Journal of Parenteral and Enteral Guidelines for the ... › wp-content › ... › 10 › ...of_Parenteral_and_Enteral_Nu… · 2 Journal of Parenteral and Enteral Nutrition XX(X)

https://doi.org/10.1177/0148607117711387

Journal of Parenteral and EnteralNutritionVolume XX Number X Month 201X 1 –37© 2017 American Society for Parenteral and Enteral Nutrition and the Society of Critical Care MedicineDOI: 10.1177/0148607117711387journals.sagepub.com/home/pen

Clinical Guidelines

This document represents the first collaboration between 2 organizations—the American Society for Parenteral and Enteral Nutrition (ASPEN) and the Society of Critical Care Medicine (SCCM)—to describe best practices in nutrition therapy for critically ill children.

Guideline Limitations

These SCCM-ASPEN clinical guidelines are based on general consensus among a group of professionals who, in developing such guidelines, have examined the available literature on the subject and balanced potential benefits of nutrition prac-tices against risks inherent with such therapies. A task force of multidisciplinary experts in clinical nutrition—representing

physicians, nurses, pharmacists, dietitians, and statisticians—was jointly convened by the 2 societies. These individuals participated in the development of the guidelines and authored this document. These practice guidelines are not intended as absolute policy statements. Use of these practice guidelines does not in any way guarantee any specific benefit in out-come or survival. The professional judgment of the attending health professionals is the primary component of quality medical care delivery. Since guidelines cannot account for every variation in circumstances, practitioners must always exercise professional judgment when applying these recom-mendations to individual patients. These clinical guidelines are intended to supplement, but not replace, professional train-ing and judgment.

711387 PENXXX10.1177/0148607117711387Journal of Parenteral and Enteral NutritionMehta et alresearch-article2017

Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Pediatric Critically Ill Patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition

Nilesh M. Mehta, MD1; Heather E. Skillman, MS, RD, CSP, CNSC2; Sharon Y. Irving, PhD, CRNP, FCCM, FAAN3; Jorge A. Coss-Bu, MD4; Sarah Vermilyea, MS, RD, CSP, LD, CNSC5; Elizabeth Anne Farrington, PharmD, FCCP, FCCM, FPPAG, BCPS6; Liam McKeever, MS, RDN7; Amber M. Hall, MS8; Praveen S. Goday, MBBS, CNSC9; and Carol Braunschweig, PhD, RD10

AbstractThis document represents the first collaboration between 2 organizations—the American Society for Parenteral and Enteral Nutrition and the Society of Critical Care Medicine—to describe best practices in nutrition therapy in critically ill children. The target of these guidelines is intended to be the pediatric critically ill patient (>1 month and <18 years) expected to require a length of stay >2–3 days in a PICU admitting medical, surgical, and cardiac patients. In total, 2032 citations were scanned for relevance. The PubMed/MEDLINE search resulted in 960 citations for clinical trials and 925 citations for cohort studies. The EMBASE search for clinical trials culled 1661 citations. In total, the search for clinical trials yielded 1107 citations, whereas the cohort search yielded 925. After careful review, 16 randomized controlled trials and 37 cohort studies appeared to answer 1 of the 8 preidentified question groups for this guideline. We used the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluation) to adjust the evidence grade based on assessment of the quality of study design and execution. These guidelines are not intended for neonates or adult patients. The guidelines reiterate the importance of nutrition assessment—particularly, the detection of malnourished patients who are most vulnerable and therefore may benefit from timely intervention. There is a need for renewed focus on accurate estimation of energy needs and attention to optimizing protein intake. Indirect calorimetry, where feasible, and cautious use of estimating equations and increased surveillance for unintended caloric underfeeding and overfeeding are recommended. Optimal protein intake and its correlation with clinical outcomes are areas of great interest. The optimal route and timing of nutrient delivery are areas of intense debate and investigations. Enteral nutrition remains the preferred route for nutrient delivery. Several strategies to optimize enteral nutrition during critical illness have emerged. The role of supplemental parenteral nutrition has been highlighted, and a delayed approach appears to be beneficial. Immunonutrition cannot be currently recommended. Overall, the pediatric critical care population is heterogeneous, and a nuanced approach to individualizing nutrition support with the aim of improving clinical outcomes is necessary. (JPEN J Parenter Enteral Nutr. XXXX;xx:xx-xx)

Keywordsadolescent; algorithm; child; critical illness; energy; enteral nutrition; guidelines; immunonutrition; indirect calorimetry; infant; intensive care unit; malnutrition; nutrition team; obesity; parenteral nutrition; pediatric; pediatric nutrition assessment; protein; protein balance; resting energy expenditure

https://journals.sagepub.com/home/pen

2 Journal of Parenteral and Enteral Nutrition XX(X)

The current guidelines represent an expanded body of lit-erature since the publication of the first guidelines in 2009.1 The guidelines offer basic recommendations that are supported by review and analysis of the current literature and a blend of expert opinion and clinical practicality. Current literature has limitations that include variability in study design, small sam-ple size, patient heterogeneity, variability in disease severity, lack of information on baseline nutrition status, and insuffi-cient statistical power for analysis. As the authors of these guidelines, we acknowledge the scarcity of high-level evidence for nutrition practices in the pediatric intensive care unit (PICU) environment. Most questions addressed in this guide-line do not have enough homogeneous high-quality trials and therefore do not lend themselves to any statistical analyses. A combination of cohort studies and trials, where available, has been summarized and used to develop practical recommenda-tions by consensus. Where randomized controlled trials (RCTs) were not available, observational studies formed the main evi-dence. Their quality was critically reviewed with GRADE methodology (Grading of Recommendations, Assessment, Development, and Evaluation) and thus guided the consensus-derived recommendations.2

Definitions

Nutrition support therapy refers to the provision of enteral nutrition (EN) by enteral access device and/or parenteral nutri-tion (PN). Standard therapy refers to provision of intravenous fluids, no EN or PN, and advancement to oral diet as tolerated.

Target Patient Population for Guideline

The target of these guidelines is intended to be the pediatric criti-cally ill patient (>1 mo and <18 years) expected to require a length of stay (LOS) >2–3 days in a PICU admitting medical,

surgical, and cardiac patients. These guidelines are not intended for neonates or adult patients. We believe that neonates are dif-ferent physiologically from older children; therefore, these guidelines do not include them. These guidelines are not intended for patients with specific diagnoses, such as burn injuries. These guidelines are directed toward generalized patient populations, but, like any other management strategy in the PICU, nutrition therapy should be tailored to the individual patient.

Target Audience

These guidelines are intended for use by all healthcare provid-ers involved in nutrition therapy of the critically ill child—pri-marily, physicians, nurses, dietitians, and pharmacists.

Methods

The GRADE process was used to develop the key questions and to plan data acquisition and conflation for these guide-lines.2 The task force of experts defined keywords to be used for the literature search; developed key questions that address major practice themes at the bedside; and determined the time frame for the literature search, target population, and the spe-cific outcomes to be addressed. Ultimately, questions related to 8 major practice areas were developed, which were reviewed and approved by the ASPEN and SCCM boards. These ques-tions and the recommendations are summarized in Table 1. Due to a dearth of well-designed RCTs, many studies address-ing these questions and relevant outcomes are either prospec-tive or retrospective observational reports of clinical outcomes associated with a strategy. In some cases, these interventions were protocolized. The evidence provided by these observa-tional studies was strengthened, however, when the effects shown were strong, when the sample size was large, or when there was a dose-response relationship. We used the GRADE

From the 1Division of Critical Care Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 2Clinical Nutrition Department, Children’s Hospital Colorado, Aurora, Colorado, USA; 3Division of Critical Care, Children’s Hospital of Philadelphia, University of Pennsylvania School of Nursing, Philadelphia, Pennsylvania, USA; 4Section of Critical Care, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, USA; 5Division of Nutrition Therapy, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; 6Department of Pharmacy, Betty H. Cameron Women’s and Children’s Hospital, New Hanover Regional Medical Center, Wilmington, North Carolina, USA; 7Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA; 8Biostatistics, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, Boston, Massachusetts, USA; 9Pediatric Gastroenterology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; and 10Division of Epidemiology and Biostatistics, Department of Kinesiology and Nutrition, University of Illinois, Chicago, Illinois, USA.

These guidelines are being copublished by the Society of Critical Care Medicine (SCCM) in Pediatric Critical Care Medicine (PCCM), 2017;XX:XX-XX. Minor differences in style may appear in each publication, but the article is substantially the same in each journal.

All authors completed both the American Society for Parenteral and Enteral Nutrition and Society of Critical Care Medicine conflicts-of-interest form for copyright assignment and financial disclosure. The authors of these guidelines have reported all potential conflicts or financial disclosures. There was no funding or contribution from industry, nor were any industry representatives present at any of the committee meetings.

Financial disclosure: None declared.

Conflicts of interest: None declared.

Received for publication September 28, 2016; accepted for publication May 3, 2017.

Corresponding Author:Nilesh M. Mehta, MD, Bader 634, Boston Children’s Hospital, 300 Longwood Avenue, Boston MA 02115 USA. Email: [email protected]

mailto:[email protected]

Mehta et al 3

Table 1. Nutrition Support Clinical Guideline Recommendations for the Critically Ill Child.

Questions and Recommendations Evidence/GRADE

Q1A: What is the impact of nutrition status on outcomes in critically ill children? Quality of evidence: very lowR1A: Based on observational studies, malnutrition, including obesity, is associated with adverse

clinical outcomes, including longer periods of ventilation, higher risk of hospital-acquired infection, longer PICU and hospital stay, and increased mortality. We recommend that patients in the PICU undergo detailed nutrition assessment within 48 h of admission. Furthermore, as patients are at risk of nutrition deterioration during hospitalization, which can adversely affect clinical outcomes, we suggest that the nutrition status of patients be reevaluated at least weekly throughout hospitalization.

GRADE recommendation: strong

Q1B: What are the best practices to screen and identify patients with malnutrition or those at risk of nutrition deterioration in the PICU?

Quality of evidence: very low

R1B: On the basis of observational studies and expert consensus, we recommend that weight and height/length be measured on admission to the PICU and that z scores for body mass index for age (weight for length <2 y) or weight for age (if accurate height is not available) be used to screen for patients at extremes of these values. In children <36 mo old, head circumference must be documented. Validated screening methods for the PICU population to identify patients at risk of malnutrition must be developed. Screening methods might allow limited resources to be directed to high-risk patients who are most likely to benefit from early nutrition assessment and interventions.


Q2A: What is the recommended energy requirement for critically ill children? Quality of evidence: lowR2A: On the basis of observational cohort studies, we suggest that measured energy expenditure

by IC be used to determine energy requirements and guide prescription of the daily energy goal.GRADE recommendation: weak

Q2B: How should energy requirement be determined in the absence of IC? Quality of evidence: very lowR2B: If IC measurement of resting energy expenditure is not feasible, we suggest that the

Schofield or Food Agriculture Organization / World Health Organization / United Nations University equations may be used without the addition of stress factors to estimate energy expenditure. Multiple cohort studies have demonstrated that most published predictive equations are inaccurate and lead to unintended overfeeding or underfeeding. The Harris-Benedict equations and the RDAs, which are suggested by the dietary reference intakes, should not be used to determine energy requirements in critically ill children.

GRADE recommendation: weak

Q2C: What is the target energy intake in critically ill children? Quality of evidence: lowR2C: On the basis of observational cohort studies, we suggest achieving delivery of at least

two-thirds of the prescribed daily energy requirement by the end of the first week in the PICU. Cumulative energy deficits during the first week of critical illness may be associated with poor clinical and nutrition outcomes. On the basis of expert consensus, we suggest attentiveness to individualized energy requirements, timely initiation and attainment of energy targets, and energy balance to prevent unintended cumulative caloric deficit or excesses.


Q3A: What is the minimum recommended protein requirement for critically ill children? Quality of evidence: moderateR3A: On the basis of evidence from RCTs and as supported by observational cohort studies, we

recommend a minimum protein intake of 1.5 g/kg/d. Protein intake higher than this threshold has been shown to prevent cumulative negative protein balance in RCTs. In critically ill infants and young children, the optimal protein intake required to attain a positive protein balance may be much higher than this minimum threshold. Negative protein balance may result in loss of lean muscle mass, which has been associated with poor outcomes in critically ill patients. Based on a large observational study, higher protein intake may be associated with lower 60-d mortality in mechanically ventilated children.


Q3B: What is the optimal protein delivery strategy in the PICU? Quality of evidence: moderateR3B: On the basis of results of randomized trials, we suggest provision of protein early in the

course of critical illness to attain protein delivery goals and promote positive nitrogen balance. Delivery of a higher proportion of the protein goal has been associated with positive clinical outcomes in observational studies.


Q3C: How should protein delivery goals be determined in critically ill children? Quality of evidence: moderateR3C: The optimal protein dose associated with improved clinical outcomes is not known. We do

not recommend the use of RDA values to guide protein prescription in critically ill children. These values were developed for healthy children and often underestimate the protein needs during critical illness.


(continued)


Questions and Recommendations Evidence/GRADE

Q4A: Is EN feasible in critically ill children? Quality of evidence: lowR4A: On the basis of observational studies, we recommend EN as the preferred mode of nutrient

delivery to the critically ill child. Observational studies support the feasibility of EN, which can be safely delivered to critically ill children with medical and surgical diagnoses and to those receiving vasoactive medications. Common barriers to EN in the PICU include delayed initiation, interruptions due to perceived intolerance, and prolonged fasting around procedures. On the basis of observational studies, we suggest that interruptions to EN be minimized in an effort to achieve nutrient delivery goals by the enteral route.


Q4B: What is the benefit of EN in this group? Quality of evidence: lowR4B: Although the optimal dose of macronutrients is unclear, some amount of nutrient delivered as EN

has been beneficial for gastrointestinal mucosal integrity and motility. Based on large cohort studies, early initiation of EN (within 24–48 h of PICU admission) and achievement of up to two-thirds of the nutrient goal in the first week of critical illness have been associated with improved clinical outcomes.


Q5A: What is the optimum method for advancing EN in the PICU population? Quality of evidence: lowR5A: On the basis of observational studies, we suggest the use of a stepwise algorithmic approach to

advance EN in children admitted to the PICU. The stepwise algorithm must include bedside support to guide the detection and management of EN intolerance and the optimal rate of increase in EN delivery.


Q5B: What is the role of a nutrition support team or a dedicated dietitian in optimizing nutrition therapy? Quality of evidence: lowR5B: On the basis of observational studies, we suggest a nutrition support team, including a

dedicated dietitian, be available on the PICU team, to facilitate timely nutrition assessment, and optimal nutrient delivery and adjustment to the patients.


Q6A: What is the best site for EN delivery: gastric or small bowel?? Quality of evidence: lowR6A: Existing data are insufficient to make universal recommendations regarding the optimal site

to deliver EN to critically ill children. On the basis of observational studies, we suggest that the gastric route be the preferred site for EN in patients in the PICU. The postpyloric or small intestinal site for EN may be used in patients unable to tolerate gastric feeding or those at high risk for aspiration. Existing data are insufficient to make recommendations regarding the use of continuous vs intermittent gastric feeding.


Q6B: When should EN be initiated? Quality of evidence: lowR6B: On the basis of expert opinion, we suggest that EN be initiated in all critically ill children, unless

it is contraindicated. Given observational studies, we suggest early initiation of EN, within the first 24–48 h after admission to the PICU, in eligible patients. We suggest the use of institutional EN guidelines and stepwise algorithms that include criteria for eligibility for EN, timing of initiation, and rate of increase, as well as a guide to detecting and managing EN intolerance.


Q7A: What is the indication for and optimal timing of PN in critically ill children? Quality of evidence: moderateR7A: On the basis of a single RCT, we do not recommend the initiation of PN within 24 h of

PICU admission.GRADE recommendation: strong

Q7B: What is the role of PN as a supplement to inadequate EN? Quality of evidence: lowR7B: For children tolerating EN, we suggest stepwise advancement of nutrient delivery via

the enteral route and delaying commencement of PN. Based on current evidence, the role of supplemental PN to reach a specific goal for energy delivery is not known. The time when PN should be initiated to supplement insufficient EN is also unknown. The threshold for and timing of PN initiation should be individualized. Based on a single RCT, supplemental PN should be delayed until 1 wk after PICU admission for patients with normal baseline nutrition state and low risk of nutrition deterioration. On the basis of expert consensus, we suggest PN supplementation for children who are unable to receive any EN during the first week in the PICU. For patients who are severely malnourished or at risk of nutrition deterioration, PN may be supplemented in the first week if they are unable to advance past low volumes of EN.


Q8: What is the role of immunonutrition in critically ill children? Quality of evidence: moderateR8: On the basis of available evidence, we do not recommend the use of immunonutrition in

critically ill children.GRADE recommendation: strong

EN, enteral nutrition; GRADE, Grading of Recommendations, Assessment, Development, and Evaluation; IC, indirect calorimetry; PICU, pediatric intensive care unit; PN, parenteral nutrition; Q, question; R, recommendation; RCT, randomized controlled trial; RDA, recommended daily allowance.

Table 1. (continued)

Mehta et al 5

criteria to adjust the evidence grade based on assessment of the quality of study design and execution. The GRADE process distinctly separates the body of evidence from the recommen-dation statements. This separation enables incorporation of the weight of the risks versus the benefits that occur from adopting the recommendation. Thus, a recommendation may be “strong” despite comparatively weak published evidence if the net ben-efits outweigh the harms from its adoption. Recommendations based mainly on expert opinion were deemed weak. Table 2 describes the standard language and rationale for the grade assigned to a recommendation.

A rigorous search of the MEDLINE/PubMed and EMBASE databases was performed spanning January 1995 through March 2016 for citations relevant to nutrition support in the critically ill pediatric population with the techniques outlined in a recent publication.3 For the MEDLINE portion of the search, Medical Subject Heading (MeSH) folders for “critical illness,” “intensive care,” and “critical care” were searched for relevant citations. To meet our search criteria, these citations also had to be indexed in MeSH folders for “nutritional support,” “malnutrition,” “nutri-tion assessment,” “energy intake,” “energy metabolism,” or “dietary proteins.” To further restrict citations to our chosen population, the terms were cross-referenced in the MeSH folders for “pediatrics,” “infant,” “child,” “adolescent,” or “young

adult.” Alternatively, we accepted citations that had the terms pediatric*, paediatric*, infan*, adolescen*, or child* in at least 1 of their PubMed/MEDLINE subject fields. Finally, all cita-tions had to be cross-referenced in the “humans” MeSH folder. The PubMed (non-MEDLINE) database was then searched with text-based terms (Figure 1). As an added protection against MeSH miscategorization of citations, this text-based search was then used to search the MEDLINE database, restricted to yield only citations carrying those terms in their title or abstract. For the clinical trials search, the MEDLINE portion was restricted to those citations categorized according to the publication type “clinical trials.” For the cohort search, the MEDLINE portion was restricted to those studies cross-referenced in the “cohort” MeSH folder, whereas the text-based portion was restricted to only those citations that were not indexed according to the publication types “clinical trial,” “review,” “case reports,” or “commentary.” An analogous search strategy focusing on EMBASE-indexed non-MEDLINE clinical trials was created and implemented for the EMBASE database.

Results

In total, 2032 citations were scanned for relevance. The PubMed/MEDLINE search resulted in 960 citations for

Table 2. Language for Guidelines Recommendations.

Quality of Evidence Weighing Risks vs Benefits GRADE Recommendations Clinical Guideline Statement

High to very low Net benefits outweigh harms Strong We recommend.

High to very low Trade-offs for patient are important

Weak We suggest.

High to very low Uncertain trade-offs Further research needed We cannot make a recommendation at this time.

GRADE, Grading of Recommendations, Assessment, Development, and Evaluation.

Figure 1. Overview of the literature search strategy.


clinical trials and 925 citations for cohort studies. The EMBASE search for clinical trials culled 1661 citations. In total, the search for clinical trials yielded 1107 citations, whereas the cohort search yielded 925. Each citation was reviewed by at least 2 reviewers to examine eligibility for inclusion in guideline development. After careful review, 16 RCTs and 37 cohort studies appeared to answer 1 of the 8 pre-identified question groups for this guideline. We then reviewed these studies and abstracted the relevant data with a standard-ized form. After review of the abstracted data, evidence tables were generated for each question. Given the evidence tables, we used an iterative process to develop practical recommenda-tions for each question with the GRADE methodology where applicable and by consensus. The recommendations for ques-tions are summarized in Table 1. The rationale for the GRADE and the language for the recommendations are described in Table 2. Tables 3–10 summarize the evidence in the form of trials and cohort studies related to each guideline question. Each table is accompanied by a discussion on the rationale for the recommendations and suggested areas for future investiga-tion for the questions.

Introduction

The role of nutrition in contributing to the outcomes of patients with critical illness is being increasingly recognized. Since the first pediatric critical care nutrition guidelines (ASPEN) pub-lished in 2009, there has been a substantial increase in research and publications related to this subject. The impact of nutrition status and nutrient delivery during critical illness has been demonstrated on clinical outcomes such as mortality, infec-tious complications, and LOS.4-10 Thus, careful planning and monitoring of nutrient delivery at the bedside is attempted in most intensive care units (ICUs). As more information becomes available from higher-quality studies, the field will eventually move toward uniform evidence-based strategies for most nutri-tion practices in the PICU. However, at present, many ques-tions remain unanswered, and practices are widely variable among institutions and among providers. RCTs, while provid-ing definitive evidence, require tremendous time and resources to complete. Hence, there is a scarcity of RCTs in the pediatric critical care nutrition literature. Furthermore, results of single RCTs in the adult population have not often been replicated in subsequent studies.11-13 Despite these limitations, there have been a number of small and large studies published over the past decade. Observational cohort and case-control studies have provided meaningful information and helped develop hypotheses that can be tested by clinical trials with more robust study designs. Prospective or retrospective cohorts allow mea-surement of disease occurrence and its association with an exposure by offering a temporal dimension. These studies are described in detail in the relevant sections of this article.

The PICU is unique in terms of the heterogeneity of patients in relation to age, disease type, interventions, comorbid

conditions, and presenting nutrition status. It is therefore overly simplistic to expect that one strategy will be applicable to all patients. Nutrition support must be individualized accord-ing to the baseline nutrition status and vulnerabilities of patients, anticipated time to volitional feeding, and the risk-to-benefit ratio of intended nutrition therapies. Therefore, the rec-ommendations provided here are useful starting points on which to build customized nutrition therapy for individual patients.

Question 1A: What is the impact of nutrition status on out-comes in critically ill children?

Recommendation 1A. Based on observational studies, malnu-trition, including obesity, is associated with adverse clinical outcomes, including longer periods of ventilation, higher risk of hospital-acquired infection, longer PICU and hospital stay, and increased mortality (see Table 3). We recommend that patients in the PICU undergo detailed nutrition assessment within 48 hours of admission.

Furthermore, as patients are at risk of nutrition deterioration during hospitalization, which can adversely affect clinical out-comes, we suggest that the nutrition status of patients be reevaluated at least weekly throughout hospitalization.Quality of evidence. Very low.GRADE recommendation. Strong.

Question 1B: What are the best practices to screen and identify patients with malnutrition or those at risk of nutri-tion deterioration in the PICU?

Recommendation 1B. On the basis of observational studies and expert consensus, we recommend that weight and height/length be measured at admission to the PICU and that z scores for body mass index (BMI) for age (weight for length, <2 years) or weight for age (if accurate height is not available) be used to screen for patients at extremes of these values. For children <36 months old, head circumference must be documented.

Validated screening methods for the PICU population to identify patients at risk of malnutrition must be developed. Screening methods might allow limited resources to be directed to high-risk patients who are most likely to benefit from early nutrition interventions.Quality of evidence. Very low.GRADE recommendation. Strong.Rationale. Malnutrition is prevalent in children admitted to the PICU.6,7,14,15 Although variables used to define malnutri-tion are inconsistent across reports, underweight and over-weight status have both been associated with worse morbidity and mortality.4-6,10 More recently, guidelines to define pediatric malnutrition have become available to facilitate early identifi-cation of individuals at risk.16 A uniform approach to define pediatric malnutrition may allow determination of thresholds for interventions aimed at ameliorating nutrition deteriora-tion.17 A large portion of children admitted to the PICU is at risk for nutrition deterioration; therefore, periodic nutrition

7

Tab

le 3

. Im

pact

of

Nut

riti

on S

tatu

s on

Out

com

es a

nd B

est P

ract

ices

to D

etec

t Mal

nutr

itio

n or

Ris

k of

Nut

riti

on D

eter

iora

tion

.

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

ims

Pop

ulat

ion

(n),

Eli

gibi

lity

Res

ults

/Out

com

eC

omm

ents

Bec

hard

et

al4

Pro

spec

tive

, ob

serv

atio

nal

coho

rt

(com

bine

d da

ta s

et f

rom

2

stud

ies)

; m

ulti

cent

er (

90

PIC

Us

from

16

coun

trie

s)

To

dete

rmin

e th

e in

flue

nce

of a

dmis

sion

BM

I z

scor

e on

cli

nica

l out

com

es in

m

echa

nica

lly

vent

ilat

ed

chil

dren

in th

e P

ICU

n =

162

2M

echa

nica

lly

vent

ilat

ed,

crit

ical

ly il

l chi

ldre

n, 1

m

o to

18

y ol

d, w

ith

an

expe

cted

PIC

U s

tay

of a

t le

ast 3

d, a

nd d

epen

dent

on

ent

eral

or

pare

nter

al

nutr

itio

n su

ppor

tM

ean

age

(SD

): 4

.5 y

(5

.1 y

)

54.2

%, n

orm

al w

eigh

t; 1

7.9%

, un

derw

eigh

t; 1

4.5%

, ove

rwei

ght;

13

.4%

, obe

seO

utco

mes

(vs

nor

mal

nut

riti

on s

tatu

s)

60-d

mor

tali

ty: H

ighe

r in

un

derw

eigh

t: O

R, 1

.53

(CI

1.24

–1.8

9; P

< .0

01)

L

ikel

ihoo

d of

dis

char

ge a

live

: for

ea

ch a

ddit

iona

l day

in th

e ho

spit

al,

unde

rwei

ght h

ad 2

9% (

HR

, 0.7

1;

95%

CI,

0.6

0–0.

84; P

< .0

01)

and

obes

e ha

d 18

% (

HR

, 0.8

2; 9

5% C

I,

0.68

–0.9

9; P

= .0

4) lo

wer

cha

nce

of b

eing

dis

char

ged.

H

ospi

tal-

acqu

ired

infe

ctio

n: h

ighe

r in

und

erw

eigh

t: O

R, 1

.88

(95%

CI,

1.

18–3

.01;

P =

.008

)

Hig

her

in o

bese

: OR

, 1.6

4 (9

5% C

I,

1.33

–2.0

3; P

< .0

01)

V

FD

: Und

erw

eigh

t ass

ocia

ted

wit

h 1.

3 fe

wer

VF

D v

s no

rmal

wei

ght

(95%

CI,

−2.

1 to

−0.

6; P

= .0

01),

1.

6 fe

wer

VF

D v

s ov

erw

eigh

t (9

5% C

I, −

2.4

to −

0.9;

P <

.001

),

1.2

few

er V

FD

vs

obes

e (9

5%

CI,

−1.

9 to

−0.

6; P

< .0

01).

No

sign

ific

ant d

iffe

renc

es in

VF

D

amon

g ov

erw

eigh

t and

obe

se

45%

of

the

coho

rt w

as m

alno

uris

hed

(obe

se, o

verw

eigh

t, un

derw

eigh

t)

on a

dmis

sion

.U

nder

wei

ght a

nd o

bese

sta

tus

asso

ciat

ed w

ith

poor

out

com

es

vs n

orm

al n

utri

tion

sta

tus

on

adm

issi

on.

Lim

itat

ions

: cen

ters

fro

m th

e de

velo

ping

wor

ld, w

here

m

alnu

trit

ion

may

be

mor

e pr

eval

ent,

wer

e ex

clud

ed d

ue to

sm

alle

r P

ICU

siz

e.P

oten

tial

for

inac

cura

cy o

f w

eigh

t an

d he

ight

/len

gth

mea

sure

men

ts,

espe

cial

ly w

hen

infl

uenc

ed b

y fl

uid

shif

ts.

