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Effect of Low versus High Intravenous Amino Acid Intake on Very Low Birth Weight Infants in the Early Neonatal Period
Abstract
Greater protein intakes are required than have been commonly used to achieve fetal in utero protein accretion rates in preterm neonates. To study the efficacy and safety of more aggressive amino acid intake, we performed a prospective randomized study in 28 infants [mean wt, 946 +/- 40 g (SEM)] of 1 (low amino acid intake, LAA) versus 3 g.kg(-1).d(-1) (high amino acid intake, HAA) at 52.0 +/- 3.0 h of life. After a minimum of 12 h of parenteral nutrition, efficacy was determined by protein balance and was significantly lower in the LAA versus HAA groups by both nitrogen balance (-0.26 +/- 0.11 versus 1.16 +/- 0.15 g.kg(-1).d(-1), p < 0.00005) and leucine stable isotope (0.184 +/- 0.17 versus 1.63 +/- 0.20 g.kg(-1).d(-1), p < 0.0005) methods. Leucine flux and oxidation and nonoxidative leucine disposal rates were all significantly higher in the HAA versus LAA groups (249 +/- 13 versus 164 +/- 8, 69 +/- 5 versus 32 +/- 3, and 180 +/- 10 versus 132 +/- 8 micro mol.kg(-1).h(-1), respectively, p < 0.005), but leucine appearance from protein breakdown was not (140 +/- 15 in HAA versus 128 +/- 8 micro mol.kg(-1).h(-1)). In terms of possible toxicity with HAA, there were no significant differences between groups in the amount of sodium bicarbonate administered, degree of acidosis as determined by base deficit, or blood urea nitrogen concentration. Parenteral HAA versus LAA intake resulted in increased protein accretion, primarily by increasing protein synthesis versus suppressing protein breakdown, and appeared to be well tolerated by very preterm infants in the first days of life.
... Slow growing pigs are suggested to have a lower feed intake and lower serum concentrations of essential amino acids (He et al., 2016) compared to their fast growing siblings. The low feed intake of lightweight pigs (Nissen and Oksbjerg, 2011;Vieira et al., 2015) and possibly higher protein turnover in relation to their size (Thureen et al., 2003), suggest that lightweight pigs may exhibit improved performance when fed nutrient enriched diets that are high in essential amino acids (Tokach, 2004). The objectives of this study were: 1) to assess the influence of morphometric characteristics at birth on performance to finisher stage and whether these can differentiate between pigs that are able to exhibit an improved performance pre-and postweaning; and 2) whether a nutrient enriched starter regime could contribute to an improved post-weaning performance of piglets weaned light. ...
... Improved starter regimes tailored on the basis of lightweight piglet requirements rather than the average piglet, have been shown to be effective in improving post-weaning performance for pigs weaned light (Beaulieu et al., 2010b;Douglas et al., 2014a). The low feed intake (Nissen and Oksbjerg, 2011;Vieira et al., 2015), the lower serum concentrations of essential amino acids (He et al., 2016) and possible higher protein turnover (Thureen et al., 2003), suggest that lightweight piglets may benefit from an essential amino acids enriched diet. Piglets weaned light appear to have an immature digestive system Pluske et al., 2003) and a higher epithelial cell turnover (Wiyaporn et al., 2013), and therefore may benefit from an increased supply of threonine (Le Floc'h et al., 2012) and methionine (Chen et al., 2014). ...
... While a low level of supplementary BC may be nutritionally and immunologically ineffective, excessive BC intake could raise concerns about possible protein toxicity, especially for preterm infants [301]. In such infants, excessive protein may pose a risk for metabolic disturbance, azotemia, and acidosis, in part related to immature metabolic, hepatic, and renal functions. ...
... Plasma tyrosine levels increase in preterm pigs following BC supplementation during the first week, consistent with the relatively high tyrosine levels in BC [229]. Despite these concerns, amino acid toxicity is a rare condition, even in preterm infants, and normally excess amino acid supply would be effectively excreted as urea [301]. In preterm infants, moderately high blood urea levels (e.g., 5-10 mM) may indicate immature liver and kidney functions and/or excess protein supply, but such urea levels are not toxic, and blood urea level alone is a poor marker of adequate protein intake for growth and protein intake in preterm infants [302]. ...
Bovine colostrum (BC), the first milk produced from cows after parturition, is increasingly used as a nutritional supplement to promote gut function and health in other species, including humans. The high levels of whey and casein proteins, immunoglobulins (Igs), and other milk bioactives in BC are adapted to meet the needs of newborn calves. However, BC supplementation may improve health outcomes across other species, especially when immune and gut functions are immature in early life. We provide a review of BC composition and its effects in infants and children in health and selected diseases (diarrhea, infection, growth-failure, preterm birth, necrotizing enterocolitis (NEC), short-bowel syndrome, and mucositis). Human trials and animal studies (mainly in piglets) are reviewed to assess the scientific evidence of whether BC is a safe and effective antimicrobial and immunomodulatory nutritional supplement that reduces clinical complications related to preterm birth, infections, and gut disorders. Studies in infants and animals suggest that BC should be supplemented at an optimal age, time, and level to be both safe and effective. Exclusive BC feeding is not recommended for infants because of nutritional imbalances relative to human milk. On the other hand, adverse effects, including allergies and intolerance, appear unlikely when BC is provided as a supplement within normal nutrition guidelines for infants and children. Larger clinical trials in infant populations are needed to provide more evidence of health benefits when patients are supplemented with BC in addition to human milk or formula. Igs and other bioactive factors in BC may work in synergy, making it critical to preserve bioactivity with gentle processing and pasteurization methods. BC has the potential to become a safe and effective nutritional supplement for several pediatric subpopulations.
... Con todo esto, la recomendación del aporte proteico para los RN con más de 1.000 g es de 3.5 a 4 g/k/día y en los que están por debajo de esta cifra entre 4 y 4,5 g/kdía 23 • 25 iniciando en forma temprana, basados en una tasa obligada de pérdidas de 0,7 g/k/ día, una acreción proteica de 1,7 g/k/día con una tasa de retención proteica de 80 a 90%. 26 • 27 La indicación actual se basa en iniciar un aporte proteico desde el primer día de vida a razón de 1.5 g/k/día con aumento progresivo de 0.5 a 1 g/k/día. 19,26 Hidratos de carbono: son importantes para prevenir el catabolismo, además de ser fuente rápida de ener gía y participar en el metabolismo de los aminoácidos y ácidos grasos no esenciales, En términos generales se recomienda una infusión entre 4 y 6 mg/k/min que permite asegurar un adecuado funcionamiento cerebral, eritrocitario, de médula renal y retina. ...
... 26 • 27 La indicación actual se basa en iniciar un aporte proteico desde el primer día de vida a razón de 1.5 g/k/día con aumento progresivo de 0.5 a 1 g/k/día. 19,26 Hidratos de carbono: son importantes para prevenir el catabolismo, además de ser fuente rápida de ener gía y participar en el metabolismo de los aminoácidos y ácidos grasos no esenciales, En términos generales se recomienda una infusión entre 4 y 6 mg/k/min que permite asegurar un adecuado funcionamiento cerebral, eritrocitario, de médula renal y retina. El aporte de los carbohidratos debe oscilar entre 40 y 50% del aporte calórico total, sin superar 17 g/k/día (en general 10 a 14 g/k/día) para evitar los efectos deletéreos de la hiperglicemia y la sobrecarga de hi dratos de carbono. 2 ...
En la práctica pediátrica y neonatal cada día sube la frecuencia de recién nacidos con mayor prematurez que requieren cuidados especiales dadas sus condiciones de base, con el fin de mejorar la sobrevida y disminuir las morbilidades a largo plazo. La nutrición utilizando el aparato digestivo en estos pacientes ha sido un reto importante y cambiante en el enfoque que se da a la misma, pues se ha relacionado con patologías específicas y se ha demostrado que mejorán dola disminuiremos de manera importante las complicaciones futuras. Hay que tener en cuenta que la nutrición en el período neonatal tiene inferencia en el desarrollo y salud posterior del individuo en la edad adulta.
... Several studies have demonstrated that the administration of 1.0-2.5 g amino acids/kg body weight/day, starting within a few hours of birth, can reverse a negative nitrogen balance into a positive balance, thus leading to anabolism [26][27][28][29][30][31]. More recent studies demonstrated that the nitrogen balance can be improved further by administration of amino acids up to 3.6 g/kg body weight/day [32][33][34] when provided with additional energy. ...
Objective: To study the impact of gestational age and birth weight on blood amino acid profiles
of the neonates screened and establish a percentile chart and cutoff limits of amino acids across
various gestational age and birth weight categories and find any significant variation of amino
acids.
Subjects and Method: During study duration, dried blood samples from 2486 newborns were
collected and levels of amino acids measured using Tandem Mass Spectrometry 3200MD Q-
Trap modified with Ionics upgrade. Among them, 767 were preterm (upto 37 completed weeks)
and 1719 were full term babies (37 weeks and above) and were categorized into various
Gestational age and birth weight categories. Non-parametric comparison of amino acid
distributions based on gestational age and birth weight categories were performed using the
Kruskal-Wallis test for independent samples.
Results: Trends of significant amino acid variation (p <0.05) was noted with various gestational
age and birth weight categories. Higher levels of amino acids are found to be significant (p
<0.05) in preterm newborns as compared with term newborns with exception of Citrulline
whose levels remained constant. 2.5th
, 5th , 95th , 97.5th percentiles were calculated for amino
acids with respect to gestational age and birth weight categories.
Conclusion: Preterm newborns have higher levels of amino acids as compared with their term
counterparts except Citrulline whose values remained constant. Amino acid percentiles can be
used to establish cut-off values across various gestational ages and birth weight categories to
aid in efficacy of Newborn Screening in India.
... 45 Parenteral supplementation of amino acids within the first 52 h of life at 3 g/kg/day in very low BW infants restores plasma amino acid concentrations to levels seen during the second and third trimesters of pregnancy. 46 Preterm infants receiving parenteral amino acid supplementation within 24 h of life have greater weight gain than infants receiving the supplementation after 24 h of life. 47 But knowledge of the optimal amino acid composition for preterm growth is still limited. ...
Nutritional deprivation occurring in most preterm infants postnatally can induce hyperglycemia, a significant and independent risk factor for suppressing physiological retinal vascularization (Phase I retinopathy of prematurity (ROP)), leading to compensatory but pathological neovascularization. Amino acid supplementation reduces retinal neovascularization in mice. Little is known about amino acid contribution to Phase I ROP. In mice modeling hyperglycemia-associated Phase I ROP, we found significant changes in retinal amino acids (including most decreased L-leucine, L-isoleucine, and L-valine). Parenteral L-isoleucine suppressed physiological retinal vascularization. In premature infants, severe ROP was associated with a higher mean intake of parenteral versus enteral amino acids in the first two weeks of life after adjustment for treatment group, gestational age at birth, birth weight, and sex. The number of days with parenteral amino acids support independently predicted severe ROP. Further understanding and modulating amino acids may help improve nutritional intervention and prevent Phase I ROP.
... Initial doses investigated were as low as 0.5-1 g/kg/day, which would be expected to keep preterm infants in a net negative nitrogen balance. 11,13,15,18,23,56 The maximum doses in lower-AA groups ranged from 2.5 to 3.5 g/kg/day, and maximum doses in higher-AA groups ranged from 3 to 4.5 g/kg/day. Only one study specifically targeted an AA dose of >4 g/kg/day, 19 although infants in another trial did receive AA doses >4 g/kg/day based on the study protocol intending to provide an additional 1 g/day in the intervention T A B L E 3 Clinical trial summary for question 1: In preterm infants, compared with later initiation, is early initiation of PN macronutrients associated with growth outcomes? ...
Background:
Parenteral nutrition (PN) is prescribed for preterm infants until nutrition needs are met via the enteral route, but unanswered questions remain regarding PN best practices in this population.
Methods:
An interdisciplinary committee was assembled to answer 12 questions concerning the provision of PN to preterm infants. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) process was used. Questions addressed parenteral macronutrient doses, lipid injectable emulsion (ILE) composition, and clinically relevant outcomes, including PNALD, early childhood growth, and neurodevelopment. Preterm infants with congenital gastrointestinal disorders or infants already diagnosed with necrotizing enterocolitis or PN-associated liver disease (PNALD) at study entry were excluded.
Results:
The committee reviewed 2460 citations published between 2001 and 2023 and evaluated 57 clinical trials. For most questions, quality of evidence was very low. Most analyses yielded no significant differences between comparison groups. A multicomponent oil ILE was associated with a reduction in stage 3 or higher retinopathy of prematurity (ROP) compared to an ILE containing 100% soybean oil. For all other questions, expert opinion was provided.
Conclusion:
Most clinical outcomes were not significantly different between comparison groups when evaluating timing of PN initiation, amino acid dose, and ILE composition. Future clinical trials should standardize outcome definitions to permit statistical conflation of data, thereby permitting more evidence based recommendations in future guidelines. This guideline has been approved by the ASPEN 2022-2023 Board of Directors.
... Studies in very low birth weight infants receiving 2.4 mg/kg/d or 3.6 mg/kg/d amino acids found a higher albumin synthesis rate, protein synthesis rate and nitrogen balance in the group with a higher dose of amino acid administration (35,36,43). Protein balance, determined by nitrogen balance as well as by the leucine stable isotope method, was higher in infants receiving 3 g/ kg/d amino acids instead of 1 g/kg/d (44). In adults with non-oliguric acute kidney injury (AKI), a higher amino acid intake (150 g/d versus 75 g/d) led to an increase in nitrogen balance (24). ...
Objective
To evaluate the effect of parenteral amino acid application in hospitalized hypoalbuminemic dogs.
Materials and methods
Medical records of client-owned hypoalbuminemic dogs (albumin ≤ 25 g/L) were analyzed. Dogs receiving amino acids for only 1–2 days, receiving transfusions or surgery, or <6 months of age were excluded. Dogs were grouped as those receiving intravenous amino acids (AA, 80 dogs) over 3 days and longer, and those without additional amino acid treatment (CON, 78 dogs). Duration of hospitalization, albumin, and total protein concentrations were compared between groups by Mann–Whitney U test. Course of albumin and total protein concentration was evaluated by Friedman test and Dunn’s multiple comparison test. Significance was set to p ≤ 0.05.
Results
Dogs in group AA received 10% amino acid solution intravenously over median 4 days (3–11 days). No significant differences regarding survival and adverse effects were observed between groups. Dogs of group AA had significantly longer duration of hospitalization (median 8 days; 3–33 days) compared to group CON dogs (median 6 days, 3–24 days; p < 0.001). Initial albumin concentration was lower in group AA compared to CON (p < 0.001). This difference was no longer present on day 2 (p = 0.134).
Conclusions and clinical relevance
Intravenous application of 10% amino acid solution in hypoalbuminemic dogs can improve albumin concentration after 2 days, but does not influence outcome.
... Preterm yenidoðanlara erken, yoðun parenteral aa verilmesine baðlý geliþebilecek hiperamonyemi, azotemi ve metabolik asidoz yönünden çekinceler mevcuttur. Yapýlan birçok çalýþmada ADDAlý yenidoðanlarda bile yeterli kalori desteðiyle birlikte erken ve yoðun (3 g/kg/g) parenteral aa baþlanmasýnýn metabolik yan etki olmaksýzýn güvenli ve pozitif nitrojen dengesi açýsýndan oldukça efektif olduðu bildirilmiþtir (2,8,9,(24)(25)(26)(27). Erken parenteral aa verilen yenidoðanlardaki artmýþ BUN düzeyleri protein intoleransýný deðil artmýþ protein döngüsünü ve kullanýmýný gösterir. ...
