EHD-04030; No of Pages 7 Early Human Development xxx (2014) xxx–xxx
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Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice S. Uthaya ⁎, N. Modi 1 Imperial College London, UK Chelsea Westminster Hospital NHS Foundation Trust, London, UK
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Available online xxxx Keywords: Parenteral nutrition Amino acids Prematurity Newborn intensive care Nutrition Infant Intravenous lipids
a b s t r a c t Current practice in relation to the prescribing, compounding and administration of parenteral nutrition for extremely preterm infants is inconsistent and based on largely historical evidence. Increasingly there are calls for more ‘aggressive’ nutritional interventions to prevent ‘postnatal growth failure’. However the evidence base for these recommendations is weak, and there are no long-term studies examining the impact of such practices. Here we summarise the evidence for preterm parenteral nutrition interventions. We suggest principles to guide practice based on evidence from a systematic search and review of evidence to date, and recommend actions necessary to advance the understanding of this important aspect of preterm care. © 2014 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Early versus later introduction of PN . . . . . . . . . 3.2. Early versus later administration of amino acids . . . . 3.3. Low versus high intake of amino acids . . . . . . . . . 3.4. Early versus late initiation of lipid and lipid composition 3.5. Standardised versus individualised PN . . . . . . . . . 4. Conclusions from the evidence . . . . . . . . . . . . . . . 5. Problems with the evidence . . . . . . . . . . . . . . . . . 6. Recommendations for practice . . . . . . . . . . . . . . . 7. What is needed now? . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Current practice in relation to preparation, prescribing and administration of preterm parenteral nutrition (PN) is variable, inconsistent and a potential clinical risk. Two UK reports summarise these concerns (http://www.rpharms.com/support-pdfs/minimising-risk-pn-children-
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(6).pdf) [1]. Working groups such as those from the European Society of Paediatric Gastroenterology Hepatology and Nutrition acknowledge the limited evidence base for current guidelines [2]. Here we present a summary of a systematic search and review of the literature and set out principles upon which to base practical aspects of PN in preterm infants. 2. Methods
⁎ Corresponding author at: Imperial College London, UK and Chelsea and Westminster Hospital NHS Foundation Trust, UK. Tel.: +44 20 3315 8000. E-mail addresses: [email protected] (S. Uthaya), [email protected] (N. Modi). 1 Tel.: +44 20 3315 8000.
We conducted an initial search to identify clinical trials of PN in preterm infants and categorised these by types of intervention. We then conducted separate literature searches of each intervention. We confined all searches to preterm infants, defined as infants born less
http://dx.doi.org/10.1016/j.earlhumdev.2014.09.002 0378-3782/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article as: Uthaya S, Modi N, Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.09.002
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S. Uthaya, N. Modi / Early Human Development xxx (2014) xxx–xxx
than 37 weeks of gestational age, receiving PN. We excluded studies involving infants with short-gut syndrome, PN associated liver disease, and studies of PN exposure to light. All outcomes were included. We searched Embase 1980 to the week of the search (week 34 of 2014) using population search terms neonat$.mp. or newborn intensive care/or prematurity/. We confined our search to human studies, preterm studies and English language papers. All abstracts were screened for relevance and eligibility. Papers were excluded by reading the abstracts. We excluded conference abstracts, and papers relating to long term PN in the management of intestinal failure. We included observational studies where there was no RCT. Where a systematic or Cochrane Library review was found, we replicated the search using the same criteria. If more recent studies since the publication of the review were not found, the review, not the individual studies, was summarised and included in the results. Studies included in this review are shown in Table 1.
3. Results Interventions that were identified in the initial search were: 1) early versus later introduction of PN, 2) early versus late administration of amino acids, 3) incremental versus recommended daily intake or low versus high intake of amino acids, 4) early versus late initiation of lipid and lipid composition, and 5) standardised versus individualised PN.
3.1. Early versus later introduction of PN We identified a systematic review of early versus late administration of PN on growth outcomes; this included observational studies and RCT [3]. Eight RCTs and 13 observational studies met the inclusion criteria of the systematic review but the meta-analysis was limited by multiple growth outcome measures. Other outcomes including mortality, necrotising enterocolitis, sepsis, chronic lung disease, intraventricular haemorrhage, cholestasis and neurodevelopmental outcome were included. The definition of early and late in the included studies varied widely. Early was defined from immediately after delivery to b48 h after birth. Late administration was defined from 12 h to 6 days after birth. Early PN reduced the time to regain birth weight by 2.2 days (95% CI 1.1, 3.2 d) and by 3.2 days (95% CI 2.0, 4.4 d) in observational studies. The maximum percentage weight loss with early PN was lower by 3.1 percentage points (95% CI 1.7, 4.5 percentage points) for RCT and by 3.5 percentage points (95% CI 2.6, 4.3 percentage points) for observational studies. Early PN improved weight at discharge or 36 weeks of postmenstrual age by 14.9 g (95% CI 5.3, 24.5 g) (observational studies only), but no statistically significant differences were identified in length, head circumference or mortality.
3.2. Early versus later administration of amino acids We identified a Cochrane review of the impact of early versus late administration of amino acid solution with or without other PN constituents, on a variety of outcomes [4]. An improvement in nitrogen balance was found in four of the seven studies included in this review. One study found that the group that received amino acids in the first 24 h had an advantage in length of stay, days to enteral nutrition, duration of admission and days to regain birth weight. The review identified no short-term differences in length and occipito-frontal circumference between the experimental and control groups. Early administration of amino acids on the other primary outcomes of interest, weight gain, discharge weight, neurodevelopmental outcome at two years of age, and all-cause mortality at 28 days and before discharge, was not reported in the included studies.
3.3. Low versus high intake of amino acids No prior review was identified hence we carried out a search using the population search term as above and combined with the criteria *amino acid/ct, iv, pa [Clinical Trial, Intravenous Drug Administration, Parenteral Drug Administration]. We found seven RCTs comparing low and incremental versus high intake of amino acids (we excluded studies that compared early versus late introduction of amino acids, that is the subject of the Cochrane review in the section above) [5–10]. The low intakes varied from commencing at 1.0 g/kg/day to 2.4 g/kg/day to a maximum of 2.5 g/kg/day. The high intakes varied between 3 and 4 g/kg/day with some studies commencing at lower intakes and increasing over the first few days. One study showed no improvement in early growth [7], one showed worse growth in the high amino acid group [8] and one showed no further improvement in nitrogen balance between the groups that received 2.4 versus 3.6 g/kg/day than occurred with the concurrent administration of early lipid from birth [6]. One study reported on the 2-year neurodevelopmental outcomes (as a secondary outcome) of low versus high amino acid intake and found no differences between the groups but overall growth was poorer in the high amino acid group [9]. A non-blinded RCT that did not feature in the search results but was identified in PubMed compared the intake of low and incremental amino acid (commencing at 1.5 g/kg/day increasing to a maximum of 2.5 g/kg/day) with high and incremental amino acid (commencing at 2.5 g/kg/day and increasing to 4 g/kg/day) on body size at 36 weeks and found no difference between the two groups. Follow-up of the cohort showed no difference in neurodevelopment at 2 years of age [10]. A further study that was identified in the initial search for studies of PN but not in the individual search comparing low versus high amino acid intake aimed to compare control PN (10% glucose, 2.8 g/kg per day protein/lipid) with Standardised, Concentrated With Added Macronutrients Parenteral (SCAMP) nutrition regimen (12% glucose, 3.8 g/kg per day protein/lipid) on early head growth [11]. A significant difference in change in head circumference between birth and 28 days was found that persisted to 36 weeks of corrected gestational age. Neurodevelopment was not assessed. 3.4. Early versus late initiation of lipid and lipid composition We found a systematic review of 14 eligible RCTs investigating early (defined as in the first 2 postnatal days) versus late (defined as after age 2 days) initiation of lipids that showed no differences in a variety of outcome measures including growth. In relation to the type of lipid emulsion there was a weak association with lower rates of sepsis in the nonsoya-bean emulsion group but larger RCTs investigating the impact of lipid emulsions that are not purely soya-bean oil based are recommended [12]. 3.5. Standardised versus individualised PN No prior review was identified hence we carried out a search using the criteria: standard$ parenteral nutrition.mp. or. individual$ parenteral nutrition.mp. combined with the population search criteria as described above. There is limited evidence to suggest benefit of one over the other. There were no RCTs identified in the search so observational cohort studies were included. Some studies showed that the group receiving standardised PN received more protein and calories [13–15]. Other studies found that those receiving individualised PN received more nutrition and had better growth outcomes [16–18]. 4. Conclusions from the evidence The majority of studies investigating the impact of PN macronutrient content have focused on safety and short-term biochemical indices (serum urea, liver function tests, and metabolic acidosis) or surrogate markers of protein accretion (nitrogen balance) [5,19]. A few studies
Please cite this article as: Uthaya S, Modi N, Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.09.002
Author
Year of Aim publication
Early versus late introduction of PN Moyses, HE 2013 Whether earlier administration of PN benefits growth outcomes in preterm infants.
