Review Article

Page 1 of 15

The role of parenteral nutrition in paediatric critical care, and its

consequences on recovery
Renate D. Eveleens, Sascha C. A. T. Verbruggen, Koen F. M. Joosten

Paediatric Intensive Care, Department of Paediatrics and Paediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands
Contributions: (I) Conception and design: All authors; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV)
Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of
manuscript: All authors.
Correspondence to: Prof. dr. Koen F. M. Joosten, MD, PhD. Erasmus MC-Sophia Children’s Hospital, Wytemaweg 80, 3015 CN, Rotterdam, The
Netherlands. Email: k.joosten@erasmusmc.nl.

Abstract: The goal of nutritional support during critical illness is to provide the appropriate amount of
nutrition accounting for the acute, stable and recovery phase in order to accelerate recovery and to improve
short-term and long-term outcomes. Although the preferred route to provide nutritional support during
paediatric critical illness is via enteral route, reaching target intakes is often difficult due to (perceived)
feeding intolerance, fluid restriction, and interruptions around procedures. Because undernourishment
in these children has been associated with impaired outcome, parenteral nutrition (PN) has therefore
been viewed as an optimal alternative for reaching early and high nutritional targets. However, PN
recommendations regarding timing, dose and composition varied widely and were based on studies using
intermediate or surrogate endpoints and observational studies. It was not until the paediatric early versus
late PN in critically ill children (PEPaNIC) randomized controlled trial (RCT) that the advice to reach
high and early macronutrient goals via PN was challenged. The PEPaNIC study showed that omitting
supplemental PN during the first week of paediatric intensive care unit (PICU) admission as compared with
early initiation of PN (<24 hours) reduced new acquired infections and accelerated recovery. The provision
of amino acids in particular was negatively associated with short-term outcomes, probably explained by the
suppression of the activation of autophagy. Autophagy is an evolutionary conserved intracellular degradation
process and it is crucial for maintaining cellular integrity and function, which becomes even more important
during acute stress. Results of the long-term PEPaNIC follow-up study showed that withholding early PN
did not negatively affect anthropometrics and health status but improved neurocognitive and psychosocial
development 2 and 4 years later. Current guidelines therefore advise to consider withholding parenteral
macronutrients for the first week of PICU admission, while providing micronutrients. Although parenteral
restriction during the first week of critical illness has been found beneficial, further research beyond the
acute phase is warranted to determine the best role of PN in terms of optimal timing, dose and composition
in order to improve short-term recovery and long-term developmental outcomes.

Keywords: Parenteral nutrition (PN); enteral nutrition (EN); critical illness; paediatric

Received: 11 September 2020; Accepted: 23 November 2020; Published: 30 November 2020.

doi: 10.21037/pm-20-88
View this article at: http://dx.doi.org/10.21037/pm-20-88

Introduction to both cure and cause diseases, and with this viewpoint in
mind, the role of parenteral nutrition (PN) has developed
Providing optimal nutrition is essential for normal growth, substantially over de last decade. During critical illness
health and development of children. Nutrition is known the child is subjected to hormonal and metabolic changes,

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Page 2 of 15 Pediatric Medicine, 2020

Table 1 Definitions of the three phases of the stress response in critically ill children (1) including the nutritional considerations per phase
Phase Definition Nutritional considerations

Acute phase First phase after event, characterized by requirement of (escalating) Energy acquired via endogenous production.
(catabolic) vital organ support. Phase when the patient requires vital organ support Intake requirement lower than REE
(sedation, mechanical ventilation, vasopressors, fluid resuscitation)

Start of enteral nutrition and accepting low

and slowly inclining intakes up to 1 times
REE, while monitoring patients EN tolerance

Withhold PN during the acute phase (first

7 days) to allow autophagy and improve
clinical outcomes

Be aware of hypo- and hyperglycaemia

Stable phase Stabilisation or weaning of vital organ support, while the different Stepwise inclining EN intakes, while
(catabolic – aspects of the stress response are not (completely) resolved. The patient monitoring patients EN tolerance
anabolic) is stable on, or can be weaned, from this vital support

Provide PN from day 8 onwards

Be aware of hyperglycaemia and IFALD

Recovery Clinical mobilisation with normalisation of neuro-endocrine, immunologic Higher caloric and protein requirements with
phase and metabolic alterations, characterized by a patient who is mobilizing EN and/or additional PN might be necessary
(anabolic) to account for increasing physical activity,
tissue repair, and long-term development
EN, enteral nutrition; PN, parenteral nutrition; REE, resting energy requirement; IFALD, intestinal failure associated liver disease.

