Systematic Review of the Association Between Protein Intake and Health Outcomes in Hospitalized Children (0-19 yrs)

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Systematic Review of the Association Between

Protein Intake and Health Outcomes in

Hospitalized Children (0-19 yrs)

Authors: Lisa Smeehuijzen and Tessa van der Goot Number of thesis: 2016111

Company: Amsterdam University of Applied Sciences, Lectorate Weight Management Bachelor: Nutrition and Dietetics

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1 School of Sports and Nutrition

Bachelor program Nutrition and Dietetics

Systematic Review of the Association Between

Protein Intake and Health Outcomes in

Hospitalized Children (0-19 yrs)

Names and Student numbers: Tessa van der Goot (500607781) Lisa Smeehuijzen (500663070)

Date: 3 January 2016

Period of thesis project: 1 September 2015 / 29 January 2016 Number of thesis: 2016111

Company: Amsterdam University of Applied Sciences, Lectorate Weight Management

Supervising Lecturer: Dr M.T. Streppel

Examiner: V. Rashid MSc

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Preface

This thesis is the closure of the four year study period in order to achieve our bachelor of applied science degree in nutrition and dietetics. Knowledge we obtained in the last years is applied to conduct this systematic review.

Working on this thesis has been an enrichment to our knowledge about clinical nutrition and provided us with the skills of performing literature research. Our project is part of the PROSYST project which studies the literature about optimal protein intake in hospitalized patients. We wrote this thesis to contribute in the scientific field by providing an overview of the knowledge about optimal protein intake in hospitalized children. We were equally involved in conducting this thesis.

We thank Dr M.T. Streppel for guidance and shared knowledge which was of great value in conducting the search in a systematic way and writing this thesis, and for the help with obtaining full-text papers. We thank K. van Dam for reviewing this thesis on language.

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Abstract

The aim of this systematic review was to assess the evidence behind the association between protein intake and health outcomes in hospitalized children. The results in this review were based on clinical outcomes, nitrogen balance, and protein turnover. Included studies were prospective cohort studies, case-control studies, and (randomized) controlled trials published between 1945 and December 2014. Out of 786 studies provided by the search, 10 studies met the eligibility criteria and were included in this review. The results from individual studies are summarized in evidence tables and quality was graded as A (lowest level of bias), B, or C. For clinical outcomes, high protein intakes have small effects on growth compared to standard protein intakes, but in general these effects were so small they can be considered as insignificant. Lower losses in birth weight and shorter time to regain birthweight was observed in one study. Body length and head circumference was not significantly different in patients on high protein diets compared to standard protein diets. Length of hospitalization was not affected by higher protein intakes in included studies in this review. Nitrogen balance studies show higher retentions of nitrogen at increased protein intake, but no significant benefits were found. Nitrogen balance became positive more often in patients on high protein diets, but was not significantly higher than in patients on standard protein diets who generally remained in negative nitrogen balance. Protein turnover studies showed an increased protein synthesis and catabolism by higher protein intakes with positive protein balances. This effect was not observed in patients on standard protein diets. One study found that anabolism occurred in infants at a protein intake of 1.1 g/kg/d. The quality of the included studies was generally low and the subjects were predominantly infants. It was hard to combine data and make conclusions due to the differences between studies. Based on the results, higher protein intake did not meet the expectations of the individual studies. Clinical interventions with adequate dietary assessment methods to get a more precise view of dietary intakes are necessary.

Keywords: Protein, amino acids, health outcomes, nitrogen balance, protein turnover, hospitalized children.

Abbreviations

ASPEN: The American Society for Clinical Nutrition and Metabolism BUN: blood urea nitrogen

EFSA: European Food Safety Authority ELBW: extreme low birth weight EN: enteral nutrition

FAO: Food and Agriculture Organization LOS: length of hospital stay

NNR5: Nordic Nutrition Recommendations 5th edition PICU: pediatric intensive care unit

PN: parenteral nutrition

RCT: randomized controlled trial TPN: total parenteral nutrition UUN: urine urea nitrogen UNU: United Nations University VLBW: very low birth weight WHO: World Health Organization

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Table of contents (continued)

Appendix I Search strategy 23

Appendix II Excluded full-text articles 27

Appendix III Evidence table of clinical outcomes 34

Appendix IV Evidence table of nitrogen balance 42

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1. Introduction

The physical growth and development of a child is closely related to its nutritional status (1). An adequate intake of dietary protein is needed to replace the degraded and catabolized body protein and stay in positive protein balance. Protein synthesis is essential in maintaining tissue and the synthesis of new tissue during growth (2). In 2007, the World Health Organization (WHO), the Food and Agriculture Organization (FAO), and the United Nations University (UNU) Expert Consultation published protein requirements and reference values for healthy children (see table 1) (3). The European Food Safety Authority (EFSA) revised and approved these guidelines in 2012, based on the same studies as used by the WHO/FAO/UNU in 2007 (4). These requirements reflect the minimum amount of protein intake that enables a positive nitrogen balance providing growth and maintenance in infants and children who have an appropriate body composition, are in energy balance, and have moderate physical activity. The WHO and EFSA have corrected the requirements for protein intake with 58% to compensate for the efficiency of dietary protein utilization (3,4).

Table 1. Protein recommendations for healthy infants, children and adolescents (g/kg/d) (3,4)

Protein turnover is the continuous process of degradation and (re)synthesis of body protein. Due to this mechanism, the body is able to replace the damaged and degraded proteins and regulate the amounts of proteins in the body in response to environmental changes. Amino acids can also be catabolized to provide compounds for energy metabolism or other non-protein compounds. This involves nitrogen removal and catabolism of the carbon skeleton. The nitrogen is excreted primary as urea and ammonia in the urine. Because proteins are the only dietary source with significant amounts of nitrogen, the excretion reflects protein degradation and can be expressed in nitrogen balance (2).

In ill children, the need for protein is higher because of the increased protein breakdown, tissue repair, and the synthesis of acute phase proteins, known as whole body protein turnover (5,6). These reactions, also known as stress responses, are mediated by stress hormones and cytokines and lead to decreased protein synthesis and mobilizing amino acids primary from skeletal muscle. These mobilized amino acids serve as substrate for synthesis of acute phase proteins in the liver, resulting in an increased total plasma protein value (2). It is demonstrated that the protein degradation in infants is 25% higher after surgery and that the urinary nitrogen excretion is 100% increased in case of bacterial sepsis (7). Inadequate nutrition causes an aggravation of protein degradation exceeding protein synthesis which results in increased losses of lean body mass. This may cause aggravation of the problems of the underlying disease and can even cause complications (8,9). Even though studies with high protein diets in ill adults have not shown beneficial effects on neither nitrogen balance or prognosis (10), studies in preterm infants have demonstrated that infusion of amino acids have resulted in a positive nitrogen balance (11,12). Other studies showed that early administration of nutritional support to prevent weight loss in hospitalized children reduce the length of hospital stay, prevent re-hospitalization, and is more cost-effective (13–15). However, there is still too little evidence about the optimal protein intake for hospitalized children. This results in a large population suffering from protein malnutrition during their state of illness. (8,16).

Today’s reference values for protein intake in ill children do not distinguish between a stable state or an exacerbation of the disease. Because of the increased loss of nitrogen during illness, an even

Age (years) Boys Girls 0.5 1.31 1.31 1 1.14 1.14 1.5 1.03 1.03 2 0.97 0.97 3 0.90 0.90 4-6 0.87 0.87 7-10 0.92 0.92 11-14 0.90 0.89 15-18 0.87 0.84

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7 higher loss during exacerbation, generally leading to hospitalization, is plausible to assume (3,10). The guidelines for protein intake for critically ill children, published by The American Society for Clinical Nutrition and Metabolism (ASPEN), are based on limited evidence and estimate the protein needs in a scale of 1.5-3 g/kg/d (7). These recommendations are based on nitrogen balance studies, which are possibly not adequate enough to determine the optimal protein need (17). Apart from these studies, clinical outcomes can be useful to determine an optimal protein intake. Therefore, the aim of this systematic review is to provide an overview of what is already known in the scientific literature about the association between protein intake and different types of health outcomes in hospitalized children. The results of this study can be used to improve guidelines about optimal protein intake during illness. Improved guidelines may prevent protein malnutrition and encourage healing from illness. In addition, good knowledge about the changes in the need for protein during exacerbation of illness can prevent deterioration of the nutritional status when exacerbation actually happens.

