Original Paper
Service de Médicine néonatale, Hôpital Port-Royal, Paris, France
Energy Expenditure in Premature Newborns with Bronchopulmonary Dysplasia
KeyWords
Abstract
Energy expenditure Bronchopulmonary dysplasia Premature newborn Medium chain triglycerides
Five premature newborns (birth weight, mean ± SD , 960 ± 145 g; gestational age 28 ± 1 weeks) with bronchopulmonary dysplasia (BPD) according to the criteria of Bancalari, and 6 controls (birth weight 1,320 ± 210 g; gestational age 30 ± 2 weeks) were studied for energy expenditure (EE) by indirect calorimetry. The measurement of total EE was performed when the intake of the infants in both groups was the same and when the respiratory condition had stabilized (control group: postnatal age 31 ± 6 days, 1,950 ± 200 g; BPD group: postna tal age 105 ± 45, postnatal weight 2,440 ± 380). The BPD group had a higher VCH ( 11.15 vs. 8.04 ml/kg/min, p < 0.01 ), V C O 2 (9.13 vs. 7.74 ml/kg/min, p < 0.02) and total EE (76 vs. 61 kcal/kg/day, p < 0.02). The highest values were encoun tered in the 3 more severely ill infants: mean VCH 11.03 ml/kg/min, mean EE 82 kcal/kg/min. In these cases, administration of medium chain triglycerides limits the in crease in V C O 2 and lowers the respiratory quotient (0.87 vs. 0.96 in controls).
E. de Gamarra
Introduction Improvements in techniques of neonatal care have resulted in the survival of newborns of lower and lower birth weights and gesta tional ages, together with an improvement in overall prognosis. The quality of growth is one
among many factors affecting the quality of outcome [1]. The ideal postnatal growth rate of the pre mature infant is not known. The reference commonly used is the fetus of the same gesta tional age [2], This growth rate, whose compo sition is estimated by energy balance studies
E. dc Gamarra Service de Médecine néonatale Hôpital de Port-Royal 123, boulevard de Port-Royal F-75674 Paris Cedex 14 (France)
© 1992 S. Karger A G , Basel 0006-3126/92/ 0616-0337S2.75/0
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Biol Neonate 1992;61:337-344
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rimetry in 5 premature infants with BPD compared with a group of 6 controls with no respiratory impairment receiving the same energy intake. Possible methods of manage ment are discussed.
Patients and Methods Eleven infants were included in the study. All were born prematurely and were admitted at birth to the intensive care unit o f Port Royal Hospital because o f severe illness, essentially respiratory. Criteria for entry to the study were: absence o f progressive disease, espe cially infectious, and no mechanical ventilation re quired. The mean gestational age ( ± SD ) was 29 ± 2 weeks; The mean birth was 1,155 ± 245 g. Five infants had B PD according to the criteria o f Bancalari et al. [ 18] and formed the B P D group. All o f them still had respiratory distress and characteristic chest radiography abnormalities at the time o f the study. The other 6 infants, who had recovered from their respiratory distress and had none o f these signs and whose weights were appropriate for conceptional age ( > 10th percentile o f the Lubchenco curves), served as controls. Individual data are given in ta ble 1. A t birth, the B P D group was slightly younger com pared to the control group (28 vs. 30 weeks, p < 0.01) and body weight was lower (960 vs. 1,320 g, p < 0.05). In addition, one infant (SF) already showed growth retardation. Initial respiratory pathology was more severe in the 5 infants o f the B PD group (4 cases o f severe hyaline membrane disease, 1 wet lung, 1 feto-maternal infec tion, 3 patent ductus arteriosus, 2 bacterial superinfec tions, and 4 gastroesophageal refluxes) than in the 6 controls (1 mild case o f hyaline membrane disease, 3 wet lung, 3 maternofetal infections). Four infants o f the control group (LM , C L , D E , A K ) later developed recurrent apnea requiring prolonged mechanical venti lation. Duration o f ventilation is given in table 1, and is higher in the B PD group (64 vs. 21 days, p < 0.01). The same is true for the duration o f oxygen therapy. At the time the sequelae were stabilized, weight, postnatal and hence conceptional age (table 1) were both higher and showed a high variability in the B P D group. In this group, all infants were older than 2 months and 2 o f them (SF. MS) had a conceptional age greater than 40 weeks - their poor state o f health having made earlier examination impossible. Lastly, the B P D group con-
Energy Expenditure in Bronchopulmonary Dysplasia
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and indirect calorimetry, can be obtained in healthy premature infants fed human milk enriched in minerals and protein [3], During the course of the neonatal period, some premature infants suffer from broncho pulmonary dysplasia (BPD) that extends beyond the first month [4], The incidence of this respiratory insufficiency is high. In 1985 in the region of Paris, 13% of the infants born before 33 weeks of gestation and surviving until the 28th day had respiratory sequelae [5, 6]. The occurrence is favored by immaturity and also by specific nutritional deficiencies and undernutrition [7], themselves conse quences of prematurity, neonatal pathology, and the poor tolerance of any fluid [8] and/or metabolic load [9], Later, these children show growth retardation and failure to catch up [10], though their nutritional intake seems to be sufficient [11], The only study of total energy expenditure (EE) measured by indirect calorimetry in BPD has been published by Yeh et al. [12] and included 5 cases. Compared to controls, total EE was raised resulting in a less positive energy balance, this latter factor appears to be sufficient to explain the growth retardation. Other authors [13-17] have measured only the resting energy expenditure over short peri ods of time in a total of 18 infants. According to Kurzner et al. [13, 14] resting EE is higher only in infants who also have growth retarda tion. However, their control group consisted of infants delivered at term. Yunis and Oh [15] also found that resting energy expendi ture was higher in infants with BPD. Two other studies involved a total of 21 measure ments of V O i. Veinsteinand Oh [16] reported that V O 2 was 25% higher in patients than in controls. Kao et al [ 17] found values consid ered to be high (7.65 ml/kg/min), but did not use a control group. The aim of this study was to report further values of total EE measured by indirect calo
Table 1. Characteristics o f the 2 groups Infants
A t birth
On the day o f study
gestational birth age, weeks weight, g
postnatal age, days
LM HJ CL DE SR AK
27 31 27 30 31 32
1,100 1,400 1,050 1,330 1,600 1,440
Mean SD
30 2
SF MS NF IR BK Mean SD
Duration, days
g
conceptional age, weeks
oxygen therapy
mechanical ventilation
45 20 52 45 34 38
1,760 1,650 2,010 2,000 2,110 2,160
35 34 35 36 36 37
0 1 1 25 20 3
29 7 33 25 20 15
1,320 210
31 6
1,950 200
36 1
8 10
21 9
29 27 30 26 28
860 830 1,130 870 1,100
160 140 67 87 75
3,080 2,300 2,430 2,310 2,080
51 47 40 38 39
133 34 54 71 65
79 20 48 75 97
28 1
960 145
105 45
2,440 380
71 32
64 27
p < 0 .0 1
p < 0.01
weight
Control group
BPD group
p < 0 .0 1
p < 0.05
p < 0.01
Gestational age is given in completed weeks; weights are rounded to the nearest 10 g.