commonly referred to as acute stress response, which influence on reduction of oxidative stress and maintaining
temporarily inhibits the normal developmental process in the immune response and gastrointestinal mucosal integrity
order to survive. Furthermore, the gut is subjected to many limiting bacterial translocation via the gut. However, the
adverse influences such as ischemia, altered blood flow, lack clinical impact of these positive modulations of EN is
of enteral nutrition (EN) and medication. As such, the goal unknown. Due to many reasons, such as (perceived) feeding
of nutritional support is to provide the appropriate amount intolerance, fluid restriction, fasting around (bedside)
of feeding during the different phases of disease in order to procedures, target caloric and protein goals are often not
accelerate recovery and to have beneficial effects on short- achieved via enteral route and discrepancies between the
term and long-term outcome. Nutritional requirements amounts prescribed and delivered ranges up to 60% (6-11).
of critically ill children depend on many factors, including Observational studies have found that malnourishment
nutritional status on admission, the underlying and actual and underfeeding due to macronutrient deficits are
diagnosis. Furthermore, the awareness of the changes associated with delayed wound healing, reduced immune
in amino acid, lipid, carbohydrate and micronutrient response, malabsorption, bacterial overgrowth and
metabolism during the different phase of the acute increased morbidity and mortality (8,9,12,13). Overfeeding
stress response is essential in determining the dynamic in its turn may lead to intestinal failure associated liver
metabolic and nutritional support, and thereby counteract disease (IFALD), hyperglycaemia and increased respiratory
malnourishment and overfeeding (Table 1). burden due to the increase in CO2 production present by
lipogenesis from carbohydrates (14,15). Besides short-term
consequences, both underfeeding and overfeeding have
Nutritional support
been associated with impaired growth, cognitive functioning
The preferred route to provide nutritional support during and emotional and behavioural problems in non-critically ill
paediatric critical illness is via enteral route (2-5). EN children (16,17). Thus far, the long-term consequences of
or even trophic feeding is supposed to have a positive underfeeding and overfeeding in critically ill children have

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Pediatric Medicine, 2020 Page 3 of 15

not been established. Stable and recovery phase

Due to the inability to achieve caloric and protein goals via
Although restriction of PN during the acute phase of
EN, PN is often initiated in critically ill children. A world-
illness, continuing this course beyond the acute phase
wide survey investigating PN practises in the paediatric
seems detrimental for short-term and long-term outcome.
intensive care units (PICUs) showed a wide variety between
Currently, it is not known at which point in time safe
macronutrient and caloric targets, as well as estimation of
parenteral restriction ends and the potential detrimental
energy requirements during critical illness and timing of
effects of macronutrient starvation starts.
initiation, amount and composition of PN (18,19). What
During the stable and recovery phases, PN should focus
should be considered as optimal PN during critical illness
on allowing normal or even catch up growth and successful
is controversial due to the majority of findings that are
provision is usually monitored through anthropometric
being derived from observational studies and the inability to
measurements, muscle strength and function and tissue
provide a causal relationship between nutrition and short-
repair (e.g., wound healing). Nutritional needs can rise
term or long-term recovery and outcomes. To understand
above normal requirements for healthy children (24),
the optimal role of PN during paediatric critical illness, the
however, it is unclear how fast optimal feeding goals can be
following two fundamental questions should be answered:
achieved. A stepwise caloric enhancement is recommended
(I) What is the optimal timing of PN?
while providing EN, however, the guidelines do not provide
(II) What is the optimal dose and composition of PN?
recommendations for stepwise enhancement of PN (4).

Timing of PN
Autophagy
Acute phase
The leading explanation behind the counter-intuitive
The paediatric early versus late PN in critically ill finding of the PEPaNIC RCT is the consequence of early
children (PEPaNIC) RCT, published in 2016 was the first and high nutritional intake to suppress the fasting response,
randomized controlled trial (RCT) that aimed to determine which induces ketosis and activates autophagy (25-28).
optimal timing in critically ill children (20). This large Autophagy is an evolutionary conserved intracellular
multicentre RCT involving 1,440 critically ill children degradation process and it is crucial for maintaining cellular
showed that withholding supplemental PN for 7 days (Late integrity and function. This becomes even more important
PN), as compared with initiating PN within 24 hours after during acute stress, as children suffer from extensive cell
admission (early PN), improved short-term outcome such and organ damage, leading to organ failure and muscle
as new acquired infections and length of stay (20). EN was weakness. Animal studies showed that impaired autophagic
provided in both groups when possible and tolerated within control caused by early PN let to liver and skeletal muscle
24 hours and PN was supplemented up to total caloric need deficiency (27). This process was confirmed by a study in
following the randomisation groups. When more than 80% adults establishing that early PN did not prevent muscle
of total caloric need was reached enterally, supplemental wasting and even increased adipose tissue deposition in the
PN was stopped. Weight deterioration during PICU muscle (25). These studies open perspectives for therapies
admission was not affected by the intervention, however, a that activate autophagy during critical illness. Although
decrease in weight-for-age z-score itself was associated with still controversial, possible endeavours can lie within
worse clinical outcomes in both groups (21). Furthermore, pharmacological agents inducing autophagy. For instance,
secondary analyses of the PEPaNIC RCT showed that an animal experiment found that stimulation of autophagy
even term neonates and undernourished children upon in the kidney with rapamycin correlated with protection of
admissions benefited from this intervention (22,23). The renal function (29).
results of the PEPaNIC RCT had a great impact on
international guidelines which currently advise to consider
Intermittent PN
(supplemental) PN beyond day 7 of critical illness while
providing micronutrients (2-5). So far, it is still the only PN can be provided continuously over 24 hours as well as
RCT focusing on optimal initiation of PN in critically ill intermittently, meaning a period of withholding PN. Several
children in the first week of admission in the PICU. intermittent techniques have been described, including

