Assessing the effect of disease on nutrition of the preterm infant

ClinicalBiochemistry,Vol.29, No.5, pp. 399417, 1996 Copyright© 1996TheCanadianSocietyofClinicalChemists Printedin the USA.Allrightsreserved 0009-9120/96 $15.00+ .00 ELSEVIER

S0009-9120(96)00062-8

Assessing the Effect of Disease on Nutrition of the Preterm Infant WILLIAM Department

of P e d i a t r i c s , U n i v e r s i t y

W. HAY, JR.

of C o l o r a d o

Objective: To review existing data on nutritional requirements of extremely low birth weight (ELBW) and very low birth weight (VLBW) preterm infants (those who weigh < 1000 g and 1000-1500 g at birth, respectively), and the effects of diseases on these nutritional requirements. Data sources: A literature search was conducted on applicable articles related to nutritional req~uirementsof preterm ELBW and VLBW infants and the effects of diseases in these infants on their nutritional and metabolic requirements. Data synthesis: The literature was analyzed to determine nutritional requirements of preterm ELBW and VLBW infants, to select the most common diseases that have significant and important effects on nutrition and metabolism in these infants, and to make recommendations about diagnostic and therapeutic approaches to nutritional problems as affected by diseases in ELBW and VLBW infants. Conclusions: Many diseases unique to preterm infants, either directly or by enhancing the effects of stress on the metabolism of such infants, provide important changes in the nutrient requirements. The overriding observation from all studies, however, is that ELBW and VLBW preterm infants are underfed during the early postnatal period and that this condition, combined with additional stresses from various diseases, increases the dsk of long-term neurological sequelae. The value of achieving a specific body composition and growth weight is less certain. There remains a critical need for determining the right quality as well as quantity of nutrients for these infants.

KEY WORDS: preterm infants; nutrition; low birth weight; growth; hypoglycemia; hyperglycemia; amino acids; metabolism; pulmonary disease; enterocolitis; sepsis; short bowel syndrome.

Introduction reterm infants, especially those who are born p very early witha less t h a n 1000-g birth weight, have a variety of unique features t h a t m u s t be considered when assessing nutritional requirements and responses to nutritional management. Principal examples are shown in Table 1 (1). Also, these special infants suffer a large variety of unique diseases

Presented at the 6th International Congress on Pediatric Laboratory Medicine, Vancouver, July 21-24, 1995. Correspondence: William W. Hay, Jr., M.D., Professor of Pediatrics, Box B195, University of Colorado School of Medicine, 4200 E. Ninth Ave, Denver, CO 80262, U.S.A. Manuscript received January 21, 1996; revised and accepted March 29, 1996. CLINICALBIOCHEMISTRY,VOLUME29, OCTOBER 1996

S c h o o l of M e d i c i n e ,

Denver, CO 80262 U.S.A.

or pathophysiological conditions t h a t have a marked impact on their nutritional needs, including, for example, necrotizing enterocolitis, short bowel syndrome, patent ductus arteriosus, in utero growth failure, h e a r t failure, s u r f a c t a n t deficiency, and o t h e r forms of acute r e s p i r a t o r y insufficiency, chronic lung disease including bronchopulmonary dysplasia, and sepsis. The overriding observation from all studies is t h a t preterm infants usually are underfed during the immediate postnatal period. The risk of long-term neurological sequelae from such a practice appears real and very likely of clinical importance. The value of achieving a specific body composition is less certain. There continues to be a critical need for determining the right quality, as well as the right quantity, of nutrients for these infants.

Nutritional requirements unique to extremely low birth weight infants ASSESSING GROWTH The simplest and most traditional way of assessing nutrition in preterm infants is to measure their growth rate (see Table 2 for terminology basic to measurements of growth). Over the second half of gestation, h u m a n fetuses increase their weight 6- to 8-fold at approximately 15 g/day/kg and increase their length 2.5-fold at approximately 1 cm/day (Figure 1) (2). Weight-specific growth rates for small (SGA) and large (LGA) for gestational age infants are proportional to the 50th percentile for average or appropriate (AGA) for gestational age infants. Most of the increase in weight is accounted for by lean body mass. Extensive fat deposition also takes place, increasing progressively towards term, at which point it accounts for approximately 18% of body weight; this fat deposition accounts for about 50% of the total caloric intake of the fetus over this gestational period (i.e., about 40-50 out of 90-100 kcal/ day/kg in an AGA fetus) and 80% of the caloric value of new tissue accretion (3). In most ELBW and VLBW preterm infants, an399

HAY TABLE 1

Special Nutritional Conditions in ELBW Infants 1. Low energy reserves (both carbohydrate and fat) 2. Higher metabolic rate (intrinsically, due to a higher body content of more metabolically active organs: brain, heart, liver) 3. Higher protein turnover rate (especially when growing) 4. Higher glucose needs for energy and brain metabolism 5. Higher lipid needs to match the in utero rate of fat deposition 6. Excessive evaporative rates and occasionally very high urinary water and solute losses (depending on intake) 7. Low rates of gastrointestinal peristalsis 8. Limited production of gut digestive enzymes and growth factors 9. Higher incidence of stressful events (hypoxemia, respiratory distress, sepsis) 10. Abnormal neurological outcome if not fed adequately Adapted from (1). thropometric measurements of weight, length, and head circumference have shown a significant delay in weight gain, sometimes over 3 weeks in duration (Figure 2). The factors t h a t contribute to this delay in weight gain are not well understood, although, as shown in Figure 2 (1), providing less nourishment t h a n is present when the babies are growing well, and certainly less t h a n they were receiving in utero by reasonable estimates from fetal animal models and h u m a n accretion data (4), is clearly a principal factor. Interestingly, however, most of these infants continue to increase their lengths and head circumferences at rates faster t h a n their weight change, although still at rates less t h a n expected from normal in utero growth rates (5,6). Over the past several years, improvements in the rates of growth of all of these anthropometric indices have paralleled improved overall neonatal management, as well as a more aggressive approach to earlier and greater amounts of nutrient supply. Whether or not it is appropriate to apply fetal nutrient accretion rates to the ELBW infant remains to be determined but, indirectly, this process has been confirmed by noting empirically t h a t higher weightspecific n u t r i e n t intakes are necessary to produce growth in such infants compared with older, more mature infants. For example, 3 to 4 g/day/kg of protein appears necessary to support the estimated in utero growth rates in healthy, growing ELBW infants compared to 1.5 to 2.5 g/day/kg for infants of 34 to 40 weeks gestation. This difference has led to the enrichment of preterm formulas to > 2 g protein per

100 mL, although term infants grow normally using milk and formulas with only 1.2-1.5 g protein per 100 mL (7,8). WATER AND SOLUTES

After an initial oliguric phase in the first 1 to 3 days of life, ELBW and VLBW infants can lose vast amounts of water (and solutes) from their kidneys and water from their skin (evaporation) (9). Increased water intake is important to prevent these losses, which may amount to as much as 8-12 mL/ kg/h in babies who weight less t h a n 1000 g, made up of evaporative losses approaching 4-6 mL/h/kg and urinary flow rates of 4-6 mL/h/kg (10). These infants also are born with a relative excess of extracellular fluid and renal m a t u r a t i o n requires a reduction in ECF before water and salt retention can develop normally (11). Early nutrition, however, may be a better approach t h a n the more commonly practiced use of dehydration to reduce the excess extracellular water in these infants. Recent studies have shown, in fact, t h a t over the first week of life infants weighing approximately 1.2 to 1.4 kg at birth will increase their body solids and their intracellular space with a relative decrease in extracellular space as fractions of total body weight when fed mixed nutrients at total fluid rates t h a t m a i n t a i n body weight close to birth weight (Figure 3) (12). Although such an aggressive approach to nutrition in the first week of life may be less successful in physiologically unstable and medically complicated extremely low