The nutritional needs of premature infants are usually dependent upon parenteral nutrition (PN) during early postnatal life, especially for very low birth weight (VLBW) infants (birth weight of less than 1500 g). In these infants, full enteral feedings are generally delayed because of the severity of medical problems associated with prematurity, such as immature lung function (which often requires endotracheal intubation and mechanical ventilation), hypothermia, infections, and hypotension. In addition, early enteral feeds are also delayed because of concerns that aggressive feeding may lead to complications such as feeding intolerance or necrotizing enterocolitis. As a result, the nutritional requirements of VLBW infants are rarely met by enteral feeds in the first two weeks after birth. There is growing evidence that inadequate nutrition in the first weeks of life of premature infants results in growth failure that is often difficult to correct and may lead to permanent detrimental effects. The early use of adequate PN minimizes weight loss and improves growth outcome. Therefore, parenteral nutrition (PN) in the premature infant including its composition will be reviewed here.
... Our result is consistent with the study conducted by Thureen et al., they found that giving higher amino acid (3g/kg/day) early in life, increased protein accretion by increasing protein synthesis and suppressing protein breakdown without showing any toxicity (16). Hence, we can conclude that administration of early high dose amino acids reduces the time to regain birth weight by preventing protein catabolism due to a negative protein balance in preterm infants. ...
Objective: Preterm infants may face difficulty on getting the nutrition required for growth due to incompetence of sucking and immaturity of the gastrointestinal. Preterm infants require higher amounts of amino acids and protein to support the growth of lean body mass and tissue. Administrating amino acid supplementation during the first hour of life is the key to preventing early neonatal malnutrition and can be beneficial in the growth of the neonates. Objectives: Aim of this study is to determine the effects of early high dose parenteral amino acids administration versus low dose in preterm infants from all collected studies. Methods: This is a meta-analysis study that studies were collected MedLine, PubMed, and Cochrane Central Register of Controlled Trials comparing early high dose parenteral amino acids versus low dose. High-quality studies, as assessed by Jadad Criteria, were used to evaluate outcomes such as anthropometric data, length of hospital stays, and morbidities. Results: A total of 9 Randomized controlled trials (RCTs) with total of 960 participants were included in the analysis. Analysis of these studies showed a statistically significant reduction in the time to regain birth weight in the group of early high-dose amino acids administration in the preterm infants. Reductions were 0.79 day (MD 0.79 day, 95% CI 0.06 to 1.52 day; participants = 655; studies = 6; I2 = 0%) (P= 0.03). It also showed a statistically significant reduction in the length of stay with a reduction of 2.09 days in the early high-dose parenteral amino acids groups (MD 2.09 days, 95% CI 1.01 to 3.17 day; participants = 500; studies = 5; I2 = 0%) (P= 0.0002). No significant difference in morbidity of each group was found. Conclusion: Administration of early high-dose amino acids reduced the time to regain birth weight and the length of hospitalization in preterm infants. The analysis did not show any significant increase in the risk of morbidity.
... 53,54 It is suggested to start amino acid in higher doses of 2-3 g/kg/ day immediately after preterm birth. 55,56 along with lipids in dose of 1-2 g/kg/day in early hours of life 57 and subsequently increase the doses as recommended. -Minimal enteral nutrition: Minimal amounts of human milk (minimal enteral nutrition/trophic feeds) ranging from 10 to 20 mL/kg, starting as early as possible, must be a part of the standard feeding guideline. ...
Extra-uterine growth restriction (EUGR) is frequently seen in premature and critically ill infants. Even though advancements in neonatal intensive care have improved the survival of these high-risk infants, many new questions have emerged about the relationship between postnatal growth and neurodevelopmental outcome of these infants. EUGR has traditionally been ascribed to caloric restriction during postnatal periods of critical illness. Nutritional compromise, particularly during the first few weeks of life, may affect the overall growth and could also cause long- term neurodevelopmental impairment. The accidental and premature interruptions of pregnancy could also alter the normal mobilization and utilization of major nutrients from the ways that would have otherwise occurred during the last trimester of pregnancy, which is normally a period of maximal in utero growth. In this article, we review our current understanding of defining EUGR, various risk factors for EUGR, its pathophysiology, and possible ways with which our current healthcare protocols could prevent EUGR.
Keywords: Development, Growth restriction, IUGR, Premature, Skeletal.
... For very low birth weight (ELBW) newborns, we normally start amino acids (1 g/kg per day) on the second day of life and gradually increase to 3 g/kg per day with 1 g/kg daily increments. Protein should be supplied with a maximum of 15% calories [13,25,26]. ...
Often in extremely preterm newborns in the early postnatal daysproblems in fluid and electrolyte balance occur Due to excessive insensible water loss and renal immaturity. The dietary care of newborn newborns is challenged by the demands of growth and organ development. The stress of a serious disease makes it much more difficult to get enough nourishment. Newborns andespecially premature newborns must be assessed thoroughly for fluid and electrolytes balance. Calculating the fluid and electrolyte demand for sustaining metabolic activities, replacing losses (evaporative, third space, external), and considering pre-existing fluid imbalance are all part of effective fluid and electrolyte management. When a neonate's size or condition prevents them from receiving enteral nutrition, parenteral nutrition can help them grow and thrive. Although eating through the gastrointestinal tract is the recommended method of nutritional management, some situations necessitate the use of PN as an adjuvant or sole treatment. In this article we discuss fluid electrolytes and Nutritional management using parenteral nutrition.
... In a study comparing high-dose and low-dose intake of AAs, high-dose AA intake was similar to the second and third trimesters of pregnancy. [17]. Here, we propose that the AA dose in the current protocol for ELBW infants at GA22-25 weeks reduced the gradient of weight loss during the weight loss period after birth, then led to weight gain during the subsequent catchup period. ...
The effect of early aggressive nutrition (EAN) on extremely low birth weight (ELBW) infants is unknown. The purpose of this study was to investigate the effect of EAN on ELBW infants, especially premature neonates of 22–23 weeks gestational age (GA22–23-week). Twenty-eight preterm infants of less than 26 weeks were divided into two groups (GA22–23-week group, 10 infants; GA24–25-week group, 18 infants) and compared. Each preterm infant received more than 3.0 g/kg/day of amino acids in the first day after birth and 1.0 g/kg/day of lipid emulsion from the next day. The GA22–23-week group had significantly smaller head circumference (20.4 ± 1.0 cm vs. 22.2 ± 1.4 cm, P = 0.002) and body weight at birth (539 ± 68 g vs. 697 ± 155 g, P = 0.003), but there were no differences in early postnatal weight loss (10.4% ± 6.3% vs. 8.1% ± 6.3%, P = 0.37), and body weight at 37 weeks postmenstrual age (1906 ± 321 g vs. 2081 ± 379 g, P = 0.17). Blood urea nitrogen levels were higher in the GA22–23-week group (59.7 ± 16.6 mg/dl vs. 45.0 ± 10.8 mg/dl, P = 0.004), but there were no differences in direct-bilirubin, bile acids, and ammonia levels. After discharge, there was no significant difference in developmental quotient at 2 years of age (71.3 ± 15.1 vs. 78.1 ± 22.6, P = 0.20) between the two groups.
Conclusion: We suggest that EAN reduces the rate of early postnatal weight loss in ELBW infants and contributes to weight gain until full term age.
... Average water loss in term infants is 20-40 mL/kg/day but in infants with gestation age of less than twenty-six weeks, this loss can be over or equal to 200 mL/kg/day. Another factor that contributes towards hypernatremia is nephrogenesis in the neonate which is achieved completely in the neonate at the 34-36 weeks of gestation [20]. In preterm neonates, this means that the kidneys are not fully functional and correlate to a glomerular filtration rate that is pretty low and nephrons that are still immature. ...
The purpose of this study is to distinguish the important risk factors that contribute to intraventricular hemorrhage (IVH) and hypernatremia in early postnatal life of the preterm neonates having extremely low birth weight. The study seeks to find a relationship between the two pathologies in neonates born before term and its relevance in this era and age. Intracerebral hemorrhage ends in the damage of the hypothalamic nuclei, a decrease in the secretion of antidiuretic hormones, and hypernatremia; hence, hypernatremia in preterm neonates with severe IVH may be the conclusion of severe brain damage. Contrary to this, hypernatremia had been shown to cause brain shrinkage. A chronological study would be used to compare both, and the goal is thus, to analyze and form an opinion about the topic on the basis of research in a chronological order.
... The supply of specific amino acids is critical not only for normal embryonic and fetal development during gestation but also during the rapid postnatal growth period (Bell et al., 1987;Thureen et al., 2003;Wu and Morris Jr., 2004;Regnault et al., 2005;Wu et al., 2009;Wu et al., 2013;Lin et al., 2014;Wu et al., 2018). Because Arg interacts with key amino acids in specific ways, RP-Arg supplementation has restored the concentration of many circulating amino acids in restricted ewes to that of control-fed ewes (Zhang et al., 2016). ...
Multiparous Rambouillet ewes (n = 32) were allocated in a completely randomized design to determine if rumen-protected L-arginine (RP-Arg) supplementation during mid- and late gestation would 1) alter maternal carotid artery hemodynamics and 2) affect circulating amino acids associated with arginine metabolism in dams from day 54 of gestation to parturition and in their offspring from birth to 54 d of age. Ewes were assigned to one of three treatments from day 54 ± 3.9 to parturition: control (CON; 100% nutrient requirements), restricted (RES; 60% of CON), and RES plus 180 mg RP-Arg•kg BW-1•d1 (RES-ARG). Ewes were penned individually in a temperature-controlled facility. Carotid artery hemodynamics was measured via Doppler ultrasound at day 50 and 130 of gestation. Maternal serum was collected at day 54 and 138 of gestation and at parturition. At parturition, lambs were immediately removed from their dams and reared independently. Lamb serum samples were collected at birth and 1, 3, 7, 33, and 54 d of age. Pulsatility index was the only hemodynamic measurement altered by dietary treatment, where day 130 measurements were greater (P ≤ 0.04) for RES and RES-ARG compared with CON. The change in pulsatility index was greater (P < 0.01) for RES compared with CON but tended to be intermediate (P ≥ 0.12) for RES-ARG. Maternal serum Arg, Cit, and Asp at day 138 were greater (P < 0.01) for CON compared with RES and RES-ARG; serum Orn at day 138 was greater (P = 0.04) for CON compared with RES. Maternal serum Cit at parturition was greater (P ≤ 0.03) for CON and RES-ARG compared with RES. Offspring serum Arg was affected by a maternal treatment by day of age interaction (P = 0.03), where at day 3, CON and RES-ARG had greater (P ≤ 0.03) serum Arg concentrations than RES, and at day 54, RES-ARG was greater than (P = 0.002) CON and RES was intermediate and did not differ from (P ≥ 0.09) CON and RES-ARG. Offspring serum Orn and Cit were less (P ≤ 0.03) for RES and RES-ARG compared with CON. Results indicate that distal tissue blood perfusion decreased due to maternal RES, and RES-ARG was able to improve perfusion but not to the level of CON ewes. Further, maternal RP-Arg altered offspring Arg and related amino acid concentrations during the postnatal period.
... 41,42 Nutritional management suppresses the increased catabolic state and the subsequent muscle breakdown. 43,44 At present, it is unclear how much energy and protein are required in infants, especially in preterm infants. 45,46 The assessment of sufficient nutrition is difficult to determine. ...
Urinary titin N-fragment levels have been used to assess the catabolic state, and we used this biomarker to evaluate the catabolic state of infants.
We retrospectively measured urinary titin N-fragment levels of urinary samples. The primary outcome was its changes according to postmenstrual age. The secondary outcomes included differences between gestational age, longitudinal change after birth, influence on growth, and relationship with blood tests.
This study included 219 patients with 414 measurements. Urinary titin N-fragment exponentially declined with postmenstrual age. These values were 12.5 (7.1–19.6), 8.1 (5.1–13.0), 12.8 (6.0–21.3), 26.4 (16.4–52.0), and 81.9 (63.3–106.4) pmol/mg creatinine in full, late, moderate, very, and extremely preterm infants, respectively (p < 0.01). After birth, urinary levels of titin N-fragment exponentially declined, and the maximum level within a week was associated with the time to return to birth weight in preterm infants (ρ = 0.39, p < 0.01). This was correlated with creatine kinase in full-term infants (ρ = 0.58, p < 0.01) and with blood urea nitrogen in preterm infants (ρ = 0.50, p < 0.01).
The catabolic state was increased during the early course of the postmenstrual age and early preterm infants.
Catabolic state in infants, especially in preterm infants, was expected to be increased, but no study has clearly verified this.
In this retrospective study of 219 patients with 414 urinary titin measurements, the catabolic state was exponentially elevated during the early postmenstrual age.
The use of the urinary titin N-fragment clarified catabolic state was prominently increased in very and extremely preterm infants.
... And, the maximum amino acid intake was 3.5 (3.2, 3.8) g/kg/d. Clinicians were still not used to initiating PN amino acid at a higher level despite evidence from studies demonstrating the safety of providing higher levels of amino acids as early as the first day of postnatal life [22][23][24][25]. A secondary analysis revealed that ELBW infants who received a minimum of 3 g/kg/d of parenteral amino acid in the first 5 days of life were found to have significantly better growth outcomes [26], suggesting that ELBW infants can tolerate the amino acid dose of 3-3.5 g/kg/d well within the first few days of life. ...
Aim
European Society for Clinical Nutrition and Metabolism released the guidelines on pediatric parenteral nutrition in 2018. We aimed to compare the parenteral nutrition (PN) regimen with the current guidelines, evaluate weight gain and explore the correlation of parenteral macronutrient and energy intakes with weight gain outcome in preterm infants with birth weight less than 1500 g.
Methods
A prospective observational study was conducted. Parenteral macronutrients and energy intakes were described. Weight gain during PN was assessed. Nutritional factors associated with weight gain outcome after PN were identified using a cox proportional hazards model.
Results
A total of 163 infants were included in this study, in which 41 were extremely low birth weight (ELBW) infants and 122 were very low birth weight (VLBW) infants. Average glucose, amino acid, lipid, and energy during the first postnatal week were 7.5 g/kg/d, 2.4 g/kg/d, 0.8 g/kg/d, 48 kcal/kg/d. Median maximum glucose, amino acid, lipid, and energy were 11.1 g/kg/d, 3.5 g/kg/d, 3 g/kg/d, 78 kcal/kg/d. Median days to maximum glucose, amino acid, lipid, and energy were 10, 9, 12, 11 days. The proportion of appropriate for gestational age (AGA) infants was 76.9%. The ratio of infants without poor weight gain outcome after PN was 38%. With every 0.1 g/kg/d decrease of maximum amino acid and average lipid during the first postnatal week, the probability of appropriate weight gain outcome decreased by 77.6 and 74.4% respectively. With each additional day to maximum glucose and energy, the probability of appropriate weight gain outcome decreased by 5.6 and 6.1% respectively.
Conclusions
Most preterm infants with birth weight less than 1500 g remain below the latest recommended nutrition goals. The poor weight gain outcome of these infants after PN is related to insufficient parenteral macronutrient and energy intakes. PN strategies should be improved according to the latest evidence-based recommendations.