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Page 4 of 15 Pediatric Medicine, 2020

cyclic feeding with a period of fasting (10–12 hours) levels, except from vitamin K which can be provided weekly
throughout the night or day. A cyclic regime in non- without harmful side effects (39-41).
critically ill children with long-term PN, i.e., children
with short bowel syndrome or intestinal failure, has been
Dose of parenteral macronutrients
used for many years and was shown not to change the
intestinal microbiome (30) and decreased the risk of IFALD Energy
and cholestasis (31). Furthermore, a reduction of serum
The actual energy requirement of the child will depend on
bilirubin levels and livers enzymes was seen, which was
many factors including medication, need for mechanical
associated with a reduction in both hyperinsulinaemia and
ventilation, temperature, (lack of) physical activity and
fat deposition in the liver (32,33). Metabolic studies showed
on the phase of the disease. During the acute phase,
that lipid oxidation was higher and dextrose use was lower
endogenous energy production accounts for a substantial
during cyclic PN (34,35). Overall, cyclic PN was well
tolerated without a higher risk for hypo- or hyperglycaemia, proportion of energy requirement (up to 75%) irrespective
however, using a tapering technique can be considered in of the energy provision via exogenous source (42).
younger children as abrupt discontinuation had may cause Therefore, the energy requirement from EN or PN can be
hypoglycaemia (36). Based on this evidence cyclic PN is much lower than the calculated or measured resting energy
currently recommended in stable patients during and after expenditure (REE) (Figure 1). During the recovery phase
hospital admission (37). the focus shifts from acute interventions to optimizing
Also, there is currently no evidence for continuous activity, tissue repair and physical and neurocognitive
versus cyclic PN in critically ill children. Cyclic feeding development. There is an increasing demand in energy
has some additional hypothetical benefits in critical ill during this phase to allow normal development of the child
children compared to continuous provision of nutrients, and even to catch up (2,4,43).
e.g., fasting induces activation of autophagy, preservation of
the circadian rhythm and even enhanced protein synthesis Amino acids
(28,38). This strategy remains controversial, however,
the findings in the non-critically ill paediatric population Amino acid dose requirement is lower via PN than EN due
underpin the rationale for a cyclic feeding strategy opposed to the bypass of the utilization by the gastro-intestinal tract.
of continuous feeding which is standard of care in most A secondary analysis from the PEPaNIC study showed
PICUs and opens perspectives for intervention studies in that during the acute phase higher doses of parenteral
critically ill children to define an optimal fasting period to administered amino acids was negatively associated with
allow autophagy and potentially improve clinical outcomes. PICU length of stay, new acquired infections and duration
of mechanical ventilation (44). Even low doses of parenteral
amino acids during the acute phase were found to be harmful,
Parenteral micronutrients
whereby a maximal risk of harm was reached with a median
Micronutrients, consisting of vitamins, trace elements daily dose of 1.15 g/kg for children <10 kg, 0.83 g/kg for
and electrolytes, are considered to have an important children between 10–20 kg, and 0.75 g/kg for children >20 kg.
role in body metabolism, immune response and tissue Therefore, the current guidelines suggest to withhold amino
function, and are therefore essential during critical acids via PN during the first week of illness (45).
illness. While the current guidelines on PN in critically After the acute phase muscle wasting often continues due
ill children recommended to consider withholding PN to immobilization and undernourishment. Therefore, the
for the first week of admission, they advise to maintain ESPGHAN/ESPEN/ESPR/CPNN guidelines advise from
supplementation of micronutrients during this time window day 8 onwards to provide a minimum amino acid intake of
(2-5). In addition, the ESPGHAN/ESPEN/ESPR/CSPEN 1.0 mg/kg/min in stable term infants and 0.7 mg/kg/min
guidelines recommend to provide micronutrients daily in children from 1 month to 18 years to avoid a negative
because this prohibits adverse reactions from transient high nitrogen balance while the maximum amino acid intake

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Pediatric Medicine, 2020 Page 5 of 15

Acute Stable Recovery

Catabolic Anabolic

Risk of overfeeding with PN Risk of underfeeding without PN

200
= Exogenous energy
requirement

150
% REE

100
Endogenous energy = REE
production

50

↑Start stepwise EN ↑ Start supplemental PN

0
1 2 3 4 5 6 7 8 9 days of admission 

Figure 1 Dynamic energy need during the different phases of critical illness. PN, parenteral nutrition; REE, resting energy expenditure.