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2. Methods

This systematic review is conducted according to the 5th_{edition of the Nordic Nutrition}

Recommendations (NNR5) working group guideline for systematic reviews (18).

2.1 Research question

The main research question was formulated as follows:

‘What is known about the association between protein intake and clinical health outcomes, nitrogen balance, and protein turnover in hospitalized children (0-19 yrs)?’

This main research question has been specified into the following sub questions: What is known about the aforementioned association for:

- different age categories (i.e. newborns, infants, (preschool) children, and adolescents)? - different types of protein (i.e. whole protein, peptides, and amino acids)?

- different sources of protein (i.e. enteral feeding, parenteral feeding, and supplements)? - different types of diagnoses?

Clinical health outcomes include growth (body weight and body length and/or BMI, head

circumference), body composition (adipose tissue and lean body mass), cross-infections and nosocomial infections, in-hospital mortality, hospitalization (length of stay, patient admission and readmission, patient transfer, and hospital costs), and physical fitness (muscle strength and fatigue and/or weakness).

Nitrogen balance and protein turnover outcomes include blood urea nitrogen (BUN), urine urea

nitrogen (UUN), nitrogen retention, protein balance, protein flux, protein anabolism, and protein catabolism.

2.2 Eligibility criteria

2.2.1 Types of interventions

The interventions of the studies were high protein or essential amino acid intake versus low protein intake or placebo, and early versus standard or late administration. Protein intake or essential amino acid intake, administered either by enteral (EN) or parenteral nutrition (PN), from regular nutrition, supplements or formulas of any dose and formulation were included. Studies about protein or amino acid intake in combination with other nutrients, like immunonutrition, were excluded. The interventions had to take place in the hospital, so outpatient treatments were not included.

2.2.2 Patients

The subjects were children between 0 and 19 years old, hospitalized for observation, treatment or diagnosis for various diseases, transplantation or surgery. Palliative care was excluded. Pre-term newborns and newborns with a (very or extreme) low birth weight (VLBW or ELBW) were also included.

2.2.3 Study types

Prospective cohort studies, case-control studies, controlled clinical trials, and randomized clinical trials (RCT) were included. There were no restrictions for the duration of the study, length of follow up, and number of participants. These aspects were taken into account in the quality assessments.

2.2.4 Publication type

Besides the original articles, systematic reviews and meta-analysis were included. The publication language was English.

2.2.5 Time period of publication

Articles published between 1945 until December 2014 were eligible for this review. Table 2 summarizes the eligibility criteria of the included studies.

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9 Table 2. Eligibility criteria

Population Purpose of admission Diseases Sources Protein Types of protein

Study type and design Publication type Children (birth to 19 yrs old) Preterm newborn Newborns with a (very or extremely) low birth weight (≤1250 g) Observation Care* Diagnose Treatment Transplantation Surgery Various diseases, not specified Comorbidity Foods Enteral feeding Parenteral feeding Supplements Protein Peptides Essential amino acids Prospective observational cohort studies Case control studies Randomized controlled studies Nitrogen balance studies Protein turnover studies English language Original articles Meta-analyses Systematic review

*Palliative care excluded

2.3 Search protocol

An initial Medline search, conducted in the OvidSP platform in early 2015, was focused on hospitalized patients of all ages (19). For the current review, the search was adjusted on October 8, 2015, to include only hospitalized children. The MeSH terms infant, child, and adolescent were added to the initial search (19). See appendix I for the entire search strategy.

2.4 Data collection and analysis

2.4.1 Selection procedure

The articles from the adjusted search were divided over the two reviewers and were screened on titles. The same was done with the screening of the abstracts. Articles which did not met the inclusion criteria were excluded. In this phase, the reviewers independently selected articles for inclusion and reviewed all the results of the screening procedure. Next, full texts were obtained and screened by both of the reviewers. If only one of the two reviewers included an article, the article was screened a second time and the decision for in- or exclusion was made together. Doubts and disagreements during the selection procedure were discussed and resolved.

2.4.2 Data extraction

The reviewers both extracted evidence from all the selected articles and created evidence tables. Extracted data included information about the population, outcomes, interventions, results, and potential confounders. The evidence tables were discussed and disagreements were resolved. Evidence tables were sorted by outcome and separated into clinical outcomes, nitrogen balance, and protein turnover.

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2.4.3 Quality assessments

The quality tools of the NNR5 working group guideline were used to identify the risk of bias in the included studies (18). These checklists assess the study design, participants and compliance, dietary intervention and outcomes, results, and statistical analysis. The answers were yes, no, can’t tell or not applicable. The study quality was summarized in A, B or C quality. Studies with A quality contained an acceptably low level of bias. B quality studies had some bias, but not that much to invalidate the results. C quality studies contained a significant level of bias that may invalidate the results, therefore they were discussed separately in the results. The results of the quality assessments were included in the evidence tables. The quality assessments were performed by the reviewers separately. Doubts and disagreements were discussed and resolved.

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3. Results

The Medline search resulted in 786 articles selected for screening (Fig. 1). Of these, 91 articles were selected for screening of the full-text. The total selection procedure provided 10 articles graded with mainly B and C quality. A list of reasons for the exclusion of full-text articles is provided in appendix II. The publication dates of the included articles cover the years 1976 to 2013.

Figure 1. Flow chart of the systematic literature review process

3.1 Clinical outcomes

3.1.1 Growth

A total of seven studies provided data of parameters to measure growth in children. Among the studies with A and B quality, three were RCTs (20–22), and one was a controlled clinical trial (23). Among the C quality studies, there was one RCT (24), one clinical trial (25), and one prospective cohort study (26). Specific data are shown in appendix III.

Burattini et al. (20), Maggio et al. (21), and Porcelli et al. (23) studied ELBW infants on standard (control group) or high (intervention group) amino acid intake (n=144, n=56, n=88, respectively). All three studies used TrophAmine (Baxter Healthcare corporation) as the amino acid solution, administered through PN and additional to EN. In the studies of Maggio et al. (21) and Porcelli et al. (23), the TrophAmine solution was replaced by an enteral formula based on fortified human milk in all patients if they were clinically stable. No significant differences in body weight were found between the control and intervention groups at the entry and at the end of the study periods in all three studies. The patients in Maggio et al. (21) who were allocated in the intervention group had a significant lower percentage of postnatal weight loss and a shorter time to regain birth weight than the subjects in the control group. Porcelli et al. (23) found a direct correlation between corrected parenteral amino acid administration at postnatal week one and weight change from birth to postnatal week two in all patients. Burattini et al. (20) and Maggio et al. (21) also obtained body length and head circumference data, but did not found significant differences in these parameters during the study period between the control and intervention groups. The two-year follow up of Burattini et al. (20) showed no

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12 significant differences in body length and head circumference between the control and the intervention group. Zlotkin et al. (22) included newborns (n=22) on total parenteral nutrition (TPN) which were allocated in the Aminosyn or in the Vamin group (different types of amino acid solutions). The mean gestational age was 39.2±0.3 weeks and the mean birth weight was 3.1±0.19 kg (similar between both groups). Nitrogen intakes ranged from 300-600 mg/kg/d in all patients and were similar between the two study arms. The mean weight of the infants was similar at entry and at the end of the study period. The average of weight change over six days was 35±4.6 g/d and was found to be independent of nitrogen intake.