Cro

ss-s

ecti

onal

stu

dy (

no

inte

rven

tion

s)

Cas

till

o et

al5

Pro

spec

tive

, ob

serv

atio

nal;

si

ngle

cen

ter

To

asse

ss th

e as

soci

atio

n be

twee

n m

orta

lity

and

nu

trit

ion

stat

us o

f ch

ildr

en

rece

ivin

g C

RR

T

n =

174

PIC

U p

atie

nts

rece

ivin

g C

RR

TM

alnu

trit

ion:

< th

ird

perc

enti

le f

or b

ody

wei

ght f

or a

geM

edia

n ag

e (I

QR

): 1

8.5

mo

(4.0

–81.

8 m

o)

35%

of

the

coho

rt w

as m

alno

uris

hed

Maj

orit

y of

mal

nour

ishe

d pa

tien

ts

wer

e <

1 y

old

Low

inci

denc

e of

obe

sity

Hyp

oalb

umin

emia

in 2

8%M

orta

lity

was

hig

her

(42.

6%)

in

mal

nour

ishe

d ch

ildr

en

A th

ird

of th

e co

hort

was

m

alno

uris

hed.

Mal

nutr

itio

n w

as a

ssoc

iate

d w

ith

high

er m

orta

lity

.L

imit

atio

ns: b

ody

wei

ght w

as u

sed

to d

eter

min

e nu

trit

ion

stat

us, a

nd

seru

m a

lbum

in le

vel w

as u

sed

to

dete

rmin

e pr

otei

n st

atus

. (con

tinu

ed)

8

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

ims

Pop

ulat

ion

(n),

Eli

gibi

lity

Res

ults

/Out

com

eC

omm

ents

de S

ouza

M

enez

es

et a

l6

Pro

spec

tive

, ob

serv

atio

nal;

si

ngle

cen

ter

To

dete

rmin

e th

e nu

trit

ion

stat

us o

f ch

ildr

en a

dmit

ted

to a

PIC

U a

nd to

ass

ess

the

effe

ct o

f m

alnu

trit

ion

as

an in

depe

nden

t ris

k fa

ctor

af

fect

ing

outc

ome

(the

ou

tcom

e va

riab

les

wer

e 30

-d

mor

tali

ty, l

engt

h of

IC

U s

tay,

an

d du

rati

on o

f m

echa

nica

l ve

ntil

atio

n)

n =

385

Mal

nutr

itio

n (z

sco

re, <

–2)

base

d on

wei

ght f

or a

ge

(<2

y) o

r B

MI

(≥2

y) a

nd

heig

ht f

or a

ge (

if c

hron

ic

dise

ase)

Med

ian

age

(IQ

R):

18.

3 m

o (3

.9–6

3.3

mo)

45.5

% w

ere

mal

nour

ishe

d on

adm

issi

on. 9

.14%

of

the

mal

nour

ishe

d gr

oup

and

11.9

% o

f th

e no

nmal

nour

ishe

d gr

oup

died

.M

alnu

trit

ion

was

ass

ocia

ted

wit

h lo

nger

dur

atio

n of

MV

and

PIC

U

LO

S b

ut n

ot m

orta

lity

on

univ

aria

te

anal

ysis

.M

alnu

trit

ion

was

ass

ocia

ted

wit

h lo

nger

dur

atio

n of

mec

hani

cal

vent

ilat

ion

on m

ulti

ple

logi

stic

re

gres

sion

mod

elin

g (O

R, 1

.76;

95%

C

I, 1

.08–

2.88

; P =

.024

).

Cen

ter

wit

h hi

gh p

reva

lenc

e of

m

alnu

trit

ion

show

ing

inde

pend

ent

impa

ct o

n du

rati

on o

f M

V.

Lim

itat

ions

: sin

gle-

cent

er s

tudy

; m

etho

dolo

gic

issu

es w

ith

sam

ple

size

cal

cula

tion

.

Del

gado

et

al7

Ret

rosp

ecti

ve,

obse

rvat

iona

l;

sing

le c

ente

r

To

eval

uate

the

inci

denc

e of

m

alnu

trit

ion

in th

e fi

rst 7

2 hr

af

ter

PIC

U a

dmis

sion

.E

xam

ine

diff

eren

ces

in

IL-6

, CR

P, L

OS

, sep

sis,

an

d m

orta

lity

bet

wee

n th

e m

alno

uris

hed

and

wel

l-no

uris

hed

grou

ps.

n =

107

7M

alnu

trit

ion

base

d on

w

eigh

t-fo

r-ag

e z

scor

e:

mod

erat

e, −

1 to

−2;

se

vere

, <−

2M

edia

n ag

e:

mal

nour

ishe

d, 2

5.6

mo;

w

ell n

ouri

shed

, 10.

7 m

o

No

sign

ific

ant d

iffe

renc

es b

etw

een

wel

l nou

rish

ed a

nd m

alno

uris

hed

for

CR

P, P

ICU

LO

S, h

ospi

tal m

orta

lity

, or

inci

denc

e of

sep

sis

IL-6

was

sig

nifi

cant

ly d

iffe

rent

be

twee

n w

ell n

ouri

shed

and

m

alno

uris

hed

over

tim

e (P

= .0

43).

>50

% o

f pa

tien

ts a

dmit

ted

to

this

Bra

zili

an P

ICU

wer

e m

alno

uris

hed.

Mal

nour

ishe

d pa

tien

ts h

ad h

ighe

r in

flam

mat

ory

mar

kers

vs

wel

l-no

uris

hed

pati

ents

.

BM

I, b

ody

mas

s in

dex;

CR

P, C

-rea

ctiv

e pr

otei

n; C

RR

T, c

onti

nuou

s re

nal r

epla

cem

ent t

hera

py; H

R, h

azar

d ra

tio;

IC

U, i

nten

sive

car

e un

it; I

L, i

nter

leuk

in; I

QR

, int

erqu

arti

le r

ange

; LO

S, l

engt

h of

sta

y;

MV

, mec

hani

cal v

enti

lati

on; O

R, o

dds

rati

o; P

ICU

, ped

iatr

ic in

tens

ive

care

uni

t; V

FD

, ven

tila

tor-

free

day

s.

Tab

le 3

. (c

onti

nu

ed)

Mehta et al 9

reevaluation is essential.15,18 Nutrition assessment must include a dietary history, detection of changes in anthropometry, func-tional status, and nutrition-focused physical examination. A nutrition-focused physical examination in this cohort allows for determination of individualized nutrient needs, interven-tions, and monitoring to optimize nutrient intake during illness. The subjective global nutrition assessment is correlated with anthropometric variables in 1 study but has not been shown to predict outcomes in critically ill children.19

In a limited resource setting, timely and detailed nutrition assessment of every patient in the PICU may not be feasible. A validated method to screen critically ill children for malnutri-tion risk may help allocate resources to high-risk patients. However, such a screening method is not currently available. The Pediatric Yorkhill Malnutrition Score, the Screening Tool for the Assessment of Malnutrition in Pediatrics, and the Screening Tool for Risk of Impaired Nutritional Status and Growth (STRONGKids) were recently evaluated among 2567 patients from multiple centers in Europe.20 These screens var-ied significantly in their ability to identify and classify malnu-trition risk and were unable to detect a significant proportion of children with abnormal anthropometrics. The authors con-cluded that none of these screens could be recommended for use in clinical practice. Admission z scores based on weight for age and BMI for age (or weight for length for children <2 years) in relation to population reference standards have been used to classify patients as undernourished or obese. Admission BMI z scores predicted mortality in a large multicenter cohort of children receiving mechanical ventilation.4 Due to the con-sistent associations with LOS, duration of mechanical ventila-tion, and mortality, BMI z scores may be useful to screen for patients at risk of poor outcomes in the PICU.17 Despite the inherent challenges of obtaining accurate anthropometric mea-surements at admission to the PICU, the routine evaluation of weight-for-age and BMI-for-age or weight-for-length z scores must be prioritized. Indeed, in a majority of tertiary centers, documentation of anthropometric measurements at admission is seen as the standard of care.Future direction. A validated nutrition screen for timely and accurate identification of malnourished PICU patients is needed. This tool will facilitate allocation of resources, early interventions, and close monitoring of nutrition status in high-risk patients. A uniform definition of malnutrition must be employed, and validated methods for nutrition assessment must be developed and implemented in the PICU. Subse-quently, the impact of malnutrition on clinical outcomes in the PICU population should be examined.

Question 2A: What is the recommended energy require-ment for critically ill children?

Recommendation 2A. On the basis of observational cohort studies, we suggest that measured energy expenditure by indi-rect calorimetry (IC) be used to determine energy requirements and guide prescription of the daily energy goal (see Table 4).

Quality of evidence. Low.GRADE recommendation. Weak.

Question 2B: How should energy requirement be deter-mined in the absence of IC?

Recommendation 2B. If IC measurement of resting energy expenditure is not feasible, we suggest that the Schofield or Food Agriculture Organization / World Health Organization (WHO) / United Nations University equations may be used without the addition of stress factors to estimate energy expen-diture. Multiple cohort studies have demonstrated that most published predictive equations are inaccurate and lead to unin-tended overfeeding or underfeeding.

The Harris-Benedict equations and the recommended daily allowances (RDAs), which are suggested by the dietary refer-ence intakes, should not be used to determine energy require-ments in critically ill children.Quality of evidence. Very low.GRADE recommendation. Weak.

Question 2C: What is the target energy intake in critically ill children?

Recommendation 2C. On the basis of observational cohort studies, we suggest achieving delivery of at least two-thirds of the prescribed daily energy requirement by the end of the first week in the PICU. Cumulative energy deficits during the first week of critical illness may be associated with poor clinical and nutrition outcomes. Per expert consensus, we suggest attentiveness to individualized energy requirements, timely initiation and attainment of energy targets, and energy balance to prevent unintended cumulative caloric deficit or excesses.

Quality of evidence. Low.GRADE recommendation. Weak.Rationale. Metabolic alterations are common in critical ill-ness, and patients present with a variety of metabolic states that cannot be predicted, including hypometabolism (measured resting energy expenditure [MREE], <90% of predicted), nor-mal metabolism (MREE, 90%–110% predicted), and hyperme-tabolism (MREE, >110% predicted).21-25 Currently available equations fail to estimate energy expenditure within ±10% of MREE in a majority of critically ill children; IC is the only available method to accurately determine energy requirements for this population.21,28-33 Energy expenditure measured by IC for critically ill children is independent of nutrition status, ini-tial diagnosis, or severity of the acute illness.30-32,34 MREE may be decreased during deep sedation, neuromuscular blockade, or severe hypothyroidism, or increased with temperature >38°C and distress/activity.30,31,33 In cohort studies, MREE did not significantly vary within the same patient over time.21,28,35 After the baseline MREE is performed (ideally during the first week of critical illness); repeat measurements may be obtained in patients with significant changes in clinical status.27,35 Patients at high risk for metabolic alterations are appropriate

10

Tab

le 4

. R

ecom

men

ded

Ene

rgy

Req

uire

men

t for

Cri

tica

lly

Ill C

hild

ren.

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

im(s

)P

opul

atio

n (n

),

Eli

gibi

lity

Res

ults

/Out

com

eC

omm

ents

Jott

eran

d C

hapa

rro

et a

l36

Pro

spec

tive

co

hort

; sin

gle

cent

er

To

asse

ss p

rote

in a

nd e

nerg

y re

quir

emen

ts to

ach

ieve

ni

trog

en a

nd e

nerg

y ba

lanc

e an

d to

com

pare

MR

EE

wit

h th

e D

RIs

n =

76

Mec

hani

call

y ve

ntil

ated

, cri

tica

lly

ill c

hild

ren

Med

ian

age

(IQ

R):

21

mo

(4–3

5 m

o)

402

IC m

easu

rem

ents

Mea

n M

RE

E 5

5 kc

al/k

g/d

(95%

CI,

54–

57)

MR

EE

was

sta

ble

for

firs

t 10

dM

RE

E d

ecre

ased

6%

wit

h ne

urom

uscu

lar

bloc

kade

(P

= .0

31)

and

incr

ease

d by

8%

pe

r de

gree

cen

tigr

ade

body

tem

pera

ture

(P

= .0

03).

DR

I st

rong

ly o

vere

stim

ated

MR

EE

P

rote

in in

take

≥1.

5 g/

kg/d

pro

tein

and

en

ergy

inta

ke ≥

58 k

cal/

kg/d

nee

ded

for

nitr

ogen

and

ene

rgy

bala

nce

Stu

dy s

ugge

sts

a th

resh

old

for

opti

mal

ene

rgy

inta

ke a

nd a

re

lati

onsh

ip b

etw

een

ener

gy

inta

ke a

nd p

rote

in b

alan

ce.

Lim

itat

ions

: pro

tein

bal

ance

w

as d

eter

min

ed v

ia n

itro

gen

bala

nce

mea

sure

men

ts

Won

g et

al44

Ret

rosp

ecti

ve

coho

rt; s

ingl

e ce

nter

To

desc

ribe

nut

riti

on s

uppo

rt a

nd

iden

tify

ade

quat

e ca

lori

c in

take

by

chi

ldre

n w

ith

AR

DS

and

to

dete

rmin

e w

heth

er p

rovi

sion

of

adeq

uate

nut

riti

on is

ass

ocia

ted

wit

h im

prov

ed c

lini

cal

outc

omes

.

n =

107

Chi

ldre

n w

ith

AR

DS

Med

ian

age

(IQ

R):

5.2

y

(1.0

–10.

4 y)

Inad

equa

te v

s ad

equa

te c

alor

ic in

take

and

ou

tcom

esA

dequ

ate

calo

ries

def

ined

as ≥8

0%

Sch

ofie

ld e

quat

ion

by th

ird

day

of A

RD

SP

ICU

mor

tali

ty: 6

0.5%

vs

34.6

%; P

= .0

03PI

CU

-fre

e da

ys: 0

(0–1

5) v

s 0

(0–1

7);P

= .6

87V

enti

lato

r-fr

ee d

ays:

0 (

0–4)

vs

3 (0

–12)

; P

= .0

68M

ulti

ple

orga

n dy

sfun

ctio

n: 7

2.5%

vs

53.8

%; P

= .0

93

Stu

dy s

ugge

sts

that

inad

equa

te

ener

gy in

take

is a

ssoc

iate

d w

ith

poor

er c

lini

cal o

utco

mes

.L

imit

atio

ns: o

utco

mes

bas

ed o

n es

tim

ated

ene

rgy

requ

irem

ents

Dok

ken

et a

l21O

bser

vati

onal

co

hort

wit

h re

peat

ed

mea

sure

s;

sing

le c

ente

r

To

desc

ribe

the

agre

emen

t of

the

deli

vere

d en

ergy

wit

h M

RE

E

and

to e

xplo

re th

e ro

le o

f R

Q in

th

e de

live

ry o

f nu

trit

ion

supp

ort

n =

30

Mec

hani

call

y ve

ntil

ated

chi

ldre

nM

edia

n ag

e (r

ange

):

15.5

mo

(3 m

o to

14

y)

104

IC m

easu

rem

ents

Und

erfe

edin

g: 2

2 d

(21.

2%)

Ade

quat

e fe

edin

g: 1

9 d

(18.

3%)

Ove

rfee

ding

: 63

d (6

0.5%

)R

Q <

0.85

: sen

siti

vity

27%

, spe

cifi

city

87%

fo

r un

derf

eedi

ngR

Q >

1.0:

sen

siti

vity

21%

, spe

cifi

city

98%

fo

r ov

erfe

edin

gS

igni

fica

nt v

aria

bili

ty in

MR

EE

am

ong

pati

ents

: med

ian,

37.

2 kc

al/k

g/d

(ran

ge,

16.8

–66.

4)S

mal

l var

iabi

lity

in M

RE

E w

ithi

n pa

tien

ts

The

stu

dy d

escr

ibes

the

vari

abil

ity

in m

etab

olic

sta

te

and

inab

ilit

y of

RQ

to d

etec

t un

der/

over

feed

ing.

Lim

itat

ions

: sm

all s

ampl

e si

ze;

hete

roge

neou

s sa

mpl

e fo

r ag

e, w

eigh

t, an

d di

agno

sis;

IC

mea

sure

men

ts p

erfo

rmed

at

dif

fere

nt ti

mes

dur

ing

the

illn

ess

cour

se; a

nd n

o ou

tcom

es r

epor

ted.

Mta

weh

et a

l24P

rosp

ecti

ve

coho

rt; s

ingl

e ce

nter

To

com

pare

MR

EE

to e

stim

ated

B

MR

(H

arri

s-B

ened

ict a

nd

Sch

ofie

ld e

quat

ions

)

n =

13

Mec

hani

cally

ve

ntila

ted

child

ren

with

sev

ere

trau

mat

ic

brai

n in

jury

(Gla

sgow

C

oma

Scal

e, <

9)M

ean

age

(SD

): 9

.8

y (1

.4)

32 I

C m

easu

rem

ents

MR

EE

vs

Har

ris-

Ben

edic

t: 5

of

32 I

C

mea

sure

men

ts g

reat

er th

an e

stim

atio

nM

RE

E: 7

0.2%

± 3

.8%

of

Har

ris-

Ben

edic

tM

RE

E v

s S

chof

ield

: 3 o

f 32

IC

m

easu

rem

ents

gre

ater

than

est

imat

ion

MR

EE

: 69%

± 4

.5%

of

Sch

ofie

ld

The

stu

dy d

emon

stra

tes

a pr

eval

ence

of

hypo

met

abol

ism

in

cri

tica

lly

ill c

hild

ren

wit

h se

vere

trau

mat

ic b

rain

inju

ry.

Lim

itat

ions

: sm

all s

ampl

e si

ze;

ener

gy in

take

not

rep

orte

d; a

nd

no o

utco

mes

rep

orte

d (con

tinu

ed)

11

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

im(s

)P

opul

atio

n (n

),

Eli

gibi

lity

Res

ults

/Out

com

eC

omm

ents

Mey

er e

t al32

Pro

spec

tive

, ob

serv

atio

nal

coho

rt;

mul

tice

nter

3 P

ICU

s

To

deve

lop

equa

tion

s to

est

imat

e en

ergy

req

uire

men

ts a

nd to

co

mpa

re 3

new

equ

atio

ns w

ith

MR

EE

and

cur

rent

equ

atio

ns

used

to e

stim

ate

rest

ing

ener

gy

expe

ndit

ure

(Sch

ofie

ld, F

AO

/W

HO

/UN

U, W

hite

)

n =

175

Mec

hani

call

y ve

ntil

ated

chi

ldre

nM

edia

n ag

e (r

ange

):

54 m

o (1

–91

mo)

369

IC m

easu

rem

ents

3 eq

uati

ons

deve

lope

d, R

2 >0.

8 fo

r ea

ch

equa

tion

Inot

rope

s, n

euro

mus

cula

r bl

ocka

de,

tem

pera

ture

, C-r

eact

ive

prot

ein,

and

org

an

dysf

unct

ion

scor

es d

id n

ot im

pact

MR

EE

3 ne

w e

quat

ions

vs

curr

ent e

quat

ions

vs

MR

EE

(n

= 3

0): 2

5% o

f es

tim

ates

, in

clud

ing

3 ne

w e

quat

ions

, wit

hin

10%

of

MR

EE

; 75%

of

esti

mat

ions

, inc

ludi

ng

3 ne

w e

quat

ions

, var

ied

26%

–29%

fro

m

MR

EE

Whi

te: d

iffe

red

up to

82%

fro

m

MR

EE

The

res

earc

h de

mon

stra

tes

that

ne

w a

nd e

xist

ing

equa

tion

s ar

e no

t acc

urat

e w

ithi

n 10

%

of M

RE

E in

a m

ajor

ity

of

crit

ical

ly il

l chi

ldre

n.L

imit

atio

ns: l

arge

r sa

mpl

e si

ze

nece

ssar

y to

dev

elop

and

test

ne

w e

quat

ions

; did

not

incl

ude

all a

ges;

con

stra

ints

of

MR

EE

(i

e, e

xclu

sion

of

pati

ents

who

ca

nnot

hav

e M

RE

E m

easu

red)

, an

d no

out

com

es r

epor

ted

Meh

ta e

t al8

Pro

spec

tive

, co

hort

wit

h co

nsec

utiv

e pa

tien

ts

enro

lled

; m

ulti

cent

er31

PIC

Us

in 8

co

untr

ies

To

exam

ine

vari

able

s as

soci

ated

w

ith

achi

evin

g op

tim

al E

N,

expl

ore

rela

tion

ship

bet

wee

n en

ergy

inta

ke a

dequ

acy

and

clin

ical

out

com

es; p

rim

ary

outc

ome:

60-

d m

orta

lity

n =

500

Chi

ldre

n re

quir

ing

mec

hani

cal

vent

ilat

ion

for

>48

hM

ean

age

(SD

): 4

.5 y

(5

.1 y

)

Mor

tali

ty lo

wer

wit

h en

ergy

inta

ke 3

3.3%

–66

.6%

vs

<33

.3%

pre

scri

bed

goal

(O

R,

0.27

[95

% C

I, 0

.11–

0.67

]), w

ith

>66

.7%

vs

<33

.3%

(O

R, 0

.14

[95%

CI,

0.0

3–0.

61])

; P =

.002

Stu

dy s

ugge

sts

that

ade

quat

e en

ergy

inta

ke is

ass

ocia

ted

wit

h lo

wer

mor

tali

ty.

Lim

itat

ions

: lim

ited

use

of

indi

rect

cal

orim

etry

and

re

lian

ce o

n eq

uati

ons

to

esti

mat

e en

ergy

req

uire

men

tsS

ever

ity

of il

lnes

s sc

ores

m

issi

ng in

31%

—al

thou

gh a

ll

pati

ents

wer

e m

echa

nica

lly

vent

ilat

ed f

or >

48

h

Meh

ta e

t al22

Pro

spec

tive

co

hort

; sin

gle

cent

er

To

exam

ine

the

role

of

IC

in d

etec

ting

the

adeq

uacy

of

ene

rgy

inta

ke a

nd th

e ri

sk o

f cu

mul

ativ

e en

ergy

im

bala

nce

in a

sub

grou

p of

cr

itic

ally

ill c

hild

ren

wit

h su

spec

ted

alte

rati

ons

in e

nerg

y ex

pend

itur

e

n =

33

Chi

ldre

n in

the

PIC

UM

edia

n ag

e (r

ange

): 2

y

(0.1

–28

y)

Hig

h in

cide

nce

(72%

) of

alt

erat

ions

in

ener

gy e

xpen

ditu

reP

redo

min

ance

of

hypo

met

abol

ism

in th

ose

adm

itte

d to

the

med

ical

ser

vice

PIC

U le

ngth

of

stay

was

sig

nifi

cant

ly

high

er f

or p

atie

nts

wit

h hy

perm

etab

olis

m

(med

ian,

142

d; P

= .0

4) v

s no

rmal

(m

edia

n, 3

3 d)

or

hypo

met

abol

ism

(m

edia

n, 5

0 d)

The

stu

dy d

escr

ibed

the

risk

of

cum

ulat

ive

ener

gy im

bala

nce

wit

h eq

uati

ons

to e

stim

ate

ener

gy r

equi

rem

ents

and

pr

opos

ed th

e co

ncep

t of

targ

eted

IC

wit

h se

lect

ion

crit

eria

for

pat

ient

s at

ris

k of

al

tere

d m

etab

olis

m.

Lim

itat

ions

: sm

all s

ampl

e si

ze.

Not

e: m

ajor

ity

wer

e lo

ng-s

tay

pati

ents

.

(con

tinu

ed)

Tab

le 4

. (c

onti

nu

ed)

12

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

im(s

)P

opul

atio

n (n

),

Eli

gibi

lity

Res

ults

/Out

com

eC

omm

ents

Tei

xeir

a-C

intr

a et

al23

Pro

spec

tive

, ob

serv

atio

nal

coho

rt; s

ingl

e ce

nter

To

esta

blis

h th

e am

ount

of

prot

ein

and

ener

gy in

take

ne

eded

to m

inim

ize

cata

boli

sm

foll

owin

g ca

rdia

c su

rger

y

n =

11

Mec

hani

call

y ve

ntil

ated

infa

nts

in

the

PIC

U f

ollo

win

g ca

rdia

c su

rger

yM

edia

n ag

e (r

ange

):

54 d

(6–

163

d)

Pos

itiv

e vs

neg

ativ

e pr

otei

n ba

lanc

e w

as

asso

ciat

ed w

ith

incr

ease

d en

ergy

inta

ke

(54

vs 1

7 kc

al/k

g/d)

, P <

.000

1; p

osit

ive

corr

elat

ion

betw

een

prot

ein

bala

nce

and

ener

gy in

take

(r

= 0

.77;

P <

.000

1)

The

stu

dy s

ugge

sts

a th

resh

old

for

ener

gy in

take

and

a

rela

tion

ship

bet

wee

n en

ergy

an

d pr

otei

n in

take

to p

osit

ivel

y im

pact

pro

tein

bal

ance

.L

imit

atio

ns: s

mal

l sam

ple

size

an

d 3

subj

ects

wer

e <

30 d

old

Uri

nary

ure

a ni

trog

en e

xcre

tion

m

ay u

nder

esti

mat

e to

tal

nitr

ogen

exc

reti

on.

Meh

ta e

t al41

Pro

spec

tive

co

hort

; sin

gle

cent

er

To

exam

ine

if a

mod

el f

or

targ

etin

g IC

mea

sure

men

ts to

a

sele

ct g

roup

of

PIC

U p

atie

nts

by a

ded

icat

ed n

utri

tion

team

co

uld

prev

ent u

nint

ende

d ex

cess

es o

r de

fici

ts in

ene

rgy

bala

nce

n =

14

Cri

tica

lly

ill c

hild

ren

50%

pos

tope

rati

veM

ean

age

(ran

ge):

11

.2 y

(1.

6 m

o to

32

y)

Alt

ered

met

abol

ism

: 13

of 1

4 su

bjec

ts, 1

5 of

16

mea

sure

men

ts (

94%

)A

vera

ge d

aily

ene

rgy

bala

nce:

200

kca

l/d

(ran

ge, −

518

to 8

59 k

cal/

d)P

oor

agre

emen

t bet

wee

n M

RE

E a

nd

esti

mat

ed e

nerg

y ex

pend

itur

e: m

ean

bias

72

.3 ±

446

kca

l/d

(lim

its

of a

gree

men

t:

801.

9 to

+94

6.5

kcal

/d)

No

corr

elat

ion

betw

een

subj

ects

’ m

etab

olic

st

atus

and

sev

erit

y of

illn

ess

scor

es, i

niti

al

diag

nosi

s, a

ge, a

nd b

ody

mas

s in

dex

Ene

rgy

inta

ke: 1

32%

± 6

8% o

f M

RE

EM

ean

RQ

: 0.9

4N

o co

rrel

atio

n be

twee

n R

Q a

nd e

nerg

y ba

lanc

e

The

stu

dy s

how

s a

disp

arit

y be

twee

n es

tim

ated

ene

rgy

expe

ndit

ure,

ene

rgy

inta

ke,

and

MR

EE

. The

met

abol

ic

stat

e di

d no

t cor

rela

te w

ith

stan

dard

cli

nica

l cha

ract

eris

tics

an

d th

eref

ore

coul

d no

t be

accu

rate

ly p

redi

cted

.L

imit

atio

ns: s

mal

l sam

ple

size

.