should not exceed 2.1 mg/kg/min in neonates, 1.7 mg/kg/min for the production of nitric oxide without an effect on
in infants and children up to 3 years and 1.4 mg/kg/min in arginine synthesis (51). Nonetheless, due to the overall
older children (45). lack of evidence the SCCM/ESICM guidelines advised
against the use of glutamine, arginine, supplementation
in children with septic shock or sepsis-associated organ
Specific amino acids
dysfunction.
Amino acids are classified into essential (cannot be
synthesized from other elements), semi-essential and
Carbohydrates
non-essential (can be synthesize from other elements).
There is little evidence regarding specific amino acids Carbohydrates or glucose are one of the main and preferred
administration during critical illness. Moreover, the energy sources during health and during critical illness.
available evidence focusses primarily on (pre)term Glucose levels are among others influenced by the route
neonates. Although, trials in adults providing glutamine, carbohydrates are provided and administration of glucose
a semi-essential amino acid, as a single nutrient or in outside of the main feeding sources, such as medication.
combination with other nutritional supplements did find a Plasma glucose levels are a balance between glucose
reduction in sepsis and mortality (46) and was found safe utilization and exogenous glucose intake and endogenous
in 19 infants after surgical interventions (47), there seems glucose production (glycogenolysis and gluconeogenesis).
to be no evidence for glutamine in PN in infants and During critical illness glucose metabolism is affected
young children as this failed to show a beneficial effect on due to insulin resistance and β-cell dysfunction, which
outcome and is currently not advised in PN in children up increases the risk of developing hyperglycaemia. Due to
to 2 years (48-50). The semi-essential amino acid arginine the restricted glucose utilisation in the acute phase lower
has, among others, a role the endogenous nitric oxide doses are advised during this acute phase compared to the
synthesis. A small study in critically ill septic children aged acute and stable phase. Recommended doses per phase and
6–16 years found arginine to increase arginine oxidation weight are presented for children from 28 days to 18 years

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Page 6 of 15 Pediatric Medicine, 2020

Table 2 Advised parenteral glucose dose during acute, stable and recovery phase according to the ESGPHAN/ESPEN/ESPR/CSPEN guideline
per age or weight class (52)
Phase 28 d–10 kg 11–30 kg 31–45 kg >45 kg

Acute phase (mg/kg/min) 2–4 1.5–2.5 1–1.5 0.5–1

Stable phase (mg/kg/min) 4–6 2–4 1.5–3 1–2

Recovery phase (mg/kg/min) 6–10 3–6 3–4 2–3

in Table 2 (52). For term neonates it is recommended to which serve as coenzymes in these metabolic pathways,
start with 2.5–5 mg/kg/min gradually increasing towards will rise. Simultaneously, the cell breakdown results in
5–10 mg/kg/min. Additionally, during stable and recovery release of intracellular elements ensuring the availability of
phase the concomitant provision of protein and lipids many elements. During anabolic phase the micronutrient
should be incorporated in the amount of glucose provision. need rises to allow normal of even catch-up development
It is important to maintain normal plasma levels of glucose and patients presenting with deficiencies are more likely
as hyperglycaemia and hypoglycaemia are both associated during the anabolic phase after a prolonged catabolic phase
with impaired outcomes and carbohydrate tolerance should (54,55). Increased losses, e.g., zinc deficiency as a result of
be controlled through glycemic monitoring (<8 mmol/L in diarrhoea, potassium with vomiting, may also interfere with
critically ill; <10 mmol/L sepsis or traumatic brain injury) maintaining optimal levels.
(5,52). When depletions passed the subclinical phase, it may
manifest in encephalopathy, muscle weakness, neuropathy,
wound healing and affect cardiac and other organ functions
Lipids
and as a final stage result in death (54). Critical illness and
Parenteral lipid provision should be a fundamental part inflammation are known to have an effect on the plasma
of PN in critically ill children during stable and recovery levels of micronutrients and associations with deficiencies
phase. Normally, lipid intake accounts for 25–50% of the have been made with continuous renal replacement therapy
non-protein caloric intake in parenterally fed patients, and cardiac surgery. Low micronutrient levels are reported
however, critical illness can result in acceleration of the lipid for thiamine, riboflavin, folate, vitamin B6, vitamin B12,
metabolism. Providing lipid emulsions is essential because vitamin A, b-carotene, zinc, selenium, iron and chromium,
this allows a high energy supply without administering were high or unchanged levels were found for vitamin
high doses of carbohydrates as an iso-osmolar solution in a E, vitamin B6, copper and manganese (4). The clinical
low volume. The supply of fatty acids, with a minimum of interpretation of blood plasma levels can be misleading
linoleic acid intake of 0.1 g/kg/day, is essential to prevent during critical illness and might not reflect true intracellular
essential fatty acid deficiencies (53). The provided dosage deficiencies (56). Furthermore, the actual relevance of
of lipids should not exceed the capacity for lipid clearance micronutrient deficiencies or redistribution in critically
and should be lowered in case of hyperlipidaemia [serum ill children remains uncertain, nonetheless reported
triglyceride level is >265 mg/dL (>3.0 mmol/L) in infants, prevalence’s are high and associations have been made with
>400 mg/dL (>4.5 mmol/L) in children]. It is currently adverse outcome (4,57-60).
advised not to exceed a lipid intake of 4 and 3 g/kg/day via
PN in infants and children respectively.
Supplementation