Diet In the control group, infants o f conceptional age lower than 35 weeks (LM , H J, C L) received fortified human milk (for 100 ml: Alfare®, 4 g; sodium chlo ride, 1 mEq). Infants aged more than 35 weeks re ceived infant formula without medium chain triglycer ides (M CT). SR received his own mother’s fortified milk. The diet was unchanged for at least 3 days before the measurements. The calculated mean energy intake was 124 kcal/kg/day (range 112-137). In the B PD group, 2 infants o f 39 weeks (IR, BK) were still receiving fortified human milk. The 3 most severely ill infants, whose state necessitated fluid re
striction (SF, M S , and N F) received a concentrated formula enriched with 2% M C T (Liprocyl®). This for mula is routinely used when fluid restriction would result in limitation o f energy intake. It provides per 100 ml: 2.6 g protein, 5.7 g fat, 89kcal. More than 50% o f the non-proteic energy intake is derived from fat. For the whole B P D group, calculated mean energy intake was 129 kcal/kg/day (range 124-132). For the control and B P D groups, the calculated mean proteic intake was 2.97 and 2.98 g/kg/day, re spectively.
Energy Expenditure E E was measured by open circuit indirect calorim etry. Expired gas was collected in a hood carefully adjusted around the neck, which allows continuous measurements. The hood was flown through by a fan (Micronel, Tagelswangen, Switzerland) with a flow reg ulator. Flow was measured by a massic flow-meter (M F 400. Setaram, Caluire, France). Small samples o f
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sisted o f infants with respiratory impairment o f vari able severity. Three o f them (SF, M S , N F) showed the serious sign o f chronic hypercapnia, 2 o f them (SF, BK) were receiving theophylline, and one (BK) still required supplemental oxygen. Three infants in this group also had a marked weight deficit (SF, M S, BK).
Statistics The significance o f the differences between the means of each group was determined using Student’s t test.
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Results Table 2 shows the individual values of V O 2, V C O 2, the nutrients oxidized, and EE. Gas Exchange The mean V O 2 was more elevated in the BPD patients than in the control group (10.15 vs. 8.04 ml/kg/min, p < 0.01). V C O 2 was also higher in the former group (9.13 vs. 7.74, p < 0.02). Energy Expenditure The mean EE of the BPD group was higher than that of controls (76 vs. 61 keal/kg/day, p < 0.02). The highest values in the BPD group occurred in infants with more severe pathology (chronic hypercapnia, SF, M S, NF) and the longest duration of the disorder (SF, MS). The mean value in these 3 cases was 82 keal/kg/day. Nutrients Oxydation The nutrients composition (table 2) of the energy expenditure was not different for in fants receiving a similar energy composition: enriched mother’s milk or appropriate infant formula. This was the case for all control infants and 2 infants of the BPD group (IR and BK). The 3 most severely ill BPD infants (SF, M S, NF; table 2) received supplementation of fat without an increase in total energy intake. Their metabolic activity was higher (mean V O 2 11.03 vs. 8.04 ml/kg/min in controls). For these 3 infants, the difference in V C O 2 (9.64 vs. 7.74 ml/kg/min) is proportionately less compared to the 6 controls since the RQ were 0.87 and 0.96, respectively. The other 2 BPD infants not receiving M C T had a mean R Q of 0.95, similar to that of controls. This can be related to the increase in net oxidized fat in the 3 severely ill infants (3.2 vs. 0.64 g/ kg/day in controls). This represents 27% of
Energy Expenditure in Bronchopulmonary Dysplasia
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collected and reference gases were directed by a pump to a dual chanel magneto pneumatic oxygen analyzer (Magnos 4 G , Hartmann and Braun, Frankfurt, F R G ) and to a dual chanel infrared carbon dioxide analyzer (Uras 3 G , Hartmann and Braun). The fraction o f oxy gen inspired in air (FiO j) was measured by an oxygen analyzer (O A 570 Servomex Ltd, Crowborough, U K ). After taking urinary nitrogen into account, V CL, respi ratory quotient (RQ ) and EE were calculated according to Jequier’s [ 19] formulae. The accuracy o f the system was checked by two means. First by infusing a gas in the hood at a rate mea sured by an accurate flow-meter (Rosemount, Rungis, France) and corrected to standard conditions [20]. This simulates a known oxygen consumption when nitrogen (N50, C F P O ) was infused or a known carbon dioxide production when C O 2 (N45, C F P O ) was in fused. The system was considered as sufficiently accu rate when 95% V O 2 and V C O 2 were obtained. Second by burning a known output o f butane [21], at a rate measured by a massic flow-meter (5850 T R , Rosemount, Rungis, France). The mean V O 2 was 98.8 ± 1.6% o f the expected value; the mean V C O 2 was 97.7 ± 1.5%and the mean R Q was 0.61 ± 0.002. Stability o f the conditions o f measurement in the infants was verified by non invasive monitoring o f 8 parameters: heart and respiratory rate; transcutaneous oxygen and C O 2 partial pressures; skin temperature at 3 sites, and ambient temperature. This continuous moni toring was carried out by the following apparatus on-line with a computer: cardiac monitor (111, Roche Kontron; Microgras 7640, Kontron Instruments Ltd, Watford, U K ), and 4 temperature sensors. An apparatus was spe cially developed to count respiratory movements. Infants were studied in the supine position, in their incubators at their nursing temperatures. It was not nec essary to interrupt measurements for routine nursing care. Measurements lasted from 4 to 24 h, by periods o f 8 h maximum and o f 4 h only in the most seriously ill infants. The mean duration o f measurements was the same in both groups (table 2); controls were matched with BPD infants for duration o f measurements. Over the same period o f time, urine was collected on thymol (10% solution in isopropyl alcohol) and fro zen. An aliquot was used to assay nitrogen by Kjeldahl’s method. The amount o f protein oxidized (g/kg/ day) was calculated from the urinary output o f nitro gen (N X 6.25).