O’Neill et al. (25), Shepherd et al. (24), and Teixeira-Cintra et al. (26) were graded with C quality. O’Neill et al. (25) studied the effects of crystalline L-amino acid supplementation in children and infants (n=90) with various diseases. All patients received the same treatment consisting of approximately 130 ml/kg of a standard amino acid solution which contained 4.6 g/liter of nitrogen, meaning the average nitrogen intake was 0,6 g/kg/d. During the study period, 73 patients gained body weight, eight patients maintained body weight, and nine patients lost small amounts of body weight. The patients only grew in length when they were treated for a minimum of 30 days. There was no control group inserted. Shepherd et al. (24) studied the effect of a high nitrogen peptide formula (intervention group) (Criticare, HM) versus no supplementation (control group) in children with exacerbation of cystic fibrosis (n=22). The age of the patients ranged from six to seventeen years old. The change in body weight during the study period was not significantly different between the two study arms. Teixeira-Cintra et al. (26) observed the efficacy of an enteral (partially hydrolyzed) cow’s milk formula in preventing postoperative weight loss in infants (n=11) with congenital heart disease undergoing surgery. The protein intakes ranged from 0.6 to 1.4 g/kg/d. The median preoperative weight was 3.7 kg. At pediatric intensive care unit (PICU) discharge and at hospital discharge, the median weight was 3.6 kg. Mid-arm muscle circumference was 8.8 cm preoperative, 8.2 cm at PICU discharge, and 8.6 cm at hospital discharge. Triceps skinfold thickness was 4.5 mm preoperative, 4.0 mm at PICU discharge, and 3.8 mm at hospital discharge.

3.1.2 Infection (sepsis)

The incidence of sepsis was only examined by Burattini et al. (20). There were no differences observed in the incidence of sepsis between the standard (standard protein intake) and the intervention group (high protein intake). Specific data were not provided.

3.1.3 Length of hospital stay

Maggio et al. (21) and Porcelli et al (23). provided data about length of hospital stay. Neither of those studies observed significant differences in hospital stay between the standard and intervention group (standard versus high protein intakes). Although populations characteristics were similar, length of hospital stay in the study of Maggio et al. was about 20 days longer than in the study of Porcelli et al. Table 4 shows the length of hospital stay of the two studies.

Table 4. Length of hospital stay (LOS) in days

Protein intake in g/kg/d LOS in days in Maggio et al. (21)

LOS in days in Porcelli et al. (23)

Standard group 3 83.8 ± 18.5 60.5 ± 25.6

Intervention group 3,5-4 81.6 ± 21.3 51.6 ± 23.6

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3.2 Nitrogen balance

Studies used to assess the evidence behind the association between protein intake and nitrogen balance included four clinical trials (22,25,27,28). O’Neill et al. (25) appeared to have significant bias that might invalidate the results, and was judged as C quality. Only Maggio et al. was judged as an A quality study (21). Specific data are shown in appendix IV.

Botrán et al. (28) investigated standard protein (control group) intake versus high protein intake (intervention group), based on a breast milk and/or cow’s milk based pediatric formula. The median intake of the intervention and control group was 3.1 and 1.5 g/kg/day of protein, respectively. The median age of the patients was seven months and the mean weight was 7.7 kg. There were no significant differences between the two study arms in any clinical or anthropometric variables at baseline, and nitrogen balance was negative in both groups (control group: 1.7; intervention group: -2.3 g/kg/d).There was no significant difference in nitrogen balance between the groups at each day of evaluation. Nitrogen balance became positive at day five in the intervention group (0.5 g/kg/d) and remained negative in the control group (-0.4 g/kg/d). Bell et al. (27) used an enteral or parenteral modular diet which provided 2.5 g/kg/d of protein (whole egg powder alone or in conjunction with egg white solids) and the calories were twice the predicted basal metabolic rate (BMR). There was no control group inserted. The analyzed results include measurements done on days the calorie intake was at least 2/3 of the modular diet. The average age of the children was 5±3 years old. The average of protein goal supplied by the modular diet was 87%±10%. The mean duration of the study period was 18±2 days. In 98%±3% of the days positive nitrogen balances were observed. Zlotkin et al. (22) investigated nitrogen balance using TPN enriched with Vamin or Aminosyn. There was a significant correlation observed between increasing nitrogen intake and increased nitrogen retention in both groups. The mean percentage of nitrogen retained was 62.4%±9.5% of intake.

O’Neill et al. (25) investigated the effects of a crystalline amino acid solution on nitrogen balance in infants and children on TPN. Nitrogen balance general became positive within 48 hours after PN initiation, but maximum levels of retention were usually not achieved until day four or five. The degree of positive balance was related to the amount of infusion given and the clinical state of the patient.

3.2.1 Blood urea nitrogen (BUN)

In total four studies measured the BUN as an outcome of the interventions, of which three judged with A or B quality (20,21,23), and one with C quality (29).

Burattini et al. (20) showed a significantly higher BUN at an intake of 4 g/kg protein (intervention group) than 2.5 g/kg protein intake (control group), 65 mg/dL versus 40.6 mg/dL respectively. Maggio

et al. (21) showed no significant difference in mean BUN between the intervention (high protein

intake) and the control group (standard protein intake). Mean protein intake was significantly higher in the intervention group, 3.1±0.2 versus 2.5±0.2 g/kg/day in the first 14 days of life. Mean BUN of the intervention group was 18.6±6.5 mg/dL against a mean BUN of the control group of 19.6±6 mg/dL. Porcelli et al. (23) showed that the BUN concentration in the intervention group (protein intake of 4 g/kg protein) in postnatal week two was unchanged from postnatal week one, but was 49% higher than in the control group (protein intake of 3 g/kg protein)(18.2 versus 12.2 mg/dL, respectively).

Ridout et al. (29) investigated the nitrogen balance at a mean amino acid intake of 1.8±0.9 g/kg/d (range 0-3.7 g/kg/d) in 121 infants using PN. The mean gestational age was 27.8±1.8 weeks with a mean birth weight of 985±245 g. There was no correlation found between BUN and amino acid intake. There was a significant inverse correlation between BUN and birth weight and age.

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3.3 Protein turnover

Only two studies of C quality provided protein turnover data of which one was a prospective cohort study in 11 infants (26) and one was a RCT in 15 children (24). Specific data are shown in appendix V.

Shepherd et al. (24) evaluated protein synthesis (Psyn) and protein catabolism (Pcat) which provided the protein deposition (Pdep/protein balance). Within the control group (standard protein intake), no significant differences in Psyn, Pcat, and Pdep were found between the start and at the end of the treatment. Within the intervention group (high protein intake), there were significant changes in Psyn, Pcat, and Pdep found between the start and the end of the treatment. Between the two groups, the changes of Psyn, Pcat, and Pdep over the study period were significantly different. Higher rates of Psyn and Pcat, and a positive protein balance were observed in the intervention group, where the control group remained in negative protein balance. In the study by Teixeira-Cintra et al. (26), all patients were in negative protein balance at day one of the study (median protein balance: -0.7 g/kg/d, range: -1.8 to -0.3 g/kg/d). During the intervention, six of the eleven patients became in positive protein balance and five remained in negative protein balance. A significant correlation between protein intake and protein balance was observed. A median protein intake of 1,1 g/kg/d was associated with an increased protein synthesis.

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4. Discussion

The main finding of this systematic review is that protein intake on itself does not have the advantages as often expected by the researchers of individual studies. In general, small effects are observed but the interventions do not have significant beneficial effects on the included outcomes. Additionally, the evidence is judged with low quality and is mainly focused on young to very young children and infants. Studies providing proteins in conjunction with anabolic agents, such as insulin or drugs to inhibit catabolic agents, are more likely to be effective during hypercatabolism, but these studies are not included in the current review (2,30).

4.1 Clinical outcomes

Malnutrition and poor growth in critically ill children is commonly multifactorial, but inadequate nutritional support explains approximately half of the growth variation and retardation (31–34). Growth includes body weight which is closely related to nutritional support, body length which reflects bone growth, and head circumference which reflects brain growth and development. These measurements should all be considered together because the individual parameters can be masked by aspects of diseases, like edema and tumor growth (32).