... Gut immaturity, congenital and acquired gastrointestinal disorders, which all occur frequently in preterm infants, can preclude enteral feeding necessitating the use of parenteral nutrition. Different centers have differing protocols regarding when to commence and how to advance parenteral nutrition; particularly relating to amino acid delivery (6)(7)(8)(9)(10). Some maintain that parenteral nutrition should be initiated within the first 24 h after birth with high amino acid intake (3.0-3.5 g.kg −1 .d ...
... Our results are in line with the main metabolic role of protein intake in promoting nitrogen retention and increasing protein synthesis [15]. Early amino acid administration could also increase insulin secretion and contribute to greater protein deposition [16]. Several reports have described relations between a low albumin concentration and morbidity and mortality rates in premature neonates [17,18] and in the fasting state, albumin concentrations drop 2-3 g/L in the first 24 h after birth [19]. ...
Background: Several studies have demonstrated that Administration of Amino Acids (AAs) in the first days of life decreases protein losses and maintains a positive nitrogen balance. This study aimed to determine whether high and early doses of intravenous AAs would improve postnatal weight gain and metabolic control in preterm neonates. Method: A prospective matched control trial was conducted in Neonatal Intensive Care Unit (NICU) at Nasser Medical Complex (NMC) in which 68 preterm neonates were matched for birth weight, gestational age and gender and allocated into two groups. The intervention group consisting of 34 neonates received high and early doses of AAs and the control group consisting of 34 neonates received standard dose of AAs. Data were collected at admission to NICU, at day 3 and at day 7. Results: The result reported that within the control group, the mean weight decreased by 94.40 g between admission and 3rd day, decreased by 78.00 g between admission and 7th day, and increased by 16.40 g between 3rd day and 7th day. For the intervention group, the mean weight decreased by 128.79 g between admission and 3rd day, decreased by 83.90 g between admission and 7th day, and increased by 44.88 g between 3rd day and 7th day. The results also showed that neonates from the intervention group had significantly higher levels of total protein, but there were no significant differences in serum albumin. Conclusion: The study concluded that administering of early and high protein to premature neonates could improve protein balance, increase protein accretion and can reduce the duration of hospitalization.
... Early introduction of protein is vital in promoting anabolism. It leads to a larger increase in protein synthesis than the increase in protein breakdown, and results in net protein accretion without substantial side effects [38]. Net protein accretion occurs even in the first day of life and we feel there is no need to postpone introduction of amino acids [39]. ...
One of the most vital elements of management for patients with inborn errors of intermediary metabolism is the promotion of anabolism, the state in which the body builds new components, and avoidance of catabolism, the state in which the body breaks down its own stores for energy. Anabolism is maintained through the provision of a sufficient supply of substrates for energy, as well as critical building blocks of essential amino acids, essential fatty acids, and vitamins for synthetic function and growth. Patients with metabolic diseases are at risk for decompensation during prolonged fasting, which often occurs during illnesses in which enteral intake is compromised. During these times, intravenous nutrition must be supplied to fully meet the specific nutritional needs of the patient. We detail our approach to intravenous management for metabolic patients and its underlying rationale. This generally entails a combination of intravenous glucose and lipid as well as early introduction of protein and essential vitamins. We exemplify the utility of our approach in case studies, as well as scenarios and specific disorders which require a more careful administration of nutritional substrates or a modification of macronutrient ratios.
... Historically, it was believed that premature infants tolerated fluid and calorie restriction without negative long-term effects (177), but in the late 1950s and early 1960s experimental studies showed that early malnutrition permanently affected the growth of organs, including the brain (177,178). Since then, a myriad of studies have investigated the safety and efficacy of the timing of nutrient supply after birth in very preterm infants (143,144,167,(179)(180)(181)(182)(183)(184)(185)(186)(187)(188)(189)(190)(191)(192)(193)(194)(195)(196). Based on this body of evidence, current European guidelines for PN in children advocate early initiation of PN in preterm infants, including 1.5-2.5 g Á kg À1 Á day À1 of amino acids and 1-2 g Á kg À1 Á day À1 of lipids, with a gradual increase to target within a few days (129,149). ...
Objectives:
The nutritional management of critically ill term neonates and preterm infants varies widely, and controversies exist in regard to when to initiate nutrition, mode of feeding, energy requirements, and composition of enteral and parenteral feeds. Recommendations for nutritional support in critical illness are needed.
Methods:
The ESPGHAN Committee on Nutrition (ESPGHAN-CoN) conducted a systematic literature search on nutritional support in critically ill neonates, including studies on basic metabolism. The Medline database and the Cochrane Library were used in the search for relevant publications. The quality of evidence was reviewed and discussed before voting on recommendations, and a consensus of 90% or more was required for the final approval. Important research gaps were also identified.
Results:
This position paper provides clinical recommendations on nutritional support during different phases of critical illness in preterm and term neonates based on available literature and expert opinion.
Conclusion:
Basic research along with adequately powered trials are urgently needed to resolve key uncertainties on metabolism and nutrient requirements in this heterogeneous patient population.
... The beneficial effect of insulin use to prevent severe ROP development therefore remains unclear. Alternative strategies aiming at improving glycemic control in the first weeks of life by stimulating endogenous insulin secretion, such as early provision of sufficient protein intake [39][40][41] and early enteral feeding [41,42], as well as preventing hypophosphatemiawhich is associated with an increased risk of hyperglycemia [43]-may be interesting to explore, possibly in an integrated approach to prevention. ...
Background
Hyperglycemia in preterm infants may be associated with severe retinopathy of prematurity (ROP) and other morbidities. However, it is uncertain which concentration of blood glucose is associated with increased risk of tissue damage, with little consensus on the cutoff level to treat hyperglycemia. The objective of our study was to examine the association between hyperglycemia and severe ROP in premature infants.Methods and findingsIn 2 independent, monocentric cohorts of preterm infants born at
... 21 Studies have confirmed that parenteral nutrition containing 3 g/kg/ day initiated on the first day of life would reduce the postnatal growth restriction and subsequently improve growth and developmental outcomes in infancy and early childhood. 22,23 Despite compliance with reaching the maximum recommended daily allowance of 3-4 g/kg/day of intravenous protein in premature infants to maintain positive nitrogen balance, the non-aggressive protocol in our unit could have contributed to the higher rate of EUGR observed in our infant population. The absence of proper TPN service to provide infants with premixed TPN solutions in addition to the restricted use of intravenous lipid supply to the < 750-g extremely premature infants in our unit plays an important role. ...
Purpose:
To identify the clinical and nutritional factors associated with extrauterine growth restriction (EUGR) among very low birth weight infants (VLBW) in a tertiary hospital in Jordan.
Patients and methods:
We conducted a retrospective analysis of all VLBW infants admitted at King Abdullah University Hospital between July 2015 and June 2020. Clinical factors, nutritional intake, and growth parameters were collected and analyzed. A multilogistic regression model was applied to identify factors associated with EUGR.
Results:
Of the 247 VLBW infants included in analysis, 112 (45%) were males, 30 (12%) were below 1000 g, and 72 (29%) were small for gestational age (SGA). EUGR was diagnosed in 198 (80%) at discharge. The rates of EUGR among SGA and non-SGA infants were 97% and 73%, respectively. The EUGR infants had a higher gestational age (30.7 vs 29.8 weeks, p=0.04), a lower birth weight (1209 vs 1300 g, p=0.005), a longer ventilatory support (5.7 vs 2.2 days, p=0.03), a higher incidence of sepsis (23% vs 10%, p=0.05), and a longer hospitalization (46 vs 38 days, p=0.03). With multilogistic regression model, the factors associated with EUGR include small-for-gestational age (AOR 9, 95% C.I. 2, 50), >3-day delay in feeding initiation (AOR 3.8, 95% C.I. 1.2,10), >14-day delay in achieving full feeds (AOR 3.3, 95% C.I. 1.2, 8), <3 g/kg of protein intake on the 8th day (AOR 2.1, 95% C.I. 1.1, 4.1), <100 kcal/kg of total caloric intake on the 15th day (AOR 3.8, 95% C.I. 1.6, 8.9), and occurrence of sepsis (AOR 3, 95% C.I. 1.1, 9).
Conclusion:
The rate of EUGR in our unit is high. In addition to being SGA at birth, sepsis and suboptimal protein and caloric intake in the first two weeks of life were significantly associated with this complication. A more aggressive enteral and parenteral nutritional approach is needed to minimize postnatal growth delay.
... Historically, preterm infant neurodevelopment has been found to be strongly associated with poor nutrition intakes [1]. In the 1980s, it was common practice to only provide nutrition cautiously and slowly to preterm infants in the early neonatal period due to concerns about potential intolerance [2]. For example, Georgieff et al. observed that preterm infants who had deprived nutrition intakes (<85 kcal/kg/day) had below normal development at 1 year of corrected age [1]. ...
Objective
To assess diagnostic accuracy of 36-week anthropometric weight, length, and head circumference <10th and <3rd percentiles to predict preterm infant cognitive impairment.
Study design
Cohort study of 898 preterm <30-week very-low-birth weight (<1500 g) infants. Anthropometric measures’ accuracy to predict cognitive impairment (Bayley-III Cognitive Composite score) <80, 21-months corrected age (CA) and Wechsler Preschool and Primary Scale of Intelligence Quotient (intellectual outcomes) <70, 36-months CA, were determined using receiver operating characteristic (ROC) curves.
Result
Thirty-six-week weight, length or head circumference <10th or <3rd percentile did not predict cognitive impairment; areas under ROC curves were <0.6. Sensitivities and specificities for 10th and 3rd percentile cut points were all poor, with most not exceeding 70%, whether the Fenton 2013 or INTERGROWTH 2015 growth charts were used. Brain injury and low maternal education were better predictors of cognitive impairment.
Conclusion
Preterm infant 36-week anthropometric measurements are not accurate predictors of cognitive impairment.
... Parenteral amino acid infusion In our study, higher parenteral amino acid intake was associated with lower glucose concentrations. These findings support multiple previous studies, including a meta-analysis, that reported that parenteral amino acid infusion in preterm infants have an insulinogenic glucose-decreasing effect, thereby decreasing the risk for hyperglycemia (76,(122)(123)(124). ...
Background
Survival among very low birth weight (VLBW) and extremely preterm (EPT) infants has increased markedly during the last decades. Neonatal hyperglycemia is common in these infants and is known to be associated with adverse outcomes. However, much about neonatal hyperglycemia is still unknown: which mechanisms are responsible for it, its long-term risk profile, how to treat it and even how to define it. This thesis focuses on neonatal hyperglycemia in preterm-born infants - its prevalence, possible causes (including postnatal nutrition and its possible programming effect of later outcomes), consequences and treatment.
Methods
Two cohorts were studied in this thesis. The EXtremely PREterm infants in Sweden Study (EXPRESS) – a national population-based cohort - included all infants born before completed 27 gestational weeks during the years 2004-2007 in Sweden. Nutritional data as well as glucose measurements (n=9850) and insulin treatment data for the first 28 days of life were obtained for 580 infants. In a sub-cohort of 171 children, blood pressure measurements were obtained at a follow-up visit at 6.5 years of age. Neurodevelopment was assessed at 6.5 years of age in 436 children. Intellectual ability was assessed using Wechsler Intelligence Scale for Children IV (WISC-IV; n=355). Gross and fine motor function were assessed using Movement Assessment Battery for Children 2 (MABC-2; n=345).
The very Low birth weight Infants - Glucose and Hormonal profiles over Time (LIGHT) study was a prospective cohort study that included 50 VLBW infants born in Umeå, Sweden, between 2016-2019. Infants were placed on continuous glucose monitoring (CGM) for a 48-hour period when a postmenstrual age (PMA) of 36 gestational weeks was reached (n=35).
Results
Daily prevalence of hyperglycemia > 10 mmol/L in EPT infants was high during the first two weeks of life (up to 30%), followed by a slow decrease thereafter. Protracted hyperglycemia > 8 mmol/L was detected in more than half of VLBW infants at PMA 36 weeks.
In EPT infants, glucose concentrations during the first 28 days of life were increased by 1.6% on the day following an increase of 1 g/kg/day in parenteral carbohydrate intake. Male sex, amnionitis and prior hypoglycemia and hyperglycemia episodes were risk factors for hyperglycemia at PMA 36 weeks in VLBW infants.
In EPT infants, neonatal hyperglycemia > 10 mmol/L was associated with increased 28-day mortality. Neonatal hyperglycemia, its severity and duration were associated with increased diastolic blood pressure (DBP) and lower MABC-2 scores at 6.5 years of age. Insulin treatment was associated with improved 28- and 70-day survival but not with BP or neurodevelopmental outcomes at 6.5 years of age.
Higher protein intake during the first eight weeks of life was associated with higher DBP at 6.5 years of age. An increase of the carbohydrate intake by 1 g/kg/day during this period was associated with an increase of 0.18 SDS in systolic (SBP) and 0.14 SDS in DBP at 6.5 years. Growth during the same period was not associated with BP at 6.5 years.
Conclusions
Neonatal hyperglycemia during the first four weeks of life was more common in EPT infants than has previously been described. Remaining glucose disturbances were common at PMA 36 weeks in VLBW infants. Parenteral glucose intakes within the range given seems to have had low contribution to glucose concentration variability. Neonatal hyperglycemia was associated with increased 28-day mortality as well as with increased blood pressure and reduced motor skills at 6.5 years of age. Carbohydrate intake in the immediate postnatal period was indepentently associated with increased blood pressure at 6.5 years of age. The results add to the knowledge regarding important risk factors and health effects of neonatal hyperglycemia. Different treatment options for neonatal hyperglycemia should be evaluated in animal models and in randomized controlled clinical trials in premature infants.
... They suggested that decrease in blood glucose might be due to the stimulatory effect of AA on insulin secretion [22]. Thureen and colleagues demonstrated higher insulin concentrations in infants receiving AA at 3 gm/ kg/day compared to those receiving 1 gm/kg/day [23]. Murdock et al. showed that early introduction of AA and lipids lowers serum blood glucose levels [24]. ...
Background
As brain activity depends greatly on the functions provided by lipid membranes, dietary fat in early life can affect the developing nervous system. Despite the adoption of an early more aggressive parenteral nutrition approach with amino acid infusions still reluctance to the early use of intravenous lipids in neonates.
Aim
To compare the effect of delayed versus early introduction of intravenous lipid in preterm on the biochemical parameters and on brain development by the cortical auditory evoked potential (CAEP) latency and amplitude.
Methods
This is a comparative study included 49 neonates admitted at the ain shams university NICUs. Participants were divided into two groups: 26 in group of early lipid infusion and 23 in late lipid infusion, Demographic data, and biochemical parameters were documented during the 1st 2 weeks of life. The CAEP was performed at age of 6 months. The latency and amplitude of P1 were recorded and compared between both groups.
Results
In the present work we found that group of early lipid infusion had reach their full oral intake earlier with shorter duration of parenteral nutrition and length of stay. They had better weight gain and significantly better glucose level control than group of late lipid infusion. There was no significant difference in the other chemical parameters between both groups expect for the higher incidence of cholestasis in the group of late lipid infusion. At 6 months of age, the group of early lipid infusion had significantly shorter latency and amplitude of P1 than the group of late lipid infusion.