Table 2. Results o f indirect calorim etry Infants
RQ Duration o f vo 2 vco 2 measure ml/kg/min ml/kg/min ment (h)
Carbohydrates Fat oxidized oxidized g/kg/day g/kg/day
Protein oxidized g/kg/day
EE kcal/kg/day
13.5 19.5 13.0 11.8 11.5 10.3
0.58 -1.52 0.67 1.48 1.20 1.46
0.52 0.57 0.80 0.85 0.18 1.20
61 65 61 64 57 69
13.26 3.26
0.64 0.39
0.69 0.35
61 3
11.1 12.1 12.5 13.7 13.6
3.89 3.41 2.30 0.66 1.25
1.28 1.55 1.46 1.16 0.76
86 81 79 66 69
12.6 1.09
2.30 1.37
1.24 0.31
76 8
Control group LM HJ CL DE SR AK
4 6 22 18 4 4
Mean SD
9.7 7.4
8.02 8.23 7.95 8.49 7.70 7.86
7.74 8.80 7.68 7.83 7.20 7.18
8.04 0.28
7.74 0.59
11.50 11.50 10.10 8.37 9.32
9.81 10.00 9.10 8.03 8.71
10.15 1.37
9.13 0.80
p < 0.01
p < 0.02
0.96 1.06 0.96 0.92 0.94 0.91
BPD group SF a M Sa NF3 IR BK Mean SD
4 4 4 15 21 9.6 7.1
0.85 0.86 0.90 0.96 0.93
p < 0.02
EE vs. 63% of carbohydrate origin. The pro portion is 10 and 84%. respectively, of the mean EE in the control group.
Discussion In a group of 5 premature infants with BPD compared to a group of 6 controls, we have shown that: ( 1) EE expenditure is higher; (2) it is higher in themore severely ill infants, and (3) in these infants the administration of M C T by the gastrointestinal route limits the increase in VCCb, since R Q is lower.
Control Group At birth the group who served as control had higher mean weights and gestational ages than those in the BPD group. These differ ences can be explained by the fact that early prematurity and very low birth weight are major risk factors in BPD [22], The control group consists of premature babies studied when mechanical ventilation was removed. Under the same conditions, our BPD group is made up of maturer and heavier babies. Simi larly, at the time of the study in the BPD group, the ages, weights, and degree of sever ity were very varied. This is due to the course of the disease which sometimes requires pro longed mechanical ventilation. Other authors
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Infants receiving M C T (mean R Q = 0.87).
Energy’ Expenditure The mean value of total EE in the control group (61 kcal/kg/day) agrees with the litera ture data for infants of equivalent age and receiving the same energy intake. The average EE was 76 kcal/kg/day in our BPD group, identical to that found by Yeh et al. [12], whose control group had an expenditure of 58.5 kcal. Kurzner et al. [14] reported that the resting expenditure was raised (72 kcal/kg/ day) only in the most seriously ill infants. The 6 other BPD infants had an expenditure com parable to fullterm newborn controls (50 kcal/ kg/day). Yunis and Oh [15] measured resting expenditure before glucose loading and found it slightly raised: 53.8 vs. 45 kcal/kg/day in controls. Many factors can explain this hyperme tabolism. First of all, a difference in nutri tional intake. Actually, this could not have been a confounding factor in our study since the energy intake was the same in both groups even in the 3 severer cases (SF, MS, NF). In these cases, M C T only compensated the en ergy limitation induced by fluid restriction. In those conditions, M C T accounted neither for an increase in energy intake nor for such an
important increase in energy expenditure, even if M C T are oxidized up to 50% in pre mature babies [23, 24], The increase in the cost of breathing related to respiratory dis tress only has a small effect. For Wolfson et al. [25], a decrease in respiratory distress results in only a minimum energy saving. Kao et al. [17] showed that VCF is not reduced after administration of furoscmide and/or theoph
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ylline to improve ventilatory conditions. Two other factors play a role, one is the presence of intrapulmonary inflammatory foci, the other is the administration of theophylline which also increases energy expenditure [26, 27], Two of our infants received theophylline (SF, BK; table 2). Growth retardation is accompanied by in creased EE and 3 of our BPD infants had a marked growth deficit. The metabolic rate is also dependent on previous nutritional status. Growth-retarded infants demonstrate a rela tive hypermetabolism when compared with similar appropriately sized infants [28-30], It has been proposed that this hypermetabolism may be due to a larger ratio of brain to body weight or to a faster rate of growth [28], Unfortunately, this was not the case in our BPD group. Kurzner et al. [14] found that infants with BPD and growth retardation had increased metabolic demands that were corre lated with a body weight deficit. This is per haps due in part to the expression of results per kilogram of total body weight, which re sults in an underestimation of the lean mass in infants with growth retardation. At the present time there is no simple and reproduc ible method for measuring lean body mass in the newborn [31]. Measures aimed at saving energy are fi nally limited: improvement in the ventilatory condition; treatment of obvious infectious foci, and limitation of indications for theoph ylline. Only increased energy intake can cover the increased expenditure and permit growth. However, the increase in dietary substrates, especially carbohydrates, runs the risk of in creasing VCO? and leading to respiratory fail ure [9, 15, 32, 33]. Nutrient Oxydation Only the results of the 3 infants who re ceived M CT (table 2) will be discussed, even though they are preliminary. Oxidation of
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have encountered the same difficulties. Kurzner et al. [13, 14] compares infants that were born prematurely and had BPD with fullterm infants. Yeh et al. [12] and Yunis and Oh [ 15] compared them with other premature infants who also have slightly different weights and ages than the BPD group.