In this review only Burattini et al. (20) and Maggio et al. (21) investigated all these three parameters (20,21). Based on the results, high protein intake seems to have no significant effects on body weight, body length, and head circumference in comparison with standard protein intake. Porcelli et al. (23) only provided body weight outcomes which were roughly equal to the body weight outcomes of Burattini et al. (20) and Maggio et al. (21). The patients of these three studies were ELBW infants so these outcomes could not be considered for the whole population of infants until adolescents. All three studies started with parenteral amino acid administration (TrophAmine, Baxter Health Care Corporation), but in Maggio et al. (21) and Porcelli et al. (23) the PN was stopped when the subjects tolerated enteral feedings, and TrophAmine was replaced by fortified human milk. Shepherd et al. (24) also studied high protein intake versus standard protein intake but they used an enteral peptide formula. Even though this study is judged with C quality, just like the three studies discussed above this one did not find significant differences in body weight either. Zlotkin et al. (22) compared two different amino acid solutions (Aminosyn and Vamin) and mean body weights of the patients remained similar between both study arms. However, the patients in Shepherd et al. (24) had ages of six to seventeen years old, and the subjects of Zlotkin et al. (22) were full-term newborns with normal birth weights and neither of them should be compared with the subjects of Burattini et al. (20), Maggio et

al. (21), and Porcelli et al. (23) because of the differences in ages and birth weights. Therefore,

conclusions about the effect of the types and sources of proteins on body weight should not be made but an assumption could be made. Since all the studies individually show no difference in effects on the clinical outcomes, it may be plausible that the types and sources of protein have no effect on the body weight.

The aim of O’Neill et al. (25) was to compare the effects of crystalline L-amino acid supplementation with protein hydrolysates supplementation. However, there was only one study arm and all the patients received the amino acid solution. Patients gained in weight but length gain was poor, which makes it dubious if the results reflect growth because weight gain can be caused by aspects of disease. Teixeira-Cintra et al. (26) observed the efficacy of EN and PN therapy after surgery. Mid arm muscle circumference and triceps skinfold thickness were studied. Together these two parameters reflect upper arm muscle and fat stores (32). Teixeira-Cintra et al. (26) showed a small decrease in both parameters, however, the preoperative values of these parameters were already considerably lower than the reference values (35).

None of the above mentioned studies have considered possible effects of the diagnosis on the results on the need for protein (20–26,36). Even though all the results are roughly in the same direction and the different diagnosis of the included studies seem to have no comprehensive different effects on the need for protein, the conclusion could not be made because of the different interventions and populations of the studies.

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16 The length of hospital stay is associated with the effect of the therapy and thus reflecting improvement of health status (37–39). This outcome measurement is studied by Maggio et al. (21) and Porcelli et al. (23), but neither of those studies found a significant difference in length of hospital stay between standard protein intakes and high protein intakes. It is to be noted that both studies only focused on ELBW infants. On the other hand, these results correspond to the results of a RCT among 119 critically ill adolescents and adults (40). Because the types and sources of protein were equal in both studies (21,23), it is not possible to draw conclusions about the effect of the different types and sources of protein on length of hospital stay. The length of stay in Maggio et al. (21) was approximately 20 days longer than in Porcelli et al. (23). The subjects of Maggio et al. (21) were admitted to the intensive care unit, where the subjects of Porcelli et al. (23) were not. Based on this data it is more plausible that the diagnosis affects the length of stay more than the interventions concerning protein intakes.

4.2 Nitrogen balance

Nitrogen balance is commonly used as a measure to determine an adequate intake of amino acids. In children it is assumed that the body nitrogen is maximally increased for growth in case of an adequate intake of amino acids (3). However, there is no direct evidence that this maintenance requirement reflects health (17). Despite the limitations in using nitrogen balance studies for recommendations of protein intake, it is still the most sufficient method (3). Due to development in the measurement of nitrogen losses and analyze techniques, in combination with other methods, it is assumable that nitrogen balance is a reliable method to determine protein needs.

Four of the included studies used nitrogen balance as a measure to determine an adequate intake of amino acids (22,25,27,28). In O’Neill et al. (25), the amount of protein intake was not provided but could be calculated from the infusion of TPN rates and body weights. The quality of this study was judged as C, but the results are comparable to the results of Bell et al.(27) which was judged with B quality. The results of the RCT’s of Botrán et al.(28) and Zlotkin et al.(22) could not be considered together because the interventions were different. However, all patients in the included studies were in positive nitrogen balance during the study period (protein intakes >1,9 g/kg/d), except from the control group (protein intake of 1,5 g/kg/d) of Botrán et al.(28). Even though these results show consistency, the association between protein intake and nitrogen balance, and the effects of age, type and source of protein, and diagnosis on this association remains inconclusive because of the differences between the studies.

Burratini et al. (20), Maggio et al. (21), Porcelli et al. (23), and Ridout et al. (29) all studied BUN in infants with ELBW. Burattini et al. (20), and Porcelli et al. (23) both showed a higher BUN at higher protein intakes. Maggio et al. (21) showed no significant differences in mean BUN between high or standard protein intakes and Ridout et al. (29) showed no correlation between BUN and amino acid intake. Because of the inconsistency of these results, the association between protein intake and BUN in ELBW infants remains inconclusive. Burratini et al. (20), Maggio et al. (21), and Porcelli et al. (23) all used both PN and EN, and only Ridout et al. (29) used simply PN. Thus, no comparison could be made about the association between protein intake and BUN, and the use of PN or EN, types of protein, and the effect of ages and diagnosis.

One of the important aspects in the use of nitrogen balance to determine an adequate protein intake is an accurate quantification of the nitrogen intake (3). Some of the included studies which have investigated nitrogen balance do not provide a detailed description of the dietary assessment, which means the possible errors occurred during dietary assessment can result in false nitrogen balance values (22,24,26). Another important aspect in measuring the nitrogen balance is the need for accurate measurements of nitrogen losses. The three ways the body loses nitrogen need to be considered during the nitrogen balance measurements are: the losses through urine, feces, and skin. Alternate losses through the skin, depending on different influences such as dietary intake, can result in under- or overestimating the total nitrogen loss. Underestimating losses can lead to a false positive nitrogen balance, which assumes an adequate protein intake (3). The four included nitrogen balance studies

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17 used all three methods of measuring the nitrogen losses (22,25,27,28). The body needs time to adapt to the implemented exposure. The report of a Joint FAO/WHO/UNU Expert Consultation from 1985 (41) concludes an adaption period of minimal a week is needed for the metabolism to adjust. Two of the included studies used an adaptation period of more than seven days (21,23). The WHO/FAO/UNU expert group from 2007 (3) refers to other studies which conclude that longer adaption periods are needed for accurate measurements, however they do have the disadvantage of a reduced compliance of the intervention.

4.3 Protein turnover

Nutritional support can alter the progression of the disease by providing amino acids as a substrate for beneficial responses by the body and saving loss of body protein (2). The RCT of Shepherd et al. (24) shows a significant improvement in protein balance in patients on higher protein diets and the prospective cohort study Teixeira-Cintra et al. (26) observed that anabolism occurred in infants by a protein intake of 1.1 g/kg/d. The age categories in these two studies range from infants to adolescents, but with a majority of children. Because of that these results should be considered with caution, especially for adolescents. Both studies used peptides or whole proteins and no amino acids were used thus no PN. The diagnosis of the two studies were incomparable because the stress responses after cardiac surgery differ from the responses in pulmonary exacerbation (2). Additionally, the quality of these two studies was C, so the results are actually not adequate enough to make conclusions about protein intake and protein balance. Nevertheless, the results are corresponding with other studies, also showing improvement in protein balance due to higher protein intakes (11,42).