Early versus late administration of amino acids Trivedi, A 2013 To determine the effect of early administration of amino acids in premature newborns on growth, neurodevelopmental outcome, mortality and clinically important side effects.
Low versus high intake of amino acids Thureen, PJ 2004 To study the efficacy and safety of more aggressive amino acid intake
Methods
Results
Authors' conclusions
Systematic review of randomised controlled trials (RCTs) and observational studies.
Eight RCTs and 13 observational studies met the inclusion criteria. Early PN reduced the time to regain birth weight by 2.2 days (1.1, 3.2 days) for RCTs and 3.2 days (2.0, 4.4 days) in observational studies. Early PN improved weight at discharge or 36 weeks of postmenstrual age by 14.9 g (5.3, 24.5 g) (observational studies only), but no benefit was shown for length or head circumference.
Early PN provides a benefit for some short-term growth outcomes.
Cochrane systematic review
Seven randomised controlled trials were included in this review. One randomised controlled trial reported no difference in crown-heel length and occipito-frontal head circumference by day 10. Four trials showed positive nitrogen balance (the mean difference with 95% CI was 250.42 (224.91 to 275.93) P value b 0.00001). Early administration of amino acids did not result in metabolic acidosis in the first 24 h.
There is no available evidence of the benefits of early administration of amino acids on mortality, early and late growth and neurodevelopment.
Randomised controlled trial comparing low (LAA) 1 g/kg/day vs. high (HAA) 3 g/kg/day on protein balance (N = 28).
Protein balance was significantly lower in the LAA versus HAA groups by both nitrogen balance (−0.26 ± 0.11 versus 1.16 ± 0.15 g/kg/day, P b 0.00005) and leucine stable isotope (0.184 ± 0.17 versus 1.63 ± 0.20 g/kg/day, P b 0.0005) methods. There was no significant difference in growth by day 28 after birth (median weight gain: 12.9 and 11.4 g/ kg per day for the 3.5 and 2.5 g/kg per day groups, respectively), and the incidences of secondary morbidities were similar in the 2 groups. On day 7, blood levels of several amino acids and the serum urea nitrogen level were higher in the 3.5 g/kg per day group, compared with the 2.5 g/kg per day group; none of the amino acid levels were lower. The gain in weight, length and head circumference at 28 days were significantly lower in the high AA group. The average weight gain at 28 days was 8.67 g/kg/d in the high AA group and 13.15 g/kg/d in the Low AA group (mean difference 123.12, 95% CI 46.67 to 199.37, P b 0.001). Mental Developmental Index (MDI) and Psychomotor Developmental Index were similar between groups; however, the early and high AA group had a lower MDI at 18 months. This difference disappeared at 2 years of age. The early and high AA group z score means for weight, length, and head circumferences were significantly lower than the standard AA group at most visits. Nitrogen balance on day 2 was significantly greater in both intervention groups compared with the control group. Greater amounts of AA administration did not further improve nitrogen balance compared with standard AA dose plus lipids and was associated with high plasma urea concentrations and high rates of urea appearance. No differences in other biochemical variables, growth, or clinical outcomes were observed. Body weight, length, and head circumference at
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.
Clark, RH
2007
To measure the effects of 2 strategies for parenteral nutrition on neonatal growth and blood amino acid profiles in premature infants
RCT. In one group amino acid supplementation was started at 1.0 g/kg per day and advanced by 0.5 g/kg per day to a maximum of 2.5 g/kg per day. The other group received amino acids starting at 1.5 g/kg per day and advancing by 1.0 g/kg per day to a maximum of 3.5 g/kg per day (N = 122).
Balasubramanian, H
2013
To evaluate the effects of two different doses of parenteral amino acid supplementation on postnatal growth in very low birth weight (VLBW) infants receiving partial parenteral nutrition (PPN).
Blanco, CL
2012
To examine the effects of early and high intravenous (IV) amino acid (AA) supplementation on growth, health, and neurodevelopment of extremely-low-birth-weight (ELBW) infants throughout their first 2 years of life.
Double blind RCT. Two different initial doses of parenteral amino acids (AA) in the PPN solutions— low AA group: 1 g/kg/d versus high AA group: 3 g/ kg/d from day 1 of life with increment by 1 g/kg every day till a maximum of 4 g/kg/d, until babies tolerated 75% enteral feeds (N = 150). Double blind RCT. Treatment for 7 days with either IV AA starting at 0.5 g/kg/day and increased by 0.5 g/kg/day every day to 3 g/kg/day or starting at 2 g/kg/day of IV AA and advanced by 1 g/kg/day every day to 4 g/kg/day (N = 43).
Vlaardingerbroek, 2013 H
To assess the efficacy and safety of early parenteral lipid and high-dose amino acid (AA) administration from birth onwards in very low birth weight (VLBW, birth weight b1500 g) infants.
RCT. 2.4 g/kg/day of amino acid (control group), vs. 2.4 g/kg/day AA plus 2–3 g/kg/day lipids. (AA + lipid group), or 3.6 g/kg/day AA plus 2–3 g/kg/day lipids (high AA + lipid group) from birth onwards. The primary outcome was nitrogen balance (N = 144).
Burattini, I
To compare the effect of 2.5 vs. 4 g/kg/d of amino
RCT. Primary outcome was body size at 36 weeks
2013
Higher doses of amino acid supplementation did not improve neonatal growth and were associated with increased blood amino acid and urea nitrogen levels.
Higher initial parenteral amino acid supplementation, in settings where partial parenteral nutrition is administered, results in poor growth in VLBW infants due to inadequate nonprotein calorie intake.
S. Uthaya, N. Modi / Early Human Development xxx (2014) xxx–xxx
Please cite this article as: Uthaya S, Modi N, Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.09.002
Table 1 Summary of studies included in this review.
ELBW infants who received early and high IV AA during the first week of life were associated with poor overall growth at 2 years.
Parenteral AA combined with lipids from birth onwards improved conditions for anabolism and growth, as shown by improved nitrogen balance. Greater levels of AA administration did not further improve the nitrogen balance but led to increased AA oxidation.
The high AA group had higher blood urea levels and
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Table 1 (continued) 4
Morgan, C
Year of publication
2014
Aim
Methods
Results
Authors' conclusions
acid (AA) in PN of extremely low birth weight infants on metabolic tolerance, short-term growth, and neurodevelopment.
(N = 114).
better glucose control. An extra 8 g/kg of AA over the first 10 days of life did not improve growth and neurodevelopment.
To compare the change in HC (ΔHC) and HC SD score (ΔSDS) achieved at day 28 in infants b29 weeks of gestational age randomly assigned to receive Standardised, Concentrated With Added Macronutrients Parenteral (SCAMP) nutrition or a control standardised, concentrated PN regimen.
RCT. Control PN (10% glucose, 2.8 g/kg per day protein/lipid) was started within 6 h of birth. Infants were randomly assigned to either start SCAMP (12% glucose, 3.8 g/kg per day protein/lipid) or remain on the control regimen (N = 148).
36 weeks and 2 years were similar between groups. Bayley Scales of Infant and Toddler Development, Third Edition score was 94 ± 13 in the standard AA group and 97 ± 15 in the high AA group (P = .35). The SCAMP group had a greater ΔHC at 28 days (P b .001) that persisted to 36 weeks of corrected gestational age.