M C T having been demonstrated in prema ture infants [23, 24], the advantage of fat is that, for a given quantity of energy supplied, they lead to a lower C O : production than car bohydrates. Oxidation of 1 kcal of glucose releases 201 ml of C O 2 compared to 154 ml for fat [34]. To the extent that it appears that improvement in the energy balance during BPD involves an increase in energy intake, replacement of part of the energy intake by fat seems to be a promising addition for infants as in adults with respiratory insufficiency [32, 33]. Success depends, of course, on the fat being oxidized and not stored in excess in adi pose tissue [35].
Conclusion Premature newborns with BPD have an increased total EE, and this is more marked in cases when the respiratory sequelae are se
verer and when there is growth retardation. With the recommended energy intake ( 130 kcal/kg/day), the energy balance is not sufficiently positive to allow for adequate growth. However, increasing nutritional in take runs the risk of inducing respiratory fail ure. The M C T represent an interesting energy supplement. When EE increases, oxidation of M C T can ensure a supplementary energy sup ply with a lesser increase inVC0 2, which could perhaps result in better respiratory tol erance.
Acknowledgements This study and the construction o f the indirect calorimeter were supported by a ‘Contrat Externe IN S E R M ’ 87.3.35.04E financed by Caisse Nationale d’Assurance Maladie. We thank Prof. Jéquier and his team for their advice, and M r. Bonoris, Mr. Bru, Mr. Haye, Mr. Hube, and M r. Masson, student engineers at the Ecole Nationale Supérieure d’Electronique et ses Applications who computerized the apparatus.
References 6 Zupan V , Dehan M , Rougeot C , et al: Evaluation précoce du risque de dysplasie broncho-pulmonaire. Arch Fr Pédiatr 1990:47:565-569. 7 Frank L, Sosenko 1RS: Undernutrition as a major contributing factor in the pathogenesis o f bronchopul monary dysplasia. Am Rev Respir D is 1988;138:725-729. 8 Bell EF. Warburton D . Stonestreet BS, et al: Effect o f fluid administra tion on the development of symp tomatic patent ductus arteriosus and congestive heart failure in pre mature infants. N Engl J Med 1980; 302:598-604. 9 Askanazi J , Weissman C , Rosen baum SH , et al: Nutrition and the respiratory system. Crit Care Med 1982;10:163-172.
10 Markestad T , Fitzhardinge PM: Growth and development in chil dren recovering from bronchopul monary dysplasia. J Pediatr 1981; 98:597-602. 11 Davidson S, Schrayer A , Wielunsky E, et al: Energy intake, growth and development in ventilated V L B W infants with and without broncho pulmonary dysplasia. Am J Dis Child 1990;144:553-559. 12 Yeh T F , McClenan D A , Ajayi O A , et al: Metabolic rate and energy bal ance in infants with bronchopul monary' dysplasia. J Pediatr 1989; 114:448-451. 13 KurznerSI, G a rg M . Bautista D B , et al: Elevated metabolic rates corre lates with growth failure in broncho pulmonary dysplasia. Clin Res 1987;35:235.
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1 Senterre J : Contribution à l’étude de l’alimentation optimale du préma turé. Liège, Vaillant-Carmanne, 1976. 2 Rcichman B, Chessex P, Putet G , et al: Diet, fat accretion and growth in premature infants. N Engl J Med 1981;305:1495-1500. 3 Putet G . Rigo J , Salle B, et al: Sup plementation o f human milk with casein hydrolysate: Energy and ni trogen balance and weight gain com position in very low birth weight infants. Pediatr Res 1987:21:458461. 4 Moriette G : La dysplasie broncho pulmonaire. Arch Fr Pédiatr 1990: 47:555-557. 5 Dehan M , Vodovar M , Goujard J , et al: Devenir des prématurés de moins de 33 semaines d’âge gesta tionnel. Arch Fr Pédiatr 1989;46: 157-159.
23 Whyte R K , Campbell D , Stanhope R , et al: Energy balance in low birth weight infants fed formula ofhigh or low medium chain triglyceride con tent. J Pediatr 1986;108:964-971. 24 Putet G , Thelin A , Philipossian G , et al: Medium chain triglycerides as a source o f energy in premature in fants; in Horisberger M , Bracco U (eds): Lipids in Modern Nutrition. New York, Raven Press, 1987, pp 42-49. 25 Wolfson M R , Bhutani V K , Shaffer Y H , et al: Mechanics and energetics o f breathing helium in infants with bronchopulmonary dysplasia. J Pe diatr 1984;104:752-757. 26 Gerhart T , McCarthy J , Bancalari E: Effect o f aminophylline on respira tory center activity and metabolic rate in premature infants with idio pathic apnea. Pediatrics 1979;63: 537-540. 27 de Gamarra E , Cauderay M , Schütz Y , et al: Dépense énergétique et composition du poids gagr.é chez des nouveau-nés prématurés eutro phiques recevant de la téophylline et chez des nouveau-nés prématurés hypotrophiques; in Relier JP (ed): Progrès en Néonatologie. Basel, Karger, 1988, vol 8, pp 300-304. 28 Mestyan J: Energy metabolism and substrate utilisation in the newborn; in Sinclair J C (ed): Temperature Regulation and Energy' Metabolism in the Newborn. New York, Grune & Stratton, 1978, pp 39-74. 29 Chessex P, Reichman B, Verellen G , et al: Metabolic consequences o f intra-uterinc growth retardation in V L B W infants. Pediatr Res 1984; 18:709-713.