Adult studies in critically ill patients confirm the association

Dose of parenteral micronutrients
between micronutrient deficiency and stress response,
Comparable to the macronutrients, the micronutrient however, recent RCTs and meta-analyses failed to find a
needs may also differ during the course of paediatric causality between single or combination of supplemented
critical illness. During the catabolic acute phase energy micronutrients (i.e., selenium, copper, zinc, thiamine and
expenditure is altered and protein breakdown is increased. vitamins vitamin B12, D, C & E) and clinical outcomes
The demand for trace elements and water-soluble vitamins, including mortality, length of stay and time to recover from

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Pediatric Medicine, 2020 Page 7 of 15

sepsis (61-70). Several recent studies have invested in the refeeding syndrome. This syndrome is further characterized
combination of vitamin C, thiamine and hydrocortisone by hyperglycaemia and fluid retention causing oedema and
as a potential therapy to accelerate recovery (69,71-75). can be managed by parenteral trace mineral supplementation
An observational study in paediatric septic patients who and/or caloric feeding restriction (80). Vitamin B1 serve
received vitamin C, thiamine in addition to hydrocortisone as a co-factor in the substrate oxidation and depletions are
showed improved short-term outcomes compared to known to affect the neuro and cardiovascular system causing
hydrocortisone alone (71). Though, the benefit of this diseased as Beriberi, Wernicke’s and Korsakoff syndrome.
supplementation therapy was not confirmed by a RCT During critical illness depletions in this micronutrient
performed in adults (69). may occur after introduction of feeding after a period of
Because there is currently no evidence for the optimal malnutrition (81).
micronutrient doses accounting for paediatric critical illness (4),
the recommendations provided in the guidelines for Zinc
parenteral micronutrients are based upon dietary intake Zinc serves as a cofactor for over 300 body enzymes
recommendations for healthy children and do not account including DNA synthesis and RNA transcription and
for the phase of illness, potential increased demands or deficiency is characterized by impaired immune function,
altered losses (Table 3) (3,39-41,76). glucose homeostasis wound healing and growth retardation.
Some comments can be made for specific micronutrients: Zinc supplementation during critical illness is the only
element investigated in critical ill children with two RCTs.
Sodium The first trial showed in 24 critically ill children that by
Critically ill children are at risk to develop hyponatremia. providing 500 μg/kg/d plasma levels could be restored
A meta-analysis showed that isotonic maintenance fluids to the near 50th percentile (82). While the second RCT
with sodium concentrations similar to blood plasma reduce providing whey protein, zinc, glutamine, selenium and
the risk of developing hyponatraemia when compared with metoclopramide versus whey protein in 298 critically ill
hypotonic intravenous fluids (77). The evidence suggests to children and found no differences on the immune status of
use isotonic fluids for at least the first 24 hours of critical these children. Additionally, this trial was terminated for
illness or post-operative care, while using the Holliday futility before half the children were enrolled (83).
and Segar formula to calculate the amount of maintenance
fluid required (76,78,79). In patients with excessive sodium Selenium
losses sodium chloride solutions can be switched to sodium Selenium is an essential antioxidant and serves as a cofactor
lactate or sodium acetate to decrease the chloride intake for glutathione peroxidase, an enzyme that is linked to
and thereby the risk of metabolic acidosis associated resolving oxidative tissue damage. It is also involved in
hyperchloraemia (76). iodothyronine deiodinase and thioredoxin and thereby
having a role in the thyroid metabolism which is affected in
Iron the acute phase of critical illness (84). Selenium deficiency
Due to the risk of overload via PN iron is preferably has been associated with, e.g., muscle weakness, immune
provided enterally and in children receiving short-term PN disorders and carcinogenesis in adults, while selenium toxicity
(<3 weeks) iron supplementation is not recommended (40). have been reported in association with gastrointestinal
disturbance, skin lesions, liver dysfunction and paralysis (85).
Calcium, phosphorus, magnesium, potassium and The only RCT performed in critically ill children is the
vitamin B1 (thiamine) previously described RCT which included selenium as one of
Adequate threshold of calcium, phosphorus and magnesium the added nutrients which showed no favourable outcomes
are required for normal growth and bone mineralization. of supplementation of selenium together with whey protein,
The risk of developing hypophosphatemia, hypomagnesemia, zinc, glutamine and metoclopramide (83). Systematic reviews
hypocalcaemia, and hypokalaemia is associated with the in preterm neonates and adults showed that supplementation
provision of nutrients. Especially high nutrient incline after of selenium resulted in decreased mortality and duration
a period of malnutrition placed critically ill children at risk of ICU stay, however supplemented amounts and methods
of developing these depletions, commonly referred to as the varied substitutional and no dose recommendations were