TABLE 2

Terminology Basic to Growth Studies Term

Low birth weight (LBW) Very low birth weight (VLBW) Extremely low birth weight (ELBW) Preterm Small-for-gestational age (SGA) Appropriate-for-gestational age (AGA) Large-for-gestational age (LGA) Intrauterine growth restriction (IUGR) 400

Definition

birth weight < 2500 g birth weight < 1500 g birth weight < 1000 g gestational age < 38 weeks <10th percentile (birth weight for gestational age) >10th and <90th percentile (birth weight for gestational age) >90th percentile (birth weight for gestational age) Abnormally slow rate of fetal growth CLINICAL BIOCHEMISTRY, VOLUME 29, OCTOBER 1996

DISEASE AND NUTRITION OF THE PRETERM INFANT

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handicaps, the result of inadequate nutrient supply to meet the high energy needs of the preterm infant's brain. Providing some support for this position was a study by Lucas and colleagues, in which progressively lower motor and intelligence developmental scores were found in preterm infants who had an increasingly higher incidence (>5 episodes) of documented plasma glucose concentrations below approximately 2.8 mmol/L (15). Although this was a retrospective observation and may have reflected a higher occurrence of hypoglycemic episodes in infants who were neurologically handicapped to begin with, or destined to be so independent of glucose

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birth weight infants, such results demonstrate that it is both possible and preferable to increase intracellular relative to extracellular water space with nutrients as opposed to dehydration. Other studies have also emphasized that excessive intakes of water and salt should be avoided because salt and water accumulation have been linked directly to the development of patent ductus arteriosus and chronic lung disease (13).

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Hypoglycemia in preterm infants H u m a n s are unique among all animals in having the largest brain-to-body weight ratio, and this is particularly exaggerated in the preterm infant who has the highest brai~a-to-body weight ratio of all newborn animals. Glucose is the principal energy substrate of the brain and, thus, it is expected that glucose will be n e c e s s a r y at r e l a t i v e l y h i g h e r weight-specific rates of glucose supply than required in term infants (7). In fact, the midgestation fetus has a 2-fold greater body weight-specific glucose requirement than does the term fetus (-40-50 ~mol/ min/kg at midgestation vs ~20-25 ~mol/min/kg at term), which is neces,,;ary for the much higher glucose needs of the more metabolically active organs, particularly the brain (14). If not fed this glucose requirement, even more amino acids and other substrates m a y be needed to sustain glucose production to meet these high glucose needs. Based on these observations, m a n y clinicians and investigators have assumed that repeated episodes of acute hypoglycemia or chronic, b u t more sustained, hypoglycemia m a y be associated with neurodevelopmental

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Figure 2 - - The upper panel shows postnatal weights for two infants, the top curve representing an AGA (appropriate weight for gestational age) infant born at 950 grams at 26 weeks gestation who had early growth delay followed by an increase in weight gain, but no catch-up growth, and the lower curve representing an SGA (small for gestational age) infant born at 475 grams but at 29 weeks gestation, who had delayed postnatal weight gain and never did achieve a "normal" rate of growth. The lower panel shows the mean daily caloric intake for both infants and demonstrates that, even in the AGA infant, growth did not occur until daily caloric intake reached about 120 kcal/kg/ day. The failure of the SGA infant to increase growth rate toward normal implies a long-standing adaptation to a reduced rate of growth. Adapted from (1). 401

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Figure 3 -- Weight loss and change in body fluid composition in two groups of preterm infants at 1 and 7 days of age. Fluid compartments are expressed in absolute values and as percentages of current weight. Group 1 (two bars on the left) represents infants who were allowed to dehydrate after birth to achieve a reduction in ECV (extracellular volume). Group 2 (two bars on the right) represents infants who were fed more aggressively. These infants showed a similar reduction in ECV relative to ICV (intracellular volume), but they also had a significant increase in ICV that may be related to the earlier onset of growth. Reprinted from (12).

disorders, nevertheless, it indicates t h a t there is a direct and quantitatively important association between hypoglycemia and poor developmental outcome even if this is not causally determined. As a result, the issue remains controversial. Other information suggests t h a t hypoglycemia may not be such a direct cause of neurological compromise, at least as studied by Lucas and colleagues. For example, studies in both adult and fetal animal models have shown that, although acute hypoglycemia decreases total and regional cerebral glucose utilization rates, chronic hypoglycemia demonstrates a progressive return toward normal glucose utilization rates and this progressive improvement is accompanied by increases in brain glucose transporter concentration (16,17). Additionally, preterm and growth-restricted infants are deficient in lipid stores (3,5) and, thus, in the capacity to produce keto acids in response to the increased lipid turnover and fatty acid oxidation. Keto acids are well known to provide an alternate substrate for cerebral energy metabolism (18). Thus, deficiencies of other substrates may be as or more important t h a n glucose, itself, in brain energy insufficiency with subsequent neurological deficit. 402

Stress and hyperglycemia Hyperglycemia (generally defined as a plasma glucose concentration > 6-7 mmol/L) is a particularly common problem in extremely low birth weight infants who are subjected to considerable stress and simultaneously receive aggressive intravenous glucose infusions (19). Stress-reactive phenomena in such infants have not been studied to any great extent. In older infants, children, and adults, pain, trauma, hypoxemia, surgery, and prolonged difficult deliveries have been shown to result in sudden increases in plasma concentrations of stress-reactive hormones, p a r t i c u l a r l y the catecholamines, epinephrine, and norepinephrine, as well as glucagon and cortisol (Figure 4) (20). Data from fetal animal models indicate t h a t all of these hormones potentially are responsive in the midgestation fetus, particularly catecholamines, which have a m a r k e d effect of producing glycogenolysis and inhibiting insulin action and insulin secretion, thereby contributing to rapid and marked hyperglycemia (21). Catecholamine concentrations also increase progressively with dopamine administration, a commonly used drug to support blood pressure in very small preterm infants (e.g. from 62 _+ 11 to 364 _+ 107 pg/ mL of epinephrine as dopamine infusion rates increase from zero to 5-10 (txg/min/kg), (22). If allowed to persist, conditions of stress may increase cortisol secretion, which not only enhances the activation of enzymes responsible for gluconeogenesis, but also produces proteolysis and an increased supply of glucogenic amino acids (23). It is not surprising, therefore, t h a t small p r e t e r m , p a r t i c u l a r l y growthrestricted infants frequently develop a syndrome over the first 2-4 postnatal days recognized by progressive and often severe hyperglycemia, frequently accompanied by hyperkalemia (24). This syndrome, in milder form, can be treated by reducing the intravenous glucose infusion rate (<20 ixmol/min/kg) and an overall improvement in physiological condi-

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Figure 4 -- Hormonal and metabolic responses and inter-

actions involved in stressful events known to adversely affect normal metabolism and the capacity for growth. Data to define these responses and interactions in human preterm infants are limited, but at least qualitatively support this schema. Adapted from (29). CLINICAL BIOCHEMISTRY, VOLUME 29, OCTOBER 1996

DISEASE AND NUTRITION OF THE PRETERM INFANT

WEIGHT ( g/kg/day )

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TRICEPS SKINFOLD THICKNESS ( mm/wk )

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AMINO ACID METABOLISM AND NUTRITION

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cate t h a t amino acids are capable of enhancing glucose-stimulated insulin secretion, even quite close to midgestation (26,27).