30 Cauderay M , Schütz Y , Micheli JL , Calame A , Jéquier E: Energy protein balances and protein turn over in small and appropriate for gesta tional age low birth weight infants. E u r JC li Nutr 1988;42:125-136. 31 Salas JS , Moukarzcl E, Dozio E, et al: Estimating resting energy expen diture by simple lean-body-mass in dicators in children on total paren teral nutrition. Am J Clin Nutr 1990;51:958-962. 32 Trunet P, Dreyfuss D , Bonnet JL , et al: Augmentation de la pression par tielle artérielle en gaz carbonique due à la nutrition entérale au cours de la ventilation artificielle. Presse Méd 1983;12:2927-2930. 33 Delafosse B, Bouffard Y , Viale JP , et al: Respiratory changes induced by parenteral nutrition in post-oper ative patients undergoing inspira tory pressure support ventilation. Anesthesiology 1987;66:393-396. 34 Silberman H , Silberman AW : Par enteral nutrition, biochemistry and respiratory gas exchange. J Parent Ent Nutr 1986;10:151-154. 35 Elia M , Livcsey G : Theory and va lidity o f indirect calorimetry during net lipid synthesis. Am J Clin Nutr 1988;47:591-607.
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14 Kurzner SI, Garg M , Bautista D B , et al: Growth failure in infants with bronchopulmonary dysplasia: N u trition and elevated resting meta bolic expenditure. Pediatrics 198S; 81:379-384, 15 Yunis K A , Oh W: E ffectsof intrave nous glucose loading on oxygen con sumption, carbon dioxide produc tion and resting energy expenditure in infants with bronchopulmonary dysplasia. J Pediatr 1989; 115:127— 132. 16 Veinstein M R , O h W: Oxygen con sumption in infants with broncho pulmonary dysplasia. J Pediatr 1981:99:958-961. 17 Kao L C . Durand D J , N ickerson BG: Improving pulmonary' function does not decrease oxygen consumption in infants with bronchopulmonary dysplasia. J Pediatr 1988; 112:616— 621. 18 Bancalari E, Abdenour G E , Feller R , et al: Bronchopulmonary dyspla sia: Clinical presentation. J Pediatr 1979;95:819-823. 19 Jéquier E: Métabolisme énergéti que. Encycl Méd Chir Nutr (Paris) 1980;10371(A10), 11:1-14. 20 Kappagoda C R , Linden R J: A criti cal assessment o f an open circuit technique for measuring oxygen consumption. Cardiovasc Res 1972; 6:589-598. 21 Stettler ER: Développement d’un calorimètre indirect pour prématu rés; thèse, Lausanne, 1983. 22 Boynton BR: The epidemiology o f bronchopulmonary dysplasia; in Merritt T A , Northway W H , Boyn ton BR (eds): Bronchopulmonary Dysplasia. Boston, Blackwell Scien tific, 1988, pp 19-32.
Service de Médicine néonatale, Hôpital Port-Royal, Paris, France
Energy Expenditure in Premature Newborns with Bronchopulmonary Dysplasia
KeyWords
Abstract
Energy expenditure Bronchopulmonary dysplasia Premature newborn Medium chain triglycerides
Five premature newborns (birth weight, mean ± SD , 960 ± 145 g; gestational age 28 ± 1 weeks) with bronchopulmonary dysplasia (BPD) according to the criteria of Bancalari, and 6 controls (birth weight 1,320 ± 210 g; gestational age 30 ± 2 weeks) were studied for energy expenditure (EE) by indirect calorimetry. The measurement of total EE was performed when the intake of the infants in both groups was the same and when the respiratory condition had stabilized (control group: postnatal age 31 ± 6 days, 1,950 ± 200 g; BPD group: postna tal age 105 ± 45, postnatal weight 2,440 ± 380). The BPD group had a higher VCH ( 11.15 vs. 8.04 ml/kg/min, p < 0.01 ), V C O 2 (9.13 vs. 7.74 ml/kg/min, p < 0.02) and total EE (76 vs. 61 kcal/kg/day, p < 0.02). The highest values were encoun tered in the 3 more severely ill infants: mean VCH 11.03 ml/kg/min, mean EE 82 kcal/kg/min. In these cases, administration of medium chain triglycerides limits the in crease in V C O 2 and lowers the respiratory quotient (0.87 vs. 0.96 in controls).
E. de Gamarra
Introduction Improvements in techniques of neonatal care have resulted in the survival of newborns of lower and lower birth weights and gesta tional ages, together with an improvement in overall prognosis. The quality of growth is one
among many factors affecting the quality of outcome [1]. The ideal postnatal growth rate of the pre mature infant is not known. The reference commonly used is the fetus of the same gesta tional age [2], This growth rate, whose compo sition is estimated by energy balance studies
E. dc Gamarra Service de Médecine néonatale Hôpital de Port-Royal 123, boulevard de Port-Royal F-75674 Paris Cedex 14 (France)
© 1992 S. Karger A G , Basel 0006-3126/92/ 0616-0337S2.75/0
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Biol Neonate 1992;61:337-344
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rimetry in 5 premature infants with BPD compared with a group of 6 controls with no respiratory impairment receiving the same energy intake. Possible methods of manage ment are discussed.