4.4 Strengths and weaknesses

Utilization and deposition of protein are energy-dependent. Adequate non-protein energy from carbohydrate or fat are necessary to ensure amino acids are used to provide growth and maintenance, and are used as little as possible for energy (2,3). In most of the included studies the energy intake was based on requirements (20–27,29). One study obtained energy needs based on energy expenditure measurements (28). Energy intakes were adequate provided and appropriate in all included studies. However, Zlotkin et al. (22), Shepherd et al. (24), Teixeira-Cintra et al. (26), Ridout et al. (29), and Bell

et al. (27) did not clearly provide the dietary assessment method. Under- or over estimating of intakes

could probably have affected their results, and thus the conclusions of the current review.

In this review, there were no criteria set for duration of the study period and of length of follow-up. According to the NNR5 working group (18) the duration of intervention studies should be at least four weeks but specific criteria should be defined depending on the outcomes, and the follow-up period of observational studies should be at least four to five years. None of the included studies had the answer ‘no’ in the quality assessments at the question about if the duration of the study was suited to the research hypothesis. However, comparing the studies with the criteria of the NNR5 guideline, only Burattini et al. (20) and Maggio et al. (21) would meet these criteria.

No hand-search is performed, however during checks of references used in other articles, some new articles appeared to be appropriate for the current review. This is why it is assumable that the search strategy has failed to provide all the evidence concerning protein intake an health outcomes in hospitalized children. This, and the low quality of the articles, can be explained by the use of one single database which perhaps may not enclose all the existing evidence of this topic.

4.5 Semi-essential amino acids

Several studies about the association between glutamine and cysteine and health outcomes appeared from the search. Because glutamine and cysteine are considered to be non-essential amino acids in healthy conditions, they were excluded from this review. However, in some conditions glutamine and cysteine, as well as a few other non-essential amino acids, appear to be essential (4). The two studies

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18 about semi-essential amino acids obtained by the search are recently performed systematic reviews judged with A quality.

Moe-Byrne et al. (43) included eleven studies of 2771 pre-term VLBW or ELBW infants with glutamine supplementation (intervention group) versus no supplementation (control group), either enteral or parenteral. In a meta-analysis of the data, no significant differences were found in the onset of infection, length of hospital stay, and weight gain between the intervention and the control group. In an additional subgroup analysis of enteral glutamine supplementation versus parenteral supplementation, the enteral supplemented group had a lower incidence of invasive sepsis.

Soghier et al. (44) included six trials, of which five small trials that investigated the effect of short-term cysteine supplementation of cysteine-free PN and one large RCT which evaluated short-short-term N-acetylcysteine supplementation of cysteine-containing PN in ELBW (≤1000 g). Among the studies that compared short-term cysteine with placebo supplementation of cysteine-free PN, there was no significant effect found on either weight gain, length gain or head circumference. In four of these studies cysteine supplementation significantly increased nitrogen retention. One large RCT showed no significant association between N-acetylcysteine supplementation and weight gain. It also did not significantly affect the risk of death by 36 weeks of corrected age, as well as the risk of other types of morbidity. It is to be noted that a few limitations of these trials occurred: small size, lack of adequate or unclear evidence of allocation blinding, and abstract publication only.

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19

5. Conclusion and recommendations for further research

None of the included studies investigated the effects of the ages, types and sources of protein, or diagnosis on health outcomes. Comparing the included studies on these aspects, no consistency could be found. Additionally, the different interventions and study designs make it hard to combine the data and to draw conclusions about the consistency. Based on the results about the association between protein intake and health outcomes, it is known that dietary protein intake attenuates the hypercatabolic state of the ill body, but it does not completely prevent loss of body protein. Overall high protein intakes cause no significant benefits on health outcomes in the included studies.

In general, the quality of the included studies was low, and the subjects were predominantly infants. Because the majority of included studies investigated infants, adolescents are not well represented in this review. More high quality clinical trials in children and adolescents would make a great contribution to the knowledge about the optimal protein intake for these populations. Also clinical interventions with adequate dietary assessment methods to get a more precisely view of dietary intakes are profitable.

There is a need for further research in understanding the protein metabolism for improvement of techniques to obtain protein utilization in the body. Additionally, protein intake should not be seen as an individual parameter to improve health status but should be considered together with anabolic agents and pharmacotherapy to reduce the loss of body protein on cellular level.

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20

References

1. Shaw V, Lawson M. Clinical paediatric dietetics. 3rd ed. Oxford: Blackwell Publishing; 2007. 2. Anthony T, McNurlan M. Protein synthesis and degradation. In: Stipanuk M, Caudill M,

editors. Biochemical, physiological and molecular aspects of human nutrition. 3rd ed. Elsevier; 2013. p. 256–83.

3. WHO/FAO/UNU. Protein and amino acid requirements in human nutrition. World Health Organ Tech Rep Ser. 2007;(935):1–265.

4. EFSA Panel on Dietetic Products Nutrition and Allergies. Scientific opinion on Dietary Reference Values for Protein. EFSA J. 2012;10(2):2557.

5. Adamkin DH. Pragmatic approach to in-hospital nutrition in high-risk neonates. J Perinatol. 2005;25:7–11.

6. Hulst J, van Goudoever J. The role of initial monitoring of routine biochemical nutritional markers in critically ill children. J Nutr Biochem. 2006;17:57–62.

7. Mehta NM, Compher C, Directors ASPEN. ASPEN Clinical Guidelines: Nutrition Support of the Critically Ill Child. 2009;260–76.

8. Coss-Bu JA, Klish WJ, Walding D, Stein F, Smith EO, Jefferson LS. Energy metabolism, nitrogen balance, and substrate utilization in critically ill children. Am J Clin Nutr. 2001 Nov

1;74(5):664–9.

9. Goulet O. Nutritional support in malnourished paediatric patients. Baillieres Clin Gastroenterol. 1998;12(4):843–76.

10. Powanda MC, Beisel WR. Metabolic effects of infection on protein and energy status. J Nutr. 2003;133(1):322S – 327S.

11. Ishibashi N, Plank LD, Sando K, Hill GL. Optimal protein requirements during the first 2 weeks after the onset of critical illness. J Crit care Med. 1998;26(9):1529–35.

12. Larsson J, Lennmarken C, Mårtensson J, Sandstedt S, Vinnars E. Nitrogen requirements in severely injured patients. Br J Surg. 1990;77(4):413–6.

13. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006;117(4):1253–61.

14. Pichard C, Kyle UG, Morabia A, Perrier A, Vermeulen B, Unger P. Nutritional assessment: lean body mass depletion at hospital admission is associated with an increased length of stay. Am J Clin Nutr. 2004;79(4):613–8.

15. Kruizenga HM, Van Tulder MW, Seidell JC, Thijs A, Ader HJ, Van Bokhorst-De Van Der Schueren ME. Effectiveness and cost-effectiveness of early screening and treatment of malnourished patients. Am J Clin Nutr. 2005;82(5):1082–9.

16. Oosterveld MJS, Van Der Kuip M, De Meer K, De Greef HJMM, Gemke RJBJ. Energy expenditure and balance following pediatric intensive care unit admission: a longitudinal study of critically ill children. Pediatr Crit Care Med. 2006;7(2):147–53.

17. Weijs PJM. Fundamental determinants of protein requirements in the ICU. Curr Opin Clin Nutr Metab Care. 2014 Mar;17(2):183–9.

(22)

21 Literature Reviews for the 5th edition of the Nordic Nutrition Recommendations. Revised ed. Copenhagen: Nordic Council of Ministers; 2011.

19. PROSYST - Kenniscentrum KIK - Hogeschool van Amsterdam. Available from:

http://www.hva.nl/kik/projecten/content/projecten-gewichtsmanagement/prosyst.html 20. 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 Nov;163(5):1278–82.e1.

21. Maggio L, Cota F, Gallini F, Lauriola V, Zecca C, Romagnoli C. Effects of high versus standard early protein intake on growth of extremely low birth weight infants. J Pediatr Gastroenterol Nutr. 2007;44(1):124–9.

22. Zlotkin SH. Intravenous nitrogen intake requirements in full-term newborns undergoing surgery. Pediatrics. 1984;73(4):493–6.