Early versus late initiation of lipid and lipid composition Vlaardingerbroek, 2013 The objective was to summarise the effects of Systematic review of RCTs H initiation of lipids within the first 2 days of life and the effects of different lipid compositions on growth and morbidities in VLBW infants.
Early postnatal head growth failure in very preterm infants can be ameliorated by optimising PN.
The search yielded 14 studies. No differences were observed in growth or morbidity with early lipid initiation. A weak favourable association of nonpurely soybean-based emulsions with the incidence of sepsis (RR: 0.75; 95% CI: 0.56, 1.00) was observed.
The initiation of lipids within the first 2 days of life in VLBW infants appears to be safe and well tolerated; however, beneficial effects on growth could not be shown for this treatment nor for the type of lipid emulsion.
RCT of standardised regime versus individualised PN regimens from day 2 to day 7 of life (N = 58).
Infants in the standardised PN group received less sodium (P b 0.01) and no potassium on day 2 as required, more protein (P b 0.02) every day, and more calcium and phosphate (P b 0.02 from day 4).
Use of standardised computerised parenteral nutrition protocols and regimens compared to prescriptions by individual neonatologists on outcomes of weight changes, adequacy of parenteral nutrition, days of hospitalisation, clinical outcome. To evaluate the impact of a newly implemented standardised PN regimen
Non-randomised comparison of two cohorts. Allocation not described (N = 60).
Retrospective comparative study (N = 140).
Standardised protocols provided more energy (Pvalue: 0.05), protein (P-value: 0.023) and micronutrients than the non-standardised. Neonates that received standardised PN gained more weight (+44 ± 114 g) than those in the individualised group during PN administration. Amino-acid intakes on day 3 were higher in the standard group (1.5+/−0.2 g/kg/d vs. 0.9+/−0.5, P b 0.001), and the calcium phosphate intakes were better balanced. The cumulative intake of amino acids for the first week was greater in the standard group (+20%; P = 0.0003). Biochemical parameters were similar in both groups. Insulin infusions were less frequent in the standard group (P b 0.06). Infants receiving IND-PN showed significantly greater weight gain SDS during the 1st week (P = 0.036) and the 1st month of life (P = 0.0004), and higher discharge weight SDS (P = 0.012) and head circumference SDS (P = 0.006) and received higher mean daily caloric intakes. They also had significantly shorter durations of exclusive PN and needed less electrolyte corrections. Parenteral protein intake during the first week of life and parenteral lipid, glucose and energy intakes during the first and second weeks of life were significantly higher in infants assessed after the introduction of computerised parenteral nutrition ordering. There was significant reduction in the cumulative energy deficit over the first 28 days of life. The mean weight gain in Group 1 (4.9 g/day) was significantly less than in Group 2 (11.8 g/day) (P less than 0.02). The amount of protein provided to Group 2 (2.2 g/kg/day) was significantly greater than that to Group 1 (1.9 g/kg/day) (P less than 0.01). The number of calories provided per day was greater for Group 2 (63 kcal/kg/day) than for Group 1 (53 kcal/ kg/day) (p less than 0.001). The mean daily cost was greater for Group 2.
No significant clinical and statistical differences in biochemical responses in those who received standardised versus individualised PN regimes during the first week of life. The economic cost of PN provision using standardised PN formulation was approximately 30% lower The use of standardised protocols in preterm neonates resulted in more adequate provision of nutrients, weight gain and better blood count profile compared with protocols prescribed by individual physicians.
Standardised versus individualised PN Yeung, MY 2003 To evaluate the difference in nutrient intakes and biochemical responses in newborn infants b33 weeks of gestation who received standardised versus individualised PN regimens.
Skouroliakou, M
2009
Lenclen, R
2006
Smolkin, T
2010
To compare individualised (IND-PN) and standard (STD-PN) on nutritional and growth parameters, complications and cost.
Eleni-dit-Trolli, S
2009
To determine the effects of computerising PN orRetrospective cohort study N = 40 dering on the composition of PN solutions and early clinical outcomes of preterm infants born b or =28 weeks of gestation
Dice, JE
1981
To study the clinical contribution and cost effectiveness of pharmacist involvement in peripheral-vein PN in a neonatal intensive-care unit
Retrospective observational study. Comparison with historical cohort (N = 20).
Non-randomised trial. Alternate allocation. Group 1 received standardised PN with no pharmacist monitoring whereas Group 2 received individualised PN with pharmacist monitoring (N = 28).
Standardised parenteral formulations provided higher early intakes of amino acid and glucose, a better calcium phosphate ratio, and a greater amount of amino-acid intakes during the first week while maintaining the same biochemical parameters.
Infants receiving IND-PN achieved significantly better growth without added clinical or laboratory complications, had a shorter period of exclusive PN and less electrolyte corrections.
Computerising the PN ordering process improves the nutrient content of the PN solutions and early postnatal outcome.
Pharmacist monitoring of an individualised programme of PN in neonates provided a greater mean daily weight gain, allowed a greater amount of nutrients to be provided, and was cost effective.
S. Uthaya, N. Modi / Early Human Development xxx (2014) xxx–xxx
Please cite this article as: Uthaya S, Modi N, Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.09.002
Author
S. Uthaya, N. Modi / Early Human Development xxx (2014) xxx–xxx
have included growth and other anthropometry as outcome measures [11,20,21]. No trials have involved the a priori study of the impact of macronutrient content on body composition, brain development or functional outcomes such as neurodevelopment and long term metabolic health. 5. Problems with the evidence The majority of the studies found in this search and review of the literature on PN in preterm infants focused on short-term outcomes, safety and tolerability. A cardinal continuing difficulty in defining preterm nutritional requirements is that the regimen that results in optimal long-term health is not known. Intrauterine nutrient accretion is interrupted after birth, a challenge that is particularly marked and prolonged when birth is preterm. Data from the National Data Analysis Unit show that year on year more infants born at less than 30 weeks of gestational age commence PN within the first 48 h after birth, but to-date around a quarter to a fifth of babies in the UK have not commenced PN by day 3 (Fig. 1). Thus preterm babies are vulnerable to substantial cumulative nutritional deficits [22, 23]. Deficits accumulated in the period after birth combined with factors that increase requirements result in a progressive deficit that increases the magnitude of later catch-up growth and the risk of later cardiometabolic ill health [24]. Preterm infants have altered body composition and are at risk of insulin resistance in later life [25–27]. We have described aberrant adipose tissue partitioning, increased intrahepatocellular lipid content and increased insulin resistance in preterm infants at term age equivalent compared to healthy term infants [28,29]. At pre-pubertal age preterm infants have insulin resistance compared to term born infants [30]. As adults, compared to term born adults, they have higher blood pressure [31,32], glucose intolerance [33], insulin resistance and dyslipidaemia [34]. Insulin resistance in pre-pubertal children born extremely preterm is associated with neonatal nutrition. The diet of all the preterm infants was characterised by being low in protein in the first month and subsequently high in fat. Those that had a higher carbohydrate intake in the first month and gained most weight in infancy were most insulin
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resistant [35]. It has also been suggested that there are critical periods in development during which nutrition induces permanent effects on later health [36]. A period of nutritional deprivation (though not specifically in any one macronutrient) in the early postnatal period may have beneficial effects on insulin resistance in preterm infants in adolescence [37]. The quality and quantity of nutrition in the early postnatal period have the potential to influence not just short-term outcomes but the long-term neurodevelopmental and metabolic health of this vulnerable group of infants but this remains to be tested in high quality studies. Weight gain does not reflect weight gain composition and cannot be used to determine the optimum nutritional intake of preterm infants [38] . Body composition is related to metabolic health in children and adults, but whether this is true in infancy and whether body composition tracks from infancy to childhood and adult life, are not known. Head circumference, while often used as a surrogate for brain growth, is not adequately predictive of future neurodevelopmental or neurocognitive outcome. Slower growth is associated with adverse neurodevelopmental outcome [39] but there are no RCTs that have targeted more rapid growth velocity and shown improved neurodevelopmental and neurocognitive outcomes. Indeed the converse is the case, with infants fed exclusive human milk diets showing both slower growth velocity and improved neurodevelopmental outcomes [40]. Other data indicate that ‘overnutrition’ may be detrimental to neurodevelopmental outcome [41]. Recommendations for postnatal nutrient intake that are based on intrauterine accretion rates are based upon the unproven assumption that the growth velocity of preterm infants should be based upon reaching – by 40 weeks of gestation – the size of a baby born at full term. This is a potentially dangerous assumption as rapid weight gain in infancy is related to adverse metabolic health in later life. The optimum growth pattern that preserves neurodevelopmental outcomes and promotes long-term health has not been determined. 6. Recommendations for practice The number and quality of studies conducted to date are inadequate to provide firm recommendations. Commencing PN soon after birth is safe and well tolerated. Delaying PN, for example, until a central line is inserted, is not necessary. There is no evidence for level of osmolarity/
Fig. 1. Time that PN was first given to babies born b30 + 6 weeks by birth year in all neonatal units in England and Wales, as reported in the National Neonatal Research Database between 01 January 2010 and 31 December 2013. (N = 3646, 4047, 4090, 4123 in 2010, 2011, 2012 and 2013 respectively). Data courtesy of the Neonatal Data Analysis Unit, Imperial College London.