Patients and Methods Eleven infants were included in the study. All were born prematurely and were admitted at birth to the intensive care unit o f Port Royal Hospital because o f severe illness, essentially respiratory. Criteria for entry to the study were: absence o f progressive disease, espe cially infectious, and no mechanical ventilation re quired. The mean gestational age ( ± SD ) was 29 ± 2 weeks; The mean birth was 1,155 ± 245 g. Five infants had B PD according to the criteria o f Bancalari et al. [ 18] and formed the B P D group. All o f them still had respiratory distress and characteristic chest radiography abnormalities at the time o f the study. The other 6 infants, who had recovered from their respiratory distress and had none o f these signs and whose weights were appropriate for conceptional age ( > 10th percentile o f the Lubchenco curves), served as controls. Individual data are given in ta ble 1. A t birth, the B P D group was slightly younger com pared to the control group (28 vs. 30 weeks, p < 0.01) and body weight was lower (960 vs. 1,320 g, p < 0.05). In addition, one infant (SF) already showed growth retardation. Initial respiratory pathology was more severe in the 5 infants o f the B PD group (4 cases o f severe hyaline membrane disease, 1 wet lung, 1 feto-maternal infec tion, 3 patent ductus arteriosus, 2 bacterial superinfec tions, and 4 gastroesophageal refluxes) than in the 6 controls (1 mild case o f hyaline membrane disease, 3 wet lung, 3 maternofetal infections). Four infants o f the control group (LM , C L , D E , A K ) later developed recurrent apnea requiring prolonged mechanical venti lation. Duration o f ventilation is given in table 1, and is higher in the B PD group (64 vs. 21 days, p < 0.01). The same is true for the duration o f oxygen therapy. At the time the sequelae were stabilized, weight, postnatal and hence conceptional age (table 1) were both higher and showed a high variability in the B P D group. In this group, all infants were older than 2 months and 2 o f them (SF. MS) had a conceptional age greater than 40 weeks - their poor state o f health having made earlier examination impossible. Lastly, the B P D group con-
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and indirect calorimetry, can be obtained in healthy premature infants fed human milk enriched in minerals and protein [3], During the course of the neonatal period, some premature infants suffer from broncho pulmonary dysplasia (BPD) that extends beyond the first month [4], The incidence of this respiratory insufficiency is high. In 1985 in the region of Paris, 13% of the infants born before 33 weeks of gestation and surviving until the 28th day had respiratory sequelae [5, 6]. The occurrence is favored by immaturity and also by specific nutritional deficiencies and undernutrition [7], themselves conse quences of prematurity, neonatal pathology, and the poor tolerance of any fluid [8] and/or metabolic load [9], Later, these children show growth retardation and failure to catch up [10], though their nutritional intake seems to be sufficient [11], The only study of total energy expenditure (EE) measured by indirect calorimetry in BPD has been published by Yeh et al. [12] and included 5 cases. Compared to controls, total EE was raised resulting in a less positive energy balance, this latter factor appears to be sufficient to explain the growth retardation. Other authors [13-17] have measured only the resting energy expenditure over short peri ods of time in a total of 18 infants. According to Kurzner et al. [13, 14] resting EE is higher only in infants who also have growth retarda tion. However, their control group consisted of infants delivered at term. Yunis and Oh [15] also found that resting energy expendi ture was higher in infants with BPD. Two other studies involved a total of 21 measure ments of V O i. Veinsteinand Oh [16] reported that V O 2 was 25% higher in patients than in controls. Kao et al [ 17] found values consid ered to be high (7.65 ml/kg/min), but did not use a control group. The aim of this study was to report further values of total EE measured by indirect calo
Table 1. Characteristics o f the 2 groups Infants
A t birth
On the day o f study
gestational birth age, weeks weight, g
postnatal age, days
LM HJ CL DE SR AK
27 31 27 30 31 32
1,100 1,400 1,050 1,330 1,600 1,440
Mean SD
30 2
SF MS NF IR BK Mean SD
Duration, days
g
conceptional age, weeks
oxygen therapy
mechanical ventilation
45 20 52 45 34 38
1,760 1,650 2,010 2,000 2,110 2,160
35 34 35 36 36 37
0 1 1 25 20 3
29 7 33 25 20 15
1,320 210
31 6
1,950 200
36 1
8 10
21 9
29 27 30 26 28
860 830 1,130 870 1,100
160 140 67 87 75
3,080 2,300 2,430 2,310 2,080
51 47 40 38 39
133 34 54 71 65
79 20 48 75 97
28 1
960 145
105 45
2,440 380
71 32
64 27
p < 0 .0 1
p < 0.01
weight
Control group
BPD group
p < 0 .0 1
p < 0.05
p < 0.01
Gestational age is given in completed weeks; weights are rounded to the nearest 10 g.
Diet In the control group, infants o f conceptional age lower than 35 weeks (LM , H J, C L) received fortified human milk (for 100 ml: Alfare®, 4 g; sodium chlo ride, 1 mEq). Infants aged more than 35 weeks re ceived infant formula without medium chain triglycer ides (M CT). SR received his own mother’s fortified milk. The diet was unchanged for at least 3 days before the measurements. The calculated mean energy intake was 124 kcal/kg/day (range 112-137). In the B PD group, 2 infants o f 39 weeks (IR, BK) were still receiving fortified human milk. The 3 most severely ill infants, whose state necessitated fluid re
striction (SF, M S , and N F) received a concentrated formula enriched with 2% M C T (Liprocyl®). This for mula is routinely used when fluid restriction would result in limitation o f energy intake. It provides per 100 ml: 2.6 g protein, 5.7 g fat, 89kcal. More than 50% o f the non-proteic energy intake is derived from fat. For the whole B P D group, calculated mean energy intake was 129 kcal/kg/day (range 124-132). For the control and B P D groups, the calculated mean proteic intake was 2.97 and 2.98 g/kg/day, re spectively.