Sy

et a

l25P

rosp

ecti

ve

coho

rt; s

ingl

e ce

nter

To

esti

mat

e M

RE

E w

ith

bica

rbon

ate

kine

tics

and

to

com

pare

bic

arbo

nate

kin

etic

s w

ith

MR

EE

est

imat

ed v

ia F

AO

/W

HO

/UN

U a

nd S

chof

ield

eq

uati

ons

in 3

gro

ups:

1

rece

ivin

g P

N, 1

rec

eivi

ng

EN

, and

1 r

ecei

ving

glu

cose

-el

ectr

olyt

es

n =

31

Cri

tica

lly

ill c

hild

ren

Mea

n ag

e (S

D),

PN

gr

oup

(n =

12)

: 7.8

y

(7.4

y)

EN

gro

up (

n =

7):

3.3

y

(4.1

y)

Glu

cose

-ele

ctro

lyte

s gr

oup

(n =

12)

: 6.3

y

(5.0

y)

PN

gro

upF

AO

/WH

O/U

NU

200

1: 1

55%

of

bica

rbon

ate

kine

tics

, 195

% o

f S

chof

ield

Bic

arbo

nate

kin

etic

s: 1

20%

of

Sch

ofie

ldE

nter

al n

utri

tion

gro

up a

nd g

luco

se-

elec

trol

ytes

gro

upF

AO

/WH

O/U

NU

200

1: 1

42%

of

bica

rbon

ate

kine

tics

, 167

% o

f S

chof

ield

Bic

arbo

nate

kin

etic

s: n

ot s

igni

fica

ntly

di

ffer

ent f

rom

Sch

ofie

ld

The

stu

dy d

emon

stra

tes

equa

tion

s, e

spec

iall

y th

ose

deve

lope

d fo

r gr

owth

in

heal

thy

infa

nts

and

chil

dren

, ar

e no

t acc

urat

e w

ithi

n 10

%

of M

RE

E in

a m

ajor

ity

of

crit

ical

ly il

l chi

ldre

nL

imit

atio

ns: s

mal

l sam

ple

size

an

d no

out

com

es r

epor

ted

Zap

pite

lli

et a

l26R

etro

spec

tive

co

hort

; sin

gle

cent

er

To

desc

ribe

pro

tein

and

ene

rgy

inta

ke d

urin

g C

RR

Tn

= 1

95C

hild

ren

requ

irin

g C

RR

TM

ean

age

(SD

): 8

.8 y

(6

.8 y

)

Max

imum

pro

tein

: 2 ±

1.5

g/k

g/d

Max

imum

ene

rgy:

48.

2 ±

31.5

kca

l/kg

/dP

redi

ctor

s of

hig

her

ener

gy a

nd p

rote

in

inta

ke: y

oung

er a

ge, h

ighe

r pr

otei

n or

ca

lori

e in

take

at C

RR

T in

itia

tion

, lon

ger

CR

RT

dur

atio

n

Des

crip

tive

rep

ort o

f en

ergy

and

pr

otei

n in

take

dur

ing

CR

RT

Lar

ge v

aria

tion

bet

wee

n ce

nter

s in

pro

tein

and

ene

rgy

deli

very

Lim

itat

ions

: no

outc

omes

re

port

ed

(con

tinu

ed)

Tab

le 4

. (c

onti

nu

ed)

13

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

im(s

)P

opul

atio

n (n

),

Eli

gibi

lity

Res

ults

/Out

com

eC

omm

ents

Fra

mso

n et

al28

Pro

spec

tive

co

hort

wit

h re

peat

ed

mea

sure

s;

sing

le c

ente

r

To

desc

ribe

the

vari

atio

n in

en

ergy

exp

endi

ture

dur

ing

PIC

U c

ours

e an

d ev

alua

te th

e ac

cura

cy o

f W

hite

equ

atio

n fo

r es

tim

atin

g en

ergy

exp

endi

ture

n =

44

Chi

ldre

n in

the

PIC

UM

ean

age

(SD

): 5

.16

y (5

.87

y)

20%

of

MR

EE

mea

sure

men

ts w

ere

>11

0%

esti

mat

ed, 3

2% w

ere

<90

% e

stim

ated

, 45

% w

ere

90%

–110

% e

stim

ated

Mea

n M

RE

E d

id n

ot v

ary

in th

e sa

me

pati

ent o

ver

tim

eT

he W

hite

equ

atio

n es

tim

ate

was

w

ithi

n 10

% o

f M

RE

E f

or o

nly

30%

of

mea

sure

men

ts

The

stu

dy d

emon

stra

tes

the

vari

abil

ity

in m

etab

olic

st

ate

and

the

inac

cura

cy o

f es

tim

ated

ene

rgy

expe

ndit

ure

by W

hite

equ

atio

n in

a

maj

orit

y of

this

coh

ort.

Lim

itat

ions

: sm

all s

ampl

e si

ze

and

no o

utco

mes

rep

orte

d.

van

der

Kui

p et

al34

Pro

spec

tive

co

hort

; sin

gle

cent

er

To

obta

in M

RE

E (

via

IC),

T

EE

(vi

a do

ubly

labe

led

wat

er te

chni

que)

, PA

L d

urin

g th

e w

eek

foll

owin

g P

ICU

ad

mis

sion

n =

20

Chi

ldre

n w

ith

seve

re

seps

is o

r se

ptic

sh

ock

or f

ollo

win

g m

ajor

abd

omin

al,

thor

acic

, or

trau

ma

surg

ery

Mea

n ag

e (S

D):

5 y

(6

y)

TE

E w

as a

ppro

xim

atel

y 12

2% o

f M

RE

EN

o di

ffer

ence

s in

TE

E, M

RE

E, a

ctiv

ity-

rela

ted

ener

gy e

xpen

ditu

re, P

AL

bet

wee

n se

psis

and

sur

gery

gro

ups

Chi

ldre

n w

ith

seps

is a

nd s

urge

ry

have

no

diff

eren

ce in

TE

E o

r M

RE

E, a

nd p

hysi

cal a

ctiv

ity

cont

ribu

tes

to T

EE

.L

imit

atio

ns: s

mal

l sam

ple

size

; pot

enti

al f

or f

luid

sta

tus

chan

ges,

esp

ecia

lly

in s

epti

c sh

ock

pati

ents

, aff

ecti

ng T

EE

as

sess

men

t; a

nd n

o ou

tcom

es

repo

rted

Hav

alad

et a

l30R

etro

spec

tive

co

hort

; sin

gle

cent

er

To

com

pare

MR

EE

wit

h B

MR

est

imat

ed b

y H

arri

s-B

ened

ict,

FA

O/W

HO

/UN

U,

Sch

ofie

ld, a

nd W

hite

equ

atio

ns

in m

echa

nica

lly

vent

ilat

ed

chil

dren

wit

h se

vere

trau

mat

ic

brai

n in

jury

(G

lasg

ow C

oma

Sca

le, ≤

8)

n =

30

Med

ian

age

(ran

ge):

10

.9 y

(6.

1–16

.2 y

)

40%

of

esti

mat

es w

ithi

n 10

% o

f M

RE

E43

% p

atie

nts

had

MR

EE

gre

ater

than

the

esti

mat

eB

land

-Alt

man

: poo

r ag

reem

ent b

etw

een

MR

EE

and

all

4 e

quat

ions

No

corr

elat

ion

betw

een

MR

EE

and

sev

erit

y of

illn

ess

scor

es, w

eigh

t-fo

r-ag

e z

scor

e

The

stu

dy s

how

s a

prev

alen

ce

of h

ypom

etab

olis

m a

nd

hype

rmet

abol

ism

in c

riti

call

y il

l chi

ldre

n w

ith

seve

re

trau

mat

ic b

rain

inju

ryL

imit

atio

ns: s

mal

l sam

ple

size

; M

RE

E o

btai

ned

once

in th

e fi

rst 2

4 h

of a

dmis

sion

; ene

rgy

inta

ke n

ot r

epor

ted;

and

act

ual

MR

EE

val

ues

not r

epor

ted.

Har

dy e

t al29

Pro

spec

tive

co

hort

; sin

gle

cent

er

To

com

pare

MR

EE

wit

h B

MR

es

tim

ated

by

vari

ous

met

hods

n =

52

35 v

enti

late

d17

spo

ntan

eous

ly

brea

thin

gM

edia

n ag

e (r

ange

):

4.5

y (0

–22

y)

Dif

fere

nce

betw

een

all e

quat

ions

and

in

divi

dual

IC

mea

sure

men

ts w

as la

rge

and

high

ly v

aria

ble.

4%–1

0% o

f es

tim

ates

wer

e w

ithi

n 10

% o

f M

RE

ES

tron

g re

lati

onsh

ip b

etw

een

seve

rity

of

illn

ess

scor

es a

nd M

RE

E: r

= 0

.72,

P <

.01

Equ

atio

ns b

oth

over

esti

mat

ed a

nd

unde

rest

imat

ed M

RE

E

The

stu

dy d

emon

stra

tes

the

vari

abil

ity

in m

etab

olic

sta

te

and

the

inac

cura

cy o

f se

vera

l eq

uati

ons

to e

stim

ate

ener

gy

expe

ndit

ure.

Lim

itat

ions

: sin

gle

IC

mea

sure

men

t dur

ing

the

PIC

U

cour

se; n

o ou

tcom

es r

epor

ted

AR

DS

, acu

te r

espi

rato

ry d

istr

ess

synd

rom

e; B

MR

, bas

al m

etab

olic

rat

e; C

RR

T, c

onti

nuou

s re

nal r

epla

cem

ent t

hera

py; D

RI,

Die

tary

Ref

eren

ce I

ntak

e; E

N, e

nter

al n

utri

tion

; FA

O/W

HO

/UN

U, F

ood

Agr

icul

ture

Org

aniz

atio

n / W

orld

Hea

lth

Org

aniz

atio

n / U

nite

d N

atio

ns U

nive

rsit

y; I

C, i

ndir

ect c

alor

imet

ry; I

QR

, int

erqu

arti

le r

ange

; MR

EE

, mea

sure

d re

stin

g en

ergy

exp

endi

ture

; OR

, odd

s ra

tio;

PA

L,

phys

ical

act

ivit

y le

vel;

PIC

U, p

edia

tric

inte

nsiv

e ca

re u

nit;

PN

, par

ente

ral n

utri

tion

; RQ

, res

pira

tory

quo

tien

t; T

EE

, tot

al e

nerg

y ex

pend

itur

e.

Tab

le 4

. (c

onti

nu

ed)


candidates for targeted MREE with IC, especially if this resource is limited (Appendix).31

If IC is not feasible, the Schofield weight-height or weight equations or the WHO equations may be used to estimate energy expenditure.37-39 However, stress factors must be used selectively with caution, as their routine use might result in unintended overfeeding. In recent studies, hypometabolism has been demonstrated in patients, after major cardiac surgery, and following hematopoietic stem cell transplantation.40,41 When an equation to estimate energy requirements is used, it is essential to vigilantly monitor for potential signs of overfeed-ing (hyperglycemia, hypertriglyceridemia, increased CO2 pro-duction, increased arm circumference, and rapid or excessive weight gain) and underfeeding (weight loss, decreased arm circumference, malnutrition, prolonged dependency on mechanical ventilation, and increased length of PICU stay). In particular, equations such as the Harris-Benedict and the RDAs developed for healthy adults and growing children, respec-tively, overpredict energy requirements and should not be used to determine energy requirements in critically ill children. Because IC is not widely available clinically and predictive equations are consistently inaccurate, innovative efforts must focus on discovering more accessible surrogates of MREE. A simplified equation based on measured volumetric CO2 (VCO2) was recently developed among children receiving mechanical ventilation and found to be more accurate than equation-estimated energy expenditure.42,43 The increased use of devices that provide bedside VCO2 measurement in the PICU may allow this equation to replace the Schofield or WHO equations for determination of energy requirement in patients receiving mechanical ventilation.

Observational data suggest a positive association between adequacy of energy intake and improved outcomes in the PICU population.8,36,44 Intake of > two-thirds of estimated energy goal in a large multicenter prospective cohort and >80% of estimated energy goal in a smaller single-center ret-rospective cohort was significantly associated with reduced mortality in critically ill children receiving mechanical venti-lation.8,44 Higher energy intake of 54–58 kcal/kg/d is posi-tively correlated with achieving protein balance and anabolism.36,45 Based on hypometabolic states described in a variety of pediatric illnesses and reduced mortality associated with intake of > two-thirds of energy goal, achievement of 100% of estimated energy requirement may not be necessary in all patients.8,24,25,40,41

Future direction. Future studies must examine the optimal energy dose that is associated with improved nutrition and clinical outcomes in critically ill children. The impact of route of nutrition delivery must be examined when discussing this dose-outcome relationship.

Question 3A: What is the minimum recommended protein requirement for critically ill children?

Recommendation 3A. On the basis of evidence from RCTs and support from observational cohort studies, we recommend

a minimum protein intake of 1.5 g/kg/d (see Table 5). Protein intake higher than this threshold has been shown to prevent cumulative negative protein balance in RCTs. In critically ill infants and young children, the optimal protein intake required to attain a positive protein balance may be much higher than this minimum threshold. Negative protein balance may result in loss of lean muscle mass, which has been associated with poor outcomes in critically ill children. Based on a large observa-tional study, higher protein intake may be associated with lower 60-day mortality in children receiving mechanical ventilation.Quality of evidence. Moderate.GRADE recommendation. Strong.

Question 3B: What is the optimal protein delivery strategy in the PICU?

Recommendation 3B. On the basis of results of randomized trials, we suggest provision of protein early in the course of critical illness to attain protein delivery goals and promote positive nitrogen balance. Delivery of a higher proportion of the protein goal has been associated with positive clinical out-comes in observational studies.Quality of evidence. Moderate.GRADE recommendation. Weak.

Question 3C: How should protein delivery goals be deter-mined in critically ill children?

Recommendation 3C. The optimal protein dose associated with improved clinical outcomes is not known. We do not rec-ommend the use of RDA values to guide protein prescription in critically ill children. These values were developed for healthy children and often underestimate the protein needs during criti-cal illness.Quality of evidence. Moderate.GRADE recommendation. Strong.Rationale. Randomized clinical trials of protein supplemen-tation have included small sample sizes, heterogeneous patient populations, use of enteral and parenteral (and com-bined) routes, and varied protein doses (0.7–5 g/kg/d) in the experimental group. Higher protein doses were associated with positive nitrogen balance, a surrogate for protein bal-ance. These studies evaluated protein turnover and balance by stable isotope-labeled amino acid methods or with urinary urea nitrogen to obtain nitrogen balance.46-53 Variation in the methods used to assess protein balance further limits the interpretation of absolute values. These studies indicate an association between higher protein dose and positive protein balance. In a systematic review of studies of patients receiv-ing mechanical ventilation in the PICU, a minimum protein intake of 1.5 g/kg/d and a minimum energy intake of 54 kcal/kg/d were associated with achievement of positive nitrogen balance.45 In a cohort study of 76 children receiving mechani-cal ventilation, a minimum daily threshold delivery of 1.5 g/kg protein and 58 kcal/kg energy was required to achieve a positive nitrogen and energy balance.36 In a recent large pro-spective multicenter (n = 59) observational study of 1245

15

Tab

le 5

. R

ecom

men

ded

Pro

tein

Req

uire

men

t for

Cri

tica

lly

Ill C

hild

ren.

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

ims

Pop

ulat

ion

(n),

E

ligi

bili

tyIn

terv

enti

onR

esul

ts/O

utco

me

Com

men

ts

Ran

dom

ized

con

trol

led

tri

als

Geu

kers

et a

l49R

CT

(do

uble

bl

ind)

; sin

gle

cent

er

To

inve

stig

ate

the

shor

t-te

rm (

<48

h)

effe

cts

of h

igh

prot

ein

diet

ary

inta

ke o

n w

hole

bod

y pr

otei

n sy

nthe

sis

and

bala

nce,

who

le b

ody

vali

ne k

inet

ics,

and

rat

e of

alb

umin

syn

thes

is o

n en

docr

ine

resp

onse

n =

28

(n =

20

anal

yzed

)P

ostc

ardi

ac s

urge

ryM

edia

n ag

e (r

ange

):

expe

rim

enta

l gro

up,

7 m

o (3

–14

mo)

; co

ntro

l gro

up, 1

2 m

o (3

–15

mo)

EN

init

iate

d w

ithi

n 24

h

foll

owin

g P

ICU

adm

issi

on.

Sch

ofie

ld e

quat

ion

used

to

dete

rmin

e en

ergy

nee

dsE

xper

imen

tal g

roup

: hig

h pr

otei

n, 5

g/k

g/d

Con

trol

gro

up: n

orm

al p

rote

in,

2 g/

kg/d

Exp

erim

enta

l vs

cont

rol g

roup

Val

ine

synt

hesi

s ra

te: 2

.73

vs 2

.26

μmol

/kg/

min

Net

val

ine

bala

nce:

0.5

4 vs

0.2

4 μm

ol/

kg/m

inN

o di

ffer

ence

s be

twee

n gr

oups

re

gard

ing

card

iac

intr

aope

rati

ve ti

mes

Una

ble

to d

emon

stra

te

impr

ovem

ent i

n pr

otei

n ba

lanc

e (w

ith

stab

le

isot

opes

and

val

ine

as a

n in

dica

tor)

or

a di

ffer

ence

be

twee

n th

e gr

oups

in

frac

tion

al s

ynth

esis

rat

e.L

imit

atio

ns: n

ot p

ower

ed to

te

st th

e pr

imar

y ou

tcom

e.

1 de B

etue

et a

l50

and

2 de B

etue

et

al48

RC

T; 2

cen

ters

1 Hyp

othe

size

d th

at p

rote

in-

enri

ched

for

mul

a w

ould

st

imul

ate

amin

o ac

id

(arg

inin

e) a

ppea

ranc

e an

d ni

tric

oxi

de s

ynth

esis

.2 T

o st

udy

the

effi

cacy

of

incr

ease

d pr

otei

n an

d en

ergy

inta

ke to

pro

mot

e pr

otei

n sy

nthe

sis

n =

18

Infa

nts

wit

h R

SV

br

onch

ioli

tis

requ

irin

g m

echa

nica

l ve

ntil

atio

nM

ean

age

(SD

):

expe

rim

enta

l, 2.

7 m

o (1

.4 m

o);

cont

rol,

2.9

mo

(1.8

m

o)

EN

sta

rted

wit

hin

24 h

of

PIC

U

adm

issi

on; a

dvan

ced

by 2

5%

of ta

rget

vol

ume

ever

y 12

hE

xper

imen

tal g

roup

: Pro

tein

-en

ergy

–enr

iche

d fo

rmul

a:

2.6

g pr

otei

n/10

0 m

L, 1

00

kcal

/100

mL

Con

trol

gro

up: S

tand

ard

form

ula:

1.4

g p

rote

in/1

00

mL

, 67

kcal

/100

mL

Exp

erim

enta

l vs

cont

rol g

roup

Day

5 n

utri

tion

inta

ke: 1

19 ±

25

vs 8

4 ±

15 k

cal/

kg/d

; 3.1

± 0

.3 g

/kg/

d vs

1.7

±

0.2

g/kg

/d p

rote

inW

hole

bod

y pr

otei

n ba

lanc

e: 0

.73

± 0.

5 vs

0.0

2 ±

0.6

g/kg

/h (

P =

.026

)P

rote

in s

ynth

esis

: 9.6

± 4

.4 v

s 5.

2 ±

2.3

g/kg

/d (

P =

.019

)P

rote

in b

reak

dow

n: 8

.9 ±

4.3

vs

5.2

± 2.

6 g/

kg/d

(P

= .0

46)

Nit

roge

n ba

lanc

e: 2

74 ±

127

vs

137

± 53

mg/

kg/d

(P

< .0

5)N

o si

gnif

ican

t dif

fere

nces

in d

urat

ion

of m

echa

nica

l ven

tila

tion

or

PIC

U

leng

th o

f st

ay; n

o in

tole

ranc

e or

co

mpl

icat

ions

fro

m th

e fe

edin

g re

gim

ens

Bot

h st

udie

s de

mon

stra

ted

that

pro

tein

ene

rgy–

enri

ched

for

mul

a im

prov

ed

prot

ein

synt

hesi

s, p

rote

in

met

abol

ism

, pro

tein

an

abol

ism

, and

nit

roge

n ba

lanc

e vs

sta

ndar

d fo

rmul

a.L

imit

atio

ns: c

oint

erve

ntio

ns

wer

e no

t des

crib

ed a

nd

smal

l sam

ple

size

Ver

brug

gen

et a

l52R

CT

(cr

osso

ver

tria

l); s

ingl

e ce

nter

To

inve

stig

ate

the

effe

cts

of in

suli

n in

fusi

on a

nd

incr

ease

d P

N A

A in

take

s on

who

le b

ody

prot

ein

bala

nce,

glu

cose

kin

etic

s,

and

lipo

lysi

s

n =

9C

riti

call

y il

l, in

suli

n-re

sist

ant,

sept

ic a

dole

scen

ts

rece

ivin

g P

NM

ean

age

(SD

): 1

5.0

y (1

.2 y

)

Exp

erim

enta

l gro

up: h

igh

(3.0

g/

kg/d

) P

N A

AC

ontr

ol g

roup

: sta

ndar

d (1

.5 g

/kg

/d)

PN

AA

Pri

med

sta

ble

isot

ope

trac

er in

fusi

on w

ith

hype

rins

ulin

emic

eug

lyce

mic

cl

amp

Hig

h A

A in

take

impr

oved

pro

tein

ba

lanc

e (P

< .0

5); i

nsul

in d

id n

ot h

ave

an a

ddit

ive

effe

ctA

t hig

h A

A in

take

, end

ogen

ous

gluc

ose

prod

ucti

on w

as n

ot s

uppr

esse

d by

in

suli

n an

d li

poly

sis

rate

s in

crea

sed

Sta

ndar

d P

N A

A w

as

insu

ffic

ient

, and

hig

h A

A

was

nee

ded

to s

uppo

rt

posi

tive

pro

tein

bal

ance

Lim

itat

ions

: no

disc

ussi

on o

f im

pact

of

find

ings

on

PIC

U

mor

tali

ty o

r le

ngth

of

stay

an

d sm

all s

ampl

e si

ze

(co

ntin

ued)

16

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

ims

Pop

ulat

ion

(n),

E

ligi

bili

tyIn

terv

enti

onR

esul

ts/O

utco

me

Com

men

ts

Bot

ran

et a

l46R

CT

; sin

gle

cent

erT

o de

term

ine

if in

crea

sed

prot

ein

deli

very

impr

oves

pr

otei

n m

etab

olis

m w

ith

mea

sure

men

ts o

f se

rum

an

d ur

ine

mar

kers

and

to

eva

luat

e sa

fety

and

ef

fica

cy o

f in

crea

sed

prot

ein

dose

n =

51

chil

dren

(41

an

alyz

ed)

All

req

uire

d m

echa

nica

l ve

ntil

atio

n >

72 h

Med

ian

age

(IQ

R):

7

mo

(3–1

3 m

o)

Uni

t fee

ding

pro

toco

l:

Con

tinu

ous

EN

sta

rted

wit

hin

24 h

of

PIC

U a

dmis

sion

to

reac

h ap

prox

imat

ely

60 k

cal/

kg/ d

wit

hin

firs

t 24

hIC

, nit

roge

n ba

lanc

e, s

erum

ur

ea, s

erum

alb

umin

leve

l, to

tal p

rote

ins,

pre

albu

min

, tr

ansf

erri

n, r

etin

ol b

indi

ngS

tudy

mea

sure

men

t tim

es:

base

line

, 24

h, 7

2 h,

5 d

Con

trol

die

t: b

reas

t mil

k (p

rote

in, 1

.1 g

/100

mL

) or

co

w m

ilk–

base

d fo

rmul

a (p

rote

in, 1

.6 g

/100

mL

), o

r pe

diat

ric

form

ula

(pro

tein

, 2.6

g/

100

mL

)E

xper

imen

tal d

iet:

sam

e as

co

ntro

l wit

h su

pple

men

tati

on

of p

rote

in, 1

.1 g

/100

mL

Inte

rven

tion

die

t wel

l tol

erat

edN

o di

ffer

ence

in I

C m

easu

rem

ents

be

twee

n gr

oups

Exp

erim

enta

l vs

cont

rol n

utri

tion

inta

ke

Mea

n 71

.9 v

s 65

.9 k

cal/

kg/d

(no

t si

gnif

ican

t)

Mea

n 3.

1 vs

1.7

g/k

g/d

(P =

.004

) pr

otei

nP

osit

ive

nitr

ogen

bal

ance

ach

ieve

d by

da

y 5

in e

xper

imen

tal g

roup

Pro

tein

sup

plem

enta

tion

re

sult

ed in

pos

itiv

e ni

trog

en

bala

nce.

Lim

itat

ions

: 10

pati

ents

did

no

t com

plet

e th

e st

udy

(6

cont

rol,

4 ex

peri

men

tal)

; no

disc

ussi

on o

n as

soci

atio

ns

wit

h m

orta

lity

, dur

atio

n of

m

echa

nica

l ven

tila

tion

, or

leng

th o

f st

ay; a

nd s

mal

l sa

mpl

e si

ze a

naly

zed

van W

aard

enbu

rg

et a

l51

RC

T (

doub

le

blin

d); 2

ce

nter

s

To

com

pare

nut

rien

t de

live

ry, e

nerg

y an

d ni

trog

en b

alan

ce, a

nd

plas

ma

amin

o ac

ids

wit

h a

prot

ein

ener

gy–e

nric

hed

form

ula

vs a

sta

ndar

d fo

rmul

a an

d al

so to

ass

ess

tole

ranc

e an

d sa

fety

of

the

prot

ein

ener

gy–e

nric

hed

form

ula

n =

20

(n =

18

for

anal

ysis

)In

fant

s w

ith

RS

V

bron

chio

liti

s re

quir

ing

mec

hani

cal

vent

ilat

ion

wit

h ex

pect

ed le

ngth

of

stay

> 9

6 h

Mea

n ag

e (S

D):

ex

peri

men

tal,

2.7

mo

(0.5

mo)

; co

ntro

l, 3.

0 m

o (0

.6

mo)

Con

tinu

ous

EN

targ

et =

130

m

L/k

g/d;

sta

rted

at 2

5% o

f ta

rget

, adv

ance

d 25

% e

very

12

hS

tudy

per

iod:

5 d

Exp

erim

enta

l gro

upP

rote

in e

nerg

y–en

rich

ed

form

ula:

100

kca

l/10

0 m

L,

2.6

g/10

0 m

LC

ontr

ol g

roup

Sta

ndar

d fo

rmul

a: 1

.4 g

pr

otei

n/10

0 m

L, 6

7 kc

al/1

00

mL

Exp

erim

enta

l vs

cont

rol g

roup

sD

ay 5

nut

riti

on in

take

: 112

± 1

3 vs

82

± 4

kcal

/kg/

d (P

< .0

1); 2

.8 ±

0.3

vs

1.5

± 0.