Please cite this article as: Uthaya S, Modi N, Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.09.002
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glucose concentration at which risk outweighs benefits. Fluid requirements should be considered separately from nutritional requirements. Preterm infants should not be fluid restricted routinely and in the absence of indications such as renal or heart failure, the volume that allows the delivery of optimal nutrition should be administered. Amino acids should be commenced as soon as possible after birth and no later than 24 h. It is safe to commence 2–3.5 g/kg/day of amino acids from day one. The benefits of higher amino acid intakes on short or long-term outcomes remain to be established. Lipid should be commenced on day one. There is currently no evidence to support the routine use of third generation lipids such as SMOF Lipid. Carbohydrate intake may be commenced at 8–10 g/kg/day and may be increased depending on glucose control. There is no evidence for preferring the use of insulin to reducing glucose intake to manage hyperglycaemia. There are several benefits for the use of standardised over individualised PN in babies that do not have specific nutritional requirements. These include reduction in the risk of errors in prescribing, compounding and administration of PN, reduction in the risk of infection and cost effectiveness. Electrolyte requirements can be met without interfering with the prescription of PN and nutrition by using parallel infusions of normal saline or potassium. 7. What is needed now? In order to make firm recommendations for practice, RCTs with sufficient power to address functional outcomes in childhood and later life are necessary. Neurodevelopmental and metabolic outcomes are key functional outcomes of interest. There is also a need for standardised reporting of outcomes. Cardinal unresolved questions are the optimal protein and energy intakes and the growth velocity that is predictive of optimal long-term health. In the absence of such data the focus of early nutritional support in extremely preterm infants should be the prevention of early nutritional deficits and avoidance of the need for catch up growth. Conflict of interest statement SU has received grant support from the National Institute of Health Research and the Department of Health. In the last five years NM has received consultancy fees from Ferring Pharmaceuticals, speaker honorarium for an educational meeting funded by Nestle International in which they had no organisational involvement, and grants from the National Institute of Heath Research, Westminster Children's Trust Fund, Child Growth Foundation, Action Medical Research, HCA International, Danone, Bliss, British Heart Foundation, and Department of Health. References [1] Mason DG, Puntis JW, McCormick K, Smith N. Parenteral nutrition for neonates and children: a mixed bag. Arch Dis Child 2011;96(3):209–10. [2] Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R, Parenteral Nutrition Guidelines Working G, et al. 1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr 2005;41(Suppl. 2):S1–S87. [3] Moyses HE, Johnson MJ, Leaf AA, Cornelius VR. Early parenteral nutrition and growth outcomes in preterm infants: a systematic review and meta-analysis. Am J Clin Nutr 2013;97(4):816–26. [4] Trivedi A, Sinn JK. Early versus late administration of amino acids in preterm infants receiving parenteral nutrition. Cochrane Database Syst Rev 2013;7:CD008771. [5] Thureen PJ, Melara D, Fennessey PV, Hay Jr WW. Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res 2003;53(1):24–32. [6] Vlaardingerbroek H, Vermeulen MJ, Rook D, van den Akker CH, Dorst K, Wattimena JL, et al. Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants. J Pediatr 2013; 163(3):638–44 [e1-5]. [7] Clark RH, Chace DH, Spitzer AR, Pediatrix Amino Acid Study G.. Effects of two different doses of amino acid supplementation on growth and blood amino acid levels in premature neonates admitted to the neonatal intensive care unit: a
randomized, controlled trial. Pediatrics 2007;120(6):1286–96. [8] Balasubramanian H, Nanavati RN, Kabra NS. Effect of two different doses of parenteral amino acid supplementation on postnatal growth of very low birth weight neonates, a randomized controlled trial. Indian Pediatr 2013;50(12):1131–6. [9] Blanco CL, Gong AK, Schoolfield J, Green BK, Daniels W, Liechty EA, et al. Impact of early and high amino acid supplementation on ELBW infants at 2 years. J Pediatr Gastroenterol Nutr 2012;54(5):601–7. [10] Burattini I, Bellagamba MP, Spagnoli C, D'Ascenzo R, Mazzoni N, Peretti A, et al. Targeting 2.5 versus 4 g/kg/day of amino acids for extremely low birth weight infants: a randomized clinical trial. J Pediatr 2013;163(5):1278–82 [e1]. [11] Morgan C, McGowan P, Herwitker S, Hart AE, Turner MA. Postnatal head growth in preterm infants: a randomized controlled parenteral nutrition study. Pediatrics 2014;133(1):e120–8. [12] Vlaardingerbroek H, Veldhorst MA, Spronk S, van den Akker CH, van Goudoever JB. Parenteral lipid administration to very-low-birth-weight infants—early introduction of lipids and use of new lipid emulsions: a systematic review and meta-analysis. Am J Clin Nutr 2012;96(2):255–68. [13] Yeung MY, Smyth JP, Maheshwari R, Shah S. Evaluation of standardized versus individualized total parenteral nutrition regime for neonates less than 33 weeks gestation. J Paediatr Child Health 2003;39(8):613–7. [14] Skouroliakou M, Koutri K, Stathopoulou M, Vourvouhaki E, Giannopoulou I, Gounaris A. Comparison of two types of TPN prescription methods in preterm neonates. Pharm World Sci 2009;31(2):202–8. [15] Lenclen R, Crauste-Manciet S, Narcy P, Boukhouna S, Geffray A, Guerrault MN, et al. Assessment of implementation of a standardized parenteral formulation for early nutritional support of very preterm infants. Eur J Pediatr 2006;165(8):512–8. [16] Smolkin T, Diab G, Shohat I, Jubran H, Blazer S, Rozen GS, et al. Standardized versus individualized parenteral nutrition in very low birth weight infants: a comparative study. Neonatology 2010;98(2):170–8. [17] Eleni-dit-Trolli S, Kermorvant-Duchemin E, Huon C, Mokthari M, Husseini K, Brunet ML, et al. Early individualised parenteral nutrition for preterm infants. Arch Dis Child Fetal Neonatal Ed 2009;94(2):F152–3. [18] Dice JE, Burckart GJ, Woo JT, Helms RA. Standardized versus pharmacist-monitored individualized parenteral nutrition in low-birth-weight infants. Am J Hosp Pharm 1981;38(10):1487–9. [19] Ibrahim HM, Jeroudi MA, Baier RJ, Dhanireddy R, Krouskop RW. Aggressive early total parental nutrition in low-birth-weight infants. J Perinatol 2004;24(8):482–6. [20] Kotsopoulos K, Benadiba-Torch A, Cuddy A, Shah PS. Safety and efficacy of early amino acids in preterm b28 weeks gestation: prospective observational comparison. J Perinatol 2006;26(12):749–54. [21] Scattolin S, Gaio P, Betto M, Palatron S, De Terlizzi F, Intini F, et al. Parenteral amino acid intakes: possible influences of higher intakes on growth and bone status in preterm infants. J Perinatol 2013;33(1):33–9. [22] Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics 2001;107(2):270–3. [23] Vasu V, Durighel G, Thomas L, Malamateniou C, Bell JD, Rutherford MA, et al. Preterm nutritional intake and MRI phenotype at term age: a prospective observational study. BMJ Open 2014;4(5):e005390. [24] Kerkhof GF, Willemsen RH, Leunissen RW, Breukhoven PE, Hokken-Koelega AC. Health profile of young adults born preterm: negative effects of rapid weight gain in early life. J Clin Endocrinol Metab 2012;97(12):4498–506. [25] Tinnion R, Gillone J, Cheetham T, Embleton N. Preterm birth and subsequent insulin sensitivity: a systematic review. Arch Dis Child 2014;99(4):362–8. [26] Piemontese P, Liotto N, Garbarino F, Morniroli D, Taroni F, Bracco B, et al. Effect of prematurity on fat mass distribution and blood pressure at prepubertal age: a follow-up study. Pediatr Med Chir 2013;35(4):166–71. [27] Uthaya S, Thomas EL, Bell J, Modi N. Adipose tissue quantity and distribution in healthy term infants using magnetic resonance imaging. Pediatr Res 2005;58:354–428. [28] Thomas EL, Uthaya S, Vasu V, McCarthy JP, McEwan P, Hamilton G, et al. Neonatal intrahepatocellular lipid. Arch Dis Child Fetal Neonatal Ed 2008;93(5):F382–3. [29] Uthaya S, Thomas EL, Hamilton G, Dore CJ, Bell J, Modi N. Altered adiposity