Increased protein-energy intake promotes anabolism in critically ill infants with viral bronchiolitis: a double-blind randomised controlled trial.
ABSTRACT The preservation of nutritional status and growth is an important aim in critically ill infants, but difficult to achieve due to the metabolic stress response and inadequate nutritional intake, leading to negative protein balance. This study investigated whether increasing protein and energy intakes can promote anabolism. The primary outcome was whole body protein balance, and the secondary outcome was first pass splanchnic phenylalanine extraction (SPE(Phe)).
This was a double-blind randomised controlled trial. Infants (n=18) admitted to the paediatric intensive care unit with respiratory failure due to viral bronchiolitis were randomised to continuous enteral feeding with protein and energy enriched formula (PE-formula) (n=8; 3.1 ± 0.3 g protein/kg/24 h, 119 ± 25 kcal/kg/24 h) or standard formula (S-formula) (n=10; 1.7 ± 0.2 g protein/kg/24 h, 84 ± 15 kcal/kg/24 h; equivalent to recommended intakes for healthy infants <6 months). A combined intravenous-enteral phenylalanine stable isotope protocol was used on day 5 after admission to determine whole body protein metabolism and SPE(Phe).
Protein balance was significantly higher with PE-formula than with S-formula (PE-formula: 0.73 ± 0.5 vs S-formula: 0.02 ± 0.6 g/kg/24 h) resulting from significantly increased protein synthesis (PE-formula: 9.6 ± 4.4, S-formula: 5.2 ± 2.3 g/kg/24 h), despite significantly increased protein breakdown (PE-formula: 8.9 ± 4.3, S-formula: 5.2 ± 2.6 g/kg/24 h). SPE(Phe) was not statistically different between the two groups (PE-formula: 39.8 ± 18.3%, S-formula: 52.4 ± 13.6%).
Increasing protein and energy intakes promotes protein anabolism in critically ill infants in the first days after admission. Since this is an important target of nutritional support, increased protein and energy intakes should be preferred above standard intakes in these infants. Dutch Trial Register number: NTR 515.
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ABSTRACT: Dietary restrictions required to manage individuals with Inborn Errors of Metabolism (IEM) are essential for metabolic control, however may result in an increased risk to both short and long- term nutritional status. Dietary factors most likely to influence nutritional status include energy intake, protein quality and quantity, micronutrient intake and the frequency and extent to which the diet must be altered during periods of increased physical or metabolic stress. Patients on the most restrictive diets, including those with intakes consisting of low levels of natural protein or those with recurrent illness or frequent metabolic decompensation carry the most nutritional risk. Due to the difficulties in determining condition specific requirements, dietary intake recommendations and nutritional monitoring tools used in patients with IEM are the same as, or extrapolated from, those used in healthy populations. As a consequence, evidence is lacking for the safest dietary prescriptions required to manage these patients long term, as tolerance to dietary therapy is generally described in terms of metabolic stability rather than long term nutritional and health outcomes. As the most frequent therapeutic dietary manipulation in IEM is alteration in dietary protein, and as protein status is critically dependent on adequate energy provision, the use of a Protein to Energy ratio (P:E ratio) as an additional tool will better define the relationship between these critical components. This could accurately define dietary quality and ensure that not only an adequate, but also a safe and balanced intake is provided.Molecular Genetics and Metabolism 08/2014; · 2.83 Impact Factor