Energy Expenditure E E was measured by open circuit indirect calorim etry. Expired gas was collected in a hood carefully adjusted around the neck, which allows continuous measurements. The hood was flown through by a fan (Micronel, Tagelswangen, Switzerland) with a flow reg ulator. Flow was measured by a massic flow-meter (M F 400. Setaram, Caluire, France). Small samples o f
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sisted o f infants with respiratory impairment o f vari able severity. Three o f them (SF, M S , N F) showed the serious sign o f chronic hypercapnia, 2 o f them (SF, BK) were receiving theophylline, and one (BK) still required supplemental oxygen. Three infants in this group also had a marked weight deficit (SF, M S, BK).
Statistics The significance o f the differences between the means of each group was determined using Student’s t test.
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Results Table 2 shows the individual values of V O 2, V C O 2, the nutrients oxidized, and EE. Gas Exchange The mean V O 2 was more elevated in the BPD patients than in the control group (10.15 vs. 8.04 ml/kg/min, p < 0.01). V C O 2 was also higher in the former group (9.13 vs. 7.74, p < 0.02). Energy Expenditure The mean EE of the BPD group was higher than that of controls (76 vs. 61 keal/kg/day, p < 0.02). The highest values in the BPD group occurred in infants with more severe pathology (chronic hypercapnia, SF, M S, NF) and the longest duration of the disorder (SF, MS). The mean value in these 3 cases was 82 keal/kg/day. Nutrients Oxydation The nutrients composition (table 2) of the energy expenditure was not different for in fants receiving a similar energy composition: enriched mother’s milk or appropriate infant formula. This was the case for all control infants and 2 infants of the BPD group (IR and BK). The 3 most severely ill BPD infants (SF, M S, NF; table 2) received supplementation of fat without an increase in total energy intake. Their metabolic activity was higher (mean V O 2 11.03 vs. 8.04 ml/kg/min in controls). For these 3 infants, the difference in V C O 2 (9.64 vs. 7.74 ml/kg/min) is proportionately less compared to the 6 controls since the RQ were 0.87 and 0.96, respectively. The other 2 BPD infants not receiving M C T had a mean R Q of 0.95, similar to that of controls. This can be related to the increase in net oxidized fat in the 3 severely ill infants (3.2 vs. 0.64 g/ kg/day in controls). This represents 27% of
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collected and reference gases were directed by a pump to a dual chanel magneto pneumatic oxygen analyzer (Magnos 4 G , Hartmann and Braun, Frankfurt, F R G ) and to a dual chanel infrared carbon dioxide analyzer (Uras 3 G , Hartmann and Braun). The fraction o f oxy gen inspired in air (FiO j) was measured by an oxygen analyzer (O A 570 Servomex Ltd, Crowborough, U K ). After taking urinary nitrogen into account, V CL, respi ratory quotient (RQ ) and EE were calculated according to Jequier’s [ 19] formulae. The accuracy o f the system was checked by two means. First by infusing a gas in the hood at a rate mea sured by an accurate flow-meter (Rosemount, Rungis, France) and corrected to standard conditions [20]. This simulates a known oxygen consumption when nitrogen (N50, C F P O ) was infused or a known carbon dioxide production when C O 2 (N45, C F P O ) was in fused. The system was considered as sufficiently accu rate when 95% V O 2 and V C O 2 were obtained. Second by burning a known output o f butane [21], at a rate measured by a massic flow-meter (5850 T R , Rosemount, Rungis, France). The mean V O 2 was 98.8 ± 1.6% o f the expected value; the mean V C O 2 was 97.7 ± 1.5%and the mean R Q was 0.61 ± 0.002. Stability o f the conditions o f measurement in the infants was verified by non invasive monitoring o f 8 parameters: heart and respiratory rate; transcutaneous oxygen and C O 2 partial pressures; skin temperature at 3 sites, and ambient temperature. This continuous moni toring was carried out by the following apparatus on-line with a computer: cardiac monitor (111, Roche Kontron; Microgras 7640, Kontron Instruments Ltd, Watford, U K ), and 4 temperature sensors. An apparatus was spe cially developed to count respiratory movements. Infants were studied in the supine position, in their incubators at their nursing temperatures. It was not nec essary to interrupt measurements for routine nursing care. Measurements lasted from 4 to 24 h, by periods o f 8 h maximum and o f 4 h only in the most seriously ill infants. The mean duration o f measurements was the same in both groups (table 2); controls were matched with BPD infants for duration o f measurements. Over the same period o f time, urine was collected on thymol (10% solution in isopropyl alcohol) and fro zen. An aliquot was used to assay nitrogen by Kjeldahl’s method. The amount o f protein oxidized (g/kg/ day) was calculated from the urinary output o f nitro gen (N X 6.25).
Table 2. Results o f indirect calorim etry Infants
RQ Duration o f vo 2 vco 2 measure ml/kg/min ml/kg/min ment (h)
Carbohydrates Fat oxidized oxidized g/kg/day g/kg/day
Protein oxidized g/kg/day
EE kcal/kg/day
13.5 19.5 13.0 11.8 11.5 10.3
0.58 -1.52 0.67 1.48 1.20 1.46
0.52 0.57 0.80 0.85 0.18 1.20
61 65 61 64 57 69
13.26 3.26
0.64 0.39
0.69 0.35
61 3
11.1 12.1 12.5 13.7 13.6
3.89 3.41 2.30 0.66 1.25
1.28 1.55 1.46 1.16 0.76
86 81 79 66 69
12.6 1.09
2.30 1.37
1.24 0.31
76 8
Control group LM HJ CL DE SR AK
4 6 22 18 4 4
Mean SD
9.7 7.4
8.02 8.23 7.95 8.49 7.70 7.86
7.74 8.80 7.68 7.83 7.20 7.18
8.04 0.28
7.74 0.59
11.50 11.50 10.10 8.37 9.32
9.81 10.00 9.10 8.03 8.71
10.15 1.37
9.13 0.80
p < 0.01
p < 0.02
0.96 1.06 0.96 0.92 0.94 0.91
BPD group SF a M Sa NF3 IR BK Mean SD
4 4 4 15 21 9.6 7.1
0.85 0.86 0.90 0.96 0.93
p < 0.02
EE vs. 63% of carbohydrate origin. The pro portion is 10 and 84%. respectively, of the mean EE in the control group.