after extremely preterm birth. Pediatr Res 2005;57(2):211–5. [30] Hofman PL, Regan F, Jackson WE, Jefferies C, Knight DB, Robinson EM, et al. Premature birth and later insulin resistance. N Engl J Med 2004;351(21):2179–86. [31] Irving RJ, Belton NR, Elton RA, Walker BR. Adult cardiovascular risk factors in premature babies. Lancet 2000;355(9221):2135–6. [32] Rotteveel J, van Weissenbruch MM, Twisk JW, Delemarre-van de Waal HA. Infant and childhood growth patterns, insulin sensitivity, and blood pressure in prematurely born young adults. Pediatrics 2008;122(2):313–21. [33] Hovi P, Andersson S, Eriksson JG, Jarvenpaa AL, Strang-Karlsson S, Makitie O, et al. Glucose regulation in young adults with very low birth weight. N Engl J Med 2007;356(20):2053–63. [34] Rotteveel J, van Weissenbruch MM, Twisk JW, Delemarre-van de Waal HA. Abnormal lipid profile and hyperinsulinaemia after a mixed meal: additional cardiovascular risk factors in young adults born preterm. Diabetologia 2008;51(7):1269–75. [35] Regan FM, Cutfield WS, Jefferies C, Robinson E, Hofman PL. The impact of early nutrition in premature infants on later childhood insulin sensitivity and growth. Pediatrics 2006;118(5):1943–9. [36] Wiedmeier JE, Joss-Moore LA, Lane RH, Neu J. Early postnatal nutrition and programming of the preterm neonate. Nutr Rev 2011;69(2):76–82. [37] Singhal A, Fewtrell M, Cole TJ, Lucas A. Low nutrient intake and early growth for later insulin resistance in adolescents born preterm. Lancet 2003;361(9363): 1089–97. [38] Putet G, Senterre J, Rigo J, Salle B. Energy balance and composition of body weight. Biol Neonate 1987;52(Suppl. 1):17–24.
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S. Uthaya, N. Modi / Early Human Development xxx (2014) xxx–xxx [39] Latal-Hajnal B, von Siebenthal K, Kovari H, Bucher HU, Largo RH. Postnatal growth in VLBW infants: significant association with neurodevelopmental outcome. J Pediatr 2003;143(2):163–70. [40] Lucas A, Morley R, Cole TJ, Gore SM. A randomised multicentre study of human milk versus formula and later development in preterm infants. Arch Dis Child Fetal Neonatal Ed 1994;70(2):F141–6.
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[41] Morley R, Fewtrell MS, Abbott RA, Stephenson T, MacFadyen U, Lucas A. Neurodevelopment in children born small for gestational age: a randomized trial of nutrient-enriched versus standard formula and comparison with a reference breastfed group. Pediatrics 2004;113(3 Pt 1):515–21.
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Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice S. Uthaya ⁎, N. Modi 1 Imperial College London, UK Chelsea Westminster Hospital NHS Foundation Trust, London, UK
a r t i c l e
i n f o
Available online xxxx Keywords: Parenteral nutrition Amino acids Prematurity Newborn intensive care Nutrition Infant Intravenous lipids
a b s t r a c t Current practice in relation to the prescribing, compounding and administration of parenteral nutrition for extremely preterm infants is inconsistent and based on largely historical evidence. Increasingly there are calls for more ‘aggressive’ nutritional interventions to prevent ‘postnatal growth failure’. However the evidence base for these recommendations is weak, and there are no long-term studies examining the impact of such practices. Here we summarise the evidence for preterm parenteral nutrition interventions. We suggest principles to guide practice based on evidence from a systematic search and review of evidence to date, and recommend actions necessary to advance the understanding of this important aspect of preterm care. © 2014 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Early versus later introduction of PN . . . . . . . . . 3.2. Early versus later administration of amino acids . . . . 3.3. Low versus high intake of amino acids . . . . . . . . . 3.4. Early versus late initiation of lipid and lipid composition 3.5. Standardised versus individualised PN . . . . . . . . . 4. Conclusions from the evidence . . . . . . . . . . . . . . . 5. Problems with the evidence . . . . . . . . . . . . . . . . . 6. Recommendations for practice . . . . . . . . . . . . . . . 7. What is needed now? . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Current practice in relation to preparation, prescribing and administration of preterm parenteral nutrition (PN) is variable, inconsistent and a potential clinical risk. Two UK reports summarise these concerns (http://www.rpharms.com/support-pdfs/minimising-risk-pn-children-
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(6).pdf) [1]. Working groups such as those from the European Society of Paediatric Gastroenterology Hepatology and Nutrition acknowledge the limited evidence base for current guidelines [2]. Here we present a summary of a systematic search and review of the literature and set out principles upon which to base practical aspects of PN in preterm infants. 2. Methods
⁎ Corresponding author at: Imperial College London, UK and Chelsea and Westminster Hospital NHS Foundation Trust, UK. Tel.: +44 20 3315 8000. E-mail addresses: [email protected] (S. Uthaya), [email protected] (N. Modi). 1 Tel.: +44 20 3315 8000.
We conducted an initial search to identify clinical trials of PN in preterm infants and categorised these by types of intervention. We then conducted separate literature searches of each intervention. We confined all searches to preterm infants, defined as infants born less
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Please cite this article as: Uthaya S, Modi N, Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.09.002
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than 37 weeks of gestational age, receiving PN. We excluded studies involving infants with short-gut syndrome, PN associated liver disease, and studies of PN exposure to light. All outcomes were included. We searched Embase 1980 to the week of the search (week 34 of 2014) using population search terms neonat$.mp. or newborn intensive care/or prematurity/. We confined our search to human studies, preterm studies and English language papers. All abstracts were screened for relevance and eligibility. Papers were excluded by reading the abstracts. We excluded conference abstracts, and papers relating to long term PN in the management of intestinal failure. We included observational studies where there was no RCT. Where a systematic or Cochrane Library review was found, we replicated the search using the same criteria. If more recent studies since the publication of the review were not found, the review, not the individual studies, was summarised and included in the results. Studies included in this review are shown in Table 1.
3. Results Interventions that were identified in the initial search were: 1) early versus later introduction of PN, 2) early versus late administration of amino acids, 3) incremental versus recommended daily intake or low versus high intake of amino acids, 4) early versus late initiation of lipid and lipid composition, and 5) standardised versus individualised PN.
3.1. Early versus later introduction of PN We identified a systematic review of early versus late administration of PN on growth outcomes; this included observational studies and RCT [3]. Eight RCTs and 13 observational studies met the inclusion criteria of the systematic review but the meta-analysis was limited by multiple growth outcome measures. Other outcomes including mortality, necrotising enterocolitis, sepsis, chronic lung disease, intraventricular haemorrhage, cholestasis and neurodevelopmental outcome were included. The definition of early and late in the included studies varied widely. Early was defined from immediately after delivery to b48 h after birth. Late administration was defined from 12 h to 6 days after birth. Early PN reduced the time to regain birth weight by 2.2 days (95% CI 1.1, 3.2 d) and by 3.2 days (95% CI 2.0, 4.4 d) in observational studies. The maximum percentage weight loss with early PN was lower by 3.1 percentage points (95% CI 1.7, 4.5 percentage points) for RCT and by 3.5 percentage points (95% CI 2.6, 4.3 percentage points) for observational studies. Early PN improved weight at discharge or 36 weeks of postmenstrual age by 14.9 g (95% CI 5.3, 24.5 g) (observational studies only), but no statistically significant differences were identified in length, head circumference or mortality.