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ABSTRACT: Dietary recommendations for patients with urea cycle disorders (UCDs) are designed to prevent metabolic decompensation (primarily hyperammonaemia), and to enable normal growth. They are based on the 'recommended daily intake' guidelines, on theoretical considerations and on local experience. A retrospective dietary review of 28 patients with UCDs in good metabolic control, at different ages, indicates that most patients can tolerate a natural protein intake that is compatible with metabolic stability and good growth. However, protein aversion presents a problem in many patients, leading to poor compliance with the prescribed daily protein intake. These patients are at risk of chronic protein deficiency. Failing to recognise this risk, and further restricting protein intake because of persistent hyperammonaemia may aggravate the deficiency and potentially lead to episodes of metabolic decompensation for which no clear cause is found. These patients may need on-going supplementation with essential amino acids (EAA) to prevent protein malnutrition. Current recommendations for the management of acute metabolic decompensation include cessation of protein intake whilst increasing energy (calorie) intake in the first 24h. We have found that plasma concentrations of all EAA are low at the time of admission to hospital for metabolic decompensation, with correlation between low EAA concentrations, particularly branched-chain amino acids, and hyperammonaemia. Thus, supplementation with EAA should be considered at times of metabolic decompensation. Finally, it would be advantageous to treat patients in metabolic decompensation through enteral supplementation, whenever possible, because of the contribution of the splanchnic (portal-drained viscera) system to protein retention and metabolism.Molecular Genetics and Metabolism 05/2014; · 2.83 Impact Factor
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ABSTRACT: Nutrition is an essential component of patient management in the pediatric intensive care unit (PICU). Poor nutrition status accompanies many childhood chronic illnesses. A thorough assessment of the critically ill child is required to inform the plan for nutrition support. Accurate and clinically relevant nutritional assessment, including growth measurements, provides important guidance. Indirect calorimetry provides the most accurate measurement of resting energy expenditure, but is too often unavailable in the PICU. To prevent inappropriate caloric intake, reassessment of the child's nutrition status is imperative. Enteral nutrition is the recommended route of intake. Human milk is preferred for infants.Critical Care Nursing Clinics of North America 06/2014; 26(2):199-215. · 0.43 Impact Factor
Arch Dis Child 2011;96:817–822. doi:10.1136/adc.2010.185637 817
Accepted 27 April 2011
Published Online First
14 June 2011
Objective The preservation of nutritional status and
growth is an important aim in critically ill infants, but
diffi cult to achieve due to the metabolic stress response
and inadequate nutritional intake, leading to negative
protein balance. This study investigated whether
increasing protein and energy intakes can promote
anabolism. The primary outcome was whole body
protein balance, and the secondary outcome was fi rst
pass splanchnic phenylalanine extraction (SPE Phe ).
Design This was a double-blind randomised controlled
trial. Infants (n=18) admitted to the paediatric
intensive care unit with respiratory failure due to
viral bronchiolitis were randomised to continuous
enteral feeding with protein and energy enriched
formula (PE-formula) (n=8; 3.1±0.3 g protein/kg/24 h,
119±25 kcal/kg/24 h) or standard formula (S-formula)
(n=10; 1.7±0.2 g protein/kg/24 h, 84±15 kcal/
kg/24 h; equivalent to recommended intakes for healthy
infants <6 months). A combined intravenous-enteral
phenylalanine stable isotope protocol was used on day
5 after admission to determine whole body protein
metabolism and SPE Phe .
Results Protein balance was signifi cantly higher with
PE-formula than with S-formula (PE-formula: 0.73±0.5
vs S-formula: 0.02±0.6 g/kg/24 h) resulting from
signifi cantly increased protein synthesis (PE-formula:
9.6±4.4, S-formula: 5.2±2.3 g/kg/24 h), despite
signifi cantly increased protein breakdown (PE-formula:
8.9±4.3, S-formula: 5.2±2.6 g/kg/24 h). SPE Phe was
not statistically different between the two groups
(PE-formula: 39.8±18.3%, S-formula: 52.4±13.6%).
Conclusions Increasing protein and energy intakes
promotes protein anabolism in critically ill infants in the
fi rst days after admission. Since this is an important
target of nutritional support, increased protein and
energy intakes should be preferred above standard
intakes in these infants.
Dutch Trial Register number: NTR 515.
