The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l s

Parenteral Nutrition in Critically Ill Children

NileshM. Mehta, M.D.

Adequate nutrient delivery may help to offset the
catabolic burden imposed by critical illness, pre-
venting nutritional deterioration and improving
outcomes. However, questions regarding the most
appropriate dose of macronutrients, the route of
delivery, and particularly the timing of supple-
mental parenteral nutrition in critically ill chil-
dren remain unanswered (Table 1). Enteral nutri-
tion is preferable in patients with a functioning
gut but may not always be feasible. Intestinal
failure was incompatible with life until the
1960s, when the development of stable intrave-
nous amino acid solutions and lipid emulsions
allowed the administration of life-sustaining
nourishment through the parenteral route.1 Par-
enteral nutrition was subsequently extended to
critically ill patients when enteral nutrition was
insufficient or contraindicated. As awareness of
the unintended side effects of parenteral nutrition
has increased, patient selection and the timing
of administration are being investigated and the
optimization of enteral nutrition emphasized.2
The benefits of early parenteral nutrition dur-
ing critical illness in children have been ques-
tioned, given the results of studies in adults.3,4
When enteral nutrient intake is insufficient in
critically ill children, two distinct strategies are
now considered: some medical centers initiate
early parenteral nutrition to prevent macronutri-
ent deficits, while others, concerned about side
effects, delay supplementary parenteral nutrition
for a week while providing enteral nutrition.5
Fivez et al. now address this area of uncertainty
in the Journal by reporting the results of a three-
center trial, Early versus Late Parenteral Nutrition
in the Pediatric Intensive Care Unit (PEPaNIC).6
In the trial, 1440 patients with insufficient
enteral nutrition were randomly assigned to a
control group in which parenteral nutrition was
administered within 24 hours after admission

Table 1. Areas of Consensus and Controversy in Critical Care Nutrition for Children.

Area Consensus Controversy or Gaps in Knowledge

Energy requirement
Protein requirement
Route of nutrient delivery
Enteral intolerance
Immunonutrition
Estimates from equations are often unreliable Role of hypocaloric diet in nonobese
children
Requirement is increased owing to catabolic Role of specific amino acids
response during critical illness; delivery
may be inadequate in most patients
Enteral route is preferred if gut is functional; Effects of postpyloric feeding and ant-
supplemental parenteral nutrition should acids in delivery of enteral nutrition
be delayed and enteral nutrition optimized
Intolerance impedes delivery of enteral nutri- Use of gastric residual volume as
tion; stepwise approach aids delivery of marker of intolerance
enteral nutrition
Supplementation with a combination of micro-
nutrients and glutamine is not beneficial