23. Porcelli Jr PJ, Sisk PM. Increased parenteral amino acid administration to extremely low-birth-weight infants during early postnatal life. J Pediatr Gastroenterol Nutr. 2002;34(2):174–9. 24. Shepherd RW, Holt TL, Cleghorn G, Ward LC, Isles A, Francis P. Short-term nutritional

supplementation during management of pulmonary exacerbations in cystic fibrosis: a controlled study, including effects of protein turnover. Am J Clin Nutr. 1988;48(2):235–9. 25. O’Neill JA, Meng HC, Caldwell MD, Stahlman MT. Metabolic evaluation of a synthetic amino

acid mixture for parenteral nutrition in infants and children. J Pediatr Surg. 1976;11(6):979– 85.

26. Teixeira-Cintra MAC, Monteiro JP, Tremeschin M, Trevilato TMB, Halperin ML, Carlotti AP. Monitoring of protein catabolism in neonates and young infants post-cardiac surgery. Acta Paediatr. 2011;100(7):977–82.

27. Bell SJ, Molnar JA, Carey M, Burke JF. Adequacy of a modular tube feeding diet for burned patients. J Am Diet Assoc. 1986 Oct;86(10):1386–91.

28. Botrán M, López-Herce J, Mencía S, Urbano J, Solana MJ, García A. Enteral nutrition in the critically ill child: comparison of standard and protein-enriched diets. J Pediatr. 2011 Jul;159(1):27–32.e1.

29. Ridout E, Melara D, Rottinghaus S, Thureen PJ. Blood urea nitrogen concentration as a marker of amino-acid intolerance in neonates with birthweight less than 1250 g. J Perinatol.

2005;25(2):130–3.

30. Herndon DN, Tompkins RG. Support of the metabolic response to burn injury. Lancet. 2004;363:1895–902.

31. Berry MA, Abrahamowicz M, Usher RH. Factors associated with growth of extremely premature infants during initial hospitalization. Pediatrics. 1997;100(4):640–6.

32. Cooke L, Lowden J. Peadiatric clinical dietetics and childhood nutrition. In: Gandy J, editor. Manual of Dietetic Practice. 5th ed. Wiley Blackwell; 2014. p. 159–68.

33. 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. 34. Olsen IE, Richardson DK, Schmid CH, Ausman LM, Dwyer JT. Intersite differences in weight

growth velocity of extremely premature infants. Pediatrics. 2002;110(6):1125–32. 35. Frisancho AR. Triceps norms skin fold and for assessment upper arm muscle size of

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22 nutritional. Am J Clin Nutr. 1974;(27):1052–8.

36. Phillips R, Ott L, Young B, Walsh J. Nutritional support and measured energy expenditure of the child and adolescent with head injury. J Neurosurg. 1987;67(6):846–51.

37. Englert J, Davis KM, Koch KE. Using clinical practice analysis to improve care. Jt Comm J Qual Improv. 2001;27(1070-3241):291–301.

38. O’Keefe GE, Jurkovich GJ, Maier R V. Defining excess resource utilization and identifying associated factors for trauma victims. J Trauma. 1999;46(3):473–8.

39. Mehta NM, Duggan CP. Nutritional Deficiencies During Critical Illness. Pediatr Clin North Am. 2009 Oct;56(5):1143–60.

40. Ferrie S, Allman-Farinelli M, Daley M, Smith K. Protein Requirements in the Critically Ill: A Randomized Controlled Trial Using Parenteral Nutrition. JPEN J Parenter Enteral Nutr. 2015 Dec 3;

41. WHO/FAO/UNU. Energy and protein requirements. World Health Organ Tech Rep Ser. 1985;724:1–154.

42. Bechard LJ, Parrott JS, Mehta NM. Systematic review of the influence of energy and protein intake on protein balance in critically ill children. J Pediatr. 2012 Aug;161(2):333–9.e1. 43. Moe-Byrne T, Wagner JVE, McGuire W. Glutamine supplementation to prevent morbidity and

mortality in preterm infants. Cochrane database Syst Rev. 2012;3:CD001457.

44. Soghier LM, Brion LP. Cysteine, cystine or N-acetylcysteine supplementation in parenterally fed neonates. Cochrane database Syst Rev. 2006;(4):CD004869.

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23

Appendix I Search strategy

# Searches Results

1 exp Dietary Proteins/ 83449

2 exp Fish Proteins/ 12595

3 exp Soybean Proteins/ 5018

4 ((egg* or yolk* or milk or dairy or animal* or meat* or poultry or fish or seafood* or

shellfish or diet*) adj3 protein*).tw. 40111

5 ((soy or soy bean* or soybean* or plant or vegetable*) adj3 protein*).tw. 12762

6 Amino Acids/ or exp Amino Acids, Essential/ 295923

7 (amino adj2 acid* adj4 (essential* or nonessential* or non essential* or dispensable*

or nondispensable* or non dispensable*)).tw. 8039

8 Diet, Protein-Restricted/ or exp Diet, Vegetarian/ 4916

9 (diet* adj3 (low protein* or protein restricted or protein free or high protein)).tw. 7087

10 ((vegan* or vegetarian*) and protein*).tw. 599

11 Proteins/me 71493

12 Nitrogen/me 23447

13 ((diet* or balance*) adj3 nitrogen*).tw. 5600

14 ((protein adj2 (turnover or synthesis or breakdown)) or "amino acid oxidation").tw. 73840

15 or/1-14 558166

16 (intake* or timing* or frequen* or requirement* or utilization* or feeding* or

supplement*).tw. 2202713

17 nutritional requirements/ 17748

18 16 or 17 2210463

19 15 and 18 76376

20 exp Hospitalization/ 177376

21 ("length of stay" or "length of hospital stay").tw. 45636 22 ((patient? or hospital?) adj2 (discharg* or admission? or admitting or readmission? or

transfer?)).tw. 93411

23 or/20-22 259132

24 Hospital Costs/ 8628

25 Health Care Costs/ 30462

26 ((hospital? or health care) adj2 cost?).tw. 21567

27 or/24-26 53862

28 exp Cross Infection/ 53126

29 ((cross or hospital? or nosocomial) adj2 infection?).tw. 21839

30 ventilator associated pneumonia?.tw. 3810

31 or/28-30 63665

32 Postoperative Complications/ or Intraoperative Complications/ 326985

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24 34 (((intraoperative or peroperative) adj2 complication?) or surgical injur*).tw. 7571

35 or/32-34 358082

36 Mortality/ 36723

37 mortal*.tw. 538698

38 ((fatalit* or death* or survival) adj2 rate*).tw. 143572

39 (excess adj2 mortalit*).tw. 5350

40 or/36-39 664901

41 exp Body Composition/ 41921

42 (body adj2 composition*).tw. 25801

43 (body adj2 fat* adj3 (distribution* or pattern*)).tw. 3024

44 ((fat free or lean) adj3 body mass).tw. 6782

45 (body adj2 size).tw. 15642

46 adiposity.tw. 16862

47 Body Mass Index/ 93281

48 (body adj2 mass adj3 index).tw. 121707

49 bmi.tw. 91113

50 exp Abdominal Fat/ or exp Adipose Tissue/ 79949

51 ((visceral or abdominal or body or pad) adj2 fat*).tw. 42414

52 Waist-Hip ratio/ 3234

53 (waist adj2 hip).tw. 9199

54 exp Body Weight/ 379160

55 ((body or gain or los* or reduc* or decreas* or chang*) adj2 weight*).tw. 273432 56 (obesit* or obese or leanness or thinness or underweight or under weight or

overweight or over weight).tw. 223567

57 (emaciation* or cachexia).tw. 6907

58 or/41-57 796482

59 exp Muscular Atrophy/ 10645

60 exp Muscle Strength/ 21241

61 Muscle Fatigue/ 6321

62 Muscle Weakness/ 6267

63 ((muscle or muscular) adj2 (atrop* or strength* or fatigue* or weak* or wasting)).tw. 46861

64 ((hand adj2 strength) or (grip* or grasp*)).tw. 26839

65 sarcopenia.tw. 2788

66 exp Physical Endurance/ 26633

67 Physical Fitness/ 23460

68 (physical* adj2 (fitness or endur*)).tw. 7462

69 or/59-68 139398

70 Quality of Life/ 134305

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25

72 or/70-71 226976

73 Heart Failure/ 92598

74 ((heart or cardiac or myocardial) adj2 (failure or decompensation)).tw. 131684

75 Pulmonary Disease, Chronic Obstructive/ 26567

76 ("chronic obstructive" adj2 (pulmonary or airway or lung) adj3 disease?).tw. 35872 77 (COPD or COAD or "chronic airflow obstruction").tw. 30850

78 exp Inflammatory Bowel Disease/ 66680

79

((("inflammatory bowel" or crohn*) adj disease) or ((crohn* or regional or

granulomatous) adj enteritis) or ((terminal or regional) adj ileiti*) or granulomatous colitis or ileocolitis).tw.