The preservation of nutritional status and growth
is a specifi c aim in critically ill children, but dif-
fi cult to achieve. This is due to a metabolic stress
response with profound changes in protein metab-
olism leading to a negative protein balance and loss
of lean body mass. Inadequate nutritional intake
in the paediatric intensive care unit (PICU), often
due to fl uid restriction, further leads to protein
and energy defi cits, especially early after admis-
sion. 1 Other factors that hinder adequate nutrition
are impaired intracellular insulin signalling, 2
impaired glucose uptake 3 and reduced mitochon-
drial capacity during critical illness. 4 These fac-
tors are probably the reason why protein-energy
malnutrition is observed in 16–24% of critically ill
children 5 6 and is associated with adverse clinical
outcome. 7 – 9
A common but threatening disease in infants is
viral bronchiolitis, which in severe cases leads to
respiratory failure with need for ventilatory sup-
port and PICU admission. Adequate nutritional
support in these critically ill infants is important,
with protein anabolism as goal. However, up to
now common practice has been to use standard
infant formulas to provide approximately 1.5 g
protein/kg/day and 100 kcal/kg/day.
Increased protein intake with adequate
energy provision promotes anabolism in pre-
term infants, 10 – 12 in neonates undergoing sur-
gery 13 and in children with burns 14 and cystic
fi brosis. 15 In relation to these observations, it
is important to note that protein synthesis is a
high-energy consuming process 16 and energy
defi ciency worsens nitrogen balance. 17 18 Hence,
to induce net protein anabolism, it is essential to
provide an adequate energy intake. We therefore
hypothesised that increasing protein and energy
Appendices 1–4 are available
online only. To view these fi les
please visit the journal online
1 Department of Paediatrics,
Medical Center, Maastricht,
2 Department of Paediatric
Surgery, Erasmus MC– Sophia
Children’s Hospital, Rotterdam,
3 Currently working:
Department of Paediatric
Children’s Hospital, Rotterdam,
4 Department of Surgery,
Maastricht University Medical
Center, Maastricht, the
5Currently working: Center
for Translational Research in
Aging and Longevity, Donald
W Reynolds Insitute on Aging,
University of Arkansas for
Medical Sciences, Little Rock,
6Department of Paedatrics,
VU University Medical Center,
Amsterdam, the Netherlands
7Department of Paediatrics,
Emma Children’s Hospital-
AMC, Amsterdam, the
8Department of Paediatrics,
Hospital, Rotterdam, the
Dick A van Waardenburg,
Department of Paediatrics,
Maastricht University Medical
Center, PO Box 5800, 6202 AZ
Maastricht, The Netherlands;
C T de Betue and D A van
Waardenburg are joint fi rst
Increased protein-energy intake promotes anabolism
in critically ill infants with viral bronchiolitis: a
double-blind randomised controlled trial
Carlijn T de Betue, 1,3 Dick A van Waardenburg, 1,2 Nicolaas E Deutz, 4,5 Hans M van Eijk, 4
Johannes B van Goudoever, 6,7,8 Yvette C Luiking, 3,4 Luc J Zimmermann, 2 Koen F Joosten 8
Critical illness in children is associated with
increased protein breakdown, negative protein
balance and adverse clinical outcome.
Inadequate nutritional support further leads to
protein-energy malnutrition during admission
to the paediatric intensive care unit.
What is already known on this topic
Protein anabolism in critically ill infants can be
achieved in the fi rst days after admission by
increasing protein and energy intakes above
The higher protein balance resulted from
stimulated protein synthesis exceeding the rate
of concomitant stimulated protein breakdown.
Increased protein and energy intakes are
recommended in critically ill infants with viral
What t his study adds
Arch Dis Child 2011;96:817–822. doi:10.1136/adc.2010.185637 818
intakes would induce net protein anabolism in critically ill
Stable isotope amino acid methods are used to determine net
protein balance. 19 During feeding, amino acids appearing in
the circulation originate from protein breakdown and from the
fraction of meal-derived amino acids that are not retained in the
splanchnic area. Protein synthesis during feeding can be calcu-
lated from the disappearance of essential amino acids (EAAs)
such as phenylalanine from the circulation, corrected for non-
protein synthesis related disposal (eg, oxidation, hydroxyla-
tion). Therefore, all these factors need to be considered if whole
body net protein anabolism during feeding is to be calculated. 20
21 Splanchnic extraction (SPE) of meal-derived amino acids has
not been reported before in critically ill children.