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Page 8 of 15 Pediatric Medicine, 2020

Table 3 Advised parenteral micronutrient dose according to the ESGPHAN/ESPEN/ESPR/CSPEN guideline per age class
Nutrient Term–6 m 6–12 m >12 m

Sodium Day 1: 0–2 mmol/kg/d 2–3 mmol/kg/d 1–3 mmol/kg/d

Days 2–4: 1–3 mmol/kg/d

> Day 7: 2–3 mmol/kg/d

Potassium Days 1–3: 0–3 mmol/kg/d 1–3 mmol/kg/d 1–3 mmol/kg/d

Days 4–7: 2–3 mmol/kg/d

> Day 7: 1.5–3 mmol/kg/d

Calcium 0.8–1.5 mmol/kg/d 0.5 mmol/kg/d 0.25–0.4 mmol/kg/d

Magnesium 0.1–0.2 mmol/kg/d 0.15 mmol/kg/d 0.1 mmol/kg/d

Phosphate 0.7–1.3 mmol/kg/d 0.5 mmol/kg/d 0.2–0.7 mmol/kg/d

Chloride Day 1: 0–3 mmol/kg/d 2–4 mmol/kg/d 2–4 mmol/kg/d

Day 2–4: 2–5 mmol/kg/d

> Day 7: 2–3 mmol/kg/d

Iron Not recommended in short-term Not recommended in short-term Not recommended in short-term
PN PN PN

Zinc 250 µg/kg/d (term—3 months) 100 µg/kg/d (max. 5 mg/d) 50 µg/kg/d (max. 5 mg/d)

100 µg/kg/d (3–6 months)

Copper 20 µg/kg/d (max. 0.5 mg/d) 20 µg/kg/d (max. 0.5 mg/d) 20 µg/kg/d (max. 0.5 mg/d)

Iodine At least 1 µg/kg/d At least 1 µg/kg/d At least 1 µg/kg/d

Selenium 2–3 µg/kg/d (max. 100 µg/kg/d) 2–3 µg/kg/d (max. 100 µg/d) 2–3 µg/kg/d (max. 100 µg/d)

Manganese Max. 1 µg/kg/d Max. 1 µg/kg/d Max. 1 µg/kg/d

Molybdenum 0.25 µg/kg/d (max. 5.0 µg/d) 0.25 µg/kg/d (max. 5.0 µg/d) 0.25 µg/kg/d (max. 5.0 µg/d)

Chromium Not recommended in PN Not recommended in PN Not recommended in PN

Vitamin A 150–300 µg/kg/d 150–300 µg/kg/d 150 µg/d

Vitamin D 400 IU/d (or 40–150 IU/kg/d) 40–150 IU/kg/d 400–600 IU/d

Vitamin E 2.8–3.5 IU/kg/d 2.8–3.5 IU/kg/d 11 IU/d

Vitamin K 10 µg/kg/d 10 μg/kg/d 200 μg/d

Vitamin C 15–25 mg/kg/d 15–25 mg/kg/d 80 mg/d

Thiamine 0.35–0.5 mg/kg/d 0.35–0.5 mg/kg/d 1.2 mg/d

Riboflavin 0.15–0.2 mg/kg/d 0.15–0.2 mg/kg/d 1.4 mg/d

Pyridoxine 0.15–0.2 mg/kg/d 0.15–0.2 mg/kg/d 1.0 mg/d

Niacin 4–6.8 mg/kg/d 4–6.8 mg/kg/d 17 mg/d

Vitamin B12 0.3 µg/kg/d 0.3 µg/kg/d 1 µg/d

Pantothenic acid 2.5 mg/kg/d 2.5 mg/kg/d 5 mg/d

Biotin 5–8 µg/kg/d 5–8 µg/kg/d 20 µg/d

Folic acid 56 µg/kg/d 56 µg/kg/d 140 µg/d

© Pediatric Medicine. All rights reserved. Pediatr Med 2020;3:24 | http://dx.doi.org/10.21037/pm-20-88