Conclusion
Early effective nutrition positively affect feeding tolerance and weight gain and maturation of higher brain centers brain.
Background:
Observational studies in preterm newborns suggest that delay in administering amino acids (AA) could result in a protein catabolic state and impact on growth and development.
Objectives:
The objective of this review was to compare the efficacy and safety of early versus late administration of intravenous AA in neonates born at < 37 weeks of gestation.
Search methods:
We searched CENTRAL, MEDLINE, Embase, and trial registries in March 2023. We checked the reference lists of included studies and studies/systematic reviews where subject matter related to the intervention or population examined in this review.
Selection criteria:
We included randomised controlled trials (RCTs) comparing early administration of AA with late administration in premature newborn infants. We defined early administration of AA solution as the administration of AA in isolation or with total parenteral nutrition within the first 24 hours of birth, and late administration as the administration of AA in isolation or with total parenteral nutrition after the first 24 hours of birth.
Data collection and analysis:
We used standard Cochrane methodological procedures. We used the GRADE approach to assess the certainty of the evidence.
Main results:
Nine studies (383 participants) were eligible for inclusion in the review. All study participants were born at < 37 weeks of gestation and were inpatients in neonatal intensive care units. No studies reported growth during the first months of life as assessed by difference in weight. Early administration of AA may have little or no effect on growth in the first month of life as measured by length (mean difference (MD) 0.00, 95% confidence interval (CI) -0.41 to 0.41; 1 study; 21 participants; low-certainty evidence) and head circumference (MD 0.05, 95% CI -0.03 to 0.14; 2 studies; 87 participants; low-certainty evidence). No studies reported the discharge weight outcome. Early administration of AA may result in little to no difference in neurodevelopmental outcome assessed by Mental Developmental Index (MDI) of < 70 at two years of age (odds ratio 0.83, 95% CI 0.21 to 3.28; 1 study; 111 participants; low-certainty evidence). No studies reported all-cause mortality at 28 days and before discharge. Early administration of AA may result in a large increase in positive nitrogen balance in the first three days of life (MD 250.42, 95% CI 224.91 to 275.93; 4 studies; 93 participants; low-certainty evidence).
Authors' conclusions:
Low-certainty evidence suggests that there may be little to no difference between early and late administration of AA in growth (measured by length and head circumference during the first month after birth) and neurodevelopmental outcome (assessed by MDI of < 70). No RCTs reported on weight in the first month of life, mortality (all-cause mortality at 28 days and before discharge), or discharge weight. Low-certainty evidence suggests a large increase in positive nitrogen balance in preterm infants who received AA within 24 hours of birth. The clinical relevance of this observation is unknown. The number of infants in the RCTs included in the review was small, and there was clinical heterogeneity amongst trials. Adequately powered trials in infants < 37 weeks' gestation are required to determine optimal timing of initiation of AA. We identified two ongoing studies. Both studies will be recruiting infants ≥ 34 weeks of gestation and may or may not add to the outcome data for this review.
Close attention to nutritional management is essential for optimizing growth and neurodevelopment of the preterm infant. Protein intake and the protein to energy ratio are the main determinants of growth and body composition. Yet large, multi-center, randomized controlled trials are lacking to guide protein delivery for the preterm infant. Until these studies are pursued, smaller trials must be used to inform clinical practice. This review summarizes the randomized controlled trials that have been performed to test the impact of higher vs. lower protein delivery to the preterm infant. We consider the trials that varied protein delivery rates during parenteral and enteral phases of nutrition. Considerable heterogeneity exists across study designs. Still, cumulative evidence from these trials provides a framework for current recommendations for protein intake in the preterm infant.
Use of parenteral nutrition (PN) in the neonatal intensive care unit (NICU) requires evaluating the need for central venous catheters, potential drug incompatibilities, unintentional exposures, and suboptimal energy and nutrient intake during the transition to full enteral nutrition. Risks of photooxidation reactions in PN components, refeeding syndrome, and excess early amino acid intake should prompt the reevaluation of routine practices. The goal of this paper is to review the practicalities, challenges, and conundrums of administering PN in the NICU.
Neonatal nutrition has a pivotal role in normal child development and is of even greater importance in the sick or premature neonate. This 2006 edition includes a comprehensive account of the basic science, metabolism and nutritional requirements of the neonate, and a greatly expanded number of chapters dealing in depth with clinical issues ranging from IUGR, intravenous feeding, nutritional therapies for inborn errors of metabolism, and care of the neonatal surgical patient. Evolving from these scientific and clinical aspects, the volume highlights the important long-term effects of fetal and neonatal growth on health in later life. In addition, there are very practical chapters on methods and techniques for assessing nutritional status, body composition, and evaluating metabolic function.
Refeeding syndrome (RS) in preterm infants develops following in‐utero fetal nutrient deprivation, often with coinciding growth restriction. This article is protected by copyright. All rights reserved.
Aim
It is challenging to provide extremely low gestational age neonates (ELGANs) with adequate protein supply. This study aimed to investigate whether amino acid (AA) infusion in the umbilical artery catheter (UAC) in ELGANs is safe and enhances protein supply and growth.
Method
A before and after study including infants born <27 weeks, treated in Uppsala, Sweden, during 2004-2007, compared those receiving normal saline/10% dextrose in water with those receiving AA infusion in the UAC. Data were retrieved from the Extremely Preterm Infants in Sweden Study, hospital records, and the Swedish Neonatal Quality Register. Group comparisons, univariate and multivariate analyses were conducted.
Results
AA group (n=41, females 39%) received on average approximately 0.3 g/kg/day more protein during the first postnatal week, compared to control group (n=30, females 40%) (unstandardised coefficient (B) 0.26, p 0.001) but no difference was noted during 8-28 postnatal days. The type of infusion was not associated with growth variables. The incidence of neonatal morbidities and UAC-related thrombosis did not differ between the groups.
Conclusion
AA infusions in the UACs in ELGANs is safe, and enhances protein supply during the first postnatal week. However, this practice is not associated with growth during the first 28 postnatal days.
Refeeding syndrome (RS) has not been well defined in the neonatal population, although hypophosphatemia is identified as the most common manifestation. The American Society for Parenteral and Enteral Nutrition recently provided recommendations for the prevention and management of RS in children and adults; however, specific neonatal recommendations were not provided. In an effort to provide an overview of the incidence of RS or hypophosphatemia in the neonatal population and the impact of patient-specific and nutrition factors, a review of the literature was conducted. The literature search included articles published in the English language in Medline, PubMed, and EPub between 1946 and December 2020. Relevant citations within identified articles were also reviewed. Sixteen studies representing 3688 neonates were included. There was variation in the incidence of hypophosphatemia (20%–90%), hypokalemia (8.8%–66.7%), and hypomagnesemia (1%–8.3%) between studies. There was significant variability in definitions of hypophosphatemia, patient populations (e.g., gestational age, small for gestational age status, intrauterine growth restriction), and initial nutrition between studies (i.e., initial amino acid intake, calcium and phosphate ratio), proving it difficult to identify the overall incidence of neonatal RS. Clinical outcomes associated with hypophosphatemia identified in the studies included increased duration of mechanical ventilation, development of bronchopulmonary dysplasia, and increased mortality. Vigilant monitoring of serum phosphate, potassium, and magnesium is required in the first week of life. In addition, early addition of phosphate in a 1:1 molar ratio with calcium is recommended in the first week of life for patients who are at greatest risk for RS.
Surgical procedures are not infrequent among patients admitted to regional neonatal intensive care units. Adequate nutrition in the newborn period, especially during times of critical illness and “stress,” is necessary to decrease the morbidity and mortality associated with malnutrition. Additionally, many surgical patients are at risk for long-term growth failure and nutritional deficiencies. This chapter aims to address critical elements in understanding the metabolic stress response and the nutritional management of surgical neonates.
Introduction
Aggressive parenteral nutrition with delivery of high amino acid and energy doses is used to improve growth and neurodevelopmental outcomes in very low birth weight (VLBW) preterm infants. Recent findings, however, suggest that this approach may cause electrolyte imbalances. The aim of our study was to compare the prevalence of hypercalcaemia, hypophosphataemia, and hypokalaemia in 2 groups of preterm infants that received parenteral nutrition with different amounts of amino acids and to analyse perinatal and nutritional variables associated with the development of electrolyte imbalances.
Methods
We conducted a retrospective observational study comparing 2 groups of preterm infants born before 33 weeks’ gestation with birth weights of less than 1500 g managed with parenteral nutrition. One of the groups received less than 3 g/kg/day of amino acids and the other received 3 g/kg//day of amino acids or more. We analysed the prevalence of electrolyte imbalances and possible associations with aggressive parenteral nutrition, adjusting for potential confounders.
Results
We studied 114 infants: 60 given less than 3 g/kg/day of amino acids (low-intake group) and 54 given at least 3 g/kg/day (high-intake group). The prevalence of electrolyte imbalances was similar in both groups. The prevalence of hypercalcaemia was 1.67% in the low-intake group and 1.85% in the high-intake group (P > .99), the prevalence of severe hypophosphataemia 11.7% vs 9.3%, and the prevalence of hypokalaemia 15.0% vs 11.1% (P > .99). A calcium to phosphorus ratio greater than 1.05 had a protective effect against hypophosphataemia (P = .007).
Conclusions
We did not find an association between hypercalcaemia, hypophosphataemia, and hypokalaemia and the amino acid dose delivered by PN in the high-intake group of preterm infants.
Introduction:
Aggressive parenteral nutrition with delivery of high amino acid and energy doses is used to improve growth and neurodevelopmental outcomes in very low birth weight (VLBW) preterm infants. Recent findings, however, suggest that this approach may cause electrolyte imbalances. The aim of our study was to compare the prevalence of hypercalcaemia, hypophosphataemia, and hypokalaemia in 2 groups of preterm infants that received parenteral nutrition with different amounts of amino acids and to analyse perinatal and nutritional variables associated with the development of electrolyte imbalances.
Methods:
We conducted a retrospective observational study comparing 2 groups of preterm infants born before 33 weeks' gestation with birth weights of less than 1,500 g managed with parenteral nutrition. One of the groups received less than 3 g/kg/day of amino acids and the other received 3 g/kg/day of amino acids or more. We analysed the prevalence of electrolyte imbalances and possible associations with aggressive parenteral nutrition, adjusting for potential confounders.
Results:
We studied 114 infants: 60 given less than 3 g/kg/day of amino acids (low-intake group) and 54 given at least 3 g/kg/day (high-intake group). The prevalence of electrolyte imbalances was similar in both groups. The prevalence of hypercalcaemia was 1.67% in the low-intake group and 1.85% in the high-intake group (p > .99), the prevalence of severe hypophosphataemia 11.7 vs. 9.3%, and the prevalence of hypokalaemia 15.0 vs. 11.1% (p > .99). A calcium to phosphorus ratio greater than 1.05 had a protective effect against hypophosphataemia (p = .007).
Conclusions:
We did not find any association between hypercalcemia, hypophosphatemia, and hypokalemia and amino acid intake by PN in the population of premature infants with quite high amino acid intake values.
Background:
Branched-chain amino acids (BCAAs) play a vital role in neonatal nutrition. Optimal BCAA supplementation might improve neonatal nutrient storage, leading to better physical and neurological development and other outcomes.
Objectives:
To determine the effect of BCAA supplementation on physical growth and neurological development in term and preterm neonates. We planned to make the following comparisons: parenteral nutrition with and without BCAA supplementation; enteral BCAA supplementation versus no supplementation; and any type of supplementation including enteral, parenteral and both ways versus no supplementation. To investigate the supplementation effectiveness for different dosages assessed in the eligible trials.
Search methods:
We conducted comprehensive searches using Cochrane Neonatal's standard search strategies: Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 6), MEDLINE, Embase and CINAHL (up to July 2016). We updated the search with CENTRAL (2019, Issue 8), MEDLINE, Embase and CINAHL (up to August 2019). We also searched clinical trials registries and reference lists of retrieved articles.
Selection criteria:
We planned to include individual and cluster-randomised and quasi-randomised controlled trials comparing BCAA supplementation versus placebo or no supplementation in term and preterm neonates. We excluded trials presented only as abstracts and cross-over trials.
Data collection and analysis:
Two review authors independently assessed the eligibility of all potential studies identified from the search strategy. We planned to extract data using a pilot-tested standard data extraction form and assess risk of bias of the included studies following the methods described in the Cochrane Handbook for Systematic Reviews of Interventions. We planned to analyse treatment effects and report their effect estimates as per dichotomous or continuous data with 95% confidence intervals. We planned to conduct subgroup analysis to investigate heterogeneity, and perform sensitivity analysis where possible. We planned to use fixed-effect meta-analysis to combine data wherever appropriate. We planned to assess evidence quality using the GRADE approach.
Main results:
We did not identify any potentially eligible studies that met the inclusion criteria in this review.
Authors' conclusions:
We found no trial data to support or refute the idea that BCAA supplementation affects physical and neurological development and other outcomes in term and preterm neonates.
Background
The concept of parental nutritional care for premature infants has been applied and advanced over the past decade. This study compared the clinical outcomes before and after nutrition practice (NP) implementation and evaluated the effects of implementation on growth velocity and weight gain in premature infants.
Methods
Descriptive data of premature infants (gestational age < 30 weeks; body weight ≤ 1250 g) born 4 years before and after NP implementation were retrospectively reviewed in a neonatal intensive care unit at a hospital in Taiwan. Nutrient intake, growth velocity, weight gain, and nutrition-related biochemical markers were compared at weeks 1, 2, and 4 after delivery.
Results
A total of 77 premature infants were enrolled before NP implementation (non-NP group), whereas 89 were enrolled after implementation (NP group). The non-NP group consumed less fat and energy in week 1, and less protein, fat, and energy in weeks 2 and 4 compared with the NP group. Growth velocity was slower in the non-NP group. Fat intake was significantly positively correlated with body weight at week 4 in the non-NP group. However, protein and fat intake were significantly associated with body weight at week 1, fat and energy intakes were significantly associated with body weight at week 2, and fat intake was significantly associated with body weight at week 4 in the NP group.
Conclusion
These findings indicate that the NP implemented in this study is relatively safe and can improve growth velocity and body weight gain in premature infants.
Background
Blood urea is considered a marker of amino acid utilization in preterm infants on routine parenteral nutrition. However, the association between blood urea and intravenous amino acid intake remains debated.
Aims
To evaluate the association between blood urea and both nutrition and clinical data, in a large cohort of preterm infants.
Subjects
and methods: Consecutively admitted preterm infants with a gestational age of less than 32 weeks and a birth weight lower than 1250 g on routine parenteral nutrition from the first hour of life were studied. Clinical and nutrition data collected hourly during the hospitalization were used in multiple linear regression analysis.
Results
We studied 674 patients and 1863 blood urea determinations. Blood urea concentration was positively associated with blood creatinine concentration, intravenous amino acid intake, patent ductus arteriosus and respiratory distress syndrome, and negatively associated with intravenous non-protein energy intakes, daily weight change, gestational age, being small for gestational age, antenatal steroids therapy and reverse flow in the umbilical artery (p<0.001; R=0.7).
Conclusions
From a nutrition perspective, in our large cohort of small preterm infants blood urea was positively correlated with intravenous amino acid intake and negatively correlated with intravenous non-protein energy intake. This is in line with current knowledge in human physiology and suggest that a reduction of intravenous amino acid intake based on blood urea concentrations was justified.