The present study was part of a larger study on the nutritional
and metabolic effects of increased protein and energy intakes
using a protein and energy enriched formula (PE-formula)
compared with a standard infant formula (S-formula). 22 In the
present study we studied the effi cacy of increased protein and
energy intakes to promote protein anabolism and the underly-
ing mechanisms by using intravenous-enteral phenylalanine/
tyrosine stable isotope method protocol. The primary out-
come measure was whole body protein balance (WbPBal) at
day 5 after admission. SPE of phenylalanine was a secondary
outcome measure. The 24 h nitrogen balance was used as alter-
native method to assess protein balance. To gain more insight
into the role of separate amino acids in protein kinetics, corre-
lations between plasma amino acid concentrations and protein
metabolism were assessed.
Setting and patients
Infants admitted to the PICU of Maastricht University Medical
Center (MUMC) or ErasmusMC-Sophia Children’s Hospital
(ErasmusMC) meeting the following inclusion criteria were
enrolled: (1) respiratory failure due to viral bronchiolitis; (2)
age 4 weeks to 12 months; (3) >40 weeks postmenstrual age;
(4) ability to start enteral feeding <24 h after admission; (5)
expected length o f stay >96 h; and (6) venous and arterial
catheters present. Exclusion criteria were as follows: (1) gastro-
intestinal, metabolic or chromosomal disorder; (2) parenteral
nutrition other than intravenous dextrose; and (3) breast feed-
ing. The inclusion and exclusion criteria were chosen to create
a homogenous population of infants. Inclusion criteria 4, 5 and
6 were necessary for performance of the study protocol.
The Central Committee on Research Involving Human
Subjects (CCMO, The Hague, The Netherlands) and local eth-
ics committees approved this study. Written informed consent
was obtained from parents or caregivers.
Anthropometric characteristics a nd severity of illness
(Paediatric Risk of Mortality II) 23 were assessed at inclusion.
Duration of mechanical ventilation and length of PICU stay
were noted. T o determine the metabolic state of the patients,
plasma amino acid concentrations were determined in arterial
blood collected in the fed state at the start of the stable isotope
protocol on day 5 using fully automated high-performance liq-
uid chromatography as described before. 24 The roles of specifi c
amino acids were identifi ed through correlation with whole
body protein metabolism (WbPM).
Patients were randomised (randomisation and blinding as
described before 22 ) within 24 h after admission to receive
continuous enteral feeding with PE-formula (Infatrini: 2.6 g
protein/100 ml, 100 kcal/100 ml) or with S-formula (Nutrilon 1:
1.4 g protein/100 ml, 67 kcal/100 ml) both from Nutricia
Advanced Medical Nutrition, Zoetermeer, The Netherlands.
Compositions are summarised in appendix 1. Formulas were
administered as previously described, starting 25.3±5.6 versus
23.4±5.4 h after PICU-admission in the PE-group and S-group,
respectively. 22 The ranges of protein and energy intakes on
day 5 in the S-group (1.7±0.2 g protein/kg/24 h, 84±15 kcal/
kg/24 h) covered recommended intakes for healthy infants
<6 months (1.14–1.77 g protein/kg/24 h, 81–113 kcal/kg/24 h,
depending on age in months). 16 25 The ranges were signifi cantly
higher in the PE-group (3.1±0.3 g protein/kg/24 h, p<0.001;
119±25 kcal/kg/24 h, p<0.001) and were 175–272% and
105–147% of recommended intakes for protein and energy,
respectively. Intake by volume was not signifi cantly different
between groups; 120.6±13.4 ml/kg/24 h in the PE-group versus
118.5±13.4 ml/kg/24 h in the S-group. As the target volume
was 130 ml/kg/day, this was the maximum achievable intake
for both groups for medical reasons (eg, fl uid restriction) as
decided by the treating physician. Details of nutritional intake
are summarised in appendix 2.