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 Editorials
or to an intervention group in which parenteral
nutrition was withheld until day 8. All patients
received early enteral nutrition followed by step-
wise, standardized advancement to the pre-
scribed goal. The sites used different methods to
determine energy requirements, parenteral nutri-
tion strategies, and targets for glycemic control.
An absolute reduction in the risk of new infec-
tions (7.8 percentage points) and a reduced time
to readiness for discharge from the intensive
care unit (ICU) were recorded in the group re-
ceiving late parenteral nutrition as compared with
that receiving early parenteral nutrition. The
duration of mechanical ventilation and the odds
of renal replacement were also lower in the late-
parenteral-nutrition group. The internal validity
of the study was high in terms of sample size,
randomization, concealed allocation, adherence to
the protocol, standardization of the intervention,
and statistical analysis. To determine the exter-
nal validity of the study, some design elements
must be discussed the population selected,
the generalizability of the protocol, and the rele-
vance of the outcomes.
More than 55% of the patients in the control
group were discharged by day 4. These patients
would not be considered candidates for paren-
teral nutrition within 24 hours after admission
in most medical centers. More than 77% of pa-
tients in the group receiving late parenteral nu-
trition were discharged by day 8 without having
received any parenteral nutrition. The equations
used to determine energy requirements are un-
reliable.7 The true adequacy of energy delivered,
and the potential caloric underfeeding and over-
feeding, cannot be determined in the absence of
the measurement of energy expenditure. The dose
of enteral nutrient delivery beyond which the
risks of supplemental parenteral nutrition offset
its benefits is unknown. A threshold enteral
delivery of less than 80% of the nutrient target
triggered supplementation with parenteral nutri-
tion in this trial, whereas enteral delivery of 66%
of the nutrient target has been associated with
improved outcomes in children receiving me-
chanical ventilation.8 The poor outcomes in the
group receiving early parenteral nutrition may
represent the risks associated with the parenteral
route of delivery or the effects of caloric over-
feeding. The device investigators used to calcu-
late the risk of malnutrition, the Screening Tool
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for Risk on Nutritional Status and Growth
(STRONGkids), is based on a simple question-
naire without anthropometric variables.9 The use
of STRONGkids has not been validated in criti-
cally ill children and may not be a reliable indica-
tor of severe malnutrition.10 According to z scores
for body-mass index, only a small fraction of
patients in this trial had moderate or severe
malnutrition. Standard outcomes related to in-
fection, such as ventilator-associated pneumonia
and catheter-associated bloodstream infections,
were not recorded. The intensive care team deter-
mining the pragmatic readiness for discharge
outcome was not masked to patient randomiza-
tion, which introduces the potential for bias.
Despite the above limitations, the results of this
landmark trial will change practice in centers
that supplement insufficient enteral nutrition
with parenteral nutrition on day 1 and will pro-
vide data that support the strategy of delayed
parenteral nutrition practiced in other centers.
Further examination is required to determine
the best possible timing for the introduction of
supplemental parenteral nutrition in severely
malnourished children in the pediatric ICU.
Ideally, nutrition therapy for critically ill chil-
dren must be individualized. The presupposition
that a uniform approach would apply to all is too
simplistic. On the basis of the results of the
PEPaNIC trial, delaying parenteral nutrition, along
with early initiation and stepwise advancement
of enteral nutrition, seems prudent in patients
who are not severely malnourished. Patience and
substantial resources will be required to sys-
tematically address unresolved questions through
randomized, controlled trials. As the tapestry of
evidence is gradually woven, we must be circum-
spect in our interpretation of study results, invest
in mechanistic and hypothesis-generating stud-
ies, and explore relevant long-term outcomes.
The PEPaNIC trial represents an important step
forward, and its results will help to recalibrate
the safe application of parenteral nutrition in
critically ill children.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From Harvard Medical School and the Division of Critical Care
Medicine, Department of Anesthesiology, Perioperative and Pain
Medicine, Boston Childrens Hospital both in Boston.
This article was published on March 15, 2016, and updated on
March 15, 2016, at NEJM.org.