Background
Postnatal growth failure (PGF) in very low birthweight (VLBW) infants is a result of factors such as prematurity, acute illness and suboptimal nutritional support. Before this project began, 84% of appropriately grown VLBW infants in our neonatal intensive care unit experienced PGF. The aims of this quality improvement project were to reduce the percentage of infants discharged with PGF to less than 50% within 2 years and to maintain a rate of PGF under 50%.
Methods
All inborn VLBW infants were eligible for this study. Infants with congenital anomalies were excluded. We determined key drivers for optimal nutrition and identified potentially better practices (process measures) based on a review of the literature, which included more rapid initiation of starter total parenteral nutrition (TPN), aggressive use and advancement of regular TPN, and fortification of human milk when the volume of intake reached 80 mL/kg/day. Three Plan-Do-Study-Act (PDSA) cycles were tested.
Results
Time to initiation of starter TPN was significantly reduced from 5.5 hours to under 3 hours. Regular TPN provided the goals for amino acids and lipids at increased frequency after the first two PDSA cycles. The proportion of infants whose milk was fortified at 80 mL/kg/day increased after the third PDSA cycle.
Conclusions
We found a sustained decrease in the percentage of infants discharged with PGF from 84% at baseline to fewer than 50% beginning in 2010–2011 through 2016, with 23.1% of infants experiencing PGF in 2016. We have achieved improved nutritional support for VLBW infants using the model for improvement.
Background: Prematurity is the most important cause of mortality in Under-5 children responsible for one million deaths/ year. Premature babies are not able to store enough nutrients for their optimal survival; it is essential to provide them total parenteral nutrition. Intravenous lipid infusion in neonates is linked with high risk of sepsis and thrombocytopenia. PN with amino acids and glucose can be imparted to achieve nutritional goal. This trial was intended to assess the effects of various components of amino acid PN on postnatal growth in VLBW and ELBW newborns.Methods: A prospective observational study was conducted from January 2018 - May 2019 in NICU of TMMC and RC which included preterm newborns with birth weight of less than 1500gms who received aminoven infusion. Anthropometric measurements, incidence of hypo/hypercalcaemia, hypo/hyperglycaemia, direct hyperbilirubinemia, incidence of sepsis were evaluated.Results: Out of 22 patients, 12 neonates received high dose aminoven therapy whereas 10 neonates received low dose aminoven therapy. It was seen that rapid rate of increment of amino acids had adequate weight on discharge, 72.72% have adequate growth among the rapid group compared to 36.36% among slower group. No significant changes in calcium metabolism or glucose metabolism were seen in both the groups.Conclusions: In resource limited settings, parenteral nutrition with intravenous amino acids have a better effect on the weight of preterm newborns at discharge when high doses of amino acids infusion started early with rapid increment in the dose.
Z GİRİŞ ve AMAÇ: Prematüre bebeklerde yüksek miktarda proteinin ilk gün başlanması ile büyüme ve nöromotor gelişimin olumlu etkilendiği bildirilmiştir. Ancak yüksek protein miktarının biyokimyasal parametreler üzerine etkisi tam olarak bilinmemektedir. Bu çalışmada prematüre bebeklerde düşük ve yüksek doz protein uygulamasının biyokimyasal parametreler üzerine olan etkisinin araştırılması amaçlanmıştır. YÖNTEM ve GEREÇLER: Bu retrospektif çalışmaya 34 hafta ve altında doğan prematüre bebekler dahil edildi. Olgular düşük (DP; ilk gün 1 g/kg/gün, günlük 1 g arttırarak maksimum 3 g/kg/gün) ve yüksek protein (YP; ilk gün 3 g/kg/gün, maksimum 3,5-4 g/kg/gün) alımlarına göre iki gruba ayrılarak antenatal ve postanatal özellikler, biyokimyasal sonuçlar ve büyüme gelişmeleri bakımından karşılaştırıldı. BULGULAR: YP grubunda 264, DP grubunda 100 olmak üzere çalışmaya toplam 364 hasta alındı. Biyokimyasal belirteçler bakımından gruplar karşılaştırıldığında; YP grubundaki olgularda kan üre azotu değerlerinin, protein alımı ile korele olarak arttığı görüldü, ancak böbrek fonksiyonlarında bozulma saptanmadı. Her iki grupta elektrolit bozukluğu açısından anlamlı farklılık gözlenmedi. YP grubu ile karşılaştırıldığında, DP grubunda ki olguların taburculuktaki ağırlık, boy ve baş çevresi persentillerinin daha fazla oranda 3 persentilin altında olduğu saptandı.
Objective:
To study whether there is an association between nutritional intake during the first week of life and severity of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants.
Methods:
In a retrospective cohort study, medical records of all ELBW infants admitted to our Neonatal Intensive Care Unit (2010-2017) were reviewed for infants' demographics, clinical characteristics, nutritional intake during their first week of life, and BPD risk factors.
Results:
During the study period 226 infants were identified of whom 67% (151/226) had moderate-severe BPD and the rest served as controls. Overall infants with moderate-severe BPD were younger, smaller, and spent more time on mechanical ventilation than their controls [(mean±standard deviation) 24.7±1.7 vs. 26.8±2.0 weeks gestational age (p < 0.001); 678±154 vs. 837±129 grams (p < 0.001); and 37.9±23.6 vs. 13.7±15.3 days (p < 0.001) respectively]. During the first week of life, the average caloric, carbohydrate, protein and lipid intakes were significantly lower, and the average fluid intake was significantly higher in the moderate-severe BPD than the control group. After adjustment for confounders, fluid intake, and days on mechanical ventilation were significantly associated with moderate-severe BPD with an odds ratio [OR (95% confidence interval)] of 1.03 (1.01-1.04), and 1.05 (1.03-1.07) respectively. Low caloric intake was associated with an increased risk for moderate-severe BPD [OR: 0.94 (0.91-0.97)].
Conclusion:
Low caloric intake, and high fluid intake during the first week of life are associated with the severity of BPD in ELBW infants.
We investigated the extent to which the altered weight gain of rat pups suckled in litters of varying sizes (4, 10, and 16 pups/litter) is attributable to differences in milk nutrient intake. Milk intake was estimated from the rate of dilution over 2 days of a dose of 3H2O administered at 4, 8, and 14 days of age after correction for the water and milk carbon deposited in body tissues over the measurement period. Protein and energy intakes were estimated from the volume of milk consumed by individual pups and the composition of milk from each dam. Significant effects of litter size on milk fat and protein concentration were observed. Weight gain was highly correlated with energy intake in pups suckled in litters of 4 and 10 but not 16. These findings were attributed to a higher energy expenditure of pups less than 10 days old suckled in litters of 16; specifically these pups had higher maintenance energy needs than pups suckled in litters of 4 and 10 and a higher energy cost of tissue synthesis. The latter was ascribed to an ability of immature pups to maximize the efficiency of protein utilization, thereby blunting the deleterious effects of a reduced nutrient intake on protein deposition.
Serial 24 hour balance studies of nitrogen and energy were carried out over 10 days in two groups of ventilator dependent preterm infants, of comparable weight and gestational age. In one group (n = 10) a parenteral amino acid source (Vamin 9) was started within 24 hours of birth, and in the other group (n = 11) it was not started until 72 hours. The feeding protocol was otherwise identical. The nitrogen intake (286 compared with 21 mg/kg/day), energy intake (188 compared with 151 kJ), and nitrogen retention (120 compared with -133 mg/kg/day), were all significantly higher during the first three days of life in the group in which the amino acid solution was started early. There were no differences by 7-10 days. The early introduction of amino acids improves the early nutritional state of sick preterm infants.
We examined the effect of insulin and plasma amino acid concentrations on leucine kinetics in 15 healthy volunteers (age 22 +/- 2 yr) using the euglycemic insulin clamp technique and an infusion of [1-14C]leucine. Four different experimental conditions were examined: (a) study one, high insulin with reduced plasma amino acid concentrations; (b) study two, high insulin with maintenance of basal plasma amino acid concentrations; (c) study three, high insulin with elevated plasma amino acid concentrations; and (d) study four, basal insulin with elevated plasma amino acid concentrations. Data were analyzed using both the plasma leucine and alpha-ketoisocaproate (the alpha-ketoacid of leucine) specific activities. In study one total leucine flux, leucine oxidation, and nonoxidative leucine disposal (an index of whole body protein synthesis) all decreased (P less than 0.01) regardless of the isotope model utilized. In study two leucine flux did not change, while leucine oxidation increased (P less than 0.01) and nonoxidative leucine disposal was maintained at the basal rate; endogenous leucine flux (an index of whole body protein degradation) decreased (P less than 0.01). In study three total leucine flux, leucine oxidation, and nonoxidative leucine disposal all increased significantly (P less than 0.01). In study four total leucine flux, leucine oxidation, and nonoxidative leucine disposal all increased (P less than 0.001), while endogenous leucine flux decreased (P less than 0.001). We conclude that: (a) hyperinsulinemia alone decreases plasma leucine concentration and inhibits endogenous leucine flux (protein breakdown), leucine oxidation, and nonoxidative leucine disposal (protein synthesis); (b) hyperaminoacidemia, whether in combination with hyperinsulinemia or with maintained basal insulin levels decreases endogenous leucine flux and stimulates both leucine oxidation and nonoxidative leucine disposal.
1. The effects of meal consumption on plasma leucine and alanine kinetics were studied using a simultaneous, primed, continuous infusion of L-[I- ¹³ C]leucine and L-[3,3,3- ² H 3 ]alanine in four healthy, young, adult male subjects. The study included an evaluation of the effect of sampling site on plasma amino acid kinetics, with blood being drawn simultaneously from an antecubital and dorsal heated hand vein.
2. In comparison with the postabsorptive state, the ingestion of small hourly meals resulted in a 35% increase in plasma leucine flux and a 77% increase in leucine oxidation. Calculated entry of leucine into the plasma compartment from endogenous sources decreased by 65%. Plasma alanine flux more than doubled, indicating a significant enhancement in de now alanine synthesis. ¹³ C enrichment of leucine in venous and arterialized plasma did not differ significantly, but alanine flux calculated from isotopic measurement in venous plasma was substantially greater than that based on analysis of arterialized blood plasma.
1. Measurements have been made of whole-body and skeletal muscle protein synthesis in fed and fasted adults with l-[1-13C]leucine.
2. The marked increase in whole-body synthesis on feeding largely reflects the changes in protein synthesis in muscle, which doubles on feeding, compared with a 40% increase in that of the rest of the body.
3. Skeletal muscle in fed man contributes more than half to total protein synthesis occurring in the whole body.
To assess the response of protein turnover to graded levels of amino acid (AA) intakes, leucine kinetics were determined in six 8- to 16-yr-old patients in a stable nutritional status receiving home parenteral nutrition (PN) for short-bowel syndrome or intestinal pseudo-obstruction syndrome. Although daily energy intake was kept constant at 68.7 +/- 13 kcal/kg lean body mass (LBM) with 25.4 +/- 3.6% lipid, patients were given, for three consecutive 7-day periods, 0.7, 1.5, or 2.5 g AA.kg LBM-1.day-1, with the order of the regimens being randomized. On day 7 of each period, a 4-h infusion of L-[1-13C]leucine was performed during intravenous feeding; plasma [13C]ketoisocaproate and expired 13CO2 enrichments were used to assess whole body leucine turnover (Ra), oxidation rate (Ox), nonoxidative disposal [an estimate of protein synthesis (S)], and leucine derived from protein breakdown (B). Urine collection (24 h) was performed for determination of nitrogen excretion. Results indicate a dose-dependent rise in plasma leucine concentration, Ra, and Ox but no significant change in B. There was a significant increase of S (P = 0.04 analysis of variance) with increased AA intakes as well as net leucine balance (P = 0.02). Results are consistent with improved leucine balance, when leucine intake increases, despite increased leucine oxidation. The net protein gain observed with higher AA intakes may suggest a beneficial effect for children receiving long-term PN.
To determine to what extent intravenous nutrition can reduce proteolysis in very immature and normal newborns, and to assess the capacity of preterm and normal newborns to convert phenylalanine to tyrosine, phenylalanine and leucine kinetics were measured under basal conditions and during parenteral nutrition in clinically stable, extremely premature (approximately 26 wk of gestation) infants and in normal term newborns. In response to parenteral nutrition, there was significantly less suppression (P < 0.001) of endogenous leucine and phenylalanine rate of appearance in extremely premature infants compared with term infants. Phenylalanine utilization for protein synthesis during parenteral nutrition increased significantly (P < 0.01) and by the same magnitude (approximately 15%) in both extremely premature and term infants. Phenylalanine was converted to tyrosine at substantial rates in both extremely premature and term infants; however, this conversion rate was significantly higher (P < 0.05) in extremely premature infants during both the basal and parenteral nutrition periods. These data provide clear evidence that there is no immaturity in the phenylalanine hydroxylation pathway. Furthermore, although parenteral nutrition appears to produce similar increases in protein synthesis in extremely premature and term infants, proteolysis is suppressed much less in extremely premature newborns. The factors responsible for this apparent resistance to suppression of proteolysis in the very immature newborn remain to be elucidated.
Protein intake is frequently delayed in ill neonates because of concerns about their ability to metabolize substrates.
We aimed to determine the factors affecting protein balance in ventilated, parenterally fed newborns during the first week of life.
Leucine kinetic studies were performed in 19 neonates by using the [1-(13)C]leucine tracer technique after 24 h of a stable total parenteral nutrition (TPN) regimen. TPN intakes were prescribed by rotating attending physicians, enabling assessment of protein metabolism over a range of clinically used nutrient intakes.
Mean (+/-SD) birth weight was 1.497 +/- 0.779 kg, gestational age at birth was 30.3 +/- 4.0 wk, and age at study was 3.9 +/- 1.4 d. Amino acid intakes (AAIs) ranged from 0.0 to 2.9 g x kg(-1) x d(-1). Based on leucine kinetic data, protein balance was calculated as the difference between protein synthesis and catabolism. By multiple regression analysis, AAI was the only predictor associated independently with protein balance (P < 0.01); energy intake, lipid intake, glucose intake, birth weight, and gestational age were not. Both leucine oxidation and nonoxidative leucine disposal rates were significantly correlated with leucine intake (P < 0.0005 and P < 0.01, respectively). Of the 12 infants with AAIs > 1 g x kg(-1) x d(-1), only 1 infant was significantly catabolic (protein balance <-1 g x kg(-1) x d(-1)). There was no evidence of protein intolerance as determined by elevated creatinine (69 +/- 31 micromol/L), plasma urea nitrogen (6.7 +/- 2.53 mmol/L), or metabolic acidosis (pH: 7.36 +/- 0.05).
Ill neonates can achieve a positive protein balance in the first days of life without laboratory evidence of protein toxicity.
To study sequentially the effect of meal feeding and the effect of protein source and quantity on whole-body protein metabolism, 12 elderly women consumed 3 diets differing in both the quantity and source of protein (diet A: 5.3% of energy intake provided by animal protein and 5.0% by vegetable protein; diet B: 14.5% of energy provided by animal protein and 5.1% by vegetable protein; diet C: 5.0% of energy provided by animal protein and 15.1% by vegetable protein). The diets were consumed for 2 wk with a 2-wk interval between diets. At the end of each dietary period, nitrogen balance and protein turnover were measured. Protein turnover was measured during 4 h of fasting followed by 4 h of feeding. Comparisons were made between fasted and fed periods (within one diet) and between the diets to study the effect of the protein source and quantity. Mean nitrogen balance did not differ significantly from zero during diets B and C and was not affected by the protein source. Meal feeding resulted in increased protein flux and protein oxidation and decreased protein breakdown compared with the postabsorptive values; there was no effect of feeding on protein synthesis. With the high-vegetable-protein diet, protein breakdown in the absorptive state was not inhibited to the same extent as during the high-animal-protein diet, resulting in less net protein synthesis during the high-vegetable-protein diet than during the high-animal-protein diet.