55619

80 (idiopathic proctocolitis or ulcerative colitis or colitis graves).tw. 30250

81 Short Bowel Syndrome/ 2552

82 "short bowel syndrome".tw. 2542

83 Geriatrics/ 27595

84 (geriatric? or gerontolog*).tw. 38779

85 Critical Illness/ 19496

86 (critical* adj (illness? or ill)).tw. 34603

87 Multiple Organ Failure/ 9324

88 (organ failure? or organ dysfunction syndrome?).tw. 15910

89 exp Renal Insufficiency, Chronic/ 92941

90 (chronic adj (kidney or renal) adj2 (insufficienc* or disease* or failure)).tw. 55191

91 exp Acute Kidney Injury/ 37116

92 (acute adj (kidney or renal) adj2 (injur* or insufficienc* or disease* or failure)).tw. 32626

93 exp Renal Dialysis/ 100508

94 (((renal or extracorporeal or peritoneal) adj dialys*) or hemodialys* or

hemodiafiltration).tw. 70979

95 Fatty Liver, Alcoholic/ 1246

96 (alcoholic adj ("fatty liver" or steatohepatitis)).tw. 5728

97 exp Liver Cirrhosis/ 76588

98 ((liver or hepatic) adj (cirrhos* or fibros*)).tw. 38426

99 exp Pancreatitis/ 46042

100 pancreatiti*.tw. 48825

101 Neoplasms/ 325953

102 (neoplasm? or cancer?).tw. 1336974

103 Surgical Procedures, Operative/ 51715

104 (surgical procedure? or surgery or surgeries).tw. 903500

105 exp Tissue Transplantation/ 170558

106 exp Organ Transplantation/ 181502

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26

108 exp patients/ 74506

109 (inpatient? or in-patient? or patient?).tw. 5134032

110 or/73-109 6910572 111 19 and 23 and 110 390 112 19 and 27 and 110 37 113 19 and 31 and 110 50 114 19 and 35 and 110 283 115 19 and 40 and 110 965 116 19 and 58 and 110 3388 117 19 and 69 and 110 394 118 19 and 72 and 110 278 119 or/111-118 4730

120 (animals not humans).sh. 4060674

121 119 not 120 4182

122 limit 121 to lg=en 3750

123 limit 122 to yr="1946-2014" 3629

124 limit 123 to "review articles" 724

125 exp infant/ 997529

126 (infan* or newborn? or neonate?).tw. 484450

127 exp child/ 1648152 128 child*.tw. 1092954 129 adolescent/ 1730862 130 adolescen*.tw. 197417 131 (teen? or teenager?).tw. 18589 132 youth?.tw. 46665 133 toddler?.tw. 6917 134 (girl? or boy?).tw. 184726 135 (pediatric? or paediatric?).tw. 236110 136 or/125-135 3491203 137 123 and 136 786

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27

Appendix II Excluded full-text articles

Article Reason for exclusion

Total parenteral nutrition: value of a standard feeding regimen. Br.Med.J.(Clin.Res.Ed) 1983;286(6374):1323-1327.

Not the effect of protein; age 15-85 yrs

Beddhu S, Ramkumar N, Pappas LM. Normalization of protein intake by body weight and the associations of protein intake with nutritional status and survival. J.Ren.Nutr. 2005;15(4):387-397.

Adults

Blau J, Sridhar S, Mathieson S, Chawla A. Effects of protein/nonprotein caloric intake on parenteral nutrition associated cholestasis in premature infants weighing 600-1000 grams. JPEN J.Parenter.Enteral Nutr. 2007;31(6):487-490.

Not the effect of protein

Borschel MW, Antonson DL, Murray ND, Oliva-Hemker M, Mattis LE, Kerzner B, et al. Two single group, prospective, baseline-controlled feeding studies in infants and children with chronic diarrhea fed a hypoallergenic free amino acid-based formula. BMC Pediatr. 2014;14:136.

Not hospitalized

Crill CM, Helms RA. The use of carnitine in pediatric nutrition. Nutr.Clin.Pract. 2007;22(2):204-213.

No protein

Eyre S, Attman PO. Protein restriction and body

composition in renal disease. J.Ren.Nutr. 2008;18(2):167-186.

Age >19 yrs

Giordano C, De Santo NG, Senatore R. Effects of catabolic stress in acute and chronic renal failure. Am.J.Clin.Nutr. 1978;31(9):1561-1571.

Adults

Guzzo I, Mancini E, Wafo SK, Rava L, Picca S. Residual renal function and nutrition in young patients on chronic hemodialysis. Pediatr.Nephrol. 2009;24(7):1391-1397.

Outpatients

Huemer M, Huemer C, Moslinger D, Huter D, Stockler-Ipsiroglu S. Growth and body composition in children with classical phenylketonuria: results in 34 patients and review of the literature. J.Inherit.Metab.Dis. 2007;30(5):694-699.

Outpatients

Jadeja YP, Kher V. Protein energy wasting in chronic kidney disease: An update with focus on nutritional interventions to improve outcomes. Indian.J.Endocrinol.Metab. 2012;16(2):246-251.

Adults

Jesudason DR, Pedersen E, Clifton PM. Weight-loss diets in people with type 2 diabetes and renal disease: a

randomized controlled trial of the effect of different dietary protein amounts. Am.J.Clin.Nutr. 2013;98(2):494-501.

18-75 yrs

Jones RW, Dalton N, Start K, El-Bishti MM, Chantler C. Oral essential amino acid supplements in children with advanced chronic renal failure. Am.J.Clin.Nutr. 1980;33(7):1696-1702.

Only 10 days hospitalized of the 6 month observation

Kalantar-Zadeh K, Cano NJ, Budde K, Chazot C, Kovesdy CP, Mak RH, et al. Diets and enteral supplements for

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28 improving outcomes in chronic kidney disease.

Nat.Rev.Nephrol. 2011;7(7):369-384.

Lands LC, Iskandar M, Beaudoin N, Meehan B, Dauletbaev N, Berthiuame Y. Dietary supplementation with

pressurized whey in patients with cystic fibrosis. J.med.food 2010;13(1):77-82.

Outpatients

Laviano A, Aghilone F, Colagiovanni D, Fiandra F, Giambarresi R, Tordiglione P, et al. Metabolic and clinical effects of the supplementation of a functional mixture of amino acids in cerebral hemorrhage. Neurocrit Care. 2011;14(1):44-49.

Adults

Berard MP, Zazzo JF, Condat P, Vasson MP, Cynober L. Total parenteral nutrition enriched with arginine and glutamate generates glutamine and limits protein catabolism in surgical patients hospitalized in intensive care units. Crit.Care Med. 2000;28(11):3637-3644.

Adults

Acosta PB. Recommendations for protein and energy intakes by patients with phenylketonuria. Eur.J.Pediatr. 1996;155(Suppl 1):S121-4.