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I - Protein 2.24 g / k o / d ~ Energy 115 k c l l / k o / d r~:'t It - Protein 3.6 g / k g / d , Energy 1 I($ k c l l l k g l d r ~ l iii . Protein 3.6 g / k g / d , Energy 14~I k c l l l k g / d '[' - Sig*lllicant dilleronce I 0'0.05 )

Figure 5 - - Rates of growth in weight, length, head circumference, and triceps skin folds in 3 groups of preterm infants fed nutrient mixtures of moderate or high protein content and moderate or high energy content. The higher protein intake i~,creases growth of body weight, length, and head circumtbrence, and increased energy increases weight and triceps skin fold thickness, which is suggestive of increased adiposity. Adapted from (8), and from (1 and 32). tion. When severe, it can be acutely treated successfully with constant infusions of insulin (360 pmol/h/ kg) to counteract the anti-insulin effects of catecholamines, glucagon, a n d cortisol (24,25). Several investigators also have recommended early administration of i n t r a v e n o u s amino acids (at least 2 grams/day/kg) to such infants (24,25). Amino acids are essential for insulin secretion, as well as to suppress proteolysis. Micheli and colleagues, for example, have shown a marked decrease (>50%) in the incidence of hyperglycemic, hyperkalemic syndrome in preterm infants by changing policy in their newborn intensive care unit to start amino acid infusions more aggressively on the first day of postnatal life (24). Although changes in insulin secretion rate and p l a s m a insulin concentration by such early postnatal amino acid administration have not been documented, there is experimental evidence to indi-

Studies in fetal sheep have shown t h a t persistent hypoglycemia from short-term maternal fasting results in nearly a doubling of the fractional leucine oxidation rate (from 25% to 40% of leucine disposal rate) (28). Hypoglycemia and hypoinsulinemia also result in increased rates of proteolysis and a higher contribution of fetal tissue leucine to the fetal plasma leucine pool (29). Although such measurements have not been made in extremely low birth weight preterm infants, it is reasonable to assume t h a t such infants may develop proteolysis and increased amino acid oxidation if sufficient energy, in the form of glucose, lipid, or both, is not provided. Under such conditions, provision of extra amino acids tends to counteract the energy deficiency and restrict proteolysis, although clearly the best results are obtained when sufficient glucose, lipids, and amino acids are provided (Figure 5) (30-32). In the past, clinicians have been r e l u c t a n t to provide amino acids aggressively to extremely low birth weight preterm infants, especially soon after birth. Such reluctance has been based on earlier observations of marked h y p e r a m m o n e m i a (>100 i~mol/L) and high amino acid concentrations, particularly of potentially neurotoxic amino acids such as phenylalanine" and methionine (>100 and >50 ~mol/L, respectively), suggesting inadequate rates of amino acid utilization and urea production (33-35). Such problems largely have disappeared from most intensive care units, however, as overall medical management of these infants has improved. Furthermore, Rivera and colleagues, among several recent investigations, have shown normal amino acid concentrations and markedly improved nitrogen balance in VLBW and ELBW infants who were fed both intravenous glucose (>20 ~mol/min/kg) and amino acids (1-1.5 g/day/kg) starting on the first day of postnatal life (Table 3A and B, Figure 6) (36-38). W h e n coupled with observations of enhanced growth rate and persistent positive nitrogen balance in infants fed increased rates of amino acids and energy as glucose and lipids, it is clear t h a t m a n y previous deficiencies of growth and metabolism of amino ac-

TABLE3A Biochemical Measurements (Mean _+SD) in VLBW Newborn Infants*

Energy intake (kcal/kg/day) Plasma NH 3 (~mol/L) Serum urea (mmol/L) CO2(mmol/L)

dl-G

dl-G+AA

d2-G

29 _+ 7 65 _+20 4.6-+ 1.4 22 -+ 2

35 -+ 8 83 _+24 5.0 -+ 2.1 23 -+ 5

32 ± 10

d2-G+AA 50-+ 19t

d3-G 35 _+12 65 ± 14 4.6_+ 1.4 22 ± 2

d3-G+AA 54 ± l l t 59 ± 14 6.1 _+ 2.9 24 +_ 4

* About 1.0 kg at b i r th at about 28 weeks gestation, over the first 3 days of life ( d l - d 3 ) who were fed i n t r a v e n o u s l y w i t h glucose alone (G, n = 12) or with glucose plus amino acids (G+AA, n = 11). A d ap t ed from (36). CLINICAL BIOCHEMISTP~Y, VOLUME 29, OCTOBER 1996

403

HAY TABLE 3B

Mean (± SD) Changes in Selected Metabolic Measurements Over the First Three Days of Life for the Two Groups of Infants Shown in Table 3A Glucose Nitrogen i n t a k e (mg/kg/d) U r i n a r y nitrogen excretion (mg/kg/d) Nitrogen balance (mg/kg/d)

Protein synthesis (g/kg/d) Protein breakdown (g/kg/d) Synthesis-breakdown (g/kg/d)

0 135 -135

-+ 0 ± 45 _+45

5.0 ± 1.2 6.7 -+ 1.0 -1.6 ± 0.7

Glucose + Amino acids 250 ± 156 ± 88 ± 6.9± 7.4± -0.5±

8 52 54* 1.1" 1.5 0.9

* G+AA different from G, p < 0.05. Adapted from (36). ids were simply the result of inadequate energy and amino acid supply (Figure 7) (39). In addition to quantitative concerns about amino acid supply, recent studies suggest that the quality of amino acids supplied to newborn infants can be improved, and can also result in enhanced amino acid metabolism and infant growth. For example, recent studies have shown improved weight gain and nitrogen retention (17 g/day/kg and 270 mg/day/ kg, respectively, 25% greater than in infants fed a traditional intravenous amino acid mixture formulated for adults). They also showed plasma concentrations of essential amino acids in preterm infants, who received an intravenous amino acid solution designed to produce plasma amino acid concentrations, that were similar to those of the healthy term newborn infant who is fully nourished by his own mother's milk (40,41). At the same time, there was a decrease toward normal of the plasma concentrations of amino acids such as glycine, methionine, and phenylalanine; these amino acids have been associated with neurotoxicity. The newer formulations of intravenous amino acid mixtures designed for 3OO 250 200 150 E

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either no nitrogen (open bars) or 250 mg/kg/day of nitrogen as i.v. amino acids (closed bars) starting on the first postnatal day. Urinary nitrogen excretion was similar in both groups. The nitrogen-fed infants had a positive nitrogen balance on day 3 of life and the infants fed only glucose had a negative nitrogen balance. These data show that even ELBW infants, even in the immediate postnatal period, can benefit from more aggressive nutrient supply. Adapted from data in (36). 404

ENERGY BALANCE AND METABOLIC RATE

Balance

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preterm and term newborn infants also have been given with supplements of cysteine, which is unstable in solution with other amino acids. Cysteine has been considered an essential amino acid in preterm infants due to deficient hepatic cystathionase, which is required for endogenous conversion of cystathonine to cysteine. Studies in which cysteine was added to the intravenous amino acid mixtures given to selected preterm infants have shown improved weight gain and nitrogen retention (e.g. 1.0 vs -9.8 g/d weight change and 150 v s 114 mg/day/kg nitrogen retention), b u t only in those infants who received total amino acid and nitrogen intakes that were less than necessary for normal rates of growth (240 v s 400 mg/day/kg nitrogen intake), thus defining cysteine as a semiessential amino acid (42,43). Overall, the midgestation fetus has a much a higher (2-3 fold) fractional protein turnover rate than the term fetus, due in large part to a greater body proportion of organs with higher rates of protein synthesis (44,45). This, plus a rapid increase in cell number and size, produces a higher fractional growth rate (2-3 fold) than occurs in the near-term fetus. These conditions are also true for the ELBW infant who is fed to "normal" i n u t e r o growth rates of -15 g/day/kg. At least 3.5-4.0 g/day/kg of protein orally or 3 to 3.5 g/day/kg of amino acids intravenously, plus appropriate energy supply (>80 kcal/ day/kg), appear necessary to support the normal i n u t e r o growth rates in healthy, growing ELBW infants (Figure 8) (30-32).