Discussion In a group of 5 premature infants with BPD compared to a group of 6 controls, we have shown that: ( 1) EE expenditure is higher; (2) it is higher in themore severely ill infants, and (3) in these infants the administration of M C T by the gastrointestinal route limits the increase in VCCb, since R Q is lower.
Control Group At birth the group who served as control had higher mean weights and gestational ages than those in the BPD group. These differ ences can be explained by the fact that early prematurity and very low birth weight are major risk factors in BPD [22], The control group consists of premature babies studied when mechanical ventilation was removed. Under the same conditions, our BPD group is made up of maturer and heavier babies. Simi larly, at the time of the study in the BPD group, the ages, weights, and degree of sever ity were very varied. This is due to the course of the disease which sometimes requires pro longed mechanical ventilation. Other authors
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Infants receiving M C T (mean R Q = 0.87).
Energy’ Expenditure The mean value of total EE in the control group (61 kcal/kg/day) agrees with the litera ture data for infants of equivalent age and receiving the same energy intake. The average EE was 76 kcal/kg/day in our BPD group, identical to that found by Yeh et al. [12], whose control group had an expenditure of 58.5 kcal. Kurzner et al. [14] reported that the resting expenditure was raised (72 kcal/kg/ day) only in the most seriously ill infants. The 6 other BPD infants had an expenditure com parable to fullterm newborn controls (50 kcal/ kg/day). Yunis and Oh [15] measured resting expenditure before glucose loading and found it slightly raised: 53.8 vs. 45 kcal/kg/day in controls. Many factors can explain this hyperme tabolism. First of all, a difference in nutri tional intake. Actually, this could not have been a confounding factor in our study since the energy intake was the same in both groups even in the 3 severer cases (SF, MS, NF). In these cases, M C T only compensated the en ergy limitation induced by fluid restriction. In those conditions, M C T accounted neither for an increase in energy intake nor for such an
important increase in energy expenditure, even if M C T are oxidized up to 50% in pre mature babies [23, 24], The increase in the cost of breathing related to respiratory dis tress only has a small effect. For Wolfson et al. [25], a decrease in respiratory distress results in only a minimum energy saving. Kao et al. [17] showed that VCF is not reduced after administration of furoscmide and/or theoph
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ylline to improve ventilatory conditions. Two other factors play a role, one is the presence of intrapulmonary inflammatory foci, the other is the administration of theophylline which also increases energy expenditure [26, 27], Two of our infants received theophylline (SF, BK; table 2). Growth retardation is accompanied by in creased EE and 3 of our BPD infants had a marked growth deficit. The metabolic rate is also dependent on previous nutritional status. Growth-retarded infants demonstrate a rela tive hypermetabolism when compared with similar appropriately sized infants [28-30], It has been proposed that this hypermetabolism may be due to a larger ratio of brain to body weight or to a faster rate of growth [28], Unfortunately, this was not the case in our BPD group. Kurzner et al. [14] found that infants with BPD and growth retardation had increased metabolic demands that were corre lated with a body weight deficit. This is per haps due in part to the expression of results per kilogram of total body weight, which re sults in an underestimation of the lean mass in infants with growth retardation. At the present time there is no simple and reproduc ible method for measuring lean body mass in the newborn [31]. Measures aimed at saving energy are fi nally limited: improvement in the ventilatory condition; treatment of obvious infectious foci, and limitation of indications for theoph ylline. Only increased energy intake can cover the increased expenditure and permit growth. However, the increase in dietary substrates, especially carbohydrates, runs the risk of in creasing VCO? and leading to respiratory fail ure [9, 15, 32, 33]. Nutrient Oxydation Only the results of the 3 infants who re ceived M CT (table 2) will be discussed, even though they are preliminary. Oxidation of
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have encountered the same difficulties. Kurzner et al. [13, 14] compares infants that were born prematurely and had BPD with fullterm infants. Yeh et al. [12] and Yunis and Oh [ 15] compared them with other premature infants who also have slightly different weights and ages than the BPD group.
M C T having been demonstrated in prema ture infants [23, 24], the advantage of fat is that, for a given quantity of energy supplied, they lead to a lower C O : production than car bohydrates. Oxidation of 1 kcal of glucose releases 201 ml of C O 2 compared to 154 ml for fat [34]. To the extent that it appears that improvement in the energy balance during BPD involves an increase in energy intake, replacement of part of the energy intake by fat seems to be a promising addition for infants as in adults with respiratory insufficiency [32, 33]. Success depends, of course, on the fat being oxidized and not stored in excess in adi pose tissue [35].
Conclusion Premature newborns with BPD have an increased total EE, and this is more marked in cases when the respiratory sequelae are se
verer and when there is growth retardation. With the recommended energy intake ( 130 kcal/kg/day), the energy balance is not sufficiently positive to allow for adequate growth. However, increasing nutritional in take runs the risk of inducing respiratory fail ure. The M C T represent an interesting energy supplement. When EE increases, oxidation of M C T can ensure a supplementary energy sup ply with a lesser increase inVC0 2, which could perhaps result in better respiratory tol erance.
Acknowledgements This study and the construction o f the indirect calorimeter were supported by a ‘Contrat Externe IN S E R M ’ 87.3.35.04E financed by Caisse Nationale d’Assurance Maladie. We thank Prof. Jéquier and his team for their advice, and M r. Bonoris, Mr. Bru, Mr. Haye, Mr. Hube, and M r. Masson, student engineers at the Ecole Nationale Supérieure d’Electronique et ses Applications who computerized the apparatus.
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