1 g

prot

ein/

kg/ d

(P <

.01)

Cum

ulat

ive

nitr

ogen

bal

ance

, day

s 2–

5:

866

± 11

3 vs

297

± 7

1 m

g/kg

/ d (P

<

.01)

Incr

ease

d ga

stri

c re

sidu

al v

olum

es in

pr

otei

n-en

hanc

ed f

orm

ula

grou

p

(P <

.01)

No

into

lera

nce

repo

rted

No

diff

eren

ces

betw

een

the

grou

ps in

m

echa

nica

l ven

tila

tion

dur

atio

n an

d P

ICU

leng

th o

f st

ayP

osit

ive

nitr

ogen

bal

ance

ach

ieve

d on

da

y 2

in e

xper

imen

tal g

roup

vs

up to

da

y 4

for

cont

rol g

roup

Pro

tein

ene

rgy–

enri

ched

fo

rmul

a im

prov

ed e

nerg

y an

d ni

trog

en b

alan

ceG

astr

ic r

esid

ual v

olum

es

wer

e st

atis

tica

lly

high

er

in th

e pr

otei

n en

ergy

–en

rich

ed f

orm

ula

but

clin

ical

ly in

sign

ific

ant

Lim

itat

ions

: sm

all s

ampl

e si

ze

Cha

loup

ecky

et

al47

RC

T; s

ingl

e ce

nter

To

eval

uate

the

effe

ct o

f nu

trit

ion

supp

ort o

n th

e hy

perc

atab

olic

rea

ctio

n w

ithi

n 7

d fo

llow

ing

card

iac

surg

ery

n =

37

Pos

tcar

diac

sur

gery

Mea

n ag

e (S

D):

6.7

m

o (3

.4 m

o)

EN

intr

oduc

ed d

ay 2

Exp

erim

enta

l gro

up: P

N w

ith

AA

0.8

± 0

.1 g

/kg/

dC

ontr

ol g

roup

: 10%

dex

tros

e co

ntai

ning

intr

aven

ous

flui

ds

wit

hout

AA

Mea

sure

men

ts: p

lasm

a A

A,

urin

e 3-

met

hylh

isti

dine

, ni

trog

en b

alan

ce

Exp

erim

enta

l vs

cont

rol g

roup

Nit

roge

n ba

lanc

e: −

114

± 81

vs

244

± 86

mg/

kg/d

(P

= .0

01)

Inve

rse

rati

o be

twee

n ni

trog

en b

alan

ce

and

urin

e 3-

met

hylh

isti

dine

exc

reti

on

in b

oth

grou

psN

o m

orta

lity

Gro

up r

ecei

ving

PN

wit

h A

A

supp

lem

enta

tion

had

less

ne

gati

ve n

itro

gen

bala

nce

com

pare

d w

ith

cont

rol

grou

p re

ceiv

ing

no A

AL

imit

atio

ns: s

mal

l sam

ple

size

Tab

le 5

. (c

onti

nu

ed)

(co

ntin

ued)

17

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

ims

Pop

ulat

ion

(n),

E

ligi

bili

tyIn

terv

enti

onR

esul

ts/O

utco

me

Com

men

ts

Ob

serv

atio

nal

stu

die

s

Jott

eran

d C

hapa

rro

et a

l36

Pro

spec

tive

co

hort

; sin

gle

cent

er

To

asse

ss a

mou

nt o

f pr

otei

n an

d en

ergy

nec

essa

ry

to a

chie

ve n

itro

gen

and

ener

gy b

alan

ce a

nd to

co

mpa

re p

rote

in a

nd

ener

gy r

equi

rem

ents

w

ith

the

AS

PE

N

reco

mm

enda

tion

s an

d D

RIs

n =

76

Chi

ldre

n re

quir

ing

mec

hani

cal

vent

ilat

ion ≥7

2 h

Med

ian

age

(IQ

R):

21

mo

(4–3

5 m

o)

Min

imum

1.5

g/k

g/d

prot

ein

and

58

kcal

/kg/

d re

quir

ed to

ach

ieve

nit

roge

n an

d en

ergy

bal

ance

in c

hild

ren

up to

4

y ol

d; D

RIs

und

eres

tim

ated

pro

tein

ne

eds

The

stu

dy e

stab

lish

es a

th

resh

old

for

ener

gy in

take

an

d a

rela

tion

ship

bet

wee

n en

ergy

and

pro

tein

inta

ke.

AS

PE

N g

uide

line

s w

ere

clos

e to

stu

dy r

esul

ts

(exc

ept i

n ol

der

chil

dren

, 4–

8 y)

Lim

itat

ions

: sm

all n

umbe

r of

old

er c

hild

ren

stud

ied

and

pati

ents

wit

h lo

nger

P

ICU

sta

ys h

ad m

ore

mea

sure

men

ts w

hich

may

in

flue

nce

resu

lts

Won

g et

al44

Ret

rosp

ecti

ve

coho

rt; s

ingl

e ce

nter

To

desc

ribe

nut

riti

on

supp

ort a

nd id

enti

fy

adeq

uate

am

ount

of

prot

ein

rece

ived

by

chil

dren

wit

h A

RD

S a

nd

to d

eter

min

e w

heth

er

prov

isio

n of

ade

quat

e nu

trit

ion

is a

ssoc

iate

d w

ith

decr

ease

d P

ICU

mor

tali

ty

and

impr

oved

cli

nica

l ou

tcom

es.

Ade

quat

e pr

otei

n in

take

de

fine

d as

1.5

g/k

g/d

by

thir

d da

y of

AR

DS

n =

107

Chi

ldre

n w

ith

AR

DS

Med

ian

age

(IQ

R):

5.

2 y

(1.0

–10.

4 y)

Inad

equa

te v

s ad

equa

te p

rote

in in

take

IC

U m

orta

lity

: 60.

2% v

s 14

.3%

; P

= .0

02

PIC

U-f

ree

days

: 0 (

0–15

) vs

0

(0–1

4); P

= .9

40

Ven

tila

tor-

free

day

s: 0

(0–

4) v

s 12

(3

–19)

; P =

.005

M

ulti

ple

orga

n dy

sfun

ctio

n: 7

0.7%

vs

50%

; P =

.136

Inad

equa

te p

rote

in d

eliv

ery,

Ped

iatr

ic

Inde

x of

Mor

tali

ty 2

sco

re, a

nd

oxyg

enat

ion

inde

x w

ere

inde

pend

ent

pred

icto

rs o

f in

crea

sed

PIC

U

mor

tali

ty

Ear

ly in

itia

tion

of

nutr

itio

n su

ppor

t wit

h ad

equa

te

prot

ein

was

ass

ocia

ted

wit

h im

prov

ed o

utco

mes

in

chil

dren

wit

h A

RD

SL

imit

atio

ns: n

utri

tion

sta

tus

was

not

doc

umen

ted,

and

it

s im

pact

on

outc

omes

is

not

sho

wn;

mea

sure

d re

stin

g en

ergy

exp

endi

ture

w

as n

ot u

sed

Meh

ta e

t al9

Pro

spec

tive

co

hort

; m

ulti

cent

er; 5

9 P

ICU

s in

15

coun

trie

s

To

exam

ine

the

asso

ciat

ion

betw

een

prot

ein

inta

ke a

nd

60-d

mor

tali

ty

N =

124

5C

riti

call

y il

l ch

ildr

en r

equi

ring

m

echa

nica

l ve

ntil

atio

n (≥

48 h

)M

edia

n ag

e (I

QR

):

1.7

y (0

.4–7

.0 y

)

n =

985

rec

eive

d E

NM

ean

perc

enta

ge d

eliv

ery

of p

resc

ribe

d:

ener

gy, 3

6% ±

35%

; pro

tein

, 37%

±

38%

Ade

quat

e en

tera

l pro

tein

inta

ke w

as

sign

ific

antl

y as

soci

ated

wit

h 60

-d

mor

tali

ty (

P <

.001

) af

ter

adju

stm

ent

for

dise

ase

seve

rity

, sit

e, P

ICU

day

s,

and

ener

gy in

take

Mea

n en

tera

l pro

tein

inta

ke <

20%

vs

≥60%

of

pres

crib

ed g

oal,

OR

for

60-

d m

orta

lity

: 0.1

4 (9

5% C

I, 0

.04–

0.52

; P

= .0

03)

Ade

quat

e pr

otei

n in

take

w

as a

ssoc

iate

d w

ith

low

er

mor

tali

tyR

esul

ts g

ener

aliz

able

to

chil

dren

on

mec

hani

cal

vent

ilat

ion

in P

ICU

s w

ith

>8

beds

Lim

itat

ions

: no

nint

erve

ntio

nal,

obse

rvat

iona

l stu

dy (co

ntin

ued)

Tab

le 5

. (c

onti

nu

ed)

18

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

ims

Pop

ulat

ion

(n),

E

ligi

bili

tyIn

terv

enti

onR

esul

ts/O

utco

me

Com

men

ts

Car

lott

i et a

l54P

rosp

ecti

ve

obse

rvat

iona

l co

hort

; sin

gle

cent

er

Det

erm

ine

if n

egat

ive

bala

nce

of in

trac

ellu

lar

cons

titu

ents

are

mar

kers

of

cel

l cat

abol

ism

and

to

eval

uate

eff

ecti

vene

ss o

f nu

trit

ion

ther

apy

on r

ate

of

crea

tini

ne e

xcre

tion

n =

17

Chi

ldre

n w

ith

seve

re

trau

mat

ic b

rain

in

jury

(G

lasg

ow

Com

a S

cale

, ≤8

) re

quir

ing

mec

hani

cal

vent

ilat

ion

wit

h se

dati

on a

nd

anal

gesi

cs ±

ne

urom

uscu

lar

bloc

kade

Med

ian

age

(ran

ge):

6

y (2

–14

y)

Ana

boli

sm w

as a

ssoc

iate

d w

ith

incr

ease

d pr

otei

n in

take

: med

ian

1.1

(ran

ge, 0

.7–2

.2)

g/kg

/d v

s ca

tabo

lism

m

edia

n 0.

1 (0

–1.8

) g/

kg/d

(P

< .0

001)

Pos

itiv

e co

rrel

atio

n: p

rote

in in

take

and

ba

lanc

e, R

= 0

.63

(P <

.000

1)P

osit

ive

bala

nce

for

phos

phat

e an

d m

agne

sium

wit

h pr

otei

n in

take

0.5

–1

g/kg

/dN

egat

ive

corr

elat

ion:

cre

atin

ine

clea

ranc

e an

d pr

otei

n ba

lanc

e, R

=

−0.

45 (

P <

.000

1)N

egat

ive

prot

ein

bala

nce

asso

ciat

ed

wit

h pn

eum

onia

, sep

sis,

incr

ease

d cr

eati

nine

exc

reti

on

Pat

ient

s w

ith

trau

mat

ic

brai

n in

jury

wit

h ne

gati

ve

prot

ein

bala

nce

also

had

ne

gati

ve b

alan

ces

in o

ther

in

trac

ellu

lar

mar

kers

; to

geth

er th

ese

find

ings

su

gges

t los

ses

of le

an b

ody

mas

sM

inim

um in

take

of

1 g/

kg/d

pr

otei

n an

d ≥5

0% o

f go

al

ener

gy w

ith

the

Hol

lida

y-S

egar

for

mul

a w

ere

asso

ciat

ed w

ith

a po

siti

ve

prot

ein

bala

nce,

exc

ept i

n se

ptic

pat

ient

s.L

imit

atio

ns: s

mal

l sam

ple

size

Zap

pite

lli e

t al26

Ret

rosp

ecti

ve

coll

abor

ativ

e re

gist

ry

To

eval

uate

pro

tein

and

ca

lori

c pr

escr

ipti

on a

nd to

ev

alua

te f

acto

rs a

ssoc

iate

d w

ith

over

pre

scri

ptio

n an

d un

derp

resc

ript

ion

of

prot

ein

and

calo

ries

n =

195

Cri

tica

lly

ill c

hild

ren

and

youn

g ad

ults

w

ith

acut

e ki

dney

in

jury

rec

eivi

ng

CR

RT

Mea

n ag

e (S

D):

8.8

y

(6.8

y)

Max

imum

pro

tein

: 2 ±

1.5

g/k

g/d

Med

ian

prot

ein

dose

by

day

5: >

2 g

/kg

/dM

axim

um e

nerg

y: 4

8.2

± 31

.5 k

cal/

kg/d

Pre

dict

ors

of h

ighe

r pr

otei

n an

d ca

lori

e in

take

: you

nger

age

(P

= .0

4), h

ighe

r in

itia

l pro

tein

or

calo

ries

at i

niti

atio

n of

CR

RT

(P

< .0

001)

, lon

ger

dura

tion

of

CR

RT

(P

< .0

03)

Stu

dy r

epor

ts f

easi

bili

ty

of a

dequ

ate

prot

ein

pres

crip

tion

in p

atie

nts

on

CR

RT

.L

imit

atio

ns: n

o re

com

men

dati

ons

for

prot

ein

or c

alor

ic d

oses

and

di

d no

t ass

ess

nutr

itio

n or

cl

inic

al o

utco

mes

AA

, am

ino

acid

s; A

RD

S, a

cute

res

pira

tory

dis

tres

s sy

ndro

me;

AS

PE

N, A

mer

ican

Soc

iety

for

Par

ente

ral a

nd E

nter

al N

utri

tion

; CR

RT

, con

tinu

ous

rena

l rep

lace

men

t the

rapy

; DR

I, D

ieta

ry R

efer

ence

In

take

; EN

, ent

eral

nut

riti

on; I

C, i

ndir

ect c

alor

imet

ry; I

QR

, int

erqu

arti

le r

ange

; OR

, odd

s ra

tio;

PIC

U, p

edia

tric

inte

nsiv

e ca

re u

nit;

PN

, par

ente

ral n

utri

tion

; RC

T, r

ando

miz

ed c

ontr

olle

d tr

ial;

RS

V,

resp

irat

ory

sync

ytia

l vir

us.

Tab

le 5

. (c

onti

nu

ed)

Mehta et al 19

children receiving mechanical ventilation from 15 countries, 985 subjects received EN; delivery of >60% of prescribed enteral protein goal was significantly associated with decreased 60-day mortality (<20% vs >60%; odds ratio, 0.14 [95% CI, 0.04–0.52]; P = .003) after adjustment for disease severity, site, PICU days, and energy intake.9 Hence, at the very minimum, a protein intake of 1.5 g/kg/d must be ensured to avoid cumulative protein deficits in critically ill children. The optimal protein intake threshold for infants and young children is likely to be higher than this value. Specific sub-groups, such as infants and young children admitted with bronchiolitis or other causes of respiratory failure requiring mechanical ventilation, require 2.5–3 g/kg protein daily to improve protein balance.46,48,51 Protein intake was well toler-ated in these studies. However, the safety of protein intake >3 g/kg/d in children >1 month old has not been adequately demonstrated and may be associated with increased blood urea nitrogen. The effect of the route of protein delivery, enteral versus parenteral, on clinical outcomes is unclear. In particular, the role of early parenteral protein intake has not been shown, and most studies demonstrating the benefits of higher protein intake have utilized the enteral route.

Current evidence for increased protein dosing in criti-cally ill children exceeds RDA recommendations and rec-ommendations from WHO. These recommendations are calculated estimates from derived equations of protein deposition in healthy children and do not account for the increased protein breakdown that occurs during critical ill-ness.9,36,39 The use of RDA recommendations to guide pro-tein intake during critical illness may lead to unintended negative protein balance. The determination of protein requirements for obese patients in the PICU may be chal-lenging. The recommendation of a minimum of 1.5 g/kg/d should also be applied to this population, based on ideal body weight. This population is at risk of undetected lean body mass erosion. A reliable method to monitor the body composition for the critically ill pediatric population, par-ticularly obese children, is needed to better address their optimal macronutrient needs.Future direction. Future studies are needed to determine the optimal dose of protein that improves protein balance, nutri-tion status (eg, muscle mass and function), and relevant clini-cal outcomes (eg, duration of mechanical ventilation, PICU LOS, and mortality). Future studies must also examine the effect of specific protein sources and the route of delivery on outcomes.

Question 4A: Is EN feasible in critically ill children?

Recommendation 4A. On the basis of observational studies, we recommend EN as the preferred mode of nutrient delivery to the critically ill child (see Table 6). Observational studies support the feasibility of EN, which can be safely delivered to critically ill children with medical and surgical diagnoses and to those receiving vasoactive medications. Common barriers to EN in the PICU include delayed initiation, interruptions due to

perceived intolerance, and prolonged fasting around proce-dures. On the basis of observational studies, we suggest that interruptions to EN be minimized in an effort to achieve nutri-ent delivery goals by the enteral route.Quality of evidence. Low.GRADE recommendation. Strong.

Question 4B: What is the benefit of EN in this group?

Recommendation 4B. Although the optimal dose of macronu-trients is unclear, some amount of nutrient delivered as EN has been beneficial for gastrointestinal mucosal integrity and motility. Based on large cohort studies, early initiation of EN (within 24–48 hours of PICU admission) and achievement of up to two-thirds of the nutrient goal in the first week of critical illness have been associated with improved clinical outcomes.Quality of evidence. Low.GRADE recommendation. Weak.

Rationale. The enteral route is the preferred modality to provide nutrition support to adults and children. Animal studies have demonstrated the beneficial effects of EN on gut-associated lymphoid tissue, mucosal immunity, and improved survival after Escherichia coli–induced peritoni-tis and brief intestinal ischemia.56-60 Early initiation of EN is preferred in most PICUs. However, a variety of challenges impedes early initiation and maintenance of EN in children during critical illness.61-63,67,68 Many of these perceived bar-riers to EN may be avoidable.61 In large cohorts of patients on vasoactive medications in the PICU, EN was adminis-tered without any significant adverse events.64,65 Although the physician’s decision to start EN may have been biased by the clinical condition of the patient, gastrointestinal com-plications (vomiting, diarrhea, bleeding, and abdominal distension), other severe feeding-related complications, or mortality were not increased in the group who received vasoactive medications.65

Cohort studies of children admitted to the PICU have reported improved survival with optimal nutrient intake by the enteral route. In 2 large international prospective cohort studies of children receiving mechanical ventilation, enteral delivery of > two-thirds of the energy goal and >60% of the protein goal was significantly associated with lower 60-day mortality.8,9 These benefits were not seen for nutrients deliv-ered via the parenteral route. In a large retrospective multi-center study of 5105 patients from 12 centers, the provision of one-fourth goal calories enterally over the first 48 hours of admission was associated with reduced PICU mortality.66 In a retrospective cohort of 107 children with acute respira-tory distress syndrome, enteral delivery of adequate calories (≥80% estimated goal) and protein (≥1.5 g/kg/d) was associ-ated with a reduction in ICU mortality.44 Hence, EN is fea-sible during acute critical illness and must be prioritized as the preferred route for nutrient delivery.Future direction. Future studies evaluating the feasibility of EN in critically ill children should examine its impact on

20

Tab

le 6

. F

easi

bili

ty a

nd B

enef

its

of E

nter

al N

utri

tion

.

Ref

eren

ceS

tudy

Des

ign;

No.

of

Sit

esS

tudy

Aim

sP

opul

atio

n (n

), E

ligi

bili

tyR

esul

ts/O

utco

me

Com

men

ts

Won

g et

al44

Ret

rosp

ecti

ve c

ohor

t;

sing

le c

ente

rT

o de

term

ine

whe

ther

th

e pr

ovis

ion

of

adeq

uate

nut

riti

on

is a

ssoc

iate

d w

ith

impr

oved

cli

nica

l ou

tcom

es

n =

107

Cri

tica

lly

ill c

hild

ren

wit

h A

RD

SM

edia

n ag

e: 5

.2 y

(IQ

R,

1.0–

10.4

y)

28 (

26.2

%)

of p

atie

nts

rece

ived

ear

ly E

N

(wit

hin

24 h

of

AR

DS

)P

ICU

mor

tali

ty w

as lo

wer

in p

atie

nts

who

re

ceiv

ed a

dequ

ate

calo

ries

(34

.6%

vs

60.5

%;

P =

.025

) an

d ad

equa

te p

rote

in (

14.3

% v

s 60

.2%

; P =

.002

) co

mpa

red

wit

h th

ose

who

di

d no

t

The

aut

hors

rep

ort a

n as

soci

atio

n be

twee

n ad

equa

cy o

f en

ergy

and

pro

tein

inta

ke a

nd

surv

ival

in c

hild

ren

wit

h A

RD

S.

Lim

itat

ions

: und

erpo

wer

ed s

tudy

; nut

riti

on

pres

crip

tion

was

dep

ende

nt o

n th

e cl

inic

al

prac

titi

oner

pre

fere

nce;

and

ene

rgy

need

s w

ere

esti

mat

ed w

ith

equa

tion

s

Meh

ta e

t al9

Pro

spec

tive

coh

ort;

m

ulti

cent

er59

PIC

Us

in 1

5 co

untr

ies

To

exam

ine

the

asso

ciat

ion

betw

een

prot

ein

inta

ke a

nd

60-d

mor

tali

ty in

m

echa

nica

lly

vent

ilat

ed

chil

dren

n =

124

5C

riti

call

y il

l chi

ldre

n re

ceiv

ing

mec

hani

cal

vent

ilat

ion

for ≥4

8 h

Med

ian

age

(IQ

R):

1.7

(0

.4–7

.0)

y

n =

985

rec

eive

d E

NT

he m

ean

± S

D d

eliv

ery

of e

nter

al e

nerg

y an

d pr

otei

n w

as 3

6% ±

35%

and

37%

± 3

8%,

resp

ecti

vely

.T

he a

dequ

acy

of e

nter

al p

rote

in in

take

was

si

gnif

ican

tly

asso

ciat

ed w

ith

60-d

mor

tali

ty

(P <

.001

) af

ter

adju

stm

ent f

or d

isea

se

seve

rity

, sit

e, P

ICU

day

s, a

nd e

nerg

y in

take

.

Lar

ge m

ulti

cent

er p

rosp

ecti

ve c

ohor

t stu

dy

foun

d an

ass

ocia

tion

wit

h ad

equa

cy o

f en

tera

l pro

tein

inta

ke a

nd d

ecre

ased

m

orta

lity

.L

imit

atio

ns: o

nly

PIC

Us

wit

h >

8 b

eds

wer

e in

clud

ed; t

he e

nerg

y in

take

goa

ls w

ere

esti

mat

ed b

y di

etit

ians

at e

ach

site

; and

va

riab

ilit

y of

nut

riti

on p

ract

ices

at t

he

part

icip

atin

g si

tes

Mik

hail

ov

et a

l66R

etro

spec

tive

coh

ort

stud

y; m

ulti

cent

er

data

base

To

dete

rmin

e w

heth

er

earl

y E

N (

wit

hin

48

h of

adm

issi

on)

is

asso

ciat

ed w

ith

low

er

mor

tali

ty, s

hort

er L

OS

, an

d sh

orte

r du

rati

on o

f m

echa

nica

l ven

tila

tion

n =

510

5C

riti

call

y il

l chi

ldre

n w

ith

PIC

U L

OS

≥96

hM

edia

n ag

e (I

QR

): 2

.4

(0.5

–9.8

) y

Ear

ly E

N w

as a

chie

ved

by 2

7.1%

of

pati

ents

Chi

ldre

n re

ceiv

ing

earl

y E

N w

ere

less

like

ly

to d

ie th

an th

ose

who

did

not

(O

R, 0

.51

[95%

CI,

0.3

4–0.

76];

P =

.001

), a

djus

ted

for

prop

ensi

ty s

core

, Ped

iatr

ic I

ndex

of

Mor

tali

ty

2 sc

ore,

age

, and

cen

ter

LO

S a

nd d

urat

ion

of m

echa

nica

l ven

tila

tion

w

ere

not d

iffe

rent

bet

wee

n th

e gr

oups

that

re

ceiv

ed e

arly

EN

vs

the

grou

p th

at d

id n

ot.

The

aut

hors

rep

ort a

n as

soci

atio

n be

twee

n re

ceiv

ing

earl

y E

N a

nd im

prov

ed s

urvi

val.

Pro

pens

ity

anal

yses

dem

onst

rate

d th

is

rela

tion

ship

in th

eir

larg

e da

taba

se.

Lim

itat

ions

: ene

rgy

need

s es

tim

ated

by

equa

tion

s; n

ot a

ll s

ourc

es o

f en

ergy

wer

e in

clud

ed; p

atie

nts

wer

e in

clud

ed o

nly

if

PIC

U s

tay

was

≥96

h; a

nd in

accu

raci

es o

f nu

trit

ion

data

rec

orde

d in

hea

lth

reco

rds

Pan

chal

et a

l65R

etro

spec

tive

coh

ort;

si

ngle

cen

ter

To

eval

uate

the

safe

ty

of e

nter

al f

eedi

ng in

cr

itic

ally

ill c

hild

ren

rece

ivin

g va

soac

tive

m

edic

atio

ns

n =

339

rec

eive

d ≥1

va

soac

tive

dru

gn

= 1

88 f

ed a

nd n

= 1

55

nonf

ed b

ased

on

EN

re

ceiv

ed th

e fi

rst 4

d o

f ad

mis

sion

to P

ICU

Pat

ient

s in

the

fed

grou

p w

ere

youn

ger

(P <

.0

01)

and

had

a lo

wer

mor

tali

ty (

P <

.01)

vs

the

nonf

ed g

roup

.T

he V

asoa

ctiv

e-In

otro

pic

Sco

re in

the

nonf

ed

grou

p w

as h

ighe

r on

ly o

n da

y 1

(P <

.05)

vs

the

fed

grou

p. G

astr

oint

esti

nal o

utco

mes

wer

e no

t dif

fere

nt b

etw

een

the

2 gr

oups

.

The

aut

hors

fou

nd n

o ad

vers

e ef

fect

s w

ith

the

use

of v

asoa

ctiv

e m

edic

atio

ns d

urin

g E

N

deli

very

.L

arge

sam

ple

size

Lim

itat

ions

: the

eff

ect o

f >

1 v

asoa

ctiv

e dr

ug o

n in

tole

ranc

e to

EN

is n

ot k

now

n.

Ret

rosp

ecti

ve s

tudy

wit

h li

mit

atio

ns o

f cl

inic

al a

nd n

utri

tion

dat

a in

hea

lth

reco

rds

Kyl

e et

al67

Ret

rosp

ecti

ve c

ohor

t;

sing

le c

ente

rT

o de

scri

be e

nerg

y an

d pr

otei

n E

N d

eliv

ery

in

PIC

U p

atie

nts

wit

h an

d w

itho

ut A

KI

n =

167

Cri

tica

lly

ill c

hild

ren

wit

h P

ICU

LO

S >

3 d

n =

65

wit

h A

KI

n =

102

wit

hout

AK

I

Ove

rall

(P

N a

nd E

N)

prot

ein

inta

ke w

as 1

9%

and

ener

gy in

take

was

55%

of

goal

.A

KI

(inj

ury

and

fail

ure)

had

hig

her

like

liho

od

of f

asti

ng d

ays

and

ener

gy p

rovi

sion

<90

%

BM

R.

The

stu

dy s

how

ed th

at p

atie

nts

wit

h vs

w

itho

ut A

KI

are

mor

e li

kely

to b

e un

derf

ed.

Lim

itat

ions

: doe

s no

t des

crib

e ou

tcom

es

rela

ted

to n

utri

ent a

dequ

acy.

Kyl

e et

al68

Ret

rosp

ecti

ve c

ohor

t;

sing

le c

ente

rT

o ex

amin

e cu

rren

t nu

trit

ion

prac

tice

s an

d th

e ad

equa

cy o

f nu

trit

ion

supp

ort i

n th

e P

ICU

n =

240

, cri

tica

lly

ill c

hild

ren

wit

h P

ICU

LO

S >

48 h

Doc

umen

ted

nutr

ient

inta

ke

by a

ll r

oute

s (P

N a

nd E

N)

in th

e fi

rst 8

d in

PIC

U

Act

ual e

nerg

y in

take

for

all

pat

ient

-day

s w

as

75.7

% ±

56.

7% o

f es

tim

ated

BM

R.

Act

ual p

rote

in in

take

for

all

pat

ient

-day

s w

as

40.4

% ±

44.

2% o

f es

tim

ated

req

uire

men

ts.

Pat

ient

s in

this

larg

e te

rtia

ry P

ICU

stu

dy

rece

ived

< h

alf

of r

ecom

men

ded

prot

ein

inta

ke.

Lim

itat

ions

: res

ults

may

not

be

appl

icab

le to

ot

her

PIC

Us;

and

ene

rgy

and

prot

ein

need

s ba

sed

on r

efer

ence

val

ues

(co

ntin

ued)

21

Ref

eren

ceS

tudy

Des

ign;

No.

of

Sit

esS

tudy

Aim

sP

opul

atio

n (n

), E

ligi

bili

tyR

esul

ts/O

utco

me

Com

men

ts

Meh

ta e

t al8

Pro

spec

tive

coh

ort

stud

y; m

ulti

cent

er,

31 P

ICU

s in

8

coun

trie

s

To

eval

uate

ade

quac

y of

ene

rgy

and

prot

ein

inta

ke in

the

PIC

U a

nd

thei

r re

lati

onsh

ip to

cl

inic

al o

utco

mes

n =

500

Chi

ldre

n on

mec

hani

cal

vent

ilat

ion

Mea

n ag

e (S

D):

4.5

y (

5.1

y)

Mea

n pr

escr

ibed

goa

ls f

or e

nerg

y an

d pr

otei

n in

take

wer

e 64

kca

l/kg

/d a

nd 1

.7 g

/kg/

d,

resp

ecti

vely

; EN

was

use

d in

67%

of

the

pati

ents

and

was

init

iate

d w

ithi

n 48

h o

f ad

mis

sion

.A

hig

her

perc

enta

ge o

f go

al e

nerg

y in

take

via

en

tera

l rou

te w

as s

igni

fica

ntly

ass

ocia

ted

wit

h lo

wer

60-

d m

orta

lity

.M

orta

lity

at 6

0 d

was

8.4

%.