The ELBW infant has an energy reserve of less than 200 kcal/kg body weight (30). Glucose alone, even at 2-3 times normal rates of administration (i.e. > 55 ~mol/min/kg), is insufficient to prevent protein breakdown, even if some protein is provided as amino acids. Glucose plus lipid (in a 2 to 1 caloric ratio) at greater than 80 kcal/kg/day usually are needed to provide sufficient energy for maintenance of energy balance and to allow for early growth to take place (46,47). Assessment of energy balance and metabolic rate in preterm infants has relied largely on measurements of these processes by indirect calorimetry CLINICAL BIOCHEMISTRY, VOLUME 29, OCTOBER 1996

DISEASE AND NUTRITION OF THE PRETERM INFANT 10

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lized to carbon dioxide (in units of kcal/time/weight), but also the relative contributions to metabolic rate and carbon oxidation from carbohydrates, lipids, and protein. Most applications of indirect calorimetry to assess energy metabolism in newborn infants have involved measurements made in infants who are breathing room air because higher concentrations of oxygen in the inspired gas result in decreasing oxygen concentration differences between expired and inspired gas, making estimates of oxygen consumption extremely unreliable (49). Other studies have shown that short-term measurements of energy balance and respiratory gas exchange in such infants are not reliable indicators of overall energy balance (50,51). Recent attempts to improve calorimetry measurements in preterm infants have met with considerable success (52). Tank rather than wall oxygen, for example, has provided a much more consistent supply of oxygen with little fluctuation in concentration or delivery rate. Improved flow meters have allowed more precise measurements of inspired and expired gas flow, and paramagnetic oxygen analyzers and infrared carbon dioxide analyzers have considerably improved the accuracy of oxygen and carbon dioxide concentration measurements of inspired and expired gases. Hood-within-a-hood incubator design has improved the consistency of oxygen mixing prior to gas breathing by the infant, and improved expired gas measurements. Such hoodwithin-a-hood designs also improve the capacity for more frequent nursing care, allowing measurements of energy balance to be made over longer periods, thus, providing more stable and reliable results. More recently, long-term energy balance studies have been made using doubly labeled water (53,54). This methodology involves either oral or intravenous administration of tracer doses of H2Zso and 2H20 with initial and at least one additional subsequent measurement of their plasma concentrations. The difference in disappearance rates, calculated

+ amino acids

Figure 7 - - The top panel shows how components of protein balance are affected by feeding v s fasting: with feeding, protein synthesis is increased, protein breakdown is decreased, and protein oxidation is increased. In the middle panel, the same effects produced by feeding on components of protein balance as are shown in the top panel are produced in fasting patients by i.v. infusion of amino acids, leading to an increase in overall protein balance. In the bottom panel, insulin is shown to exert an independent effect of decreased protein breakdown from that of amino acid feeding; in fasting subjects. Both feeding and increased amino acid supply are associated with increased insulin concentrations in preterm infants; all are associated with increased protein balance, primarily by decreasing protein breakdown. Adapted from data in (36) and from information in (39).

(Table 4) (48). Indirect calorimeters measure rates of oxygen consumption and carbon dioxide production; these measurements plus knowledge or measurement of urinary nitrogen excretion can be used to derive, not only the ral;e at which carbon is metaboCLINICAL BIOCHEMISTRY,VOLUME 29, OCTOBER 1996

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A m i n o Acid or Protein Intake (g/day/kg) Figure 8 - - Gain in protein balance in preterm infants, partitioned as the difference between protein synthesis and protein breakdown, as a function of amino acid or protein intake. These data define a positive effect of amino acid or protein supply on protein balance even up to 4-5 grams/kg/day. Based on data of Micheli (2) and Heird (30). 405

HAY

TABLE4 Results of Several Studies of Total Energy Expenditure and Its Components in Preterm Infants Reichman Number of Patients Birth weight Study age (days) BMR (kcal/day/kg) Activity EE (kcal/day/kg) Thermic effect of food (kcal/day/kg) TEE (kcal/day/kg)

13 1155 21 47 (75.1) 4.3 (6.9) 11.3 (18.0) 62.6

Mestyan

Mestyan

Freymond

Brooke

9 1600 10 35.4 (80.1) 3.0 (6.8) 5.8 (13.1) 44.2

4 1615 12 39.7 (72.2) 6.0 (10.9) 9.3 (16.9) 55.0

9 1740 21 61.6 (90.0) 3.6 (5.3) 3.2 (4.7) 68.4

15 1581 14,27,42 58.6 (66.4) 23.2 (26.3) 6.4 (6.3) 88.2

Adapted from Bronstein MN, (48). BMR, basal metabolic rate; EE, energy expenditure; TEE, total energy expenditure. Numbers in parentheses are percentages of TEE. over several days for these two isotopes, represents the contribution of oxygen in the tracer water molecules t h a t is lost to carbon dioxide, compared to t h a t lost to evaporation and urine production. This allows an estimate of carbon dioxide production from which calculations can be made of energy expenditure and energy stored, protein stored, lipid stored, and water stored. Such calculations also require accurate information about the nutrient mixture t h a t is fed to the infant during the period of study and urinary nitrogen excretion. Such sophisticated measurements of energy balance and nutrient utilization for oxidation and storage have allowed more precise estimates of how nutrients are handled by extremely low birth weight infants. It is clear from several studies, for example, t h a t energy expenditure is directly related to metabolizable energy intake (Figure 9) (55), whether this is provided solely by glucose or by a mixture of glucose, lipid, and amino acid. This information is valuable because previous estimates of caloric expenditure in ELBW infants, which showed relatively low rates (e.g. 30-40 kcal/day/kg), were interpreted as evidence of low rates of energy requirements. In fact, when fed more, such infants showed expected ENERGY EXPENDITURE (kcal/kg.day) 75 70 65 t

60 55

•-°

• •

•

•

@•

-.