3.2. Early versus later administration of amino acids We identified a Cochrane review of the impact of early versus late administration of amino acid solution with or without other PN constituents, on a variety of outcomes [4]. An improvement in nitrogen balance was found in four of the seven studies included in this review. One study found that the group that received amino acids in the first 24 h had an advantage in length of stay, days to enteral nutrition, duration of admission and days to regain birth weight. The review identified no short-term differences in length and occipito-frontal circumference between the experimental and control groups. Early administration of amino acids on the other primary outcomes of interest, weight gain, discharge weight, neurodevelopmental outcome at two years of age, and all-cause mortality at 28 days and before discharge, was not reported in the included studies.
3.3. Low versus high intake of amino acids No prior review was identified hence we carried out a search using the population search term as above and combined with the criteria *amino acid/ct, iv, pa [Clinical Trial, Intravenous Drug Administration, Parenteral Drug Administration]. We found seven RCTs comparing low and incremental versus high intake of amino acids (we excluded studies that compared early versus late introduction of amino acids, that is the subject of the Cochrane review in the section above) [5–10]. The low intakes varied from commencing at 1.0 g/kg/day to 2.4 g/kg/day to a maximum of 2.5 g/kg/day. The high intakes varied between 3 and 4 g/kg/day with some studies commencing at lower intakes and increasing over the first few days. One study showed no improvement in early growth [7], one showed worse growth in the high amino acid group [8] and one showed no further improvement in nitrogen balance between the groups that received 2.4 versus 3.6 g/kg/day than occurred with the concurrent administration of early lipid from birth [6]. One study reported on the 2-year neurodevelopmental outcomes (as a secondary outcome) of low versus high amino acid intake and found no differences between the groups but overall growth was poorer in the high amino acid group [9]. A non-blinded RCT that did not feature in the search results but was identified in PubMed compared the intake of low and incremental amino acid (commencing at 1.5 g/kg/day increasing to a maximum of 2.5 g/kg/day) with high and incremental amino acid (commencing at 2.5 g/kg/day and increasing to 4 g/kg/day) on body size at 36 weeks and found no difference between the two groups. Follow-up of the cohort showed no difference in neurodevelopment at 2 years of age [10]. A further study that was identified in the initial search for studies of PN but not in the individual search comparing low versus high amino acid intake aimed to compare control PN (10% glucose, 2.8 g/kg per day protein/lipid) with Standardised, Concentrated With Added Macronutrients Parenteral (SCAMP) nutrition regimen (12% glucose, 3.8 g/kg per day protein/lipid) on early head growth [11]. A significant difference in change in head circumference between birth and 28 days was found that persisted to 36 weeks of corrected gestational age. Neurodevelopment was not assessed. 3.4. Early versus late initiation of lipid and lipid composition We found a systematic review of 14 eligible RCTs investigating early (defined as in the first 2 postnatal days) versus late (defined as after age 2 days) initiation of lipids that showed no differences in a variety of outcome measures including growth. In relation to the type of lipid emulsion there was a weak association with lower rates of sepsis in the nonsoya-bean emulsion group but larger RCTs investigating the impact of lipid emulsions that are not purely soya-bean oil based are recommended [12]. 3.5. Standardised versus individualised PN No prior review was identified hence we carried out a search using the criteria: standard$ parenteral nutrition.mp. or. individual$ parenteral nutrition.mp. combined with the population search criteria as described above. There is limited evidence to suggest benefit of one over the other. There were no RCTs identified in the search so observational cohort studies were included. Some studies showed that the group receiving standardised PN received more protein and calories [13–15]. Other studies found that those receiving individualised PN received more nutrition and had better growth outcomes [16–18]. 4. Conclusions from the evidence The majority of studies investigating the impact of PN macronutrient content have focused on safety and short-term biochemical indices (serum urea, liver function tests, and metabolic acidosis) or surrogate markers of protein accretion (nitrogen balance) [5,19]. A few studies
Please cite this article as: Uthaya S, Modi N, Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.09.002
Author
Year of Aim publication
Early versus late introduction of PN Moyses, HE 2013 Whether earlier administration of PN benefits growth outcomes in preterm infants.
Early versus late administration of amino acids Trivedi, A 2013 To determine the effect of early administration of amino acids in premature newborns on growth, neurodevelopmental outcome, mortality and clinically important side effects.
Low versus high intake of amino acids Thureen, PJ 2004 To study the efficacy and safety of more aggressive amino acid intake
Methods
Results
Authors' conclusions
Systematic review of randomised controlled trials (RCTs) and observational studies.
Eight RCTs and 13 observational studies met the inclusion criteria. Early PN reduced the time to regain birth weight by 2.2 days (1.1, 3.2 days) for RCTs and 3.2 days (2.0, 4.4 days) in observational studies. Early PN improved weight at discharge or 36 weeks of postmenstrual age by 14.9 g (5.3, 24.5 g) (observational studies only), but no benefit was shown for length or head circumference.
Early PN provides a benefit for some short-term growth outcomes.
Cochrane systematic review
Seven randomised controlled trials were included in this review. One randomised controlled trial reported no difference in crown-heel length and occipito-frontal head circumference by day 10. Four trials showed positive nitrogen balance (the mean difference with 95% CI was 250.42 (224.91 to 275.93) P value b 0.00001). Early administration of amino acids did not result in metabolic acidosis in the first 24 h.
There is no available evidence of the benefits of early administration of amino acids on mortality, early and late growth and neurodevelopment.
Randomised controlled trial comparing low (LAA) 1 g/kg/day vs. high (HAA) 3 g/kg/day on protein balance (N = 28).
Protein balance was significantly lower in the LAA versus HAA groups by both nitrogen balance (−0.26 ± 0.11 versus 1.16 ± 0.15 g/kg/day, P b 0.00005) and leucine stable isotope (0.184 ± 0.17 versus 1.63 ± 0.20 g/kg/day, P b 0.0005) methods. There was no significant difference in growth by day 28 after birth (median weight gain: 12.9 and 11.4 g/ kg per day for the 3.5 and 2.5 g/kg per day groups, respectively), and the incidences of secondary morbidities were similar in the 2 groups. On day 7, blood levels of several amino acids and the serum urea nitrogen level were higher in the 3.5 g/kg per day group, compared with the 2.5 g/kg per day group; none of the amino acid levels were lower. The gain in weight, length and head circumference at 28 days were significantly lower in the high AA group. The average weight gain at 28 days was 8.67 g/kg/d in the high AA group and 13.15 g/kg/d in the Low AA group (mean difference 123.12, 95% CI 46.67 to 199.37, P b 0.001). Mental Developmental Index (MDI) and Psychomotor Developmental Index were similar between groups; however, the early and high AA group had a lower MDI at 18 months. This difference disappeared at 2 years of age. The early and high AA group z score means for weight, length, and head circumferences were significantly lower than the standard AA group at most visits. Nitrogen balance on day 2 was significantly greater in both intervention groups compared with the control group. Greater amounts of AA administration did not further improve nitrogen balance compared with standard AA dose plus lipids and was associated with high plasma urea concentrations and high rates of urea appearance. No differences in other biochemical variables, growth, or clinical outcomes were observed. Body weight, length, and head circumference at
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.
Clark, RH
2007
To measure the effects of 2 strategies for parenteral nutrition on neonatal growth and blood amino acid profiles in premature infants
RCT. In one group amino acid supplementation was started at 1.0 g/kg per day and advanced by 0.5 g/kg per day to a maximum of 2.5 g/kg per day. The other group received amino acids starting at 1.5 g/kg per day and advancing by 1.0 g/kg per day to a maximum of 3.5 g/kg per day (N = 122).