Lar

ge m

ulti

cent

er p

rosp

ecti

ve c

ohor

t stu

dy

foun

d an

ass

ocia

tion

bet

wee

n hi

gher

ent

eral

en

ergy

inta

ke a

nd lo

wer

mor

tali

ty.

Lim

itat

ions

: ene

rgy

need

s es

tim

ated

by

equa

tion

s; a

lmos

t one

-thi

rd o

f th

e pa

tien

ts

had

mis

sing

sev

erit

y of

illn

ess

scor

es;

only

PIC

Us

wit

h >

8 be

ds w

ere

incl

uded

; va

riab

ilit

y in

sta

ff s

kill

s, a

vail

abil

ity

and

adhe

renc

e to

pro

toco

ls, a

nd r

esou

rce

avai

labi

lity

cou

ld h

ave

infl

uenc

ed th

e re

sult

s

Meh

ta e

t al61

Pro

spec

tive

coh

ort;

si

ngle

cen

ter

To

iden

tify

ris

k fa

ctor

s as

soci

ated

wit

h av

oida

ble

inte

rrup

tion

s to

EN

in c

riti

call

y il

l chi

ldre

n. A

lso,

to

eval

uate

the

freq

uenc

y of

avo

idab

le E

N

inte

rrup

tion

s an

d th

eir

impa

ct o

n nu

trie

nt

deli

very

n =

117

PIC

U p

opul

atio

n w

ith

LO

S

≥24

hM

edia

n ag

e (I

QR

): 7

.2 y

(1

.7–1

5.3

y)

68%

rec

eive

d E

N (

20%

pos

tpyl

oric

) fo

r a

tota

l of

381

EN

day

s (m

edia

n, 2

d).

Med

ian

tim

e to

EN

init

iati

on w

as <

1 d.

EN

was

inte

rrup

ted

in 3

0% a

t an

aver

age

of 3

.7

± 3.

1 ti

mes

per

pat

ient

(ra

nge,

1–1

3), f

or a

to

tal o

f 88

epi

sode

s ac

coun

ting

for

148

3 h

of

EN

dep

riva

tion

in th

is c

ohor

t.51

of

88 (

58%

) ep

isod

es o

f E

N in

terr

upti

ons

wer

e de

emed

avo

idab

le in

15

of 8

0 pa

tien

ts.

Avo

idab

le E

N in

terr

upti

on w

as a

ssoc

iate

d w

ith

incr

ease

d re

lian

ce o

n P

N a

nd im

pair

ed

abil

ity

and

tim

e re

quir

ed to

rea

ch c

alor

ic g

oal

and

incr

ease

d co

sts.

Thi

s st

udy

high

ligh

ts f

acto

rs s

uch

as

prol

onge

d fa

stin

g ar

ound

pro

cedu

res

and

into

lera

nce,

whi

ch im

pede

opt

imal

EN

de

live

ry. E

N is

fre

quen

tly

inte

rrup

ted

in th

e P

ICU

; >50

% o

f in

terr

upti

ons

are

“avo

idab

le.”

Infa

nts

and

thos

e on

mec

hani

cal v

enti

lati

on a

t ri

sk f

or E

N in

terr

upti

ons

Lim

itat

ions

: pra

ctic

es a

nd c

hall

enge

s m

ight

be

diff

eren

t in

othe

r ce

nter

s.

de O

live

ira

Igle

sias

et

al62

Pro

spec

tive

coh

ort;

si

ngle

cen

ter

To

com

pare

pre

scri

bed

vs d

eliv

ered

ene

rgy;

id

enti

fy E

N b

arri

ers

in

firs

t 5 d

of

PIC

U s

tay

n =

58

Pat

ient

s ad

mit

ted

to P

ICU

an

d re

ceiv

ed E

N f

or >

48 h

Dai

ly a

vera

ge in

take

met

60%

req

uire

d ki

loca

lori

es a

nd 8

5% p

resc

ribe

d ki

loca

lori

esG

astr

oint

esti

nal c

ompl

icat

ions

and

use

of

vaso

acti

ve d

rugs

(α-

1 ad

rene

rgic

ago

nist

s)

wer

e as

soci

ated

wit

h lo

wer

ene

rgy

prov

isio

n.

Thi

s st

udy

high

ligh

ted

fact

ors

that

impe

de

opti

mal

del

iver

y of

EN

.L

imit

atio

ns: p

ract

ices

and

cha

llen

ges

mig

ht b

e di

ffer

ent i

n ot

her

cent

ers;

and

no

outc

omes

de

scri

bed

Kin

g et

al64

Ret

rosp

ecti

ve c

ohor

t;

sing

le c

ente

rE

valu

ate

the

tole

ranc

e of

EN

in

chil

dren

rec

eivi

ng

card

iova

scul

ar

med

icat

ions

n =

52

Rec

eive

d E

N a

nd

card

iova

scul

ar m

edic

atio

ns

in th

e sa

me

24-h

per

iod

Age

: 1 m

o to

20

y

Dop

amin

e at

≥6

μg/k

g/m

in w

as u

sed

in 1

7 pa

tien

ts (

31%

) an

d do

pam

ine

+

nore

pine

phri

ne in

23

pati

ents

(42

%).

71%

had

≥1

feed

ing

inte

rrup

tion

wit

h 70

% o

f in

terr

upti

ons

not r

elat

ed to

gas

troi

ntes

tina

l to

lera

nce;

vom

itin

g w

as r

epor

ted

in 1

2 (2

3%);

4

pati

ents

had

gas

troi

ntes

tina

l ble

edin

g.

The

stu

dy r

epor

ted

reas

onab

le E

N to

lera

nce

in p

atie

nts

rece

ivin

g ca

rdio

vasc

ular

dru

gs in

th

e P

ICU

.L

imit

atio

ns: r

etro

spec

tive

rev

iew

wit

h li

mit

atio

ns o

f cl

inic

al d

ata

in m

edic

al

reco

rds

AK

I, a

cute

kid

ney

inju

ry; A

RD

S, a

cute

res

pira

tory

dis

tres

s sy

ndro

me;

BM

R, b

asal

met

abol

ic r

ate;

EN

, ent

eral

nut

riti

on; I

QR

, int

erqu

arti

le r

ange

; LO

S, l

engt

h of

sta

y; O

R, o

dds

rati

o; P

ICU

, ped

iatr

ic

inte

nsiv

e ca

re u

nit;

PN

, par

ente

ral n

utri

tion

.

Tab

le 6

. (c

onti

nu

ed)


well-defined outcomes. Higher-quality randomized study designs should evaluate the benefits of providing adequate EN with predefined energy and protein goals.

Question 5A: What is the optimum method for advancing EN in the PICU population?

Recommendation 5A. On the basis of observational studies, we suggest the use of a stepwise algorithmic approach to advance EN in children admitted to the PICU (see Table 7). The stepwise algorithm must include bedside support to guide the detection and management of EN intolerance and the opti-mal rate of increase in EN delivery.Quality of evidence. Low.GRADE recommendation. Weak.

Question 5B: What is the role of a nutrition support team or a dedicated dietitian in optimizing nutrition therapy?

Recommendation 5B. On the basis of observational studies, we suggest that a multidisciplinary nutrition support team, including a dedicated dietitian, be available on the PICU team to facilitate timely nutrition assessment and optimal nutrient delivery and adjustment to the patients.Quality of evidence. Low.GRADE recommendation. Weak.Rationale. Despite the preference for the enteral route for nutrition delivery and benefits reported by many authors, the practice of providing EN to critically ill children is variable. There is no uniform approach to initiate and advance EN. A stepwise protocol/algorithm is expected to address barriers to EN, such as prolonged interruptions due to procedures, lack of a clear definition of feeding intolerance, and management of mechanical issues with feeding tubes, among others. The use of feeding protocols is considered safe and, in individual cen-ters, has been effective in optimizing nutrient delivery without increasing the risk of other complications.70-72 In an interna-tional multicenter cohort study, 9 of the 31 participating PICUs reported the use of an EN algorithm.73 These algorithms defined the rate of EN advancement and recommended nutri-tion screening and fasting guidelines, and most centers defined intolerance by some threshold of increased gastric residual vol-ume (GRV). Despite being commonly measured in many PICUs, the accuracy of GRV as a marker of delayed gastric emptying has been recently challenged in adult and pediatric intensive care populations.55,74 Measurement of GRV has not been correlated with risk of aspiration in adult studies, and it is no longer recommended in the recent adult critical care nutri-tion guidelines.75,76 In a recent single-center study of children eligible for EN initiation in the PICU, measured GRV did not correlate with delayed gastric emptying or with the ability to rapidly advance EN.55 The threshold volume used to define increased GRV in the PICU is variable.73,77 In the absence of pediatric trials, we cannot recommend discontinuing GRV measurement in the PICU, but the role of this practice is not

clear and might impede EN advancement. Several studies have reported rapid advancement of EN and achievement of nutrient delivery goals by a stepwise algorithmic approach.70,71,78 The use of EN algorithms/protocols has been associated with decreased time to initiation of EN, increased EN delivery and decreased reliance on PN, and increased likelihood of achiev-ing nutrient delivery goals.70,72,79

Presence of a dedicated multidisciplinary nutrition team in the ICU guides the timely initiation and management of nutri-tion support. It is suggested that the composition of the team includes personnel knowledgeable and experienced in pediat-ric critical care, pediatric nutrition, and nutrition support ther-apy. Dedicated dietitians support sound nutrition practices, such as timely assessment and documentation of nutrition sta-tus, development of an optimal nutrition prescription, serial follow-up, and monitoring for safe nutrient delivery, as some of the responsibilities of a PICU dietitian.80 In a multicenter observational cohort study of 31 PICUs, a majority of the cen-ters (93%) reported the presence of a dedicated dietitian for an average of 0.4 full-time equivalents per 10 beds.8 In a subse-quent multicenter study of 59 PICUs, the presence of a dedi-cated dietitian was a significant and independent predictor of adequate enteral protein intake.9 Hence, dietitians are essential members of the multidisciplinary care team in the PICU. It is important to develop a seamless transition of nutrition care plan as patients move across the continuum of pediatric ward to the ICU and back.Future direction. Future studies must clarify the evidence to inform stepwise decision making in the EN algorithms. These steps include selection of gastric versus postpyloric tube feed-ing, clear and practical definitions of feeding intolerance (eg, reflux, vomiting, constipation, diarrhea, and malabsorption), and the role of adjuncts such as prokinetic, antiemetic, antidiarrheal, acid suppressive, and laxative medications. In particular, the practice of measuring GRV as a marker of EN intolerance in the PICU population must be challenged. Future studies examining the role or the optimal threshold of GRV to guide EN delivery are desirable. In addition, prospective trials are needed to show the benefit of algorithmic EN advancement and dietitian inter-ventions on important nutrition and clinical outcomes.

Question 6A: What is the best site for EN delivery: gastric or small bowel?

Recommendation 6A. Existing data are insufficient to make universal recommendations regarding the optimal site to deliver EN to critically ill children (see Table 8). On the basis of observational studies, we suggest that the gastric route be the preferred site for EN in patients in the PICU. The postpy-loric or small intestinal site for EN may be used for patients unable to tolerate gastric feeding or for those at high risk for aspiration. Existing data are insufficient to make recommen-dations regarding the use of continuous versus intermittent gastric feeding.

23

Tab

le 7

. O

ptim

um M

etho

d fo

r A

dvan

cing

Ent

eral

Nut

riti

on.

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

ims

Pop

ulat

ion

(n),

E

ligi

bili

tyIn

terv

enti

onR

esul

ts/O

utco

me

Com

men

ts

Kau

fman

et

al69

Bef

ore/

afte

r co

hort

, si

ngle

cen

ter

To

exam

ine

the

role

of

a m

ulti

step

inte

rven

tion

in

clud

ing

a gu

idel

ine

in im

prov

ing

ener

gy

and

prot

ein

deli

very

.

n =

106

Pre

inte

rven

tion

n =

260

Pos

tint

erve

ntio

nP

redo

min

antl

y ne

wbo

rns

<1

mo

in th

e ca

rdia

c IC

U

The

EN

pro

toco

l: s

tart

wit

h 0.

5 m

L/k

g/h,

adv

ance

by

the

sam

e ra

te e

very

4–6

h u

ntil

goa

l is

reac

hed.

Inte

rven

tion

als

o in

clud

ed c

alor

ie

coun

ts, s

cree

ning

by

spec

iali

sts,

be

dsid

e di

scus

sion

of

deli

very

, gu

idel

ine

(ste

pwis

e) f

or n

utri

ent

deli

very

Goa

l cal

orie

s fo

r fu

ll-t

erm

in

tuba

ted

and

noni

ntub

ated

in

fant

s: 8

0 kc

al/k

g/d

and

10

0–13

0 kc

al/k

g/d,

res

pect

ivel

y.

The

per

cent

age

of p

atie

nt d

ays

in a

mon

th w

hen

dail

y ca

lori

c go

als

wer

e m

et in

crea

sed

from

50

.1%

to 6

0.7%

fro

m th

e pr

eint

erve

ntio

n to

inte

rven

tion

pe

riod

. The

per

cent

age

of p

atie

nt

days

whe

n da

ily

prot

ein

goal

s w

ere

met

incr

ease

d fr

om 5

1.6%

to

72.

7% f

rom

sim

ilar

per

iods

.

The

stu

dy in

volv

es c

hild

ren

in th

e ca

rdia

c IC

U—

pred

omin

antl

y ne

wbo

rns

and

som

e ol

der

infa

nts.

Dif

ficu

lt to

par

se th

e ol

der

chil

dren

fro

m n

eona

tes.

Ove

rall

, the

use

of

EN

al

gori

thm

res

ulte

d in

in

crea

sed

like

liho

od o

f re

achi

ng p

rote

in d

eliv

ery

goal

s.

Ham

ilto

n et

al70

Bef

ore/

afte

r co

hort

, si

ngle

cen

ter

To

exam

ine

the

role

of

a st

epw

ise

EN

adv

ance

men

t al

gori

thm

on

adeq

uacy

of

EN

del

iver

y, a

bili

ty

to r

each

goa

l, an

d ti

me

to r

each

ene

rgy

goal

.

n =

80

Pre

inte

rven

tion

n =

80

Pos

tint

erve

ntio

nH

eter

ogen

eous

PIC

U p

opul

atio

n w

ith

LO

S >

24 h

The

pro

toco

l inc

lude

d nu

trit

ion

asse

ssm

ent a

nd g

oals

, mod

e of

nut

riti

on (

EN

vs

PN

),

rout

e of

EN

(ga

stri

c vs

po

stpy

lori

c), i

niti

atio

n of

E

N, a

nd m

aint

enan

ce o

f E

N.

Als

o in

clud

ed a

ste

pwis

e E

N

algo

rith

m d

evel

opm

ent a

nd

syst

emat

ic im

plem

enta

tion

in th

e P

ICU

.

Med

ian

tim

e to

rea

ch e

nerg

y go

al

decr

ease

d fr

om 4

d to

1 d

(P

<

.05)

, wit

h a

high

er p

ropo

rtio

n of

pa

tien

ts r

each

ing

this

goa

l (99

%

vs 6

1%, P

= .0

1).

Dec

reas

e in

avo

idab

le E

N

inte

rrup

tion

s (3

vs

51, P

<

.000

1) a

nd d

ecre

ased

use

of

PN

in

this

sub

set.

The

stu

dy r

epor

ts

sign

ific

antl

y de

crea

sed

tim

e to

rea

ch a

nd

incr

ease

d li

keli

hood

of

reac

hing

nut

rien

t del

iver

y go

als

afte

r in

stit

utin

g a

step

wis

e E

N a

lgor

ithm

.L

imit

atio

ns: N

o di

ffer

ence

in

cli

nica

l out

com

es.

Yos

him

ura

et a

l72P

rosp

ecti

ve

case

ser

ies,

si

ngle

cen

ter

To

inve

stig

ate

the

safe

ty

and

effi

cacy

of

an

EN

pro

toco

l aft

er it

s im

plem

enta

tion

n =

62

Pre

inte

rven

tion

n =

47

Pos

tint

erve

ntio

n

The

EN

pro

toco

l had

cal

oric

goa

l-ba

sed

adva

ncem

ents

: The

goa

l on

day

1 w

as s

et a

t 40%

of

targ

et

dose

and

adv

ance

d by

20%

eac

h da

y to

rea

ch 1

00%

by

day

4.

The

tim

e un

til i

niti

atio

n of

EN

(m

edia

n of

22

h vs

20

h) a

nd th

e to

tal c

alor

ies

prov

ided

did

not

di

ffer

sig

nifi

cant

ly.

The

pro

port

ion

of e

nerg

y pr

ovid

ed

by E

N a

nd P

N in

the

post

grou

p w

as s

igni

fica

ntly

hig

her

and

smal

ler,

res

pect

ivel

y, v

s th

e pr

eim

plem

enta

tion

gro

up.

The

fre

quen

cy o

f vo

mit

ing

was

sig

nifi

cant

ly lo

wer

in th

e po

stgr

oup

vs th

e pr

egro

up, a

nd

the

inci

denc

e of

nec

roti

zing

en

tero

coli

tis

was

not

dif

fere

nt

betw

een

the

grou

ps.

The

stu

dy r

epor

ts

high

er p

ropo

rtio

n of

nu

trie

nt d

eliv

ery

and

low

er in

cide

nce

of

EN

into

lera

nce

afte

r im

plem

enti

ng th

e al

gori

thm

in c

hild

ren

afte

r ca

rdia

c su

rger

y.N

o in

crea

se in

nec

roti

zing

en

tero

coli

tis.

Lim

itat

ions

: No

diff

eren

ce

in c

lini

cal o

utco

mes

.

(co

ntin

ued)

24

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

ims

Pop

ulat

ion

(n),

E

ligi

bili

tyIn

terv

enti

onR

esul

ts/O

utco

me

Com

men

ts

Mey

er

et a

l79T

ime

seri

es,

sing

le c

ente

rT

o ex

amin

e th

e im

pact

of

intr

oduc

ing

a se

ries

of

ent

eral

fee

ding

pr

otoc

ols

on n

utri

tion

pr

acti

ce in

a P

ICU

ov

er a

9-y

per

iod.

n =

400

Ove

r a

9-y

peri

od

and

span

ning

4

stud

ies.

Bas

elin

e ev

alua

tion

fol

low

ed

by N

GT

fee

ding

pro

toco

ls,

spec

ifyi

ng f

eedi

ng r

ate,

type

of

fee

d an

d ga

stri

c re

sidu

al

volu

me

man

agem

ent,

wer

e in

trod

uced

and

then

fur

ther

pr

otoc

ols

(inc

ludi

ng N

JT f

eedi

ng

algo

rith

m)

wer

e in

trod

uced

.

Ove

r th

e 4

peri

ods

that

re

pres

ente

d th

e ba

seli

ne a

nd

mod

ific

atio

ns o

f an

incr

emen

tal

prot

ocol

, the

fol

low

ing

seri

al

chan

ges

wer

e no

ted:

M

edia

n ti

me

to in

itia

te E

N: 1

5,

8, 5

.5, 4

.5 h

P

atie

nts

rece

ivin

g E

N: 8

9%,

81%

, 99%

, 96%

P

atie

nts

rece

ivin

g P

N: 1

1%,

19%

, 1%

, 4%

P

atie

nts

reac

hing

50%

of

EA

R

by d

ay 3

: 15%

, 26%

, 58%

, 59

%

Pat

ient

s re

achi

ng 7

0% o

f E

AR

by

day

3: 6

%, 1

0%, 3

5%, 2

1%

EN

pro

toco

ls s

hort

ened

th

e ti

me

to E

N in

itia

tion

, in

crea

sed

the

num

ber

of

pati

ents

fed

ent

eral

ly, a

nd

decr

ease

d th

e nu

mbe

r of

pa

tien

ts f

ed p

aren

tera

lly.

Lim

itat

ions

: No

chan

ges

in

clin

ical

out

com

es.

Pet

rill

o-A

lbar

ano

et a

l71

Bef

ore/

afte

r co

hort

, si

ngle

cen

ter

To

exam

ine

the

impl

emen

tati

on o

f an

ear

ly, a

ggre

ssiv

e,

ente

ral f

eedi

ng

prot

ocol

in th

e P

ICU

an

d to

des

crib

e it

s im

pact

on

tim

e to

ach

ievi

ng

goal

fee

ding

s an

d co

mpl

icat

ions

as

soci

ated

wit

h en

tera

l fe

edin

g.

n =

91

Pre

inte

rven

tion

n =

93

Pos

tint

erve

ntio

nC

riti

call

y il

l ch

ildr

en w

ho

rece

ived

NG

T

feed

ing

Init

iati

on o

f a

feed

ing

prot

ocol

in

the

PIC

U.

The

pro

toco

l als

o in

clud

ed

guid

ance

on

EN

tole

ranc

e an

d m

anag

emen

t / p

reve

ntio

n of

co

nsti

pati

on.

Out

com

e va

riab

les

for

post

inte

rven

tion

vs

prei

nter

vent

ion

grou

ps:

T

ime

to a

chie

ve g

oal f

eedi

ng

(med

ian)

: 14

vs 3

2 h,

P <

.001

R

educ

tion

in p

erce

ntag

e of

pa

tien

ts w

ith

emes

is a

nd

cons

tipa

tion

Thi

s st

udy

dem

onst

rate

d th

at a

ste

pwis

e nu

trit

ion

prot

ocol

red

uced

tim

e to

ac

hiev

ing

goal

fee

ding

an

d im

prov

ed n

utri

tion

to

lera

nce.

Lim

itat

ions

: No

diff

eren

ces

in c

lini

cal o

utco

mes

Bri

asso

ulis

et

al78

Pro

spec

tive

st

udy,

si

ngle

cen

ter

To

inve

stig

ate

the

feas

ibil

ity,

ade

quac

y,

and

effi

cacy

of

earl

y in

trag

astr

ic f

eedi

ng

n =

71

Chi

ldre

n re

quir

ing

mec

hani

cal

vent

ilat

ion

Mea

n ag

e (r

ange

):

54 (

2–20

4) m

o

Init

iati

on o

f a

feed

ing

prot

ocol

in

the

firs

t 12

h of

adm

issi

on to

P

ICU

.

Ene

rgy

inta

ke a

ppro

ache

d pr

edic

ted

basa

l met

abol

ic r

ate

the

seco

nd d

ay (

43 ±

1.7

kca

l/kg

/d v

s 43

.2 ±

1.1

kca

l/kg

/d)

and

pred

icte

d en

ergy

exp

endi

ture

(b

ased

on

stre

ss f

acto

rs)

the

fift

h da

y (6

6.2

± 2.

7 kc

al/k

g/d

vs 6

7.7

± 6.

4 kc

al/k

g/d)

The

stu

dy s

how

ed th

e ut

ilit

y of

a p

roto

col t

o ad

vanc

e E

N in

crea

sed

calo

ric

inta

ke d

urin

g th

e fi

rst 5

d o

f ad

mis

sion

to

the

PIC

U.

Lim

itat

ions

: Ene

rgy

need

s w

ere

base

d on

equ

atio

ns

and

stre

ss f

acto

rs.

EA

R, e

stim

ated

ave

rage

req

uire

men

ts; E

N, e

nter

al n

utri

tion

; IC

U, i

nten

sive

car

e un

it; L

OS

, len

gth

of s

tay;

NG

T, n

asog

astr

ic tu

be; N

JT: n

asoj

ejun

al tu

be; P

ICU

, ped

iatr

ic in

tens

ive

care

uni

t; P

N,

pare

nter

al n

utri

tion

.

Tab

le 7

. (c

onti

nu

ed)

25

Tab

le 8

. O

ptim

al R

oute

(G

astr

ic o

r S

mal

l Bow

el)

and

Tim

ing

of E

nter

al N

utri

tion

.

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

ims

Pop

ulat

ion

(n),

Eli

gibi

lity

Inte

rven

tion

Res

ults

/Out

com

eC

omm

ents

Ran

dom

ized

con

trol

led

tri

als

Mee

rt e

t al82

RC

T; s

ingl

e ce

nter

To

eval

uate

the

effe

ct o

f ga

stri

c vs

sm

all b

owel

fee

ding

tube

po

siti

on o

n1.

Nut

rien

t del

iver

y2.

Fee

ding

com

plic

atio

ns, i

nclu

ding

m

icro

asp

irat

ion

wit

h pe

psin

in

trac

heal

asp

irat

es

n =

74

Mec

hani

call

y ve

ntil

ated

, cr

itic

ally

ill c

hild

ren

n =

32

gast

ric

n =

30

smal

l bow

el12

of

42 r

ando

miz

ed to

po

stpy

lori

c gr

oup

wer

e un

able

to

hav

e fe

edin

g tu

be p

lace

d an

d ex

ited

the

stud

y

Gas

tric

vs

post

pylo

ric

feed

ing

No

sign

ific

ant d

iffe

renc

es b

etw

een

grou

ps f

or m

orta

lity

, PIC

U

LO

S, h

ospi

tal L

OS

, pne

umon

ia,

dura

tion

of

mec

hani

cal v

enti

lati

on,

into

lera

nce

(vom

itin

g, d

iarr

hea,

and

ab

dom

inal

dis

tens

ion)

, int

erru

ptio

n to

fee

ds, o

r tr

ache

al a

spir

ates

po

siti

ve f

or p

epsi

nE

xper

imen

tal (

smal

l bow

el)

grou

p ha

d si

gnif

ican

tly

high

er e

nerg

y in

take

(m

ean,

SD

per

cent

of

goal

): 4

7% ±

22

% v

s 30

% ±

23%

; P =

.01

Thi

s ra

ndom

ized

tria

l did

not

sho

w

a si

gnif

ican

t dif

fere

nce

in r

ates

of

asp

irat

ion

or f

eedi

ng to

lera

nce

betw

een

gast

ric

and

post

pylo

ric

feed

ing

grou

ps.

Lim

itat

ions

: asp

irat

ion

dete

cted

by

a cr

ude

mar

ker

(pep

sin

in tr

ache

al

aspi

rate

s); a

larg

e pr

opor

tion

of

pati

ents

in e

ach

grou

p ha

d si

gnif

ican

t nu

mbe

r of

EN

inte

rrup

tion

s an

d di

d no

t rea

ch g

oal;

and

no

diff

eren

ce in

cl

inic

al o

utco

mes

Kam

at e

t al81

RC

T; s

ingl

e ce

nter

To

eval

uate

the

freq

uenc

y of

cl

inic

al a

nd s

ubcl

inic

al a

spir

atio

n in

mec

hani

call

y ve

ntil

ated

, cr

itic

ally

ill c

hild

ren

fed

gast

ric

vs p

ostp

ylor

ic a

nd to

com

pare

m

ethy

lene

blu

e to

glu

cose

in

trac

heal

asp

irat

e to

det

ect

aspi

rati

on

n =

44

n =

17

post

pylo

ric

Med

ian

age

(95%

CI)

: 17

mo

(6.3

–62.