1191
 The n e w e ng l a n d j o u r na l
1. Wilmore DW, Dudrick SJ. Growth and development of an
infant receiving all nutrients exclusively by vein. JAMA 1968;203:
860-4.
2. Mehta NM, Compher C. A.S.P.E.N. clinical guidelines: nutri-
tion support of the critically ill child. JPEN J Parenter Enteral
Nutr 2009;33:260-76.
3. Casaer MP, Mesotten D, Hermans G, et al. Early versus late
parenteral nutrition in critically ill adults. N Engl J Med 2011;
365:506-17.
4. Doig GS, Simpson F, Sweetman EA, et al. Early parenteral
nutrition in critically ill patients with short-term relative contra-
indications to early enteral nutrition: a randomized controlled
trial. JAMA 2013;309:2130-8.
5. Hamilton S, McAleer DM, Ariagno K, et al. A stepwise en-
teral nutrition algorithm for critically ill children helps achieve
nutrient delivery goals. Pediatr Crit Care Med 2014;15:583-9.
6. Fivez T, Kerklaan D, Mesotten D, et al. Early versus late par-
The Genetics of Dyslipidemia When Less Is More
Sander Kersten, Ph.D.
An elevated plasma level of low-density lipopro-
tein (LDL) cholesterol is a major risk factor for
coronary heart disease. Whether an elevated
plasma triglyceride level and a reduced level of
high-density lipoprotein (HDL) cholesterol also
carry an increased risk of coronary heart disease
has remained a contentious issue.1
Two groups of investigators now describe in
the Journal important genetic evidence showing a
causal role of plasma triglycerides in coronary
heart disease. Stitziel and colleagues2 tested
54,003 coding-sequence variants covering 13,715
human genes in more than 72,000 patients with
coronary artery disease and 120,000 controls.
Dewey and colleagues3 sequenced the exons of
the gene encoding angiopoietin-like 4 (ANGPTL4)
in samples obtained from nearly 43,000 partici-
pants in the DiscovEHR human genetics study.
The two groups found a significant association
between an inactivating mutation (E40K) in
ANGPTL4 and both low plasma triglyceride levels
and high levels of HDL cholesterol. ANGPTL4 is
an inhibitor of lipoprotein lipase, the enzyme
that breaks down plasma triglycerides along the
capillaries in heart, muscle, and fat.4 Extensive
research has shown that ANGPTL4 orchestrates
the processing of triglyceride-rich lipoproteins
during physiologic conditions such as fasting,
exercise, and cold exposure.4 The E40K mutation
in ANGPTL4 was previously shown to nearly
eliminate the ability of ANGPTL4 to inhibit lipo-
1192 n engl j med 374;12nejm.org March 24, 2016
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of m e dic i n e
enteral nutrition in critically ill children. N Engl J Med 2016;374:
1111-1122.
7. Hunter DC, Jaksic T, Lewis D, Benotti PN, Blackburn GL,
Bistrian BR. Resting energy expenditure in the critically ill: esti-
mations versus measurement. Br J Surg 1988;75:875-8.
8. Mehta NM, Bechard LJ, Cahill N, et al. Nutritional practices
and their relationship to clinical outcomes in critically ill chil-
dren an international multicenter cohort study. Crit Care Med
2012;40:2204-11.
9. Hulst JM, Zwart H, Hop WC, Joosten KF. Dutch national
survey to test the STRONGkids nutritional risk screening tool in
hospitalized children. Clin Nutr 2010;29:106-11.
10. Spagnuolo MI, Liguoro I, Chiatto F, Mambretti D, Guarino
A. Application of a score system to evaluate the risk of malnutri-
tion in a multiple hospital setting. Ital J Pediatr 2013;39:81.
DOI: 10.1056/NEJMe1601140
Copyright 2016 Massachusetts Medical Society.
protein lipase, a mechanism that may result in
part from the destabilization of ANGPTL4.5
The key finding in each study was that carri-
ers of the E40K mutation and other rare muta-
tions in ANGPTL4 had a lower risk of coronary
artery disease than did noncarriers, a result that
is consistent with the lower triglyceride levels
and higher HDL cholesterol levels among muta-
tion carriers. These findings confirm previous
data6 and provide convincing genetic evidence
that an elevated plasma triglyceride level increas-
es the risk of coronary heart disease. In combi-
nation with extensive recent data on other ge-
netic variants that modulate plasma triglyceride
levels, the studies suggest that lowering plasma
triglyceride levels is a viable approach to reduc-
ing the risk of coronary artery disease.
The new findings also implicate targeted in-
activation of ANGPTL4 as a potential weapon in
the war on heart disease. However, as a caution-
ary note, Talmud and colleagues7 previously found
that the presence of the E40K variant was associ-
ated with an increased risk of coronary heart
disease after adjustment for the altered plasma
lipids. Thus, it seems that the effect of the E40K
variant on coronary artery disease may involve
both an inhibitory effect through decreased tri-
glyceride and increased HDL cholesterol levels
and a stimulatory effect that is independent of
plasma lipids. Consistent with this hypothesis,
the overexpression of Angptl4 in mice was found