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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 of administration are being investigated and the
catabolic burden imposed by critical illness, pre- optimization of enteral nutrition emphasized.2
venting nutritional deterioration and improving The benefits of early parenteral nutrition dur-
outcomes. However, questions regarding the most ing critical illness in children have been ques-
appropriate dose of macronutrients, the route of tioned, given the results of studies in adults.3,4
delivery, and particularly the timing of supple- When enteral nutrient intake is insufficient in
mental parenteral nutrition in critically ill chil- critically ill children, two distinct strategies are
dren remain unanswered (Table 1). Enteral nutri- now considered: some medical centers initiate
tion is preferable in patients with a functioning early parenteral nutrition to prevent macronutri-
gut but may not always be feasible. Intestinal ent deficits, while others, concerned about side
failure was incompatible with life until the effects, delay supplementary parenteral nutrition
1960s, when the development of stable intrave- for a week while providing enteral nutrition.5
nous amino acid solutions and lipid emulsions Fivez et al. now address this area of uncertainty
allowed the administration of life-sustaining in the Journal by reporting the results of a three-
nourishment through the parenteral route.1 Par- center trial, Early versus Late Parenteral Nutrition
enteral nutrition was subsequently extended to in the Pediatric Intensive Care Unit (PEPaNIC).6
critically ill patients when enteral nutrition was In the trial, 1440 patients with insufficient
insufficient or contraindicated. As awareness of enteral nutrition were randomly assigned to a
the unintended side effects of parenteral nutrition control group in which parenteral nutrition was
has increased, patient selection and the timing 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 Estimates from equations are often unreliable Role of hypocaloric diet in nonobese
Protein requirement Requirement is increased owing to catabolic Role of specific amino acids
response during critical illness; delivery
may be inadequate in most patients
Route of nutrient delivery 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
Enteral intolerance Intolerance impedes delivery of enteral nutri- Use of gastric residual volume as
tion; stepwise approach aids delivery of marker of intolerance
enteral nutrition
Immunonutrition Supplementation with a combination of micro-
nutrients and glutamine is not beneficial

1190 n engl j med 374; March 24, 2016

The New England Journal of Medicine

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or to an intervention group in which parenteral for Risk on Nutritional Status and Growth
nutrition was withheld until day 8. All patients (STRONGkids), is based on a simple question-
received early enteral nutrition followed by step- naire without anthropometric variables.9 The use
wise, standardized advancement to the pre- of STRONGkids has not been validated in criti-
scribed goal. The sites used different methods to cally ill children and may not be a reliable indica-
determine energy requirements, parenteral nutri- tor of severe malnutrition.10 According to z scores
tion strategies, and targets for glycemic control. for body-mass index, only a small fraction of
An absolute reduction in the risk of new infec- patients in this trial had moderate or severe
tions (7.8 percentage points) and a reduced time malnutrition. Standard outcomes related to in-
to readiness for discharge from the intensive fection, such as ventilator-associated pneumonia
care unit (ICU) were recorded in the group re- and catheter-associated bloodstream infections,
ceiving late parenteral nutrition as compared with were not recorded. The intensive care team deter-
that receiving early parenteral nutrition. The mining the pragmatic readiness for discharge
duration of mechanical ventilation and the odds outcome was not masked to patient randomiza-
of renal replacement were also lower in the late- tion, which introduces the potential for bias.
parenteral-nutrition group. The internal validity Despite the above limitations, the results of this
of the study was high in terms of sample size, landmark trial will change practice in centers
randomization, concealed allocation, adherence to that supplement insufficient enteral nutrition
the protocol, standardization of the intervention, with parenteral nutrition on day 1 and will pro-
and statistical analysis. To determine the exter- vide data that support the strategy of delayed
nal validity of the study, some design elements parenteral nutrition practiced in other centers.
must be discussed the population selected, Further examination is required to determine
the generalizability of the protocol, and the rele- the best possible timing for the introduction of
vance of the outcomes. supplemental parenteral nutrition in severely
More than 55% of the patients in the control malnourished children in the pediatric ICU.
group were discharged by day 4. These patients Ideally, nutrition therapy for critically ill chil-
would not be considered candidates for paren- dren must be individualized. The presupposition
teral nutrition within 24 hours after admission that a uniform approach would apply to all is too
in most medical centers. More than 77% of pa- simplistic. On the basis of the results of the
tients in the group receiving late parenteral nu- PEPaNIC trial, delaying parenteral nutrition, along
trition were discharged by day 8 without having with early initiation and stepwise advancement
received any parenteral nutrition. The equations of enteral nutrition, seems prudent in patients
used to determine energy requirements are un- who are not severely malnourished. Patience and
reliable.7 The true adequacy of energy delivered, substantial resources will be required to sys-
and the potential caloric underfeeding and over- tematically address unresolved questions through
feeding, cannot be determined in the absence of randomized, controlled trials. As the tapestry of
the measurement of energy expenditure. The dose evidence is gradually woven, we must be circum-
of enteral nutrient delivery beyond which the spect in our interpretation of study results, invest
risks of supplemental parenteral nutrition offset in mechanistic and hypothesis-generating stud-
its benefits is unknown. A threshold enteral ies, and explore relevant long-term outcomes.
delivery of less than 80% of the nutrient target The PEPaNIC trial represents an important step
triggered supplementation with parenteral nutri- forward, and its results will help to recalibrate
tion in this trial, whereas enteral delivery of 66% the safe application of parenteral nutrition in
of the nutrient target has been associated with critically ill children.
improved outcomes in children receiving me- Disclosure forms provided by the author are available with the
chanical ventilation.8 The poor outcomes in the full text of this article at

group receiving early parenteral nutrition may From Harvard Medical School and the Division of Critical Care
represent the risks associated with the parenteral Medicine, Department of Anesthesiology, Perioperative and Pain
route of delivery or the effects of caloric over- Medicine, Boston Childrens Hospital both in Boston.