•

w

•0

50 45

/ • " O•-

•

r=.70;p(0.001 y=32 0+0.23x

" 80 9'0 1C)0 110 1:20 130 1~10 150 160 METABOLISABLE ENERGY iNTAKE ( k c o l / k g doy)

Figure 9 -- Energy expenditure in preterm infants is shown to be a direct function of metabolizable energy intake to intakes as high as 150 kcal/kg/day. Reprinted from (55). 406

increases in metabolic rate and energy expenditure (e.g. an increase in oxygen consumption rate from 0.26 to 0.43 mmol/min/kg, and an increase in energy expenditure from 38 to 63 kcal/day/kg, when a small group of preterm infants were fed about twice as much energy and protein) (52). Additionally, energy expenditure in such infants has been related to stressful events and also to circulating hormones, such as catecholamines, produced either by stress or by simultaneous administration of dopamine. Excessive a d m i n i s t r a t i o n of glucose (>70 (mol/ min/kg), particularly in the absence oflipids, results in a significant increase in carbon dioxide production (e.g. from 0.3 to 0.4 mmol/min/kg) because glucose is diverted to triglyceride formation and adipose tissue deposition (56). Such an increase in respiratory CO 2 production can lead to an increased stimulus to respiratory drive t h a t may compromise the infant already suffering from respiratory distress. This also may impose an increase in respiratory drive on an infant t h a t is marginal with respect to energy balance, as might occur in cases of acute respiratory distress or chronic respiratory conditions such as bronchopulmonary dysplasia. In fact, infants fed a high-fat (3 g/day/kg) relative to a lowfat diet (-1.0 g/day/kg) show enhanced lipid oxidation (e.g. from 0 to 0.7 _+ 0.3 g/day/kg) and significantly decreased lipogenesis from glucose (from 1.1 _+ 0.2 to 0) with little change in lipid storage (2.1 _+ 0.3 g/day&g) (57), showing how a simple shift in the balance of carbon substrates can alter how these substrates are metabolized, as well as stored. Early use and rapid advancement of lipid emulsions in the preterm infant have been made cautiously because of a variety of potential complications, including lipid intolerance (58), impaired pulmonary function, increased free bilirubin concentrations (59,60), and potential interference with imm u n e function (61,62). The n a t u r e of the lipidrelated pulmonary dysfunction includes pulmonary microemboli (63,64), a diffusion block secondary to lipid overload (65), and increases in pulmonary vascular tone secondary to infusion of precursors of the vasoactive prostanoid system (66-68). In general, however, only very high lipid infusion rates have ever been associated with such problems, let alone convincingly causing such complications. Such high CLINICAL BIOCHEMISTRY, VOLUME 29, OCTOBER 1996

DISEASE AND NUTRITION OF THE PRETERM INFANT

infusion rates, usually greater than 4-5 g/day/kg, are much greater than those used currently for i.v. lipid nutrition of low birthweight infants (69,70). Nevertheless, early introduction of lipid, which is necessary to provide essential fatty acids, usually is started conservatively at 0.5-1.0 g/day/kg with a maximum rate of 3.0 g/day/kg achieved over 3-4 days, unless relatively low plasma triglyceride concentrations (<150 mg/dL) show an increased capacity to provide lipids at j~eater rates, sooner (71,72). Twenty percent, rathe:: than 10%, lipid emulsions are recommended because they contain only half the phospholipid content fi)r the same number of calories (73). Phospholipids produce nonmetabolizable lipoprotein-like particles that compete with normal LDL chylomicron remnants for binding to liver receptors. Triglyceride hydrolysis by lipoprotein lipase is, therefore, delayed, as is plasma lipid clearance.

N u t r i t i o n a l i m p a c t o n p r e t e r m i n f a n t s of specific d i s e a s e s a n d pathological conditions GLUCOSE SUPPLY: INFANTS OF DIABETIC MOTHERS

Hypoglycemia also has occurred quite frequently in infants of diabetic mothers (74). This occurs because of persistent hyperinsulinemia, especially in response to occasional glucose boluses (usually > 400 mg/kg) that produce acute hyperglycemic-induced hyperinsulinemia. Suclh hyperinsulinemia not only enhances glucose utilization in insulin sensitive tissues, such as skeletal nmscle and adipose tissue, but also suppresses hepatic production of glucose by inhibiting both gluconeogenesis and glycogenolysis (75-78). Hyperinsulinemia also decreases lipolysis and protein breakdown, which decrease plasma fatty acid and amino acid concentrations, respectively (79,80). These !infants, therefore, are more prone to develop hypoglycemia at the same time that alternate substrate supply is reduced. Surprisingly, few of these infants develop long-term neurological complications that can be attributed directly to hypoglycemic episodes, unless such episodes are severe, protracted, and usually associated with significant seizures (81). Such infants are, however, complicated management problems. Glucose concentrations are usually quite unstable in the first 2 to 4 h after birth and such instability also is exacerbated by the occasional occm~ence of maternal and, thus, fetal hyperglycemia shortly before birth from maternal intravenous glucose infusion, as well as neonatal hyperglycemia from catecholamine secretion (82). Such glucose disturbances often are compounded by inappropriate medical responses, particularly bolus infusions of glucose that are well-intentioned to correct hypoglycemia but, in fact, produce rapid hyperglycemia that enhances fetal insulin secretion and leads to further hypoglycemia. More appropriate therapy involves persistent, carefully controlled i.v. infusions of glucose intended to diminish the wide CLINICAL BIOCHEMISTRY, VOLUME 29, OCTOBER 1996

swings in glucose concentration provided by inappropriate management, and to limit the stimulation of insulin secretion from high basal glucose concentrations. Basal glucose production and utilization rates at normoglycemia (20 ~Lmol/min/kg) are not increased in infants of diabetic mothers (measured rates using stable isotope dilution technique of 1620 ~mol/min/kg), however, in that the excess body weight, which is largely fat, does not have a high rate of glucose utilization. Also, the higher-thannormal plasma insulin concentration often present in these infants (frequently > 120 pmol/L vs < 60 pmol/L in normal infants) suppresses hepatic glucose production. The correct i.v. glucose infusion rate in such infants, therefore, should be a normal rate (20 ~mol/min/kg) adjusted for a body weight that matches the brain size (estimated from the 50th percentile head circumference for the infant's gestational age), not the birth weight. Additionally, early feeding should be provided, preferably by continuous enteral infusion of milk or formula, or small frequent feedings. Milk and formula are particularly useful because the milk sugar, lactose, provides a mixture of glucose and galactose after intestinal hydrolysis. Galactose is cleared by the liver from the portal vein almost completely, contributing to glycogen formation but not systemic hyperglycemia (83,84). Galactose also does not stimulate insulin secretion as well as glucose, either in vitro or after i.v. infusion (85,86). INTRAUTERINE GROWTH RESTRICTION

(IUGR)

Infants who have suffered intrauterine growth restriction have many unique nutritional requirements (87). Such infants have deficient nutrient stores, increased resting energy expenditures, increased rates of enteral nutrient losses due to exocrine pancreatic insufficiency, decreased capacity to use protein resulting from high urinary nitrogen losses, pancreatic insulin deficiency and peripheral insulin resistance, reduced bone mineralization, and decreased iron stores evidenced by decreased serum ferritin concentrations. IUGR infants also demonstrate significantly increased glucose requirements based on a higher-than-normal brain-to-body weight ratio (88). Furthermore, such infants do not readily produce new glucose (87,89); their glycogen stores are diminished and they have diminished rates of gluconeogenesis (90). Overall, their energy supplies are considerably decreased based on inadequate lipid stores and inadequate muscle for normal rates of proteolysis (91). Furthermore, although acute energy deficiency may result in an increase in proteolysis and amino acid oxidation, preliminary observations in an animal model of long-standing intrauterine growth restriction showed a return towards normal for fractional rates of amino acid oxidation (92). It is not clear whether or not rapid supply of amino acids to such infants may result in hyperaminoacidemia because of more limited capacities for amino acid utilization and oxidation, but this is 407