Balasubramanian, H
2013
To evaluate the effects of two different doses of parenteral amino acid supplementation on postnatal growth in very low birth weight (VLBW) infants receiving partial parenteral nutrition (PPN).
Blanco, CL
2012
To examine the effects of early and high intravenous (IV) amino acid (AA) supplementation on growth, health, and neurodevelopment of extremely-low-birth-weight (ELBW) infants throughout their first 2 years of life.
Double blind RCT. Two different initial doses of parenteral amino acids (AA) in the PPN solutions— low AA group: 1 g/kg/d versus high AA group: 3 g/ kg/d from day 1 of life with increment by 1 g/kg every day till a maximum of 4 g/kg/d, until babies tolerated 75% enteral feeds (N = 150). Double blind RCT. Treatment for 7 days with either IV AA starting at 0.5 g/kg/day and increased by 0.5 g/kg/day every day to 3 g/kg/day or starting at 2 g/kg/day of IV AA and advanced by 1 g/kg/day every day to 4 g/kg/day (N = 43).
Vlaardingerbroek, 2013 H
To assess the efficacy and safety of early parenteral lipid and high-dose amino acid (AA) administration from birth onwards in very low birth weight (VLBW, birth weight b1500 g) infants.
RCT. 2.4 g/kg/day of amino acid (control group), vs. 2.4 g/kg/day AA plus 2–3 g/kg/day lipids. (AA + lipid group), or 3.6 g/kg/day AA plus 2–3 g/kg/day lipids (high AA + lipid group) from birth onwards. The primary outcome was nitrogen balance (N = 144).
Burattini, I
To compare the effect of 2.5 vs. 4 g/kg/d of amino
RCT. Primary outcome was body size at 36 weeks
2013
Higher doses of amino acid supplementation did not improve neonatal growth and were associated with increased blood amino acid and urea nitrogen levels.
Higher initial parenteral amino acid supplementation, in settings where partial parenteral nutrition is administered, results in poor growth in VLBW infants due to inadequate nonprotein calorie intake.
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Please cite this article as: Uthaya S, Modi N, Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.09.002
Table 1 Summary of studies included in this review.
ELBW infants who received early and high IV AA during the first week of life were associated with poor overall growth at 2 years.
Parenteral AA combined with lipids from birth onwards improved conditions for anabolism and growth, as shown by improved nitrogen balance. Greater levels of AA administration did not further improve the nitrogen balance but led to increased AA oxidation.
The high AA group had higher blood urea levels and
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Table 1 (continued) 4
Morgan, C
Year of publication
2014
Aim
Methods
Results
Authors' conclusions
acid (AA) in PN of extremely low birth weight infants on metabolic tolerance, short-term growth, and neurodevelopment.
(N = 114).
better glucose control. An extra 8 g/kg of AA over the first 10 days of life did not improve growth and neurodevelopment.
To compare the change in HC (ΔHC) and HC SD score (ΔSDS) achieved at day 28 in infants b29 weeks of gestational age randomly assigned to receive Standardised, Concentrated With Added Macronutrients Parenteral (SCAMP) nutrition or a control standardised, concentrated PN regimen.
RCT. Control PN (10% glucose, 2.8 g/kg per day protein/lipid) was started within 6 h of birth. Infants were randomly assigned to either start SCAMP (12% glucose, 3.8 g/kg per day protein/lipid) or remain on the control regimen (N = 148).
36 weeks and 2 years were similar between groups. Bayley Scales of Infant and Toddler Development, Third Edition score was 94 ± 13 in the standard AA group and 97 ± 15 in the high AA group (P = .35). The SCAMP group had a greater ΔHC at 28 days (P b .001) that persisted to 36 weeks of corrected gestational age.
Early versus late initiation of lipid and lipid composition Vlaardingerbroek, 2013 The objective was to summarise the effects of Systematic review of RCTs H initiation of lipids within the first 2 days of life and the effects of different lipid compositions on growth and morbidities in VLBW infants.
Early postnatal head growth failure in very preterm infants can be ameliorated by optimising PN.
The search yielded 14 studies. No differences were observed in growth or morbidity with early lipid initiation. A weak favourable association of nonpurely soybean-based emulsions with the incidence of sepsis (RR: 0.75; 95% CI: 0.56, 1.00) was observed.
The initiation of lipids within the first 2 days of life in VLBW infants appears to be safe and well tolerated; however, beneficial effects on growth could not be shown for this treatment nor for the type of lipid emulsion.
RCT of standardised regime versus individualised PN regimens from day 2 to day 7 of life (N = 58).
Infants in the standardised PN group received less sodium (P b 0.01) and no potassium on day 2 as required, more protein (P b 0.02) every day, and more calcium and phosphate (P b 0.02 from day 4).
Use of standardised computerised parenteral nutrition protocols and regimens compared to prescriptions by individual neonatologists on outcomes of weight changes, adequacy of parenteral nutrition, days of hospitalisation, clinical outcome. To evaluate the impact of a newly implemented standardised PN regimen
Non-randomised comparison of two cohorts. Allocation not described (N = 60).
Retrospective comparative study (N = 140).
Standardised protocols provided more energy (Pvalue: 0.05), protein (P-value: 0.023) and micronutrients than the non-standardised. Neonates that received standardised PN gained more weight (+44 ± 114 g) than those in the individualised group during PN administration. Amino-acid intakes on day 3 were higher in the standard group (1.5+/−0.2 g/kg/d vs. 0.9+/−0.5, P b 0.001), and the calcium phosphate intakes were better balanced. The cumulative intake of amino acids for the first week was greater in the standard group (+20%; P = 0.0003). Biochemical parameters were similar in both groups. Insulin infusions were less frequent in the standard group (P b 0.06). Infants receiving IND-PN showed significantly greater weight gain SDS during the 1st week (P = 0.036) and the 1st month of life (P = 0.0004), and higher discharge weight SDS (P = 0.012) and head circumference SDS (P = 0.006) and received higher mean daily caloric intakes. They also had significantly shorter durations of exclusive PN and needed less electrolyte corrections. Parenteral protein intake during the first week of life and parenteral lipid, glucose and energy intakes during the first and second weeks of life were significantly higher in infants assessed after the introduction of computerised parenteral nutrition ordering. There was significant reduction in the cumulative energy deficit over the first 28 days of life. The mean weight gain in Group 1 (4.9 g/day) was significantly less than in Group 2 (11.8 g/day) (P less than 0.02). The amount of protein provided to Group 2 (2.2 g/kg/day) was significantly greater than that to Group 1 (1.9 g/kg/day) (P less than 0.01). The number of calories provided per day was greater for Group 2 (63 kcal/kg/day) than for Group 1 (53 kcal/ kg/day) (p less than 0.001). The mean daily cost was greater for Group 2.
No significant clinical and statistical differences in biochemical responses in those who received standardised versus individualised PN regimes during the first week of life. The economic cost of PN provision using standardised PN formulation was approximately 30% lower The use of standardised protocols in preterm neonates resulted in more adequate provision of nutrients, weight gain and better blood count profile compared with protocols prescribed by individual physicians.
Standardised versus individualised PN Yeung, MY 2003 To evaluate the difference in nutrient intakes and biochemical responses in newborn infants b33 weeks of gestation who received standardised versus individualised PN regimens.
Skouroliakou, M
2009
Lenclen, R
2006
Smolkin, T
2010
To compare individualised (IND-PN) and standard (STD-PN) on nutritional and growth parameters, complications and cost.
Eleni-dit-Trolli, S
2009
To determine the effects of computerising PN orRetrospective cohort study N = 40 dering on the composition of PN solutions and early clinical outcomes of preterm infants born b or =28 weeks of gestation
Dice, JE
1981
To study the clinical contribution and cost effectiveness of pharmacist involvement in peripheral-vein PN in a neonatal intensive-care unit
Retrospective observational study. Comparison with historical cohort (N = 20).
Non-randomised trial. Alternate allocation. Group 1 received standardised PN with no pharmacist monitoring whereas Group 2 received individualised PN with pharmacist monitoring (N = 28).
Standardised parenteral formulations provided higher early intakes of amino acid and glucose, a better calcium phosphate ratio, and a greater amount of amino-acid intakes during the first week while maintaining the same biochemical parameters.