Main outcome measures
WbPM and splanchnic phenylalanine extraction
On day 5 WbPM and splanchnic phenylalanine extraction
(SPE Phe ) were assessed by using a stable isotope protocol in
the fed state. Several methods can be used to determine pro-
tein metabolism. We used the phenylalanine/tyrosine method
because of the advantage that only blood samples are needed
instead of both blood and breath samples as for methods based
on leucine isotopes. 26 In order to attain steady state, the infu-
sion rate of enteral nutrition was not changed in the 6 h before
the start of or during the stable isotope protocol. The stable
isotope protocol was conducted by a research physician or
research nurse. Intravenous amino acid tracers were adminis-
tered continuously for 2 h with calibrated syringe pumps after
a priming dose, using the following tracers, priming doses
(μmol/kg) and infusion rates (μmol/kg/h), respectively: L-[ring-
2 H 5 ]phenylalanine, 4.4 μmol/kg, 4.5 μmol/kg/h; L-[ring- 2 H 2 ]
tyrosine, 1.9 μmol/kg, 1.5 μmol/kg/h; L-[ring- 2 H 4 ]tyrosine,
0.63 μmol/ kg. F or assessment o f SPE Phe , L-[1- 13 C]-phenylalanine
was administered as a primed-continuous enteral infusion (4.4
μmol/kg, 9.0 μmol/kg/h, respectively). Stable isotope tracers
(>98% enriched) were purchased from Cambridge Isotope
Laboratories (Woburn, Massachusetts, USA). Infusates were
prepared by the centres’ clinical pharmacists. Arterial blood
was sampled (500 μl) before isotope infusion to determine
background enrichment and at 60, 90 and 120 min of infu-
sion to determine isotopic enrichment. Samples were put on
ice and centrifuged (3500×g) for 10 min at 4°C. Plasma was
deproteinised with 5% sulfosalicylic acid, frozen in liquid
nitrogen and stored at −80°C until analysis. Tracer-to-tracee
ratios (TTRs) were analysed using a liquid chromatography–
mass spectrometry system as described before. 27 TTRs were
corrected for background enrichment and contribution to
the measured TTRs of isotopomers with lower masses as
described before. 28 Isotopic enrichment reached a steady state
after 1 h infusion, as shown by the lack of a statistically signifi -
cant slope of calculated TTRs at 60, 90 and 120 min (data not
shown). The mean enrichment was used for further calcula-
tions as described before. 19 These calculations are explained in
detail in appendix 3.
Arch Dis Child 2011;96:817–822. doi:10.1136/adc.2010.185637 819
The 24 h nitrogen balance on day 5 was assessed as described
before, with urinary urea being converted to total urinary
nitrogen (TUN) excretion. 22
Power analysis was based on protein metabolism parameters
in infants in earlier reports. 29 To detect a 20% difference in pro-
tein balance between groups with 0.05 two-sided signifi cance
and 0.80 sensitivity, eight patients per group were required.
Data were analysed on an intention-to-treat basis with the
SPSS statistical software package (v 12.0; SPSS, Chicago,
Illinois, USA). Differences between groups were assessed with
Mann–Whitney U analysis. Correlations among parameters
were tested with Spearman correlation coeffi cients. Statistical
signifi cance was defi ned as two-tailed p<0.05. Data are pre-
sented as mean±SD.
Twenty infants with respiratory failure due to viral bronchioli-
tis were enrolled (MUMC: n=10; Erasmus MC: n=10; December
2003 to February 2006). Ten patients were randomised and
allocated to receive PE-formula and 10 to receive S-formula.
All patients received the allocated formula. Two patients in
the PE-group were lost to follow-up because vascular catheters
were removed after extubation before day 5, a nd hence WbPM
could not be measured. Patient characteristics are shown in
table 1 . Gestational age was signifi cantly lower in PE-infants,
but other parameters did not differ signifi cantly. There were
no signifi cant differences in characteristics between patients
enrolled in MUMC and in Erasmus MC (data not shown).
Main outcome measures
WbPM and SPE Phe
The rates of phenylalanine kinetics on day 5 are shown in
table 2 . These values are directly derived from the pheny-
lalanine and tyrosine stable isotope tracer results and sub-
sequently used to calculate whole body protein kinetics as
shown in fi gure 1 . Whole body phenylalanine kinetics were
signifi cantly higher in the PE-group than in the S-group, apart
from phenylalanine hydroxylation, which was higher in the
PE-group but did not reach signifi cance. Al though SPE Phe
(%) tended to be higher in the S-group than in the PE-group
(p=0.08), absolute SPE was highest in the PE-group, but did not
reach signifi cance in either group.