HAY

certainly a possibility. Similar observations, for example, have been made in older children who have suffered kwashiorkor (chronic protein deficiency) as well as m a r a s m u s (chronic energy as well as protein deficiency). A judicious approach to nourishment of these infants is indicated, therefore, beginning with early glucose supply adjusted to frequent measurements of glucose concentration, and early administration of amino acids at modest rates of 2.5 to 3 grams/day/kg plus lipids at 2 grams/day/kg. Increased rates of these nutrients can be supplied after metabolic stability occurs. Recent evidence indicates that, after growth is established, protein and energy requirements of IUGR infants are at least as great as those of rapidly growing ELBW infants (1). An even more serious concern about growth failure is the marked delay in growth and worsening of growth delays after a preterm infant is born. In fact, the prevalence of growth delay increases from about 15-20% at birth to over 75% by discharge (6). Although this m a y come about by a mixture of real and imagined concerns about the potential development of pathologic processes developing from early and aggressive feeding of such infants, nevertheless, the potential harm to the developing infant postnatally may be much more far reaching and serious than that caused by intrauterine growth restriction itself. ACUTE PULMONARY DISEASE

The principal difficulty encountered by infants with acute respiratory distress is an increase in energy r e q u i r e m e n t s due to increased r e s p i r a t o r y muscle work. Oxygen consumption rates may be as much as 50% greater than normal in such infants (0.4-0.5 vs 0.3 mmol/min/kg) (93). Because such infants often receive only glucose, often at rather high rates, respiratory work also can be increased by

greater carbon dioxide production and PCO 2 values that result from lipogenesis from glucose. A relatively greater intake of lipid is necessary to limit or prevent this process. Amino acids, especially the branched-chain amino acids, also can stimulate respiration and prevent apnea, perhaps by decreasing brain tryptophan and its product, serotonin, which is a respiratory drive depressant (94-96). Infants with acute respiratory distress also are at increased risk of respiratory failure when they are not fed enough--an all too common occurrence. Starvation reduces availability of all nutrients necessary for lung development and, in particular, decreases surfactant, lung structural protein, and lung collagen production. Proteolysis augments these processes and also reduces tissue elasticity (97). The combination of these processes lead to decreased inspiratory and expiratory muscular forces (<98). CHRONIC LUNG DISEASES INCLUDING BRONCHOPULMONARY DYSPLASIA

Nutritional deficiencies in ELBW infants exacerbate many of the problems associated with chronic lung disease, in particular, bronchopulmonary dysplasia. Table 5 summarizes some of these problems (1,99). Infants who develop bronchopulmonary dysplasia frequently demonstrate increased energy requirements (100-103). Some of these infants have increased work of breathing (often due to high PCO2 levels) (104) and some infants have been treated with methylxanthines, which increase the work of breathing (105). The increased energy requirements for the work of breathing are often offset, however, by diminished activity (106). The principal nutritional deficit in these infants is one of undernutrition, usually for long periods (100,104). Thus, their overall nutrition is inadequate and their body stores

TABLE 5

Adverse Pulmonary Effects of Undernutrition in the Preterm Infant Diminished energy reserves Early onset of catabolic state Harmful effects on respiratory distress syndrome Diminished and/or abnormal forms of surfactant production Decreased respiratory muscle function Decreased protection from hyperoxia and barotrauma Decreased epithelial integrity (e.g. from insufficient vitamin A) Decreased antioxidant defense systems (antioxidant enzymes, glutathione, vitamin E, vitamin C, polyunsaturated fatty acids [PUFAs]) Decreased lung biosynthetic/cell replication processes for repair of cell injury Decreased lung repair and development of bronchopulmonary dysplasia (BPD) Decreased replacement of damaged cells Decreased replacement of damaged extracellular components (elastin, collagen)

Decreased lung growth and replication Decreased lung biosynthesis Decreased lung structural maturation (e.g. alveolarization) Increased susceptibility to pulmonary infection Decreased cellular/humoral defenses Decreased epithelial cell integrity Decreased foreign material clearance mechanisms Adapted from (1). 408

CLINICAL BIOCHEMISTRY, VOLUME 29, OCTOBER 1996

DISEASE AND NUTRITION OF THE PRETERM INFANT

of all nutrients, except carbohydrates and sometimes fat (which they usually are fed to excess), are diminished (107). Additionally, many of these infants are treated with corticosteroids to improve lung function. Recent studies have shown that corticosteroids enhance proteolysis (108) which, when coupled with energy deficiency and overall undernutrition, leads to weakened respiratory motor capacity (109) and the potential for diminished lung growth. Pulmonary disease often is exacerbated in infants with chronic lung disease because the malnutrition also makes them highbr susceptible to infection, particularly pneumonia (110). Additional respiratory compromise can occur because of osteopenia that produces a more compl[iant rib cage (111). Osteopenia and nephrocalcinosis are often aggravated by simultaneous diuretic treatment, the latter given with some success to reduce lung water and increase lung compliance. Additional studies have suggested that normal levels of vitamin A are necessary to prevent worsening of bronchopulmonary dysplasia, and some preliminary studies even indicate that maintaining vitamin A levels can help prevent bronchopulmonary dysplasia fl'om developing, as well as enhancing early lung healing (112). Similar claims have been made for vitamin E, although less strongly, largely on the basis of its role as antioxidant to prevent lung oxidant injury (113). An as yet unexplained complication in babies with bronchopulmonary dysplasia is their failure to gain weight when supplemental oxygen is arbitrarily discontinued (for example, when parents discontinue oxygen t r e a t m e n t at home, even though oximetry studies demonstrate a persistent need for oxygen treatment) (114). Mechanisms responsible for growth failure under these conditions are not clear. However, studies by Han and colleagues, have shown decreased thymidine incorporation in a variety of cells from several organs in hypoxic animal models, coupled simultaneously with decreased levels of IGF-1 (115). It is possible, therefore, that hypoxemia may lead to growth failure by disruption of insulin-like growth factor effects on cell division. CONGENITAL HEART DISEASE

In addition to medical and surgical complications in infants with congenital heart disease, those with cyanotic conditions also remain hypoxemic which, perhaps via mechanisms discussed above, may involve a decrease in insulin-like growth factor stimulation of cell replication and growth and contribute to poor growth. These infants also often have increased metabolic rate (116). This has been estimated from increased myocardial activity, increased respiratory activity, and an increased metabolic rate from the hematopoietic system. Such infants also tire easily and have increased rates of emesis (117). This leads to inadequate intake, unless force-fed, the latter often resulting in increased rates of emesis and poor gastrointestinal absorption that aggraCLINICAL BIOCHEMISTRY, VOLUME 29, OCTOBER 1996

vates malabsorption (118), especially when these infants are hypoxemic. Such infants may need more aggressive i.v. nutrition, particularly during hospital stays for staged surgical repairs or treatment of increased complications of congestive heart failure (119). NECROTIZING ENTEROCOLITIS

Necrotizing enterocolits or NEC is a final common pathway disorder in which necrosis of focal segments or diffuse areas of the small and large bowel develop. Multiple etiologic factors are involved; these include hypoxia, ischemia, infection, hypertonic feedings, too rapidly advanced feeding rates and, especially, volume of feeds, severe polycythemia with and without partial plasma exchange transfusion, milk protein allergy, and (although controversial) both the presence and especially the prolonged use of umbilical artery catheters (120). The incidence of NEC is inversely related to gestational age (121) (e.g. 6.3% of infants with birth weights of 1000 to 1250 grams, 9.2% in infants of 750 to 1000 grams, and 13.5% in infants of 500 to 750 grams at birth) (122). Most earlier studies indicated that most infants who developed NEC had been fed. Although most infants who didn't develop NEC also had been fed (123), and the feeding histories of infants who did and did not develop NEC were similar, i.v. feeding was suggested as a way to provide reasonable nutrition without the risk of enteral feeding leading to NEC. Convincing data to support this practice has been difficult to produce (123,124). Only two randomized trials of the effect of i.v. feeding or enteral feeding on the development of NEC have been reported: The combined data from both studies showed that NEC occurred in 10 of 46 enterally fed infants but in only 1 of 47 fed with i.v. feeding (125,126). This difference was significant by meta-analysis (127), although the difference was not significant in either study alone. There is more support for aggressive enteral nutrition leading to NEC; most uncontrolled studies and case-controlled studies demonstrate that NEC is significantly more common among those infants who had the most rapid increase in feeding rate and volume per feed (128131). Exclusive and prolonged used of i.v. feeding as a sole source of nutrition for preterm infants has produced several unique pathologies. Cholestasis is the most vexing and common (125-127), but metabolic bone disease and sepsis (primarily from the use of central venous catheters) are quite frequent also. Exclusive use of TPN also does not appear to promote or even allow gut maturation to take place (132-134). Enteric growth either doesn't occur or, in fact, regresses. TPN also does not promote the secretion of any of the gastrointestinal hormones that have been associated with maturation of gut growth and function, nor does it enhance the development or secretion of gut digestive enzymes (135,136). 409