Infants receiving IND-PN achieved significantly better growth without added clinical or laboratory complications, had a shorter period of exclusive PN and less electrolyte corrections.
Computerising the PN ordering process improves the nutrient content of the PN solutions and early postnatal outcome.
Pharmacist monitoring of an individualised programme of PN in neonates provided a greater mean daily weight gain, allowed a greater amount of nutrients to be provided, and was cost effective.
S. Uthaya, N. Modi / Early Human Development xxx (2014) xxx–xxx
Please cite this article as: Uthaya S, Modi N, Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.09.002
Author
S. Uthaya, N. Modi / Early Human Development xxx (2014) xxx–xxx
have included growth and other anthropometry as outcome measures [11,20,21]. No trials have involved the a priori study of the impact of macronutrient content on body composition, brain development or functional outcomes such as neurodevelopment and long term metabolic health. 5. Problems with the evidence The majority of the studies found in this search and review of the literature on PN in preterm infants focused on short-term outcomes, safety and tolerability. A cardinal continuing difficulty in defining preterm nutritional requirements is that the regimen that results in optimal long-term health is not known. Intrauterine nutrient accretion is interrupted after birth, a challenge that is particularly marked and prolonged when birth is preterm. Data from the National Data Analysis Unit show that year on year more infants born at less than 30 weeks of gestational age commence PN within the first 48 h after birth, but to-date around a quarter to a fifth of babies in the UK have not commenced PN by day 3 (Fig. 1). Thus preterm babies are vulnerable to substantial cumulative nutritional deficits [22, 23]. Deficits accumulated in the period after birth combined with factors that increase requirements result in a progressive deficit that increases the magnitude of later catch-up growth and the risk of later cardiometabolic ill health [24]. Preterm infants have altered body composition and are at risk of insulin resistance in later life [25–27]. We have described aberrant adipose tissue partitioning, increased intrahepatocellular lipid content and increased insulin resistance in preterm infants at term age equivalent compared to healthy term infants [28,29]. At pre-pubertal age preterm infants have insulin resistance compared to term born infants [30]. As adults, compared to term born adults, they have higher blood pressure [31,32], glucose intolerance [33], insulin resistance and dyslipidaemia [34]. Insulin resistance in pre-pubertal children born extremely preterm is associated with neonatal nutrition. The diet of all the preterm infants was characterised by being low in protein in the first month and subsequently high in fat. Those that had a higher carbohydrate intake in the first month and gained most weight in infancy were most insulin
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resistant [35]. It has also been suggested that there are critical periods in development during which nutrition induces permanent effects on later health [36]. A period of nutritional deprivation (though not specifically in any one macronutrient) in the early postnatal period may have beneficial effects on insulin resistance in preterm infants in adolescence [37]. The quality and quantity of nutrition in the early postnatal period have the potential to influence not just short-term outcomes but the long-term neurodevelopmental and metabolic health of this vulnerable group of infants but this remains to be tested in high quality studies. Weight gain does not reflect weight gain composition and cannot be used to determine the optimum nutritional intake of preterm infants [38] . Body composition is related to metabolic health in children and adults, but whether this is true in infancy and whether body composition tracks from infancy to childhood and adult life, are not known. Head circumference, while often used as a surrogate for brain growth, is not adequately predictive of future neurodevelopmental or neurocognitive outcome. Slower growth is associated with adverse neurodevelopmental outcome [39] but there are no RCTs that have targeted more rapid growth velocity and shown improved neurodevelopmental and neurocognitive outcomes. Indeed the converse is the case, with infants fed exclusive human milk diets showing both slower growth velocity and improved neurodevelopmental outcomes [40]. Other data indicate that ‘overnutrition’ may be detrimental to neurodevelopmental outcome [41]. Recommendations for postnatal nutrient intake that are based on intrauterine accretion rates are based upon the unproven assumption that the growth velocity of preterm infants should be based upon reaching – by 40 weeks of gestation – the size of a baby born at full term. This is a potentially dangerous assumption as rapid weight gain in infancy is related to adverse metabolic health in later life. The optimum growth pattern that preserves neurodevelopmental outcomes and promotes long-term health has not been determined. 6. Recommendations for practice The number and quality of studies conducted to date are inadequate to provide firm recommendations. Commencing PN soon after birth is safe and well tolerated. Delaying PN, for example, until a central line is inserted, is not necessary. There is no evidence for level of osmolarity/
Fig. 1. Time that PN was first given to babies born b30 + 6 weeks by birth year in all neonatal units in England and Wales, as reported in the National Neonatal Research Database between 01 January 2010 and 31 December 2013. (N = 3646, 4047, 4090, 4123 in 2010, 2011, 2012 and 2013 respectively). Data courtesy of the Neonatal Data Analysis Unit, Imperial College London.
Please cite this article as: Uthaya S, Modi N, Practical preterm parenteral nutrition: Systematic literature review and recommendations for practice, Early Hum Dev (2014), http://dx.doi.org/10.1016/j.earlhumdev.2014.09.002
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glucose concentration at which risk outweighs benefits. Fluid requirements should be considered separately from nutritional requirements. Preterm infants should not be fluid restricted routinely and in the absence of indications such as renal or heart failure, the volume that allows the delivery of optimal nutrition should be administered. Amino acids should be commenced as soon as possible after birth and no later than 24 h. It is safe to commence 2–3.5 g/kg/day of amino acids from day one. The benefits of higher amino acid intakes on short or long-term outcomes remain to be established. Lipid should be commenced on day one. There is currently no evidence to support the routine use of third generation lipids such as SMOF Lipid. Carbohydrate intake may be commenced at 8–10 g/kg/day and may be increased depending on glucose control. There is no evidence for preferring the use of insulin to reducing glucose intake to manage hyperglycaemia. There are several benefits for the use of standardised over individualised PN in babies that do not have specific nutritional requirements. These include reduction in the risk of errors in prescribing, compounding and administration of PN, reduction in the risk of infection and cost effectiveness. Electrolyte requirements can be met without interfering with the prescription of PN and nutrition by using parallel infusions of normal saline or potassium. 7. What is needed now? In order to make firm recommendations for practice, RCTs with sufficient power to address functional outcomes in childhood and later life are necessary. Neurodevelopmental and metabolic outcomes are key functional outcomes of interest. There is also a need for standardised reporting of outcomes. Cardinal unresolved questions are the optimal protein and energy intakes and the growth velocity that is predictive of optimal long-term health. In the absence of such data the focus of early nutritional support in extremely preterm infants should be the prevention of early nutritional deficits and avoidance of the need for catch up growth. Conflict of interest statement SU has received grant support from the National Institute of Health Research and the Department of Health. In the last five years NM has received consultancy fees from Ferring Pharmaceuticals, speaker honorarium for an educational meeting funded by Nestle International in which they had no organisational involvement, and grants from the National Institute of Heath Research, Westminster Children's Trust Fund, Child Growth Foundation, Action Medical Research, HCA International, Danone, Bliss, British Heart Foundation, and Department of Health. References [1] Mason DG, Puntis JW, McCormick K, Smith N. Parenteral nutrition for neonates and children: a mixed bag. Arch Dis Child 2011;96(3):209–10. [2] Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R, Parenteral Nutrition Guidelines Working G, et al. 1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr 2005;41(Suppl. 2):S1–S87. [3] Moyses HE, Johnson MJ, Leaf AA, Cornelius VR. Early parenteral nutrition and growth outcomes in preterm infants: a systematic review and meta-analysis. Am J Clin Nutr 2013;97(4):816–26. [4] Trivedi A, Sinn JK. Early versus late administration of amino acids in preterm infants receiving parenteral nutrition. Cochrane Database Syst Rev 2013;7:CD008771. [5] Thureen PJ, Melara D, Fennessey PV, Hay Jr WW. Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res 2003;53(1):24–32. [6] Vlaardingerbroek H, Vermeulen MJ, Rook D, van den Akker CH, Dorst K, Wattimena JL, et al. Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants. J Pediatr 2013; 163(3):638–44 [e1-5]. [7] Clark RH, Chace DH, Spitzer AR, Pediatrix Amino Acid Study G.. Effects of two different doses of amino acid supplementation on growth and blood amino acid levels in premature neonates admitted to the neonatal intensive care unit: a
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