Figure 1 depicts the rates of whole body protein synthesis
(WbPS), whole body protein balance breakdown (WbPBal) and
WbPBal in g/kg/24 h. It shows that WbPBal on day 5 was posi-
tive in the PE-group, while in the S-group it did not differ sig-
nifi cantly from zero (0.73±0.5 vs 0.02±0.6 g/kg/24 h, p=0.026).
The higher WbPBal was achieved through higher WbPS in
the PE-group (9.6±4.4 vs 5.2±2.3 g/kg/24 h, p=0.019), despite
concomitant higher WbPB (8.9±4.3 vs 5.2±2.6 g/ kg/24 h,
p=0.046). Negative WbPBal, refl ecting catabolism, was found
Table 1 Patient characteristics of the study population
PE-group (n=8) S-group (n=10) p Value
Medical centre (MUMC/
Weight at inclusion (g)
Birth weight (g)
Gestational age (weeks)
Postmenstrual age (weeks)
Crown–heel length (cm)
CRP on admission (mg/l)
Mechanical ventilation (days)
Length of PICU stay (days)
Data are presented as number of subjects or mean±SD.
CRP, C-reactive protein; Erasmus MC, Erasmus Medical Center;
MUMC, Maastricht University Medical Center; PE-group, protein and energy
enriched formula fed group; PICU, paediatric intensive care unit; PRISM,
Paediatric Risk of Mortality; S-group, standard infant formula fed group.
Table 2 Whole body and splanchnic phenylalanine kinetics on day 5
PE-group (n=8) S-group (n=10) p Value
Whole body Phe kinetics
WbPhe utilised for PS
WbPhe from PB
Splanchnic Phe kinetics
Dietary Phe intake
SPE Phe (%)
All data are in µmol/kg/h unless otherwise specifi ed and are presented as
ASPE Phe , absolute splanchnic phenylalanine extraction; PE-group, protein and
energy enriched formula fed group; Phe, phenylalanine; PheI SPE , phenylalanine
intake, corrected for SPE Phe , thus available for peripheral protein synthesis and
oxidation; S-group, standard formula fed group; SPE Phe , splanchnic phenylalanine
extraction; Tyr, tyrosine; WbOH Phe→Tyr , whole body hydroxylation of phenylalanine
to tyrosine; WbPhe balance, whole body phenylalanine balance; WbPhe from PB,
whole body phenylalanine originating from protein breakdown; WbPhe utilised for
PS, whole body phenylalanine used for protein synthesis; WbRa, whole body rate
Figure 1 Rates of protein kinetics (g/kg/24 h) in both study groups
on day 5. Data are presented as mean±SD. *p<0.05. PE-group,
protein and energy enriched formula fed group; S-group, standard
formula fed group; WbPB, whole body protein breakdown; WbPBal,
whole body protein balance; WbPS, whole body protein synthesis.
WbPS and WbPB were signifi cantly higher in the PE-group than in
the S-group. Consequently, a positive WbPBal was achieved in the
PE-group, which was signifi cantly higher than in the S-group.
Arch Dis Child 2011;96:817–822. doi:10.1136/adc.2010.185637 820
in one subject (13%) in the PE-group, but in four infants in the
Whole body protein turnover in the PE-group was higher
than in the S-group (10.7±4.3 vs 5.8±2.6 g/kg/24 h, p=0.012).
Whole body protein oxidation, calculated from hydroxylation
of phenylalanine to tyrosine, was higher with the PE-formula
than with the S-formula, but not signifi cantly so (1.2±0.8 vs
0.7±0.4 g/kg/24 h, p=0.25).