The interpretation of growth rates for very low birth weight infants is obscured by limited data, recent changes in perinatal care, and the uncertain effects of multiple therapies.
To develop contemporary postnatal growth curves for very low birth weight preterm infants and to relate growth velocity to birth weight, nutritional practices, fetal growth status (small- or appropriate-for-gestational-age), and major neonatal morbidities (chronic lung disease, nosocomial infection or late-onset infection, severe intraventricular hemorrhage, and necrotizing enterocolitis).
Large, multicenter, prospective cohort study.
Growth was prospectively assessed for 1660 infants with birth weights between 501 to 1500 g admitted by 24 hours of age to 1 of the 12 National Institute of Child Health and Human Development Neonatal Research Network centers between August 31, 1994 and August 9, 1995. Infants were included if they survived >7 days (168 hours) and were free of major congenital anomalies. Anthropometric measures (body weight, length, head circumference, and midarm circumference) were performed from birth until discharge, transfer, death, age 120 days, or a body weight of 2000 g. To obtain representative data, nutritional practices were not altered by the study protocol.
Postnatal growth curves suitable for clinical and research use were constructed for body weight, length, head circumference, and midarm circumference. Once birth weight was regained, weight gain (14.4-16.1 g/kg/d) approximated intrauterine rates. However, at hospital discharge, most infants born between 24 and 29 weeks of gestation had not achieved the median birth weight of the reference fetus at the same postmenstrual age. Gestational age, race, and gender had no effect on growth within 100-g birth weight strata. Appropriate-for-gestational age infants who survived to hospital discharge without developing chronic lung disease, severe intraventricular hemorrhage, necrotizing enterocolitis, or late onset-sepsis gained weight faster than comparable infants with those morbidities. More rapid weight gain was also associated with a shorter duration of parenteral nutrition providing at least 75% of the total daily fluid volume, an earlier age at the initiation of enteral feedings, and an earlier age at achievement of full enteral feedings.
These growth curves may be used to better understand postnatal growth, to help identify infants developing illnesses affecting growth, and to aid in the design of future research. They should not be taken as optimal. Randomized clinical trials should be performed to evaluate whether different nutritional management practices will permit birth weight to be regained earlier and result in more rapid growth, more appropriate body composition, and improved short- and long-term outcomes.
A controlled study comparing two intravenous fluid regimens was performed in sick, premature infants. The regimens were isocaloric at 60 calories/kg/day, one providing glucose alone, the other glucose plus 2.5 gm/kg of amino acids. There was no difference in changes in body weight between the two groups; infants receiving glucose alone were in negative nitrogen balance; those receiving glucose plus amino acids were in positive nitrogen balance. Plasma amino acid values were compared to published, postprandial normal values. The TEAA and TAA of infants receiving amino acids were not different from normal. Values of TEAA and TAA of infants receiving glucose alone were significantly lower. Essential fatty acid deficiency developed in infants receiving amino acids but not in those receiving glucose alone. It is concluded that the glucose plus amino acid regimen results in anabolism without undue metabolic costs.
34 preterm infants with birthweights < 1200 g were randomly assigned to total parenteral nutrition (TPN) or oral (Milk) feeding regimens for the first 2 weeks after birth. Infants in the TPN group were started on a modified Vamin-based glucose amino-acid infusion and Intralipid. The daily amounts of carbohydrate, amino-acids, and fat infusions were increased. In the Milk group, infants were started on intermittent gavage feeding, supplemented with a glucose-electrolyte infusion as necessary. The overall mortality rate did not differ in the two groups. Four infants in the Milk group developed necrotising enterocolitis but none did in the TPN group. Despite mean daily energy intakes which were not greatly different, there were much higher mean daily intakes of carbohydrate and protein in the TPN group compared with the Milk group. Fat intake in the TPN group was lower than in the Milk group in the 1st week because of neonatal jaundice which contraindicated the use of Intralipid. There was no difference in the mean daily fat intake by the 2nd week. Although mean daily weight loss in the 1st week and the maximum postnatal weight loss in the two groups were similar, infants in the TPN group had a greater mean daily weight gain in the 2nd week and took less time to regain and maintain birthweight. Metabolic complications were equally common in both groups and were reversible with early recognition. Limits of tolerance for water and most nutrients tended to be variable and the nutritional programme had to be adjusted for each baby. Nevertheless, we found that TPN, when properly managed, is an effective and safe procedure in very low birthweight infants.
We have described a technique whereby the time necessary to reach an equilibrium enrichment of expired CO2 during a primed-constant infusion of [U-13C]glucose was shortened from 7 to 8 h to 1 hour or less. We applied the theory of the primed-constant infusion technique to the bicarbonate pool, with the "constant infusion" of labeled carbon dioxide originating from oxidation of the infused [13C]glucose rather than from a labeled infusion of bicarbonate.
1. We investigated the effects of starting amino acid administration on post-natal day 2 on protein turnover and nitrogen balance in appropriate-for-gestational-age, very-low-birth-weight infants. Eighteen infants were divided into two groups. Group A received from day 2 onwards an amino acid solution, whereas group B started on this solution after day 4. Both groups were exclusively parenterally fed, 200 kJ day−1 kg−1 on post-natal days 3 and 4. Group A (birth weight 1.5 ± 0.3 kg) received 4.6 g of glucose, 1.9 g of fat and 2.3 g of amino acids day−1 kg−1 body weight. Group B (birth weight 1.4 ± 0.2 kg) received 7.0 g of glucose and 1.9 g of fat day−1 kg−1 body weight.
2. At post-natal day 3, a primed constant infusion of 3 mg of [15N]glycine day−1 kg−1 was given. Protein flux, protein synthesis and protein breakdown were calculated from the 15N enrichment in urinary ammonia. In five out of nine infants in group B no plateau of 15N enrichment in urinary urea could be detected, whereas in group A two out of nine infants did not reach a plateau. For this reason we did not use the end product urea for our calculations.
3. The administration of the amino acids resulted in a higher protein flux (6.9 ± 1.5 g day−1 kg−1 versus 5.2 ± 0.9 g day−1 kg−1) and a higher protein synthesis rate (6.0 ± 1.4 g day−1 kg−1 versus 4.6 ± 0.8 g day−1 kg−1) in group A. There was no statistically significant difference in protein breakdown. The administration of amino acids reversed a negative protein balance (−0.6 ± 0.2 g day−1 kg−1) into a positive one (1.4 ± 0.2 g day−1 kg−1. No adverse effects of the amino acid infusion were seen.
4. We conclude that the early introduction of amino acids has, even at this relatively low energy intake of 200 kJ day−1 kg−1, a positive effect on protein balance by increasing protein synthesis.
Severity-of-illness scales have proven valuable in assessing clinical outcomes and resource consumption in adult and pediatric intensive care, but they have been less extensively developed for neonatal care. The National Therapeutic Intervention Scoring System (NTISS) was created by modifying the Therapeutic Intervention Scoring System (TISS). From the 76 original TISS items, 42 were deleted and 28 added to form the NTISS. Like TISS, NTISS assigns score points from 1 to 4 for various intensive care therapies. Admission-day NTISS scores were calculated for 1643 newborns admitted to three neonatal intensive care units (NICUs) between November 1, 1989, and September 30, 1990. NTISS scores ranged from 0 to 47 with a mean of 12.3 +/- 8.7 (SD). There was little correlation with birth weight (r = -.11) or gestational age (r = -.17), but NTISS scores were highly correlated with expected markers of illness severity, including mortality risk estimates by neonatal attending physicians (r = .70, P < .0001), in-hospital mortality rates (P < .05), and a measure of nursing acuity (Medicus) (r = .69, P < .0001). In addition, admission-day NTISS scores were found to be predictive of both NICU length of stay (r = .37, P < .0001) and total hospital charges for survivors (r = .65, P < .0001). It is concluded that NTISS is a valid measure of therapeutic intensity that is independent of birth weight and can be used as an indicator of neonatal illness severity and resource utilization. Further validation in other NICUs is required.
To examine how leucine and protein metabolism is affected by feeding, leucine kinetics were determined in 11 normal term newborns during feeding using a prime constant tracer infusion of 1-13C leucine combined with respiratory calorimetry. Fed newborns were compared with previously studied fasting newborns. Feeding and fasting newborns had similar rates of leucine oxidation (34 +/- 3 mumol/kg/h versus 31 +/- 4 mumol/kg/h) and leucine release from existing protein (156 +/- 16 mumol/kg/h versus 164 +/- 8 mumol/kg/h). In contrast, nonoxidative disposal rates of leucine (a reflection of protein synthesis) were significantly greater in feeding newborns (170 +/- 13 mumol/kg/h versus 129 +/- 9 mumol/kg/h). A significant positive correlation between birth weight and leucine flux was demonstrated in both feeding and fasting newborns. These results suggest that 1) newborns may accomplish protein accretion primarily by increases in protein synthesis rather than suppression of protein breakdown; 2) an estimate can be made of the minimal leucine intake required to replace irreversible leucine oxidative losses (816 mumol/kg/d, 107 mg/kg/d); and 3) the positive correlation between birth weight and leucine flux in both feeding and fasting newborns may be a result of differences in previous protein and energy supplies.
The length vs. active force relationship (L-F) may provide information about changes in smooth muscle contractile protein interactions as muscle length changes. To characterize the L-F in single toad stomach smooth muscle cells, cells were attached to a force measurement system, electrically stimulated, and isometric force and elastic modulus (an estimate of the number of attached cross bridges) determined at different cell lengths. Cells generated maximum stress (Pmax = 152.5 mN/mm2) and elastic modulus (Eact = 0.68 x 10(4) mN/mm2) at their rest length (Lcell = 78.0 microns; distance between cell attachments). At shorter lengths, active force and elastic modulus declined proportionally with active force eliminated at 0.4 Lcell. Stretching the relaxed cells up to 1.4 Lcell shifted the subsequent L-F along the length axis by the amount of the stretch but did not change Pmax or the shape of the L-F. In activated cells, force was a function of cell length rather than of shortening history. We interpret these findings as evidence that 1) Lcell is close to the optimum length for force generation, 2) the decline in force at lengths less than Lcell results from a reduced number of attached cross bridges, and 3) stretching relaxed smooth muscle cells may not move the contractile units to new positions on their L-F.
During the first few days of life, the ill premature infant is usually subjected to acute semistarvation because the provision of nutritional support is considered cumbersome and unnecessary. However, the absence of readily recognizable adverse effects of semistarvation does not rule out the existence of significant short-term adverse effects, nor does it rule out possible adverse sequelae in the long run. Similar concerns pertain to the later neonatal period, during which nutritional deprivation is less severe but of longer duration. Evidence is presented that qualitative malnutrition, characterized by inadequate intake of protein and relatively excessive intake of energy, is common with current feeding regimens and is responsible for increased body fat deposition in growing small premature infants.
The reliability of shorter nitrogen balance determinations was evaluated in order to facilitate the nutritional assessment of parenterally fed infants. The intraindividual day-to-day variations of nitrogen intake, excretion, and retention were analyzed in 23 parenterally fed newborn infants (birth weight: 785-2630 g). Nitrogen retentions measured over 3 consecutive days were highly correlated (r = 0.90-0.96), and the reliability for a single 24-hr collection was estimated by r1 = 0.93. Nitrogen balance data obtained over a 24-hr period are reliable for the purpose of clinical investigations, provided the nutrient intake is constant.
Fetal plasma amino acid concentrations were obtained by cordocentesis at midgestation in 11 normal (appropriate for gestational age) fetuses and at late gestation in 12 small-for-gestational-age fetuses, and at cesarean section in 14 normal term infants. In normal fetuses total molar amino acid concentrations and fetal/maternal total molar concentration ratios did not change significantly between the second and third trimesters. Fetal and maternal concentrations of most amino acids were significantly correlated at both midgestation and late gestation. Small-for-gestational-age fetuses had significantly lower concentrations of total alpha-aminonitrogen; this was mainly because of a reduction of the branched chain amino acids valine, leucine, and isoleucine, and of lysine and serine. Maternal arterial concentrations of phenylalanine, arginine, histidine, and alanine were elevated in small-for-gestational-age pregnancies. Thus there are only minor changes in amino acid concentrations between midgestation and late gestation in normal fetuses with a constant fetal/maternal ratio. In small-for-gestational-age infants a significant reduction in alpha-aminonitrogen and in most essential amino acids was demonstrable in utero weeks before delivery.
Tracer methods using both carbon-13 and -14 have been utilized for determination of ovine fetal amino acid disposal and the results compared in seven animals. We infused [1-13C]leucine simultaneously with [1-14C]leucine into the fetal circulation of pregnant sheep chronically catheterized during late gestation. Radioactive and stable isotope enrichments of leucine (Leu) and stable isotope enrichments of ketoisocaproic acid (KIC) in the umbilical artery and vein and the maternal artery and uterine vein were measured. Stable isotope enrichments and concentrations of both Leu and KIC were determined from a single 0.2-ml sample by the use of internal standards and electron ionization GC/MS analysis after a simple isolation and derivatization procedure. The KIC/Leu enrichment ratio was measured for the first time in fetal arterial plasma and was 0.66 +/- 0.05 (SE). Fetal leucine disposal rate was 9.0 +/- 0.5 (SE) micron/min/kg. Disposal rates determined by stable isotopes were not different from those determined by radioactive isotopes. The GC/MS stable isotope method provided higher precision in both leucine concentration and enrichment measurements and has been shown to be a general method for the determination of concentration and isotopic enrichment of other amino acids and their corresponding keto acids. Furthermore, this method is ideally suited to clinical studies where large numbers of samples of rather small volume can easily be studied with a short turnaround time.