Pediatric Medicine, 2020 Page 9 of 15

extracted (66,86). an affected body composition and a higher fat mass

compared to healthy subjects (93). Therefore, the success
Vitamin B12, vitamin C and vitamin D of PN support should be measured by body composition
The anti-inflammatory vitamin B12 supports macronutrient measurements which includes knowledge on lean body mass
metabolism and DNA synthesis in health and deficiencies and fat mass and accompanied with muscle mass function and
may results in anaemia and neurodegenerative demyelination. functional status (94,95). Furthermore. IFALD, cholestasis,
The absorption of this vitamin can be affected by metabolic syndrome and catheter-related bloodstream
gastrointestinal surgery, feeding via post-pyloric tube and infections are commonly described long-term consequences
using proton pump inhibitors, all common in the PICU (87). of PN therapy in children requiring PN due to short bowel
Measured plasma levels are unreliable which hinders syndrome or low birth-weight infants (93,96-98). The
detecting deficiencies and clinical trials regarding optimal pathogenesis is multifactorial, and association have been
supplementation are non-existent. The isolated provision made with imbalances in amino acids composition, duration
of vitamin C has been investigated and high doses up to of PN and providing PN continuous (non-cyclical) (99).
66 mg/kg/hour may lead to reduced duration of mechanical In addition, the occurrence of cholestasis or IFALD is
ventilation and vasopressor support in critically ill adults, highly associated with intravenous lipid emulsions (ILEs)
without reporting adverse effects. However, no effect was composition. Although there is no evidence suggesting
seen of this antioxidant on mortality in a systematic review an effect of different ILEs during short-term PN use
combining the 5 RCTs (88). Vitamin D has been a topic of on cholestasis or bilirubin levels, during long-term PN
interest for many years in critical illness due to its important multicomponent ILEs (with fish oil) may contribute
role in calcium and bone homeostasis, cardiovascular system to a decrease in bilirubin levels and cholestasis (100).
and inflammation (89). A recent systematic review including Furthermore, composite ILEs are found to be superior
52 studies in critically ill children found a deficiency to pure soybean ILEs as they have less inflammatory
prevalence of 55% which was indeed associated with properties, are immune modulating, have higher antioxidant
mortality (90). Again, when the 6 available RCTs evaluating content and prevent against cholestasis and IFALD
vitamin D supplementation either enteral of parenteral in (101,102), however, no study has assessed the pro- and anti-
critically ill adults were combined in a systematic review, no inflammatory effects of these different ILEs in critically ill
benefit regarding recovery or mortality was found. children. Therefore, for PN lasting longer than a few days,
Besides acknowledging the potential modulatory effect pure soybean ILEs should not be used and composite ILEs
of micronutrients on the acute stress response, the risk of with or without fish oil are the first-choice treatment (53).
intoxication caused by over supplementing should not be Provision of pure soybean oil ILEs can be considered in
dismissed. It is an uncommon reported phenomenon during short-term PN with the knowledge that this may provide
critical illness, nonetheless, safe upper intake levels most a less balanced nutrition than composite ILEs. Long-term
be verified to find the balance between both deficiency neurocognitive development of children requiring long-
and toxicity (91). The limited available paediatric research term PN was investigated in 13 studies. The reported
restrains the guidance for lower and upper levels in the prevalence for normal neurocognitive development varied
substantial and ranged between 29–100%, with 80–90%
different phases of illness, therefore it might be a practical
of the children in mainstream schools (97). There was no
solution to aim for future research on the micronutrients
evidence favouring specific timing (cyclic or continuous) or
who require more routine measurements in instable patients.
other variables related to PN such as duration for its long-
Currently, daily or weekly laboratory measurements are
term consequences on neurocognitive development.
advised for electrolytes (sodium, potassium, chloride, calcium,
phosphorus and magnesium), trace minerals (iron, selenium,
zinc and copper) and vitamin B12 (92). Critically ill children

Due to the advances in medical therapy and thereby

Long-term consequences of PN increasing PICU survivorship, it becomes more and more
important to consider long-term developmental outcomes
Children requiring long-term PN
of PN. Overall, studies investigating PICU survivors find
Children requiring long-term PN are shorter and have lower scores for neurocognitive functioning as compared

© Pediatric Medicine. All rights reserved. Pediatr Med 2020;3:24 | http://dx.doi.org/10.21037/pm-20-88