Plasma amino acid concentrations on day 5 are shown in
appendix 4. The concentrations of fi ve EAAs (methionine, his-
tidine, phenylalanine, lysine and valine) and ornithine were
signifi cantly higher in the PE-group. The sums of branched
chain amino acids (BCAAs) and EAAs were also signifi cantly
higher. WbPS was positively correlated with concentrations
of the EAAs histidine (r=0.46, p<0.05), methionine (r=0.64,
p<0.01), tryptophan (r=0.51, p<0.05), leucine (r=0.56, p<0.05)
and isoleucine (r=0.47, p<0.05) and with sums of BCAAs
(r=0.51, p<0.05) and EAAs (r=0.51, p<0.05). WbPBal was
positively correlated with isoleucine (r=0.52, p<0.05), valine
(r=0.46, p<0.05) and the sum of BCAA (r=0.53, p<0.05).
The 24 h nitrogen balance on day 5 was signifi cantly higher
in PE-infants (274±127 vs 137±53 mg/kg/24 h, p<0.05).
Multiplication of the results by 6.25 (the average amount of
nitrogen in protein) resulted in protein balances of 1.71 vs
0.85 g/kg/24 h for the PE-group and S-group, respectively.
TUN excretion on day 5, as a measure of amino acid oxidation,
was higher in PE-infants, but not signifi cantly so (171±81 vs
103±54 mg/kg/24 h, respectively, p=0.37).
The present study is the fi rst to show that protein anabo-
lism, an important target of nutritional support in critically ill
infants, can be achieved within the fi rst days after admission
to the PICU by increasing enteral protein and energy intakes
above dietary reference levels using a protein-energy enriched
formula. This target was not achieved with a standard infant
formula. The higher protein balance resulted from stimulated
protein synthesis exceeding the rate of concomitant stimu-
lated protein breakdown. Nitrogen balance data confi rmed our
Our fi ndings of increased protein synthesis and protein bal-
ance are in agreement with several studies in premature and
term neonates evaluating the effects of amino acid supplemen-
tation. 10 – 13 29 – 33 This is also true for protein breakdown which
was either increased 33 or not affected by amino acid supple-
mentation. 11 13 29 31 Although Poindexter 30 has also reported
suppression of proteolysis, this was in healthy instead of
critically ill infants, receiving short term supplementation.
Our fi nding of both increased protein synthesis and protein
breakdown with higher protein and energy intakes is probably
due to overall stimulation of protein turnover, as shown by the
increased whole body protein turnover rate in the PE-group. 34
Increased protein intake promotes protein anabolism,
but may lead to increased amino acid oxidation with urea
formation as seen in neonates with increasing amino acid
supplementation, 11 13 31 when exceeding needs. However,
in the present study, neither phenylalanine hydroxylation
nor TUN excretion (both refl ecting amino acid oxidation),
nor plasma urea concentrations (as described in our previous
report) 22 differed signifi cantly between groups, suggesting
that protein intake up to, and probably above, 3.1 g/kg/day
does not exceed these infants’ needs.
We are aware that using a PE-formula makes it diffi cult
to discern the infl uences of separate macronutrients on pro-
tein metabolism. However, studies in adults and children
have shown that protein is the major dietary determinant of
WbPM as long as energy intake is suffi cient. 35 Additionally,
supporting this hypothesis, the fi nding of a positive relation-
ship between plasma EAAs and protein synthesis and balance
suggests that EAA availability plays a crucial role in increas-
ing protein synthesis and protein balance. It also agrees
with previous observations in healthy adults indicating that
( essential) amino acids are the primary stimulus for (muscle)
protein synthesis. 36
In these critically ill infants, receiving large amounts of intra-
venous fl uids and medications, 120 ml/kg/day was the maxi-
mum achievable nutritional volume intake. Despite these fl uid
restrictions, an anabolic state was obtained within 5 days after
admission using a protein-energy enriched formula, thereby
limiting delay of growth and neurodevelopment during criti-
cal illness as much as possible. We have previously reported
that the PE-formula is safe, well tolerated and improves nitro-
gen and energy balance at days 1–5 after admission. 22 This
type of formula is thus preferable to standard formulas to
achieve adequate nutrition in comparable clinical settings.