HAY

Based on the lack of conclusive evidence that TPN can significantly reduce the incidence or the severity of NEC, and the complications actually caused by using TPN, many investigators and clinicians have turned to early, minimal enteral nutrition as a preventative measure. Several studies have shown that infants fed by this approach (whether provided by small continuous infusion rates of 1 to 2 mL/kg/h or by small intermittent bolus feedings) (131,137-140) have enhanced gastrointestinal maturation, including better enteral feeding tolerance after the feedings were begun, decreased time to full enteral feedings, less dependence on intravenous feeding, and a more rapid weight gain. Early minimal enteral nutrition increases the rate of intestinal adaptation, including growth, enzymatic development, and motility (141-144). This is true in normal infants and infants who have gut injury and gut resections. Many studies now document a marked increase in intestinal motility between 26 and 29 weeks of gestation (145). If simply fed formula, Berseth and colleagues have shown markedly enhanced intestinal activity and feeding tolerance (Fig. 10) (146). In other studies, Lucas and colleagues have shown that even infants with respiratory distress develop increased secretion rates of a variety of important gastrointestinal hormones, including enteroglucagon, gastrin, gastric-inhibitory peptide, motilin, and neurotensin, that positively affect growth and intestinal motility (147). Minimal enteral feeding does not appear to increase or decrease the incidence of NEC (123,142144,148). An exception involves the use of h u m a n milk. Breast milk does appear to reduce the incidence and severity of NEC; this is especially true in high-risk, ELBW infants (149). Part of the difficulty in interpreting all of the studies that have addressed the relationships between NEC and either i.v. or enteral feeding is that many confounding variables are 70 Formula Fed •

60

Water Fed [ ] 50 ,~ 40 a

30 20 10 0

.n_ i I i i

i

Days Feeding Intol,

Days Feeding Withheld

Days to Full Enteral Feeding

Days to Full Nipple Feeding

Days to Exceed B. Wt.

Age at Discharge Days

Figure 10 - - Formula-fed preterm infants are shown to develop enhanced gastrointestinal capacity to increase enteral feeding compared to water fed-infants Intol., intolerance; B. Wt., birth weight. Adapted from data presented in (146). 410

not randomly and equally present among all of the studies. For example, pharmacological interventions, such as simultaneous infusions of catecholamines and indomethacin for blood pressure support and patent ductus arteriosus closure, may be associated with an increased incidence of NEC, although the relative roles of catecholamines and indomethacin v s the associated hypoxemia and ischemia has not been sorted out. Few studies provide such information. As a practical matter, then, feedings are best withheld during such therapy, although data to support this position are not available (150). Continued minimal enteral feedings with breast milk may be as, or more, beneficial as long as enteral feeding is not continued when evidence of intestinal dysfunction is present. SHORT BOWEL SYNDROME

Either as the result of combined intestinal damage and surgical resection of NEC, or as a result of resection of anatomical defects, such as omphalocoele, gastroschisis, Hirschschprung syndrome, or intestinal atresias, short bowel syndrome represents one of the most severe complications in preterm infants and produces some of the most chronically debilitated infants in modern intensive care nurseries. Early on, short bowel syndrome involves considerable malabsorption, as well as intestinal dysfunction (151). This combination not only prevents adequate feeding volumes but, at any feeding volume, increases the loss of nutrients through surgical stomas necessary for appropriate decompression or from the colon as a result of a variety of malabsorption defects (152,153). The most common malabsorption defect is a loss of enzymatic capacity for both digestion and absorption, resulting from villus atrophy in the proximal and middle portions of the small bowel (154,155). Most investigators and clinicians have assumed that, to best treat the infant with short bowel syndrome, i.v. feeding is critical, and quickly should be at full capacity. This concern is based on the reasonable assumption that much of the delay in resolving malabsorption and developing successful gut adaptation may be due simply to persistent under- or malnutrition (156). This is particularly germane to smaller infants, in whom nutritional status was probably less than optimal even before the development of problems, such as NEC, that led to short bowel syndrome. Infants who receive no exogenous protein intake have very low plasma amino acid concentrations (157) and excrete nitrogen at rates of 130-180 mg/kg/day (158,159), amounting to a loss of 1% per day of endogenous protein stores. Although there is little definitive data to show that i.v. feeding improves the survival of these infants, most such infants did not fare well and often died before i.v. feeding was instituted as common practice. Furthermore, there is good evidence that the negative nitrogen and energy balances due to fasting, even in otherwise healthy infants, can be reversed or markedly limited with i.v. feeding (160) and that, among CLINICAL BIOCHEMISTRY, VOLUME 29, OCTOBER 1996

DISEASE AND NUTRITION OF THE PRETERM INFANT

sick infants who haw~ received i.v. glucose only, their negative nitrogen balance can be reversed by the simple addition of i.v. amino acids (158,159). SEPSIS

There is a significantly increased risk of sepsis and organ-specific infections that occur with persistent malnutrition and undernutrition in preterm infants (161-163). This results from diminished hostdefense mechanisms, including cell-mediated immunity, bactericidal function of neutrophils, more limited activity of the complement system, and diminished secretory IGA responses (164,165). Retinol deficiency limits airway epithelial growth and differentiation and, thus, airway barrier integrity, including cell repair processes, t-cell proliferative responses, and cell growth in general (166). Vitamin A m a y enhance phagocytic immunoregulatory activity found in polymorphonuclear cells, as well as promote epithelial cell repair processes in growth (167). Vitamin E deficiency also compromises cellular and humoral immunity and antimicrobial phagocytic action, although too much vitamin E can result in excessive scavenging of oxygen free radicals and, thus, bacterial killing in the i n t r a c e l l u l a r phagocytic vacuoles (168). I n c r e a s e d s y m p a t h e t i c - n e r v o u s system activity and hypermetabolism have been noted with increased oxygen consumption rates during sepsis, requiring increased glucose delivery to meet the hypermetabolic needs (169). Finally, decreased branched-chain amino acid concentrations have been observed, although the exact mechanisms are not clear. These m a y relate to enhanced amino acid oxidation, as well ;as poor peripheral amino acid exchange between plasma and cells (170-172). Neurological outcome A variety of studies have now shown quite clearly that extremely low birth weight preterm infants fed inadequate calorie and protein supplies for extended postnatal periods, particularly when coupled with evidence of intrauterine growth restriction, develop significant n e u r o d e v e l o p m e n t a l delays affecting both motor and intellectual development (173-175). Interestingly, h u m a n milk m a y confer a developmental advantage, especially when the mother's milk is supplemented to protein and energy contents similar to those of "preterm enriched" formulas. Larger infants m a y do even better t h a n formula-fed infants when fed with breast milk alone.