The effect of feeding on whole-body protein turnover was measured in six healthy volunteers using the essential amino acid, L-[1-13C]leucine, as a tracer for protein metabolism. Varied lengths of periods of feeding and isotope infusion produced different apparent responses to feeding. When parameters of protein turnover were estimated from 8-hour infusions, the change from post-absorptive in the first four hours to mixed feeding during the final four hours was found to produce positive leucine balance by decreasing degradation from 89.5 +/- 5.0 to 31.7 +/- 7.3 mumol leucine/kg/h (P less than .001), with no apparent change in synthesis. By contrast, when tracer was infused for 24 hours with 12 hours of feeding followed by 12 hours of fasting, the estimate of protein synthesis during feeding was 35% higher than during fasting (P less than .01). However, when tracer infusion during the 12-hour feeding/12-hour fasting protocol was limited to the last four hours of each nutritional period, the estimates of fed and fasted protein synthesis showed no significant difference, 71.3 +/- 6.5 and 66.2 +/- 5.6 respectively, while the calculated rate of protein degradation was 43% lower during feeding (P less than .002). As relatively higher levels of enrichment in plasma leucine were detected in comparable nutritional states following longer infusions, the possibility of significant recycling of label was investigated. Residual tracer was still detectable in both breath and plasma 12 hours after cessation of a 12-hour tracer infusion, supporting the conclusion that significant errors in estimates of protein turnover due to recycling of label arise with prolonged infusions.(ABSTRACT TRUNCATED AT 250 WORDS)
Leucine (LEU) kinetics were assessed using a primed-continuous infusion of L-[1-14C]LEU in normal overnight-fasted male volunteers during a basal period and an experimental period where insulin (INS) was infused at either 0.6, 1.2, 2.5, 5.0, 10, or 20 mU.kg-1.min-1 with euglycemia maintained. Two protocols were used: 1) subjects were allowed to develop hypoaminoacidemia or 2) plasma essential amino acids (AA) were maintained near basal levels by frequently monitoring plasma LEU in conjunction with variable infusions of an AA solution (LEU infused = 0.41, 0.72, 0.93, 1.03, 1.31, and 1.35 mumol.kg-1.min-1 at escalating INS doses, respectively). Basal rates of LEU appearance (Ra), nonoxidative disappearance (NORd) and oxidative disappearance (OXRd) were similar in both protocols (means = 1.74, 1.40, and 0.36 mumol.kg-1.min-1, respectively). INS infusions without AA resulted in a progressive decrement in LEU Ra (14 to 45%), NORd (16-41%), and OXRd (3-56%) compared with basal values. The infusion of AA resulted in an additional reduction in endogenous Ra (P less than 0.01; approximately 100% suppression achieved at plasma INS greater than 1,000 microU/ml) and a blunting of NORd reduction (P less than 0.05) at each dose of INS. Observed differences in INS's suppression of LEU Ra between the two protocols suggests the existence of a component of whole body proteolysis that is highly dependent on circulating plasma AA. Therefore, hypoaminoacidemia associated with INS treatment would appear to blunt the responsiveness of INS's suppression of protein breakdown and in the presence of near basal plasma AA, proteolytic suppression by INS is enhanced.
A mixture of amino acids designed to maintain normal plasma amino acid concentrations in infants and children requiring parenteral nutrition was evaluated in 28 low birth weight (LBW) infants (birth weight, 750 to 1750 g; postnatal age, 1 to 4 weeks) who required parenteral nutrients for optimal nutritional management. Sixteen babies received only parenteral nutrients for five to 21 days. Ten of these received a typical regimen by peripheral vein (1.91 +/- 0.16 g/kg/d of amino acids and 44.7 +/- 4.4 kcal/kg/d) and six received a typical regimen through a central vein (2.39 +/- 0.11 g/kg/d of amino acids and 95.9 +/- 14.5 kcal/kg/d). Mean weight gain of the peripheral vein subgroup was 10.3 +/- 10.6 g/kg/d; mean nitrogen balance was 230 +/- 66 mg/kg/d. Both the mean rate of weight gain (17.2 +/- 5.1 g/kg/d) and the mean rate of nitrogen retention (267 +/- 49 g/kg/d) of the central vein subgroup were similar to intrauterine rates. In these two subgroups as well as the total population, plasma concentrations of all amino acids except phenylalanine were within the 95% confidence limits of the plasma concentrations observed in LBW infants fed sufficient amounts of human milk to result in a rate of weight gain similar to the intrauterine rate. However, although plasma tyrosine and cyst(e)ine concentrations were within the 95% confidence limits of the plasma concentrations goals, the LBW infant's ability to use N-acetyl-L-tyrosine and cysteine HCl appears to be even less than that of the term infant and older child. In toto, these data support the efficacy of the amino acid mixture evaluated for LBW infants. Of equal importance, they suggest that the LBW infant's ability to use parenterally delivered amino acids is not as limited as commonly thought.
Total carbohydrate oxidation, plasma glucose oxidation, and glucose carbon recycling were measured in 11 fasting newborns using a constant infusion of D-[U-13C]glucose combined with respiratory calorimetry. The "true" rate of glucose appearance (Ra) was quantified from the enrichment of the nonrecycling tracer species (m + 6), while the "apparent" rate of glucose appearance was quantified from the enrichment of glucose C - 1. The plasma glucose concentration remained constant at approximately 50 mg/dl (2.8 mM) throughout the study. The true rate of glucose production was 5.02 +/- 0.41 mg X kg-1 X min-1, (means +/- SD). Glucose was oxidized at a rate of 2.67 +/- 0.34 mg X kg-1 X min-1 and represented 53% of the glucose turnover. Recycling of glucose carbon represented 36% of the glucose production rate, or 1.87 +/- 0.74 mg X kg-1 X min-1. The oxidation of plasma glucose provided 15.8 +/- 2.0 kcal X kg-1 X day-1, whereas total carbohydrate oxidation (measured by respiratory calorimetry) provided 19.9 +/- 6.6 kcal X kg X day. The data indicate that 1) recycling of glucose carbon accounts for about one-third of glucose production, demonstrating active gluconeogenesis in the fasting newborn; 2) the oxidation of plasma glucose represents only 80% of total carbohydrate oxidation, the remaining 20% possibly representing the local oxidation of tissue glycogen stores; and 3) as the measured rate of glucose oxidation will be insufficient to supply the entire calculated cerebral metabolic requirements, these data suggest that fuels in addition to glucose may be important for cerebral metabolism in the fasting human newborn.
The accuracy of a 6‐hr vs a 24‐hr urine collection for the determination of urinary urea nitrogen was studied in 15 infants. Patient's age ranged from 2 weeks to 3 yr, encompassing a wide variety of diagnoses. All patients had normal renal function at the time of the study.
Participants had indwelling foley catheters throughout the study. Urine specimens were collected over a continuous 24‐hr period. Aliquots obtained from urine collected over 0 to 6 hr and the total urine collection were analyzed utilizing the urease enzymatic method in the Astra.
Statistical analysis was performed comparing the actual 24‐hr determination to the estimation based on the 6‐hr collection, utilizing linear regression. The analysis of data produced a highly significant correlation ( r = 0.904, p < 0.0001).
When a 24‐hr urine collection is not possible, a 6‐hr collection is a useful alternative for the calculation of nitrogen balance in infants. ( Journal of Parenteral and Enteral Nutrition 10: 517–518, 1986)
The use of 13CO2 excretion to measure the oxidation of 13CO2 labeled substrates is increasing as it is both noninvasive and lacks the radiation exposure associated with the use of 14C. No standards are available for 13CO2 recovery in breath from the bicarbonate pool in the neonate. A primed constant infusion of NaH13CO3 over 4 h was used with open circuit indirect calorimetry in 15 appropriate for gestational age newborn infants (gestational age 28-39 wk; postnatal age 2-52 days), on varying amounts of intravenous feeding (37-114 kcal X kg-1 X day-1). Following a bolus of 6.9 mumol X kg-1 of NaH13CO3, a maintenance infusion of 4.6 mumol X kg-1 X h-1 was started. The 13C enrichment in breath rose rapidly to reach a plateau by 90 min with less than 5% variation of the plateau. Recovery of the tracer in breath ranged from 69.6-83.5% and was significantly correlated with 1) energy intake (37-114 kcal X kg-1 X day-1); 2) metabolic rate (34.6-56.1 kcal X kg-1 X day-1); 3) VCO2 (4.86-7.43 ml X kg X -1 X min-1). There was no correlation with the level of protein or fat intake. We provide an equation that can be used to calculate the correction factor when doing constant infusion substrate oxidation studies with a 13C label in neonates.
Leucine metabolism in vivo can be determined from a primed, continuous infusion of L-[1-13C]leucine by measuring, at isotopic steady state, plasm [-13C]leucine enrichment, expired 13CO2 enrichment, and CO2 production rate. With an appropriate priming dose of L-[1-13C]leucine and NaH13CO3, isotopic steady state is reached in less than 2 h, and the infusion is completed in 4 h. The method can determine rates of leucine turnover, oxidation, and incorporation into protein with typical relative uncertainties of 2, 10, and 4%, respectively. The method requires no more than 1 ml of blood and uses stable isotope rather than radioisotope techniques. Thus, the method is applicable to studies of human beings of all ages. L-[1-13C]leucine may be infused with a second amino acid labeled with 15N for simultaneous determination of the kinetics of two amino acids.
In ten postoperative neonates and young infants the effect of three isocaloric, isovolemic intravenous nutritional regimens (glucose alone, amino acids + glucose, amino acids + lipid) on nitrogen balance, energy, and substrate metabolism were tested. Each regimen was given for 24 hours to each infant through three consecutive days, providing the same daily amino acid intake when the amino acid mixture was combined with glucose or lipid. Oxygen consumption and RQ were followed through three or four hours during each study period. The participation of three main nutrients in energy metabolism was calculated from the urinary N excretion and nonprotein RQ. Administration of glucose infusion alone was associated with a negative N balance. Addition of amino acids with glucose produced a marked N retention. This positive N balance remained unchanged when lipid was substituted for glucose as a nonprotein energy source. Alpha amino-nitrogen excretion and participation of protein catabolism in total energy metabolism were found to be identical during the three nutritional regimens, indicating that the amino acids together with glucose or lipid were either retained in nonprotein pools or were utilized for protein synthesis.
Whole-body leucine and lysine metabolism was explored in young adult men by a primed constant intravenous infusion of a mixture of L-[1-13C]leucine and L-[alpha-15N]lysine over a 4-h period. Subjects were studied after an overnight fast (postabsorptive state) or while consuming hourly meals (fed state) after adaptation to diets providing either a surfeit level of protein (1.5 g.kg body-1.day-1), a level approximating maintenance requirements (marginal intake) (0.6 g.kg body wt-1.day-1), or a grossly inadequate level (0.1 g.kg-1.day-1). The change in protein intake from a marginal to a surfeit level was associated with an increased leucine flux and incorporation of leucine into body protein. In the fed state, oxidation of leucine increased sharply and release of leucine from tissue protein diminished. When dietary protein intake was reduced from the requirement to inadequate level, leucine flux and body protein synthesis and protein breakdown were reduced, together with a smaller reduction in leucine oxidation. The response of the metabolism of [15N]lysine was responsible for maintenance of leucine and other essential amino acid economy, and they appear to be related to the nitrogen and amino acid requirements of the subject. These findings also demonstrate an effect of meals, modulated by their protein content, on the dynamics of whole-body amino acid metabolism.
Net nitrogen retention (NNR) and rates of whole-body protein turnover (Q), synthesis, and breakdown (B) were measured in 24 intravenously fed premature infants, birthweight less than 1600 g, at the end of the first week of life. Four regimes were used: Amigenglucose +/- Intralipid; Vamin-glucose +/- Intralipid. Mean protein intake was 2.7 g/kg/day. Mean energy intakes were 68 to 98 kcal/kg/day. Vamin was a better protein source (p less than 0.01), evidence by a higher NNR; 72 +/- 2%, cf. 56 +/- 4% at high-energy intakes. The high-energy intake also improved (p less than 0.01) protein retention (NNR); 64 cf. 50%. Infants receiving 2.9 g of Vamin (394 mg N)/ kg/day and 85 kcal/kg/day of nonprotein intake retained nitrogen at intrauterine rates (282 +/- 7 mg/kg/day). Diet had no effect on Q, synthesis, or B. However, the protein source had a significant effect (p less than 0.01) on the fraction of N-flux coming from protein breakdown (B/Q); 71.7% for Vamin, cf. 77.1% for Amigen. Similarly, energy intake had a significant effect (p less than 0.01) on the fraction N-flux utilized for protein synthesis (S/Q); 91.3% high energy cf. 87.0% low energy. These results suggest that an increased energy intake improved N-retention by enhancing amino acid reutilization for protein synthesis, whereas a higher quality protein improved N-retention by limiting protein breakdown..3% high energy cf. 87.0% low energy. These results suggest that an increased energy intake improved N-retention by enhancing amino acid reutilization for protein synthesis, whereas a higher quality protein improved N-retention by limiting protein breakdown..3% high energy cf. 87.0% low energy. These results suggest that an increased energy intake improved N-retention by enhancing amino acid reutilization for protein synthesis, whereas a higher quality protein improved N-retention by limiting protein breakdown.
In order to determine the intravenous energy and nitrogen intakes required to achieve intrauterine rates of nitrogen accretion and growth, 30 studies were completed in 22 premature infants who were provided with various intakes of amino acids and energy (glucose +/- lipid) by peripheral vein infusion. At constant nitrogen intake, increasing energy intake (as lipid) from 50 to 80 nonprotein kcal/kg/day resulted in significant increases in nitrogen retention and weight gain. Increasing nitrogen intake from 494 to 655 mg/kg/day at constant low energy intake (mean = 53 kcal/kg/day) had no effect on nitrogen retention or weight change; however, at higher energy intakes (mean = 81 kcal/kg/day) increasing nitrogen intake correlated significantly with increasing nitrogen retention. At energy intakes greater than 70 kcal/kg/day the major determinant of nitrogen retention was nitrogen intake. When energy intake was greater than 70 kcal/kg/day, the infusion of nitrogen providing 430 to 560 mg/kg/day (2.7 to 3.5 gm protein/kg/day) resulted in the duplication of intrauterine nitrogen accretion rates.
Measurements of whole-body protein turnover in preterm infants have been made using different stable isotope methods. Large variation in results has been found, which could be due to different clinical conditions and/or the use of different tracers. We studied 14 appropriate for gestational age and nine small for gestational age orally fed preterm infants using [15N]glycine and [1-(13)C]leucine simultaneously, which allowed us to make a comparison of commonly used methods to calculate whole-body protein turnover. Whole-body protein turnover was calculated from 15N enrichment in urinary ammonia and urea after [15N]-glycine administration and from the 13C enrichment in expired CO2 after administration of [1-(13)C]leucine. Enrichment of alpha-ketoisocaproic acid after [1-(13)C]leucine constant infusion was measured as a direct parameter of whole-body protein turnover. Group means for whole-body protein turnover using [15N]glycine or [1-(13)C]leucine ranged from 10 to 14 g.kg-1.d-1, except when using the end product method that assumes a correlation between leucine oxidation and total nitrogen excretion. We found very low 15N enrichment of urinary urea in the majority of small for gestational age infants. These infants also had a lower nitrogen excretion in urine and oxidized less leucine. Nitrogen balance was higher in small for gestational age infants (416 +/- 25 mg.kg-1.d-1) compared with appropriate for gestational age infants (374 +/- 41 mg.kg-1.d-1, p = 0.003). [15N]Glycine does not seem to exchange its label with the body nitrogen pool to a significant degree and is therefore not always suitable as a carrier for 15N in protein turnover studies in premature infants.