Since the subjects were a typical sample of infants with respi-
ratory insuffi ciency due to viral bronchiolitis, we suggest that
the results apply to the general population of these critically
Our study is also the fi rst to report values of fi rst pass SPE Phe
in continuously enterally fed critically ill infants. In this pop-
ulation, fi rst pass SPE Phe did not differ between groups with
an average of 46.8%. Comparable values have been described
in healthy adults after a meal 21 and in enterally fed piglets. 37
There is discussion about correcting protein intake for SPE in
calculations of WbPBal, since these retained amino acids are
used for constitutive or secreted (glyco-)proteins in the gut, 38 39
which is then considered part of WbPS. We have therefore also
calculated the data without correction for SPE (not shown) and
found that protein breakdown was 15–19% lower and protein
balance 2.7–3.9 times higher. Only the absolute values are
affected by this calculation, and the main conclusion of the
study is not affected.
There are several limitations to this study. Despite using
a randomised design, gestational age was signifi cantly lower
in the group receiving protein-energy enriched formula. This
might have biased our results of protein metabolism as protein
turnover decreases with increased (post-)conceptional age. 40
Furthermore, the proportion of female subjects was rela-
tively high. Protein deposition has been shown to be similar
for healthy male and female children prior to adolescence and
it is recommended that estimates of protein requirements for
healthy children are calculated for both sexes combined. 25
However, in children with burns (8 years of age on average),
females had a less negative net muscle protein balance com-
pared to males, and females gained lean body mass whereas
males lost lean body mass. These differences were possibly
due to the observed attenuated hypermetabolic response in
females. 41 Assuming that the same differences are true for
critically ill infants, this would mean that the achievement of
protein anabolism in the fi rst days after admission in our study
population could have been biased by the high proportion of
females. However, gender differences in protein kinetics have
not been described for critically ill infants. Moreover, our study
population of infants with a viral infection is distinctly differ-
ent from children with burns, who are subject to an extended
Arch Dis Child 2011;96:817–822. doi:10.1136/adc.2010.185637821
hypermetabolic stress response with high infl ammation. 41
Also, when comparing the female with the male subjects
within the PE- and S-groups of our study, the only notable
difference was a non-signifi cant trend towards higher protein
turnover, synthesis and breakdown in the females compared
to the males within the PE-group, but resulting in similar pro-
tein balances in both sexes. Therefore it seems unlikely that
our results were affected by gender differences, despite the
high proportion of females. Since the female subjects were
equally distributed among both groups in our study, neither
did it infl uence the comparison of groups.
Another limitation is that protein synthesis and protein
breakdown were derived by extrapolating phenylalanine
metabolism, which in fact only refl ects the effects on the
kinetics of this particular EAA. Other amino acid tracers may
have shown different patterns, although the phenylalanine/
tyrosine and leucine methods are considered to be reference
methods to obtain reliable estimates of whole-body protein
metabolism in most physiological conditions. 26 The present
study was not designed to establish exact protein and energy
needs in critically ill infants. Neither was it adequately pow-
ered to detect clinical effects. Dose–response studies and
studies into the clinical effects of improved protein balance in
larger groups of critically ill infants are therefore necessary.
In conclusion, protein anabolism in critically ill infants with
viral bronchiolitis can be achieved in the fi rst days after admis-
sion by increasing protein and energy intakes above reference
levels. Since protein anabolism is an important goal of nutri-
tional support in these infants, increased protein and energy
intakes should be preferred over standard intakes.
Acknowledgements The authors would like to thank the participating children
and their parents. They also thank Marianne Maliepaard for patient enrolment and
data collection, and the nursing and medical staff of the paediatric intensive care
units of Maastricht University Medical Center and ErasmusMC–Sophia Children’s
Hospital for their support.
Funding This study was fi nancially supported by a grant from Nutricia Advanced
Medical Nutrition, Zoetermeer, The Netherlands. Nutricia was not involved in the
study design, in the collection, analysis and interpretation of data or in the decision
to submit the paper.
Competing interests None.
Ethics approval This study was conducted with the approval of the Central
Committee on Research Involving Human Subjects (CCMO, The Hague, The
Netherlands) and the local ethics committees of Maastricht University Medical
Center, Maastricht, The Netherlands and Erasmus Medical Center–Sophia
Children’s Hospital, Rotterdam, The Netherlands.
Provenance and peer review Not commissioned; externally peer reviewed.
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