The factors in h u m a n milk that may produce such an advantage are not known. One recent line of research addressing this issue involves the unique supply in milk of certain essential fatty acids (Table 6). Linoleic acid and linolenic acid produce arachidonic acid and docosahexanoic acid, respectively. These fatty acids are essential for membrane structure and function; deficiencies have been linked to selected neurological functional deficits, including discrimination learning and visual acuity (176). These fatty acids also are essential precursors for circulating eicosanoids (177). But, they are energy substrates as well and, when energy supply is deficient, they will be used for fuel and not for essential structure (178). Essential structural formation includes oligodendrocyte synthesis of myelin; this requires unsaturated and monounsaturated fatty acids and cholesterol (179). Synthesis rates are ext r a o r d i n a r i l y high during myelination, which is greatest in the 20-30-week period of gestation (180). U n d e r n u t r i t i o n in general, and lack of essential fatty acids will decrease myelin synthesis and, in animal models at least, result in an increased association of neurodevelopmental deficits (181). On one hand, then, providing adequate e n e r g y and adequate amounts of these essential fatty acids (EFAs) is critical for normal neuronal development. On the other hand, an imbalance in the relative rates at which selected EFAs are supplied m a y be detrimental. Heird's group showed, for example, that 4%, rather t h a n 1%, 18:3¢o3 fatty acid supply (linolenic acid) increased plasma concentrations of ~3 fatty acids and 22:6~3 (docosahexanoic acid), but only to 50% of those concentrations found in milk-fed babies at term; furthermore, it lowered the plasma concentrations of 20:4¢o6 (arachidonic acid) and the rate of weight gain. Also, there was no benefit to visual development (182). Thus, as with essential amino acids, the quality as well as the quantity of EFAs are critical to normal development, as well as to normal rates of growth. Conclusions Postnatally, ELBW infants do not grow well; in fact, often they do not grow for weeks. This leads to a virtual "growth deficit" that has unknown consequences but which, for the most part, is probably not good and requires excessive feeding later on to catch up to normal growth rates and body composition. When undernutrition is compounded by increased metabolic requirements produced from a variety of

TABLE 6 Essential F a t t y Acids i n the Diet M a t u r e h u m a n milk

Linoleic (18:2¢o-6) Linoleic (18:3o~-3) Arachidonic (20:4¢o-6) Docosshexanoic (22:6¢o-3)

10 0.5 0.4 0.2 -

CLINICAL BIOCHEMISTRY, VOLUME 29, OCTOBER 1996

16% 1.0% 0.7% 0.4%

P a r e n t e r a l lipid emulsions

50 - 66% 4 - 8% small small 411

HAY TABLE 7 Practical Suggestions for Fluid, Enteral, Parenteral, Glucose, Lipid, Amino Acid, and Protein Feeding of Infants Weighing Less Than 1000 Grams at Birth, at Less Than 27 Weeks Gestation Postnatal days Intravenous (i.v.) fluid rate (mL/kg/day) Enteral fluid rate (mL/kg/day) Total fluid rate (mL/kg/day) Glucose (i.v.) (mg/kg/min) Lipids (i.v.) (g/kg/day) Amino acids (i.v.) (g/kg/day) Protein (g/kg/day) Total protein: amino acids plus protein (g/kg/day)

1

2

3

4

5

6

7

8

9

10

11

12

13

80

90

100

110

120

110

100

90

80

70

60

40

20

5

10

20

30

40

50

60

70

80

90

100

120

140

85

100

120

140

160

160

160

160

160

160

160

160

160

6

8

8

8

8

8

8

6

6

6

6

4

2

1

2

2

2.5

2.5

3

3

3

2

2

2

1

1

2.5 0.1

2.5 0.2

2.5 0.4

2.5 0.7

2.5 0.9

2.5 1.1

2.5 1.3

2.5 1.5

2.0 1.8

2.0 2.0

2.0 2.2

1.5 2.6

1.0 3.0

2.6

2.7

2.9

3.2

3.4

3.6

3.8

4

4

4

4.2

4.1

4

stop

Totals should be maintained; thus, use more i.v. feeding if enteral feedings must be held. Adapted from (2).

stressful disease states, the consequences of u n d e r n u t r i t i o n a n d m a l n u t r i t i o n become m o r e severe. The m a j o r f u t u r e challenge for n u t r i t i o n of t h e s e i n f a n t s is to define m o r e a c c u r a t e l y t h e i r n u t r i t i o n a l req u i r e m e n t s , p a r t i c u l a r l y in the e a r l y p o s t n a t a l period, to feed t h e m more a p p r o p r i a t e l y , r e d u c e to a m i n i m u m t h e n u t r i t i o n a l a n d g r o w t h deficits t h a t t h e y so c o m m o n l y develop, a n d p r e v e n t neurodevelo p m e n t a l h a n d i c a p s t h a t are t h e r e s u l t of n u t r i tional deficiencies. To m e e t t h e s e challenges, m u c h m o r e aggressive feeding r e g i m e n s t h a n t r a d i t i o n a l l y u s e d h a v e b e e n r e c o m m e n d e d . O n e e x a m p l e is s h o w n in Table 7 (2); it is a i m e d at combined goals of p r e v e n t i n g n u t r i t i o n a l deficiencies, s t a r t i n g postnatal g r o w t h earlier, a n d p r e v e n t i n g n e u r o n a l i n j u r y or a b n o r m a l development. W h e t h e r or not more aggressive n u t r i t i o n of t h e E L B W and V L B W i n f a n t will d e c r e a s e m o r b i d i t y a n d m o r t a l i t y , i n c r e a s e g r o w t h r a t e s , a n d p r e v e n t l o n g - t e r m neurological deficits r e m a i n s to be proven. As discussed in this review, h o w e v e r , t h e r e is e v i d e n c e a l r e a d y t h a t g r o w t h r a t e s of E L B W a n d V L B W i n f a n t s are increased with greater protein and energy intakes t h a n c o m m o n l y h a v e b e e n used, t h a t e n r i c h e d form u l a s e n h a n c e g r o w t h a n d neurological outcome in r e l a t i o n to dilute f o r m u l a s a n d b a n k e d b r e a s t milk, a n d t h a t h u m a n milk w i t h k n o w n a n d y e t u n k n o w n p r o p e r t i e s also can e n h a n c e neurological outcome relative to s t a n d a r d t e r m i n f a n t formula. T h e r e is also evidence t h a t earlier use of i.v. lipids can improve e n e r g y balance, r e d u c e CO 2 p r o d u c t i o n r a t e s and, p e r h a p s , also e n h a n c e n e u r o n a l m a t u r a t i o n , t h a t h u m a n milk can r e d u c e g a s t r o i n t e s t i n a l complications of aggressive e a r l y e n t e r a l feeding, t h a t earlier use p o s t n a t a l l y of i.v. amino acid solutions t h a t produce more n o r m a l p l a s m a c o n c e n t r a t i o n s of 412

amino acids leads to more positive nitrogen balance and growth rates, and that slow priming of the gastrointestinal tract with milk or formula can promote gastrointestinal development, peristalsis, and nutrient digestion and absorption. In relation also to the many additional nutritional problems imposed on ELBW and VLBW infants by specific morbidities, it is now quite reasonable to attempt a more aggressive and, hopefully, more promising approach to nutritional management of these special infants.

Acknowledgements This work was supported in part by GCRC Grant 00069 from the National Institutes of Health.

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