8 m

o)n

= 2

7 ga

stri

cM

edia

n ag

e (9

5% C

I): 4

.2 m

o (1

.5–5

5.9

mo)

2 of

19

rand

omiz

ed to

po

stpy

lori

c gr

oup

wer

e un

able

to

hav

e fe

edin

g tu

be p

lace

d af

ter

24 h

and

4 a

bdom

inal

ra

diog

raph

s; m

oved

to th

e ga

stri

c gr

oup

Gas

tric

vs

post

pylo

ric

feed

ing

Met

hyle

ne b

lue:

0.2

m

L/1

00 m

L f

orm

ula

End

otra

chea

l spe

cim

en

ever

y 8

h: b

edsi

de

test

for

glu

cose

, sp

ectr

opho

tom

etry

to

dete

ct m

ethy

lene

blu

e

Exp

erim

enta

l vs

cont

rol g

roup

T

ime

to s

tart

fee

ds: m

edia

n (9

5%

CI)

, 24

(18–

24)

vs 6

(6–

12)

h;

P =

.000

2M

edia

n (9

5% C

I) n

umbe

r of

ab

dom

inal

rad

iogr

aphs

: 4 (

3–4)

vs

1 (1

–1);

P =

.001

No

bene

fit o

f po

stpy

lori

c ov

er g

astr

ic

feed

s.T

he p

ostp

ylor

ic g

roup

exp

erie

nced

si

gnif

ican

t del

ays

in E

N in

itia

tion

due

to

the

tim

e re

quir

ed f

or f

eedi

ng tu

be

plac

emen

t.C

ente

rs w

ith

grea

ter

prof

icie

ncy

wit

h po

stpy

lori

c fe

edin

g tu

bes

may

sec

ure

plac

emen

t mor

e qu

ickl

y.L

imit

atio

ns: s

tudy

und

erpo

wer

ed

to s

how

a d

iffe

renc

e in

asp

irat

ion

betw

een

grou

ps; g

luco

se in

trac

heal

as

pira

tes

lack

s sp

ecif

icit

y an

d is

not

a

mar

ker

of a

spir

atio

n; a

nd m

ethy

lene

bl

ue is

no

long

er u

sed

due

to s

afet

y co

ncer

ns

1 Hor

n et

al77

an

d 2 H

orn

and

Cha

boye

r83

RC

T—

conv

enie

nce

sam

ple;

sin

gle

cent

er

1 To

exam

ine

the

rela

tion

ship

be

twee

n 2

gast

ric

feed

ing

regi

men

s—co

ntin

uous

and

in

term

itte

nt—

and

tole

ranc

e as

m

easu

red

by th

e nu

mbe

r of

sto

ols

and

prev

alen

ce o

f di

arrh

ea (≥3

st

ools

/24

h) a

nd v

omit

ing

2 To

exam

ine

the

effe

ct o

f ga

stri

c fe

edin

g re

gim

ens,

eit

her

cont

inuo

us o

r in

term

itte

nt, o

n G

RV

, def

ined

as

>5

mL

/kg

n =

46

n =

22

cont

inuo

us f

eedi

ngM

edia

n ag

e: 6

mo

(0–1

46 m

o)n

= 2

4 in

term

itte

nt f

eedi

ng

(1 s

ubje

ct r

emov

ed d

ue to

onl

y 1

d of

fee

ding

; fin

al n

= 2

3)M

edia

n ag

e: 8

mo

(1–1

53 m

o)R

ando

m a

ssig

nmen

t to

feed

ing

regi

men

Exp

erim

enta

l gro

up:

cont

inuo

usly

fed

wit

h pu

mp

Con

trol

gro

up: f

eedi

ngs

deli

vere

d ev

ery

2 h

over

20–

30 m

in w

ith

grav

ity

met

hod

(sta

ndar

d pr

acti

ce)

1 No

sign

ific

ant d

iffe

renc

es in

mea

n st

ool v

olum

e, d

iarr

hea,

vom

itin

g,

use

of p

roki

neti

c ag

ents

, or

anti

biot

ic u

se2 E

xper

imen

tal g

roup

vs

cont

rol g

roup

: no

sig

nifi

cant

dif

fere

nces

in v

olum

e of

for

mul

a re

ceiv

ed, G

RV

val

ues,

or

inci

denc

e of

GR

V >

5 m

L/k

g.

Tim

e to

init

iati

on o

f fe

eds

(h),

m

edia

n (r

ange

): 1

3.0

(1–6

3) v

s 18

.5

(3–2

31);

P =

.05

No

diff

eren

ce in

fee

ding

tole

ranc

e or

GR

V b

etw

een

cont

inuo

us a

nd

inte

rmit

tent

fee

ding

gro

ups

Lim

itat

ions

: tim

ing

of e

nrol

lmen

t, in

re

lati

on to

cri

tica

l ill

ness

is u

ncle

ar;

accu

rate

ade

quac

y of

fee

ding

not

av

aila

ble;

use

d no

nval

idat

ed c

rite

ria

(GR

V >

5 m

L/k

g); a

nd s

mal

l sam

ple

size

(co

nven

ienc

e sa

mpl

e) (co

ntin

ued)

26

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

ims

Pop

ulat

ion

(n),

Eli

gibi

lity

Inte

rven

tion

Res

ults

/Out

com

eC

omm

ents

Ob

serv

atio

nal

stu

die

s

Can

arie

et a

l89R

etro

spec

tive

co

hort

; m

ulti

cent

er6

PIC

Us

To

dete

rmin

e th

e fa

ctor

s as

soci

ated

w

ith

dela

yed

EN

Pat

ient

s di

vide

d in

to 2

gro

ups:

ear

ly

EN

(≤4

8 h)

and

del

ayed

EN

(>

48

h) f

rom

PIC

U a

dmis

sion

n =

444

Med

ian

age

(IQ

R):

4.0

y

(0.5

–11.

9 y)

EN

was

sta

rted

at m

edia

n of

20

h88

of

444

chil

dren

(19

.8%

) ha

d de

laye

d E

NR

isk

fact

ors

asso

ciat

ed w

ith

dela

yed

EN

: non

inva

sive

(O

R, 3

.37

[95%

C

I, 1

.69–

6.72

]) a

nd in

vasi

ve

posi

tive

-pre

ssur

e ve

ntil

atio

n (O

R, 2

.06

[95%

CI,

1.1

5–3.

69])

, se

veri

ty o

f il

lnes

s (O

R f

or e

very

0.1

in

crea

se in

PIM

2 sc

ore,

1.3

9 [9

5%

CI,

1.1

4–1.

71])

, pro

cedu

res

(OR

, 3.

33 [

95%

CI,

1.6

7–6.

64])

, and

ga

stro

inte

stin

al d

istu

rban

ces

(OR

, 2.

05 [

95%

CI,

1.1

4–3.

68])

wit

hin

48

h af

ter

adm

issi

on to

the

PIC

U

Lar

ge m

ulti

cent

er r

epor

t of

EN

pra

ctic

es

in c

riti

call

y il

l chi

ldre

n, h

ighl

ight

ing

the

role

of

noni

nvas

ive

vent

ilat

ion,

pr

oced

ures

, gas

troi

ntes

tina

l di

stur

banc

es, a

nd h

igh

illn

ess

seve

rity

as

fac

tors

that

res

ult i

n de

laye

d E

N

deli

very

.L

imit

atio

ns: a

ccur

acy

of c

lini

cal a

nd

nutr

itio

n da

ta f

rom

ret

rosp

ecti

ve c

hart

re

view

at d

iffe

rent

sit

es c

anno

t be

assu

red

and

deci

sion

mak

ing

was

not

pr

otoc

oliz

ed, t

here

fore

rat

iona

le f

or

wit

hhol

ding

EN

may

be

unce

rtai

n

Mik

hail

ov e

t al66

Ret

rosp

ecti

ve

coho

rt s

tudy

; m

ulti

cent

er12

PIC

Us

To

exam

ine

the

asso

ciat

ion

of e

arly

E

N w

ith

mor

tali

ty a

nd m

orbi

dity

Ear

ly E

N d

efin

itio

n: p

rovi

sion

of

25%

of

cum

ulat

ive

goal

EN

ca

lori

es o

ver

the

firs

t 48

h of

ad

mis

sion

n =

510

5C

riti

call

y il

l chi

ldre

n w

ith

PIC

U

LO

S ≥

96 h

Med

ian

age

(IQ

R):

2.

4 y

(0.5

–9.8

y)

27.1

% a

chie

ved

earl

y E

NM

orta

lity

: 5.3

%D

iffe

renc

e in

out

com

es b

etw

een

earl

y E

N v

s no

ear

ly E

N (

adju

sted

for

P

IM2,

age

, cen

ter)

Mor

tali

ty: O

R, 0

.51

(95%

CI

0.34

–0.7

6); P

= .0

01N

o di

ffer

ence

in L

OS

or

mec

hani

cal

vent

ilat

ion

dura

tion

Ear

ly E

N w

as a

ssoc

iate

d w

ith

redu

ced

mor

tali

ty in

this

larg

e m

ulti

cent

er

coho

rtL

imit

atio

ns: a

ccur

acy

may

be

lim

ited

by

the

retr

ospe

ctiv

e na

ture

of

the

stud

y an

d re

lian

ce o

n ch

arts

and

dat

abas

e fo

r de

tail

ed n

utri

ent d

eliv

ery

data

Meh

ta e

t al8

Pro

spec

tive

co

hort

stu

dy;

mul

tice

nter

31 P

ICU

s in

8

coun

trie

s

To

eval

uate

ade

quac

y of

ene

rgy

and

prot

ein

inta

ke in

the

PIC

U

and

thei

r re

lati

onsh

ip to

cli

nica

l ou

tcom

es

n =

500

Cri

tica

lly

ill c

hild

ren

requ

irin

g m

echa

nica

l ven

tila

tion

≥48

hM

ean

age

(SD

): 4

.5 y

(5.

1 y)

Mea

n pr

escr

ibed

goa

lsE

nerg

y: 6

4 kc

al/k

g/d

Pro

tein

: 1.7

g/k

g/d

EN

sta

rted

in ≤

48 h

fro

m a

dmis

sion

in

67%

of

pati

ents

60-d

mor

tali

ty: 8

.4%

A h

ighe

r pe

rcen

tage

of

goal

ene

rgy

inta

ke v

ia E

N w

as s

igni

fica

ntly

as

soci

ated

wit

h lo

wer

60-

d m

orta

lity

Hig

her

ente

ral e

nerg

y in

take

was

as

soci

ated

wit

h lo

wer

mor

tali

ty in

this

la

rge

mul

tice

nter

pro

spec

tive

coh

ort

stud

y.L

imit

atio

ns: e

nerg

y ne

eds

wer

e es

tim

ated

by

diet

itia

ns a

t par

tici

pati

ng

site

s (m

ostl

y by

equ

atio

ns);

sev

erit

y of

il

lnes

s sc

ores

not

ava

ilab

le in

a th

ird

of th

e co

hort

; onl

y P

ICU

s w

ith

≥ 8

beds

wer

e in

clud

ed; a

nd v

aria

bili

ty in

nu

trit

ion

prac

tice

and

res

ourc

es c

ould

ha

ve in

flue

nced

the

perf

orm

ance

of

indi

vidu

al s

ites

Tab

le 8

. (c

onti

nu

ed)

(co

ntin

ued)

27

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

ims

Pop

ulat

ion

(n),

Eli

gibi

lity

Inte

rven

tion

Res

ults

/Out

com

eC

omm

ents

Tah

a et

al86

Ret

rosp

ecti

ve

coho

rt; s

ingl

e ce

nter

To

eval

uate

the

impa

ct o

f th

e ti

me

of in

itia

tion

of

nutr

itio

n su

ppor

t an

d ac

hiev

ing

full

cal

oric

inta

ke

on P

ICU

LO

S a

nd d

ispo

siti

on

stat

us a

t dis

char

ge

n =

109

Med

ian

age

(ran

ge):

13

y (8

–18

y)C

hild

ren

wit

h se

vere

isol

ated

T

BI

Med

ian

Gla

sgow

Com

aS

cale

on

adm

issi

on to

the

ICU

: 3

19 p

atie

nts

died

bef

ore

star

ting

nu

trit

ion

and

7 di

ed b

efor

e ac

hiev

ing

full

cal

oric

inta

keT

he ti

me

to s

tart

nut

riti

on s

uppo

rt

was

cor

rela

ted

wit

h P

ICU

LO

S (

r =

0.

49; P

< .0

1)P

ICU

LO

S w

as s

hort

er w

hen

pati

ents

ac

hiev

ed f

ull c

alor

ic in

take

soo

ner

(r =

0.5

7; P

< .0

1)

In c

hild

ren

wit

h se

vere

TB

I, e

arly

and

ad

equa

te e

nerg

y in

take

was

ass

ocia

ted

wit

h sh

orte

r le

ngth

of

PIC

U s

tay.

Lim

itat

ions

: est

imat

ed e

nerg

y go

als,

he

nce

true

req

uire

men

t not

kno

wn

and

resu

lts

may

not

be

extr

apol

ated

to

othe

r ce

nter

s w

ith

diff

erin

g nu

trit

ion

and

disc

harg

e po

lici

es

Tum

e et

al87

Pro

spec

tive

co

hort

; sin

gle

cent

er

1. T

o co

mpa

re a

ctua

l cal

orie

inta

ke

wit

h es

tim

ated

req

uire

men

ts2.

Det

erm

ine

whe

ther

fee

ding

gu

idel

ine

adhe

renc

e re

sult

ed in

im

prov

ed n

utri

tion

inta

ke

n =

47

Med

ian

age

(ran

ge):

10

mo

(0.0

3–16

8 m

o)

EN

init

iati

on ≤

6 h

post

adm

issi

on

targ

et: 4

6%55

% r

ecei

ved

<50

% e

stim

ated

nee

dsA

dher

ence

to g

uide

line

s w

as r

epor

ted

in 3

5% o

f th

e co

hort

.In

chi

ldre

n w

ho w

ere

fed

foll

owin

g th

e gu

idel

ines

, ene

rgy

inta

ke w

as

75%

vs

38%

of

esti

mat

ed g

oal,

P

= .0

04

A m

ajor

ity

of p

atie

nts

rece

ived

<50

% o

f pr

escr

ibed

ene

rgy

goal

. Adh

eren

ce to

fe

edin

g gu

idel

ines

impr

oved

nut

riti

on

inta

ke.

Lim

itat

ions

: sm

all s

ampl

e si

ze; s

tudy

li

mit

ed to

24

h; a

nd n

o cl

inic

al

outc

omes

rep

orte

d

Lóp

ez-H

erce

et a

l84P

rosp

ecti

ve

coho

rt; s

ingl

e ce

nter

Eva

luat

e to

lera

nce

and

adve

rse

effe

cts

of p

ostp

ylor

ic E

N in

cr

itic

ally

ill c

hild

ren

wit

h sh

ock

vs w

itho

ut s

hock

n =

526

Cri

tica

lly

ill c

hild

ren

adm

itte

d to

P

ICU

and

rec

eive

d po

stpy

lori

c E

Nn

= 6

5 w

ith

shoc

kM

edia

n ag

e (r

ange

): 1

2 m

o (0

.7–2

64 m

o)n

= 4

61 w

itho

ut s

hock

Med

ian

age

(ran

ge):

5 m

o (0

.1–2

28 m

o); P

= .0

001

Pat

ient

s w

ith

shoc

k vs

thos

e w

itho

ut

shoc

k:M

ore

gast

roin

test

inal

com

plic

atio

ns:

20 (

30.7

%)

vs 4

2 (9

.1%

), P

= .0

20;

mor

e ga

stri

c di

sten

tion

/res

idue

: 10

(15.

4%)

vs 2

3 (5

%),

P =

.004

; mor

e di

arrh

ea: 1

3 (2

0%)

vs 2

1 (4

.6%

),

P =

.000

1; 1

vs

0 du

oden

al

perf

orat

ion

resu

ltin

g in

dea

th;

defi

nite

sus

pens

ion

of E

N: 6

(9.

2%)

vs 5

(1%

), P

= .0

001;

hig

her

mor

tali

ty: 1

8 (2

7.7%

) vs

32

(6.9

%),

P

= .0

001

Thi

s is

a la

rge

coho

rt o

f ch

ildr

en f

ed

via

the

post

pylo

ric

rout

e. P

atie

nts

wit

h sh

ock

had

mor

e ga

stro

inte

stin

al

com

plic

atio

ns c

ompa

red

wit

h th

ose

wit

hout

sho

ck.

Lim

itatio

ns: d

ata

colle

ctor

s kn

ew b

oth

expo

sure

and

out

com

es a

t tim

e of

dat

a co

llect

ion;

EN

tole

ranc

e ca

n be

dif

ficu

lt to

obj

ectiv

ely

asse

ss; a

nd p

atie

nts

with

sh

ock

rece

ived

sig

nifi

cant

ly h

ighe

r do

ses

of d

opam

ine,

epi

neph

rine

, m

ilrin

one,

mid

azol

am, f

enta

nyl,

and

vecu

roni

um.

Sán

chez

et a

l88P

rosp

ecti

ve

coho

rt; s

ingl

e ce

nter

To

com

pare

tole

ranc

e an

d co

mpl

icat

ions

ass

ocia

ted

wit

h ea

rly

vs la

te tr

ansp

ylor

ic E

NE

arly

EN

def

init

ion:

<24

h f

rom

P

ICU

adm

issi

on

n =

526

Cri

tica

lly

ill c

hild

ren

adm

itte

d to

PIC

U a

nd r

ecei

ved

tran

spyl

oric

EN

n =

202

ear

ly E

Nn

= 3

24 la

te E

N

Ear

ly v

s la

te E

N:

EN

init

iati

on: 0

.7 ±

0.2

vs

5.3

± 7.

4 d,

P <

.001

No

diff

eren

ce in

mor

tali

ty, n

osoc

omia

l pn

eum

onia

, max

imum

cal

orie

in

take

, dia

rrhe

aSu

pple

men

tal p

aren

tera

l nut

ritio

n: 0

.2

± 1.

4 vs

0.9

± 2

.8 d

Low

K+ (1

6.3%

vs

29.9

%; P

< .0

5)L

ow C

a++ (3

.5%

vs

12.1

%; P

< .0

5)A

bdom

inal

dis

tent

ion:

3.5

% v

s 7.

8%;

P <

.05

Ear

ly E

N <

24 h

was

ach

ieve

d in

> o

ne-

thir

d of

chi

ldre

n in

this

larg

e st

udy

Ear

ly E

N g

roup

rec

eive

d le

ss s

edat

ion

vs la

te E

N—

thes

e m

edic

atio

ns m

ay

affe

ct a

bdom

inal

dis

tent

ion

and

EN

to

lera

nce.

Lim

itat

ions

: abd

omin

al d

iste

ntio

n, h

igh

GR

V, a

nd d

iarr

hea

are

not s

peci

fic

or

accu

rate

mea

sure

s of

into

lera

nce

and

illn

ess

seve

rity

not

ass

esse

d

Tab

le 8

. (c

onti

nu

ed)

(co

ntin

ued)

28

Ref

eren

ceS

tudy

Des

ign;

N

o. o

f S

ites

Stu

dy A

ims

Pop

ulat

ion

(n),

Eli

gibi

lity

Inte

rven

tion

Res

ults

/Out

com

eC

omm

ents

Lóp

ez-H

erce

et a

l85P

rosp

ecti

ve

coho

rt; s

ingl

e ce

nter

Com

pare

tole

ranc

e of

tran

spyl

oric

E

N in

chi

ldre

n w

ith

AR

F v

s ot

her

crit

ical

ly il

l chi

ldre

nA

RF

def

ined

as

acut

e in

crea

se in

cr

eati

nine

>2×

upp

er n

orm

al f

or

age,

wit

h or

wit

hout

cha

nge

in

diur

esis

and

/or

need

for

ren

al

repl

acem

ent t

hera

py

n =

526

Cri

tica

lly

ill c

hild

ren

adm

itte

d to

PIC

U a

nd r

ecei

ved

tran

spyl

oric

EN

n =

53

(10%

) w

ith

AR

FM

edia

n ag

e (r

ange

): 1

8 m

o (0

.6–2

64 m

o)n

= 4

73 w

itho

ut A

RF

Med

ian

age

(ran

ge):

5 m

o (0

.1–2

16 m

o); P

= .0

01n

= 3

8 (7

1.6%

) of

pat

ient

s w

ith

AR

F r

equi

red

cont

inuo

us r

enal

re

plac

emen

t the

rapy

AR

F v

s no

AR

F

Max

imum

inta

ke: 7

7 (2

6.7)

vs

85

(24.

9) k

cal/

kg/d

; P =

.029

S

hock

: 49%

vs

8.2%

; P =

.000

1

Mor

talit

y: 3

0.1%

vs

7.1%

; P =

.000

1

Gas

troi

ntes

tina

l com

plic

atio

ns:

24.5

% v

s 9.

9%; P

= .0

08

Abd

omin

al d

iste

ntio

n, h

igh

gast

ric

resi

dual

vol

ume:

17%

vs

5%;

P =

.003

E

N s

uspe

nded

: 1.2

vs

9.4%

; P

= .0

001

EN

init

iati

on <

48 h

of

adm

issi

on w

as

not d

iffe

rent

bet

wee

n gr

oups

Pat

ient

s w

ith

AR

F r

ecei

ved

less

en

ergy

fro

m E

N a

nd e

xper

ienc

ed

mor

e ga

stro

inte

stin

al c

ompl

icat

ions

co

mpa

red

wit

h th

ose

wit

hout

AR

F.

Lim

itat

ions

: dat

a co

llec

tors

not

bli

nded

to

mod

e of

fee

ding

; EN

tole

ranc

e ca

n be

dif

ficu

lt to

obj

ecti

vely

ass

ess;

and

sa

me

popu

lati

on r

epor

ted

in 2

oth

er

stud

ies.

Pet

rill

o-A

lbar

ano

et a

l71R

etro

spec

tive

, be

fore

/aft

er

coho

rt; s

ingl

e ce

nter

To

exam

ine

the

impl

emen

tati

on

of a

n ea

rly

EN

pro

toco

l (≤6

h

from

adm

issi

on)

and

to d

escr

ibe

its

impa

ct o

n ti

me

to a

chie

ve

goal

fee

ding

s an

d co

mpl

icat

ions

as

soci

ated

wit

h E

N

n =

91

Pre

inte

rven

tion

Med

ian

age

(IQ

R):

29.

7 m

o (5

.7–1

19.8

mo)

n =

93

Pos

tint

erve

ntio

nM

edia

n ag

e (I

QR

): 2

1.6

mo

(2.9

–88.

8 m

o)

Pos

tint

erve

ntio

n vs

pre

inte

rven

tion

T

ime

to g

oal E

N, m

edia

n (I

QR

): 1

4 (9

–21.

5) v

s 32

(12

–78)

h;

P <

.000

1

Les

s di

arrh

ea: P

= .0

09

Les

s co

nsti

pati

on: P

= .0

12

Thi

s st

udy

dem

onst

rate

d th

at a

ste

pwis

e nu

trit

ion

prot

ocol

red

uced

tim

e to

ach

ieve

goa

l EN

and

impr

oved

fe

edin

g to

lera

nce.

Lim

itat

ions

: abd

omin

al d

iste

ntio

n an

d di

arrh

ea m

ay n

ot b

e sp

ecif

ic o

r ac

cura

te m

easu

res

of in

tole

ranc

e.

Bri

asso

ulis

et a

l78P

rosp

ecti

ve

stud

y; s

ingl

e ce

nter

To

inve

stig

ate

the

feas

ibil

ity,

ad

equa

cy, a

nd e

ffic

acy

of e

arly

ga

stri

c fe

edin

g (≤

12 h

fro

m

adm

issi

on)

n =

71

Cri

tica

lly

ill c

hild

ren

requ

irin

g m

echa

nica

l ven

tila

tion

Med

ian

age

(ran

ge):

54

mo

(2–2

04 m

o)

Cal

oric

inta

ke a

ppro

ache

d pr

edic

ted

BM

R o

n da

y 2

and

esti

mat

ed n

eeds

(B

MR

× 1

.5)

on d

ay 5

Cor

rela

tion

bet

wee

n ca

lori

e in

take

and

se

veri

ty o

f il

lnes

s: p

edia

tric

Ris

k of

M

orta

lity

sco

re: r

= −

0.35

; P =

.003

; T

hera

peut

ic I

nter

vent

ion

Sco

ring

S

yste

m: r

= −

0.37

; P =

.002

Thi

s st

udy

show

ed th

at u

se o

f a

gast

ric

EN

pro

toco

l inc

reas

ed c

alor

ic in

take

du

ring

the

firs

t 5 d

of

adm

issi

on to

th

e P

ICU

AR

F, a

cute

ren

al f

ailu

re; B

MR

, bas

al m

etab

olic

rat

e; E

N, e

nter

al n

utri

tion

; GR

V, g

astr

ic r

esid

ual v

olum

e; I

QR

, int

erqu

arti

le r

ange

; LO

S, l

engt

h of

sta

y; O

R, o

dds

rati

o; P

IM2,

Ped

iatr

ic I

ndex

of

Mor

tali

ty 2

; RC

T, r

ando

miz

ed

cont

roll

ed tr

ial;

TB

I, tr

aum

atic

bra

in in

jury

.

Tab

le 8

. (c

onti

nu

ed)

Mehta et al 29

Quality of evidence. Low.GRADE recommendation. Weak.

Question 6B: When should EN be initiated?

Recommendation 6B. On the basis of expert opinion, we suggest that EN be initiated in all critically ill children, unless it is contra-indicated. Given the observational studies, we suggest early initia-tion of EN, within the first 24–48 hours after admission to the PICU, in eligible patients. We suggest the use of institutional EN guidelines and stepwise algorithms that include criteria for eligi-bility for EN, timing of initiation, and rate of increase.Quality of evidence. Low.GRADE recommendation. Weak.Rationale. Gastric feeding is physiologic and is the preferred EN route for critically ill children, unless the child has perceived or demonstrated risks of aspiration of gastric contents into the tra-cheobronchial tree. The use of small intestinal (postpyloric) feed-ing in 2 small RCTs did not demonstrate reduced aspiration when compared with gastric feeding.81,82 The postpyloric route was associated with a higher proportion of goal nutrition delivery in 1 study82 but a delay in the initiation of nutrition via the postpyloric route in a second study.81 The provision of EN into the small bowel requires the placement of a feeding tube past the pylorus. This can be accomplished by several methods but requires time and expertise and incurs higher costs. In a single-center study, mechanical problems with postpyloric tubes led to frequent EN interruptions and failure to achieve delivery of goal nutrients.61 In centers with the necessary expertise and resources to successfully place postpyloric feeding tubes, this route may be used with cau-tion to improve nutrient delivery. Gastric feeding has been administered to critically ill children as either a continuous or an intermittent modality. In 2 RCTs comparing continuous versus intermittent gastric feeding, authors reported no differences in EN tolerance.77,83 Single-center observational studies have dem-onstrated the feasibility of postpyloric EN among cohorts of criti-cally ill children with a higher prevalence of EN intolerance, such as those with shock and acute kidney injury.84,85

Wide variability in the definition of early EN for the criti-cally ill child has been reported in the published literature. A majority of the studies have described initiation as early as 6 hours and as late as 48 hours after admission to the PICU.66,71,89 In a multicenter study of nutrient delivery in the PICU, early EN—defined as delivery of one-quarter of cumulative goal enteral energy over the first 48 hours—was associated with a survival benefit.66 In a multicenter retrospective examination of EN initiation in the PICU, feeding was delayed >48 hours from admission in 20% of the patients.89 Positive-pressure invasive and noninvasive ventilation, procedures, and gastro-intestinal disturbances were common risk factors associated with delayed EN. The use of stepwise protocols or guidelines for EN delivery in the PICU has been associated with signifi-cant reductions in the time to start EN.71,78

Future direction. Future large-scale RCTs should evaluate the benefits of gastric versus small bowel feeding, early versus

delayed EN (<24 vs ≥48 hours), and bolus/intermittent versus continuous gastric feeding. These studies must have clear defi-nitions of EN delivery targets and intolerance and must include important clinical outcomes, including hospital-acquired com-plications, PICU and hospital LOS, and duration of mechanical ventilation.

Question 7A: What is the indication for and optimal timing of PN in critically ill children?

Recommendation 7A. On the basis of a single RCT, we do not recommend the initiation of PN within 24 hours of PICU admission (see Table 9).Quality of evidence. Moderate.GRADE recommendation. Strong.

Question 7B: What is the role of PN as a supplement to inadequate EN?

Recommendation 7B. For children tolerating EN, we suggest stepwise advancement of nutrient delivery via the enteral route and delaying commencement of PN. Based on current evidence, the role of supplemental PN to reach a specific goal for nutrient delivery is not known. The time when PN should be initiated to supplement insufficient EN is also unknown. The threshold for and timing of PN initiation should be individualized.