feeding. The device investigators used to calcu- This article was published on March 15, 2016, and updated on
late the risk of malnutrition, the Screening Tool March 15, 2016, at

n engl j med 374; March 24, 2016 1191

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

1. Wilmore DW, Dudrick SJ. Growth and development of an enteral nutrition in critically ill children. N Engl J Med 2016;374:
infant receiving all nutrients exclusively by vein. JAMA 1968;203: 1111-1122.
860-4. 7. Hunter DC, Jaksic T, Lewis D, Benotti PN, Blackburn GL,
2. Mehta NM, Compher C. A.S.P.E.N. clinical guidelines: nutri- Bistrian BR. Resting energy expenditure in the critically ill: esti-
tion support of the critically ill child. JPEN J Parenter Enteral mations versus measurement. Br J Surg 1988;75:875-8.
Nutr 2009;33:260-76. 8. Mehta NM, Bechard LJ, Cahill N, et al. Nutritional practices
3. Casaer MP, Mesotten D, Hermans G, et al. Early versus late and their relationship to clinical outcomes in critically ill chil-
parenteral nutrition in critically ill adults. N Engl J Med 2011; dren an international multicenter cohort study. Crit Care Med
365:506-17. 2012;40:2204-11.
4. Doig GS, Simpson F, Sweetman EA, et al. Early parenteral 9. Hulst JM, Zwart H, Hop WC, Joosten KF. Dutch national
nutrition in critically ill patients with short-term relative contra- survey to test the STRONGkids nutritional risk screening tool in
indications to early enteral nutrition: a randomized controlled hospitalized children. Clin Nutr 2010;29:106-11.
trial. JAMA 2013;309:2130-8. 10. Spagnuolo MI, Liguoro I, Chiatto F, Mambretti D, Guarino
5. Hamilton S, McAleer DM, Ariagno K, et al. A stepwise en- A. Application of a score system to evaluate the risk of malnutri-
teral nutrition algorithm for critically ill children helps achieve tion in a multiple hospital setting. Ital J Pediatr 2013;39:81.
nutrient delivery goals. Pediatr Crit Care Med 2014;15:583-9. DOI: 10.1056/NEJMe1601140
6. Fivez T, Kerklaan D, Mesotten D, et al. Early versus late par- Copyright 2016 Massachusetts Medical Society.

The Genetics of Dyslipidemia When Less Is More

Sander Kersten, Ph.D.

An elevated plasma level of low-density lipopro- protein lipase, a mechanism that may result in
tein (LDL) cholesterol is a major risk factor for part from the destabilization of ANGPTL4.5
coronary heart disease. Whether an elevated The key finding in each study was that carri-
plasma triglyceride level and a reduced level of ers of the E40K mutation and other rare muta-
high-density lipoprotein (HDL) cholesterol also tions in ANGPTL4 had a lower risk of coronary
carry an increased risk of coronary heart disease artery disease than did noncarriers, a result that
has remained a contentious issue.1 is consistent with the lower triglyceride levels
Two groups of investigators now describe in and higher HDL cholesterol levels among muta-
the Journal important genetic evidence showing a tion carriers. These findings confirm previous
causal role of plasma triglycerides in coronary data6 and provide convincing genetic evidence
heart disease. Stitziel and colleagues2 tested that an elevated plasma triglyceride level increas-
54,003 coding-sequence variants covering 13,715 es the risk of coronary heart disease. In combi-
human genes in more than 72,000 patients with nation with extensive recent data on other ge-
coronary artery disease and 120,000 controls. netic variants that modulate plasma triglyceride
Dewey and colleagues3 sequenced the exons of levels, the studies suggest that lowering plasma
the gene encoding angiopoietin-like 4 (ANGPTL4) triglyceride levels is a viable approach to reduc-
in samples obtained from nearly 43,000 partici- ing the risk of coronary artery disease.
pants in the DiscovEHR human genetics study. The new findings also implicate targeted in-
The two groups found a significant association activation of ANGPTL4 as a potential weapon in
between an inactivating mutation (E40K) in the war on heart disease. However, as a caution-
ANGPTL4 and both low plasma triglyceride levels ary note, Talmud and colleagues7 previously found
and high levels of HDL cholesterol. ANGPTL4 is that the presence of the E40K variant was associ-
an inhibitor of lipoprotein lipase, the enzyme ated with an increased risk of coronary heart
that breaks down plasma triglycerides along the disease after adjustment for the altered plasma
capillaries in heart, muscle, and fat.4 Extensive lipids. Thus, it seems that the effect of the E40K
research has shown that ANGPTL4 orchestrates variant on coronary artery disease may involve
the processing of triglyceride-rich lipoproteins both an inhibitory effect through decreased tri-
during physiologic conditions such as fasting, glyceride and increased HDL cholesterol levels
exercise, and cold exposure.4 The E40K mutation and a stimulatory effect that is independent of
in ANGPTL4 was previously shown to nearly plasma lipids. Consistent with this hypothesis,
eliminate the ability of ANGPTL4 to inhibit lipo- the overexpression of Angptl4 in mice was found

1192 n engl j med 374; March 24, 2016

The New England Journal of Medicine

Downloaded from on March 9, 2017. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.