Review

Andrassy RJ, Chwals WJ. Nutritional support of the pediatric oncology patient. Nutrition 1998;14(1):124-129.

Review

Armitstead J, Kelly D, Walker-Smith J. Evaluation of infant feeding in acute gastroenteritis.

J.Pediatr.Gastroenterol.Nutr. 1989;8(2):240-244.

Outpatients

Briassoulis G, Filippou O, Hatzi E, Papassotiriou I, Hatzis T. Early enteral administration of immunonutrition in critically ill children: results of a blinded randomized controlled clinical trial. Nutrition 2005;21(7-8):799-807.

Adamkin DH. Pragmatic approach to in-hospital nutrition in high-risk neonates. J.Perinatol. 2005;25(Suppl 2):S7-S11.

Review

Aronson AS, Furst P, Kuylenstierna B, Nyberg G. Essential amino acids in the treatment of advanced uremia: twenty-two months' experience in a 5-year-old girl. Pediatrics 1975;56(4):538-543.

Report

Dichi I, Dichi JB, Papini-Berto SJ, Angeleli AY, Bicudo MH, Rezende TA, et al. Protein-energy status and 15N-glycine kinetic study of child a cirrhotic patients fed low- to high-protein energy diets. Nutrition 1996;12(7-8):519-523.

Adults

Dichi JB, Dichi I, Maio R, Correa CR, Angeleli AY, Bicudo MH, et al. Whole-body protein turnover in malnourished patients with child class B and C cirrhosis on diets low to high in protein energy. Nutrition 2001;17(3):239-242.

Adults

Gormican A, Catli E. Nutritional and clinical responses of immobilized patients to a sterile milk-base feeding. J.Chronic Dis. 1972;25(5):291-303.

Adults

Hausmann D, Mosebach KO, Caspari R, Rommelsheim K. Combined enteral-parenteral nutrition versus total parenteral nutrition in brain-injured patients. A

comparative study. Intensive Care Med. 1985;11(2):80-84.

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29 Heird WC, Winters RW. Total parenteral nutrition. The

state of the art. J.Pediatr. 1975;86(1):2-16.

Review

Heird WC, Driscoll JM Jr, Schullinger JN, Grebin B, Winters RW. Intravenous alimentation in pediatric patients. J.Pediatr. 1972;80(3):351-372.

Review

Imura K, Okada A. Perioperative nutrition and metabolism in pediatric patients. World J.Surg. 2000;24(12):1498-1502.

Review

Jones R, Dalton N, Turner C, Start K, Haycock G, Chantler C. Oral essential aminoacid and ketoacid supplements in children with chronic renal failure. Kidney Int. 1983;24(1):95-103.

Outpatients

Kelly DA. Nutrition and growth in patients with chronic liver disease. Indian J.Pediatr. 1995;62(5):533-544.

Review

Kopple JD, Levey AS, Greene T, Chumlea WC, Gassman JJ, Hollinger DL, et al. Effect of dietary protein restriction on nutritional status in the Modification of Diet in Renal Disease Study. Kidney Int. 1997;52(3):778-791.

Adults

Mehta NM, Duggan CP. Nutritional deficiencies during critical illness. Pediatr.Clin.North Am. 2009;56(5):1143-1160.

Review

Motil KJ, Grand RJ, Maletskos CJ, Young VR. The effect of disease, drug, and diet on whole body protein metabolism in adolescents with Crohn disease and growth failure. J.Pediatr. 1982;101(3):345-351.

Outpatients

Ney D, Bay C, Saudubray JM, Kelts DG, Kulovich S, Sweetman L, et al. An evaluation of protein requirements in methylmalonic acidaemia. J.Inherit.Metab.Dis. 1985;8(3):132-142.

Report

Nielsen AA, Nielsen JN, Gronbaek H, Eivindson M, Vind I, Munkholm P, et al. Impact of enteral supplements enriched with omega-3 fatty acids and/or omega-6 fatty acids, arginine and ribonucleic acid compounds on leptin levels and nutritional status in active Crohn's disease treated with prednisolone. Digestion 2007;75(1):10-16.

Borresen HC, Coran AG, Knutrud O. Metabolic results of parenteral feeding in neonatal surgery: a balanced parenteral feeding program based on a synthetic 1-amino acid solution and a commercial fat emulsion. Ann.Surg. 1970;172(2):291-301.

Robinson D, Drumm LA. Maple syrup disease: a standard of nursing care. Pediatr.Nurs. 2001;27(3):255-258.

Review

Miras A, Boveda MD, Leis MR, Mera A, Aldamiz-Echevarria L, Fernandez-Lorenzo JR, et al. Risk factors for developing mineral bone disease in phenylketonuric patients. Mol.Genet.Metab. 2013;108(3):149-154.

Outpatients

Peng X, Yan H, You Z, Wang P, Wang S. Clinical and protein metabolic efficacy of glutamine granules-supplemented enteral nutrition in severely burned patients. Burns 2005;31(3):342-346.

(31)

30 Pierro A, Koletzko B, Carnielli V, Superina RA, Roberts EA,

Filler RM, et al. Resting energy expenditure is increased in infants and children with extrahepatic biliary atresia. J.Pediatr.Surg. 1989;24(6):534-538.

Outpatients

Powell-Tuck J. Protein metabolism in inflammatory bowel disease. Gut 1986;27(Suppl 1):67-71.

Outpatients

PrayGod G, Range N, Faurholt-Jepsen D, Jeremiah K, Faurholt-Jepsen M, Aabye MG, et al. The effect of energy-protein supplementation on weight, body composition and handgrip strength among pulmonary tuberculosis HIV-co-infected patients: randomised controlled trial in Mwanza, Tanzania. Br.J.Nutr. 2012;107(2):263-271.

Age >15, no distinction between ages

Prelack K, Cunningham JJ, Sheridan RL, Tompkins RG. Energy and protein provisions for thermally injured children revisited: an outcome-based approach for determining requirements. J.Burn Care Rehabil. 1997;18(2):177-181.

The effect of protein and energy uptake

Ribeiro Junior Hda C, Lifshitz F. Alanine-based oral rehydration therapy for infants with acute diarrhea. J.Pediatr. 1991;118(4 Pt 2):S86-90.

Outpatients

Rocha JC, van Spronsen FJ, Almeida MF, Ramos E,

Guimaraes JT, Borges N. Early dietary treated patients with phenylketonuria can achieve normal growth and body composition. Mol.Genet.Metab. 2013;110(Suppl):S40-3.

Outpatients

Rodney S, Boneh A. Amino Acid Profiles in Patients with Urea Cycle Disorders at Admission to Hospital due to Metabolic Decompensation. JIMD rep. 2013;9:97-104.

Outcome: plasma amino acid concentration

Savica V, Santoro D, Ciolino F, Mallamace A, Calvani M, Savica R, et al. Nutritional therapy in chronic kidney disease. Nutr.Clin.Care. 2005;8(2):70-76.

Protein intake of CKD patients in general. Not inpatient children.

Scharli AF. Parenteral nutrition in pediatric surgery. World J.Surg. 1986;10(1):77-83.

Schwarz SM, Gewitz MH, See CC, Berezin S, Glassman MS, Medow CM, et al. Enteral nutrition in infants with congenital heart disease and growth failure. Pediatrics 1990;86(3):368-373.

Outpatients

Shepherd RW, Thomas BJ, Bennett D, Cooksley WG, Ward LC. Changes in body composition and muscle protein degradation during nutritional supplementation in nutritionally growth-retarded children with cystic fibrosis. J.Pediatr.Gastroenterol.Nutr. 1983;2(3):439-446.

Outpatients

Sherman JO, Hamly CA, Khachadurina AK. Use of an oral elemental diet in infants with severe intractable diarrhea. J.Pediatr. 1975;86(4):518-523.

Not the effect of protein, but the effect of a supplement with different elements

Shils ME. Nutritional therapy of the cancer patient: guidelines for enteral and parenteral feeding. Curr.Probl.Cancer 1979;4(3):66-76.