Based on a single RCT, supplemental PN should be delayed until 1 week after PICU admission for patients with normal baseline nutrition state and low risk of nutrition deterioration. On the basis of expert consensus, we suggest PN supplementa-tion in children who are unable to receive any EN during the first week in the PICU. For patients who are severely malnour-ished or at risk of nutrition deterioration, PN may be supple-mented in the first week if they are unable to advance past low volumes of EN.Quality of evidence. Low.GRADE recommendation. Weak.Rationale. As previously discussed, EN is the preferred route of nutrition support for the critically ill child; however, PN should be considered when EN is not feasible or is contraindi-cated. The use of PN as a supplement to EN, the timing of supplemental PN initiation, and the targeted macronutrient goal are key questions that will require an evidence-based approach. Unfortunately, there is little evidence to guide these practices. In a recent 3-center RCT (PEPaNIC trial [ie, “Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit”]) addressing timing of supplemental PN in critically ill children, the group with late initiation of PN (on day 8) demon-strated better outcomes (fewer new infections and shorter length of PICU stay) when compared with the early PN group (receiving PN within 24 hours of admission).90 Also, the late PN group was likely to have an earlier live discharge from the PICU, shorter duration of mechanical ventilation, and lower odds of renal replacement therapy.

The finding that can be strongly generalizable from this study is that PN should not be started within 24 hours of PICU

30

Tab

le 9

. In

dica

tion

and

Opt

imal

Tim

ing

of P

aren

tera

l Nut

riti

on in

Cri

tica

lly

Ill C

hild

ren.

Ref

eren

ceS

tudy

Des

ign;

No.

of

Sit

esP

opul

atio

n (n

),

Eli

gibi

lity

Stu

dy A

ims

Inte

rven

tion

Res

ults

/Out

com

eC

omm

ents

Fiv

ez e

t al90

Ran

dom

ized

co

ntro

lled

tria

l; 3

ce

nter

s

n =

144

0T

erm

new

born

—17

y>

24

h ex

pect

ed P

ICU

st

ayS

TR

ON

GK

ids

Nut

riti

on s

core

>

2 (0

, low

ris

k of

m

alnu

trit

ion;

1–3

, m

ediu

m r

isk;

4–5

, hi

gh r

isk)

To

inve

stig

ate

whe

ther

a

late

PN

str

ateg

y (w

ithh

oldi

ng P

N

up to

day

8)

in th

e P

ICU

is c

lini

call

y su

peri

or to

an

earl

y P

N s

trat

egy

(sta

rtin

g P

N w

ithi

n 24

h o

f ad

mis

sion

)P

rim

ary

end

poin

ts:

new

PIC

U-a

cqui

red

infe

ctio

ns, d

urat

ion

of

PIC

U d

epen

denc

y

Exp

erim

enta

l gr

oup:

late

P

N—

star

ted

on

the

mor

ning

of

eigh

th P

ICU

day

if

una

ble

to r

each

at

leas

t 80%

ca

lori

c go

al b

y E

N.

Con

trol

gro

up:

earl

y P

N—

star

ted

wit

hin

24

h of

adm

issi

on,

disc

onti

nued

w

hen

EN

m

eeti

ng a

t lea

st

80%

of

the

goal

.

Out

com

es in

exp

erim

enta

l vs

con

trol

gro

ups

N

o si

gnif

ican

t di

ffer

ence

s be

twee

n th

e gr

oups

for

PIC

U,

hosp

ital

, or

90-d

m

orta

lity

P

ICU

LO

S (

mea

n ±

SD

):

6.5

± 0.

4 vs

9.2

± 0

.8;

P <

.001

P

atie

nts

in P

ICU

≥8

d:

159

of 7

17 v

s 21

6 of

72

3; P

< .0

01

Hos

pita

l LO

S: 1

7.2

± 1.

0 vs

21.

3 ±

1.3;

P <

.001

A

cqui

red

infe

ctio

ns:

77 v

s 13

4; P

< .0

01;

sign

ific

ant d

iffe

renc

es in

bl

oods

trea

m a

nd a

irw

ay

infe

ctio

ns

Mec

hani

cal v

enti

lati

on

dura

tion

(d)

: 4.4

± 0

.3 v

s 6.

4 ±

0.7;

P =

.001

H

ypog

lyce

mia

(<

40 m

g/dL

in f

irst

wee

k): 6

5 vs

35

; P =

.001

PN

use

wit

hin

24 h

of

adm

issi

on

in a

ll c

hild

ren

in P

ICU

is n

ot

supe

rior

to la

te P

N s

trat

egy.

Lim

itat

ions

: The

ext

erna

l va

lida

tion

of

this

tria

l res

ults

is

lim

ited

. Cau

tion

mus

t be

used

w

ith

extr

apol

atio

n to

sev

erel

y m

alno

uris

hed

chil

dren

, who

w

ere

not a

dequ

atel

y re

pres

ente

d.S

TR

ON

Gki

ds is

not

val

idat

ed in

cr

itic

ally

ill c

hild

ren.

Def

init

ion

of c

alor

ic a

nd p

rote

in

goal

s no

t sta

ndar

dize

d ac

ross

st

udy—

equa

tion

s us

ed to

es

tim

ate

ener

gy r

equi

rem

ents

in

maj

orit

y of

coh

ort.

Gly

cem

ic m

anag

emen

t and

the

com

posi

tion

of

EN

and

PN

wer

e no

t sta

ndar

dize

d ac

ross

stu

dy

cent

ers.

Def

init

ion

of in

fect

ions

was

not

st

anda

rd a

nd p

rese

nce

or a

bsen

ce

of c

athe

ters

was

not

pro

vide

d.

EN

, ent

eral

nut

riti

on; L

OS

, len

gth

of s

tay;

PIC

U, p

edia

tric

inte

nsiv

e ca

re u

nit;

PN

, par

ente

ral n

utri

tion

; ST

RO

NG

Kid

s, S

cree

ning

Too

l for

Ris

k of

Im

pair

ed N

utri

tion

al S

tatu

s an

d G

row

th.

Mehta et al 31

admission. For reasons outlined below, we recommend caution in broadly applying the delayed PN strategy (8 d until initia-tion) used in the control group of this study. Children in this study received significant enteral calories: mean of 30 kcal/kg/d (300 kcal/d) by day 4. It is possible that most of these children could have been sustained enterally through a robust EN protocol.70,71 Children in this study were discharged at rates that are standard in most PICUs: 50% left the PICU by day 4 and 74% by day 8. As only 24% of the late PN cohort was exposed to PN, the intervention arm of the trial was more rep-resentative of a “no PN” strategy. Again, this supports the con-clusion that initiation of PN within the first 24 hours of admission is not advisable as a general strategy in the PICU.

Our expert consensus is that PN should not be withheld until day 8 as a universal strategy in critically ill children. Since most children were receiving significant amounts of EN, the results of the PEPaNIC trial may not be extrapolated to children receiv-ing no EN. The proportion of severely malnourished children in the study is unclear and likely to be low. The nutrition assess-ment/screening tool used in the study (STRONGkids) has not been validated for critically ill children, and its accuracy in hos-pitalized children has been questioned.20 Also, BMI z scores of patients in the study suggest that most children were well nour-ished at PICU admission. Therefore, the results cannot be extrapolated to severely malnourished children or those at risk of malnutrition, who may not tolerate a week of cumulative nutrient deficit accrued by the late PN strategy. Finally, other vulnerable groups—such as children admitted to the PICU with contraindications to EN, intestinal failure, or requiring extra-corporeal membrane oxygenation—often rely on PN to meet nutrient needs. In these subgroups, the optimal timing of PN to supplement or replace EN as the mode of nutrient delivery will need to be determined by future trials.

The PEPaNIC investigators chose an EN energy delivery threshold of <80% goal to trigger supplemental PN at the 2 time points. A majority of children in this study had energy expenditure estimated with equations that have been discred-ited in critically ill children (see recommendations and ratio-nale for question 2B). Hence, it is possible that a significant portion of children in the early PN arm of this study were over-fed. In addition, glycemic control protocols were different in the 3 centers. Multiple problems exist with 1 of the primary outcomes in this study: new infections acquired during the ICU stay. The investigators used nonstandard definitions of acquired infections such as ventilator-associated pneumonia and cathe-ter-related bloodstream infection. The presence of indwelling devices (eg, central venous catheters) in the 2 groups was not reported. It is not clear how the investigators distinguished an infection present at baseline from a new infection.

The role of PN initiated from 2 to 7 days in the PICU cannot be determined by this study, and the findings of this study need to be confirmed by future RCTs. Until then, EN should be initi-ated and actively advanced in eligible children in the PICU. The optimal timing of supplemental PN in children failing to

meet their nutrient delivery goals enterally must be individual-ized based on the nutrition and clinical status of the patient, and anticipated nutrient deficits during the course of illness.Future direction. Future studies should focus on determining the optimal timing for PN supplementation in cases where EN is insufficient to meet the nutrition requirements during the first week of critical illness. These trials must account for the varying baseline nutrition status of patients and their individu-alized energy and protein goals.

Question 8: What is the role of immunonutrition in criti-cally ill children?

Recommendation 8. On the basis of available evidence, we do not recommend the use of immunonutrition in critically ill children (see Table 10).Quality of evidence. Moderate.GRADE recommendation. Strong.Rationale. Several dietary components—including glutamine, arginine, nucleotides, ω-3 fatty acids, fiber, antioxidants, sele-nium, copper, and zinc—have been used in various combina-tions to modulate dysregulated immune responses induced by critical illness, injury, and surgery. The aim is to achieve a therapeutic benefit (eg, to attenuate inflammation or provide nutrients depleted by stress). Terms used to describe this therapy include immunonutrition, immunonutrients, immuno-nutrient-enhanced diet, immune-enhancing nutrition, immune-modulating nutrition, pharmaconutrition, pharmaconutrients, and pharmaceutical nutrients. RCTs comparing immunonutri-tion with standard nutrition among critically ill children have used a variety of nutrients, delivered via the enteral or paren-teral route, in heterogeneous populations, and with different methods to estimate energy needs. In some studies, a combina-tion of interventions has been studied; therefore, the impact of any single immunonutrient is difficult to interpret. In 1 pilot RCT and 1 retrospective cohort, investigators examined the use of an enteral formula containing ω-3 fatty acids, γ-linolenic acid, and antioxidants in critically ill children with acute respi-ratory distress syndrome.91,92 Although the specialty formulae were feasible and tolerated in these studies, neither study was powered to show difference in outcomes. Small single-center studies randomizing critically ill children with respiratory fail-ure, septic shock, and traumatic brain injury to an enteral for-mula containing glutamine, arginine, antioxidants, fiber, and ω-3 fatty acids or to a standard pediatric formula were also underpowered and unable to demonstrate outcome differ-ences.93,94 In 2 studies, infants requiring PN were randomized to receive intravenous lipid emulsion as ω-3 fatty acids, alone or in combination with medium-chain and long-chain (ω-6) fats or a 100% soybean oil–based lipid (ω-6).95,96 These studies were designed to evaluate the effects of the 2 lipid formula-tions on inflammatory biomarkers; relevant clinical outcomes for critically ill children were not evaluated. Lipids containing ω-3 versus 100% ω-6 fatty acids were associated with lower plasma proinflammatory cytokines and potential for reduced

32

Tab

le 1

0. R

ole

of I

mm

unon

utri

tion

.

Ref

eren

ceS

tudy

Des

ign

Stu

dy A

ims

Pop

ulat

ion

(n),

Eli

gibi

lity

Inte

rven

tion

Res

ults

/Out

com

eC

omm

ents

Jord

an e

t al98

RC

TT

o de

term

ine

whe

ther

GL

N

supp

lem

enta

tion

has

a

role

mod

ifyi

ng b

oth

the

oxid

ativ

e st

ress

and

the

infl

amm

ator

y re

spon

se o

f cr

itic

ally

ill c

hild

ren

n =

101

. C

riti

call

y il

l chi

ldre

n w

ith

seve

re s

epsi

s or

aft

er

maj

or s

urge

ry r

equi

ring

P

N f

or a

t lea

st 5

d.

Exp

erim

enta

l gro

up (

n =

49)

: sta

ndar

d P

N +

GL

N.

Con

trol

gro

up (

n =

49)

: sta

ndar

d P

N

At d

ay 5

, pat

ient

s in

the

PN

+ G

LN

gro

up

had

sign

ific

antl

y hi

gher

leve

ls o

f H

SP

-70

as c

ompa

red

wit

h co

ntro

ls (

68.6

vs

5.4,

P =

.0

14).

No

sign

ific

ant d

iffe

renc

es in

IL

-10

or I

L-6

(no

re

duct

ions

wit

h gl

utam

ine)

.N

o si

gnif

ican

t dif

fere

nces

bet

wee

n th

e gr

oups

fo

r P

ICU

LO

S o

r ho

spit

al L

OS

.N

o ad

vers

e ev

ents

in e

ithe

r gr

oup.

GL

N s

uppl

emen

tati

on in

PN

ad

min

iste

red

to c

riti

call

y il

l ch

ildr

en f

aile

d to

sho

w a

ny

diff

eren

ces

in c

lini

cal o

utco

mes

, bu

t hel

ped

to m

aint

ain

leve

ls o

f H

SP

-70

by d

ay 5

.L

imit

atio

ns: E

vent

ual s

ampl

e si

ze

was

not

pow

ered

to d

emon

stra

te

clin

ical

out

com

es.

1 Lar

sen

et a

l95 a

nd

2 Lar

sen

et a

l97R

CT

Exa

min

e ef

fect

s of

2

diff

eren

t lip

id e

mul

sion

s on

1 plas

ma

phos

phol

ipid

s an

d 2 im

mun

e bi

omar

kers

n =

32

Infa

nts

wit

h co

ngen

ital

he

art d

isea

se s

ched

uled

fo

r op

en h

eart

sur

gery

w

ith

card

iopu

lmon

ary

bypa

ssM

ean

age

(SD

): 4

0 (0

.6)

wk

gest

atio

nal a

ge, 3

.5

+ 0

.5 k

g, a

nd 1

0.6

d at

ti

me

of s

urge

ry

n =

16

Exp

erim

enta

l gro

up:

L

ipop

lus:

50%

med

ium

-cha

in

trig

lyce

ride

s, 4

0% lo

ng-c

hain

tr

igly

ceri

des,

10%

fis

h oi

ln

= 1

6 C

ontr

ol g

roup

:

Intr

alip

id: 1

00%

soy

bean

oil

Sub

ject

s w

ere

rand

omiz

ed to

rec

eive

1

of 2

lipi

d em

ulsi

ons

wit

h T

PN

, fo

r 1–

4 d

preo

pera

tive

and

10

d po

stop

erat

ive

Lip

ids

star

ted

at 0

.5 g

/kg,

incr

ease

d to

m

ax 3

.5 g

/kg/

dE

nter

al in

take

was

lim

ited

to a

t 30

kcal

/kg/

d

1 Exp

erim

enta

l vs

cont

rol g

roup

s: lo

wer

pr

ocal

cito

nin

1 da

y po

stop

erat

ivel

y (P

= .0

1),

low

er ω

-6 to

ω-3

rat

io (

P =

.000

1), h

ighe

r ω

-3 c

once

ntra

tion

(P

= .0

01),

hig

her

plas

ma

phos

phol

ipid

EP

A (

P <

.05)

; α-l

inol

enic

aci

d,

arac

hido

nic

acid

, and

doc

osah

exae

noic

aci

d re

mai

ned

cons

tant

An

incr

ease

in p

lasm

a ph

osph

olip

id E

PA

w

as a

ssoc

iate

d w

ith

a de

crea

se in

pla

sma

phos

phol

ipid

LT

B4

conc

entr

atio

n (P

< .0

5)O

n po

stop

erat

ive

day

10, t

hose

wit

h hi

gh P

RIS

M

III

scor

es e

xhib

ited

a 4

5% lo

wer

lym

phoc

yte

conc

entr

atio

n (P

< .0

5)2 T

NF

-α c

once

ntra

tion

was

low

er in

the

expe

rim

enta

l vs

cont

rol g

roup

(5.

9 vs

14.

8 pg

/m

L, P

= .0

03)

Pla

sma

TN

F-α

was

pos

itiv

ely

corr

elat

ed w

ith

hosp

ital

LO

S in

the

cont

rol g

roup

(P

= .0

1),

and

nega

tive

ly c

orre

late

d w

ith

LO

S in

the

trea

tmen

t gro

up (

P =

.004

), w

ith

a si

gnif

ican

t ti

me

by tr

eatm

ent i

nter

acti

on (

P =

.02)

An

IV li

pid

emul

sion

wit

h ω

-3

fats

pro

vide

s a

mor

e be

nefi

cial

in

flam

mat

ory

and

imm

une

stat

us

com

pare

d w

ith

a li

pid

emul

sion

w

ith

ω-6

fat

s in

infa

nts

wit

h co

ngen

ital

hea

rt d

isea

se r

equi

ring

op

en-h

eart

sur

gery

. It i

s un

know

n if

this

dif

fere

nce

wou

ld tr

ansl

ate

to

clin

ical

out

com

es.

Neh

ra e

t al96

RC

Tn

= 1

9N

eona

tes

and

infa

nts

<3

mo

wit

h a

dire

ct b

ilir

ubin

<

1.0

mg/

dL a

nd P

N

depe

nden

t

To

asse

ss th

e sa

fety

an

d ef

fica

cy o

f a

fish

oi

l–ba

sed

intr

aven

ous

fat

emul

sion

in r

educ

ing

the

inci

denc

e of

cho

lest

asis

in

neo

nate

s co

mpa

red

wit

h th

e tr

adit

iona

l so

ybea

n oi

l–ba

sed

intr

aven

ous

fat e

mul

sion

Bot

h gr

oups

rec

eive

d in

trav

enou

s fa

t em

ulsi

on a

t 1 g

/kg/

d an

d ke

pt

cons

tant

dur

ing

the

stud

y pe

riod

.E

xper

imen

tal g

roup

: rec

eive

d fi

sh

oil–

base

d in

trav

enou

s fa

t em

ulsi

onC

ontr

ol g

roup

: rec

eive

d so

ybea

n oi

l–ba

sed

intr

aven

ous

fat e

mul

sion

Pat

ient

s w

ith

pers

iste

ntly

ele

vate

d di

rect

bil

irub

in >

2 m

g/dL

wer

e co

nsid

ered

trea

tmen

t fai

lure

s an

d w

ere

cros

sed

over

to th

e ot

her

stud

y ar

m.

Dev

elop

men

tal a

sses

smen

t was

co

nduc

ted

at 6

and

24

mo

of

corr

ecte

d ag

e.

No

sign

ific

ant d

iffe

renc

e in

cho

lest

asis

(m

axim

um d

irec

t bil

irub

in)

betw

een

the

grou

ps.

Inte

rim

ana

lysi

s di

d no

t sho

w

diff

eren

ces,

pos

sibl

y be

caus

e of

a

low

inci

denc

e of

cho

lest

asis

am

ong

the

pati

ents

enr

olle

dU

nder

pow

ered

stu

dy; (

requ

ired

n

= 3

0).

Add

itio

nall

y bo

th g

roup

s w

ere

held

at

1 g

/kg/

d of

fat

em

ulsi

on. T

his

is le

ss th

an s

tand

ard

fat e

mul

sion

ad

vanc

emen

t. P

erha

ps li

mit

ing

fat i

ntak

e in

pat

ient

s to

1 g

/kg/

d sh

ould

be

eval

uate

d.

(co

ntin

ued)

33

Ref

eren

ceS

tudy

Des

ign

Stu

dy A

ims

Pop

ulat

ion

(n),

Eli

gibi

lity

Inte

rven

tion

Res

ults

/Out

com

eC

omm

ents

Jaco

bs e

t al91

RC

T, p

ilot

fe

asib

ilit

yT

o de

term

ine

if c

onti

nuou

s fe

edin

g of

ent

eral

nu

trit

ion

cont

aini

ng E

PA

, G

LA

, and

ant

ioxi

dant

s w

as f

easi

ble

in c

riti

call

y il

l chi

ldre

n w

ith

AL

I or

A

RD

S

n =

26

Cri

tica

lly

ill c

hild

ren

rece

ivin

g m

echa

nica

l ve

ntil

ator

y su

ppor

t wit

h A

LI

or A

RD

SM

ean

age

(SD

) 6.

2 (0

.9)

y

Exp

erim

enta

l gro

up (

n=14

):R

ecei

ved

EN

for

mul

a w

ith

EP

A +

G

LA

Con

trol

gro

up (

n =

12)

Rec

eive

d st

anda

rd p

edia

tric

ent

eral

fo

rmul

aG

oal i

ntak

e de

fine

d as

>75

% o

f S

chof

ield

BM

R ×

1.3

wit

hin

48 h

of

init

iati

on o

f E

N.

No

sign

ific

ant d

iffe

renc

es b

etw

een

the

2 gr

oups

, fo

r P

ICU

LO

S, h

ospi

tal L

OS

, dur

atio

n of

MV

, or

ene

rgy

inta

ke.

Pro

tein

inta

ke w

as h

ighe

r in

exp

erim

enta

l gro

up:

2.35

± 0

.2 v

s 1.

63 ±

0.1

, P =

.007

EP

A a

nd G

LA

sup

plem

enta

tion

in

EN

adm

inis

tere

d to

cri

tica

lly

ill c

hild

ren

wit

h A

LI

or A

RD

S

fail

ed to

sho

w a

ny d

iffe

renc

es

in c

lini

cal o

utco

mes

. How

ever

, im

mun

onut

rien

t del

iver

y w

as

feas

ible

(to

lera

ted

and

calo

ric

goal

re

ache

d).

Lim

itat

ions

: Sm

all s

ampl

e si

ze; t

oo

man

y ex

clus

ion

crit

eria

Car

cill

o et

al10

0R

CT

To

eval

uate

whe

ther

dai

ly

supp

lem

enta

tion

wit

h zi

nc, s

elen

ium

, glu

tam

ine,

an

d m

etoc

lopr

amid

e,

com

pare

d w

ith

whe

y pr

otei

n, p

rolo

ngs

the

tim

e to

nos

ocom

ial i

nfec

tion

/se

psis

in c

riti

call

y il

l ch

ildr

en

n =

293

Cri

tica

lly

ill c

hild

ren

wit

h en

dotr

ache

al tu

be,

cent

ral v

enou

s or

uri

nary

ca

thet

er a

nd a

ntic

ipat

ed

to h

ave

arte

rial

or

veno

us a

cces

s fo

r bl

ood

draw

s an

d a

feed

ing

tube

en

roll

ed w

ithi

n 48

h o

f P

ICU

adm

issi

on

Exp

erim

enta

l gro

up: e

nter

al: 2

0 m

g/d

zinc

; sel

eniu

m, 1

–3 y

: 40

mcg

/d,

3–5

y: 1

00 m

cg/d

, 5–1

2 y:

200

m

cg/d

, ado

lesc

ent:

400

mcg

/d; 0

.3

g/kg

/d g

luta

min

e; I

V: 0

.2 m

g/kg

/d

(<10

mg/

dose

) m

etoc

lopr

amid

e ev

ery

12 h

, fro

m <

72 h

of

adm

issi

on

unti

l PIC

U d

isch

arge

or

<28

dC

ontr

ol g

roup

: Not

inte

nded

as

a co

ntro

l gro

up, i

nten

ded

as a

co

mpa

rati

ve e

ffec

tive

ness

tria

l. R

ecei

ved

0.3

g/kg

/d b

enep

rote

in

(whe

y pr

otei

n)

Exp

erim

enta

l vs

cont

rol g

roup

s: 2

8-d

mor

tali

ty:

10.3

% (

15/1

45)

vs 5

.8%

(8/

139)

; P =

.16

PIC

U L

OS

: med

ian

9 vs

11

d; P

= .1

6N

o si

gnif

ican

t dif

fere

nce

in in

fect

ious

co

mpl

icat

ions

No

diff

eren

ces

in d

urat

ion

of M

VM

ean

rate

s of

nos

ocom

ial i

nfec

tion

/sep

sis

per

pati

ent p

er 1

00 s

tudy

day

s (9

5% C

I): I

mm

une

com

prom

ised

pat

ient

s—1.

57 (

0.53

–3.7

3) v

s 6.

09 (

3.33

–10.

32);

P =

.011

No

diff

eren

ce in

imm

une

com

pete

nt p

atie

nts.

Enr

ollm

ent t

erm

inat

ed f

or f

util

ity

afte

r se

cond

inte

rim

ana

lysi

s in

dica

ted

the

cond

itio

nal p

ower

to

det

erm

ine

a be

nefi

cial

eff

ect

of z

inc,

sel

eniu

m, g

luta

min

e,

met

oclo

pram

ide,

com

pare

d w

ith

whe

y pr

otei

n, w

as <

10%

.T

here

was

no

sign

ific

ant d

iffe

renc

e be

twee

n gr

oups

in te

rms

of

infe

ctio

ns o

r ot

her

impo

rtan

t ou

tcom

es. H

owev

er, i

mm

une

com

prom

ised

pat

ient

s (a

ver

y sm

all

num

ber

of p

atie

nts)

exp

erie

nced

a

sign

ific

ant r

educ

tion

in n

osoc

omia

l in

fect

ions

/sep

sis

wit

h th

e st

udy

inte

rven

tion

com

pare

d w

ith

the

whe

y pr

otei

n gr

oup.

1 Bri

asso

ulis

et a

l,93

2 Bri

asso

ulis

et a

l,94

and

3 Bri

asso

ulis

et

al99

RC

TT

o co

mpa

re o

utco

mes

in

crit

ical

ly il

l chi

ldre

n re

ceiv

ing

an im

mun

e-en

hanc

ing

form

ula

or

stan

dard

for

mul

a1 N

B, n

utri

tion

indi

ces,

an

tiox

idan

t cat

alys

ts2,

3C

ytok

ines

, hos

pita

l ac

quir

ed in

fect

ions

, nu

trit

ion

indi

ces

1 n =

50

crit

ical

ly il

l ch

ildr

en2 n

= 3

8 (3

0 an

alyz

ed)

crit

ical

ly il

l chi

ldre

n w

ith

sept

ic s

hock

3 n

= 4

0 cr

itic

ally

ill

chil

dren

wit

h se

vere

TB

I

Ran

dom

ized

to im

mun

onut

riti

on

form

ula

(GL

N, L

-arg

inin

e,

anti

oxid

ants

, and

ω-3

fat

ty a

cids

, fi

ber,

vit

amin

E, β

car

oten

e, z

inc,

co

pper

, sel

eniu

m)

or s

tand

ard

pedi

atri

c fo

rmul

aF

eeds

wer

e m

aske

d an

d de

live

red

thro

ugh

an N

GT

sta

rtin

g <

12 h

of

adm

issi

onE

nerg

y in

take

was

cal

cula

ted

to

prov

ide

0.5,

1, 1

.25,

1.5

, and

1.5

of

pred

icte

d B

MR

(ca

lcul

ated

usi

ng

the

Sch

ofie

ld e

quat

ion)

on

days

1–5

, re

spec

tive

ly

Exp

erim

enta

l vs

Con

trol

gro

ups:

1,

2,3 N

o si

gnif

ican

t dif

fere

nces

for

, ene

rgy

and

prot

ein

inta

ke, m

orta

lity

, PIC

U

LO

S, p

neum

onia

, inf

ecti

ons,

mec

hani

cal

vent

ilat

ion

dura

tion

1,

2,3 D

iarr

hea

sign

ific

antl

y m

ore

freq

uent

1,

3 Pos

itiv

e N

B in

sig

nifi

cant

ly h

ighe

r pr

opor

tion

of

pati

ents

on

day

5

1,3 S

igni

fica

ntly

few

er p

osit

ive

gast

ric

cult

ures

2 S

igni

fica

ntly

low

er I

L-6

and

hig

her

IL-8

on

day

5

3 Sig

nifi

cant

ly lo

wer

IL

-8 a

nd n

o di

ffer

ence

in

IL-6

on

day

5

Imm

unon

utri

tion

is f

easi

ble

in

crit

ical

ly il

l chi

ldre

n.T

hese

sm

all s

ingl

e-ce

nter

stu

dies

of

imm

unon

utri

tion

vs

stan

dard

fo

rmul

a ar

e un

derp

ower

ed to

de

mon

stra

te im

port

ant o

utco

me

diff

eren

ces

AL

I, a

cute

lung

inju

ry; A

RD

S, a

cute

res

pira

tory

dis

tres

s sy

ndro

me;

BM

R, b

asal

met

abol

ic r

ate;

EP

A, e

icos

apen

taen

oic

acid

; GL

A, γ

-lin

olen

ic a

cid;

GL

N, g

luta

min

e; H

SP

-70,

hea

t sho

ck p

rote

in 7

0; I

L, i

nter

leuk

in; I

V, i

ntra

veno

us;

LO

S, l

engt

h of

sta

y; L

TB

4, le

ukot

rien

e B

4; M

V, m

echa

nica

l ven

tila

tion

; NB

, nit

roge

n ba

lanc

e; N

GT

, nas

ogas

tric

tube

; PIC

U, p

edia

tric

inte

nsiv

e ca

re u

nit;

PN

, par

ente

ral n

utri

tion

; PR

ISM

III

, Ped

iatr

ic R

isk

of M

orta

lity

sco

re;

RC

T, r

ando

miz

ed c

ontr

olle

d tr

ial.

