement, in theory, would be affected less by supplemental oxygen. In the study of Yunis and Oh, 6 Vco2 was not different in infants
Energy consumption in infants with BPD
663
with BPD and control infants at low rates of glucose infusion. If energy consumption is calculated from ~/coa rates, with the RQ in BPD infants and control infants assumed to be the same, no differences in the two groups are observed. Kurzner et al. 8' 9 found no difference in Vo2 (and energy expenditure) between control subjects and normally growing BPD infants studied at 6 months of age.The studies were performed in room air, which eliminated the difficulties of measuring X)o2 in high ambient oxygen concentration. However, they did show a significantly higher ')02 in BPD infants with growth failure, as defined by height and weight at less than the 10th percentile. These infants were clinically well, were at home, and were not receiving supplemental oxygen. They were therefore i n a recovery phase, and their lower prealbumin levels suggested a recent state of protein calorie malnutrition. Because infants recovering from malnutrition are known to have high rates of postprandial energy expenditure, 17 the higher '~o2 measured in those with BPD and growth failure may be a reflection of the recovery phase of previous malnutrition and may not be related to BPD per se, We return to the primary question: Is energy consumption increased in infants with bronchopulmonary dysplasia? We believe that the answer may be yes for infants who have increased mechanical work of respiration. However, we anticipate the magnitude of increase to be small because of the chronicity of the problem and the small contribution of the respiratory muscles to overall energy consumption. ~8 Although energy consumption by respiratory muscles can increase acutely, data regarding sustained increase for a prolonged period are lacking, particularly in infants and children. In this context, the study of Kao et al. I~ is significant in that improvement in pulmonary mechanics and reduction in mechanical power of breathing by theophylline and diuretics did not change the ~'o2 in infants with BPD. Thus further accurate information is necessary before we start high-calorie supplemental feedings to meet the energy demands of infants with BPD. Satish C. Kalhan, MBBS, FRCP Scott C. Denne, MD Division of Neonatology, Department of Pediatrics Case Western Reserve University Cleveland, OH 44106 Indiana University Indianapolis, IN 46202 REFERENCES
I. Vohr BR, Bell EF, Oh W. Infants with bronchopulmonary dysplasia: growth pattern and neurological and developmental outcome. Am J Dis Child 1982;136:443-7. 2. Markestad T, Fitzhardinge PM. Growth and development in children, recovering from bronchopulmonary dysplasia. J PEbtAXR 198 t ;98:597-602. 3. Yu VYH, Orgill AA, Luin SB, Bajuk B, Astbury J. Growth
664
4.
5. 6.
7.
8.
9.
10.
Kalhan and Denne
The Journal of Pediatrics April 1990
and development of very low birthweight infants recovering from bronchopulmonary dysplasia. Arch Dis Child 1983; 58:791-4. Frank L, Sosenko IRS. Undernutrition as a major contributing factor in the pathogenesis of bronchopulmonary dysplasia. Am Rev Respir Dis 1988;138:725-9. Weinstein MR, Oh W. Oxygen consumption in infants with bronehopulmonary dysplasia. J PEDIATR 1981 ;99:958-6 l. Yunis KA, Oh W. Effects of intravenous glucose loading on oxygen consumption, carbon dioxide production, and resting energy expenditure in infants with bronchopulmonary dysplasia. J PED1A'rR 1989;115:127-32. Yeh TF, McClenan DA, Ayahi OA, Pildes RS. Metabolic rate and energy balance in infants with bronchopulmonary dysplasia. J PEDIATR 1989;114:448-51. Kurzner SI, Garg M, Bautista DB, Sargent CW, Bowman CM, Keens TG. Growth failure in bronchopulmonary dysplasia: elevated metabolic rates and pulmonary mechanics. J PEOIATR 1988;112:73-80. Kurzner SI, Garg M, Bautista DB, ct al. Growth failure in infants with bronchopulmonary dysplasia: nutrition and elevated resting metabolic expenditure. Pediatrics 1988;81:379-84. Kao LC, Durand D J, Nickerson BG. Improving pulmonary function does not decrease oxygen consumption in infants with bror~chopulrno~ary dysplas~a. J PEDIATR 1988; ~] 2:6 ! 6-2 ].
11. Kalhan SC, Gilfillan CA. Intrauterine nutrition and the newborn. Proceedings of the Oxford Symposium. In: Jones CT, Nathanielsz PW, eds. The physiological development of the fetus and newborn. New York: Academic Press, 1985:739-46. 12. Wolfe RR, Allsop JR, Burke JF. Glucose metabolism in man: responses to intravenous glucose infusion. Metabolism 1979; 28:210-20. 13. Mosora F, Lefebvre P, Pirnay F, Lacroix M, Luyckx A, Duchesne J. Quantitative evaluation of the oxidation of an exogenous glucose load using naturally labeled 13C-glucose. Metabolism 1976;25:1575-82. 14. Irving CS, Lifschitz CH, Wong WW, Boutlon TW, Nichols B1, Klein PD. Characterization of HCO~-/COz pool sizes and kinetics in infants~ Pediatr Res 1985;19:358-63. 15. Denne SC, Kalhan SC. Glucose carbon recycling and oxidation in human newborns. Am J Physiol 1986;251:E71-7. 16. Marks KH, Coen P, Kerrigan JR, Francalancia NA, Nardis EE, Snider MT. The accuracy and precision of an open-circuit system to measure oxygen consumption and carbon dioxide production in neonates. Pediatr Res 1987;21:58-65 17. Brooke OG, Ashworth A. The influence of malnutrition on the postprandial metabolic rate and respiratory quotient. Br J Nutr 1972;27:407-15, 18. Roussos C, Macklem PT. The respiratory muscles. N Engl J Med 1982;307:786-97.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the 1990 issues of THE JOURNAL OF PEDIATRICS are available to subscribers (only) from the Publisher, at a cost of $48.00 ($64.00 international) for Vol. 116 ( J a n u a r y - J u n e ) and Vol. 117 (July-December), shipping charges included. Each bound volume contains subject and a u t h o r indexes, and all advertising is removed, Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram, with the Journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C.V. Mosby Company, Circulation D e p a r t m e n t , 11830 Westline Industrial Dr., St. Louis, M O 63146-3318, U S A / 8 0 0 - 3 2 5 - 4 1 7 7 , ext. 7351.
Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.