Page 10 of 15 Pediatric Medicine, 2020

with a healthy population or normative scores. Additionally, Conclusions

health-related quality of life, physical and mental health
Enteral intake is often insufficient in critically ill children
status can also be affected after PICU admission (103).
which might result in a need for PN. Understanding the
Additional to the evaluation of body composition and
course of metabolic needs during the acute stress response
commonly described PN complications, the effect of PN
is essential before providing PN. Based upon the findings of
therapy on organ function and short-term and long-term
the landmark PEPaNIC RCT, the current recommendations
consequences should be monitored when critically ill
changed to withhold PN during the first week of admission
children are concerned (104).
while continue to provide micronutrients (2-5). Although
The PEPaNIC RCT was the first interventional study
this parenteral macronutrient restriction during the acute
to investigate long-term developmental effects of a PN
phase has been found beneficial for critically ill children
intervention. Two years after admission, PICU survivors
regarding physical and neurocognitive short-term and long-
had worse outcomes on anthropometrics, health status, and
term consequences, further research is required to obtain
neurocognitive development as compared with matched
healthy control children. Furthermore, the omission of the optimal timing, dose and composition of PN during
PN during the acute phase of critical illness caused no stable and recovery phase as well as the determination of
harm and even resulted in better scores for visuomotor the role of parenteral micronutrients. Furthermore, cyclic
integration, and parent-reported executive functioning, feeding or pharmacologic interventions allowing autophagy
in particular inhibitory control (105). Due to the large are controversies to overcome.
number of young infants in this trial and the plasticity
of the developing brain, a longer assessment period was Acknowledgments
warranted to investigate the effect on all long-term physical,
neurocognitive, and psychosocial developmental domains. Funding: None.
The 4-year post-randomisation follow-up study affirmed
that omitting supplemental PN during the first week of Footnote
critical illness caused no harm and even resulted in less
parent-reported emotional and behavioural problems (103). Provenance and Peer Review: This article was commissioned
These emotional and behavioural problems can arise from by the editorial office, Pediatric Medicine for the series
poor executive functioning, such as poor inhibitory control “Nutrition in the Critically Ill Child”. The article was sent
which was already affected at the 2-year post-PICU time for external peer review.
point (106,107). These clinical findings were supported
by differences in telomere length and DNA methylation Conflicts of Interest: The authors have completed the ICMJE
between children who received early-PN and late-PN, uniform disclosure form (available at https://pm.amegroups.
which substantiates plausible molecular basis of detrimental com/article/view/10.21037/pm-20-88/coif). The series
long-term consequences of high and early provision of “Nutrition in the Critically Ill Child” was commissioned
parenteral macronutrients (108,109). However, further by the editorial office without any funding or sponsorship.
research is needed to unravel the underlying mechanisms of Dr. SCATV served as the unpaid Guest Editor of the series,
the long-term harm caused by high and early PN. and serves as an unpaid editorial board member of Pediatric
To be able to provide optimal PN beneficial for short- Medicine from Oct 2019 to Sep 2021. Dr. RDE reports
term and long-term outcomes, the timing, amount, grants from ESPEN Research Grant, outside the submitted
composition and concomitant provision of EN should be work. Dr. SCATV reports grants from ESPEN Research
integrated into a comprehensive approach incorporating Grant, grants from Sophia Research Foundation, grants
all these features. First, the optimal timing should be from Nutricia Research BV, outside the submitted work.
defined for the individual patient which is now based Dr. KFMJ reports grants from Fonds NutshOhra, grants
on the PEPaNIC RCT on day 7, followed by a steady from Erasmus Trustfonds, grants from Nutricia Research
stepwise incline towards energy and protein targets to avoid BV, grants from AGIS Zorginnovatie, during the conduct of
refeeding syndrome. the study; grants from ESPEN Research Grant, grants from

© Pediatric Medicine. All rights reserved. Pediatr Med 2020;3:24 | http://dx.doi.org/10.21037/pm-20-88

Pediatric Medicine, 2020 Page 11 of 15

Sophia Research Foundation, outside the submitted work. pediatric intensive care units: an international multicenter
cohort study. Nutr Clin Pract 2014;29:360-7.
Ethical Statement: The authors are accountable for all 8. Mehta NM, Bechard LJ, Cahill N, et al. Nutritional
aspects of the work in ensuring that questions related practices and their relationship to clinical outcomes in
to the accuracy or integrity of any part of the work are critically ill children--an international multicenter cohort
appropriately investigated and resolved. study*. Crit Care Med 2012;40:2204-11.
9. Mehta NM, Bechard LJ, Zurakowski D, et al. Adequate
Open Access Statement: This is an Open Access article enteral protein intake is inversely associated with 60-d
distributed in accordance with the Creative Commons mortality in critically ill children: a multicenter, prospective,
Attribution-NonCommercial-NoDerivs 4.0 International cohort study. Am J Clin Nutr 2015;102:199-206.
License (CC BY-NC-ND 4.0), which permits the non- 10. Mehta NM, McAleer D, Hamilton S, et al. Challenges to
commercial replication and distribution of the article with optimal enteral nutrition in a multidisciplinary pediatric
the strict proviso that no changes or edits are made and the intensive care unit. JPEN J Parenter Enteral Nutr
original work is properly cited (including links to both the 2010;34:38-45.
formal publication through the relevant DOI and the license). 11. Tume LN, Eveleens RD, Verbruggen SCAT, et al.
See: https://creativecommons.org/licenses/by-nc-nd/4.0/. Barriers to Delivery of Enteral Nutrition in Pediatric
Intensive Care: A World Survey. Pediatr Crit Care Med
2020;21:e661-e671.
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in paediatric intensive care units: a 4-year follow-up of

doi: 10.21037/pm-20-88
Cite this article as: Eveleens RD, Verbruggen SCAT, Joosten
KFM. The role of parenteral nutrition in paediatric critical
care, and its consequences on recovery. Pediatr Med 2020;3:24.

© Pediatric Medicine. All rights reserved. Pediatr Med 2020;3:24 | http://dx.doi.org/10.21037/pm-20-88