Tab

le 1

0. (

con

tin

ued

)


ICU LOS.97 Clinical outcomes of critically ill children requir-ing PN who were randomized to receive parenteral glutamine did not differ from those administered standard PN.98 In a com-parative effectiveness trial, critically ill children requiring mechanical ventilation and EN were randomized to receive enteral supplementation of a combination of glutamine, zinc, selenium, and metoclopramide or whey protein.100 The study was terminated for futility at a planned interim analysis after enrollment of 293 patients. No differences in PICU LOS, duration of mechanical ventilation, infections, or mortality were demonstrated. However, in a small subgroup of immu-nocompromised children, a significant reduction in nosoco-mial infections was seen with the study intervention as compared with whey protein (1.57 vs 6.09; P = .011). No 2 trials of immunonutrients in children are similar, and none demonstrated superiority of immunonutrition versus standard nutrition among critically ill children in terms of clinical outcomes.

Prior studies of critically ill adults have demonstrated reduced hospital LOS and mortality with glutamine-supple-mented PN.101 Based on these observations, in a recent large multicenter 2-by-2 factorial trial of critically ill adults receiving mechanical ventilation with multiple-organ failure, patients were randomized to glutamine, antioxidants, both, or pla-cebo.102 A significant increase in hospital and 6-month mortal-ity and a trend toward increased 28-day mortality were seen in the group receiving glutamine. A subsequent multicenter trial of critically ill adults receiving mechanical ventilation showed no infectious benefits and a possibility of harm, with a signifi-cantly higher 6-month mortality among medical patients ran-domized to a formula containing glutamine, ω-3 fatty acids, and antioxidants versus a standard high-protein formula.103 Arginine supplementation has been considered to improve immune func-tion and wound healing in critically ill patients but has demon-strated increased mortality in septic patients.104 The 2016 critically ill adult nutrition support therapy guidelines recom-mend that immunonutrition not be used in critically ill septic or medical patients but may be considered for those who are peri-operative or have traumatic injuries.75 Due to the potential harm of glutamine and arginine supplementation in adults and the paucity of pediatric data, immunonutrition cannot be currently recommended in critically ill children.Future direction. Future trials should examine the role of immunonutrition in select populations, such as immunocom-promised and malnourished critically ill children, with stan-dardized clinical interventions and therapies to avoid confounding results. These studies need to define immunonu-trition and specific populations where it might be tested. In addition, studies are needed to identify the optimal route of immunonutrient delivery.

Summary

In this article, we provide guidelines for some of the important steps in the provision of optimal nutrition to the critically ill child.

We selected key questions for this version of the guidelines, but we are aware that some of these and several other questions remain unanswered and will require systematic investigation. A majority of the recommendations or suggestions in these guidelines are driven by consensus or low-level evidence. We hope that our sys-tematic search strategy, followed by meticulous data abstraction, has allowed us to capture all the relevant studies. The process of converting a broad variety of evidence levels to meaningful and practically applicable recommendations is challenging. These rec-ommendations provide a starting point from where the nutrition strategy for individual patients can be customized. The guidelines reiterate the importance of nutrition assessment—particularly, the detection of malnourished patients who are most vulnerable and therefore potentially may benefit from timely nutrition interven-tion. There is a need for renewed focus on accurate estimation of energy needs and attention to cumulative energy imbalance. IC must be used to guide energy prescriptions, where feasible, and cautious use of estimating equations and increased surveillance for unintended caloric underfeeding and overfeeding are recom-mended in its absence. Optimal protein dose and its correlation with clinical outcomes is an area of great interest. The optimal route and timing of nutrient delivery are areas of intense debate and investigations. EN remains the preferred route for nutrient delivery. Several strategies to optimize EN during critical illness have emerged. The role of supplemental PN has been highlighted, and a delayed approach appears to be beneficial. Immunonutrition cannot be currently recommended. Overall, the pediatric critical care pop-ulation is heterogeneous, and a nuanced approach to individualize nutrition support with the aim of improving clinical outcomes is necessary. We have summarized key areas for future investiga-tions, which will guide us in developing the next level of evidence-based nutrition therapy in the future. Until then, multidisciplinary collaborative efforts must continue to prioritize and highlight the unique and dynamic nutrition needs of the critically ill child in the complex PICU environment.

Appendix. Targeted Indirect Calorimetry

Children who are at high risk for metabolic alterations are sug-gested candidates for targeted measurement of resting energy expenditure in the PICU.31 This includes the following:

•• Underweight, overweight, or obese•• Children with >10% weight change during ICU stay•• Failure to consistently meet prescribed energy goals•• Failure to wean or need to escalate respiratory support•• Neurologic trauma (traumatic, hypoxic, and/or

ischemic)•• Oncologic diagnoses (including children with stem cell

or bone marrow transplant)•• Children with thermal injuries or amputations•• Children requiring mechanical ventilator support for >3

days•• Children suspected to be severely hypermetabolic (sta-

tus epilepticus, hyperthermia, systemic inflammatory response syndrome, dysautonomic storms, etc) or hypo-metabolic (hypothermia, hypothyroidism, pentobarbital or midazolam coma, etc)

Mehta et al 35

Any patient with ICU LOS >4 weeks may benefit from IC to assess adequacy of nutrient intake.

References

1. Mehta NM, Compher C; ASPEN Board of Directors. ASPEN clinical guidelines: nutrition support of the critically ill child. JPEN J Parenter Enteral Nutr. 2009;33:260-276.

2. Druyan ME, Compher C, Boullata JI, et al; American Society for Parenteral and Enteral Nutrition Board of Directors. Clinical guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients: applying the GRADE system to development of ASPEN clini-cal guidelines. JPEN J Parenter Enteral Nutr. 2012;36:77-80.

3. McKeever L, Nguyen V, Peterson SJ, et al. Demystifying the search button: a comprehensive PubMed search strategy for performing an exhaustive literature review. JPEN J Parenter Enteral Nutr. 2015;39:622-635.

4. Bechard LJ, Duggan C, Touger-Decker R, et al. Nutritional status based on body mass index is associated with morbidity and mortality in mechanically ventilated critically ill children in the PICU. Crit Care Med. 2016;44:1530-1537.

5. Castillo A, Santiago MJ, López-Herce J, et al. Nutritional status and clinical outcome of children on continuous renal replacement therapy: a prospective observational study. BMC Nephrol. 2012;13:125.

6. de Souza Menezes F, Leite HP, Koch Nogueira PC. Malnutrition as an independent predictor of clinical outcome in critically ill children. Nutrition. 2012;28:267-270.

7. Delgado AF, Okay TS, Leone C, et al. Hospital malnutrition and inflam-matory response in critically ill children and adolescents admitted to a tertiary intensive care unit. Clinics (Sao Paulo). 2008;63:357-362.

8. Mehta NM, Bechard LJ, Cahill N, et al. Nutritional practices and their relationship to clinical outcomes in critically ill children-an interna-tional multicenter cohort study. Crit Care Med. 2012;40:2204-2211.

9. Mehta NM, Bechard LJ, Zurakowski D, et al. Adequate enteral protein intake is inversely associated with 60-d mortality in critically ill children: a mul-ticenter, prospective, cohort study. Am J Clin Nutr. 2015;102:199-206.

10. Ross PA, Newth CJ, Leung D, et al. Obesity and mortality risk in criti-cally ill children. Pediatrics. 2016;137:e20152035.

11. Griesdale DE, de Souza RJ, van Dam RM, et al. Intensive insulin ther-apy and mortality among critically ill patients: a meta-analysis includ-ing NICE-SUGAR study data. CMAJ. 2009;180:821-827.

12. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin ther-apy in critically ill patients. N Engl J Med. 2001;345:1359-1367.

13. Yamada T, Shojima N, Noma H, et al. Glycemic control, mortality, and hypoglycemia in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials. Intensive Care Med. 2017;43:1-15.

14. Briassoulis G, Zavras N, Hatzis T. Malnutrition, nutritional indices, and early enteral feeding in critically ill children. Nutrition. 2001; 17:548-557.

15. Hulst J, Joosten K, Zimmermann L, et al. Malnutrition in critically ill children: from admission to 6 months after discharge. Clin Nutr. 2004;23:223-232.

16. Mehta NM, Corkins MR, Lyman B, et al; American Society for Parenteral and Enteral Nutrition Board of Directors. Defining pediat-ric malnutrition: a paradigm shift toward etiology-related definitions. JPEN J Parenter Enteral Nutr. 2013;37:460-481.

17. Becker P, Carney LN, Corkins MR, et al; Academy of Nutrition and Dietetics; American Society for Parenteral and Enteral Nutrition. Consensus statement of the Academy of Nutrition and Dietetics / American Society for Parenteral and Enteral Nutrition: indicators rec-ommended for the identification and documentation of pediatric malnu-trition (undernutrition). Nutr Clin Pract. 2015;30:147-161.

18. Hulst JM, van Goudoever JB, Zimmermann LJ, et al. The effect of cumulative energy and protein deficiency on anthropometric param-eters in a pediatric ICU population. Clin Nutr. 2004;23:1381-1389.

19. Vermilyea S, Slicker J, El-Chammas K, et al. Subjective global nutri-tional assessment in critically ill children. JPEN J Parenter Enteral Nutr. 2013;37:659-666.

20. Chourdakis M, Hecht C, Gerasimidis K, et al. Malnutrition risk in hos-pitalized children: use of 3 screening tools in a large European popula-tion. Am J Clin Nutr. 2016;103:1301-1310.

21. Dokken M, Rustøen T, Stubhaug A. Indirect calorimetry reveals that better monitoring of nutrition therapy in pediatric intensive care is needed. JPEN J Parenter Enteral Nutr. 2015;39:344-352.

22. Mehta NM, Bechard LJ, Dolan M, et al. Energy imbalance and the risk of overfeeding in critically ill children. Pediatr Crit Care Med. 2011;12:398-405.

23. Teixeira-Cintra MA, Monteiro JP, Tremeschin M, et al. Monitoring of protein catabolism in neonates and young infants post-cardiac surgery. Acta Paediatr. 2011;100:977-82.

24. Mtaweh H, Smith R, Kochanek PM, et al. Energy expenditure in children after severe traumatic brain injury. Pediatr Crit Care Med. 2014;15:242-249.

25. Sy J, Gourishankar A, Gordon WE, et al. Bicarbonate kinetics and predicted energy expenditure in critically ill children. Am J Clin Nutr. 2008;88:340-347.

26. Zappitelli M, Goldstein SL, Symons JM, et al; Prospective Pediatric Continuous Renal Replacement Therapy Registry Group. Protein and calorie prescription for children and young adults receiving continu-ous renal replacement therapy: a report from the Prospective Pediatric Continuous Renal Replacement Therapy Registry Group. Crit Care Med. 2008;36:3239-3245.

27. Taylor RM, Cheeseman P, Preedy V, et al. Can energy expenditure be pre-dicted in critically ill children? Pediatr Crit Care Med. 2003;4:176-180.

28. Framson CM, LeLeiko NS, Dallal GE, et al. Energy expenditure in critically ill children. Pediatr Crit Care Med. 2007;8:264-267.

29. Hardy CM, Dwyer J, Snelling LK, et al. Pitfalls in predicting resting energy requirements in critically ill children: a comparison of predictive methods to indirect calorimetry. Nutr Clin Pract. 2002;17: 182-189.

30. Havalad S, Quaid MA, Sapiega V. Energy expenditure in children with severe head injury: lack of agreement between measured and estimated energy expenditure. Nutr Clin Pract. 2006;21:175-181.

31. Mehta NM, Bechard LJ, Leavitt K, et al. Cumulative energy imbalance in the pediatric intensive care unit: role of targeted indirect calorimetry. JPEN J Parenter Enteral Nutr. 2009;33:336-344.

32. Meyer R, Kulinskaya E, Briassoulis G, et al. The challenge of develop-ing a new predictive formula to estimate energy requirements in venti-lated critically ill children. Nutr Clin Pract. 2012;27:669-676.

33. White MS, Shepherd RW, McEniery JA. Energy expenditure in 100 ventilated, critically ill children: improving the accuracy of predictive equations. Crit Care Med. 2000;28:2307-2312.

34. van der Kuip M, de Meer K, Westerterp KR, et al. Physical activity as a determinant of total energy expenditure in critically ill children. Clin Nutr. 2007;26:744-751.

35. Oosterveld MJ, Van Der Kuip M, De Meer K, et al. Energy expen-diture and balance following pediatric intensive care unit admission: a longitudinal study of critically ill children. Pediatr Crit Care Med. 2006;7:147-153.

36. Jotterand Chaparro C, Laure Depeyre J, Longchamp D, et al. How much protein and energy are needed to equilibrate nitrogen and energy balances in ventilated critically ill children? Clin Nutr. 2016;35: 460-467.

37. van der Kuip M, Oosterveld MJ, van Bokhorst-de van der Schueren MA, et al. Nutritional support in 111 pediatric intensive care units: a European survey. Intensive Care Med. 2004;30:1807-1813.

38. Schofield WN. Predicting basal metabolic rate, new standards and review of previous work. Hum Nutr Clin Nutr. 1985;39(suppl 1):5-41.

39. World Health Organization. Energy and Protein Requirements: Report of a Joint FAO/WHO/UNU Expert Consultation. Geneva, Switzerland: World Health Organization; 1985. Technical Report Series 724.


40. Bechard LJ, Feldman HA, Venick R, et al. Attenuation of resting energy expenditure following hematopoietic SCT in children. Bone Marrow Transplant. 2012;47:1301-1306.

41. Mehta NM, Costello JM, Bechard LJ, et al. Resting energy expendi-ture after Fontan surgery in children with single-ventricle heart defects. JPEN J Parenter Enteral Nutr. 2012;36:685-692.

42. Kerklaan D, Augustus ME, Hulst JM, et al. Validation of ventila-torderived VCO2 measurements to determine energy expenditure in ventilated critically ill children. Clin Nutr. 2017;36:452-457.

43. Mehta NM, Smallwood CD, Joosten KF, et al. Accuracy of a simpli-fied equation for energy expenditure based on bedside volumetric car-bon dioxide elimination measurement-a two-center study. Clin Nutr. 2015;34:151-155.

44. Wong JJ, Han WM, Sultana R, et al. Nutrition delivery affects out-comes in pediatric acute respiratory distress syndrome [published online March 9, 2016]. JPEN J Parenter Enteral Nutr.

45. Bechard LJ, Parrott JS, Mehta NM. Systematic review of the influence of energy and protein intake on protein balance in critically ill children. J Pediatr. 2012;161:333-339.e1.

46. Botrán M, López-Herce J, Mencía S, et al. Enteral nutrition in the critically ill child: comparison of standard and protein-enriched diets. J Pediatr. 2011;159:27-32.e1.

47. Chaloupecký V, Hucín B, Tláskal T, et al. Nitrogen balance, 3-meth-ylhistidine excretion, and plasma amino acid profile in infants after cardiac operations for congenital heart defects: the effect of early nutritional support. J Thorac Cardiovasc Surg. 1997;114: 1053-1060.

48. de Betue CT, van Waardenburg DA, Deutz NE, et al. Increased protein-energy intake promotes anabolism in critically ill infants with viral bronchiolitis: a double-blind randomised controlled trial. Arch Dis Child. 2011;96:817-822.

49. Geukers VG, Dijsselhof ME, Jansen NJ, et al. The effect of short-term high versus normal protein intake on whole-body protein synthesis and balance in children following cardiac surgery: a randomized double-blind controlled clinical trial. Nutr J. 2015;14:72.

50. de Betue CT, Joosten KF, Deutz NE, et al. Arginine appearance and nitric oxide synthesis in critically ill infants can be increased with a protein-energy-enriched enteral formula. Am J Clin Nutr. 2013;98: 907-916.

51. van Waardenburg DA, de Betue CT, Goudoever JB, et al. Critically ill infants benefit from early administration of protein and energy-enriched formula: a randomized controlled trial. Clin Nutr. 2009;28:249-255.

52. Verbruggen SC, Schierbeek H, Coss-Bu J, et al. Albumin synthesis rates in post-surgical infants and septic adolescents; influence of amino acids, energy, and insulin. Clin Nutr. 2011;30:469-477.

53. Verbruggen SC, Coss-Bu J, Wu M, et al. Current recommended paren-teral protein intakes do not support protein synthesis in critically ill sep-tic, insulin-resistant adolescents with tight glucose control. Crit Care Med. 2011;39(11):2518-2525.

54. Carlotti AP, Bohn D, Matsuno AK, et al. Indicators of lean body mass catabolism: emphasis on the creatinine excretion rate. QJM. 2008;101:197-205.

55. Martinez EE, Pereira LM, Gura K, et al. Gastric emptying in criti-cally ill children [published online January 1, 2017]. JPEN J Parenter Enteral Nutr.

56. Ikeda S, Kudsk KA, Fukatsu K, et al. Enteral feeding preserves mucosal immunity despite in vivo MAdCAM-1 blockade of lymphocyte hom-ing. Ann Surg. 2003;237:677-685.

57. Kudsk KA, Stone JM, Carpenter G, et al. Enteral and parenteral feeding influences mortality after hemoglobin-E coli peritonitis in normal rats. J Trauma. 1983;23:605-609.

58. Li J, Kudsk KA, Gocinski B, et al. Effects of parenteral and enteral nutrition on gut-associated lymphoid tissue. J Trauma. 1995;39: 44-51.

59. Sano Y, Gomez FE, Kang W, et al. Intestinal polymeric immunoglobu-lin receptor is affected by type and route of nutrition. JPEN J Parenter Enteral Nutr. 2007;31:351-356.

60. Fukatsu K, Zarzaur BL, Johnson CD, et al. Enteral nutrition prevents remote organ injury and death after a gut ischemic insult. Ann Surg. 2001;233:660-668.

61. Mehta NM, McAleer D, Hamilton S, et al. Challenges to optimal enteral nutrition in a multidisciplinary pediatric intensive care unit. JPEN J Parenter Enteral Nutr. 2010;34:38-45.

62. de Oliveira Iglesias SB, Leite HP, Santana e Meneses JF, et al. Enteral nutrition in critically ill children: are prescription and delivery accord-ing to their energy requirements? Nutr Clin Pract. 2007;22:233-2339.

63. Rogers EJ, Gilbertson HR, Heine RG, et al. Barriers to adequate nutri-tion in critically ill children. Nutrition. 2003;19:865-868.

64. King W, Petrillo T, Pettignano R. Enteral nutrition and cardiovascu-lar medications in the pediatric intensive care unit. JPEN J Parenter Enteral Nutr. 2004;28:334-338.

65. Panchal AK, Manzi J, Connolly S, et al. Safety of enteral feedings in critically ill children receiving vasoactive agents. JPEN J Parenter Enteral Nutr. 2016;40:236-241.

66. Mikhailov TA, Kuhn EM, Manzi J, et al. Early enteral nutrition is asso-ciated with lower mortality in critically ill children. JPEN J Parenter Enteral Nutr. 2014;38:459-466.

67. Kyle UG, Akcan-Arikan A, Orellana RA, et al. Nutrition support among critically ill children with AKI. Clin J Am Soc Nephrol. 2013;8: 568-574.

68. Kyle UG, Jaimon N, Coss-Bu JA. Nutrition support in critically ill children: underdelivery of energy and protein compared with current recommendations. J Acad Nutr Diet. 2012;112:1987-1992.

69. Kaufman J, Vichayavilas P, Rannie M, et al. Improved nutrition deliv-ery and nutrition status in critically ill children with heart disease. Pediatrics. 2015;135:e717-e725.

70. Hamilton S, McAleer DM, Ariagno K, et al. A stepwise enteral nutri-tion algorithm for critically ill children helps achieve nutrient delivery goals. Pediatr Crit Care Med. 2014;15:583-589.

71. Petrillo-Albarano T, Pettignano R, Asfaw M, et al. Use of a feeding pro-tocol to improve nutritional support through early, aggressive, enteral nutrition in the pediatric intensive care unit. Pediatr Crit Care Med. 2006;7:340-344.

72. Yoshimura S, Miyazu M, Yoshizawa S, et al. Efficacy of an enteral feeding protocol for providing nutritional support after paediatric car-diac surgery. Anaesth Intensive Care. 2015;43:587-593.

73. Martinez EE, Bechard LJ, Mehta NM. Nutrition algorithms and bedside nutrient delivery practices in pediatric intensive care units: an interna-tional multicenter cohort study. Nutr Clin Pract. 2014;29:360-367.

74. Elke G, Felbinger TW, Heyland DK. Gastric residual volume in critically ill patients: a dead marker or still alive? Nutr Clin Pract. 2015;30:59-71.

75. McClave SA, Taylor BE, Martindale RG, et al; Society of Critical Care Medicine; American Society for Parenteral and Enteral Nutrition. Guidelines for the provision and assessment of nutrition support ther-apy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). JPEN J Parenter Enteral Nutr. 2016;40:159-211.

76. Ozen N, Tosun N, Yamanel L, et al. Evaluation of the effect on patient parameters of not monitoring gastric residual volume in intensive care patients on a mechanical ventilator receiving enteral feeding: a random-ized clinical trial. J Crit Care. 2016;33:137-144.

77. Horn D, Chaboyer W, Schluter PJ. Gastric residual volumes in criti-cally ill paediatric patients: a comparison of feeding regimens. Aust Crit Care. 2004;17:98-100, 102-103.

78. Briassoulis GC, Zavras NJ, Hatzis MD, Hatzis TD. Effectiveness and safety of a protocol for promotion of early intragastric feeding in criti-cally ill children. Pediatr Crit Care Med. 2001;2:113-121.

Mehta et al 37

79. Meyer R, Harrison S, Sargent S, et al. The impact of enteral feeding protocols on nutritional support in critically ill children. J Hum Nutr Diet. 2009;22:428-436.

80. Wakeham M, Christensen M, Manzi J, et al. Registered dietitians mak-ing a difference: early medical record documentation of estimated energy requirement in critically ill children is associated with higher daily energy intake and with use of the enteral route. J Acad Nutr Diet. 2013;113:1311-1316.

81. Kamat P, Favaloro-Sabatier J, Rogers K, et al. Use of methylene blue spectrophotometry to detect subclinical aspiration in enterally fed intubated pediatric patients. Pediatr Crit Care Med. 2008;9: 299-303.

82. Meert KL, Daphtary KM, Metheny NA. Gastric vs small-bowel feeding in critically ill children receiving mechanical ventilation: a randomized controlled trial. Chest. 2004;126:872-878.

83. Horn D, Chaboyer W. Gastric feeding in critically ill children: a ran-domized controlled trial. Am J Crit Care. 2003;12:461-468.

84. López-Herce J, Mencía S, Sánchez C, et al. Postpyloric enteral nutrition in the critically ill child with shock: a prospective observational study. Nutr J. 2008;7:6.

85. López-Herce J, Sánchez C, Carrillo A, et al. Transpyloric enteral nutri-tion in the critically ill child with renal failure. Intensive Care Med. 2006;32:1599-1605.

86. Taha AA, Badr L, Westlake C, et al. Effect of early nutritional sup-port on intensive care unit length of stay and neurological status at dis-charge in children with severe traumatic brain injury. J Neurosci Nurs. 2011;43:291-297.

87. Tume L, Latten L, Darbyshire A. An evaluation of enteral feeding prac-tices in critically ill children. Nurs Crit Care. 2010;15:291-299.

88. Sánchez C, López-Herce J, Carrillo A, et al. Early transpyloric enteral nutrition in critically ill children. Nutrition. 2007;23:16-22.

89. Canarie MF, Barry S, Carroll CL, et al; Northeast Pediatric Critical Care Research Consortium. Risk factors for delayed enteral nutri-tion in critically ill children. Pediatr Crit Care Med. 2015;16: e283-e289.

90. Fivez T, Kerklaan D, Mesotten D, et al. Early versus late paren-teral nutrition in critically ill children. N Engl J Med. 2016;374: 1111-1122.

91. Jacobs BR, Nadkarni V, Goldstein B, et al; Nutritional Immuno-modulation in Children with Lung Injury Study Group. Nutritional immunomodulation in critically ill children with acute lung injury: fea-sibility and impact on circulating biomarkers. Pediatr Crit Care Med. 2013;14:e45-e56.

92. Mayes T, Gottschlich MM, Kagan RJ. An evaluation of the safety and efficacy of an anti-inflammatory, pulmonary enteral formula in the treatment of pediatric burn patients with respiratory failure. J Burn Care Res. 2008;29:82-88.

93. Briassoulis G, Filippou O, Hatzi E, et al. Early enteral administration of immunonutrition in critically ill children: results of a blinded random-ized controlled clinical trial. Nutrition. 2005;21:799-807.

94. Briassoulis G, Filippou O, Kanariou M, et al. Comparative effects of early randomized immune or non-immune-enhancing enteral nutrition on cytokine production in children with septic shock. Intensive Care Med. 2005;31:851-858.

95. Larsen BM, Field CJ, Leong AY, et al. Pretreatment with an intrave-nous lipid emulsion increases plasma eicosapentanoic acid and down-regulates leukotriene b4, procalcitonin, and lymphocyte concentrations after open heart surgery in infants. JPEN J Parenter Enteral Nutr. 2015;39:171-179.

96. Nehra D, Fallon EM, Potemkin AK, et al. A comparison of 2 intrave-nous lipid emulsions: interim analysis of a randomized controlled trial. JPEN J Parenter Enteral Nutr. 2014;38:693-701.

97. Larsen BM, Goonewardene LA, Joffe AR, et al. Pre-treatment with an intravenous lipid emulsion containing fish oil (eicosapentaenoic and docosahexaenoic acid) decreases inflammatory markers after open-heart surgery in infants: a randomized, controlled trial. Clin Nutr. 2012;31:322-329.

98. Jordan I, Balaguer M, Esteban ME, et al. Glutamine effects on heat shock protein 70 and interleukines 6 and 10: randomized trial of gluta-mine supplementation versus standard parenteral nutrition in critically ill children. Clin Nutr. 2016;35:34-40.

99. Briassoulis G, Filippou O, Kanariou M, et al. Temporal nutritional and inflammatory changes in children with severe head injury fed a regular or an immune-enhancing diet: a randomized, controlled trial. Pediatr Crit Care Med. 2006;7:56-62.

100. Carcillo JA, Dean JM, Holubkov R, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. The randomized comparative pediatric critical illness stress-induced immune suppression (CRISIS) pre-vention trial. Pediatr Crit Care Med. 2012;13:165-173.

101. Wischmeyer PE, Dhaliwal R, McCall M, et al. Parenteral glutamine supplementation in critical illness: a systematic review. Crit Care. 2014;18:R76.

102. Heyland D, Muscedere J, Wischmeyer PE, et al; Canadian Critical Care Trials Group. A randomized trial of glutamine and antioxidants in criti-cally ill patients. N Engl J Med. 2013;368:1489-1497.

103. van Zanten AR, Sztark F, Kaisers UX, et al. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial. JAMA. 2014;312:514-524.

104. Bertolini G, Iapichino G, Radrizzani D, et al. Early enteral immuno-nutrition in patients with severe sepsis: results of an interim analy-sis of a randomized multicentre clinical trial. Intensive Care Med. 2003;29:834-840.

Documents

Journal of Parenteral and Enteral Guidelines for the ... › wp-content › ... › 10 › ...of_Parenteral_and_Enteral_Nu… · 2 Journal of Parenteral and Enteral Nutrition XX(X)