To determine whether the general reluctance to begin amino acid administration to preterm infants from birth onward might lead to loss of lean body mass and impairment of growth, we measured amino acid levels and protein kinetics in 18 preterm infants. Nine infants received amino acids (1.15 +/- 0.06 gm.kg-1.day-1) and glucose (6.05 +/- 1.58 gm.kg-1.day-1), whereas the other nine infants received only glucose (6.48 +/- 1.30 gm.kg-1.day-1) from birth onward. Protein kinetics on the first postnatal day were measured with a stable isotope dilution technique with [1-13C]leucine as a tracer. No statistically significant differences were noted in blood pH, base excess, urea concentration, or glucose levels. Both total amino acid concentration and total essential amino acid concentration were significantly lower and were below the reference range in the nonsupplemented group. Plasma amino acid levels of five essential amino acids (methionine, cystine, isoleucine, leucine, arginine) were below the reference range in the nonsupplemented group, whereas only cystine was below the reference range in the supplemented group. Nitrogen retention was improved significantly by the administration of amino acids (-110 +/- 44 mg nitrogen per kilogram per day in the glucose-only group vs +10 +/- 127 mg nitrogen per kilogram per day in the group given glucose and amino acids; p = 0.001); leucine oxidation was not significantly increased in the supplemented group (41 +/- 13 mumol.kg-1.hr-1 vs 46 +/- 16 mumol.kg-1.hr-1). Leucine balance also improved significantly (-41 +/- 13 mumol.kg-1.hr-1 vs -8 +/- 16 mumol.kg-1.hr-1; p = 0.01) because of a combination of an increased amount of leucine being used for protein synthesis and a lower amount of leucine coming from protein breakdown. Plasma cystine concentration, the only amino acid below the reference range in the supplemented group, was highly predictive for protein synthesis in that group. We conclude that the administration of amino acids to preterm infants from birth onward seems safe and prevents the loss of protein mass.
The regulation of plasma insulin-like growth factor binding proteins (IGFBPs) by energy status has been assessed in 2-month-old pigs. Energy balance was modified by altering thermoregulatory demand and energy intake, with litter-mates being kept for several weeks at either 35 or 10 degrees C on a high (H) or low (L) level of food intake (where H = 2L); plasma samples were taken 20-24 h after the last meal. The two major forms of circulating IGFBP, as estimated by Western blot analysis, were identified putatively as IGFBP-2 and IGFBP-3 (relative molecular weights of 34 and 40-45 kDa respectively). There were significant differences in IGFBP profiles between the four treatment groups of 35H, 35L, 10H and 10L: the 40-45 kDa IGFBP (putative IGFBP-3) was elevated both in the warm and on a high food intake (P < 0.001), and there was a marked reciprocal relation between the 40-45 and 34 kDa IGFBPs. The relative concentration of the 34 kDa IGFBP (putative IGFBP-2) was greatest in the 10L and least in the 35H group. It is concluded that long-term alterations in energy balance, induced by changes in either intake or thermoregulatory demand, can significantly affect the plasma profile of IGFBPs during the first two months of life.
Extremely low birthweight (ELBW) infants are unique in many developmental characteristics that determine nutritional requirements, including: low energy reserves (both carbohydrate and fat); higher metabolic rate (intrinsically, due to a higher body content of more metabolically active organs, e.g. brain, heart, liver); higher protein turnover rate (especially when growing); higher glucose needs for energy and brain metabolism; higher lipid needs to match the in utero rate of fat deposition, and for essential fatty acids for brain, neural and vascular development; excessive evaporative rates, and occasionally very high urinary water and solute losses; low rates of gastrointestinal peristalsis; limited production of gut digestive enzymes and growth factors; high incidence of stressful events (e.g. hypoxemia, respiratory distress, sepsis); and abnormal neurological outcome if not fed adequately. Postnatally, ELBW infants do not grow well, or at all, often for weeks. This leads to a virtual "growth deficit", which has unknown consequences (which for the most part are not good) and requires excessive feeding later on to catch up to normal growth rates and body composition. The major future challenge for the nutrition of these infants is to define more accurately their nutritional requirements, particularly in the early postnatal period, in order to feed them more appropriately, to reduce to a minimum the nutritional and growth deficits that they so commonly develop and to prevent neurodevelopmental handicaps that are the result of nutritional deficiencies.
Twenty-three preterm infants with respiratory distress syndrome (mean birth weight 1.07 kg, SD 0.24 kg) were randomly assigned to receive glucose alone or glucose with amino acids (1.5 g.kg-1.d-1) i.v. beginning on the 1st d of life. Blood ammonia and serum urea, CO2 content, sodium, potassium, chloride, and ionized calcium concentrations were normal and did not differ between treatment groups. Nitrogen balance was significantly greater in the group that received amino acids [88 (SD 54) versus -135 (SD 45) mg.kg-1.d-1]. In 12 infants (seven, glucose-only; five, glucose and amino acids), leucine kinetic studies were also performed on the 3rd d of life. These 12 infants received a 4-h primed constant infusion of L-[1-13C]leucine. Blood and breath were collected and analyzed for [1-13C]ketoisocaproate and 13CO2, respectively. Leucine turnover and oxidation were calculated. Both leucine turnover and oxidation were significantly higher in the group receiving amino acids than in the glucose-only group [241 (SD 38) versus 164 (SD 25) mumol.kg-1.h-1 and 71 (SD 22) versus 40 (SD 17) mumol.kg-1.h-1, respectively]. In addition, the calculated rate of protein synthesis was higher in the group receiving amino acids [6.9 (SD 1.1) versus 5.0 (SD 1.2) g.kg-1.d-1]. These data indicate that the i.v. administration of amino acids (1.5 g.kg-1.d-1) to ill preterm infants beginning on the 1st d of life improves whole-body protein balance as a result of increased protein synthesis.
The substantial variation in birth weight-adjusted mortality among neonatal intensive care units (NICUs) may reflect differences in population illness severity. Development of an illness severity measure is essential for comparisons of outcomes. The Score for Neonatal Acute Physiology (SNAP) was developed and validated prospectively on 1643 admissions (114 deaths) in three NICUs. SNAP scores the worst physiologic derangements in each organ system in the first 24 hours. SNAP showed little correlation with birth weight and was highly predictive of neonatal mortality even within narrow birth weight strata. It was capable of separating patients into groups with 2 to 20 times higher mortality risk. It also correlated highly with other indicators of severity including nursing workload (r = .59), therapeutic intensity (r = .78), physician estimates of mortality risk (r = .65), and length of stay (R2 = .59). SNAP is an important new tool for NICU research.
To examine the effect of two commonly used parenteral alimentation amino acid mixtures on whole-body leucine and urea kinetics.
Ten stable preterm infants were studied during the first 4 weeks after birth. Six infants received a mixture containing higher branched-chain amino acids, lower glycine plus added dicarboxylic acids formulation (Trophamine), and four received a standard amino acid mixture (Aminosyn). Whole-body protein turnover was measured with (1-13C)leucine tracer, and the rate of oxidation of protein was calculated by quantifying the appearance of carbon 13 from leucine in carbon dioxide as well as from rates of urea synthesis estimated by using (15N2)urea tracer. Energy consumption and substrate oxidation were quantified by indirect respiratory calorimetry. Infants were given similar quantities of energy (approximately 61 kcal/kg per day), glucose (approximately 10.7 mg/kg per minute) and protein (approximately 2.1 gm/kg per day).
There was no significant difference in the rate of appearance of leucine in the two groups. However, the fraction of leucine oxidized (p = 0.002) and total rte of oxidation of leucine was higher in the Trophamine group. Thus additional branched-chain amino acids resulted in an increased contribution of C-1 of leucine to expired CO2. The rate of urea N synthesis was also similar in the two groups (Trophamine: 2.92 +/- 0.87 mg N/kg per hour; Aminosyn: 2.70 +/- 1.18 mg N/kg per hour).
Although the use of Trophamine normalizes the blood amino acid pattern, it does not appear to improve nitrogen/protein kinetics. Furthermore, the additional branched-chain amino acids are disposed of by increased oxidation.
The effect of the route of nutrient administration on the relative rates of leucine and phenylalanine kinetics was examined in 30 low birth weight (LBW) infants using L-[1-(13)C]leucine, L-[2H5]phenylalanine, and L-[2H2]tyrosine tracers. The infants received special premature formula (PF, n = 10, 117 +/- 8 kcal.kg-1.d-1 and 3.2 +/- 0.2 g protein.kg-1.d-1) or fortified human milk (HM, n = 10, 106 +/- 6 kcal.kg-1.d-1 and 3.0 +/- 0.2 g protein.kg-1.d-1), or parenteral nutrition (PN, n = 10, 80 +/- 25 kcal.kg-1.d-1 and 1.8 +/- 0.3 g protein.kg-1.d-1). The rate of appearance (Ra) of leucine (RaLeu), was significantly higher in group PF as compared with groups HM and PN (434 +/- 51 versus 377 +/- 33 and 359 +/- 50 mumol.kg-1.h-1, p < 0.05). The Ra of phenylalanine (RaPhe) was lower in group HM as compared with group PF (94 +/- 18 versus 115 +/- 16, p < 0.05), RaPhe in group PN (108 +/- 24 mumol.kg-1.h-1) was in between group PF and HM. The relative rate of RaPhe and RaLeu expressed as RaPhe/ RaLeu ratio was lower in all groups than that expected from reported whole body protein composition and from that reported in adults. The ratio of phenylalanine hydroxylation to leucine decarboxylation was 0.202 in group PF, 0.212 in group HM, and 0.161 in group PN, suggesting a higher rate of decarboxylation of leucine relative to hydroxylation of phenylalanine. We conclude that: 1) the higher RaLeu compared with the RaPhe may be the result of either a higher turnover of a body protein enriched in leucine or the consequence of higher leucine intake in infant nutrition and 2) whole body protein kinetics calculated from a single amino acid tracer do not adequately represent whole body protein metabolism.
The study aimed to determine the developmental changes in the response of peripheral and visceral tissue protein synthesis to feeding during early postnatal life and the associated changes in circulating insulin, insulin-like growth factor (IGF-I), and amino acid concentrations. Tissue protein synthesis was measured in vivo with a large dose of L-[4(-3)H]phenylalanine in 7- and 26-day-old pigs that were either fasted for 24 h or refed for 2.75 h after a 24-h fast. Fractional rates of protein synthesis (Ks) in skeletal muscle, heart, and liver were greater in 7-than in 26-day-old pigs. Refeeding stimulated Ks in skeletal muscle, pancreas, jejunum, and liver of both 7-and 26-day-old pigs. The stimulation of skeletal muscle and jejunal Ks by refeeding was greater in 7- than in 26-day-old pigs. Plasma IGF-I concentrations were lower in 7- than in 26-day-old pigs. Plasma concentrations of insulin and amino acids increased with refeeding. The increase in plasma insulin concentrations with refeeding was greater in 7- than in 26-days-old pigs. These results indicate that the stimulation in skeletal muscle and jejunal protein synthesis by feeding is elevated in young compared with older suckling pigs. This enhanced stimulation of protein synthesis by feeding in neonatal pigs is associated with elevated circulating concentrations of insulin but not amino acids or IGF-I.
To evaluate and refine indirect calorimetry measurement techniques so that accurate metabolic measurements can be performed in mechanically ventilated and convalescing preterm infants who require supplemental oxygen.
Laboratory validation of an indirect calorimeter; clinical and laboratory assessments of technical problems in performing metabolic measurements; and clinical indirect calorimetry studies in mechanically ventilated and nonventilated preterm infants.
Neonatal intensive care unit (ICU) in a tertiary care university hospital.
Level II and level III mechanically ventilated (n = 10) and nonventilated (n = 14) neonatal ICU patients who required FIO2 levels ranging from 0.21 to 0.42.
None.
System calibration was assessed by combustion of 100% ethanol; the mean respiratory quotient was 0.667 +/- 0.001 (SEM). In addition, oxygen consumption (Vo2) and CO2 production (Vco2) were simulated by CO2/nitrogen infusions within the range expected for 0.5- to 7-kg infants. Mean relative errors were 0.6 +/- 0.3% and 1.8 +/- 0.3% for expected Vo2 and Vco2 values, respectively. In 27 mechanically ventilated patients with no audible endotracheal tube leak, measured endotracheal tube leak ranged from 0.0% to 7.5%. Fluctuations in FIO2 during mechanical ventilation were monitored in 30-min studies, using wall-source (n = 27) or tank-source (n = 11) supplemental oxygen. Mean FIO2 variation was 0.00075 +/- 0.00013 vs. 0.00011 +/- 0.00001 using wall-source and tank-source oxygen, respectively. Some of the difficulties of obtaining accurate measurements in supplemental hood oxygen studies were overcome by using tank-source vs. wall-source oxygen and a unique hood design.
Accurate indirect calorimetry studies can be performed in both ventilated and nonventilated infants weighing as little as 500 g, providing that sufficient attention is paid to technical and methodologic measurement details.
Neonatal animals utilize their dietary amino acids for protein accretion with high efficiency, and this efficiency declines during early life. The factors responsible for this developmental change are unknown. Our objectives were to determine whether amino acid (AA) utilization is stimulated by insulin in the neonate and whether this response changes during the suckling period. Two hyperinsulinemic-euglycemic clamp infusion studies, using 10-2,000 ng insulin.kg-0.66.min-1, were performed in 7- and 26-day-old pigs. In study I, no AA were provided during the infusion, and the resultant decline in plasma AA levels was defined. In study II, plasma AA were clamped at near-fasting levels, and whole body utilization of exogenous AA was determined by measuring the rate of infusion of an AA mixture necessary to maintain basal plasma lysine concentrations. In study I, the half-maximal effective dose (ED50) for the fall in AA concentrations with increasing plasma insulin concentration was lower in 7- than in 26-day-old pigs, and the nadir in AA concentration was achieved by only 20 microU/ml insulin. In study II, the utilization of exogenous AA during hyperinsulinemic-euglycemic AA clamps exhibited a higher maximum response (Rmax) (49 vs. 26 mumol AAtotal.min-1.kg-1) and a lower ED50 (18 vs. 45 microU insulin/ml) in 7- than in 26-day-old pigs. Plasma urea nitrogen concentrations did not rise with increasing insulin and AA infusion rates. These results indicate that insulin stimulates the utilization of exogenous AA in neonatal pigs and that both the insulin sensitivity and responsiveness of AA utilization decline over the suckling period. The infused AA were likely utilized for protein accretion.
To determine whether perinatal nutrition influences cognitive function at 7 1/2 - 8 years in children born preterm.
Randomised, blinded nutritional intervention trial. Blinded follow up at 7 1/2 - 8 years.
Intervention phase in two neonatal units; follow up in a clinic or school setting.
424 preterm infants who weighed under 1850 g at birth; 360 of those who survived were tested at 7 1/2 - 8 years.
Standard infant formula versus nutrient enriched preterm formula randomly assigned as sole diet (trial A) or supplements to maternal milk (trial B) fed for a mean of 1 month.
Intelligence quotient (IQ) at 7 1/2 - 8 years with abbreviated Weschler intelligence scale for children (revised).
There was a major sex difference in the impact of diet. At 7 1/2 - 8 years boys previously fed standard versus preterm formula as sole diet had a 12.2 point disadvantage (95% confidence interval 3.7 to 20.6; P<0.01) in verbal IQ. In those with highest intakes of trial diets corresponding figures were 9.5 point disadvantage and 14.4 point disadvantage in overall IQ (1.2 to 17.7; P<0.05) and verbal IQ (5.7 to 23.2; P<0.01). Consequently, more infants fed term formula had low verbal IQ (<85): 31% versus 14% for both sexes (P=0.02) and 47% versus 13% in boys P=0.009). There was a higher incidence of cerebral palsy in those fed term formula; exclusion of such children did not alter the findings.
Preterm infants are vulnerable to suboptimal early nutrition in terms of their cognitive performance--notably, language based skills--at 7 1/2 - 8 years, when cognitive scores are highly predictive of adult ones. Our data on cerebral palsy generate a new hypothesis that suboptimal nutritional management during a critical or plastic early period of rapid brain growth could impair functional compensation in those sustaining an earlier brain insult. Cognitive function, notably in males, may be permanently impaired by suboptimal neonatal nutrition.